Merzenich,.+changing+brains +applying+brain+plasticity+to+advance+and+recover+human+ability

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13 14 15 16 11 10 9 8 7 6 5 4 3 2 1
Contributors
Merav Ahissar
ELSC Center for Brain Research and the Department of Psychology, The Hebrew
University, Jerusalem, Israel
Laura C. Anderson
Yale Center for Translational Developmental Neuroscience, Yale Child Study
Center, New Haven, CT, USA
Joaquin A. Anguera
Departments of Neurology, Physiology and Psychiatry, University of California,
San Francisco, CA, USA
Bruno Biagianti
San Francisco Department of Veterans Affairs Medical Center, and Department of
Psychiatry, University of California, San Francisco, CA, USA
Ioana Carcea
Molecular Neurobiology Program, The Helen and Martin Kimmel Center for
Biology and Medicine at the Skirball Institute for Biomolecular Medicine,
Department of Physiology and Neuroscience; Department of Otolaryngology,
New York University School of Medicine, and Center for Neural Science,
New York University, New York, NY, USA
Naiyan Chen
Picower Institute for Learning and Memory, Department of Brain and Cognitive
Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
Joseph M. DeGutis
Department of Veteran Affairs, and Department of Medicine, Brigham and
Women’s Hospital, Harvard Medical School, Boston, MA, USA
Patrick Fissler
Clinical & Biological Psychology, University of Ulm, Ulm, Germany
Robert C. Froemke
Molecular Neurobiology Program, The Helen and Martin Kimmel Center for
Biology and Medicine at the Skirball Institute for Biomolecular Medicine,
Department of Physiology and Neuroscience; Department of Otolaryngology, New
York University School of Medicine, and Center for Neural Science, New York
University, New York, NY, USA
Adam Gazzaley
Robbin Gibb
Canadian Centre for Behavioural Neuroscience, University of Lethbridge,
Lethbridge, AB, Canada
v
vi Contributors
Seth A. Hays
The University of Texas at Dallas, School of Behavioral Brain Sciences, and
The University of Texas at Dallas, Texas Biomedical Device Center, Richardson,
TX, USA
Takao K. Hensch
FM Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical
School, Boston, and Center for Brain Science, Department of Molecular & Cellular
Biology, Harvard University, Cambridge, MA, USA
Nori Jacoby
Interdisciplinary Center for Neural Computation, The Hebrew University,
Jerusalem, and Music Department, Bar Ilan University, Ramat Gan, Israel
Michael P. Kilgard
The University of Texas at Dallas, School of Behavioral Brain Sciences, and
The University of Texas at Dallas, Texas Biomedical Device Center, Richardson,
TX, USA
Robert T. Knight
Department of Neurological Surgery, University of California—San Francisco, San
Francisco; Helen Wills Neuroscience Institute, and Department of Psychology,
University of California Berkeley, Berkeley, CA, USA
Iris-Tatjana Kolassa
Bryan Kolb
Nina Kraus
Auditory Neuroscience Laboratory, Northwestern University; Communication
Sciences; Institute for Neuroscience; Neurobiology and Physiology, and
Otolaryngology, Evanston, IL, USA
Olivia Küster
Hyunkyu Lee
Brain Plasticity Institute at Posit Science Corporation, San Francisco, CA, USA
Michael M. Merzenich
Jyoti Mishra
Arif Muhammad
Contributors vii
Richelle Mychasiuk
Ikue Nagakura
Mor Nahum
Brain Plasticity Institute at Posit Science Corporation, San Francisco, and
Department of Optometry, University of California, Berkeley, CA, USA
Lindsay Oberman
Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess
Medical Center, Harvard Medical School, Boston, MA, USA
Devon Oosting
Alvaro Pascual-Leone
Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess
Medical Center, Harvard Medical School, Boston, MA, USA
Brian N. Pasley
Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley,
CA, USA
Kevin A. Pelphrey
Robert L. Rennaker
The University of Texas at Dallas, School of Behavioral Brain Sciences;
The University of Texas at Dallas, Texas Biomedical Device Center, and The
University of Texas at Dallas, Erik Jonsson School of Engineering and Computer
Science, Richardson, TX, USA
Winfried Schlee
Hiroki Sugihara
Mriganka Sur
Anne E. Takesian
FM Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical
School, Boston, MA, USA
viii Contributors
Paula Tallal
Rutgers, The State University of New Jersey, Center for Molecular and Behavioral
Neuroscience, Newark, NJ, USA
Edward Taub
Department of Psychology, University of Alabama at Birmingham, Birmingham,
AL, USA
Adam Tierney
Auditory Neuroscience Laboratory, Northwestern University, and Communication
Sciences, Evanston, IL, USA
Gitendra Uswatte
Department of Psychology, and Department of Physical Therapy, University of
Alabama at Birmingham, Birmingham, AL, USA
Thomas M. Van Vleet
Brain Plasticity Institute at Posit Science Corporation, San Francisco, and
Department of Veteran Affairs, Martinez, CA, USA
Pamela E. Ventola
Sophia Vinogradov
San Francisco Department of Veterans Affairs Medical Center, and Department of
Psychiatry, University of California, San Francisco, CA, USA
David A. Ziegler
Introduction
The science of neuroplasticity has resulted in a new level of understanding of the
neurological origins of human ability (Merzenich, 2013). From this science, the
“rules” governing learning and behavioral control have been further defined, in in-
creasingly complete and elaborate detail, in terms of the neurological processes that
underlie them. That scientific elucidation has led to the development of a new class
of therapeutic tools that exploit neuroplasticity to achieve strengthening or corrective
neurological changes in the brains of many classes of neurologically impaired indi-
viduals. A description of this science, the therapeutic strategies that stem from it, and
the initial application of this science to treat psychiatric and neurological clinical in-
dications is the subject of this volume.
It should be noted that the development and medical application of neuroplasticity-
based therapeutics is a result of a sea change in how we view development of the
physical brain and the personal evolution of our operational abilities across our life
spans. In the late nineteenth and early twentieth centuries, most neurologically focused
scientists viewed the brain as “plastic,” that is, physically modified by our experiences
in ways that accounted for the acquisition and improvement of skills and abilities
underlying our remarkable behavioral evolution across our passage through life (see
Boring, 1929; Hebb, 1949; James, 1890; Merzenich, 2013). Primarily in the middle
decades of the last century, a “locationist” perspective emerged, then predominated.
By that view, remodeling of brain connections was limited to an early “sensitive”
or “critical period”; by the end of that developmental epoch in childhood, neuronal
connections were believed to be “hardwired,” with all brain neurons and supporting
elements achieving their mature status. Postnatal changes in the physical brain were
commonly viewed as a continuation of embryological maturation (e.g., see Hubel
and Wiesel, 2005; Hensch, Chapter 1). In sum, most neuroscientists in this era believed
that the brain rapidly completed its development postnatally and from that point for-
ward was a hardwired, aplastic machine.
This perspective arose in part because studies of brain connectivity employed rel-
atively crude strategies for tracking destination-to-destination connectivity. The ma-
jor trunk lines connecting different brain areas were shown to be modifiable in a
limited perinatal epoch, but at older ages the rerouting of major connectional path-
ways was no longer achievable. Although we now know that large-scale, station-to-
station connectional strengthening and local network changes are occurring on a
large scale, throughout life, they could not have been recorded using the crude
methods used. Studies conducted in the most heavily studied models of developmen-
tal plasticity, the emergent “ocular-dominance columns” and “orientation columns”
of the primary visual cortex (V1; Brodmann area 17), and the “barrel field” repre-
senting the facial vibrissae in the primary somatosensory cortex (S1) of rodents, also
contributed greatly to the locationist model. In normal animals, competitive pro-
cesses in an early postnatal developmental period that had a defined beginning and
ending in early prenatal life resulted in a balanced, banded division of the primary
xxi
xxii Introduction
visual cortex’s layer-4 zones separately dominated by the two eyes (and, in later
studies, segregating and topographically ordering neurons preferring different visual
stimulus orientations) (see Hubel and Wiesel, 1977, 2005) and in the elegant vibrissa-
by-vibrissa representation of sensory facial whiskers in S1 (Woolsey and Wann,
1976). As a result of closing one eye or removing vibrissae through this narrow widow
of time in early development, the open eye or remaining vibrissae competitively (plas-
tically) captured an expanded cortical territory. This territorial competition between
active versus nonactive anatomical inputs for the domination of neurons in layer 4 in
V1 or S1 was shown to be strictly limited to a several-day-to several-week-long “crit-
ical” or “sensitive” period. While some simple manipulations could shorten or
lengthen this epoch of dramatic physical and functional remodeling, it was argued that
no significant changes on that scale could be recorded in animals of an older age. How-
ever, later studies have shown that the “anatomical maturation” of ocular-dominance
and orientation columns in V1 and of “barrels” in S1 is special to these cortical zones-
and that even with their hardening, large-scale local connectional remodeling can and
does occur as a result of neurobehavioral engagement on a large scale, even in these
least-plastic cortical areas, throughout adult life. The marked plasticity of the critical
period, and the transition to “adult” plasticity, is still a very important aspect of any
deep understanding of brain plasticity. Here, that important aspect of the development
of our neurobehavioral abilities is reviewed by two major, current contributors to it,
Drs. Hensch and Kolb (Chapters 1 and 2, respectively).
Collectively, these (and many other) studies led to the predominant conclusion, in
the neuroscience mainstream and in neurological and pediatric medicine, that the
brain was aplastic from early childhood onward. Brain connectivity and local brain
circuits and the constituent neurons within them “matured” in early life to achieve an
“adult” status that was inalterable, to the end of life. By this view, once “maturation”
was fully realized, the only aspect of change in play was age-related deterioration.
NEUROPLASTICITY
In parallel with studies that so strongly entrenched a doctrine of strict “locationism,”
other experiments conducted principally by physiological psychologists across this
same era supported the view that the brain was continuously plastic. These parallel
investigations recorded physical (primarily neuroanatomical) and neuronal response
changes in adult animals resulting from exposure of animals to “enriched environ-
ments,” or from training them using Pavlovian (classical) conditioning (Pavlov,
1927). In the former case, studies beginning with seminal experiments conducted
in the University of California laboratory of Mark Rosenzweig repeatedly showed
that the cortical mantle thickened as a result of environmental enrichment
(Diamond et al., 1964; Rosenzweig et al., 1962). Those thickness and volume
changes, recorded in both subcortical and cortical areas, were primarily accounted
for by dendritic, axonal arbor, and synapse elaboration that manifested large-scale
connectional remodeling of local networks.
Introduction xxiii
In other studies conducted by physiological psychologists in the same era, re-

sponses in the brains of adult mammals were shown to be altered by aversive Pavlovian
conditioning paired with electrical or natural acoustic stimuli, with changes specific to-
and appropriately neurologically located to areas related to-representations of condi-
tioned and unconditioned stimuli and responses (for reviews, see Gluck et al., 2008;
Thompson, 1976, 2005; Weinberger, 1993; Weinberger and Diamond, 1987). Impor-
tantly, changes in neuronal responses selectively exaggerated the representations of a
reward-paired stimulus or a conditioned response, via both positive facilitatory and
negative inhibitory remodeling. Those changes, enduring as long as conditioning
was sustained, were reversed by behavioral “extinction.”
Retrospectively, it is now difficult to understand why these studies, so directly
challenging a strict locationist view, did not supersede the aplastic adult-brain per-
spective held by the majority of neuroscientists and medical practitioners across
the decades of the 1960s through the 1990s. Fortunately, seven other classes of
studies helped to demonstrate to the wider neuroscience community that the brain
was continuously plastic, on a large scale. We detail these seven classes of studies
below.
First, studies documented the phenomena of long-term potentiation and depres-
sion, ultimately explaining, in the terms of specific synaptic receptors and related
cellular, synaptic, and molecular processes, the fundamental mechanisms that under-
lie plasticity at all brain ages. Our current advanced understanding of the mecha-
nisms underlying cortical plasticity, here summarized in Chapters 3 (by Carcea
and Froemke) and 6 (Nahum et al.), is a key point of reference for all later
neuroscience-guided studies that have deployed it in an attempt to control brain
changes for therapeutic purposes.
Second, scientists began to document large-scale competitive plastic changes fol-
lowing peripheral or central injury (or stimulation) in adults, showing that those
changes appeared to be accounted for by Hebb-like (coincident input-dependent)
plasticity. That brain remodeling following injury can be massive. As Drs. Uswatte
and Taub (Chapter 15) describe in their summary of studies of stroke recovery con-
ducted in movement-impaired patients with wounded brains, large-scale neurolog-
ical remodeling provides the primary path to recovery. Drs. Pasley and Knight
(Chapter 17) provide us with another example of plasticity-mediated recovery in pa-
tients who have degraded language abilities arising from brain injury or stroke.
Third, changes explaining progressive performance improvements achieved via
operant conditioning provided a more direct and more complete accounting for the
evolution of human performance abilities, showing that the acquisition or progres-
sive improvement of a skill or ability at any age of life was directly attributable to
connectional (and other physical) remodeling (see Merzenich, 2013). These studies
also far more completely explained change phenomena in terms of local cortical net-
works and their behaviorally driven remodeling. Our own studies directly stem from
this class of experiments (see Nahum et al., Chapter 6; Tallal, Chapter 7). Most of the
computer-delivered therapeutic strategies described later in this volume apply these
neuroplasticity-informed operant-conditioning procedures.
xxiv Introduction
Fourth, scientists began to document the neurological bases of the modulation of

plasticity as a function of behavioral context, in studies richly informed by nearly a
century of empirical experience- and learning-related research contributed by exper-
imental and physiological psychology (see Buonomano and Merzenich, 1998).
These studies are especially important for our consideration here, because they fur-
ther delineate the necessary and optimum conditions for driving positive plastic
changes in the brain, and explain how inappropriately designed therapeutic regimes
can be ineffective, or can have even negative consequences. Child and adult studies
have richly drawn from this experimental psychology and neuroscience literature, to
evolve the designs of remedial training programs that are controlling and rewarding
in ways that assure therapeutic success. The elegant science elucidating the neuro-
modulatory control of plasticity led Kilgard (see Hays et al., Chapter 11) and Van
Vleet and DeGutis (Chapter 13) to the development of training strategies specifically
also targeting the plasticity of the modulatory control machinery itself, illustrating
that even the machinery that controls plasticity is plastic.
Fifth, many studies have now shown that plasticity is achieved via reversible
physicochemical change processes. We have known for many years that, at the core,
plasticity follows a Hebbian rule. That led to our understanding of how we could
refine or degrade the brain’s representation of the details of what we hear or see
or feel; in this case merely changing the time structures and distributions of inputs
delivered competitively into brain networks under the right plasticity-enabling con-
ditions (Merzenich and deCharms, 1996; Merzenich, 2000). More recently, we have
shown that the machinery of the brain “deteriorates” in virtually all functional and
physical aspects with aging, or across the course of chronic neurological illness (see
de Villers-Sidani et al., 2010, 2011). An important conclusion of these studies is that
the changes in the brain normally associated with aging or with the progressive de-
terioration in function marking most neurological and psychiatric illnesses are actu-
ally the result of progressive, “negative,” plasticity-driven changes. Moreover, and
importantly for the subject at hand, all of these physical and functional changes
marking the deterioration or degradation of brain anatomy and function are revers-
ible, via appropriate forms of training. We describe further key aspects of this science
in our own contribution to this volume (Nahum et al., Chapter 6).
Sixth, especially over the past decade, cognitive neuroscience applying modern
tools of behavior and brain recording and imaging science have shown us, now by
many examples, that human connectivity and many aspects of the brain’s physicality,
chemistry, and functionality are altered in parallel with the acquisition or loss of skill
or ability in ways that appear to account for those gains or losses. Here, Oberman and
Pascual-Leone (Chapter 4) and Jacoby and Ahissar (Chapter 5) lead us into important
introductions of this powerfully contributing and rapidly evolving contributor to
brain plasticity-guided neurorehabilitation.
Finally, we have now applied this science directly, to drive positive changes
affirmed by controlled trials, in the behavior and in the neurology of a rich variety
of human patients (see Merzenich, 2013). These practical studies richly demonstrate
the power and potential of neuroplasticity-based therapeutics. In this volume,
Introduction xxv
Chapters 7 (Tallal), 8 (Tierney and Kraus), and 10 (Ventola et al.) provide clear ex-
amples in their studies of neuroplasticity-based training designed to overcome devel-
opmental impairment and increase resilience to forestall the emergence of serious
psychiatric problems in child populations. Drs. Uswatte and Taub (Chapter 15), Pas-
ley and Knight (Chapter 17), and Van Vleet and DeGutis (Chapter 13) provide dif-
ferent compelling models showing how substantial recovery from brain injury and
stroke can result from neuroplasticity-based training. Other chapters in this volume
document plastic changes contributing to neurobehavioral strengthening and recov-
ery in adult patients with tinnitus (Hays et al., Chapter 11), schizophrenia (Biagianti
and Vinogradov, Chapter 12), in children with autism (Sur et al., Chapter 9; Ventola
et al., Chapter 10), and in aging populations (Fissler et al., Chapter 16; Mishra et al.,
Chapter 14; Nahum et al., Chapter 6). Chapters 11 (Hays et al.), Chapter 13 (Van
Vleet and DeGutis), and 4 (Oberman and Pascual-Leone) all describe important
strategies by which plasticity can be amplified by manipulating the modulatory con-
trol machinery governing learning-induced changes, either via training or by clini-
cally practical electrical stimulation of specific brain inputs or cortical areas.
Taken together, these different classes of investigation culminating in the prac-
tical demonstration of the therapeutic value of brain plasticity-based training have
established a sharp revision of our perspective about the brain. We now know that
it is continuously physically and functionally plastic; that this plasticity can be ap-
plied at any stage in life to drive positive strengthening and corrective change; and
that this science is now rapidly generating a new class of therapeutic treatments that
shall transform neurological and psychiatric medicine.
We hope that this collective report illustrates both the dramatic progress and now-
undeniable clinical possibilities of this exciting new subdiscipline of applied
neuroscience.
Michael M. Merzenich
Mor Nahum
Thomas M. Van Vleet
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CHAPTER
Balancing Plasticity/Stability
Across Brain Development
*
Anne E. Takesian*, Takao K. Hensch*,{,1
1
FM Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School,
Boston, MA, USA
{
Center for Brain Science, Department of Molecular & Cellular Biology, Harvard University,
Cambridge, MA, USA
1
Corresponding author: Tel.: 617-384-5882; Fax: 617-495-4038,
e-mail address: hensch@mcb.harvard.edu
Abstract
The potency of the environment to shape brain function changes dramatically across the lifespan.
Neural circuits exhibit profound plasticity during early life and are later stabilized. A focus on the
cellular and molecular bases of these developmental trajectories has begun to unravel mechanisms,
which control the onset and closure of such critical periods. Two important concepts have emerged
from the study of critical periods in the visual cortex: (1) excitatory–inhibitory circuit balance is a
trigger; and (2) molecular “brakes” limit adult plasticity. The onset of the critical period is deter-
mined by the maturation of specific GABA circuits. Targeting these circuits using pharmacological
or genetic approaches can trigger premature onset or induce a delay. These manipulations are so
powerful that animals of identical chronological age may be at the peak, before, or past their plastic
window. Thus, critical period timing per se is plastic. Conversely, one of the outcomes of normal
development is to stabilize the neural networks initially sculpted by experience. Rather than being
passively lost, the brain’s intrinsic potential for plasticity is actively dampened. This is demonstrated
by the late expression of brake-like factors, which reversibly limit excessive circuit rewiring beyond
a critical period. Interestingly, many of these plasticity regulators are found in the extracellular mi-
lieu. Understanding why so many regulators exist, how they interact and, ultimately, how to lift them
in noninvasive ways may hold the key to novel therapies and lifelong learning.
Keywords
critical period, GABA, parvalbumin, perineuronal net, lynx1, myelin, epigenetics
1 INTRODUCTION
Neural circuits are shaped by experience—the potency of which changes dynami-
cally across the lifespan. A focus on the cellular and molecular bases of these changes
Progress in Brain Research, Volume 207, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63327-9.00001-1
© 2013 Elsevier B.V. All rights reserved.
3
4 CHAPTER 1 Mechanisms of Critical Period Plasticity
has begun to unravel mechanisms, which control the onset and closure of such “crit-
ical periods” for plasticity. This work in animal models offers new insight for tapping
into the brain’s potential to rewire both in the clinic and classroom. Two important
concepts have emerged (Fig. 1A):
(1) Excitatory–inhibitory (E–I) circuit balance is a trigger. The classical

enduring loss of visual acuity (amblyopia) due to altered visual input early in life
fails to occur when inhibitory function is compromised (Hensch, 2005). Specific
GABA circuit maturation underlies the onset timing of plasticity and is shifted
across brain regions consistent with the cascading nature of critical periods.
Notably, premature gain of function by pharmacological agents can trigger
premature onset, while genetic disruptions lead to a delay. These manipulations
are so powerful that they can determine whether an animal is before, at the peak,
or past a plastic window. Thus, critical period timing per se is plastic.
(2) Molecular “brakes” limit adult plasticity. While it is possible that plasticity
factors are simply more abundant early in life, an emerging view is that the brain
FIGURE 1
Mechanisms controlling onset and closure of critical periods. (A) Precocious plasticity is
prevented during the precritical period by early factors, such as polysialic acid (PSA) on
neural cell adhesion molecule (NCAM), limiting PV circuit function. Critical period onset is
triggered once factors such as Otx2, BDNF, and NARP promote PV cell maturation, leading
to an optimal ratio of excitatory and inhibitory circuit activity. This triggers a sequence of
molecular events, including second messenger molecules (CaMKII, ERK), miR-132,
CREB, protein synthesis, protease (tPA) release, and homeostatic factors (TNFa), which
ultimately induce structural changes (spine pruning, regrowth, axonal rewiring). The critical
period then closes as molecular brakes gradually emerge to dampen plasticity, including
PNNs (CSPGs), Nogo receptor (NgR)—PirB signaling, Lynx1 and epigenetic changes
(HDAC).
Continued
1 Introduction 5
FIGURE 1—Cont’d
(B) Critical period triggers and brakes act at various sites within cortical microcircuits on
excitatory pyramidal cells (green), PV inhibitory cells (blue), and non-PV inhibitory cells
(gray). Many factors controlling plasticity are found within the extracellular matrix surrounding
PV cells.
is intrinsically plastic, and one of the outcomes of normal development is then to

stabilize the neural networks that are initially sculpted by experience. This is
demonstrated most clearly by the late expression of brake-like factors beyond the
critical period, which act to limit excessive circuit rewiring (Bavelier et al.,
2010). These factors include structural brakes which physically prevent neurite
pruning and outgrowth, and functional brakes acting on neuromodulatory
systems. Their removal unmasks potent plasticity in adulthood, which can be
used to correct neurodevelopmental disorders.
It is increasingly clear that the cortex does not adhere to a simplified model of shift-
ing between plastic and nonplastic states. Instead, transitions in and out of critical
periods might reflect shifts in plasticity sites or mechanisms (Wang et al., 2012)
due to evolving molecular factors or changes in cortical activity patterns
(Toyoizumi et al., 2013). Here, we review recent findings primarily in the visual cor-
tex and discuss how these principles may apply more broadly.
2 CRITICAL PERIODS: PRUNING CIRCUITS

BY EARLY EXPERIENCE
Critical periods have been observed in various systems across species (Hensch, 2004).
Primary sensory areas in particular—the brain’s first filters to the outside world—
exhibit especially striking examples of experience-dependent plasticity during defined
windows of early life. Such periods are needed to establish an optimal neural repre-
sentation of the surrounding environment to guide future action. Given the extraordi-
nary biological resources that must be devoted to rewiring neural circuitry,
concentrating the construction of accurate, immutable maps early in life for use
throughout adulthood may be an efficient strategy. However, this poses limitations
on future revisions to the circuitry. Recent cellular and molecular insights indicate that
biological mechanisms are expressed to ensure that adaptive changes are preferentially
set in place early in life while leaving the door open for lifelong plasticity.
Perhaps the best-studied model of a critical period is the enduring loss of respon-
siveness in primary visual cortex (V1) to an eye deprived of vision. The behavioral
consequence, amblyopia (poor visual acuity), afflicts 2–5% of the human population
and remains without a known cure in adulthood (Holmes and Clarke, 2006). From the
initial discovery by Hubel and Wiesel 50 years ago, a picture has emerged that inputs
from the two eyes compete with each other when they first converge in V1 onto in-
dividual neurons (Wiesel and Hubel, 1963). With the advent of gene targeting in
mice, it has become possible to directly manipulate the factors which may mediate
such functional and structural rewiring in response to imbalanced sensory
experience.
Binocular interactions are detected by the integrated action of local excitatory
and inhibitory connections in the neocortex. Strikingly, an optimal balance is re-
quired for plasticity to begin. Gene-targeted deletion of the synaptic isoform of
the GABA-synthetic enzyme, GAD65, reduces stimulus-evoked inhibition without
compromising animal survival because normal levels of the GAD67 isoform remain
(Hensch et al., 1998; Tian et al., 1999). In GAD65 knockout (KO) mice, the effects of
monocular deprivation are not observed until inhibitory transmission is restored by
enhancing the postsynaptic sensitivity to GABA with benzodiazepines (Fagiolini and
Hensch, 2000; Hensch et al., 1998). Agonists, such as diazepam (valium) or zolpi-
dem (ambien), increase the chloride flux through particular GABAA channels when
they are bound together with endogenous transmitter (Cherubini and Conti, 2001),
effectively compensating for poor presynaptic GABA release.
Both GAD65 KO mice (at any age) as well as immature wild-type animals just
after eye opening (around postnatal day P12 in mice) exhibit weak GABA release
and no loss of visual responsiveness to an eye deprived of vision. However, plasticity
can be rapidly “switched on” by just 2 days of local diazepam infusion into V1 (Iwai
et al., 2003). This represents the first direct control over critical period timing in any
system, and is surprisingly dictated by the late maturation of inhibitory function. Un-
less a favorable E–I balance is achieved, plastic changes are not engaged. Recently,
2 Critical Periods: Pruning Circuits by Early Experience 7
this principle has been extended to the cerebellum, where elimination of excessive
climbing fiber inputs onto Purkinje cells during an early critical period is regulated
by GABA levels (Nakayama et al., 2012).
Downstream of the E–I trigger, lies a sequence of structural changes which ulti-
mately execute circuit rewiring and its consolidation (Hensch, 2005). Regulated re-
lease of proteases such as tissue-type plasminogen activator (tPA) cleaves the
physical connections between pre- and postsynaptic partners to induce dendritic
spine motility (Mataga et al., 2004; Oray et al., 2004). This requires 2 days of mon-
ocular deprivation once GABA function is mature, and persists for about 1 week.
During this time, spines are lost and then gradually recover as tPA levels return
to baseline (Mataga et al., 2002, 2004).
Finally, the classical shrinkage of deprived eye axons and later sprouting of open
eye axons from the visual thalamus (LGN) is observed, requiring new protein syn-
thesis (Antonini and Stryker, 1993; Antonini et al., 1999; Taha and Stryker, 2002;
Trachtenberg and Stryker, 2001). Several factors have further been identified to cou-
ple E–I circuit balance to the physical rewiring process, such as protein kinases
(CaMKII, PKA, ERK; Di Cristo et al., 2001; Fischer et al., 2004; Taha et al.,
2002; Yang et al., 2005) and homeostatic regulators which ultimately strengthen
open eye connections (TNFa; Kaneko et al., 2008a).
Recently, an experience-dependent MicroRNA (miRNA), miR-132, has been
identified in mouse V1 that is important for ocular dominance plasticity. miRNAs
are small non-coding RNAs that regulate post-transcriptional gene expression.
Visual experience induces histone mark modifications at CRE loci close to the
miR-132 coding sequence (Tognini et al., 2011). Such modifications may underlie
the developmental upregulation of miR-132 that occurs after eye opening and per-
sists throughout the critical period. Manipulating miR-132 in vivo, by either increas-
ing levels with a double-stranded mimic (Tognini et al., 2011) or decreasing them
with a competitive inhibitor (sponge)-expressing lentivirus that sequesters endoge-
nous miR-132 (Mellios et al., 2011), completely blocks ocular dominance plasticity
during the critical period. miR-132 elevates the percentage of mushroom/stubby
spines, suggesting that it may play a role in the structural modifications that occur
during critical periods.
Notably, neither the release of tPA, pruning of spines, nor the rewiring of thala-
mocortical afferents occurs readily in adulthood. Rather than a simple loss of plas-
ticity machinery, recent evidence detailed below reveals that further rewiring is
actively gated in the mature brain. This notion of molecular “brakes” on plasticity
is already evident during the critical period. Spine maturation is normally slowed
down by cell adhesion molecules like Icam-5 (aka telencephalin; Matsuno et al.,
2006). Genetic deletion of Icam-5 accelerates tonotopic map changes in primary au-
ditory cortex (A1), effectively shortening the duration of the critical period (Barkat
et al., 2011). Windows of plasticity, therefore, arise between the maturation of an
optimal E–I balance controlling the machinery of synaptic pruning and a later set
of emerging brake-like factors, which persistently offset them (Fig. 1A).
3 CRITICAL PERIOD PLASTICITY OF EXCITATORY

AND INHIBITORY CIRCUITS
The precise response to developmental experience reflects dynamic excitatory and
inhibitory circuits displaying transient changes following sensory manipulation
(Feldman, 2009; Hooks and Chen, 2007; Levelt and Hübener, 2012). Studying these
dynamics has provided new insight into both the induction and expression of critical
period plasticity (Fig. 1B).
3.1 Excitatory Circuit Plasticity During Critical Periods

Thalamocortical synapses are appealing sites for experience-dependent plasticity, as
various studies reveal changes at these synapses that are restricted to developmental
critical periods. This concept originated from early work using thalamocortical brain
slices which preserve the thalamus, cortex, and the connections between them. For
example, in somatosensory cortex, stimulation of the thalamic afferents paired with
postsynaptic depolarization of layer (L)4 cells readily induces long-term potentiation
(LTP; Crair and Malenka, 1995) and long-term depression (LTD; Feldman et al.,
1998). However, this plasticity is diminished in older animals.
Age-restricted thalamocortical synapse plasticity has also been shown in visual
(Jiang et al., 2007) and auditory cortices (Barkat et al., 2011; Chun et al., 2013). Fur-
ther support for this site of plasticity comes from a recent study evaluating the effects
of early deprivation in monocular V1 using optogenetic stimulation of the thalamic
afferents. Three days of monocular deprivation during the critical period induces a
specific depression of thalamic inputs to L4, but leaves thalamic inputs to L6 and
cortico-cortical connections unaltered (Wang et al., 2013).
Until recently, the consensus has been that such thalamocortical plasticity is lost
in the adult. However, it was recently discovered that thalamocortical LTP and LTD
are present in animals aged far beyond critical periods and gated by modulatory sys-
tems. These include cholinergic activation of muscarinic receptors, consistent with
the role of these receptors in inducing adult in vivo tonotopic map plasticity
(Blundon and Zakharenko, 2013; Blundon et al., 2011; Chun et al., 2013). Several
studies now point to thalamocortical inputs as important loci for adult plasticity.
For example, peripheral nerve injury induced in rats aged beyond the critical period
strengthens thalamocortical connections to L4 cells in the spared rat barrel cortex (Yu
et al., 2012).
Changes within intracortical excitatory circuits are also associated with critical
periods. Whisker deprivation leads to intracortical suppression of cortical L2/3
(Drew and Feldman, 2009) by weakening L4 to L2/3 synapses (Bender et al.,
2006). Such synaptic depression only occurs after a developmental shift in the spike
timing-dependent plasticity (STDP) rule at L4-L2/3 synapses toward the end of the
second postnatal week (Itami and Kimura, 2012). Similarly, potentiation of
responses to spared whiskers is induced at L4 to L2/3 synapses (Clem and Barth,
2006) during a critical period, also occurring at the end of the second postnatal week
3 Critical Period Plasticity of Excitatory and Inhibitory Circuits 9
(Wen and Barth, 2011). Effects of deprivation within intracortical circuits have also
been shown to be age dependent in V1 by examining excitatory connections between
L4 pyramidal cells using paired recordings. Whereas deprivation during the precrit-
ical period increases the strength of these connections, the same manipulation during
the critical period leaves these synapses unaltered (Maffei et al., 2004, 2006). Such
age-dependent changes within these V1 intracortical networks may be due to devel-
opmentally-gated plasticity mechanisms. During the precritical period, LTD is read-
ily induced; however, upon critical period opening, LTD induction fails and is
replaced by LTP. This developmental switch in the sign of plasticity is prevented
by visual deprivation, suggesting that the recruitment of critical period plasticity
mechanisms is triggered by experience (Wang et al., 2012). In contrast, intracortical
excitatory plasticity within auditory cortex shows similar plasticity expression and
mechanisms throughout life (Blundon and Zakharenko, 2013).
In addition to synaptic changes, critical period plasticity may involve alterations
in intrinsic cell excitability. High-frequency firing in cortical pyramidal cells leads to
a long-lasting increase in evoked firing rates. This increased excitability depends
upon the recruitment of a signaling cascade involving PKA and calcium
(Cudmore and Turrigiano, 2004) that reduces a persistent potassium current
(IK-TEA; Nataraj et al., 2010). It has recently been suggested that such intrinsic plas-
ticity may play a role in critical periods. Cells acquire this form of plasticity at a post-
natal age that coincides with the critical period onset. However, monocular
deprivation during the critical period reduces cell excitability and increases IK-TEA
in monocular V1 (where competition from the other eye is not possible), presumably
by preventing this form of plasticity (Nataraj et al., 2010). Notably, monocular and
binocular visual cortices show distinct temporal profiles of intrinsic plasticity
expression and differential effects of deprivation (Nataraj and Turrigiano, 2011).
Immediate electrophysiological changes are followed by structural changes in
excitatory synapses and axonal projections. Across brain regions, spines are more
dynamic during early life than in adults (Alvarez and Sabatini, 2007). For example,
pruning of spines along pyramidal cell dendrites occurs in binocular V1 following
monocular deprivation during the critical period, but fails to be seen in adulthood
(Mataga et al., 2004; Oray et al., 2004). Parallel changes in thalamic axons are in-
duced by monocular deprivation, causing shrinkage of arbors arising from the closed
eye and expansion of arbors serving the open eye (Antonini and Stryker, 1993, 1996).
Structural changes may also occur in A1 during critical periods. The tonotopic crit-
ical period is associated with a rapid maturation of stubby spines (Barkat et al., 2011),
which are direct targets of thalamocortical axons (Richardson et al., 2009).
3.2 Inhibitory Circuit Plasticity During Critical Periods

There is accumulating evidence that experience-dependent changes within inhibitory
circuits also play a key role in critical periods (Aton et al., 2013; Gandhi et al., 2008;
Kameyama et al, 2010; Kuhlman et al., 2013; Yazaki-Sugiyama et al., 2009). With
the vast majority of past studies focused on excitatory synapse plasticity onto
principal cells, less attention was directed toward plasticity of inhibition. However, a
barrage of recent studies has made it clear that both GABAergic synapses and
glutamatergic synapses onto inhibitory neurons exhibit robust activity-dependent
plasticity (Kullmann et al., 2012).
Across brain regions, developing inhibitory cells are susceptible to early life sen-
sory experience (Feldman, 2009; Hensch, 2005; Le Magueresse and Monyer, 2013;
Sanes and Kotak, 2011; Takesian et al., 2009). Partial or total loss of activity in sen-
sory cortex generally leads to downregulation of GABAergic transmission. Blocking
activity with tetrodotoxin leads to a decline in miniature inhibitory current ampli-
tudes in visual cortical cultures (Kilman et al., 2002). This is consistent with the ef-
fects of sensory deprivation: dark rearing from birth (Morales et al., 2002), whisker
trimming during a critical period (Jiao et al., 2006), and early hearing loss (Kotak
et al., 2008; Takesian et al., 2010) all reduce the amplitude of inhibitory currents
recorded in cortical excitatory cells.
Such inhibitory plasticity may be developmentally regulated. Deprivation before
or after the critical period does not cause the same readjustments in inhibitory func-
tion (Maffei et al., 2010; Morales et al., 2002; Takesian et al., 2012; Yazaki-
Sugiyama et al., 2009). Experience-dependent changes of inhibitory function are
consistent with anatomical alterations in the number of inhibitory synapses. For ex-
ample, in A1, developmental hearing loss leads to a significant reduction in the num-
ber of inhibitory terminals identified by GAD immunoreactivity (Sarro et al., 2008).
In somatosensory cortex, neonatal whisker trimming reduces inhibitory synapses by
52% (Sadaka et al., 2003). Early visual deprivation leads to a decline in the inhibitory
innervation of cortical pyramidal cell somata (Chattopadhyaya et al., 2004; Kreczko
et al., 2009). Thus, sensory experience has an impact on the establishment of cortical
inhibitory projections across brain regions.
Cortical inhibitory synapses are formed by a diverse group of GABAergic inter-
neurons (Markram et al., 2004) that respond differentially to early sensory experi-
ence. Early monocular deprivation induces a robust decrease in the strength of
inhibitory connections between fast-spiking, parvalbumin (PV)-expressing cells
and pyramidal cells; however, inhibitory connections formed by regular-spiking
nonpyramidal interneurons exhibit an opposite increase in strength (Maffei et al.,
2004). Similarly, dark rearing reduces the response evoked by laser photo-uncaging
of GABA onto somatic but not axonal receptors (Katagiri et al., 2007).
Early auditory deprivation also induces cell type-specific adjustments of cortical
inhibitory pathways. The PV cell pathway exhibits both a reduction of fast excitatory
drive onto PV neurons and a reduction of inhibitory drive from PV to pyramidal neu-
rons; whereas, the low-threshold spiking inhibitory pathway does not (Takesian
et al., 2010, 2013). The divergent effects of sensory experience on inhibitory cell
subtypes suggest that these cells may play diverse roles in critical period plasticity
(see Section 4).
Single-cell recordings in vivo reveal that PV cells in V1 undergo bidirectional
plasticity in response to monocular deprivation: an early paradoxical shift toward
the closed eye inputs after 3 days of deprivation and then a later shift toward the open
4 Critical Period Triggers and Brakes 11
eye inputs (Yazaki-Sugiyama et al., 2009). This change in bias can be explained by
applying STDP rules and offers a novel mechanism for the suppression of deprived
eye responses during the early phase of ocular dominance plasticity. Recently, even
faster dynamics have confirmed decreased PV cell firing rates already 1 day after
deprivation when excitatory cells remain unaffected (Kuhlman et al., 2013). The
degree to which PV cells are suppressed within hours after closing one eye of kittens
predicts the degree to which neighboring excitatory cells will undergo ocular
dominance plasticity (Aton et al., 2013).
A similar reduction of thalamocortical drive onto PV cells occurs in the somato-
sensory (Chittajallu and Isaac, 2010) and auditory cortices (Takesian et al., 2013)
following sensory deprivation, yielding decreased feed-forward inhibition onto ex-
citatory cells (Chittajallu and Isaac, 2010). Notably, a rapid reduction of inhibition in
response to nucleus basalis (NB)-tone pairing in mature A1 may be necessary for
adult receptive field plasticity (Froemke et al., 2007). In adult V1, recent evidence
suggests a structural loss of inhibitory synapses onto pyramidal neurons is an effec-
tive component of experience-induced plasticity with limited need for rearranging
the excitatory circuitry (Chen et al., 2011; van Versendaal et al., 2012). These studies
highlight the importance of understanding the transient sensory-evoked changes in
inhibition, which may be a fundamental mechanism of cortical plasticity.
4 CRITICAL PERIOD TRIGGERS AND BRAKES

4.1 Inhibitory Control of Plasticity
Directly manipulating inhibitory transmission leads to shifts in the timing of the crit-
ical period for ocular dominance plasticity (Hensch, 2005). Critical period onset is
accelerated by activating GABAA inhibitory receptors prematurely with benzodiaz-
epines (Fagiolini and Hensch, 2000; Fagiolini et al., 2003; Hensch et al., 1998; Iwai
et al., 2003), or by promoting inhibitory circuit maturation (Di Cristo et al., 2007;
Hanover et al., 1999; Huang et al., 1999; Sugiyama et al., 2008). Instead, critical
periods are delayed into adulthood by KO or knockdown of the GABA synthesizing
enzymes, GAD65 (Fagiolini and Hensch, 2000; Hensch et al., 1998) and GAD67
(Chattopadhyaya et al., 2007).
Plasticity is conversely reopened after the critical period by reducing inhibition to
immature levels. Intracortical microperfusion of the GAD inhibitor, MPA, or the
GABAA receptor antagonist, PTX, promotes ocular dominance plasticity in adult
V1 (Harauzov et al., 2010). Remarkably, transplantation of immature inhibitory neu-
rons into the postnatal visual cortex promotes ocular dominance plasticity even after
the natural critical period (Southwell et al., 2010). Embryonic precursors of inhibi-
tory cells from the medial ganglionic eminence transplanted into the brains of mice
shortly after birth eventually integrate into the visual cortical circuits. Notably, this
induces ocular dominance plasticity only once the transplant reaches a cellular age
(1 month old) similar to that of endogenous inhibitory cells during the typical
critical period.
Only a1-containing GABAA receptors, which are preferentially expressed and

targeted by large basket PV cells, drive visual cortical plasticity (Fagiolini et al.,
2004). During development, the strength of these PV-to-pyramidal cell inputs
increases in an experience-dependent manner, reaching an optimal threshold to
promote large-scale cortical plasticity (Katagiri et al., 2007). As detailed later, the
maturational state of PV cells interestingly requires interactions with its surrounding
extracellular milieu (Fig. 1B). Thus, plasticity onset is triggered by non-cell auton-
omous factors which promote PV cell maturation, such as brain-derived neurotrophic
factor (BDNF) and orthodenticle homeobox 2 (Otx2; Sugiyama et al., 2008).
The extracellular environment may in fact prevent premature Otx2 transfer and
precocious plasticity during the precritical period. For example, polysialic acid
(PSA) attaches to neural cell adhesion molecule and entraps homeodomain proteins
(Joliot et al., 1991). PSA expression in mouse V1 declines shortly after eye opening.
Premature PSA removal promotes maturation of perisomatic GABAergic innerva-
tion and triggers a precocious critical period for ocular dominance plasticity
(Di Cristo et al., 2007). Conversely, molecular brakes such as perineuronal nets
(PNNs) and Lynx1 emerge with critical period closure to modulate PV cell function
(Beurdeley et al., 2012; Morishita et al., 2010), as discussed below.
4.2 Brain-derived neurotrophic factor

Genetic enhancement of BDNF, in particular, triggers an early ocular dominance
critical period by promoting inhibitory circuit maturation in V1 (Hanover et al.,
1999; Huang et al., 1999). Precocious BDNF expression accelerates visual acuity
(Huang et al., 1999), whereas blockade of BDNF signaling prevents the development
of ocular dominance columns in kitten V1 (Cabelli et al., 1997). Instead, TrkB
receptor kinase activity is not required for any of the plastic effects of deprivation
itself (Kaneko et al., 2008b). Other neurotrophins may act differently on visual sys-
tem development and plasticity (Lodovichi et al., 2000).
BDNF transcription, trafficking, and secretion are dynamically modulated in an
activity-dependent manner (Greenberg et al., 2009). Cortical BDNF is kept at imma-
ture levels by manipulations which delay critical periods, including dark rearing
(Castrén et al., 1992) and acoustic white noise exposure (Zhou et al., 2011).
Recently, it has been found that infusion of BDNF in auditory cortex amplifies tono-
topic map plasticity in response to pure tone exposure during the critical period
(Anomal et al., 2013). Conversely, BDNF blockade leads to distorted tonotopic or-
ganization and reduced spectral tuning. These effects were associated with changes
in GABA receptors. Thus, BDNF may control critical period timing across regions
by the activity-dependent modulation of PV cell maturational state.
4.3 Extracellular Matrix: PNNs and Otx2

PNNs, composed of chrondroitin sulfate proteoglycans (CSPGs) and other extracel-
lular matrix components, have been found to play an important role in plasticity by
modulating PV cell function (Berardi et al., 2004; Galtrey and Fawcett, 2006). These
lattice-like structures surround cell bodies and proximal neurites, preferentially

ensheathing mature PV cells (Härtig et al., 1999). The progressive developmental
increase in PNNs is thought to contribute to the closure of critical periods across di-
verse brain regions. In the visual system, PNN expression increases across postnatal
development, coincident with closure of the critical period for ocular dominance
plasticity (Pizzorusso et al., 2002; Sur et al., 1988).
PNNs similarly appear at the closure of the critical period in the mouse barrel
cortex (McRae et al., 2007). Within nucleus HVC of the zebra finch brain, the per-
centage of PV-expressing neurons with PNNs dramatically increases during song
learning and predicts song maturity (as measured by temporal variance; Balmer
et al., 2009). Finally, the emergence of PNNs in the developing amygdala is associ-
ated with the closure of a critical period for fear extinction. Whereas young mouse
pups can permanently erase an acquired fear memory by extinction training, adult
animals exhibit persistent fear behaviors that are resistant to erasure. The age at
which this developmental switch in fear memory resiliency occurs is coincident with
a sharp increase in PNN expression in the basolateral amygdala (Gogolla et al.,
2009a).
PNN expression is decreased by manipulations that delay the closure of critical
periods, such as visual deprivation in developing cats and mice (Sur et al., 1988; Ye
and Miao, 2013), whisker trimming in developing mice (McRae et al., 2007), or
acoustic isolation of developing zebra finches (Balmer et al., 2009). PNN expression
is instead not affected by adult sensory deprivation (McRae et al., 2007; Sur et al.,
1988), suggesting that there is a critical period for normal PNN development. Strong
evidence for a role of PNNs in regulating plasticity comes from studies reporting
reactivation of critical periods by degradation of PNNs. Their degradation by
chondroitinase-ABC in adult V1 reopens sensitivity to monocular deprivation and
restores visual acuity to amblyopic rats (Pizzorusso et al., 2002, 2006). Similarly,
in the adult basolateral amygdala, PNN degradation reopens a critical period during
which fear memories are once again fully erased by extinction training (Gogolla
et al., 2009a).
PNNs may limit PV cell plasticity by controlling the concentration of extracel-
lular ions that surround these cells or by sequestering molecular factors which
regulate plasticity (Härtig et al., 1999; Hensch, 2005; Sugiyama et al., 2008,
2009). For instance, PNNs permit the capture of the Otx2 homeoprotein by PV
cells. After eye opening, Otx2 is translocated into visual cortex in an activity-
dependent manner from the retina (Sugiyama et al., 2008). More recently, the cho-
roid plexus has been identified as an additional source (Spatazza et al., 2013).
The accumulation of Otx2 within PV cells accelerates and maintains their matura-
tion, elevating markers of fast-spiking PV cell function (PV, K3.1b potassium chan-
nels, GAD65, and GABAA a1 receptor subunit) and triggering plasticity onset
(Sugiyama et al., 2008).
PNNs and Otx2 colocalize in the adult visual cortex (Beurdeley et al., 2012;
Sugiyama et al., 2008), and PNN degradation leads to an 80% reduction in the num-
ber of Otx2-positive cells (Beurdeley et al., 2012). A classical glycosaminoglycan-
binding motif (RK doublet) has been identified within Otx2 that recognizes CSPGs
and mediates Otx2 binding to PNNs. Infusing an RK peptide to block this specific
recognition significantly decreases Otx2 content of PV cells (Beurdeley et al., 2012).
Strikingly, this blockade of Otx2 transfer within cortex (Beurdeley et al., 2012) or
knockdown of Otx2 synthesis from the choroid plexus (Spatazza et al., 2013) reac-
tivates ocular dominance plasticity in mature V1, enabling recovery from amblyopia.
The CSPG sulfation patterns determine the condensation of CSPGs into tight
PNNs. Developmental increases in the carbon 4-/6-sulfation ratio of CSPGs occur
in parallel with critical period closure. This shift occurs in the somatosensory cortex
before the visual cortex, consistent with the staggered windows of plasticity between
these regions. Transgenic mice engineered to retain a low 4S/6S ratio exhibit deficits
in normal PNN formation and disrupted Otx2 transfer into PV cells (Miyata et al.,
2012). These mice, as well as those lacking the link protein that forms the PNN back-
bone (Carulli et al., 2010), then show extended plasticity into adulthood.
Together, these studies suggest that PNNs play a persistent role in controlling
plasticity by capturing Otx2 within PV cells. Otx2 regulation of plasticity can be
explained by a two-threshold model: the critical period is triggered as Otx2 is first
captured by PV cells, but then closes as maturing PNNs condense and permit even
higher levels of Otx2 to accumulate. Otx2 protein is present in PV cells across var-
ious brain regions outside of the visual cortex, including prefrontal, auditory, and
somatosensory cortices, as well as the basolateral amygdala and hippocampus, sug-
gesting that this factor may be a global regulator of PV cell maturation and associated
critical period plasticity (Spatazza et al., 2013).
4.4 Narp
In addition to Otx2, PNNs might also facilitate the accumulation of other molecules
that modulate PV cell function. For example, the build-up of neuronal activity-
regulated pentraxin (NARP) at excitatory synapses onto PV cells depends upon
the presence of PNNs. Narp is an activity-dependent protein that is secreted from
presynaptic excitatory neurons and regulates GluR4-containing AMPA receptor
levels in hippocampal PV cells. Genetic deletion of Narp prevents homeostatic upre-
gulation of excitatory input onto these PV cells during increased network activity
(Chang et al., 2010). In V1, Narp KO mice show reduced excitatory drive onto
PV cells, resulting in widespread hyperexcitability that is reminiscent of the imma-
ture cortex. Strikingly, these mice fail to express ocular dominance plasticity
throughout life, suggesting that Narp-dependent enhancement of excitatory drive
onto PV cells plays an important role in opening critical periods (Gu et al., 2013).
4.5 Myelin and Myelin-Associated Inhibitors

Emerging studies now implicate myelin and myelin-associated inhibitors in control-
ling critical periods. Proteins found in myelin, including Nogo-A/B, myelin-associated
glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein, limit axonal sprout-
ing upon binding to the Nogo receptor (NgR) and paired immunoglobulin-like receptor
B complex (PirB; Atwal et al., 2008). Adult mice lacking NgR or its ligands (Nogo-
A/B) exhibit ocular dominance plasticity well beyond the critical period (McGee et al.,
2005), as do mice lacking functional PirB, revealed by a greater cortical induction
of the activity-regulated immediate-early-gene Arc upon open eye stimulation
(Syken et al., 2006).
NgR deletion also reopens a critical period for acoustic preference in mice. Ex-
posing WT juvenile mice to music reverses their innate preference to dwell in a silent
shelter. However, WT mice exposed as adults continue to show a preference for si-
lence, suggesting that acoustic preference is shaped during an early critical period.
However, mice lacking the gene for NgR maintain an open-ended critical period,
continuing to show shifts in acoustic preference into adulthood. This shift in prefer-
ence is associated with elevated activation of the medial prefrontal cortex, as
assessed by cFos expression (Yang et al., 2012). Therefore, NgRs may limit plastic-
ity within diverse circuits beyond primary sensory regions.
Limiting structural changes may be one mode of NgR action. Two photon in vivo
imaging in somatosensory cortex reveals increased dendritic spine turnover in adult
mice lacking NgR1, similar to levels observed in juvenile mice (Akbik et al., 2013).
These mutants also exhibit more robust extinction of freezing following fear condi-
tioning (Akbik et al., 2013), a behavior that is associated with spine turnover (Lai
et al., 2012). Interestingly, NgR is also expressed in PNN-ensheathed (presumably
PV) cells in mouse V1 (Ye and Miao, 2013) and has been found to act as a receptor
for CSPGs (Dickendesher et al, 2012). Dark rearing from birth prevents the dramatic
developmental increase in NgR within PNN-bearing cells. Thus, a potential cross-
talk between myelin factors and PNNs might stabilize synapses in adulthood,
restricting spine turnover on pyramidal cells as well as input onto aspiny PV cells.
Proper development of myelin depends upon the early environment. Social experi-
ence may regulate myelination in the prefrontal cortex during a developmental critical
period. Mouse pups socially isolated for 2 weeks after weaning showed deficits in PFC-
dependent behaviors, such as sociability and working memory. These deficits were ac-
companied by alterations in oligodendrocyte morphology and a reduced expression of
myelin genes, like MAG and myelin basic protein (Makinodan et al., 2012). A specific
ErbB3 signaling pathway is essential for this experience-dependent maturation of
oligodendrocytes and behavior (Makinodan et al., 2012). Notably, these changes occur
in a juvenile critical period overlapping that of acoustic preference behaviors in PFC
(Yang et al., 2012) and are not reversed by subsequent exposure to a social environment.
Thus, changes in myelin signaling may impact a range of critical periods, shaping di-
verse neural processes from basic sensory perception to higher order cognition.
4.6 Epigenetic Regulation

Accumulating evidence suggests that brain circuits respond to environmental signals
via dynamic changes in DNA methylation and histone modifications (Fagiolini et al.,
2009). DNA methylation is the conversion of cytosine to 5-methylcytosine in CpG
dinucleotides. The process depends upon the presence of methyl donors and is
catalyzed by DNA methyltransferases. DNA methylation represses transcription

directly by interfering with the binding of transcription factors or indirectly by
recruiting repressor complexes containing histone deacetylases (HDACs) to con-
dense chromatin structure (Burgers et al., 2002; Klose and Bird, 2006).
Dynamic changes in methylation of both the glucocorticoid receptor (Zhang and
Meaney, 2010), and more recently its regulatory target FKBP5 (Klengel et al., 2013),
in response to early life stress or degree of maternal care have been well documented.
Developmental changes in such posttranslational modifications may underlie critical
period transitions. Closure of the critical period for ocular dominance is associated
with a downregulation of visual experience-induced histone acetylation and phos-
phorylation. Trichostatin A, valproate or sodium butyrate, HDAC inhibitors which
increase histone acetylation, reactivate ocular dominance plasticity after the critical
period (Putignano et al., 2007) and enable recovery from amblyopia in adulthood
(Silingardi et al., 2010). Valproate also reopens critical-period learning of absolute
pitch in humans (Gervain et al., 2013).
Epigenetic factors regulate GAD67 (Huang and Akbarian, 2007), reelin, an ex-
tracellular matrix protein preferentially secreted by GABAergic neurons (Levenson
et al., 2008; Lewis et al., 2005), and BDNF (Martinowich et al., 2003). In addition,
oligodendrocytes are known to be epigenetically dynamic (Shen et al., 2008), and
valproate treatment reopens critical periods for acoustic preference in the PFC, mim-
icking NgR deletion (Yang et al., 2012). It will be essential to determine how global
epigenetic alterations induced by HDAC inhibitors or early life stress impact the
brain in a cell-specific manner.
5 CRITICAL PERIOD GATING

5.1 How do PV Circuits Control Plasticity?
Although it is clear that PV cells are a central hub controlling critical period timing,
the way in which these cells regulate plasticity remains elusive. Recent studies have
proposed that a transient suppression of PV cells may gate cortical plasticity. For
example, excitatory drive onto PV cells is reduced by 70% as rapidly as 1 day after
monocular deprivation during the critical period (Aton et al., 2013; Kuhlman et al.,
2013; Yazaki-Sugiyama et al., 2009). Mimicking a transient 24 h reduction of inhi-
bition upon eyelid suture by selective activation of DREADD receptors within PV
cells enables plasticity beyond the critical period (Kuhlman et al., 2013).
First, it is possible that the strong perisomatic inhibition that PV cells generate in
pyramidal cells alters synaptic plasticity rules. GABA receptor antagonists increase
the probability of inducing LTP by tetanic stimulation to the white matter in rat vi-
sual cortical slices even beyond the critical period (Harauzov et al., 2010; Kirkwood
and Bear, 1994). Fast, disynaptic inhibition generated by PV cells restricts the tem-
poral window during which postsynaptic inputs can summate and potentiate by
STDP. Robust perisomatic control of back-propagating action potentials in particular
5 Critical Period Gating 17
may favor temporally coherent inputs for STDP, enhancing synaptic competition
(Hensch, 2005; Kuhlman et al., 2010).
A role for GABA in synaptic competition is elegantly demonstrated in a recent
study using two-color uncaging of glutamate and GABA onto rat hippocampal CA1
pyramidal cells. GABA uncaging induces spine shrinkage and elimination when
paired with a STDP protocol, which depends upon a signaling cascade involving
NMDA receptors, calcineurin, and actin depolymerizing factor (Hayama et al.,
2013). To examine heterosynaptic competition along a dendrite, neighboring spines
were stimulated: one spine with an LTP protocol to induce enlargement and a neigh-
boring spine with an LTD protocol to induce shrinkage. Remarkably, GABA induces
widespread spine shrinkage across the dendrite to neighboring spines, except for the
spine stimulated with the LTP protocol (Hayama et al., 2013). In this manner, GABA
promotes the competitive selection of individual spines along a dendrite, a process
that is elevated during critical periods of development (Hensch, 2005).
A second possible mechanism is that PV circuits may initiate a cascade of mo-
lecular events that create a permissive extracellular milieu for structural changes. For
example, altered inhibition may trigger a transient increase in proteolytic activity by
the tPA enzyme that degrades the extracellular matrix. tPA elevation during monoc-
ular deprivation underlies the spine pruning that is essential for ocular dominance
plasticity (Mataga et al., 2002, 2004; Oray et al., 2004). This deprivation-induced
increase in tPA, along with spine pruning, fails to occur in mature mice or those lack-
ing GAD65 (Mataga et al., 2002, 2004).
A third mechanism may involve the coordination of synchronized network activ-
ity. PV cells form networks that are interconnected by both chemical and electrical
synapses (Galarreta and Hestrin, 2002). Such networks show synchronous activity
and play an important role in generating gamma (30–100 Hz) rhythms in the cortex
and hippocampus (Cardin et al., 2009; Fuchs et al., 2007; Le Magueresse and Monyer,
2013; Sohal et al., 2009). During early postnatal life, emergence of the mature elec-
trophysiological properties of PV cells may lead to more coherent network activity of
higher gamma band frequencies (Doischer et al., 2008). It is currently unknown
whether such coordinated activity contributes to critical period plasticity.
A fourth theory is that inhibitory maturation enables the transition from precrit-
ical period to critical period plasticity by reducing spontaneous activity. This hypoth-
esis takes note of the fact that many forms of activity-dependent plasticity are equally
robust before and during the critical period. Therefore, critical period onset may not
reflect the engagement of new plasticity mechanisms, but rather when there is a shift
in the predominant learning cues from internally driven spontaneous activity to ex-
ternally driven sensory-evoked activity (Toyoizumi et al., 2013). Recordings from
awake-behaving mice confirm that critical period onset is accompanied by a reduc-
tion in the spontaneous-to-visual activity ratio. Therefore, shifts in spontaneous-to-
evoked ratios may be timed to match distinct critical periods across cortical regions,
representing a global mechanism governing developmental plasticity.
Finally, it is possible that inhibitory circuit plasticity itself underlies the changes
in cortical response properties that occur during critical periods (Aton et al., 2013;
Gandhi et al., 2008; Kameyama et al, 2010; Kuhlman et al., 2013; Ma et al., 2013;
Yazaki-Sugiyama et al., 2009). By understanding how experience-dependent alter-
ations of the PV circuit influence cortical plasticity, we will gain insight into the con-
ditions that make the circuits of the brain most labile to experience.
5.2 Modulation of PV Circuits

Various endogenous mechanisms, including modulators and extracellular factors,
may act to downregulate PV cell function to gate plasticity. First, specific disinhi-
bitory circuits, in which PV cells are suppressed by other GABAergic interneurons,
might contribute (Fig. 1B). Across cortices, it has been shown that PV cells are
highly interconnected, strongly inhibiting one another (Avermann et al., 2012;
Galarreta and Hestrin, 2002; Galarreta et al., 2008; Gibson et al., 1999; Pfeffer
et al., 2013). Furthermore, somatostatin-expressing inhibitory cells in somatosensory
(Xu et al., 2013) and visual cortices (Pfeffer et al., 2013) preferentially target PV
cells, reducing PV cell spiking and thus increasing the firing of neighboring pyrami-
dal neurons (Xu et al., 2013). Interneurons within the superficial cortical layers,
which are activated by modulators (Arroyo et al., 2012; Lee et al., 2010; Letzkus
et al., 2011) and by projections from matrix thalamic nuclei (Cruikshank et al.,
2012), also generate inhibition within PV cells (Arroyo et al., 2012; Letzkus
et al., 2011). This L1 cell-mediated disinhibitory circuit in auditory cortex is required
for fear learning (Letzkus et al., 2011). It will be important to determine whether
these disinhibitory circuits also gate plasticity during developmental critical periods.
Second, neuromodulators, such as acetylcholine or serotonin, may be critically
involved in plasticity through their impact on PV cell function. The cholinergic neu-
romodulatory system has long been a target to induce plasticity in the adult auditory
cortex (Weinberger, 2004). Tone-evoked shifts in cortical tuning are normally re-
stricted to an early life critical period (Barkat et al., 2011; de Villers-Sidani et al.,
2007); however, robust shifts in the preferred frequency of adult cortical neurons
are achieved by pairing a tone with electrical stimulation of the NB, the main source
of cortical acetylcholine (Froemke et al., 2007; Kilgard and Merzenich, 1998;
Weinberger, 2004).
Strikingly, a brief tone-NB pairing induces a rapid reduction of synaptic inhibi-
tion that persists for hours. This transient disinhibition triggered by cholinergic input
is thought to promote cortical hyperexcitability and allow for reorganization of au-
ditory cortex (Froemke et al., 2007). A recent study has found that pairing vagus
nerve stimulation (VNS) with a tone also drives long-lasting changes in auditory cor-
tical maps (Engineer et al., 2011). Moreover, VNS reverses the degraded auditory
cortical properties and behavioral deficits associated with noise-induced trauma.
VNS may lead to the release of multiple neurotransmitters, including acetycholine.
The cholinergic work in auditory cortex has primarily focused on the muscarinic
subtype of acetylcholine receptors. Indeed, cortical application of the muscarinic re-
ceptor antagonist atropine blocks NB-induced adult plasticity, suggesting an essen-
tial role for this receptor (Weinberger, 2004). However, more recent studies have
5 Critical Period Gating 19
also identified the nicotinic acetylcholine receptor (nAChR) as a regulator of cortical

plasticity (Metherate, 2004). Interestingly, the early developmental periods in audi-
tory cortex coincide with a transient upregulation in nAChRs. During the first few
postnatal weeks, there is a peak in acetylcholinesterase staining, and in the mRNA
expression and binding sites of two predominant cortical nAChR subtypes, a7 and
a4b2 (Metherate, 2004).
As cortical plasticity declines with age, nAChR expression is decreased. In ad-
dition, the function of nAChRs is actively dampened by the developmental upregu-
lation of Lynx1, a membrane-anchored protein that alters nAChR agonist binding
and desensitization kinetics (Miwa et al., 1999). Genetic deletion of Lynx1 enhances
nAChR signaling and heightens plasticity in adult V1 (Morishita et al., 2010). More-
over, adult Lynx1 KO mice can spontaneously recover acuity following an earlier
monocular deprivation during the critical period by simply reopening the closed
eye. Likewise, boosting nicotinic signaling with a cholinesterase inhibitor in adult
WT animals also enables the recovery from amblyopia.
Lynx1 (Morishita et al., 2010) and nAChRs (Arroyo et al., 2012) are expressed on
cortical GABAergic cells and may promote plasticity by adjusting E–I balance. Re-
cent work suggests that nAChRs activate the disinhibitory microcircuit (above) in
auditory cortex that is required for fear learning (Letzkus et al., 2011). In the adult
mouse barrel cortex, an upregulation of a4-containing nAChRs on GABAergic neu-
rons mediates the cortical depression associated with whisker trimming (Brown
et al., 2012). Together, these studies strongly implicate nAChR signaling as an im-
portant regulator of cortical plasticity.
Serotonin is one of the first neurotransmitters to appear in the brain (Gaspar et al.,
2003) and is involved in a variety of early developmental processes (Lesch and
Waider, 2012). Serotonergic fibers from the brainstem raphe nuclei broadly inner-
vate the cortex, influencing development of neocortical architecture. Serotonin dys-
function prevents the formation of characteristic barrel fields in the mouse
somatosensory cortex (Persico et al., 2001), and perinatal SSRI exposure alters re-
ceptive field properties in auditory cortex (Simpson et al., 2011). In humans, mater-
nal serotonin levels produce bidirectional shifts in critical periods for infant speech
perception: prenatal SSRI exposure accelerates a critical period for consonant dis-
crimination, while maternal depression (associated with decreased serotonin levels;
Jans et al., 2007) delays the critical period for nonnative sound discrimination
(Weikum et al., 2012).
The serotonergic system has thus become a target to reinstate adult plasticity.
Chronic SSRI treatment reopens a critical period for ocular dominance plasticity
in rat visual cortex and allows recovery of visual acuity from amyblyopia in adult-
hood (Maya Vetencourt et al., 2008, 2011). A similar critical period reactivation oc-
curs in the fear-conditioning network: fear erasure by extinction training, which
normally occurs only in juvenile mice (Gogolla et al, 2009a), is achieved in adults
by chronic SSRI treatment (Karpova et al., 2011). Reactivation of plasticity is asso-
ciated with an SSRI-induced enhancement of LTP (Karpova et al., 2011; Maya
Vetencourt et al., 2008, 2011; Park et al., 2012).
Similar to cholinergic enhancement, SSRIs may act to promote plasticity by reduc-

ing intracortical inhibitory function. Chronic SSRI treatment reduces basal levels of cor-
tical extracellular GABA, and benzodiazepine administration prevents SSRI-induced
adult visual plasticity (Maya Vetencourt et al., 2008). Taken together, these effects
suggest that the successful resetting of E–I balance to a juvenile, more plastic state
by endogenous neuromodulator release may underlie the efficacy of noninvasive ap-
proaches to rekindle adult plasticity, such as video-game training (Bavelier et al., 2010).
6 IMPLICATIONS
6.1 Mental Disorders
The realization that critical period timing is itself plastic offers insight into neurode-
velopmental disorders. Targeting these molecular triggers and brakes may offer ther-
apeutic strategies to reinstate plasticity when it is inappropriately timed or fails to
close properly. In the postmortem schizophrenic brain, deficient myelination,
reduced perisomatic GABA synapses, and excessive spine pruning are commonly
observed (Insel, 2010). Moreover, PNNs are compromised in the amygdala and pre-
frontal cortex (Mauney et al., 2013; Pantazopoulos et al., 2010). These are hallmarks
of a brain whose plasticity brakes have not come on fully, suggesting that the failure
to stabilize circuits at least during the prodromal stage may contribute to psychoses.
Mapping the developmental trajectory of critical period plasticity may become an
important diagnostic and potential therapeutic tool.
Likewise, E–I imbalance, in particular of PV circuits, has been noted across au-
tism spectrum disorders (Gogolla et al., 2009b; Rubenstein and Merzenich, 2003),
suggesting a mis-timing of critical period onset. Due to the hierarchical nature of
critical periods, even a small jitter in the earliest plastic windows may have a cas-
cading effect on later stages to yield complex cognitive phenotypes. Mouse models
of autism are starting to confirm such timing errors, which encouragingly can be
reversed by rebalancing circuit function. For example, in the Mecp2-deficient mouse
model of Rett syndrome, PV circuits are paradoxically hyper-mature preceding a
regression of cortical function. In the visual cortex, this can be reversed by dark rear-
ing the animals or further genetic disruption of NMDA receptor 2A subunits (Durand
et al., 2012). PV cells are preferentially sensitive to NMDA receptor function, and
low-dose ketamine treatment restores neural activity across brain regions in the
Mecp2 KO mouse (Kron et al., 2012). Other mouse models of autism, such as Fragile
X (Harlow et al., 2010), may instead show an opposite, delayed onset of plasticity
due to impoverished PV cell networks (Gogolla et al., 2009b). This would require
an appropriately timed enhancement of GABA function for rescue.
6.2 Cross-Modal Plasticity

Early blind or deaf subjects are known to re-purpose their deprived cortices to process
other sensory modalities (Kral and Sharma, 2012; Merabet and Pascual-Leone, 2010).
6 Implications 21
Strikingly, this effect declines with later onset of deprivation, while early life rewiring
conversely interferes with later recovery of function if sensory input is restored (Lee
et al., 2001). Inhibitory transmission and plasticity mechanisms are typically kept in a
refractory state of development by exposure to darkness (Huang et al., 2010; Kang
et al., 2013) or rejuvenated by environmental enrichment (Sale et al., 2007; Scali
et al., 2012), suggesting an explanation for these effects in humans.
An elegant animal model exhibiting cross-modal development in response to al-
tered early sensory input is the barn owl (Keuroghlian and Knudsen, 2007). Multi-
modal integration of auditory and visual maps is essential for proper localization and
targeted flight toward an object or prey. The microsecond inter-aural time differ-
ences (ITD) of arriving sounds emitted from a source are superimposed onto the
visual receptive fields in the optic tectum. When misaligned during development,
such as with prism goggles, an aggressive period of rewiring ensues over the follow-
ing weeks to retune ITD preferences to match the displaced visual scene of individual
neurons. This prolonged process is ultimately consolidated by the physical growth of
axons in the direction of the newly acquired tuning.
Notably, there is a further targeted growth of novel inhibitory connections as well
to silence the unused representation in the tectum (Zheng and Knudsen, 1999). In this
manner, the barn owl remains free of confusion while retaining the capacity for mul-
tiple maps to coexist. Indeed, when confronted with an environment that was previ-
ously experienced during the critical period, adult barn owls exhibit rapid and broad
shifts of ITD maps even if they are incapable of acquiring new ones. Similar ability to
shift ocular dominance is observed in adult mice that previously experienced it ear-
lier in life (Hofer et al., 2006). Inhibitory connections in V1 are also strengthened by
monocular deprivation during the critical period (Maffei et al., 2006; Skangiel-
Kramska and Kossut, 1984).
Such dramatic anatomical changes are not observed in adult barn owls
(Linkenhoker et al., 2005). However, the clever use of incremental training procedures
does enable cumulative shifts in ITD tuning even in adult owls (Linkenhoker and
Knudsen, 2002). Moreover, raising them in an enriched environment, such as active
hunting rather than cage rearing (Brainard and Knudsen, 1998), extends the duration
of the critical period. Thus, as in mouse V1, critical period plasticity per se is plastic
and can be tapped noninvasively by engaging environments where perception for ac-
tion is needed. Such strategies have recently been employed in video-game training
approaches to rescue amblyopia in adult humans (Bavelier et al., 2010).
6.3 Higher Cognition

While strict limitations on plasticity may be evident in primary sensory areas, they
gradually become less rigid in higher cognitive domains. So, the ability to hear “r”
from “l” may be lost in primary auditory cortex of native Japanese, but the acquisi-
tion of a second language per se is not. Amblyopia may become hard-wired by the
age of 8, but the ability to learn new faces (presumably in area IT) remains. These
observations reveal the remarkable plasticity that is present throughout life in higher
associational brain areas and support the hierarchical nature of critical periods. In-
terestingly, PV circuit maturation follows this gradient along the visual pathway in
primates (Condé et al., 1996).
The adult brain does not process all inputs equally, but learns through experience
that certain events are more likely to occur than others. This Bayesian view further
attests to the importance of establishing early, firm foundations in order to generate
higher cognitive function. A gradient of developmental hard wiring ensures that sta-
ble primary inputs are passed on to generate more flexible associations in higher as-
sociational areas. For example, the expansion of multimodal receptive fields to
encompass tool use in adult monkey parietal cortex is accompanied by significant
anatomical growth of new axons as the animals gradually learn their use over several
weeks (Iriki, 2006; Quallo et al., 2009). Interestingly, such evolutionarily advanced
associational cortices are the least invested in CSPGs and are known to myelinate last
(Braak and Braak, 1996; Brückner et al, 1999). Thus, the cellular and molecular con-
straints that are present at earlier stages seem to be loosened or absent. Unfortunately,
this lifelong plasticity may not be without consequence, as these regions are prefer-
entially vulnerable to neurodegeneration with age (Mesulam, 1999). Critical period
closure may then also be considered neuroprotective.
7 FUTURE DIRECTIONS
Neural circuits are molded early in life to best represent the sensory input arriving at
that time, and then eventually become hard-wired. The use of a molecular/genetic
approach has revealed that specific GABA circuits orchestrate the functional and
structural rewiring of neural networks during “critical periods” of cortical plasticity,
which become limited in adulthood by the further expression of “brake-like” factors.
Ongoing work focuses on (1) confirming to what extent these mechanisms generalize
across brain regions, and (2) translating basic animal research into therapeutic strat-
egies for devastating neurological disorders in humans.
Given the limited environments in which most animals live, critical periods may
have evolved as an effective survival strategy for their relatively short lifespan. Crit-
ical period duration is in fact correlated with average life expectancy (e.g., in V1;
Berardi et al., 2000). However, in the past century, humans have enjoyed a rapid in-
crease in longevity and the ability to drastically change their surroundings on short
timescales. Perhaps our species is now acutely feeling the limitations of critical pe-
riod biology—not only as linguistic awkwardness when immersed in a foreign land,
but more seriously manifest as neuropsychiatric disorders of developmental origin.
In order to leverage these recent insights for lifelong learning, several conse-
quences should be explored further:
(1) Individual variability in critical period timing. Appreciating the powerful role of
E–I circuit balance (in particular, one class of GABA neuron) and its sensitivity
References 23
to early exposure to drugs, adversity, sleep, or genetic perturbation predicts that

optimal plasticity windows will differ across individuals. A striking example
may be the mis-regulation of E–I balance in autism or after early life seizures,
suggesting careful mapping of critical period timing is needed in patient
populations.
(2) Lifting brakes in adulthood. The realization that the brain’s intrinsic potential for
plasticity is actively dampened by brake-like factors has overturned the
traditional view of a fixed, immutable circuitry that is consolidated early in life.
At the same time, the great biological cost to maintain multiple brakes
throughout life emphasizes the need to stabilize circuits for proper brain
function. Understanding why there are so many, how they interact, and
ultimately how to lift them in noninvasive ways may hold the keys to lifelong
learning.
Acknowledgments
Supported by the Canadian Institute for Advanced Research (A. E. T., T. K. H.) and the Nancy
Lurie Marks Family Foundation (A. E. T.).
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CHAPTER
Brain Plasticity in the

Developing Brain
Bryan Kolb1, Richelle Mychasiuk, Arif Muhammad, Robbin Gibb

2
Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, AB, Canada
1
Corresponding author: Tel.: þ1-403-329-2405; Fax: þ1-403-329-2775,
e-mail address: kolb@uleth.ca
Abstract
The developing normal brain shows a remarkable capacity for plastic change in response to a
wide range of experiences including sensory and motor experience, psychoactive drugs,
parent–child relationships, peer relationships, stress, gonadal hormones, intestinal flora, diet,
and injury. The effects of injury vary with the precise age-at-injury, with the general result
being that injury during cell migration and neuronal maturation has a poor functional outcome,
whereas similar injury during synaptogenesis has a far better outcome. A variety of factors
influence functional outcome including the nature of the behavior in question and the age
at behavioral assessment as well as pre- and postinjury experiences. Here, we review the
phases of brain development, how factors influence brain, and behavioral development in both
the normal and perturbed brain, and propose mechanisms that may underlie these effects.
Keywords
brain development, prefrontal cortex, recovery of function, types of plasticity
1 INTRODUCTION
The development of the brain and behavior is guided not only by a basic genetic blue-
print but also by a wide range of experiences that shape the emerging brain. Brains
exposed to different environmental events such as sensory stimuli, stress, injury,
diet, drugs, and social relationships show a unique developmental trajectory. The
explosion of epigenetic studies in the past few years has also demonstrated that pre-
natal, and even preconceptual, experiences modify the organization of neural
networks. The goal of this review is to consider the manner in which the developing
brain can be modified by a range of prenatal and postnatal factors that can influence
how the brain responds to other experiences later in life. Our focus will be on the
35
36 CHAPTER 2 Brain Plasticity in the Developing Brain
neocortex of the rat because the majority of our knowledge regarding the modulation
of brain development is based on studies of neocortical development. We begin with
a brief review of the stages of brain development followed by a consideration of how
factors influence brain development and behavior.
2 STAGES OF BRAIN DEVELOPMENT

The Roman philosopher Seneca concluded that an embryo is an adult in miniature
and the purpose of development was to grow bigger. By the twentieth century, it be-
came clear that this was not the case. Today, development can broadly be divided
into two phases. In mammals, the first phase is in utero and reflects a genetically
determined sequence of events that can be modulated by the maternal environment.
The principal developmental stages here are neural generation and migration. The
second phase, which is largely postnatal in species such as the rat, but both pre-
and postnatal in species such as humans where brain development is more prolonged.
The second phase of development is a period in which the emerging connectivity of
the brain is very sensitive to both environmental stimuli but also to the patterns of
brain activity produced by previous experiences.
Table 1 summarizes seven general stages of brain development characteristic of
all mammals. The generation of neurons in rats begins on embryonic (E) day 10.5–11
when the neural tube is formed with the generative zone, called the subventricular
zone, as the primary “nursery” (for reviews, see Bayer and Altman, 1991; Semple
et al., 2013). The cerebral cortex is mainly generating cells from E15–21. Once
generated in the subventricular zone, the putative neurons migrate to their appropri-
ate locations in the developing cortical plate. The migratory process can take
2–5 days, depending upon the final location (see Fig. 1) (Bayer and Altman;,
1991; Hicks and D’Amato, 1968). There are two types of migration. Pyramidal cells
migrate from the ventricular zone along radial glia to their respective cortical layers
(Rakic, 1972). Interneurons take a tangential trajectory in what Bayer and Altman
call the lateral migratory stream as illustrated in Fig. 1. These cells are generated
more laterally in the ventricular zone in a region known as the ganglionic eminence
(Cuzon et al., 2006; Jimenz et al., 2002). Errors in the migration process, including
abnormal cell proliferation, abnormal timing or migration, or abnormal cortical
Table 1 Stages of brain development

1. Cell birth (neurogenesis, gliogenesis)
2. Cell migration
3. Cell differentiation
4. Cell maturation (dendrite and axon growth)
5. Synaptogenesis (formation of synapses)
6. Cell death and synaptic pruning
7. Myelogenesis (formation of myelin)
2 Stages of Brain Development 37
Dorsomedial
neocor tex
2 days
D eo
n
or co
so r t
lat ex
er
3 days
al
Ventricular
LA
zone TE
Head
RA
LC
Ventrolateral
neocor tex
OR
TIC
Striatum
AL
STR
EAM
4 days
Reservoir
Pirifo
5 days
rm
co
Basal ?
r te
telencephalon
x
FIGURE 1
A summary figure showing cell migration in the anterior and middle parts of the developing
neocortex. Neurons generated in the ventricular zone (striped layer) migrate radially to
the dorsal cortical plate in 2 days, migrate laterally to the lateral cortical plate in 3 days and
to the ventrolateral cortical plate in 4 days. Some cells generated in the ventricular zone
migrate in the lateral cortical stream for up to 4 days and accumulate in the reservoir.
Some migrate into the pyriform cortex, whereas others migrate to as yet unidentified areas in
the basal telencephalon.
From Bayer and Altman (1991), with permission.
organization, have been implicated in disorders such as epilepsy, autism, and schizo-
phrenia among others (e.g., Mochida and Walsh, 2004). Furthermore, prenatal expo-
sure to drugs, such as diazepam (a GABA agonist), can alter migration patterns
(Cuzon et al., 2006).
Once the cells reach their appropriate locations, there is a rapid differentiation
into cell types and growth of dendrites and axons, a process that peaks at 7–10 days
postnatal (P). Synapse production begins once neurons mature with a rapid increase
beginning around P10. Micheva and Ceaulieu (1996) counted the number of GABA
and non-GABA cells and found that the cell volume peaks at about P30 in
somatosensory cortex. There was no further change in synapse number at P60, which
was the oldest age that the authors examined. It is well documented that in primates
there is an overproduction and later elimination of synapses (e.g., Huttenlocher,
1984; Petanjek et al., 2011), which in humans continues well into the third decade
of life. However, the possible overproduction and pruning of synapses is not well
studied in the rat. Although Micheva and Beaulieu did not see any change up to
P60 in somatosensory cortex, it is likely that at least some regions are shedding syn-
apses after P60. Van Eden et al. (1990) showed a decline in cortical thickness in pre-
frontal cortex from P60 to P90 and Vinish et al. (2013) showed a decrease in spine
density over a similar time period in medial prefrontal cortex (mPFC). These results
imply that a more systematic analysis of synaptic formation beyond weaning is re-
quired in the rat. The need for neuronal and synaptic pruning is likely related to the
uncertainty in the number of neurons that will reach their appropriate destinations
and the appropriateness of the connections that they form.
Three features of brain development are especially important in the current con-
text. First, the cells lining the subventricular zone include stem cells that remain ac-
tive throughout life. These stem cells can produce neural or glial progenitor cells that
are able to migrate into the cerebral white or gray matter in adulthood. The role of
these cells is poorly understood as they appear to remain quiescent for extended pe-
riods but can be activated to produce neurons or glia, especially after injury
(e.g., Kolb et al., 2007). Second, cells in the dentate gyrus of the hippocampus
are generated there throughout life, although this production declines with aging.
These cells appear to play a role in functions such as memory (e.g., Spanswick
and Sutherland, 2010). Third, dendrites and spines show remarkable plasticity in re-
sponse to experience and can form synapses within hours and possibly even minutes
after some experiences (e.g., Greenough and Chang, 1989). We discuss this in the
following section.
3 GENERAL TYPES OF BRAIN PLASTICITY

Changes in the brain can be shown at many levels of analysis (see Table 2) ranging
from behavior to molecules. There is no correct level of analysis, but rather the mea-
sure of plasticity must be suited to the research question being asked. Noninvasive
Table 2 Levels of analysis of plasticity

Behavior
Functional organization (e.g., maps)
Cell structure (e.g., dendritic organization)
Synaptic structure
Mitotic activity (e.g., neurogenesis)
Molecular structure (e.g., proteins)
Gene expression
3 General Types of Brain Plasticity 39
imaging is appropriate to study experience-dependent changes in humans but is far

more difficult to use in laboratory animals. An advantage of using laboratory ani-
mals, however, is that it is possible to measure anatomical and molecular changes
in postmortem tissue of animals with different experiences. Our bias in the current
review is to emphasize the correlation between synaptic change, using Golgi-type
stains, and epigenetic analyses, looking for changes in gene methylation and/or gene
expression.
Three types of plasticity can be distinguished in the normal brain: experience-
independent, experience-expectant, and experience-dependent (Greenough et al.,
1987; Shatz, 1992). Experience-independent plasticity is largely a prenatal develop-
mental process. It is impractical for the genome to specify the connectivity of every
connection in neuron development. Instead, the brain produces a rough structure in
which there is an overproduction of neurons, and later, connections, that are sculpted
in response to internal and external events. A good example of experience-
independent plasticity is the development of the eye-specific layers of the lateral ge-
niculate nucleus (LGN) of the cat (Campbell and Shatz, 1992). Axons arriving from
the retina eventually terminate in separate layers in the LGN, but retinal cells initially
also send axonal branches to the layer for the other eye. In order to segregate the
layers correctly, the retinal ganglion cells spontaneously fire so as to correlate their
firing with nearby cells but independent of those in the other eye. Cells that fire to-
gether increase their connections, whereas those out of synch weaken their connec-
tions and eventually die out. This type of plasticity, which is independent of external
sensory input, allows the nervous system more precise in connectivity without re-
quiring overwhelmingly complex genetic instructions.
Experience-expectant plasticity largely occurs during development. A good ex-
ample is the development of ocular dominance columns found in the primary visual
cortex. These alternating columns provide a mechanism for the inputs from the right
and left eyes to be combined to produce binocular vision. Wiesel and Hubel (1963)
showed in kittens that if one eye is kept closed after birth, the open eye expands its
territory, leading to shrinkage of the column related to the closed eye. When the
closed eye is eventually opened, its vision is compromised.
Finally, experience-dependent plasticity refers to a process of changing neuro-
nal ensembles that are already present. This can be seen in situations such as when
animals learn problems (e.g., Greenough and Chang, 1989), when topographic
maps expand or shrink in response to experience (e.g., Blake et al., 2002), when
animals receive intense environmental manipulations (e.g., Greenough and
Chang, 1989), injury (e.g., Kolb, 1995), or in response to abnormal experiences
such as psychoactive drugs (e.g., Robinson and Kolb, 2004). These types of expe-
riences both increase and decrease synapse numbers, often in the same animals, but
in different brain regions (see below). The key point is that the synaptic changes
reflect modifications of a basic phenotype formed in development. It is important
to note that although it is often assumed that experience-dependent plasticity
largely reflects the addition of synapses, it may be seen both in the addition
and/or pruning of synapses.
Table 3 Summary of the effects of frontal cortical injury at different ages

Age at
injury Result Basic reference
E18 Cortex develops with odd structure Kolb, Cioe, and Muirhead (1998)
Functional recovery
P1–6 Small brain, dendritic atrophy Kolb and Gibb (1993)
Poor functional outcome
P7–12 Dendrite and spine hypertrophy Kolb and Gibb (1993)
Cortical regrowth Kolb et al. (1998a,b)
Functional recovery
P25–35 Small brain Kolb and Whishaw (1981)
Partial recovery Nemati and Kolb (2012)
Dendritic hypertrophy
P55 No recovery Nemati and Kolb (2012)
4 FACTORS INFLUENCING BRAIN DEVELOPMENT IN THE

NORMAL BRAIN
When researchers began to study experience-dependent changes in the brain, there
was a belief that changes would be most dramatic in severely impoverished condi-
tions, such as being raised in the dark (e.g., Reisen, 1961). Such extreme experiences
did profoundly alter brain development, but it soon became clear that a wide range of
experiences, and even fairly innocuous-looking experiences, could also produce
large changes in the brain (see Table 3).
4.1 Complex housing

The simplest and most dramatic way to manipulate experience is to compare the
brain structure in animals placed in complex environments (sometimes called
enriched environments) versus that of animals housed in standard laboratory caging.
The original studies by the group at Berkley (e.g., Rozenweig et al., 1967) found
changes in cortical thickness and neurochemistry; however, it is now known that
there are changes in brain size, cortical thickness, neuron size, dendritic branching,
spine density, synapses per neuron, glial numbers and complexity, expression of neu-
rotransmitters and growth factors, and vascular arborization (e.g., Greenough and
Chang, 1989; Sirevaag and Greenough, 1988). Such changes are correlated with a
wide range of enhanced cognitive and motor abilities.
It has only been more recently that the effect of complex housing on brain devel-
opment has been investigated, especially examining the effects on the visual system
(see review by Baroncelli et al., 2010). Complex housing from birth accelerates the
maturation of visual acuity, which is associated with electrophysiological changes.
4 Factors Influencing Brain Development in the Normal Brain 41
Interestingly, complex housing can promote the development of the visual system
even in the absence of visual stimulation in animals housed in the dark (Bartoletti
et al., 2004). In fact, the latter study showed that the nonvisual effects of complex
housing could reverse the effects of raising animals in the dark. Although the mech-
anism of this effect is not known, one possibility is that pups raised in complex en-
vironments receive more maternal care (Sale et al., 2004), which is known to be a
strong factor in changing brain development (see below).
There are few studies of other cortical regions but one particular study showed
enhanced auditory functioning in rats raised in complex environments (Cai et al.,
2009). Early complex housing also alters the development of the parietal cortex.
Kolb et al. (2003a) placed weanling rats in complex environments and compared
the cortical changes to animals placed in the same environments as adults. Whereas
adult rats showed increased dendritic length and spine density after 90 days, juvenile
rats showed a similar increase in dendritic length but a decrease in spine density.
That is, the young animals showed a qualitatively different change in the distribution
of synapses on pyramidal neurons compared to the older animals. This result was
surprising, so the researchers wondered what earlier experience might do. In a
follow-up experiment, pregnant dams were placed in complex environments for
8 h a day beginning a week prior to their pregnancy and then throughout the 3-week
gestation. The brains of their offspring were examined in adulthood and showed a
decrease in dendritic length and an increase in spine density in parietal cortex
76
* * * *
74
Percent global methylation
72
Maternal enrichment
Paternal enrichment
70
Control
68
66
Hippocampus Frontal cortex
FIGURE 2
Average global DNA methylation levels in the hippocampus and frontal cortex of offspring
of males who were housed in complex environments for 28 days prior to mating with a
control female and females who were housed in complex environments for 7 days prior to
conception and for the duration of the pregnancy.
After Mychasiuk et al. (2012).
(Gibb, 2004). Thus, complex housing has qualitatively different effects at different
developmental ages. In a parallel study, Pena et al. (2009) found enduring effects of
complex housing from weaning until adulthood on pituitary–adrenal function, social
behavior, and cognitive behavior in adulthood.
Early complex housing has also been shown to attenuate the effects of exposure to
both methylphenidate and amphetamine later in life. Alvers et al. (2012) found a re-
duction in the self-administration of low, but not high, doses of methylphenidate,
whereas Li, Robinson, and Kolb (unpublished observations) found that lifetime com-
plex housing reduced amphetamine-induced behavioral sensitization as well as the
dendritic changes in mPFC and nucleus accumbens.
Finally, Mychasiuk et al. (2012b) placed male rats in complex environments for
28 days before mating the males with control females and compared the epigenetic
effects to maternal housing as in the earlier Gibb (2004) study (Fig. 2). The offspring
of the complex-environment housed males showed a significant decrease in gene
methylation, reflecting the increased expression of about 1000 genes. More surpris-
ing, however, was that the levels of gene expression changes were remarkably sim-
ilar to those observed in the offspring of females who were housed in similar
complex environments while pregnant.
In sum, complex housing during development has profound and enduring effects
on brain development and function. A key question relates to exactly what it is about
the complex housing experience that is altering brain development.
10
* * * *
9
Spines / 10 mm
Tactile
7 stimulation
Control
5
AID Amygdala Cg3-basilar Cg3-apical
FIGURE 3
The effects of neonatal tactile stimulation on spine density in mPFC (Cg3), OFC (AID), and
amygdala. Similar results were shown for dendritic length and branching.
After Richards et al. (2012).
4.2 Sensory and motor experience

As noted earlier, one explanation for the complex rearing effects is that there was an
increase in maternal behavior, including licking and grooming of the infants.
Schanberg and Field (1987) showed that tactile stimulation of preterm infants accel-
erated growth and led to earlier release from hospital. More recently, it has been
shown that tactile stimulation in preterm infants accelerates EEG maturation and
visual functions, as well as increasing serum levels of insulin growth factor I
(IGF-I) and growth hormone paralleling results found in rats (Field et al., 2008;
Guzzetta et al., 2009). Further studies in rats have also shown that early tactile stim-
ulation improves motor and cognitive functions in adulthood as well as increasing
dendritic length and spine density in mPFC (Fig. 3) (Richards et al., 2012) and
the expression of fibroblast growth factor-2 (FGF-2) in skin and brain (Gibb,
2004). Early tactile stimulation (either stimulation of the pregnant dam or postnatal
stimulation of the pups) attenuates the behavioral and anatomical effects of amphet-
amine in adulthood (Muhammad and Kolb, 2011a,b; Muhammad et al., 2011). And,
as discussed below, tactile stimulation dramatically improves recovery from early
cortical injury (Kolb and Gibb, 2010). There is little doubt that tactile stimulation
has an effect on cortical development that is nearly as large, although somewhat
different from, complex housing.
4.3 Psychoactive drugs

Alcohol has long been associated with compromised brain development, but
only recently it has been shown that many other psychoactive drugs, including pre-
scription drugs, alter brain development. Exposure to psychoactive drugs in adult-
hood produces persistent structural changes to cells in both mPFC and orbital
prefrontal cortex (OFC) and nucleus accumbens (Robinson and Kolb, 2004). There
is now growing evidence that the prenatal administration of a wide range of psy-
choactive drugs including nicotine, diazepam, and fluoxetine chronically alters both
neuronal structure and cognitive and motor behaviors (e.g., Kolb et al., 2008;
Muhammad et al., 2013; Mychasiuk et al., 2013a,b). Similarly, administration
of amphetamine, methylphenidate, haloperidol, and olanzapine in the juvenile pe-
riod also leads to impaired behavior and dendritic aberrations in rats examined in
adulthood (Diaz Heijtz et al., 2003; Frost et al., 2010; Milstein et al., 2013; Vinish
et al., 2013).
One key question is whether early exposure to psychoactive drugs alters brain
plasticity later in life. If adult rats are given nicotine, cocaine, or amphetamine
and later placed in complex environments, neuronal plasticity is blocked
(Hamilton and Kolb, 2005; Kolb et al., 2003b). If rats are given nicotine
prenatally and placed in complex environments in adolescence, there is a complex
array of dendritic/spine changes including a partial reversal of the effects of
nicotine as well as a blockade of the effects of the complex housing
(Muhammad et al., 2013).
4.4 Parent–child relationships

Developing mammals are dependent upon their parents and parent–child relation-
ships are critical for brain development. Variations in the pattern of early parent–
infant interactions can initiate long-term developmental effects that persist into
adulthood (Myers et al., 1989). This has been most extensively studied in
mother–infant interactions in rodents where the time spent in contact and the amount
of maternal licking and grooming of the infants correlate with a variety of somatic
and behavioral outcomes. For example, Meaney and his colleagues have shown that
maternal–infant interactions modulate a variety of emotional and cognitive behav-
iors in adulthood, in part through modifications of the hypothalamic–adrenal stress
response (e.g., Cameron et al., 2005) as well as changes in gene expression in
hippocampus (Weaver et al., 2005). Other studies have shown changes related to
maternal–infant interactions in the hypothalamus and amygdala (Fenoglio et al.,
2006; Moriyama et al., 2013), as well as mPFC and OFC (Muhammad and Kolb,
2011a,b).
4.5 Peer relationships

Peer relationships, and especially play, have been known to influence the develop-
ment since the studies of Harlow (e.g., Harlow and Harlow, 1965). The prefrontal
cortex plays a central role in play behavior and, in turn, its development is strongly
influenced by play. Perinatal injury to the mPFC or OFC regions compromises play
behavior, although in different ways (e.g., Pellis et al., 2006). Similarly, the amount
of play that young rats are allowed to engage in alters the development of prefrontal
cortex. Neurons of the mPFC region respond to the amount of play but not the num-
ber of playmates, whereas the OFC responds to the number of playmates and not the
amount of play (Bell et al., 2010). Furthermore, early experiences including prenatal
stress and tactile stimulation alter play behavior and prefrontal cortex (e.g.,
Muhammad et al., 2011). Indeed, it seems likely that any treatment that alters play
behavior will alter prefrontal development and function. For example, the manipu-
lation of juvenile play behavior also changes the brain’s response to psychomotor
stimulants (Himmler et al., 2013a,b).
4.6 Stress
Although it has long been known that stress alters the brain and behavior of adults, it
is only recently that the role of perinatal stress has been appreciated. For example,
prenatal stress is now known to be a risk factor in the development of schizophrenia
attention-deficit hyperactivity disorder (ADHD), depression, and drug addiction
(Anda et al., 2006; van den Bergh and Marcoen, 2004). Studies with laboratory an-
imals have also shown that perinatal stress produces a wide range of behavioral ab-
normalities, including an elevated and prolonged stress response, impaired learning
1. Dendritic branching
44 control c
a a
PS 21
41 MS
Branch order
Branch order
38 a,c 20
a,c
35
19
32
29 18
2. Excitatory synapses
a,c
# of synapses (x000)
# of synapses (x000)
2.6 a,c 1.6
a,c a b
2.3
1.5
2.0
1.7 1.4
3. Spine density
b,c
13
# of spines per 10 µm
12 a b
b,c
11
10 a,c
9 a
8
NAc AID Cg3B Cg3A
FIGURE 4
Mean ( SEM) total number of branch bifurcations (dendritic branching), number of
excitatory synapses, and spine density in Nucleus accumbens (NAc), OFC (AID), and mPFC
(Cg3Basilar field; Cg3Apical field). The mean branch order and number of synapses are in the
same scale shown on the right vertical axis for NAc, AID, and Cg3B but are in a different scale
for the Cg3A, which is on the left vertical axis. The letters “a” and “b” represent the
comparisons of the effects prenatal stress (PS) and maternal separation (MS), respectively,
compared to controls. The letter “c” represents comparisons between PS and MS
(ps <0.05 or better).
After Muhammad et al. (2012).
and memory, altered social and play behavior, increased anxiety, deficits in atten-
tion, and increased preference for alcohol (Weinstock, 2008).
Stress has long been known to alter the prefrontal cortex of adults (e.g., Liston
et al., 2006), but it has become apparent that the changes in the developing prefrontal
cortex are very different. For example, adult stress leads to a decrease in spine den-
sity in mPFC, but an increase in orbital cortex (Liston et al., 2006). In contrast,
Murmu et al. (2006) found that prenatal stress in degus from E16 to E21 produced
a decrease in both spine density and dendritic length in both mPFC and OFC in adult-
hood. Using a somewhat different paradigm, our laboratory exposed rats to gesta-
tional stress at E12–16 and found an increase in spine density in both mPFC and
OFC when the brains were examined at weaning or in adulthood (Muhammad
et al., 2012; Mychasiuk et al., 2012). We also compared the effects of prenatal stress
and postnatal maternal separation and found very different effects of the two
stressors (see Fig. 4). Thus, the effects of perinatal stress vary with the nature of
the stress, the precise embryonic age of the stress, and the age at which the brain
is examined.
One explanation for the difference between the Murmu results and our results
may be related to differences in epigenetic changes related to intensity of the stress.
Mychasiuk et al. (2012) found that mild gestational stress increased global methyl-
ation in prefrontal cortex (using a combined sample of mPFC and OFC), whereas
greater stress had the opposite effect. A whole-genome microarray showed that over
700 genes in the prefrontal cortex and hippocampus were differentially expressed
following prenatal stress, with most genes being downregulated.
The effects of gestational stress can be surprisingly subtle. Mychasiuk et al.
(2011a,b,c,d) housed pregnant females together for the duration of their pregnancies.
One rat received stress at E12–16 while the other (the bystander) did not. The off-
spring of both dams showed significant changes in methylation, gene expression, and
dendritic organization but the patterns of gene expression and dendritic changes were
qualitatively different (Mychasiuk et al., 2011a,b,c,d). It appears that both dams were
stressed but in different ways, which led to differential effects on the offspring brains.
One obvious question is to ask how prenatal stress affects the brain response to other
postnatal developmental experiences such as complex housing, tactile stimulation,
play, and so on.
4.7 Gonadal hormones

During development the most obvious effect of exposure to gonadal hormones is the
prenatal differentiation of the genitals. But the same gonadal hormone receptors are
found in the brain, so it would be surprising if there were not sex differences there
too. There are clear differences in the adult human brain (e.g., Goldstein et al., 2001)
and MRI studies of human children have shown large differences in the rate of brain
development in the two sexes (O’Hare and Sowell, 2008), with the female brain
reaching its adult volume 2–4 years earlier than the male brain. Studies in rats have
shown that neurons in the mPFC have larger dendritic fields and higher spine density
in males than females, whereas the opposite is found in OFC (e.g., Kolb and Stewart,
1991). Furthermore, there are sex differences in the effects of many perinatal expe-
riences including gestational stress, complex housing, and injury (e.g., Kolb and
Stewart, 1995; Mychasiuk et al., 2011a,b,c,d).
4.8 Intestinal flora

Gut microbiota have adapted to a symbiotic relationship with many animals. Soon
after birth, the gut of mammals is populated by a variety of indigenous microbes that
influence both gut and liver functions (e.g., Bjorkholm et al., 2009; Hooper and
Gordon, 2001). There are many similarities in the neurochemical organization of
the enteric and central nervous systems, so it is reasonable to speculate that gut
microbiota might influence brain function. Indeed, epidemiological studies have
shown an association between neurodevelopmental disorders including autism and
schizophrenia and microbial infections early in life (e.g., Finegold et al., 2002;
Mittal et al., 2008). Diaz Heijtz et al. (2011) manipulated gut bacteria in newborn
mice and found that gut bacteria influence motor and anxiety-like behaviors, which
were associated with changes in the production of synaptic-related proteins in cortex
and striatum. This finding is important because it provides a mechanism whereby
infections during development could influence brain development as well as a reason
why results in different laboratories could be different depending upon dietary selec-
tion and which gut microbiota are present in the respective colonies.
4.9 Diet
There is an extensive literature on the effects of caloric- and/or protein-restricted
diets on brain and behavioral development (e.g., Lewis, 1990) but little research
on brain plasticity and restricted diets per se. Similarly, little is known about the
effects of enhanced diets on brain development. It is reasonable to predict that
brain development might be facilitated by vitamin and/or mineral supplements.
Dietary choline supplementation during the perinatal period leads to enhanced
spatial memory in various spatial navigation tasks (e.g., Meck and Williams,
2003; Tees and Mohammadi, 1999) and increases the levels of nerve growth fac-
tor in hippocampus and neocortex (e.g., Sandstrom et al., 2002). Halliwell and
Kolb (2003) did similar studies and found increased dendritic length in pyramidal
cells across the cerebral cortex and CA1 of the hippocampus with choline
supplementation.
Halliwell (2011) also studied the effects of a vitamin/mineral supplement to the
food of lactating rats. The same dietary supplement was reported to improve mood
and aggression in adults and adolescents with various disorders (Leung et al., 2011)
and reduced social withdrawal and anger in children with autism (Mehl-Madrona
et al., 2010). Analysis of the adult offspring of lactating rats fed the same supplement
found an increase in dendritic length in pyramidal neurons in mPFC and parietal
cortex but not in OFC. Furthermore, the same diet facilitated recovery from perinatal
mPFC lesions in rats.
5 BRAIN DEVELOPMENT AFTER EARLY BRAIN INJURY

The first systematic studies on the effect of brain injury in development were
done by Margaret Kennard, beginning in the 1930s (e.g., Kennard, 1942). She
made unilateral motor cortex lesions in infant and adult monkeys and found
milder impairments in her young animals. This led her to suggest that there
was some change in the cortical organization of the infants that supported more
normal behavior (Kennard, 1942). Although Kennard was aware that her monkeys
still had deficits, she is credited with the general idea that “earlier is better,” a
conclusion that Teuber (1975) referred to as the Kennard Principle. Hebb
(1945, 1949) reached a different conclusion, however. He was studying the
effects of early frontal lobe injury in children and concluded that these children
had worse outcomes than adults with similar injuries. He suggested that the early
frontal injury was interfering with the normal development of neural networks
needed to support many adult behaviors (see also Stiles, 2012). The conclusions
of Kennard and Hebb would appear to be at odds, but over the past 30 years’ ex-
tensive studies of monkeys, cats, and rats with cortical injuries have shown that
both views are partially correct. The outcomes depend upon the precise age at
injury, the behavioral measurements used, the age at assessment, and whether
the injury is unilateral or bilateral.
5.1 Age at injury

Age at injury refers not to the actual postnatal age of animals but to their develop-
mental age. Rodents and carnivores are born less mature than primates, so birth date
is not helpful in comparing across species. We will consider the effects of cortical
lesions in rats first, with an emphasis on frontal lesions because as in monkeys
and cats, this is where most of the studies are focused. Although it is common in
the perinatal ischemia literature to make lesions on postnatal day 7 (P7) with rats
to mimic birth asphyxia in humans, this age misses much of the story.
It has become clear that in rats and mice, damage on days 1–5 has devastating
consequences on behavior, with the effect generally being worse the earlier the post-
natal injury, regardless of which cortical region is damaged. In contrast, similar dam-
age on days 7–12 permits much better functional outcome, and depending upon the
behavioral measure, there can be surprisingly normal behavior, despite the fact that
the brain is significantly smaller than normal (see Table 2). There is still a better out-
come than observed in adults when mPFC lesions are incurred in early adolescence.
We are aware of only one study of prenatal cortical lesions in rats and there was re-
markably normal behavior, in spite of a highly abnormal brain (Kolb et al., 1994a,b).
5 Brain Development After Early Brain Injury 49
There were, however, a series of studies by Sam Hicks in the 1950s in which ionizing
radiation was used to alter brain development, which in some cases led to surpris-
ingly good outcomes in spite of abnormal brains, provided there was no hydroceph-
alus (e.g., Hicks and D’Amato, 1961).
In sum, functional outcome is good if injury is during the latter part of neurogen-
esis (E18) but poor if it is during migration and the beginning of synaptogenesis. It is
better again after migration is done and synaptogenesis is burgeoning. We must note
that although we have focused on mPFC lesions, a similar pattern is seen after OFC,
motor cortex, posterior cingulate cortex, posterior parietal cortex, visual cortex, and
auditory cortex lesions (see review by Kolb et al., 2010). As might be expected, how-
ever, recovery is not equivalent across all regions, with posterior injury allowing less
recovery than anterior lesions.
Results from studies of cats and monkeys present a similar pattern, although the
dates vary because of differences in gestational rate. Villablanca and his colleagues
conducted an extensive series of studies on the behavior of cats with frontal or pre-
frontal injuries (e.g., Villablanca et al., 1993). Cats are an interesting comparison to
the rat and monkey because they are embryologically older than rats at birth with a
gestation period of about 65 days, but they are much younger at birth than monkeys.
Overall, Villablanca has found that although cats with prefrontal lesions shortly after
FIGURE 5
Photographs of brains of animals given midline frontal cortrex lersions on postnatal day 10
and then sacrificed on postoperative days 1, 3, 8, or 23. The lesion cavity is evident at day 1 but
by day 23 is only visible as a scar. By day 90 (not shown) the scar is no longer visible.
After Kolb et al. (1998a,b).
birth show good recovery relative to animals with lesions later in life, cats with pre-
natal lesions have severe behavioral impairments. Thus, the newborn cats appear
similar to P10 rats, whereas the prenatal cats are similar to P1–6 rats.
Monkeys are different again. They are born much older than rats, cats, or even
humans. Although Kennard reported better outcomes with infant lesions, as did
Harlow et al. (1964), the bulk of the later evidence largely by Goldman and col-
leagues did not report this (see reviews by Goldman, 1974; Goldman et al.,
1983). In contrast, however, prenatal lesions in monkeys allow substantial recovery
(Goldman and Galkin, 1978). The prenatal lesions are more similar in embryological
time to newborn cats and P10 rats. We can predict that if Goldman and Galkin had
made their prenatal lesions even earlier, the outcome would be similar to the prenatal
lesions in cats and lesions in newborn rats.
But what are the anatomical correlates of this recovery? Studies of unilateral mo-
tor cortex lesions (e.g., Hicks and D’Amato, 1975) found anomalous projections
from the intact hemisphere to the spinal cord, leading to the presumption that these
projections supported the functional recovery. They likely did. Similarly, there are
anomalous projections in the cat visual system that are associated with functional
recovery (Payne and Lomber, 2001) as well as extensive anomalous connections af-
ter neonatal hemidecortication in both rats and cats that are correlated with recovery.
But anomalous projections are also associated with poor outcomes. For example,
whereas rats with P1 mPFC lesions have significant abnormal connections, P10 an-
imals do not (Kolb et al., 1994a) but it is the P10 animals that show recovery, not the
rats with the rewired brain. There are several other types of anatomical changes that
support recovery in P10 rats. For example, there is widespread dendritic hypertrophy
of cortical pyramidal neurons as well as increased spine density. Furthermore,
there is evidence that for at least some types of P10 lesions, namely mPFC and pos-
terior cingulate, there is spontaneous neurogenesis that fills the lesion cavity (Fig. 5)
(Kolb et al., 1998a,b). The neurons that reform the frontal region establish connec-
tions with subcortical regions such as the striatum and have electrical activity that is
nearly normal (Driscoll et al., 2007). In the process of studying the apparent regen-
eration of the lost cortex, we discovered serendipitously that injections of the mitotic
marker, bromodeoxyuridine (BrdU), on E12–14 disrupt the postnatal activity of stem
cells (Kolb et al., 1999) and completely block the postinjury neurogenesis (Kolb
et al., 1998a,b, 2012). Not surprisingly there is no functional recovery if there is
no neurogenesis.
Finally, one other mechanism appears to be the survival of neurons in the thal-
amus that should have degenerated after the injuries. Normally, if cortical regions are
damaged, the thalamocortical projection cells die. This is true after neonatal visual
cortex lesions but not after prefrontal lesions. Cells in the dorsal medial thalamus,
which projects to prefrontal cortex, survive and form connections with remaining
frontal regions in both monkeys and rats (Goldman and Galkin, 1978) and rats
(Kolb and Nonneman, 1978), although this likely depends on the age at injury.
Van Eden et al. (1998) used unbiased stereology to count neurons after P6 mPFC
5 Brain Development After Early Brain Injury 51
lesions and found no difference from adults with similar lesions. This study should be
repeated with P10 lesions.
5.2 Behavior specificity

As a rule of thumb, cognitive functions show better functional recovery than motor
functions, which in turn show better recovery than species-typical behaviors, which
show virtually no recovery regardless of the age at injury (e.g., Kolb and Whishaw,
1981). It appears that it is easier for the brain to form new neuronal ensembles to
solve cognitive tasks than motor tasks and the neural circuits underlying species-
typical behaviors are relatively hard-wired and not easily replaced.
One surprising effect of early lesions is seen in spatial behaviors. Rats with P1–5
show poor recovery, which is not surprising given that adult rats with similar lesions
are also impaired. What is unexpected, however, is that lesions elsewhere in the ce-
rebral cortex at P1–5 also produce deficits in spatial behaviors even though similar
adult lesions do not. This effect is not unique to rats, however, as children with early
cortical lesions in either hemisphere show the same result (e.g., Akshoomoff et al.,
2002). This is in marked contrast to the recovery of language in children with peri-
natal injuries to the speech areas, although the recovery of language is less complete
than was originally believed (Thai et al., 1991).
5.3 Age at assessment

One of challenges in assessing the effects of early brain injury is the problem of
knowing when to investigate the behavior. This is nicely illustrated by the early stud-
ies of Goldman (e.g., Goldman, 1974). She was initially impressed with apparent re-
covery of functions after frontal lobe injuries in infant monkeys but as she continued
her studies it became clear that she, and others before her, had overestimated the ex-
tent of recovery because the animals were tested when they were still young. Thus,
she found that animals with dorsolateral prefrontal lesions became progressively
more impaired at cognitive tasks such as delayed alternation as the brain developed
(Goldman et al., 1983).
She tested the idea that age was important directly by studying the behavioral
effect of reversibly cooling the otherwise normal prefrontal cortex of monkeys at
different ages. On a task that monkeys with adult lesions are impaired at (delayed
response), she found that when she cooled the cortex at 9–16 months of age the an-
imals performed as well as they did in the uncooled state. However, when tested at
19–31 months the animals were impaired, and this impairment grew progressively
larger as they grew older. Thus, she was able to show that animals with early cortical
lesions “grow into their deficits,” an observation also made in children with congen-
ital brain injuries (Banich et al., 1990) and hamsters with mPFC lesions on P2 (Kolb
and Whishaw, 1985).
But age at assessment can work in reverse as well. When rats were given mPFC
lesions on P1 or P10 and then behaviorally tested at P22–25, both groups were
severely impaired relative to controls (Kolb and Gibb, 1993). However, when the
rats were tested at P52–55, the P10 rats were no longer impaired whereas the P1 rats
were. The recovery of the P10 rats was correlated with hypertrophy of cortical
pyramidal neurons that was not present in the brains of P25 animals. Thus, not only
can animals grow into deficits but out of them too.
Ipsilateral forelimb
80
Neonate
70
Adult
60
*
50
Hit percent
40
30
20
10
80
Contralateral forelimb
70
60
50
Hit percent
40
30
20
*
10
*
*
0
Control Small Med Large Hemi
FIGURE 6
Performance on a skilled reaching task by rats with adult or P5 unilateral lesions of
varying sizes (small, medium, and large) of the motor cortex or the entire neocortex
(hemidecorticate). Reaching was affected bilaterally, although more severely in the
contralateral forepaw and increased with lesion size. Rats with neonatal lesions showed
significantly better reaching with the contralateral paw than the adults.
After Whishaw and Kolb (1988).
6 Unilateral Versus Bilateral Injury 53
6 UNILATERAL VERSUS BILATERAL INJURY

An obvious difference between the unilateral and bilateral injuries is that in the for-
mer case there is an intact region homologous to the injured region, whereas in the
bilateral case there is not. Two predictions from this difference are that we would
expect better recovery from unilateral injury and the postinjury sequelae of brain
changes are likely different. Both predictions are borne out.
Hicks and D’Amato (1975) were the first to show that when infant rats sustained
unilateral lesions of the corticospinal projection neurons, they were subsequently
found to have an anomalous ipsilateral pathway from the intact hemisphere to the
spinal cord. They presumed that this pathway was responsible for the improved mo-
tor outcomes of the infants relative to adults with similar injuries. One prediction
from their study is that rats with bilateral lesions in infancy (P1) should not show
recovery because they would not have a normal hemisphere to project to the spinal
cord. This is the case (Kolb et al., 2000a,b). Furthermore, in contrast to unilateral
operates, the bilateral operates are impaired at tests of spatial navigation, in contrast
to rats with adult lesions. This spatial deficit may be related to anomalous connec-
tions from the posterior cortical regions to the spinal cord, connections that likely
were present at birth and failed to die after the early motor cortex lesions (e.g.,
O’Leary, 1989).
Although unilateral focal lesions provide an advantage in recovery, this advan-
tage is reduced as the size of the lesion increases (Whishaw and Kolb, 1988). Fur-
thermore, the larger the lesion, the greater is the impairment not only of the
contralateral limb but also of the ipsilateral limb (Fig. 6).
Table 4 Summary of the effects treatments on recovery from early brain injury
Treatment Outcome Basic reference
Behavioral therapy
Complex housing Improved behavior Kolb and Elliott (1987)
Tactile stimulation Improved behavior Kolb and Gibb (2010)
Chemical therapy
FGF-2 (P3 mPFC) Improved behavior Comeau et al. (2007a,b)
FGF-2 (P10 Motor) Nearly normal behavior Monfils et al. (2006)
Manipulation of gonadal Impaired recovery Kolb and Stewart (1995)
hormones
Prenatal experiences
FGF-2 Improved behavior Comeau et al. (2007a,b)
Tactile stimulation Improved behavior Gibb (2004)
Diazepam Improved behavior Kolb et al. (2008)
Fluoxetine Blocked recovery kolb et al. (2008)
Excessive exercise Reduced recovery Gibb (2004)
Gestational stress Blocked recovery Halliwell (2011)
The extreme form of a unilateral lesion is hemidecortication or hemispherec-

tomy. As shown in Fig. 3, hemidecorticates are severely impaired with both limbs,
but the neonatal (P2) hemidecorticates are significantly better with their contralateral
limb than the adult decorticates. This is correlated both with considerable rewiring of
the normal hemisphere and also with hypertrophy of pyramidal neurons throughout
the intact hemisphere (Kolb et al., 1992). Curiously, whereas rats with bilateral focal
lesions on P10 are always functionally advantaged relative to those with lesions at
P1–6, this is not true with hemidecortication (Kolb and Tomie, 1988). In contrast, the
early operates fare better and have more extensive anatomical remodeling. The dif-
ference between age-related differences between focal lesions and hemidecortication
begs for more study.
7 FACTORS INFLUENCING BRAIN DEVELOPMENT IN THE

INJURED BRAIN
The obvious place to look for beneficial modulating effects on the early-injured brain
is at the animals with the earliest focal lesions. After all, these are the animals with
the worst functional outcomes in the absence of treatment. Because most of the stud-
ies on modulating factors have been using rats with medial frontal lesions, our dis-
cussion will focus on this preparation, with reference to other lesions where
appropriate. We have grouped the factors into (1) behavioral therapy, (2) pharmaco-
logical therapy, and (3) prenatal therapy (see Table 4). We discuss each in turn.
7.1 Behavioral therapy

Although behavioral therapy would seem to be the most obvious type of treatment to
study, there are surprisingly few studies in either laboratory animals or human chil-
dren and virtually no evidence regarding when the optimal time might be or how
intense it ought to be. We began our studies by looking at complex housing. Placing
animals with bilateral P1–7 mPFC lesions in complex housing for 90 days beginning
at weaning stimulates significant functional improvement on tests of both cognitive
and motor behaviors and this is correlated with increased cortical thickness, brain
weight, and dendritic length (Kolb and Elliott, 1987). In contrast, placing the animals
in the complex environments as adults was ineffective (Comeau et al., 2008), unless
the lesions are unilateral (Williams et al., 2006).
Tactile stimulation is also an effective treatment. Rats were given mPFC on P3
and then beginning on P4 they received two weeks of tactile stimulation for 15 min
3 per day (Kolb and Gibb, 2010). The improvement on both spatial learning and
skilled motor function was remarkable (Fig. 4) and was correlated with increased
spine density in the tactile-stimulated mPFC rats. One possible mechanism for the
effect of tactile stimulation is that the tactile stimulation increases the expression
of FGF-2 in both skin and brain providing a possible mechanism for the therapeutic
7 Factors Influencing Brain Development in the Injured Brain 55
FIGURE 7
Sagittal brain sections illustrating normal motor cortex (A), a P10 motor cortex lesion
(B), and a P10 motor cortex lesion and FGF-2 treatment (C). Compared to control cortex,
the FGF-2 stimulated regrowth does not illustrate a laminar distribution. Scale bars in
(A), (B), and (C) are 550 mm. Scale bars in (D) and (E) are 250 mm.
After Monfils et al. (2008).
abilities of tactile stimulation (Gibb, 2004). We note parenthetically that complex

housing also increases FGF-2 expression in cortex (Kolb et al., 1998).
7.2 Chemical therapy

In view of the apparent role of FGF-2 in recovery, we subcutaneously administered
FGF-2 directly as a therapy after P4 mPFC lesions and found significant functional
improvement (Comeau et al., 2007a,b, 2008). In parallel studies, we administered
FGF-2 to rats with P3 or P10 motor cortex lesions. The FGF-2 essentially reversed
all of the motor deficits in the P10, but not the P3 lesion animals, but more impor-
tantly, the lost motor cortex tissue regenerated and formed corticospinal connections
(Monfils et al., 2006, 2008) (Fig. 7). Pretreating the rats with BrdU on E12 blocked
the FGF-2-mediated regeneration and prevented functional recovery, just as it did
after the spontaneous regeneration after P10 mPFC lesions (see above).
Not all chemical treatments are beneficial, however. Perinatal depletion of nor-
adrenaline on P1–3, administration of testosterone to female rats on P1, or blockade
of gonadal hormones by gonadectomy on P1 both block recovery and the associated
dendritic changes following P7 mPFC lesions (Kolb and Stewart, 1995; Kolb and
Sutherland, 1992). Furthermore, even FGF-2 can be detrimental. In one study
performed in our laboratory, we gave FGF-2 and placed animals in complex housing
at weaning (Hastings, 2003). This combination made the animals worse, possibly
because the combined treatments raised FGF-2 to a toxic level.
7.3 Prenatal therapy

Given that prenatal events such as gestational stress alter brain development, we
wondered if prenatal events might influence recovery from perinatal injury. They
do. Prenatal tactile stimulation (i.e., of the pregnant mom), prenatal diazepam,
and prenatal FGF-2 all enhance recovery from P3 mPFC lesions (Comeau et al.,
2008; Gibb, 2004; Kolb et al., 2008). In contrast, prenatal administration of fluox-
etine, prenatal stress, or excessive maternal exercise block recovery of rats with
P7 mPFC lesions (Day et al., 2003; Gibb, 2004; Halliwell, 2011). The powerful ef-
fects of prenatal events, both positive and negative, demand further study as they
likely can account for some of the variance in outcomes observed in children with
perinatal perturbations such as ischemia.
8 SUMMARY
We have shown that the developing normal and injured brain shows a remarkable ca-
pacity for plastic change, both for better and worse. A key remaining question is how
this happens. Although we have not discussed it here one consistent observation in both
the normal and injured brain is a sex difference in experience-dependent plasticity. It is
not simply that one sex is more plastic but rather that there is a sexual dimorphism in
both the functional and anatomical effects of experiences. One clear example is the
effect of prenatal stress on gene expression (Mychasiuk et al., 2011b). Although there
are large changes in gene expression in the prefrontal cortex of each sex, there are few
overlapping gene expression changes. But both sexes show a marked alteration in den-
dritic organization, suggesting that there are multiple mechanisms underlying the ob-
served plastic changes. This is clearly grist for future studies.
Acknowledgments
This research was supported by NSERC of Canada grants to B. K. and R. G.
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CHAPTER
Cortical Plasticity,
Excitatory–Inhibitory
Balance, and Sensory
Perception
3
Ioana Carcea*,{,{, Robert C. Froemke*,{,{,1
*
Molecular Neurobiology Program, The Helen and Martin Kimmel Center for Biology and
Medicine at the Skirball Institute for Biomolecular Medicine, Department of Physiology and
Neuroscience, New York University School of Medicine, New York, NY, USA
{
Department of Otolaryngology, New York University School of Medicine, New York, NY, USA
{
Center for Neural Science, New York University, New York, NY, USA
1
e-mail address: robert.froemke@med.nyu.edu
Abstract
Experience shapes the central nervous system throughout life. Structural and functional plas-
ticity confers a remarkable ability on the brain, allowing neural circuits to adequately adapt to
dynamic environments. This process can require selective adjustment of many excitatory and
inhibitory synapses in an organized manner, in such a way as to enhance representations of
behaviorally important sensory stimuli while preserving overall network excitability. The
rules and mechanisms that orchestrated these changes across different synapses and through-
out neuronal ensembles are beginning to be understood. Here, we review the evidence con-
necting synaptic plasticity to functional plasticity and perceptual learning, focusing on the
roles of various neuromodulatory systems in enabling plasticity of adult neural circuits. How-
ever, the challenge remains to appropriately leverage these systems and forms of plasticity to
persistently improve perceptual abilities and behavioral performance.
Keywords
neuromodulation, sensory cortex, synaptic plasticity, excitatory–inhibitory balance,
perception

65
66 CHAPTER 3 Cortical Plasticity, Excitatory–Inhibitory Balance
1 INTRODUCTION
Phylogenetic evolution ensures that sensory perception matches the type of environ-
ment experienced by an organism, largely by applying genetically encoded filters at
the level of sensory organs (e.g., audible and visible spectra) (Darwin, 1859). In ad-
dition, throughout ontogenetic development, organisms refine and optimize their sen-
sory acuity by experience-dependent mechanisms. In mammals, these mechanisms can
be rapid and long-lasting, are more pronounced during development, and rely primar-
ily on structural and functional plasticity of neocortical circuits (de Villers-Sidani and
Merzenich, 2011; de Villers-Sidani et al., 2007; Hensch, 2005).
Unlike the developing neocortex and the adult association areas, primary sensory
and motor cortices become resistant to activity-induced synaptic modifications after
maturation (Hensch, 2005). This might explain the maintenance of stable perceptual
and motor representations throughout life, a requirement for easily and successfully
navigating familiar environments. However, demanding or novel behavioral tasks
can release sensory cortices from an implastic state in order to allow adaptive mod-
ifications to internal representations (Bao et al., 2004; Dahmen and King, 2007;
Elbert et al., 2002; Flor et al., 1995; Pantev et al., 2001; Polley et al., 2006; Sterr
et al., 1998). A growing number of studies have indicated that information about be-
havioral state is conveyed to the sensory cortex by a diverse array of neuromodula-
tors (Lee and Dan, 2012). Different neuromodulators have been shown to initiate and
control plasticity in the adult brain by coordinating modifications at selected sets of
neuronal synapses. The precise set of changes that occur to synaptic transmission and
network function depends on which neuromodulatory system or systems are acti-
vated and on the extent to which intracellular Ca2þ signaling and NMDA receptor
activation are engaged by different stimulus patterns.
Understanding the synaptic mechanisms by which experience shapes functional
sensory circuits during development and adulthood is crucial for designing therapeu-
tic interventions to correct inherited and acquired defects in sensory perception.
Here, we will summarize recent research describing circuit mechanisms by which
the adult neocortex encodes salient and relevant properties of the environment,
how neuromodulators control these mechanisms, and how they contribute to percep-
tual learning. We will emphasize remaining questions that concern the contribution
of different neuromodulators to cortical plasticity and the distinctions between adult
and developmental plasticity. Although we will focus on the auditory cortex and
acoustic behavioral tasks, references to other sensory cortical areas will be made.
2 ENCODING SENSORY ENVIRONMENTS IN CORTICAL NEURAL

CIRCUITS
Brains are plastic throughout life but are particularly sensitive to external input
during development (Shatz and Stryker, 1978; Wiesel and Hubel, 1963a,b). At this
time, axons and dendrites in the neocortex arborize profusely and establish synaptic
connections (Benson et al., 2001). Neurons in sensory cortices develop stable
2 Encoding Sensory Environments in Cortical Neural Circuits 67
receptive fields when the complement of excitatory and inhibitory synaptic inputs
matures, making them differentially sensitive to one or more attributes of the envi-
ronment (Dorrn et al., 2010; Hensch and Stryker, 2004; Hensch et al., 1998; Sun
et al., 2010). In vivo intracellular electrophysiological recordings during the presen-
tation of well-defined stimulus sets can estimate the relative contribution of excit-
atory and inhibitory inputs to the synaptic receptive field of a neuron (Fig. 1A).
Excitatory inputs are isolated by clamping the membrane potential of the patched
cortical neuron at 70 mV, the reversal potential for chloride, whereas inhibitory
inputs are measured by clamping the cell at the reversal potential for sodium
(0 mV). The ratio of excitatory to inhibitory currents is then calculated for each
stimulus presented.
During development, activity in sensory circuits gradually increases the correla-
tion of cortical excitatory and inhibitory receptive fields with respect to the stimulus
set. For example, in the developing auditory cortex, evoked excitation and inhibition
are unbalanced at the time hearing begins (around postnatal day 10 in rodents) but
A B
1.5
Normalized current
1.5
1.0
Spikes/tone
1.0
0.5
EPSCs 0.5
IPSCs
0.0 0.0
0.5 1 2 4 8 16 32 0.5 1 2 4 8 16 32
Frequency (kHz) Frequency (kHz)
32
16
2
1 mm
1 KHz
FIGURE 1
Information encoding in the primary auditory cortex. (A) Excitatory and inhibitory synaptic
tuning curves of an example neuron; triangle indicates the best frequency of this neuron
(reproduced from Froemke et al., 2007). (B) Example spiking tuning profile (reproduced from
Froemke et al., 2013). (C) Tonotopic map in the primary auditory cortex based on
characteristic frequency (reproduced from Kenet et al., 2007).
become progressively balanced over the course of development, reaching a relatively

high degree of cotuning in adulthood (Dorrn et al., 2010). The correlation between
excitatory and inhibitory inputs may dictate the stability of synaptic receptive fields.
Unbalanced excitation in the developing auditory cortex allows for rapid activity-
induced retuning of synaptic inputs. In young (between postnatal days 12 and 21)
but not adult rats, patterned presentation of a pure tone with known frequency
and intensity rapidly strengthened the excitatory and inhibitory synaptic currents
evoked by the patterned tone, thus retuning the synaptic neuronal profile. In addition,
patterned stimulation increased the correlation between excitatory and inhibitory in-
puts nonspecifically, improving the overall balance in the developing auditory cortex
and thus imposing a refractory period for additional activity-induced synaptic mod-
ifications (Dorrn et al., 2010).
Developmental adjustments in the ratio of excitatory to inhibitory inputs appear
to contribute to the maturation of other sensory cortices like the somatosensory and
visual cortex (Hensch and Stryker, 2004). In the somatosensory cortex, for example,
Chittajallu and Isaac (2010) showed that the thalamic drive of feedforward inhibition
strengthens progressively during the first eleven postnatal days, leading to a doubling
of the average ratio between evoked GABA and AMPA currents on layer 4 stellate
cells. This results in a decrease of the integration window measured as the half-width
of postsynaptic potentials, which may slow down plasticity. Normal recruitment of
parvalbumin neurons in this microcircuit is experience-dependent and is impaired
after whisker trimming (Chittajallu and Isaac, 2010; Daw et al., 2007).
The relationship between the strength and timing of excitatory and inhibitory cur-
rents controls input integration and determines what stimuli evoke suprathreshold
responses and therefore the spiking tuning profile of a neuron (Fig. 1B). The most
widely studied types of receptive fields in the auditory cortex are in the frequency
and intensity domains. Neurons in the primary auditory cortex can spike with short
latency (5–10 ms) after the presentation of pure tones of different frequencies. The
frequency that evokes the strongest response is known as the best frequency of the
neuron. Generally, but not always, neurons in the auditory cortex have a single best
frequency, and this also represents their characteristic frequency, meaning the
frequency that activates them when played at threshold amplitude. In the intensity
domain, the majority of neurons in the rat primary auditory cortex and some
but not all of the other auditory fields respond monotonically to increases in sound
amplitude (Polley et al., 2007).
At the neuronal population level, the development of synaptic and spiking recep-
tive fields leads to the formation of sensory maps—for example, tonotopic map in the
auditory cortex, retinotopy, ocular dominance, and orientation columns in the visual
cortex and the whisker barrel fields in the rodent somatosensory cortex (Hubel and
Wiesel, 1963; Merzenich et al., 1973; Woolsey and Van der Loos, 1970) (Fig. 1C).
Alterations in synaptic maturation can explain changes in sensory maps induced by
developmental exposure to different environments (Chang and Merzenich, 2003;
Sengpiel et al., 1999; Zhang et al., 2001). A large body of literature documents this
dependency of sensory maps on experience, especially during particularly sensitive
3 Effects of Neuromodulation on Plasticity in Adult Sensory Cortices 69
developmental windows, called critical periods. The existence of critical periods is a

phenomenon characterized in most sensory cortices and even in structures thought to
be important for emotional learning, such as the amygdala (Gogolla et al., 2009).
Interestingly, distinct critical windows have been identified not only for different
modalities but also for different functions of the same sensory system. These stag-
gered critical periods explain the systematic and somewhat stereotyped (from simple
to complex) accumulation of perceptual abilities, as is the case in language acquisi-
tion (Insanally et al., 2009; Sanes and Woolley, 2011). Can these highly plastic con-
ditions be recapitulated in the mature brain to allow rapid and lasting enhancement of
perceptual prowess?
The relationship between synaptic plasticity and excitatory–inhibitory balance is
consistent in the adult sensory cortex in the sense that correlated synaptic inputs are
resistant to activity-induced modifications. However, when the correlation breaks
down mostly due to neuromodulatory forces and excitation becomes unbalanced
by inhibition, sensory circuits become plastic and synaptic weights adapt to best rep-
resent environmental attributes (Bakin and Weinberger, 1996; Froemke et al., 2007,
2013; Kilgard and Merzenich, 1998a,b; Letzkus et al., 2011). In the next section, we
will review recent data indicating that activation of various modulatory systems can
alter cortical excitatory–inhibitory balance and thus enable experience-dependent
synaptic modifications. The dynamics of these effects can differ substantially from
one neuromodulatory system to another, a difference that would be expected to have
a major impact on functional maps and on sensory performance.
3 EFFECTS OF NEUROMODULATION ON PLASTICITY IN ADULT

SENSORY CORTICES
Different behavioral states can be visualized in a multidimensional space, where
each dimension represents a distinct psychological variable (attention, aversion, at-
traction, motivation, or empathy) or, correspondingly, neuromodulatory system
(e.g., acetylcholine, norepinephrine, dopamine, serotonin, or peptide modulators
such as oxytocin) (Fig. 2). Different combinations of behavioral states and thus of
their biological correlates are called into action during danger, food seeking, sexual
behavior, and maternal behavior. For example, during classical fear-learning para-
digms in rodents, a sensory stimulus is paired with a foot shock. This shock has been
found to induce increased firing of noradrenergic neurons in the locus coeruleus, do-
paminergic neurons in the ventral tegmental area, and most likely cholinergic neu-
rons in the basal forebrain (Brischoux et al., 2009; Chen and Sara, 2007). Moreover,
many neuromodulatory centers in the brainstem, basal forebrain, and the hypothal-
amus are directly connected. For example, locus coeruleus neurons receive dopami-
nergic input from the ventral tegmental area and the substantia nigra pars compacta
and serotoninergic input from dorsal raphe neurons. In turn, noradrenergic fibers
from the locus coeruleus synapse on ventral tegmental area, substantia nigra, and
FIGURE 2
Multidimensionality of behavioral states. Multiple neuromodulatory systems contribute in
various combinations to creating different behavioral states. To allow visualization, only three
dimensions and three behavioral states are shown here.
basal forebrain cells. Basal forebrain neurons also receive dopaminergic and seroto-
ninergic inputs (Eggermann et al., 2001; Sara and Bouret, 2012).
Neuromodulators act on distributed neural circuits to generate and store specific
patterns of activity within neuronal ensembles important for behavioral performance.
Blocking the activity of these neuromodulators systemically or specifically in their
sensory cortex terminal fields can prevent associative and perceptual learning
(Fletcher and Wilson, 2002; Kroon and Carobrez, 2009; Letzkus et al., 2011). Recent
in vitro data on the dynamics of adult sensory cortex plasticity uncovered both shared
and specific modes of action for different neuromodulators (Kruglikov and Rudy,
2008). Can different neuromodulator combinations orchestrate adaptive synaptic plas-
ticity in sensory cortices? In answering this question further, it is important to (1) study
the effects of different neuromodulatory systems separately and at different naturalistic
activation frequencies and intensities and (2) uncover the combinatorial actions of these
neuromodulators in ratios that would be relevant for behavioral states (Fig. 2). An ex-
ample of cooperative effects of two neuromodulators was described in the visual cortex,
where integrity of both noradrenergic and cholinergic fibers is required for proper de-
velopment of the ocular dominance columns (Bear and Singer, 1986). In this example,
the two neuromodulators have a compensatory type of interaction, but in other structures
or under different conditions, they might act synergistically or additively.
Next, we will discuss recent in vivo data on the role of the basal forebrain and
other neuromodulatory systems in inducing synaptic plasticity of sensory cortices.
3.1 Basal forebrain

The basal forebrain is a collection of cholinergic, GABAergic, and glutamatergic
projection neurons and local GABAergic interneurons, distributed in three
main complexes: medial septum/ventral diagonal band complex projecting to the
hippocampus, horizontal limb of the diagonal band projecting to the olfactory bulb
and the piriform cortex, and nucleus basalis magnocellularis and substantia innomi-
nata complex projecting uniformly to the neocortex (Gritti et al., 2003, 2006; Manns
et al., 2001; Mesulam, 2004; Zaborszky, 2002; Zaborszky et al., 1999, 2005).
Nucleus basalis neurons have elevated spiking and bursting activity during wakeful-
ness and REM sleep and can also discharge in response to behaviorally relevant,
novel, or recent sensory stimuli (Cape and Jones, 2000; Duque et al., 2007; Kanai
and Szerb, 1965; Manns et al., 2000a,b; Szymusiak et al., 2000). Nucleus basalis neu-
rons can be electrically stimulated to induce acetylcholine release in their terminal
fields, which leads to desynchronization of cortical electrical activity and enhanced
cortical responsiveness to sensory stimuli (Metherate and Ashe, 1991, 1993). Pairing
of nucleus basalis stimulation with the presentation of a sensory stimulus results in
long-lasting cortical plasticity (Bakin and Weinberger, 1996; Froemke et al., 2007;
Kilgard and Merzenich, 1998b) (Fig. 3A–C). However, electrical stimulation is not
specific and can simultaneously activate other neuronal populations in the nucleus
basalis. Recently, specific stimulation of cholinergic neurons has been achieved
using optogenetics in mice and rats expressing channelrhodopsin-2 in neurons pos-
itive for choline acetyltransferase, an enzyme necessary for the biosynthesis of ace-
tylcholine (Kalmbach et al., 2012; Witten et al., 2010). Future studies using this
approach are necessary to parse out the contribution of identified cell types in the
basal forebrain to cortical activation, cortical plasticity, and behavior.
Acetylcholine release in the cortex can induce activation of pyramidal neurons
(Detari, 2000; Detari et al., 1999; Dringenberg and Vanderwolf, 1997; Linster and
Hasselmo, 2001). In the auditory cortex, two disinhibitory network mechanisms have
been described in vivo. One of them depends on activation of muscarinic receptors in
mid- and deep cortical layers, which results in a rapid depression of stimulus-evoked
inhibitory inputs on pyramidal neurons (Froemke et al., 2007; Metherate and Ashe,
1993). Most likely, this effect depends on decreased release of GABA from fast-
spiking interneurons that express presynaptic muscarinic M2 receptors (Kruglikov
and Rudy, 2008). In the adult rat primary auditory cortex, repeatedly pairing nucleus
basalis activation with the presentation of a pure tone of defined frequency and in-
tensity leads to a decrease in the inhibition evoked by the paired stimulus and there-
fore to a spectrally restricted increase in the excitatory–inhibitory ratio. At the same
time, activation of muscarinic receptors may extend the integration window for ex-
citatory inputs as is the case in the somatosensory cortex (Kruglikov and Rudy,
2008).Together, these muscarinic actions seem to permit Hebbian plasticity of excit-
atory inputs at the paired stimulus and a gradual retuning of the synaptic and spiking
receptive fields (Bakin and Weinberger, 1996; Froemke et al., 2007) (Fig. 3D and E).
At the population level, these modifications induce an overrepresentation of the
paired stimulus in the tonotopic map (Kilgard and Merzenich, 1998b).
The other mechanism by which cholinergic inputs trigger disinhibition in the au-
ditory cortex has been characterized in upper cortical layers by Letzkus et al. (2011).
Activation of nicotinic receptors on layer 1 inhibitory neurons leads to their robust
spiking, which results in the inhibition of their postsynaptic partners—layer 2–3
A B
Prepairing NB pairing Postpairing
Tone (5–15 min) (2–5 min) (15+ min)
Rec Stim
Tone
A1
NB stimulation
250 ms, 100 Hz
EPSC
(-70 mV) 50 pA
25 ms
NB IPSC
(-20 mV)
C D E
NB pairing 200 NB pairing (atropine)
Normalizad current (%)

EPSCs
150 IPSCs 150
Excitation (pA)
-90
-45 100 100
0 50
50
0.5 1 2 4 8 16 32 -20 0 20 40 60 -20 0 20 40 60
Frequency (kHz)
Time (s) Time (s)
FIGURE 3
Synaptic modifications induced by nucleus basalis pairing. (A) Sagittal drawing through the
rodent brain shows the position of the stimulating electrode in the nucleus basalis (NB) and
the recording pipette in the primary auditory cortex (A1). The extensive cortical projections of
cholinergic neurons are shown. (B) The pairing procedure: pure tones of various frequencies
are played prepairing in a pseudorandomized order, and then one frequency is paired with
nucleus basalis stimulation and then the full set of tones is again played postpairing.
Representative excitatory and inhibitory synaptic currents evoked by the paired tone were
recorded pre- and postpairing in the same cell. (C) Retuning of the excitatory synaptic curve:
the response to the paired stimulus increases and the response to the original best stimulus
decreases. (D) Fast decrease in inhibition and slower increase in excitation evoked by the
paired stimulus during pairing. (E) Blocking muscarinic receptors in the auditory cortex
prevents the effects of pairing. Artwork in (A) by Jana Pivkova.
(Reproduced from Froemke et al. (2007) and Froemke et al. (2013)).
parvalbumin-positive interneurons. The decreased firing of parvalbumin-positive in-

terneurons diminishes their inhibitory control over upper-layer pyramidal neurons.
When this disinhibitory event coincides in time with a sensory stimulus, the evoked
response in pyramidal neurons increases dramatically. It is unclear whether this
mechanism can lead to long-lasting retuning in the auditory cortex or in structures
downstream, but it is required for learning stimulus–fear associations (Letzkus
et al., 2011). Therefore, although generated by different cholinergic receptor activ-
ities and different microcircuits, a similar Hebbian form of plasticity would act in
superficial and deep layers of the sensory cortex to enlarge the representation of
the behaviorally relevant stimuli. Interestingly, the opposing effects of acetylcholine

on two types of inhibitory transmission have also been described in the visual cortex
in slices, indicating a conserved mode of cholinergic action on microcircuits across
different sensory cortical areas (Xiang et al., 1998).
What would be the advantage of having two (or more) seemingly independent yet
correlated mechanisms by which acetylcholine enhances stimulus representation in
deep and superficial cortical layers? This might allow for projection-specific fine-
tuning of evoked responses in the sensory cortex. The vast majority of upper-layer
pyramidal neurons project cortically, whereas deep-layer neurons can project either
cortically or subcortically (Koester and O’Leary, 1994). It is possible that for certain
behavioral tasks, it would be advantageous to cotune cortical circuits with different
projection patterns, whereas for other behaviors, it would be more beneficial if these
different circuits exhibited distinct sensitivities to sensory inputs or to neuromodu-
latory and behavioral control (Chen et al., 2013).
The effects of cholinergic modulation in the auditory cortex are dynamic and re-
markably specific to subsets of synapses. During the first 30 min after pairing an au-
ditory stimulus with electrical stimulation of the nucleus basalis, the strength of the
paired excitatory input increases and becomes the new peak of the tuning profile. At
the level of inhibitory inputs, after the immediate disinhibitory episode observed dur-
ing the pairing procedure, inhibition gradually and slowly retunes to balance changes
in excitation. Excitatory and inhibitory corticocortical connections appear to undergo
most of the modifications observed, whereas thalamocortical synapses are resistant to
the long-lasting effects of cholinergic modulation (Froemke et al., 2007). An extraor-
dinary level of specificity is observed in the dynamics of excitatory tuning profile of
pyramidal neurons. As the paired input increases in strength, the original best stim-
ulus evokes less and less excitation. The excitatory currents corresponding to the rest
of the stimulus set remain unchanged. This indicates that network excitability is
strictly conserved. How do neurons specifically and uniquely depress inputs corre-
sponding to the original best stimulus of each cell? This remarkable level of control
depends on the original best stimulus being present a sufficient number of times after
the pairing procedure ends. If this stimulus is not played postpairing, another pre-
sented strong input will be depressed in order to conserve excitability in the network.
These experiments show that the precisely coordinated changes in synaptic function
are activity- and history-dependent (Froemke et al., 2013). We also found that these
long-term synaptic modifications induced by acetylcholine require cortical musca-
rinic and NMDA receptor activity (Froemke et al., 2013).
Although most of the discussed physiological effects of acetylcholine on cortical
circuits have been described in the rodent auditory cortex, similar findings have been
reported in the other primary sensory cortices. We will enumerate in the succeeding
text additional recent findings in the somatosensory, visual, and piriform cortices.
Nucleus basalis activation results in muscarinic receptor-dependent decorrelation
of activity in the rodent visual cortex during the visualization of natural scenes. This
phenomenon described by Goard and Dan (2009) is believed to increase the percep-
tual capacity of the network. The authors also showed increased reliability of unitary
responses in the lateral geniculate nucleus and the visual cortex following nucleus
basalis stimulation.
In the somatosensory cortex, an additional interesting mechanism by which cho-
linergic innervation could induce plasticity has been reported by Takata, Mishima,
and colleagues. In an elegant study, they showed that acetylcholine released during
nucleus basalis stimulation activates muscarinic receptors on astrocytes, which in-
duces calcium waves in these cells and the subsequent release of D-serine. In turn,
D-serine binds neuronal NMDA receptors and, when this coincides with stimulus-
evoked activity, a long-lasting potentiation at the paired stimulus ensues (Takata
et al., 2011). Importantly, a similar role for astrocytes in cholinergic-mediated cor-
tical plasticity was later described in the visual cortex, indicating that this may be a
general mechanism to modify cortical synapses (Chen et al., 2012).
In the piriform cortex, acetylcholine released by neurons in the horizontal limb of
the diagonal band can also have immediate and long-lasting effects. Specifically,
acetylcholine depolarizes both pyramidal and inhibitory neurons, increasing their
spontaneous and stimulus-evoked spiking (Barkai and Hasselmo, 1994; Tseng and
Haberly, 1989a,b). Stimulation of basal forebrain projections initially suppresses in-
puts from association fibers but subsequently enhances these inputs, a phenomenon
thought to contribute to odor discrimination (Hasselmo and Barkai, 1995; Linster
and Hasselmo, 2001; Wilson, 2001). In the piriform cortex, an additional level of
regulation has been reported, where acetylcholine decreases both the adaptation
of pyramidal cell spiking to current injections and the afterhyperpolarization, thus
permitting Hebbian plasticity (Barkai and Hasselmo, 1994; Constanti and Sim,
1987; Saar et al., 2001).
Due to its possible role in the progression of Alzheimer’s disease, the basal fore-
brain generated a large interest in the scientific community and therefore provides a
model for exploring how neuromodulation and brain state affect processing and plas-
ticity in cortical circuits. We will next summarize some of the recent insights into
other neuromodulatory systems.
3.2 Locus coeruleus

Noradrenergic fibers originating in the locus coeruleus uniformly innervate the entire
forebrain, including sensory cortices. Changes in the tonic firing rate of locus coer-
uleus neurons and thus in noradrenaline release play an essential role in regulating
the sleep–wake cycle and cortical arousal (Aston-Jones and Bloom, 1981a,b;
Berridge et al., 1993; Constantinople and Bruno, 2011; Hobson et al., 1975;
Roussel et al., 1967). Locus coeruleus neurons discharge phasically in response to
novel sensory stimuli in all modalities (Aston-Jones and Bloom, 1981a,b; Foote
et al., 1980; Herve-Minvielle and Sara, 1995; Rasmussen et al., 1986; Sara et al.,
1994). If the sensory stimulus is associated with either reward or punishment, the
evoked responses of locus coeruleus neurons are maintained and even enhanced
(Aston-Jones et al., 1994; Bouret and Richmond, 2009; Bouret and Sara, 2004;
Jacobs et al., 1991; Sara and Segal, 1991).
Several studies reported the acute effects of locus coeruleus activation on

sensory-evoked responses. Tonic and phasic stimulations can enhance stimulus-
evoked responses in initially responsive cells of the barrel and piriform cortex
and can induce responses in previously silent cells (Bouret and Sara, 2002;
Devilbiss and Waterhouse, 2004, 2011; Lecas, 2004; McLean and Waterhouse,
1994). However, some cells in the barrel cortex can also be suppressed by tonic ac-
tivation of noradrenergic fibers (Devilbiss and Waterhouse, 2004). In the auditory
cortex of guinea pigs, ionophoretic application of noradrenaline has been reported
to suppress evoked responses (Manunta and Edeline, 1999). The circuits and synap-
tic mechanisms by which noradrenaline released from the locus coeruleus controls
cortical responses to sensory stimuli remain to be fully understood. Also, despite the
fact that locus coeruleus activity has been repeatedly linked to the learning process,
so far, few studies addressed the long-term effects of pairing a sensory stimulus with
the activation of noradrenergic neurons on cortical stimulus representations. There-
fore, a unified theory for how locus coeruleus might modulate synaptic activity in the
neocortex to recruit neuronal ensembles that aptly represent behaviorally relevant
stimuli is still missing.
3.3 Ventral tegmental area

In the mammalian forebrain, dopamine is released from dopaminergic fibers origi-
nating in the ventral tegmental area or substantia nigra. These fibers abundantly in-
nervate the striatum and regions of the prefrontal cortex but are relatively sparse in
the rest of the neocortex and thalamus, including sensory areas (Dahlstrom and Fuxe,
1964; Haber et al., 2000; Lindvall and Bjorklund, 1974; Williams and Goldman-
Rakic, 1998). However, repeatedly pairing the presentation of an auditory stimulus
with phasic stimulation of the ventral tegmental area has been shown to result in an
expansion of the paired tone representation in primary and secondary auditory cortex
(Bao et al., 2001). These effects could be supported by the few dopaminergic pro-
jections in the auditory cortex or could be generated by feedback from prefrontal
areas. Various studies in the striatum and prefrontal cortex documented the effects
of D1- versus D2-dopamine receptor activation on synaptic plasticity, but to our
knowledge, they have not been replicated in primary sensory areas. Importantly,
D2-dopmaine receptors have been implicated in the generation of perceptual psy-
chotic episodes in schizophrenia and other psychiatric disorders (Seeman, 2013).
It is therefore crucial to understand how dopamine controls processing and plasticity
in sensory circuits.
3.4 Raphé nuclei

Neurons in the dorsal and medial raphe nuclei of the midbrain secrete serotonin and
project abundantly to the entire forebrain via the medial frontal bundle (Calizo et al.,
2011; Dahlstrom and Fuxe, 1964; Hornung et al., 1990). As is the case with most
neuromodulatory systems, additional cell types reside in these nuclei (GABAergic,

glutamatergic, and peptidergic) (Calizo et al., 2011; Waselus et al., 2006).
As with dopamine, serotonin and its receptors appear to play an important role in
the generation of perceptual psychotic episodes in schizophrenia and following the
use of psychedelic drugs (Gonzalez-Maeso et al., 2008; Lesch and Waider, 2012).
Therefore, it is of crucial importance to understand the mechanisms by which sero-
tonin impacts immediate and long-lasting activity in neocortical circuits. Some of the
molecular mechanisms supporting serotonin actions started being elucidated. Both
pyramidal and inhibitory neurons in the cortex express multiple types of metabotro-
pic serotoninergic receptors. These receptors can regulate the activity of potassium
channels and the levels of intracellular calcium and can interact directly or indirectly
with AMPA, NMDA, and metabotropic glutamate receptors, thus controlling
synaptic transmission, neuron excitability, and network excitatory to inhibitory
balance (Bockaert et al., 2010; Moreau et al., 2010; Ogren et al., 2008; Yuen
et al., 2005, 2008).
An interesting role for serotonin in cross-modal communication has been recently
reported by Jitsuki and colleagues (Jitsuki et al., 2011). The study showed that visual
deprivation in rats increased serotonin in the barrel cortex, where it promoted the
phosphorylation and synaptic delivery of GluR1 glutamate receptor subunit, thus fa-
cilitating synaptic transmission at the layer 4 to layer 2/3 synapses and the sharpening
of receptive fields in layer 2/3 neurons. Given the reported association between
serotonin and perceptual synesthesia, more cross-modal and multimodal studies need
to be conducted (Brang and Ramachandran, 2008).
3.5 Oxytocinergic system in the paraventricular and supraoptic

nuclei of the hypothalamus
Oxytocin is a representative peptidergic neuromodulator synthesized in the paraven-
tricular and supraoptic nuclei of the hypothalamus. It can be released from magno-
cellular neurons in the bloodstream via the hypothalamic–hypophyseal axis, but it
can also be released by parvocellular fibers in a more targeted manner to cortical
and subcortical brain regions (Brownstein et al., 1980). In the mouse cortex, some
of these fibers innervate the temporal areas, including the auditory cortex; the insu-
lar, cingulate, and entorhinal cortex; and the frontal association areas (Knobloch
et al., 2012). Oxytocin is strongly linked to maternal behavior, being heavily released
during parturition and lactation. Therefore, a large body of research focuses on the
role of oxytocin in modulating maternal care. There is evidence that mother and
virgin mice show differential cortical responses to sensory cues, particularly to
pup ultrasound vocalizations (Cohen et al., 2011; Liu et al., 2006). Whether oxytocin
can induce this differential representation of sounds and the circuit mechanisms by
which it does so remains to be elucidated. An interesting circuit mechanism was
described in the central amygdala, where oxytocin release in the lateral central amyg-
dala activates a subset of interneurons that then inhibit pyramidal output neurons in
the medial part of the central amygdala (Knobloch et al., 2012). This circuit mediates
4 Commonalities and Differences 77
the anxiolytic effects of oxytocin (Knobloch et al., 2012; Viviani et al., 2011). It is
important to determine if similar actions underlie the tuning of responses to pup calls
in maternal auditory cortex.
4 COMMONALITIES AND DIFFERENCES BETWEEN

DEVELOPMENTAL AND ADULT PLASTICITY IN SENSORY
CORTICES
To what extent do the described modifications induced by neuromodulatory systems,
in particular the basal forebrain, in adult circuits recapitulate the developmental
critical windows? Both cases rely on somewhat transient excitatory to inhibitory im-
balances, and we hypothesize that this condition favors induction of NMDA
receptor-dependent forms of long-term synaptic modification. However, beyond this
basic feature, it is likely that developmental and adult cortical plasticity are substan-
tially different in other ways. During development, inhibitory elements are progres-
sively integrated into the network and this process dictates the closure time and
duration of staggered critical periods. In the adult brain, restricted sets of inhibitory
inputs have to be actively and specifically suppressed. Changes in sensory represen-
tations induced by early life exposure to altered environments are very long-lasting
and in many cases permanent (Hensch, 2005). On the contrary, plasticity in the adult
sensory cortex is often transient. Following nucleus basalis pairing, synaptic and
spiking profiles of neurons return to their original tuning in time and, as a conse-
quence, sensory maps recover their initial representation (Kilgard, 2012; Reed
et al., 2011). Although consecutive pairing episodes likely generate savings in the
circuit and cumulate their effects on cortical plasticity, this is not sufficient to
permanently alter adult map representations. This observation raises two important
questions. First, how can good perceptual performance be maintained in the absence
of relevant stimulus overrepresentation in the primary sensory cortex? Secondly,
how do neuronal circuits revert to their original organization?
With regard to the first question, one possible answer is that the representation of
the learned stimulus increases in multiple brain structures connected in series. In this
model, the expansion of stimulus representation in the primary sensory cortex fol-
lowing learning or nucleus basalis pairing improves performance during the initial
behavioral stages but becomes less marked and less important in time. This would
allow the sensory cortex to recover a mostly unbiased representation of the sensory
space. On the contrary, stimulus representations in structures downstream of the pri-
mary sensory cortex become progressively more defined and more important for be-
havioral performance. Recent findings support this model (Quirk et al., 1997; Sacco
and Sacchetti, 2010; Znamenskiy and Zador, 2013). For example, Sacco and col-
leagues showed that the retrieval of 1-month-old but not new sensory fear associa-
tions requires intact secondary sensory cortices (Sacco and Sacchetti, 2010).
However, the exact mechanisms by which the secondary sensory areas and other
structures like the striatum, the amygdala, and the prefrontal cortex are integrated in
the circuit remain to be determined.
Could sensory cortical plasticity contribute to this proposed progressive engage-
ment of downstream elements in the network? One possibility is that the convergent
synchronized activity of a larger pool of sensory cortical cells on a downstream post-
synaptic neuron will push the membrane potential of this neuron above the spike
threshold, thus generating a postsynaptic spike. Therefore, either classical long-term
potentiation or spike timing-dependent potentiation of synapses in structures post-
synaptically connected to sensory cortices becomes possible. As the cortical map re-
covers normal representation in time, synapses of neurons that continue to respond to
the paired stimulus maintain strong conductances with the postsynaptic cell, whereas
synapses of neurons that recover their original best stimulus will be depressed (e.g.,
through spike timing-dependent depression) (Fig. 4).
Two nonexclusive mechanisms are proposed here to answer the second
question—how do adult sensory circuits recover their original tuning following plas-
ticity? As discussed earlier, nucleus basalis pairing modifies corticocortical inputs
but spares the thalamocortical ones (Froemke et al., 2007). It is possible that these
FIGURE 4
Proposed model for how plasticity in the auditory cortex contributes to constructing memory
traces in downstream structures. Prepairing or prelearning, connections between presynaptic
neurons in the auditory cortex and postsynaptic downstream “effector” cells are weak (small
hexagons). Postpairing, the synchronous discharge of auditory neurons induced spiking of
the “effector” cell (purple color) and potentiation of synapses (large hexagons). Later on, after
auditory neurons recover their original tuning, most of the synapses are depressed but some
are still strong and capable to drive firing of the postsynaptic neuron.
5 Improving Perception by Manipulating Neuromodulation 79
spared inputs will slowly drive the network back to its original state. Alternatively or
concomitantly, synchronized spontaneous activity in cortical neurons can recalibrate
the network. In the auditory and visual cortices, neurons selectively responding to the
same stimulus feature have a higher probability to synchronize their spontaneous
activity or have a higher connectivity probability (Bao et al., 2003; Ko et al.,
2011). In their remarkable study, Ko, Hofer, and colleagues imaged calcium spikes
in the mouse visual cortex to identify neuronal ensembles responding to different
orientations and directions of the visual stimulus. They then prepared acute slices
from the imaged brains, recovered the recorded neurons, and used intracellular re-
cordings to measure the connectivity probability between pairs of cells. Neurons
had significantly higher probability of being connected to other neurons with similar
orientation and direction selectivity than to neurons with distinct selectivities. If
these properties are unaffected by nucleus basalis pairing, they can possibly drive
the sensory network back to its basal state.
Although we did not address here the role of neuromodulators during develop-
ment, this is an important issue for timing corrective or enhancing manipulations
of neuromodulatory centers. The majority of neuromodulators and neuromodulatory
receptors are abundantly expressed during development, including in primordial sen-
sory systems, when they can play important roles in cell fate determination, cell mi-
gration, axon growth and guidance, dendrite growth, and synapse formation
(Erzurumlu and Gaspar, 2012). Neuromodulation is also required for normal circuit
assembly and plasticity in developmental sensory cortices. For example, excess se-
rotonin resulting from knockout of the serotonin transporter in the mouse alters the
normal development of thalamocortical fibers in the somatosensory cortex and thus
prevents the formation of barrel fields (Persico et al., 2001). In the visual cortex, nor-
adrenergic and cholinergic fibers are required for normal ocular dominance plasticity
following developmental monocular deprivation (Bear and Singer, 1986).
5 IMPROVING PERCEPTION BY MANIPULATING

NEUROMODULATION
We discussed in previous sections different mechanisms by which neuromodulators
can promote plasticity in sensory cortices by generating excitatory to inhibitory syn-
aptic imbalances. This indicates at least two important sites in the circuit where ma-
nipulations could allow increased plasticity and behavioral improvement: cortical
inhibitory interneurons and neuromodulatory centers. Recently, multiple research
programs capitalized on the advent of optogenetic and pharmacogenetic tools and
embarked on a series of studies where different types of interneurons or of neuromo-
dulatory neurons can be specifically activated or inhibited with different patterns and
under different timescales. Some of the published work showed control over cogni-
tive and emotional behavioral performance using these approaches (Brown et al.,
2012; Chaudhury et al., 2013; Kvitsiani et al., 2013; Sohal et al., 2009; Witten
et al., 2011).
In an elegant study, Lee and colleagues showed that similar level of control could
be achieved in the perceptual domain (Lee and Dan, 2012). They showed that driving
the activity of parvalbumin interneurons optogenetically sharpened the tuning of
orientation-selective cortical neurons in the visual cortex. At the behavioral level,
this approach improved stimulus discrimination as determined by significant in-
creases in the discriminability index. However, it is unclear whether these improve-
ments in behavior endure over time. Based on the electrophysiological data
presented here, we believe that control over the neuromodulatory systems can gen-
erate robust and long-lasting improvement in behavioral performance. Next, we will
describe supporting evidence that temporally discrete manipulations of the cholin-
ergic system can improve different dimensions of auditory perception.
The functions of the auditory system are to detect, identify, and localize stimuli
that might be behaviorally relevant. These capacities are acquired during develop-
ment as a result of synaptic maturation in the sensory circuit and can be improved
by training in adulthood (Sanes and Woolley, 2011). Lesions of cortical cholinergic
fibers can result in decreased detection, identification, and localization of stimuli and
impaired learning, storage, and flexible retrieval of sensory associations (Berger-
Sweeney et al., 2000; Butt et al., 2002; Cabrera et al., 2006; Leach et al., 2013;
Vale-Martinez et al., 2002).
Sensory detection refers to the capacity to perceive the presence of a signal. As a
general rule, detection degrades with age due to alterations at the level of sensory
organs. In human auditory perception, the cumulative effect of age on hearing is
called presbycusis. It becomes manifest around age 18, when detection of high-
frequency sounds (>16 kHz) becomes greatly reduced. In time, most frequencies,
including those in the speech range (300–3400 Hz), will be perceived only at high
intensities (Liu and Yan, 2007). Pathological conditions unrelated to normal aging
can negatively impact the detection ability of sensory systems. When developed dur-
ing childhood, such pathological conditions can interfere with the normal maturation
of neuronal circuits and thus can have long-lasting effects on sensory perception. It is
therefore important to design interventions for correcting and enhancing auditory
perception.
In our studies of rodent auditory perception, we trained rats to make a nose poke
in response to a particular tone frequency (target tone, 4 kHz) and to withhold from
nose poking in response to other frequencies (Fig. 5A). During training, the target
tone was played at high amplitude, 70 dB SPL. After the animal learned the associ-
ation, we varied the amplitude of the tones from soft (20 dB SPL) to loud (80 dB
SPL). Unsurprisingly, the hit rate increased with the amplitude of the target tone,
such that low-amplitude sounds were hardly perceptible under normal conditions.
When we paired the presentation of the target tone at low amplitudes (30–40 dB
SPL) with the stimulation of the basal forebrain for 5 min, the hit rate postpairing
increased for the paired amplitude, indicating increased detection (Fig. 5B). This im-
provement was not observed when muscarinic and NMDA receptors in the auditory
cortex were blocked during the pairing procedure. Thus, engaging the cholinergic
system can lead to improved auditory detection in adults. Importantly, this occurs
5 Improving Perception by Manipulating Neuromodulation 81
A Listen to tones, withhold for nontargets, respond to target for reward
B NB + saline C Narrowband
100 100
Hits
Responses (%)
Responses (%)
50 Before 50
False
alarms After
0 0
20 40 60 80 2.8 3.4 4.0 4.8 5.7
Intensity (dB SPL) Frequency (kHz) at 70 dB SPL
FIGURE 5
Nucleus basalis pairing can improve behavioral performance on perceptual tasks. (A) The
go–no go operant conditioning task: rats learn to nose poke in response to 4 kHz tones and to
withhold from poking after other frequencies. (B) Before pairing (black lines), rats do not
detect low-intensity targets, but after pairing (red lines) a 4 kHz tone played at 30 dB SPL with
nucleus basalis pairing, detection at the paired intensity increases significantly. (C) Pairing of
the target tone with nucleus basalis stimulation improves recognition of the target tone from
foil tones that are at a small perceptual distance from each other (same color code as in b).
Reproduced from Froemke et al. (2013).
even when the pairing is done outside of the behavioral context or in anesthetized
rats, indicating that plasticity in the auditory system alone is sufficient to improve
detection and that modifications at sensory–motor circuits are not required for
achieving this (Froemke et al., 2013; Reed et al., 2011).
Perceptual identification or recognition can refer to two related concepts. First, it
refers to ability of a sensory system to identify a stimulus as a specific sensory object or
as part of such object. Secondly, it refers to the ability to discriminate or separate a
stimulus from background noise or from other coincidental stimuli. In the adult rat
primary auditory cortex, we and others found that changing synaptic weights by pair-
ing the presentation of the target tone with basal forebrain stimulation led to retuning
of spiking receptive fields and therefore to increased representation of the target stim-
ulus to the disadvantage of foil stimuli (Detari et al., 1999; Froemke et al., 2013). At the
behavioral level, the pairing resulted in improved recognition of the target tone from
foil tones even when these were at short perceptual distance from each other (one-sixth
of an octave) and therefore hard to discriminate under normal conditions (Fig. 5C).
In the future, optogenetic and pharmacogenetic control of cholinergic and other
neuromodulatory fibers will offer a more specific control of cortical circuits and will
likely result in enduring enhancement of perception.
6 CONCLUSIONS
We summarized here recent data showing that experience, via the activation of neu-
romodulatory systems, can modify cortical neural circuits to improve perception. We
stress the following points:
1. Multiple neuromodulatory systems respond during a particular behavioral task.

The effects of neuromodulators on plasticity should be studied not only in
isolation but also in behaviorally relevant combinations as well.
2. Neuromodulators can modify connections in several different microcircuits
within the same cortical column independently. This could indicate a projection-
specific modulation of synaptic inputs under various behavioral tasks.
3. Unlike developmental critical periods, plasticity in the adult sensory cortex results
from active and selective decorrelation of excitatory and inhibitory inputs.
4. Whereas experience-induced synaptic and map modifications during
development can be extremely long lasting, plasticity in adult sensory cortices is
generally transient. Although the time constant of circuit modifications
facilitated by neuromodulation and experience could vary substantially in the
adult, one hypothesis is that longer-lasting synaptic changes are more capable of
sustaining perceptual learning and require fewer repetitions to accumulate and to
construct the memory in downstream structures.
5. The function of neuromodulation can differ substantially between adult and
developing brains; therefore, corrective manipulations must be adjusted to the
age of the subject.
6. Stimulating neuromodulatory centers can enable enduring perceptual
improvements and behavioral modifications on several dimensions, even when
manipulations are done off-line.
7. Optogenetic and pharmacogenetic tools promise a more specific way to
manipulate brain circuits in order to correct and enhance sensory perception.
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CHAPTER
Changes in Plasticity
Across the Lifespan: Cause
of Disease and Target
for Intervention
4
Lindsay Oberman, Alvaro Pascual-Leone1
Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center,
Harvard Medical School, Boston, MA, USA
1
Corresponding author: Tel.: þ617-667-0203; Fax: þ617-975-5322
e-mail address: apleone@bidmc.harvard.edu
Abstract
We conceptualize brain plasticity as an intrinsic property of the nervous system enabling rapid
adaptation in response to changes in an organism’s internal and external environment. In pre-
natal and early postnatal development, plasticity allows for the formation of organized nervous
system circuitry and the establishment of functional networks. As the individual is exposed to
various sensory stimuli in the environment, brain plasticity allows for functional and structural
adaptation and underlies learning and memory. We argue that the mechanisms of plasticity
change over the lifespan with different slopes of change in different individuals. These
changes play a key role in the clinical phenotype of neurodevelopmental disorders like autism
and schizophrenia and neurodegenerative disorders such as Alzheimer’s disease. Altered plas-
ticity not only can trigger maladaptive cascades and can be the cause of deficits and disability
but also offers opportunities for novel therapeutic interventions. In this chapter, we discuss the
importance of brain plasticity across the lifespan and how neuroplasticity-based therapies offer
promise for disorders with otherwise limited effective treatment.
Keywords
plasticity, aging, lifespan, transcranial magnetic stimulation, autism spectrum disorders,
schizophrenia, Alzheimer’s disease
1 INTRODUCTION
Brain plasticity is an intrinsic property of the nervous system that allows an individ-
ual to adapt to a rapidly changing environment through strengthening, weakening,
pruning, or adding of synaptic connections and by promoting neurogenesis
91
92 CHAPTER 4 Changes in Plasticity Across the Lifespan
(Feldman, 2009; Pascual-Leone et al., 2005). Plasticity might be conceptualized as

the balanced interplay of mechanisms promoting change and those promoting stabil-
ity (homeostatic plasticity). At the synaptic level, this plays out, for example, in the
balance of long-term potentiation (LTP) strengthening connections between presyn-
aptic and postsynaptic neurons (Bliss and Gardner-Medwin, 1973) and long-term de-
pression (LTD) weakening them (Bear and Abraham, 1996). The propensity of a
synapse to undergo potentiation or depression relies on the influence of a number
of molecular mechanisms (Kandel, 2001) and the current state of the synapse
(whether it has undergone a plastic change in the recent past, the so-called metaplas-
tic influences (Abraham, 2008; Mockett and Hulme, 2008)).
The molecular mechanisms responsible for plasticity are complex involving mul-
tiple cascades eventually culminating in functional and structural changes. Many
models of plasticity propose the involvement of the NMDA receptor that, depending
on the timing and degree of depolarization of the postsynaptic cell, leads to subse-
quent synaptic LTP or LTD (e.g., Daw et al., 1993; Malenka and Nicoll, 1993;
McBain and Mayer, 1994). This process is kept in check by regulatory forms of plas-
ticity to avoid a situation whereby certain cells never fire and others fire constantly.
These feedback mechanisms include homeostatic synaptic scaling, whereby uniform
increases or decreases in network activity over several hours or days lead to an op-
posing increase or decrease in excitatory synaptic strength (Turrigiano and Nelson,
2004). Metaplasticity is another feedback mechanism, where experience-dependent
alterations in inhibitory tone, dendritic excitability, and NMDA receptor function
alter the ability of future stimuli to drive LTP and LTD (Abraham and Bear,
1996). Plasticity at the synaptic level can be studied using in vitro techniques or
in vivo in animal models. These changes at the synaptic level lead to the development
and maintenance of neural circuitry.
Characterization of plasticity in humans is possible. The consequences of brain
plasticity can be studied as changes in functional activity and anatomical connectiv-
ity using neuroimaging and neurophysiological techniques and as changes in behav-
ior captured by measures of learning, memory, and adaptation. For example, brain
imaging studies using structural and functional magnetic resonance imaging (MRI)
and diffusion tensor imaging (DTI) have provided evidence of circuit modification
suggestive of plastic changes (Guye et al., 2008; Voss and Schiff, 2009). These cir-
cuit modifications are indirect measures of what is happening at the cellular level.
Cross-sectional anatomical MRI studies have consistently identified age-
associated morphometric brain changes encompassing regional cortical thinning,
volumetric subcortical reductions, and ventricular enlargement (e.g., Fjell et al.,
2009; Walhovd et al., 2005, 2009). Longitudinal studies have demonstrated annual
atrophy rates for brain volume, hippocampus and entorhinal cortex (e.g., Fotenos
et al., 2005; Scahill et al., 2003), and atrophy in cortical brain regions over different
periods of time (Driscoll et al., 2009; Raz et al., 2005). Cortical thickness decreases
over the lifespan are estimated at 0.5% a year (Thompson et al., 2007). These
changes affect different neural systems differently: motor and visual cortices show
regional thinning, whereas nonlimbic temporal regions and parietal areas are
1 Introduction 93
relatively spared in normal aging (Raz et al., 2004; Salat et al., 2004). Furthermore,
DTI can reveal structural changes in white matter structure (myelination) and con-
nectivity. For example, DTI has demonstrated that white matter connections, largely
in frontostriatal areas, have reduced myelination as age increases (Salat et al., 2005).
Functional MRI can reveal changes in activation of brain circuits across the age
span. One example of this is a reduction in prefrontal hemispheric asymmetry in
elderly individuals, referred to as the HAROLD (hemispheric asymmetry reduction
in older adults) model (Cabeza et al., 2002). According to the HAROLD model, the
older brain displays less localizable and more bilateral activation during certain cog-
nitive tasks. A second pattern is a shift in evoked neural activity from posterior to
anterior cortex, a model referred to by Davis et al. as PASA (posterior–anterior shift
in aging) (Davis et al., 2008). The PASA model posits that the aging brain is more
likely to recruit prefrontal, rather than occipitotemporal, cortex in the service of task
execution. In addition to life-span changes in task-related brain activation patterns,
resting-state fMRI is revealing age-related differences in the functional connectivity
across large-scale brain networks. One such large-scale brain functional network, the
default mode network (DMN), has been shown to undergo notable modifications
with advancing age in health and disease (Buckner et al., 2008). Older individuals
reportedly exhibit significantly lower DMN activity in the posterior cingulate and
a tendency toward lower activity in all other DMN regions as compared to younger
subjects (Koch et al., 2010). Functional connectivity within the DMN also seems to
be reduced in older adults (Grady et al., 2010). During performance of a working
memory task, the pattern of deactivation of the DMN also seems to be affected
by aging, with older individuals showing not only decreased connectivity but also
decreased ability to suppress low-frequency oscillations of the DMN (Sambataro
et al., 2010). Age-specific changes in activation and connectivity are also seen in
the task-positive network (TPN), though the functional significance of this remains
uncertain (Grady et al., 2010; Sambataro et al., 2010). During memory encoding and
recognition, age-related changes appear to occur mainly in the long-range connec-
tions with widespread reductions associated with aging in the frontotemporal and
temporoparietal regions and a few age-related increases in the posterior parietal re-
gions (Wang et al., 2010). During developmental years, children and young adults
appear to have similar patterns of functionally connected regions but with differences
in the size of functionally connected regions and in the strength of functional con-
nectivity between brain regions (Jolles et al., 2011).
Though useful for understanding the consequences of plasticity at the circuit
level, brain imaging does not directly probe plasticity but rather reveals its conse-
quences. Direct measures of circuit-level plasticity in humans in vivo can be obtained
using novel transcranial magnetic stimulation (TMS) paradigms (Huang et al., 2005;
Huerta and Volpe, 2009; Thickbroom, 2007; Ziemann, 2004). TMS is a noninvasive
way to induce, measure, and modify local and network plasticity, and a number of
experimental TMS measures of brain plasticity have been introduced. Single-pulse
TMS combined with EMG, EEG, fMRI, or other brain imaging methods can be
used to quantify cortical reactivity before and following a given intervention
(Pascual-Leone et al., 2011). TMS can provide a controlled and quantifiable input
that can be matched across individuals of different ages. Comparison of TMS mea-
sures of cortical reactivity before and after an intervention may thus provide an index
of brain plasticity in response to said intervention. When the intervention itself in-
volves TMS (as in paired associative stimulation (PAS) or repetitive (r)TMS proto-
cols), it is possible to assess the efficacy of the mechanisms of plasticity in a defined
cortical brain region in humans in vivo. PAS builds on the Hebbian principle of spike
timing-dependent synaptic plasticity (Classen et al., 2004). In its most common form,
PAS involves repeated pairing of median nerve electric stimulation with timed TMS
over the contralateral primary motor cortex. In this form, PAS has been shown to
modulate the excitability of the motor system in either the positive (with an ISI of
25 ms) or negative (with an ISI of 10 ms) direction (Classen et al., 2004). Repetitive
TMS (rTMS) consists in the application of a train of TMS pulses of the same inten-
sity to a single brain area at a given frequency that can range from 1 to 20 or more
stimuli per second (Pascual-Leone et al., 1994). Such a train of rTMS can induce a
modulation of cortical excitability beyond the duration of the train itself. Depending
on the stimulation parameters, particularly frequency and pattern of stimulation, cor-
tical reactivity is potentiated or depressed (Pascual-Leone et al., 1994). In general, a
continuous train of lower frequencies of rTMS, in the1 Hz range, leads to a transient
suppression of excitability in the targeted cortical area, while bursts of high-
frequency stimulation ( 5 Hz) lead to a temporary increase in cortical reactivity
(Kobayashi and Pascual-Leone, 2003). Patterned bursting protocols have also been
developed that mimic paradigms used to assess synaptic plasticity in animal models
(Huang et al., 2005, 2008). Specifically, theta burst stimulation (TBS) involves ap-
plication of three bursts of 50 Hz rTMS repeated every 200 ms either continuously
for a total of 40 s or intermittently (every 8 s) for about 3 min. When applied to the
motor cortex, continuous (cTBS) and intermittent TBS (iTBS) were shown to result
in depression and potentiation of cortical reactivity as indexed through suppression
and facilitation of motor-evoked potentials (MEPs), respectively (Huang et al.,
2005). Results of animal and human studies are consistent with the notion that the
modulatory effects of TMS protocols on cortical reactivity reflect plasticity mech-
anisms (for review, see Cardenas-Morales et al., 2011).
2 IMPORTANCE OF PLASTICITY FOR BRAIN HEALTH

ACROSS THE LIFESPAN
Plasticity is a critical component of brain development and maintenance across the
lifespan. During development, brain plasticity underlies the formation of functional
networks through experience-dependent strengthening and weakening of synapses.
For example, animal studies have shown that whisker stimulation strengthens the de-
velopment of excitatory synapses through NMDA-mediated LTP in the rat somato-
sensory barrel cortex (Takahashi et al., 2003). This is not seen in rats with their
whiskers trimmed (Takahashi et al., 2003). Visual and auditory cortices also show
2 Importance of Plasticity for Brain Health Across the Lifespan 95
experience-dependent developmental plasticity. Repeated activation of a specific

sensory input (without deprivation) potentiates neural responses to that input and
is responsible for the establishment of auditory and visual receptive fields. This
can be shown experimentally by exposing young rats to specific auditory stimuli that
leads to enhancement of the representation of the presented frequencies and inten-
sities in the primary auditory cortex (A1), altering auditory tuning curves and the
tonotopic map (Frenkel et al., 2006; Keuroghlian and Knudsen, 2007). Similarly,
presentation of high-contrast oriented gratings to young mice similarly drives
orientation-specific enhancement of visual responses in the primary visual cortex
(V1) (Frenkel et al., 2006).
The degree and duration of these experience-dependent changes to cortical struc-
ture are very strictly regulated. During development, there are critical periods where
a specific region of cortex has heightened or exclusive capacity for plasticity. The
onset of these critical periods is thought to be regulated by the maturation of specific
GABAergic neurons (parvalbumin-positive basket cells) (Hensch, 2005). How these
cells control plasticity is not known but may involve setting a permissive excitatory–
inhibitory balance or editing pyramidal cell firing patterns to promote excitatory syn-
aptic plasticity. The regulation of these critical periods during development and the
resulting control of plasticity are integral to the healthy establishment of cortical cir-
cuits. Consequently, dysfunction of critical period timing, excitatory–inhibitory im-
balance, and aberrant cortical plasticity have been put forth as potential
pathophysiological mechanisms underlying developmental disorders such as autism
and schizophrenia (discussed in the succeeding text) (LeBlanc and Fagiolini, 2011;
Rubenstein and Merzenich, 2003).
During adolescence and adulthood, the brain continues to display capacity to adapt
to the ever-changing environment, showing both functional and structural changes
throughout the lifespan. For example, there is direct evidence that LTP in the hippo-
campus and amygdala occurs during and is required for adult learning and memory
(Maren, 2005; Sossin et al., 2008). Studies have also shown that motor training in adult
rats results in LTP-like strengthening of pathways within the primary motor cortex
(Rioult-Pedotti et al., 2000). Similarly, presentation of temporally precise, flashed
visual stimuli to adult rats alters functional synaptic connectivity and visual receptive
fields in the primary visual cortex and affects visual perception in a manner consistent
with induction of spike timing-dependent plasticity. In other brain regions, experience-
dependent changes in synaptic strength, or synaptic plasticity, underlie many learning
processes. In the reward circuit, for example, synaptic plasticity may serve as a cellular
substrate for goal-directed behaviors. Addictive drugs, through a surge of dopamine
released from neurons of the ventral tegmental area, induce widespread synaptic
adaptations within this neuronal circuit (Bonci and Malenka, 1999; Liu et al., 2005;
Luu and Malenka, 2008). It is thus proposed that drug-evoked synaptic plasticity
may constitute an early cellular mechanism eventually causing compulsive drug-
seeking behavior in addiction (Mameli and Luscher, 2011).
This ability to change and adapt appears to peak in young adulthood and shows a
gradual but consistent decrease into senescence. Animal studies, building on
pioneering work from Barnes (Barnes, 1979; Rosenzweig and Barnes, 2003) in the
late 1970s, have demonstrated an age-associated decline in synaptic plasticity in spe-
cific brain regions that correlates with neurocognitive impairments. In aged rodents,
thresholds for induction of the hippocampal LTP and LTD appear to increase and
decrease, respectively (Rosenzweig and Barnes, 2003). Once induced, LTP decays
faster in older rats, and this appears to be associated with a greater degree of forget-
fulness (Barnes and McNaughton, 1980; Kelly et al., 2006). Moreover, deficits in the
balance between LTP and LTD result in impaired learning and memory (Bliss, 2003;
Larson et al., 1986; Roman et al., 1987).
Direct evidence of this age-related decline in plasticity has also been shown in
humans through studies using TMS measures of plasticity. For example, in a
cross-sectional study of 36 healthy volunteers throughout the adult age span ranging
from 19 to 81 years, Freitas et al. (2011) found the duration and magnitude of corti-
cospinal excitability modulation by rTMS was inversely and significantly correlated
with age (Fig. 1). These data provide direct experimental evidence that, in humans,
LTD-like plasticity becomes increasingly less efficient with advancing age. Such de-
creasing plasticity in the motor cortex with advancing age may be associated with the
decrement of hand motor function (e.g., longer reaction time) observed during nor-
mal aging in both men and women (e.g., Carmeli et al., 2003) and to the age-related
deficits in motor learning (e.g., Brown et al., 2009). Such age-related changes in
plasticity are also linked to an individual’s cognitive ability and age-related
cognitive decline may be associated to them. An individual’s risk of age-related cog-
nitive decline (and ultimately the manifestation of symptoms of dementia) might
FIGURE 1
Schematic representation of the influence of aging on plasticity and cognitive ability.
3 Disease as a Manifestation of Aberrant Plasticity 97
then depend on the individual’s starting point and slopes of change in plasticity ef-
ficiency over the lifespan. Indeed, as will be further discussed later, studies in pa-
tients with early Alzheimer’s disease, the most common dementing illness, reveal
an abnormally suppressed efficacy of plasticity mechanisms (Freitas et al., 2011;
Koch et al., 2012).
3 DISEASE AS A MANIFESTATION OF ABERRANT PLASTICITY

AT DIFFERENT TIMES IN THE LIFESPAN
If, as we suggest, plasticity is critical for healthy brain development, it follows that
neuropsychological disorders may have a basis in aberrant plasticity mechanisms.
Recent theories of the neurological etiology of brain disorders reflect a growing
acceptance of this inference (Pascual-Leone et al., 2011; van Spronsen and
Hoogenraad, 2010). A functionally “normal” brain is thus a changing brain, a brain
whose capacity and mechanisms of change are shifting appropriately from one time
point to another in a given individual’s life. Therefore, assessing the mechanisms of
brain plasticity across the lifespan is critical to gain insight into an individual’s brain
health. The timing, site, and direction of alterations in plasticity across the lifespan
will influence what systems are affected and in turn the behavioral outcome. Impor-
tant factors to consider that likely contribute to individual differences in changes in
the efficacy of mechanisms of plasticity across the lifespan include genetic and epi-
genetic mechanisms (e.g., polymorphisms and genetic expression), hormonal factors
(e.g., gender and menstrual cycle), impact of morbidities (e.g., diabetes, cancer, or
infections), and lifetime experiences (e.g., traumatic brain injury, exposure to toxins,
stress, sleep deprivation, substance abuse, poor cognitive reserve, poor nutrition,
and sedentariness). Therefore, dissimilar “starting points” for different individuals,
distinct lifelong “slopes of change,” and events that lead to a change in the set point
or slope of change in plasticity might be postulated (Fig. 2A and B). We shall posit
that these two factors critically contribute to an individual’s predisposition to man-
ifest symptoms of disease. To illustrate this notion, we shall discuss how alterations
in plasticity might underlie developmental disorders such as autism spectrum disor-
ders (ASD) and schizophrenia and neurodegenerative disorders such as Alzheimer’s
disease (AD).
3.1 Autism spectrum disorders

Evidence for altered plasticity in ASD comes from multiple lines of research
(reviewed in Oberman, in press). First, genetic linkage studies indicate that genes
associated with ASD play critical roles in developmental and experience-dependent
plasticity. For example, BDNF (brain-derived neurotrophic factor) plays a critical
role in maintenance of synaptic potentiation (Akaneya et al., 1997; Huber et al.,
1998; Jiang et al., 2001; Korte et al., 1995; Patterson et al., 1996) and has been found
to be elevated in postmortem tissue of individuals with ASD, specifically in the basal
FIGURE 2
(A) Schematic representation of how factors such as expression of certain genes, diseases,
brain injury, or behavior can impact the slope of change in plasticity across the lifespan. (B)
Schematic representation of how degree of plasticity and cognitive ability at any given time in
the lifespan is a consequence of both a given individual’s starting point and slopes of change.
forebrain (Perry et al., 2001). Additionally, multiple studies note a reduction in

GABAergic receptors (Fatemi et al. 2009a,b, 2010) and a 50% reduction in enzymes
that synthesize GABA (glutamic acid decarboxylases (GADs) 65 and 67) (Fatemi
et al., 2002; Yip et al., 2007). These changes in the GABA system may directly con-
tribute to altered connectivity, especially between the cerebellum and the thalamus
and ultimately the cerebral cortex. This may represent a mechanism by which motor
and cognitive behaviors may be affected in ASD (Blatt and Fatemi, 2011). Other
genes coding for molecules such as neuroligins 3 and 4 that are implicated in synap-
togenesis (Jamain et al., 2003), SH3 and multiple ankyrin repeat domains 3
(SHANK3) that encodes a protein involved in dendritic development (Durand
et al., 2007) and c3orf58, sodium/hydrogen exchanger isoform 9 (NHE), and
protocadherin-10 (PCDH10) thought to be critically involved in synaptic develop-
ment and plasticity (Durand et al., 2007; Jamain et al., 2003; Morrow et al.,
2008) have all been identified as candidate genes that confer increased risk of
ASD (Cook, 2001; Lamb et al., 2000; Persico and Bourgeron, 2006).
In addition, single gene disorders associated with autism implicate proteins that
play important roles in synaptic plasticity. Among these are mutations in FMRP
(fragile X mental retardation protein), thought to contribute to the neurological def-
icits of fragile X syndrome by enhancing synaptic potentiation and favoring exag-
gerated LTD-like plasticity. Other examples include mutations in TSC1 and
TSC2 that cause tuberous sclerosis, in NF1 that cause neurofibromatosis, and in
phosphatase and tensin homolog (PTEN) that cause PTEN macrocephaly (Dolen
and Bear, 2009). Although the contributions of these genes and proteins to synaptic
plasticity are incompletely described, animal models of these human single gene syn-
dromic causes of autism predictably demonstrate aberrant synaptic plasticity. These
genetic findings have inspired others to propose that autism should be thought of as a
“synaptopathy” (Dolen and Bear, 2009) whereby proteins that are involved in syn-
aptic development and plasticity are affected.
Animal ASD models reveal abnormal plasticity mechanisms (reviewed in
Tordjman et al., 2007). For example, a recent study exploring the parvalbumin
(PV)-positive basket cell (a key player for critical period plasticity) in two animal
models of autism (valproic acid (VPA) and neuroligin 3 knockout models) found
a reduction or complete lack of PV cells in the parietal and occipital cortices
(Gogolla et al., 2009), suggesting a possible molecular mechanism underlying a pro-
posed hyperpotentiated state. When the microcircuits of these animals were inves-
tigated, their reactivity to stimulation, as measured by the number of spikes and
the number of postsynaptic potentials following stimulation, was nearly twice that
of wild-type animals (Rinaldi et al., 2008b). This hyperreactivity has been found
in multiple regions including the somatosensory cortex (Rinaldi et al., 2008b), pre-
frontal cortex (Rinaldi et al., 2008a), and amygdala (Markram et al., 2008), thus in-
dicating a widespread enhancement in reactivity of the cortical and subcortical
neurons. Synaptic responses have also been recorded in pyramidal neurons following
a Hebbian pairing stimulation protocol in these animals, and though the presynaptic
response was normal, the postsynaptic cell had a more than twofold increase in re-
sponse, indicating a state of hyperpotentiation (Rinaldi et al., 2007). Similarly, ab-
normal synaptic plasticity, specifically exaggerated LTD, has also been shown in
mouse models of genetic disorders associated with autism, namely, the FMR1-null
mouse (fragile X syndrome) and MECP2-null mouse (Rett syndrome) (Dani et al.,
2005; Huber et al., 2002).
In humans with idiopathic autism, the most consistent neuroimaging finding is

increased brain volume, with an overall increase in both gray and white matter vol-
ume (Courchesne et al., 2001). Furthermore, there is a distinct developmental trajec-
tory of brain size abnormalities in ASD whereby reduced or normal brain size is
present at birth, followed by a rapid rate of brain growth during early childhood. This
trajectory suggests that the underlying mechanism is a dynamic process with a time
line consistent with a shift toward increased potentiation of excitatory synapses dur-
ing early childhood (Courchesne and Pierce, 2005). Recent studies reveal that the
overall larger brain in individuals with ASD is primarily due to larger white matter
volumes, particularly in the outer “radiate” regions including the origins and termi-
nations of projection and sensory fibers (Herbert et al., 2004). Even when accounting
for the overall greater brain volume, the proportion of white matter still is greater
than normal, suggesting that abnormal axons and neural connections, rather than
the neuronal cell bodies themselves, may be responsible for the abnormalities in
brain structure. There is also neuropathologic data in postmortem tissue supporting
brain overgrowth, specifically in the prefrontal cortex (Courchesne et al., 2011), and
abnormalities at the minicolumn level indicating aberrant minicolumn structure with
reduced neuronal size and increased density attributable to reductions in the inhib-
itory peripheral neuropil space (Casanova et al., 2002). The authors suggest that this
lack of inhibition would lead to gross alterations in cortical connectivity.
Another common neuropathologic finding in ASD is a reduction in the number of
cerebellar Purkinje cells (Bauman and Kemper, 1996). Such a reduction is thought to
release the deep cerebellar nuclei from inhibition, producing abnormally strong
physical connectivity and potentially abnormally weak computational connectivity
along the cerebellothalamocortical circuit and, furthermore, possibly aberrant
activity-dependent plasticity along this pathway (Belmonte et al., 2004). Abnormally
high and indiscriminate physical connectivity may lead to abnormally low and inef-
fective functional connectivity due to excessive noise and poor temporal precision
secondary to activity of superfluous connections. Consistent with this assertion,
structural and functional MRI studies have confirmed anatomical and functional con-
nectivity abnormalities in individuals with ASD (for a review, see Geschwind and
Levitt, 2007).
Two recent studies have been published exploring plasticity using TMS in indi-
viduals with ASD. The first (Oberman et al., 2012) explored modulation in cortical
excitability in response to a train of rTMS in 20 adults with Asperger’s syndrome
(AS) and found them to have greater and longer-lasting modulation of cortical reac-
tivity following rTMS as compared to age-, gender-, and IQ-matched controls. The
latency to return to baseline following rTMS was on average between 80 and 90 min
in the ASD group compared to 25–30 min in the controls. This finding was con-
firmed in a separate cohort of 15 individuals (Oberman et al., 2012). Interestingly,
consistent with other studies, there was no significant group difference in measures
of basic excitability as measured by resting and active motor threshold (Enticott
et al., 2013; Oberman et al., 2012; Theoret et al., 2005) or response to single-pulse
TMS (Enticott et al. 2012a; Oberman et al., 2012). Thus, this excessive modulation
of excitability in response to stimulation (a putative measure of LTD-like and LTP-

like plasticity) is not primarily attributable to differences in baseline excitability. A
second study was subsequently published exploring response to the PAS in nine pa-
tients with high-functioning ASD (HFA)/AS and typically developing age-matched
controls. In contrast to the findings by Oberman et al. (2012), this study found that
individuals with ASD showed a marked absence of the expected modulation of ex-
citability following PAS (Jung et al., 2013). The authors contend that their results
indicate an impairment in LTP-like plasticity induced by PAS in individuals with
HFA/AS compared with typically developing participants. The conflicting findings
could reflect paradigmatic differences (i.e., Hebbian vs. non-Hebbian plasticity) or
the heterogeneity of ASD, but in any case, the effects are opposite (i.e., absent vs.
long-lasting) and emphasize the importance of large studies, with detailed clinical
and genetic information, to examine functional neurobiology in ASD. Regardless,
these TMS studies support the notion of alterations in plasticity mechanisms being
central to the pathophysiology of ASD.
3.2 Schizophrenia
Schizophrenia is another neurodevelopmental disorder where researchers are begin-
ning to implicate neuroplasticity mechanisms in its pathophysiology. Several lines of
evidence suggest that the neurotransmitter mechanisms mediating plasticity in the
cortex are altered in schizophrenia. For example, both NMDA and GABA
receptor-mediated neurotransmission have been implicated in the pathophysiology
of schizophrenia. Blockade of NMDA receptor-mediated neurotransmission is asso-
ciated with worsening of psychosis in patients with schizophrenia (Krystal et al.,
2002) and produces behaviors in healthy subjects that are similar to the positive
and negative symptoms experienced by patients with schizophrenia (Krystal
et al., 1994). Moreover, neuroanatomical (Benes and Berretta, 2001) and neurophys-
iological evidence (Daskalakis et al., 2002; Fitzgerald et al., 2002; Freedman et al.,
2000) suggests that both a decrease and a disruption of cortical GABAergic inhib-
itory neurotransmission are associated with the pathophysiological findings of
schizophrenia. In addition, genetic and postmortem studies have implicated abnor-
malities in dysbindin, neuregulin, and reelin, proteins involved in synaptic plasticity,
as possible contributors to pathological findings in schizophrenia (Fatemi et al.,
2000; Stefansson et al., 2003; Straub et al., 2002; Weeber et al., 2002).
Behaviorally, patients with schizophrenia demonstrate an inability to learn com-
plex motor skills. For example, studies suggest that patients with schizophrenia show
impaired motor learning as indexed through the rotary pursuit task and a lack of in-
crease in blood oxygen level-dependent premotor activity following one week of
training as compared to healthy subjects (Kodama et al., 2001; Schwartz et al.,
1996). A recent TMS study confirms these findings showing that following motor
training, both medicated and unmedicated patients with schizophrenia demonstrated
significantly reduced motor reorganization as indexed by TMS-induced motor-
evoked potentials compared with healthy subjects (Daskalakis et al., 2008).
Several other TMS studies have been conducted that also support plasticity
abnormalities in schizophrenia. Fitzgerald et al. (2004) showed reduced plastic brain
responses in medicated and unmedicated patients with schizophrenia. Specifically,
LTD-like suppression of cortical excitability was reduced in patients in response to a
single 15 min train of 1 Hz rTMS applied to the motor cortex, compared with a
healthy control group. Frantseva et al. (2008) conducted a study using PAS and dem-
onstrated that schizophrenia patients, compared with healthy subjects, showed def-
icits in MEP facilitation, indicating disrupted LTP-like plasticity, which appeared to
be associated with impaired motor skill learning. Finally, McClintock et al. (2011)
reported the findings of an rTMS study in a group of six first-episode patients with
schizophrenia who had 42% reduced duration of rTMS-induced aftereffects com-
pared with age- and gender-matched healthy control subjects, suggesting that corti-
comotor plasticity mechanisms are already abnormally reduced in early stages of
schizophrenia.
3.3 Alzheimer’s disease

Large strides have been conducted in investigating the pathophysiology of AD (Jack
et al., 2010). The leading hypothesis about the cause of AD argues that toxic forms of
the amyloid-b (Ab) protein initiate a cascade of events ending in synaptic dysfunc-
tion and cell death and where “plaques” and “tangles” are conceived as residues of
this pathological process (Mattson, 2004; Walsh and Selkoe, 2004). Ab is critical as
when it is isolated directly from human AD brains, it can cause impaired synaptic
plasticity and memory in rodents (Shankar et al., 2008). Furthermore, when Ab is
released into the extracellular fluid, it triggers signaling cascades on the postsynaptic
membrane, sharing remarkable similarities with LTD, including increased synaptic
AMPA receptor endocytosis and dendritic spine loss (Hsieh et al., 2006).
Consistent with the clinical observation that initial symptoms of AD include
memory impairment, the medial temporal lobe and other cortical structures linked
to memory are affected early in AD. The reason why memory structures are partic-
ularly vulnerable to AD and critically involved in disease progression remains
unclear, though proposed theories include concepts based on anatomy (Hyman
et al., 1990) and on mechanisms of plasticity (Mesulam, 2000). On the other hand,
early pathological studies and more recent morphometric brain studies also reveal
distributed cortical regions as vulnerable to AD, prompting further exploration of
systems-level causes (Saper et al., 1987). In any case, our understanding remains
insufficient to guide novel interventions and current therapeutic options remain
disappointing. Therefore, novel conceptualizations of AD pathogenesis seem worth
entertaining.
We often consider how aberrant molecular and cellular processes can affect brain
circuits and cognitive processes. However, the opposite causal direction is also pos-
sible: dysfunctional brain activity patterns may directly modulate molecular cas-
cades that are relevant to disease. We propose that AD is an illustrative example
4 The Use of TMS as a Novel Treatment Strategy 103
of this pathophysiological instance, where alterations in plasticity ultimately trigger

a cascade of maladaptive responses leading to pathology.
Direct evidence of a dysfunction in plasticity in AD is provided by recent TMS
studies. The first, conducted by Inghilleri et al. (2006), tested the effects of cortico-
motor modulation induced by suprathreshold high-frequency (5 Hz) rTMS and found
the amplitude of MEPs progressively decreased in patients while increasing in con-
trols. This suggests impaired LTP-like plasticity. Another study, conducted by
Battaglia et al. (2007), studied neocortical (motor) LTP-like plasticity in AD and
healthy individuals using a PAS protocol and found it to be significantly reduced
in AD patients.
Koch et al. (2011) studied the effects of low-frequency (1 Hz) rTMS over the pri-
mary motor cortex in a group of patients with a diagnosis of probable AD, compared
to healthy age-matched controls (HS), and tested the effects of a single dose of orally
administered L-dopa, one of the key neurotransmitters in modulating synaptic plas-
ticity mechanisms, on rTMS-induced plasticity. They found that in AD patients, the
1 Hz rTMS protocol did not induce the expected inhibitory effect, while a long-
lasting inhibition of MEP was observed in control participants. In addition, L-dopa
induced a clear form of reversal of the direction of plasticity in healthy controls that
was not evident in AD. In a follow-up study, Koch et al. (2012) applied repetitive
TMS over the primary motor cortex (M1) in AD patients and in age-matched healthy
controls. Using TBS protocols, AD patients showing consistent LTD-like effects that
were comparable to those obtained in healthy controls when submitted to 40 s of con-
tinuous TBS. Conversely, AD patients did not show any LTP-like aftereffect when
submitted to two different TBS protocols that induced an LTP-like effect in healthy
controls such as intermittent TBS and 20 s of continuous TBS followed by 1 min of
muscular contraction. These results demonstrate the impairment of LTP-like to-
gether with normal LTD-like cortical plasticity in AD patients. Finally, a study con-
ducted by Freitas et al. (2011) indicates that the duration and magnitude of the
modulation of corticospinal excitability by cTBS, an index of LTD-like plasticity,
is significantly shorter in individuals with early AD than in controls (Freitas
et al., 2011). Thus, it is unclear to what extent LTD-like plasticity is affected in
this population, but studies consistently reveal early alteration of mechanisms in
plasticity that may antedate and contribute to trigger a molecular maladaptive cas-
cade culminating in the manifestation of symptoms of dementia.
4 THE USE OF TMS AS A NOVEL TREATMENT STRATEGY

FOR NEUROPSYCHIATRIC DISORDERS OF PLASTICITY
If, as we propose, brain plasticity is critically tied to brain health across the lifespan
and a dysfunction in plasticity underlies the symptoms of many neuropsychiatric dis-
orders, then normalizing plasticity mechanisms may represent novel and effective
therapeutic interventions. In the future, interventions aimed at modulating plasticity
mechanisms could potentially prevent the structural and functional pathology
underlying these disorders and in doing so prevent the behavioral symptoms from
developing (Cramer et al., 2011).
The potential of rTMS to induce a long-lasting modulation of cortical excitabil-
ity and plasticity offers the possibility of its use for therapeutic purposes in neuro-
logical and psychological conditions thought to be a result of altered excitability or
plasticity of specific neural circuits. Studies examining behavioral performance
prior to and following rTMS have shown rTMS-induced changes in sensory
(Kosslyn et al., 1999), cognitive (Hilgetag et al., 2001; Mottaghy et al., 2002),
and affective processing (see Lee et al., 2012 for a review). Low-frequency rTMS
protocols and a specific type of theta burst stimulation (continuous, cTBS) gener-
ally induce lasting suppression of the excitability, while high-frequency rTMS and
a different type of theta burst stimulation (intermittent, iTBS) generally induce
lasting facilitation (Maeda et al., 2000). However, it should be noted that these
effects are state-dependent and there is significant intersubject and intrasubject
variability (Silvanto and Pascual-Leone, 2008). Thus, in order to induce the desired
effect, one must consider (1) the brain region, as even a small shift in the targeted
region may greatly affect the behavioral impact; (2) the current state of the
stimulated cortex as state-dependent changes have been observed; and (3) the
exact stimulation protocol being applied as opposite effects can be induced by even
slight modifications of the parameters. rTMS-based treatments are already being
proposed and tested in the aforementioned disorders.
4.1 Autism spectrum disorders

Recent studies from two sites in the United States (Harvard Medical School, Boston,
MA, and the University of Louisville School of Medicine, Louisville, KY) and one
site in Australia (Monash University, Melbourne, Australia) have reported prelimi-
nary data suggesting an improvement in both physiological indices and specific be-
havioral symptoms in individuals with ASD following rTMS.
The first of these studies was based on the finding that individuals with ASD
showed abnormal structure of minicolumns with reduced neuronal size and increased
density attributable to reductions in the inhibitory peripheral neuropil space
(Casanova et al., 2002). This finding was most prominent in the prefrontal cortex
(Casanova, 2006). Thus, using an rTMS protocol aimed at increasing inhibitory tone,
Sokhadze et al. (2009) applied low-frequency (0.5 Hz, 150 pulses) stimulation to left
dorsolateral prefrontal cortex (DLPFC) two times per week for 3 weeks in a small
sample of eight individuals with ASD. The results of this first study showed an ab-
normally increased amplitude and latency of the P300 event-related potential (ERP)
and abnormally high induced gamma frequency electroencephalographic (EEG) ac-
tivity over frontal and parietal sites at baseline in the ASD group that were normal-
ized (not significantly different from healthy controls) in amplitude and latency
following the series of rTMS sessions. There was also a reduction in repetitive–
ritualistic behavior in ASD subjects as reported by their caregivers. This result is
quite promising, though the study should be considered extremely preliminary given
its small sample size and lack of sham control condition. Following this initial study,
the same group conducted several follow-up studies with slightly larger samples. In
the first of these follow-up studies, the group replicated their previous finding of nor-
malized ERPs and a reduction in repetitive–ritualistic behaviors following the same
protocol (Sokhadze et al., 2010) in 13 individuals with ASD. In the second follow-up
study, the same investigators applied bilateral low-frequency TMS (1 Hz) once a
week for 12 weeks, with the first six treatments to the left DLPFC and the next
six to the right DLPFC in 16 patients with ASD. EEG and behavioral evaluations
pre- and post-rTMS revealed normalization of induced gamma activity and a reduc-
tion in both repetitive behaviors and irritability (Baruth et al., 2010). Using this same
protocol, this group explored error monitoring pre- and post-rTMS and found im-
provements in both ERP indices and behavioral measures of error monitoring follow-
ing 1 Hz stimulation once a week first to left then to right DLPFC in 20 individuals
with ASD (Sokhadze et al., 2012). Lastly, using a similar design, the same group also
recently published a paper describing improvements in ERP indices of visual proces-
sing, accuracy on a selective attention task, and behavioral measures of repetitive
behavior and irritability of 25 individuals with ASD following the 12-week protocol
described in the preceding text (Casanova et al., 2012). Again, these studies provide
promising preliminary data for the use of low-frequency rTMS to DLPFC for the
alleviation of aberrant behavior and physiological indices in ASD but are limited
by small sample size and unblinded designs. It is also unclear in the paradigms where
both left and right hemisphere were stimulated whether the effect was driven by one
or the other hemisphere or whether the effect was a result of the combination of both.
Finally, the behavioral improvements appear to be limited to repetitive behaviors,
irritability, and specific measures of attention.
We have also published reports showing improved performance on a behavioral
task in patients with ASD following a TMS protocol. Fecteau et al. (2011) conducted
a study where they applied a single session of low-frequency (1 Hz) rTMS to left and
right pars triangularis and pars opercularis (the two regions that comprise Broca’s
area) in 10 individuals with ASD and 10 matched neurotypical control participants
in a double-blind, pseudorandomized, sham-controlled study. Compared to the sham
condition, all 10 individuals with ASD showed reduced latency to name objects on
the Boston Naming Test following stimulation to the left pars triangularis (BA 45)
while 9/10 showed an increased latency following stimulation to the adjacent left
pars opercularis (BA44). The findings suggest that in individuals with ASD, left
BA45 exerts an abnormally excessive amount of inhibition on left BA44, thus inhi-
biting left BA45 results in a suppression of the excessive inhibitory control and a
behavioral improvement. However, this interpretation has yet to be empirically
tested. Findings from this study though short-lived, given the single-session design,
suggest that rTMS to BA45 may lead to improvements in language processing in
ASD and warrant further studies aimed at long-term improvements in this domain
(Fecteau et al., 2011). This study also demonstrated the importance of strict anatom-
ical targeting as the opposite result was found when the target region was in the
adjacent BA44 region.
Fitzgerald’s group based in Melbourne, Australia, is also exploring the potential

of rTMS to improve specific symptoms of ASD. In a recent paper, they describe a
study in which a single session of 1 Hz rTMS was applied to one of two corticomotor
regions (left M1 and supplementary motor area (SMA)) in 11 individuals with ASD.
Though not often considered a core impairment in ASD, motor dysfunction is often
noted as an associated feature. Following stimulation of M1, there was a significant
improvement in a late movement-related cortical potential (MRCP) thought to be
associated with the execution of movement while stimulation of SMA resulted in
an improvement of the early MRCP, suggesting enhanced motor preparation.
Though poststimulation improvements were seen, their MRCPs still remained out-
side of what would be considered neurotypical levels, and despite improvements in
the electrophysiological response, there was not a significant improvement in behav-
ioral measures of motor functioning (Enticott et al., 2012b).
This same group is currently conducting a sham-controlled, double-blind clinical
trial of a specific type of high-frequency rTMS (deep rTMS) to the medial prefrontal
cortex (mPFC), a region thought to play a key role in theory of mind abilities (un-
derstanding the mental state of others) (Amodio and Frith, 2006; Frith and Frith,
1999; Mitchell et al., 2006; Saxe and Powell, 2006). The goal of this study is to de-
velop a therapeutic intervention aimed at improving the individual’s capacity for un-
derstanding other’s mental states. Though this study is still ongoing, the group has
reported that several participants have responded to the treatment resulting in a re-
duction of self-reported clinical symptoms (Enticott, personal communication). An
individual who had a very pronounced response (Ms. D) was featured in a case report
(Enticott et al., 2011). This patient showed improvements on the Interpersonal
Reactivity Index (IRI), the Autism Spectrum Quotient (AQ), and the Ritvo
Autism–Asperger Diagnostic Scale. She also reported that she found eye contact
“less uncomfortable” and found social situations “more natural” even joining a social
club and making new friends. She noted that she “did not have to think so much of
what to say” and was more aware of instances when she might be making someone
uncomfortable. She also reported an increased capacity for empathy and perspective
taking, even for incidents that occurred many years before. She also experienced
greater consideration for and affection toward family members following the stim-
ulation protocol. These changes were also noted by her family. Her mother described
her as more considerate of others following the stimulation. These improvements
seemed to remain at the 1-month and 6-month follow-up (Enticott et al., 2011).
Still, other groups including one in Israel (NCT 01388179) and one in France
(NCT 01648868) also have ongoing clinical trials applying rTMS for the treatment
of specific ASD symptoms, the results of which have yet to be published.
4.2 Schizophrenia
Studies using TMS and rTMS in schizophrenia have been more extensively reviewed
in Freitas et al. (2009). Initial rTMS studies focused on the clinical efficacy of rTMS
on the positive and negative symptoms of the disease, but overall, the results were
inconsistent and effect sizes rather small. For positive symptoms (specifically audi-
tory hallucinations), the goal was to inhibit the left temporoparietal cortex via 1 Hz
rTMS, based on the rationale that increased temporal activity correlates with positive
symptoms (for a review, see Freitas et al., 2009). In regard to negative symptoms,
numerous studies attempted to increase the activity in the left prefrontal region
via high-frequency rTMS as this might regulate the dopamine release and ameliorate
the negative symptoms.
Among numerous studies that targeted the negative symptoms, only five random-
ized controlled trials assessed the cognitive effects (Fitzgerald et al., 2008; Mittrach
et al., 2010; Mogg et al., 2007; Novak et al., 2006; Schneider et al., 2008). Mogg et al.
applied 10 consecutive daily sessions of 10 Hz rTMS to the left DLPFC and reported
a significant improvement in verbal learning in a series of patients with prominent
negative symptoms. In addition, two intraindividual crossover studies applied 10 ses-
sions of 20 Hz rTMS to the left DLPFC (Huber et al., 2003; Rollnik et al., 2000), and
though initially failed to detect a significant effect of rTMS on cognition (Rollnik
et al., 2000), when analyzed stratifying for gender, an improvement of visuomotor
tracking was observed in females (Huber et al., 2003).
Further studies seem warranted, specifically considering the encouraging find-
ings of open, proof-of-principle trials. For example, Cohen et al. (1999) stimulated
the PFC bilaterally with 20 Hz using a double-cone coil, a special coil considered to
stimulate deeper brain regions compared to standard figure-of-eight coil. Following
10 sessions of rTMS, the authors reported an improvement in visual memory. In a
recent study, Levkovitz et al. (2011) performed bilateral deeper stimulation of the
prefrontal cortex (L > R) using an H-coil and reported improvement in executive
functions, spatial working memory, attention, and rapid visual information proces-
sing. It seems that indeed the use of special TMS coils that enable direct stimulation
of deeper brain structures may be important in this setting. Studies using more con-
ventional TMS coils with limited depth penetrance have yielded less encouraging
results. For example, Sachdev et al. applied 20 sessions of 20 Hz rTMS to the left
DLPFC and found no improvement in cognitive functions (Sachdev et al., 2005).
Another promising approach in schizophrenia appears to be the targeting of
nodes of identified neural networks. Specifically, targeting cerebellar vermis to have
an impact of distributed bihemispheric neural networks is an intriguing notion
(Demirtas-Tatlidede et al., 2011). Schutter et al. (2003) reported early promising re-
sults targeting the cerebellar vermis. In a carefully designed open-safety study, we
embraced this novel approach and targeted the cerebellar vermis using an intermit-
tent TBS paradigm (Demirtas-Tatlidede et al., 2010). Following 10 sessions of stim-
ulation in 5 days (twice per day with a minimum gap of 4 h), we observed an
improvement in working memory and visual learning domains while no significant
decline was found. The direction of improvement in 70% of the neuropsychological
variables suggests a trend toward improvement in cognition. A double-blind, sham-
controlled phase II study is currently underway.
Another important consideration in this setting is the possibility of employ-
ing stimulation paradigms tuned to specific brain oscillations and targeting
bihemispheric structures. The combination of TMS with EEG and specifically EEG-
gated TMS protocols enables such approaches (Shafi et al., 2012). For example,
rTMS can lower the excessive gamma oscillatory activity found in patients with
schizophrenia when applied at appropriate stimulation frequency bilaterally over
the DLPFC (Barr et al., 2011). This was associated with significant improvements
in working memory.
4.3 Alzheimer’s disease

We hypothesize that a therapy that targets specific brain circuits that are impaired in
AD in order to promote their functional integrity and restore their plasticity might
preserve cognitive function and effectively reduce the burden of the disease. Data
from several small, single-site, randomized controlled trials reveal extremely en-
couraging results. If confirmed in appropriately powered and controlled clinical ef-
ficacy trials, such an approach would represent a major advance in the treatment of
AD that could be truly transformative for the care of patients, reducing the impact on
their families and potentially producing a substantial financial saving for society.
Furthermore, such an approach might serve as a proof-of-concept for the notion
of harnessing and modulating plasticity as a cornerstone of neurological
therapeutics.
The hypothesis underlying the proposed novel therapeutic approach is that repet-
itive TMS targeting specific nodes of brain networks affected in AD can enhance
plasticity and modulate connectivity in the targeted brain circuit, thus making it more
responsive to circuit-specific CR tasks and altering the pathological metabolic
cascade.
Two randomized controlled trials have been published using TMS for AD and
both reported positive changes following consecutive sessions of rTMS application.
Cotelli et al. (2011) applied 20 sessions of 20 Hz rTMS over the left DLPFC and
performed a series of language tests in patients with moderate AD. The authors
reported a significant effect of rTMS on auditory comprehension. Secondly,
Ahmed et al. (2012) tested the effects high- and low-frequency rTMS applied over
the bilateral DLPFCs. A significant improvement in global cognitive functioning
was reported following five consecutive sessions of bilateral high-frequency stimu-
lation and this effect was maintained for 3 months.
In an open trial, Bentwich et al. (2011) tested the effects of 10 Hz rTMS together
with cognitive training in patients with AD. This combined therapy was applied for 6
weeks while the authors stimulated six different locations (Broca, Wernicke, right
and left DLPFCs, and right and left parietal somatosensory association cortices) with
an aim to cover the cognitive domains affected by the disease. A significant improve-
ment in the primary outcome measure, Alzheimer Disease Assessment Scale-
Cognitive (ADAS-cog), was detected at 6 weeks and 4.5 months. MMSE revealed
a significant change at 6 weeks only.
Subsequently, Rabey et al. (2013) completed a small, randomized double-blind
controlled study of TMS-CR in 15 patients with mild–moderate AD on
cholinesterase inhibitor therapy (stable dose for 2 months). Seven patients were
randomized to TMS-CR while eight were double sham controls. They followed ex-
actly the same protocol as our pilot study and found a mean improvement on the
ADAS-cog of 3.8 points in the active TMS-CR group, as compared with a mean im-
provement of 0.5 in the control group (p ¼ 0.04, mean difference in ADAS-cog be-
tween groups at endpoint of 4.3 points). There was also a significant improvement in
the average CGIC score in the real versus sham groups (p < 0.05): the CGIC is a 7-
point “global change” rating in which 4 ¼ no change and 3, 2, and 1 or 5, 6, and 7 is
“minimal,” “moderate,” and “marked” improvement or worsening, respectively. The
real TMS-CR group showed an average change rating of 3.6 and the sham group an
average change rating of 4.3, representing slight average improvement and worsen-
ing, respectively. The difference between means, in this case 0.7, is what represents
the degree of difference between treatments in global change. This mean difference
compares favorably to the one encountered in trials of marketed treatments, which
has been in the 0.3–0.4 range. There were no reported side effects of treatment. A
double-blind, multiple site European study is under way to confirm these promising
findings.
We have recently completed an investigator-initiated randomized, double-blind
clinical trial in 12 patients with mild–moderate AD (MMSE 18–26). Patients were
randomized to active (n ¼ 6) or sham (n ¼ 6) intervention. Patients underwent 6
weeks of daily 1 h sessions of active or sham TMS-CR as adjunct to their stable phar-
macological therapy (five sessions per week, Monday to Friday, total of 30 sessions).
A short train of repetitive TMS was applied to a given brain region immediately be-
fore cognitive training tailored to engage the targeted brain circuit. Six different
brain regions engaged in major cognitive functions affected by AD were targeted,
as identified using the patient’s own brain MRI scan. The cognitive tasks were de-
veloped to fit these regions and engaged the modulated brain circuits. The primary
outcome measure was to assess improvement relative to sham on the ADAS-cog
score at the end of the 6 weeks of intervention and at a 3-month follow-up. The active
treatment group improved by 2.9 points relative to baseline, whereas the sham treat-
ment group worsened by 2.7 points (p < 0.01). Therefore, a primary analysis for the
difference between groups at endpoint, controlling for baseline (effectively a covari-
ance analysis or a test of difference scores), revealed a mean difference in ADAS-cog
between groups at endpoint of 5.6 points, markedly greater than the reported effect of
pharmacological or nonpharmacological interventions. It is further compelling that
relative to baseline, all patients in the active TMS-CR group showed an improvement
(either immediately after the intervention or within 1 month), while none of the
patients in the sham group showed improvement.
The few trials conducted to date reveal positive effects and provide initial evi-
dence on the potential of noninvasive brain stimulation for cognitive enhancement
in AD. However, these studies have not been replicated and the evidence remains
preliminary. While the initial target in patients with mild cognitive impairment
and mild AD should be to halt the progression of the disease, cognitive enhancement
strategies in moderate to severe AD should target multiple cognitive domains in
conjunction with cognitive training in order to achieve a clinically meaningful effect.

Further systematically designed, sham-controlled trials will establish whether non-
invasive brain stimulation might prove an effective cognitive-enhancing strategy for
this implacable disease.
5 CONCLUSION
The brain changes across the lifespan. First, growing evidence demonstrates that the
brain undergoes a complex array of neuroanatomical and neurophysiological modifi-
cations from birth till death, so that concepts such as “development” and “senescence”
have become increasingly arbitrary in their definition. Instead, the lifespan and the ag-
ing process itself might be best viewed as a “lifelong developmental process,” which is
thought to constitute the underpinnings of shifts in cognition and behavior throughout
each individual’s life. Second, along with changes in brain structure and function, the
mechanisms by which structure and function can be modified (the mechanisms of
brain plasticity themselves) appear to also change over the lifespan. This developmen-
tal process is very well controlled by the processes described in the preceding text in-
cluding LTP, LTD, and homeostatic and metaplastic control of these processes. Over
the course of development, the brain goes through critical periods where a specific re-
gion of cortex has heightened or exclusive capacity for plasticity.
This chapter highlights the importance of brain plasticity throughout the lifespan
for optimal brain health. In health, local cortical and network plasticity might keep a
fine-tuned balance, which optimizes functionality (Pascual-Leone et al., 2011). Such a
“lifelong dynamic, plastically changing brain” poses several challenges, including the
definition of a functionally “normal” brain at a given point in time in a given individ-
ual. A functionally “normal” brain is a changing brain, a brain whose capacity and
mechanisms of change are shifting appropriately from one time point in life to another.
We have also highlighted how pathology of brain plasticity may underlie a num-
ber of neuropsychological disorders across the lifespan. ASD and schizophrenia may
represent two sides of the same coin with the symptoms of ASD potentially stem-
ming from uncontrolled excitatory plasticity and an overall potentiated cortex and
symptoms of schizophrenia stemming from a lack of excitatory plasticity. At the
other end of the lifespan, in late adulthood, maintaining the capacity for plastic
change may be critical for avoiding age-related cognitive decline with dementia
and AD representing an inability for plastic change.
If, as we propose, these diseases and disorders stem from aberrant plasticity
mechanisms, then modulating such systems using TMS may represent a novel alter-
native to drug treatments. Pilot studies suggest promise for the treatment of ASD,
schizophrenia, and AD using specific rTMS protocols. As of now, these treatments
should be considered highly experimental and in need for further replication in
properly powered and controlled trials. However, they offer valuable proof-of-
principle support for the concept of harnessing and guiding brain plasticity for
neurotherapeutics.
References 111
The future of translational neuroscience with the ultimate goal of understanding

the mechanisms driving brain health and disease and developing therapeutic inter-
ventions that optimally treat brain diseases depends on our ability to (1) understand
the mechanisms of plasticity across the lifespan and how they are optimized in neu-
rologically healthy individuals, (2) identify how dysfunction in these mechanisms
can account for the clinical phenotype of neuropsychological diseases across the life-
span, and finally (3) further develop approaches and tools to (ideally noninvasively)
treat disorders of brain plasticity. If one assumes that abnormalities in plasticity pre-
date any structural or functional brain alterations or any behavioral symptom, then
therapeutic approaches to normalize brain plasticity may reduce or prevent the an-
atomical and functional brain pathology underlying these disorders and in doing so
prevent the clinical manifestation of the disease.
Acknowledgments
Dr. Pascual-Leone serves on the scientific advisory boards for Nexstim, Neuronix, Starlab Neu-
roscience, Neuroelectrics, and NeoSync and is listed as an inventor on several issued and pend-
ing patents on the real-time integration of transcranial magnetic stimulation (TMS) with
electroencephalography (EEG) and magnetic resonance imaging (MRI). Work on this study
was supported by a grant from the National Institutes of Health—Harvard Clinical and Trans-
lational Science Center/Harvard Catalyst (UL1 RR025758), and the Sidney Baer Foundation.
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CHAPTER
What does It take to Show

that a Cognitive Training
Procedure is Useful?
A Critical Evaluation
5
Nori Jacoby*,{,1, Merav Ahissar{
*
Interdisciplinary Center for Neural Computation, The Hebrew University, Jerusalem, Israel
{
Music Department, Bar Ilan University, Ramat Gan, Israel
{
ELSC Center for Brain Research and the Department of Psychology, The Hebrew University,
Jerusalem, Israel
1
Corresponding author: Tel.: þ972-548132872; Fax: þ972-25881159,
e-mail address: nori.jacoby@alice.nc.huji.ac.il
Abstract
Individuals substantially improve with training, indicating that a large degree of plasticity
is retained across ages. In the past 20 years, many studies explored the ability to boost
cognitive skills (reasoning, linguistic abilities, working memory, and attention) by training
with other tasks that exploit limited cognitive resources. Indeed, individuals with long-term
training on challenging skills (musicians and action video gamers) show impressive behav-
ior on related tasks (linguistic and visual attention, respectively). However, a critical eval-
uation of training studies that last weeks to months shows typically mild effects, mainly
with respect to control groups that either did not practice or practiced with less challenging,
rewarding, or exciting conditions. These findings suggest that future training studies should
evaluate these factors carefully and assess whether they mainly impact the testing sessions
or actual longer-term skills, and whether their impact can be further strengthened. The lack
of a comprehensive theory of learning that integrates cognitive, motivational, and alertness
aspects poses a bottleneck to improving current training procedures.
Keywords
perceptual learning, working memory, musical education, cognitive training, generalization,
action video games, positive affect

121
122 CHAPTER 5 A Critical Evaluation
The potential promise in adult training is exciting. Yet, in spite of impressive evi-
dence for behavioral improvement and for neural plasticity, our understanding of
the underlying mechanisms and of the relations between training procedures and
their outcomes is extremely limited. Particularly challenging is the extent of transfer
from trained to untrained tasks and contexts. Most theories of perceptual learning
(e.g., Dosher and Lu, 2007; Seitz and Watanabe, 2005) address specific experimental
contexts and hence do not have comprehensive predictions regarding tasks or pro-
cedures that are expected to increase generalization. An exception is Reverse hier-
archy theory (RHT; though see also a recent version of a theory by Dosher et al.,
2013) that addresses the relations between training procedures and their expected
outcomes (Ahissar and Hochstein, 2004; Ahissar et al., 2009; Hochstein and
Ahissar, 2002). However, RHT’s predictions are also quite limited, since it assumes
a comprehensive understanding of the nature of hierarchical representations of stim-
uli, which we still largely lack (Ahissar, 2001). Additionally, it does not integrate
motivational, alertness, and related factors, whose impact is probably substantial
and perhaps also interacts with the training procedure.
Understanding these general factors, which relate to the state of the participant
while performing the task, is important for the formation of a systematic conceptu-
alization of the anticipated gains. These factors include time of day (May and Hasher,
1998), general emotional state (Isen, 2008), motivation and alertness (Boot et al.,
2013; Duckworth et al., 2011; Langer et al., 2010), training duration (Censor
et al., 2006), limits on response duration (Green et al., 2010), and intervals between
training sessions and sleep (Censor et al., 2006; Karni et al., 1994; Korman et al.,
2007; Stickgold, 2005; Stickgold et al., 2000). The effect of these parameters may
be larger than that of the systematically studied parameters, as we shall show in this
chapter.
Given our limited theoretical understanding of the comprehensive learning
experience, the aim of this chapter is to define operative guidelines for evaluating
the success of past and future training studies, with respect to their goals. Based
on our review, we propose further directions for future studies. An important
distinction, which was typically ignored in previous studies, is the difference be-
tween clinical and theoretical goals. Typically, the design of a given study cannot
optimize both. For example, if a procedure improves the performance of a popu-
lation on a poorly performed range of tasks, it may be a successful rehabilitation
procedure even if the mechanisms are not understood, and their control was very
crude. However, well-controlled studies that yield a very small improvement com-
pared with careful controls may have a theoretical impact but perhaps no
immediate application. The two goals are closely related in longer-term develop-
ment, where improving training procedures would gain immensely if their
underlying mechanisms would be understood. Defining priorities when designing
the studies would facilitate our understanding and hence our long-term ability to
improve training protocols.
1 What is a Good Control? 123
1 WHAT IS A GOOD CONTROL?

Finding the cause of a training-induced difference between groups is
almost impossible, since training protocols differ in more than one
parameter
1.1 Single-Arm Studies
The main drawback of having only one training group with no control and simply
comparing pre- and post-training performance (e.g., Banai and Ahissar, 2010;
Gibson et al., 2011; Holmes et al., 2010; Kronenberger et al., 2011; McArthur,
2007; McNab and Klingberg, 2007; Mezzacappa and Buckner, 2010) is that signif-
icant differences may reflect the improvement due to prior experience in the pretest
itself. Individuals who perform a task for a second time, typically (e.g., Cane and
Heim, 1950; Windle, 1954, for a review of the experimental implications see
Campbell et al., 1963), though not ubiquitously (e.g., Lemay et al., 2004), perform
better, particularly when retested with the very same items. An improvement may be
found even when participants are unaware of this repetition, as reported already by
Kolers (1976), where participants trained on reading inverted script were faster read-
ing the pages they were trained with compared with novel pages, even when tested
more than a year after being trained. Indeed, the scores in standard tests may improve
in a retest even if the interval between tests is large (Matarazzo et al., 1980). Still, if
test–retest effects for the tested interval are normed and improvement in the trained
group is clearly larger than these norms, a comparison group is not crucial for attrib-
uting some benefit to the training procedure itself.
1.2 Within-Group Control

Another alternative for a control group is a within-group control. This is the prevail-
ing concept in perceptual learning studies. In these studies, one group is trained with
a given set of parameters and tested with a different set of parameters that are pre-
sumably as difficult as the trained ones (e.g., Ahissar and Hochstein, 1993, 1997;
Cohen et al., 2013; Dosher and Lu, 1998, 1999; Karni and Sagi, 1991; Lu et al.,
2000; Polat and Sagi, 1994; Polat et al., 2004; Tsushima et al., 2008; Watanabe
et al., 2002). If performance is worse in the untrained conditions, then learning is
shown to be specific along the tested dimension. However if performance transfers
to novel conditions, one cannot delineate the limits of learning. Therefore, this ap-
proach was used in studies aimed at showing specificity and was not adopted in stud-
ies aimed to show generalization. However, if learning leads to a complex pattern of
specificities and transfer, then rehabilitation studies could also use within-group
comparisons, testing a well-designed series of tasks. For example, evaluation of gen-
eralization of training with a specific working memory task to generally enhanced
working memory skills can be obtained by testing (post-training) the trained working
memory task with completely novel stimuli, and by administering novel working
memory tasks. If there is improvement in the untrained task (i.e., scores are similar
to those attained on the trained one), the sources of this transfer would indeed be hard
to tap. Yet, most learning is quite specific to the combination of trained task and stim-
uli (e.g., Ahissar and Hochstein, 1993). Thus, the transfer to novel stimuli, with
which participants were not previously tested but whose relative difficulty is
expected to be similar to that of trained ones, is likely to be informative. See for ex-
ample, a recent use of control tasks within the experimental paradigm in Anguera
et al. (2013), which would provide a systematic characterization of the learning pro-
cess. Very few training studies (e.g., Klingberg et al., 2002, 2005; Olesen et al., 2003;
Schmiedek et al., 2010) used this within-group control for showing that transfer at least
encompassed very different stimuli or even very closely related tasks. Even when such a
test battery was used, it mainly served as a collection from which significantly improved
tasks could be pulled out rather than as a systematic characterization of the pattern of
specificity and generalization that the training induced.
In the typical case, particularly when participants’ performance in other tasks is not
systematically characterized and there are no suitable test–retest norms, a control test–
retest group should be added, in order to verify that the training process contributed to the
post-training improvement. If there is indeed a significant difference between the trained
and untrained groups, it means that some training-related improvement occurred, but we
cannot tell what this improvement should be attributed to, as the differences between
groups’ procedures encompass many aspects. Still, if the gains of the trained group
are large and much larger than those of a “no-contact” control, it means that this proce-
dure is useful for applied purposes, even though the intergroup difference may be due to a
very general aspect of practice (e.g., “positive psychology”; see Yang et al., 2013; for a
review, see Isen, 2008). An important aspect, which is difficult to determine, is whether
the potentially general effects underlying group differences reflect a difference in learn-
ing or merely a difference in performance during the testing session itself (for a critical
discussion of these issues, see Boot et al., 2011; Duckworth et al., 2011; Shipstead et al.,
2012). Since the dissociation between short- and long-term effects of general factors is
difficult to determine, one should perhaps equate within-testing factors of “positive psy-
chology” for the two groups. In general, the main limit of having a no-contact control is
that we cannot tell how to improve the training procedure. However, if the intergroup
effects are large, namely, the protocol as a whole was effective, a useful continuation
could be to determine the mechanisms that underlie the intergroup difference. For
example, it would be useful to know whether this improvement could have been obtained
without any training at all, for example, by encouraging the tested participants. Indeed,
a recent meta-analysis found that studies with greater incentive yield significantly
(0.6 standard deviations) larger scores in intelligence tests, previously considered
to robustly reflect individual cognitive abilities (Duckworth et al., 2011).
1.3 Active Control Group

A more informative control group is a group that actually goes through some alternative
training procedure, termed “active control” (e.g., Colom et al., 2010; Dahlin, 2011;
Holmes et al., 2009; Jaeggi et al., 2011; Klingberg et al., 2002, 2005; Richmond et al.,
1 What is a Good Control? 125
2011; Shavelson et al., 2008; Thorell et al., 2009; Van der Molen et al., 2010; Zhao et al.,
2011; for a review see Shipstead et al., 2012). But what should an active control group
train with? In the case of working memory training, a common solution is an active con-
trol group that is trained with an easy, fixed-stimuli task, whereas the test group is trained
with an adaptive, challenging working memory task. However, when post-training per-
formance differs between the trained groups (e.g., Jaeggi et al., 2008; Klingberg et al.,
2002, 2005), it is not clear what such improvement should be attributed to. Does it stem
from training a working memory task? Would one get similar gains if paid for successful
performance instead of training? Would one get similar gains in any challenging task?
Perhaps the participants trained with a nonadaptive procedure perform worse because
they are bored and have lost interest. In this type of control, the potentially crucial role
of motivation, excitement, and challenges that differ between the two training protocols
is overlooked when inter group differences in the outcomes are specifically attributed
to training with a working memory task. Again, one should note that here too, group
differences in the testing session may be related to the different levels of anticipation
(how well do we expect to perform) of the two tested groups. Such differences may
affect performance, even in perceptual tasks. For example, by affecting the “mind
setting” of tested individuals, so that they expect to perform better, participants actually
perform better, even in visual acuity tasks, considered a robust measure of the visual sys-
tem (Langer et al., 2010).
1.4 Active Control Equated for Difficulty

An active control whose training procedure is aimed at equating the levels of chal-
lenge and engagement (and perhaps anticipation for success) of the trained groups
was administered in a novel study of working memory training (Redick et al.,
2013). In this case, the control group was trained with a different task (visual search),
with no working memory component and with different stimuli. However, the
trained task was challenging and engaging. Under these conditions, there was no
group difference in post-training working memory or intelligence scores, suggesting
that working memory was not the important factor in training. Interestingly, the post-
training scores of the actively trained groups did not differ from a third, no-contact
control group. Namely, in this study, there was no general effect either. Given that in
this group, participants did not expect to benefit from the training procedure (based
on this groups’ previous criticism of the benefit of these training studies; Shipstead
et al., 2012), this null result implies the potential impact of the researchers’ and hence
participants’ anticipations. This aspect is difficult to avoid, and it underlies the rea-
soning of double-blind procedures. Yet, double-blind procedures do not apply when
different behavioral procedures are administered. Given that “mind setting” and
“positive psychology” (Yang et al., 2013) were shown to affect performance on
the tasks that most procedures aim to improve, it is of importance that at least the
experimenter who performs the tests will not be aware of the training procedure
assigned to the specific participant.
Finally, from a clinical perspective, when a new rehabilitation-aimed training
procedure is proposed, the most informative control is the standard of care or the best
current treatment or training procedure. For example, if there is a protocol known to

have some benefit (e.g., phonological training for reading disability), an assessment
of a novel procedure should be conducted with respect to this protocol. This type of
comparison had been conducted only to a limited degree (e.g., when training for lan-
guage impairments; e.g., see Hook et al., 2001). However, from a purely scientific
perspective, taking an existing procedure may be informative only to a limited extent
since different training procedures typically differ on how they are technically ad-
ministered (e.g., groups vs. one on one and in person vs. computer games) and in
the amount of challenge and excitement they pose (e.g., video games vs. sentence
repetition; for a review and discussion of social conditioning effects in the context
of video games, see Boot et al. (2011)). These parameters may have a larger impact
on the training gains compared with those that uniquely characterize the hypothesis
underlying the novel protocol, and therefore, differences in the impact of two differ-
ent procedures do not necessarily stem from a difference in the validity of their
underlying hypotheses.
2 INTERPRETING CORRELATIONS IN GAINS

Performance gains in initially correlated tasks are expected to be
correlated even with no transfer
The typical motivation of training studies aimed at boosting cognitive skills is to show
that an improvement in one task (the trained task) results in an improvement in the
other (the “transfer” task). In this context, it seems natural to examine whether the gain
in the trained task (performance in the posttest minus the performance in the pretest) is
correlated with the gain in the transfer task/s and interpret such a correlation as reflect-
ing a transfer effect. Indeed, several studies used such a correlation as evidence sup-
porting transfer between tasks (e.g., Anguera et al., 2013; Banai and Ahissar, 2009;
Chein and Morrison, 2010; Green and Bavelier, 2003; Jaeggi et al., 2011;
Schmiedek et al., 2010). However, a significant correlation between gains in the
trained and untrained tasks can be obtained without any transfer. For example, if
pre-training scores are initially positively correlated, but the post-training scores are
completely independent from pre-training scores and also uncorrelated, then a simple
calculation (based on the mathematical fact that the pre-training correlation contributes
to the overall correlation in gains) shows that gains are positively correlated,
even when scores in the pre- and post-training sessions were independent (i.e. in a
simulation—chosen from independent Gaussian distributions of pre- and post-training
scores). Therefore, correlations in “gains” (differences between pre- and post-training
performance) per se cannot be used as evidence for transfer.
When two tasks are initially correlated and only one task is trained so that its
performance is consequently improved, we expect that individuals who improve
to a greater extent on the trained task will be individuals with lower pre-training
scores and higher post-training scores on the trained task (selection bias). Due to
2 Interpreting Correlations in Gains 127
the pre-training correlation between the trained and untrained tasks, these individuals
will tend to have lower pre-training scores also in the untrained task. If following
training, performance is similar for the selected (higher training gain) and unselected
(lower training gain) individuals then the calculated gain of the selected individuals
will be larger due to this selection bias even when there is no transfer. Such a bias can
account for the transfer, that is, correlation in gains, reported in Jaeggi et al. (2011).
Jaeggi et al. (2011) trained two groups of third graders, one (N=32) on general
knowledge and vocabulary (“active control”) and the other (N=32) on a spatial work-
ing memory task. This initial study had null results. Namely, the two groups did not
differ in their general intelligence scores, either before or after training, suggesting
no transfer. However, rather than acknowledging null results, Jaeggi et al. (2011)
divided the group trained on the working memory task into two subgroups (median
split), with high and low gains in working memory, respectively. They found that the
subgroup that had larger working memory gains also had larger intelligence gains.
The main basis for the “transfer” claim is that individuals who had larger gains in the
trained task had larger “gains” in the transfer tasks (e.g., standard tasks for measuring
intelligence). Yet the group of individuals who had larger gains in the trained task did
not have higher post-training scores in the untrained intelligence tasks. In this study,
the reported correlation could be fully accounted for quantitatively without assuming
any transfer of learning, that is, solely on the basis of biased statistics (see for details
Jacoby and Ahissar, submitted).
The same concept of correlation in gains as supporting evidence for transfer is
used in many other training studies. For example, Chein and Morrison (2010)
claimed “a strong and statistically significant relationship between enhancement
of trained participants’ spatial complex working memory span and their improve-
ment in reading comprehension [r=.49, p<0.005].” Similarly, in an attempt to sup-
port a transfer effect between working memory and fluid intelligence in children with
ADHD, Klingberg et al. (2002) claimed that “the association between the reasoning
task and the working memory tasks is further substantiated by the significant corre-
lation between improvement on the visuo-spatial working memory task and im-
provement on Raven’s progressive matrices” (p. 789). Schmiedek et al. (2010)
reported a significant correlation between latent trained factors of episodic memory
and untrained ones and used it as supportive evidence for transfer effect. Banai and
Ahissar (2009) observed a marginally significant correlation between improvement
in a perceptual task (two-tone discrimination) and working memory (Spearman rho
0.59, p¼0.07) and interpreted it as “support (for) the suggestion that the improve-
ment in working memory scores is specifically related to the 2-tone discrimination
training.” Green and Bavelier (2003) used the correlation between improvements in
game scores and improvements in attentional skills as support for a transfer claim.
Most recently, Anguera et al. (2013) trained elderly individuals with a dual-task con-
dition of an action video game and used the correlation between improvement in this
trained condition (“multitasking”) and working memory gains to support the claim of
transfer from training multitasking in action video games to enhanced working mem-
ory capacity (see Anguera et al., 2013 figure 3d on page 99).
In summary, the intuitive interpretation of correlation in gains is misleading and

statically erroneous. In order to show transfer when studies choose to train one task
chosen from a set of correlated tasks, studies should do one of the following analyses
suggested below.
The first is to show that the experimental group had larger gains, namely, a sig-
nificant interaction on a repeated-measure ANOVA (with session as within subject
factor and group as between subject factor) using F-statistics. We emphasize that di-
vision to groups should not be based on post hoc criteria. This procedure asserts that a
real and significant effect occurred and that the training group improved more than
the control group. If this effect is large, it also has a significant practical value. Some
papers used a non repeated t-test for comparing the gain scores (post minus pre) be-
tween groups. This is in fact the same procedure, as the t-score here is the square root
of the F-test score of the repeated-measure ANOVA group session interaction
(Knapp and Schafer, 2009). An example for significant interaction using ANOVA
can be found in Anguera et al. (2013). Note, however, that their results are only sig-
nificant when both the no-contact and active control groups were used in order to
compute the interaction.
Another similar approach is to use analysis of covariance, with posttest as
dependent variable and pretest as covariate. This method uses the same data as
the first method, and in fact, it is possible to transform the test score of one into
that of the other (Knapp and Schafer, 2009). Even though these two methods
are not identical, as it is possible that only one of the tests would be significant
(Lord, 1967), in most practical scenarios, they are expected to produce comparable
results. For example, Anguera et al. (2013) used both methods and obtained very
similar results.
The third alternative is to account for the bias that the correlation structure im-
plies when computing the gains’ correlations. Namely, show that the obtained effect
is larger than that expected due to the biases that are induced by the implicit corre-
lations (see Jacoby and Ahissar, submitted). In any event, studies should supply the
full correlation matrix (which should include all relevant pretests and postests) to
enable an evaluation of the dependencies before and after the training process. This
matrix is typically not provided.
3 WHAT DO STUDIES OF “NEURAL CORRELATES” TELL US?

For clinical purposes, behavioral changes are the only ones
that validate success
Recent advances in imaging brought many novelties to brain research. In principle,
imaging studies can be informative with respect to the nature of neural modifications
that underlie behavioral improvement and as such provide important insights.
However, not all imaging studies provide insights regarding the mechanisms under-
lying behavioral improvement, even though almost all studies are interpreted as if
3 What do Studies of “Neural Correlates” Tell Us? 129
they do. Moreover, changes in brain responses are often interpreted as reflecting
“real” changes compared with behavior-only experiments, even when behavioral
modifications are the real goal of the study.
Many studies assessing the neural correlates of behavioral improvement only
show that known brain correlates of performance indeed change when performance
changes. For example, several studies (e.g., Anguera et al., 2013; François et al.,
2012; Moreno et al., 2009) showed that when behavior improves following training,
ERP components, known to correlate with performance and measured while partic-
ipants perform the task, are increased. A recent example is Anguera et al. (2013) who
trained older adults with a lab-version dual-task condition of an action video game.
They showed that age-related EEG activity (midline–frontal theta power and frontal–
posterior theta coherence) was increased after training. However, the EEG was mea-
sured on a task that is almost identical to the trained task. They did not show this
enhanced EEG activity on a different multitasking activity. For the purpose of reha-
bilitation, the important aspect is the ability to improve age-related neural mecha-
nisms in general. However, in the Anguera et al. study, the other condition that
was used for measuring multitasking—a novel dual-task paradigm—was not signif-
icantly improved in the group trained with the dual-task compared with controls
trained with one task at a time.
Another example that demonstrates this issue is the study by François et al.
(2012), who characterized the effects of music training in children that practiced mu-
sic for 2 years starting from the age of 8 years old. They showed significant changes
in performance in speech segmentation compared with a control group that practiced
painting. Following training, they also showed increased activation of frontal elec-
trodes at 450–550 ms post-stimulus onset, when performing this task. In their previ-
ous work, Francois and Schön (2011) associated this component with N400-like
component, known to be correlated with linguistic skills (Elger et al., 1997). Thus,
the observation that improved behavior is coupled with an increase in the expected
ERP component is reassuring, but does not point to any specific underlying mecha-
nism. Such observations would be more revealing regarding underlying mechanisms
if there were several known ways to attain better performance, accompanied by
different brain correlates, or if the same known brain correlate were shown to
increase in untrained conditions.
A different type of overinterpretation of imaging and ERP studies stems from
their greater susceptibility to posterior statistics and hence to spurious significant
effects, because they typically involve many more measures (voxel clusters, voxel
combinations, ERP electrodes, or electrode combinations) compared with behavioral
studies. An extreme example of this case is a recent study by Neville et al. (2013),
who administered a family-based training program designed to improve “brain sys-
tems for selective attention” in preschool children of lower socioeconomic status. A
main claim for the success of the program to boost cognitive measures compared
with an active control group was the group-specific change in ERP indices used
for assessing selective attention. Neville et al. used a selective auditory attention
paradigm and measured ERP with 29 electrodes. This myriad of electrodes allows for
many post hoc selections for analysis. In this study, the choice of electrodes for an-
alyses made the difference. Neville’s group used this ERP index in a series of pre-
vious studies. In all these studies (Coch et al., 2005; Sanders et al., 2006; Stevens
et al., 2008, 2009, 2013), they showed that the anterior and medial electrodes convey
this component, and therefore, they discarded posterior electrodes. But in Neville
et al. (2013), the experimental group showed no modifications in anterior electrodes.
Based on previous analyses, this means a null ERP result. However, these partici-
pants showed changes in posterior electrodes, and Neville et al. conducted an ante-
rior–posterior ANOVA analysis, in which the experimental group “showed a
significant increase in this response (time, P <0.05) that was largest at posterior
recording sites.”
4 HOW LARGE ARE THE MAGNITUDES OF GAINS

IN UNTRAINED CONDITIONS?
For clinical purposes, training-induced gains should be large with
respect to the amount of time dedicated to training
Assuming that transfer to untrained desired tasks is significant, a further question
is whether the amount of improvement is substantial with respect to the initial im-
pairment or with respect to the amount of time dedicated to the training process.
In the case of improving working memory, the typically reported gains are in the
range reported in studies that do not apply training, but administer positive priming
cues or other incentives. In these studies, it was shown that individuals who had
greater incentives had higher performance than those with reduced incentives.
The magnitude of these effects, as evaluated in the meta-analysis by Duckworth
et al. (2011), is about 0.64 standard deviations. For example, Yang et al. (2013) used
a priming paradigm (positive affect) where subjects were given an unexpected gift
consisting of a small bag containing hard candies and then tested on cognitive tasks.
They reported medium to large effects of the positive affect on their subjects’ per-
formance: the effect sizes were 0.58, 1.06, and 1.03 standard deviations for remote
associate, and two different measures of working memory.
In training studies, typical effect sizes are also in the range of 0.5–1 standard
deviations, when positive transfer is reported. For example, Klingberg et al.
(2005) trained 53 children with ADHD, either with an adaptive working memory
program or with a nonadaptive version. They found a small–medium difference be-
tween the groups’ gains following training. For example, the size of the transfer
effects (Cohen’s d) for digit span, response time in Stroop paradigm, and Raven’s
task (measuring fluid intelligence) was 0.59, 0.34, and 0.45, respectively. In addi-
tion, they measured these tests on a follow-up session. The results showed that
these effects were mostly retained, though slightly decreased (0.57, 0.25, and
0.30 for digit span, Stroop, and Raven’s task, respectively). These effects are within
4 How Large are the Magnitudes of Gains in Untrained Conditions? 131
the range of social conditioning and positive priming (see Boot et al., 2011). Jaeggi
et al. (2008) trained 70 young students: 35 completed a working memory training
program of 8–19 days and the other participants composed a no-contact control
group. The trained group improved their intelligence scores (Cohen’s d ¼ 0.65)
more than the control group (Cohen’s d ¼ 0.25). Lilienthal (2013) studied 52 stu-
dents who either trained with an adaptive n-back working memory task or trained
with a nonadaptive task or were only tested with a similar inter-test interval. They
found that participants in the adaptive training group also showed improvement on
a span task, which measures the capacity of the focus of attention. The effect sizes
computed from their reported data was 0.17, 0.06, and 0.86 for the no-contact,
nonadaptive, and adaptive groups, respectively. Other studies that conducted
similar training procedures (e.g., Boot et al., 2008; Owen et al., 2010; Redick
et al., 2013) did not find any transfer and naturally found only a small or very small
effect size (0–0.5).
Other studies trained participants on action video games and measured their
subsequent performance on a range of tasks, often measuring the efficiency of
spatial attention. This training was motivated by the observation that avid players
of action video games, who have thousands of hours of experience, show substantial
advantages compared with nonplayers in a range of tasks of visual attention, parti-
cularly those that require fast responses to briefly presented stimuli (Achtman et al.,
2008; Castel et al., 2005; Chisholm et al., 2010; Dye et al., 2009a,b; Green and
Bavelier, 2006a,b, 2007, 2008; Hubert-Wallander et al., 2011; Hubert-Wallander
et al., 2011; Li et al., 2009, 2010, 2011; Mishra et al., 2011). For example, Green
and Bavelier (2006b) trained individuals who do not play action video games on
either an action video game or on a control game (Tetris). They showed that training
facilitates the processing of multiple objects in a multiple-object-tracking task.
The effect sizes (calculated from their figures) were high—d ¼ 1.01 and d ¼ 1.39—
compared with the control d ¼ 0.25 and d ¼ 0.01 for tracking four and six objects,
respectively. Li et al. (2010) trained nonaction video players intensively (50 h over
9 weeks) and found reduced lateral masking with intervals of 60 and 90 ms, with effect
sizes (calculated from their figures) of d ¼ 0.77 and d ¼ 0.80, respectively. There
was almost no effect in the control group, who trained on a nonaction video game
(The Sims 2). The same group (Li et al., 2009) also trained nongamers with action
video games and showed that contrast sensitivity, which is routinely assessed in clin-
ical evaluations of vision, had improved (d ¼ 1.08 for frequency of 6 cycles/deg)
compared with a much smaller improvement (d ¼ 0.17) in a control group that trained
with a nonaction video game (The Sims 2). A recent study (Anguera et al., 2013)
trained elderly individuals on a dual-task condition of a video game (NeuroRacer
game). The effect sizes of delayed-recognition working memory task and test of
variables of attention was 0.98 and 0.89, respectively, compared to the no-contact
group. An additional group trained in a very similar task but did not have a multitasking
component. The effect size compared with this group was medium (0.67 and 0.46 to
the two earlier-mentioned tasks, respectively). However, this effect was obtained for
two tasks of a larger testing battery. One of the additional tasks was another dual-task
paradigm for which no significant improvement was found in the main group com-
pared with the other groups.
Though these effect sizes are not small, they would probably not be statistically
resilient to corrections for the total number of tasks assessed. Moreover, other groups
who trained participants on similar action video games did not obtain transfer to
other cognitive tasks (e.g., Boot et al., 2008; Lee et al., 2012). These differences
might stem from the use of slightly different experimental (e.g., the duration and
color of the masking stimulus in the functional field of view task) and recruitment
strategies. This suggests that here too, even though control groups also trained with
challenging games, the effects depend on additional components, whose nature
should be further studied. In another study, Boot et al. (2013) measured the expec-
tations of subjects (N ¼ 200) who watched videos of either an action video game or a
control game (Tetris or The Sims). They were then asked if they think that training
for many hours with the video games presented would improve their performance on
a list of other cognitive tasks that were also presented with detailed explanations and
videos. Their results show surprisingly high agreement between subjects’ expecta-
tion and the extent of transfer reported in the literature (Green and Bavelier,
2012). These results suggest that indirect effects, such as subject’s expectation,
may be crucial for the replication of training effects.
A somewhat similar case is that of musical education. Most people who study
music do so for pleasure rather than as a means for attaining other skills, just as
is the case for avid players of action video games. Yet, expert musicians were
reported to have enhanced verbal and phonological skills (Anvari et al., 2002;
Besson et al., 2007; Butzlaff, 2000; Forgeard et al., 2008; François et al., 2012;
Moreno et al., 2009) and higher intelligence (Lynn et al., 1989; Schellenberg,
2004, 2006). Although these may reflect a selection bias for people playing music,
an exciting hypothesis is that their musical education contributed to their linguistic
skills (Kraus and Chandrasekaran, 2010) or intelligence (Schellenberg, 2006).
The causal relations between training and enhanced performance were studied in
several longitudinal studies (Costa-Giomi, 1999; Flohr, 1981; Forgeard et al., 2008;
François et al., 2012; Hurwitz et al., 1975; Hyde et al., 2009; Moreno et al., 2009;
Morrongiello and Roes, 1990; Schellenberg, 2004; Thompson et al., 2004). Most
training studies reported significant improvements after medium (few months) to
long (about 2 years) trainings. For example, Schellenberg (2004) reported a small
to medium effect of increased IQ, which was significantly more prominent in
6-year-old children taking music lessons (for children that received keyboard and
voice music lessons, the effect sizes were 0.69 and 0.70, respectively), compared
with control groups that studied drama (d ¼ 0.37) or did not participate in any special
training program (d ¼ 0.40). François et al. (2012) studied the effect of music training
in children that practiced music starting at the age 8 years old. They showed signif-
icant improvement in speech segmentation in children practicing music, compared
with a control group that practiced painting; the effect size of the improvement in the
music group compared with the painting was around 1 both for 1 and 2 years of
5 Conclusions and Future Directions 133
training. However, Rickard et al. (2012) reported results with two large studies
(N ¼ 127 and N ¼ 100 children) with school-based music instruction that did not
show a cognitive enhancement. In a correlation study that we conducted (Banai
and Ahissar, 2013) among third-grade children, we found that auditory thresholds
were more correlated with verbal memory among children that were not musically
trained. Among children with about 1 year of musical education, only auditory
thresholds were better than those expected when intelligence was statistically con-
trolled for, whereas higher verbal memory scores could be accounted for by higher
general intelligence scores. Thompson et al. (2004) showed that music keyboard les-
sons do not enhance performance in identifying emotional content of semantically
neutral speech more than control (drama lessons) even after a year of training. These
mixed results leave the question of the impact of musical education (1–2 years) on
linguistic skills largely open. The effect sizes on tasks that are not closely related to
those directly trained are small. For example, in a meta-analysis of over 30 music
intervention studies by Standley (2008), the average effect size on reading skills
was small (d ¼ 0.32).
In a recent study (Hai, Granot, and Ahissar, submitted), we asked whether adult
musicians (24 years old), who had prolonged and intensive musical training, may
still have language and reading difficulties. We found that there are indeed poor
readers among musicians. Their performance in auditory, sensory, and sensorimotor
(tapping) tasks was as good as that of their musician peers and superior to that of their
nonmusician peers. But their working memory abilities were impaired compared with
their musician peers. Overall, dyslexia seems milder among musicians. Still, these
findings indicate that musical education was not sufficient for enhancing their working
memory skills to an extent that they would no longer pose a bottleneck to reading.
In summary, the evidences from working memory, action video games, and mu-
sic training are quite similar. Relatively short periods of targeted training do not pro-
vide a substantial widespread cognitive enhancement. The magnitude of these effects
is typically in the range of positive priming and enhanced motivation, implying that
the sources underlying the transfer effects should be further studied.
5 CONCLUSIONS AND FUTURE DIRECTIONS

Individuals who practice a given task show substantial improvement. This is a very
consistent observation across tasks and across populations, which provides a clear
indication of adults’ brain plasticity, as further shown in brain changes observed
in imaging studies. However, the extent of generalization to novel tasks is typically
limited, and the means for enhancing generalization are still not understood.
Several studies report mild improvement in general intelligence scores, working
memory, or attentional tasks following training. But the larger and more consistent
effects are those compared with no training (e.g., Anguera et al., 2013; Jaeggi et al.,
2008) or training with less demanding tasks (Jaeggi et al., 2011; Klingberg et al.,
2002, 2005) or perhaps less active ones (e.g., Franceschini et al., 2013; Green and
Bavelier, 2003, 2008, 2012). This pattern suggests that perhaps, the more important
aspect for generalization resides in participants’ and perhaps experimenters’ emo-
tional state (such as motivation, arousal, and reward) rather than in the specific
choice of cognitive tasks in these studies. An interesting question is whether these
emotional effects interact with cognitive states. In order to examine these intricate
questions systematically, we must add to the relevant test dimensions the emotional
and social aspects (including accurate measures of engagement and challenge) and
systematically evaluate their contribution.
Another important yet unresolved question is that of the target population. Reha-
bilitation is typically oriented toward individuals with specific impairments, compared
with the general population. But we still do not know whether individuals with specific
deficits are more or less likely to gain from training and whether similar training pro-
cedures are likely to be useful to different populations. Here too, we lack a theoretical
account for addressing this question. On the one hand, the dynamic range that may be
relevant for individuals with specific difficulties is perhaps larger. In the general pop-
ulation, it is often the case that individuals who start with poorer performance improve
more than others (e.g., see Duckworth et al., 2011). On the other hand, individuals who
did not gain sufficiently with “ecological” training conditions are perhaps more resil-
ient to practice, as suggested by the phenomenon of dyslexic musicians (Hai, Granot,
and Ahissar, submitted). For example, Oganian and Ahissar (2012) compared auditory
and reading skills of adequate readers and dyslexics with and without musical educa-
tion. They found that among adequate readers, auditory and reading skills were higher
in individuals with musical training. However, among dyslexics, auditory and reading
skills did not differ between individuals with and without formal musical education.
Taken together, the limited success of training studies in attaining generalization
would perhaps be improved when a broader range of factors will be systematically
considered and when the outcome of these studies will be integrated into a compre-
hensive theory that will guide the design of future procedures.
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CHAPTER
Principles of Neuroplasticity-
Based Rehabilitation
*
Mor Nahum*,{, Hyunkyu Lee*, Michael M. Merzenich*,1
6
{
Department of Optometry, University of California, Berkeley, CA, USA
1
Corresponding author: Phone/Fax: þ415-394-3105
e-mail address: mike.merzenich@positscience.com
Abstract
The purpose of this review is to summarize how our perspective about the neuroscience of
brain plasticity, informed by perceptual, experimental, and cognitive psychology, has led to
the designs of a new class of therapeutic tools developed to drive functionally distorted
and damaged brains in corrective directions. How does neuroplasticity science inform us about
optimal therapeutic program designs? How do we apply that science, using modern technol-
ogy, to drive neurological changes that address both the neurobehavioral distortions and the
resulting behavioral deficits that are expressed in specific neurological and psychiatric disor-
ders? By what strategies can we achieve the strongest and most complete rehabilitative cor-
rections? These are questions that we have extensively explored in our efforts to establish new
medical applications of neuroplasticity-based therapeutics. Here, we summarize the state of
this rapidly emerging area of translational neuroscience, beginning with an explanation of
the scientific premises and strategies, then describing their implementation in therapeutic soft-
ware to address two human illnesses: the treatment of social cognition deficits in chronic
schizophrenia and in autism; and the amelioration of age-related functional decline using strat-
egies designed to delay the onset of—and potentially prevent—Alzheimer’s Disease and re-
lated causes of dementia in aging.
Keywords
brain plasticity, social cognition, Alzheimer’s Disease prevention, cognitive training,
therapeutic programs, BrainHQ
1 INTRODUCTION
We begin the chapter with a description of our approach to creating brain
plasticity-based therapeutic tools to treat neurological and psychiatric impairment
attributable to “disease” and brain injury by outlining the principles derived from
141
142 CHAPTER 6 Principles of Neuroplasticity-Based Rehabilitation
the science of neuroplasticity. In Part 2 we build on these principles to describe

how we design training programs to target-specific deficits to address different
clinical indications. Part 3 briefly summarizes our strategies for evaluating a
training program’s usability and efficacy, and the goals established for outcome
trials. Finally, in Part 4 we provide two examples of therapeutic tools: a more
narrowly focused treatment for overcoming social cognition deficits in schizo-
phrenia and autism; and a broader program created to help overcome neurobeha-
vioral decline in aging, and to increase an individual’s resilience against the
possible onset of Alzheimer’s Disease (AD).
2 PART 1: PRINCIPLES OF BRAIN PLASTICITY; PREMISES

FOR THERAPEUTIC TOOL DEVELOPMENT
Before we describe specific design strategies for our development of brain
plasticity-based therapeutic tools, it is important to review our neuroscience-
informed perspective about the neurological origins of behavior, and about the plas-
ticity processes that underlie controlled rehabilitative changes in neurobehavioral
ability.
2.1 Our Behaviors are the Products of Brain Systems

A large body of science has now shown that our expressive behaviors are a product of
complex, multilevel recurrent networks (Edelman, 1987; for further discussion and
review, see Merzenich, 2013). In these networks, information is represented with
greatest resolution in detail in place, feature, and time at the lowest network (system)
levels. At successively higher levels, there is an integration of representation to pro-
gressively more complex objects, relationships and actions, as they apply in the “real
world.” At the “top” of brain systems, those most-completely-integrated neurolog-
ical representations generate enduring neural activity that is selective for their rep-
resentation. That enduring, reverberant activity, providing the neurological basis of
working memory, can be sustained in the human brain for tens of seconds to minutes
of time (see Badderley, 2012; Compte et al, 2003; Goldman Rakic, 1995; Merzenich,
2013). Representational information is continuously fed backward from this highest
(and from all other) levels. It is important to understand that in these recursive re-
current networks, the operational levels contributing to the representation of any as-
pect of input or action in brain systems are inseparable; in other words, all explicit
behaviors are a product of the system. Therefore, when evident behaviors are dis-
torted or impaired, as they are in the many ways that define the fundamental deficits
and nuances of different neurological and psychiatric clinical indications, we neces-
sarily target neurological renormalization at all system levels when designing ther-
apeutic training programs.
It should be noted that cognitive therapists and other rehabilitation specialists
have usually focused exclusively on training explicit, obviously impaired behavioral
2 Part 1: Principles of Brain Plasticity 143
abilities. If an individual has an evident failure in memory, for example, the therapist
most often engages the patient to practice remembering, or to develop compensatory
strategies to help them work around their memory loss. By contrast, from a more
neurological perspective, we focus on improving the many deficits across the
various system levels that contribute to the degradation of the neurological represen-
tation of information that the patient is struggling to record. Going back to the mem-
ory failure example, the focus of neuroplasticity-informed training would be on the
clarity, in neurological terms, with which they represent that information, the sup-
pression of distractors that disrupt remembering, the baseline levels of attention that
support all epochs of remembering (among others), all aimed at improving the dif-
ferent operations of the relevant brain network before reexercising explicit memory
abilities themselves.
2.2 Feedback Connections: Plasticity is Being Controlled

“From the Top”
Recent neuroscience studies have also shown that through recursive reentrant feed-
back, the representation of information “at the top” of our forebrain processing sys-
tems selectively enables plastic changes contributing to the progressive behavioral
success of brain systems. At highest system levels, behavioral targets are held, as
described, via sustained target-specific activities, in working memory. That sus-
tained persistently reverberant activity is projected backward down to “lower” sys-
tem levels, where it positively enables plasticity for any fed-forward activity that
can potentially contribute to a progressively improving resultant. Scientists often
call the opening of this window that controls, through this top-down biasing, what
the brain can change to, a “selective attention” process. In fact, “working memory”
and “selective attention” can be considered as two descriptors of the same persistent
reverberant activity-based representation/feedback process (see Fuster, 2008). The
neurological processes that bias networks that are feeding these highest system
levels to enable system plasticity are now understood, at a first level. Biasing is
achieved, neurologically, by disinhibition processes in cortical networks controlled
by convergent modulation “from the top” on the one hand (the working memory/
selective attention process), and from a cholinergic subcortical input source en-
gaged under conditions of focused attention, the basal nucleus of Meynert (see
Froemke et al., 2007; Sarter et al., 2001, 2006; Weinberger, 2004; Chapter 3),
on the other hand.
Ahissar and Hochstein (Ahissar et al., 2009; Hochstein and Ahissar, 2002) have
described this feedback plasticity-enabling biasing, in psychological science terms,
as the “Reverse Hierarchy Theory” (RHT). According to RHT’s perspective, the
brain holds a model of a behavioral event or training goal in working memory; that
model, fed back to lower system levels, selectively amplifies activities (through dis-
inhibition) that the brain can change to, as it progressively sharpens and refines,
through learning, the resultant - its working memory-sustained models.
Given this new understanding of the neurological processes underlying top-down

control of plasticity, we construct our training tasks with highly salient training tar-
gets held in working memory (Mahncke et al., 2006; Merzenich, 2013; Merzenich
et al., 1998).
2.3 Feed-Forward Connections: Local Response Coordination,

a Primary Product of Plastic Change, is the Principal
Determinant of Feed-Forward (and Feedback) Power
Plasticity is primarily expressed by a change in connectional strength at the synapse
level, achieved both by increasing the powers and the numbers of synapses specif-
ically supporting a progressively improving behavior. Processes that control plastic-
ity strengthen all synapses that are activated together at each brief moment in time
that have contributed to just-past behavioral success. The great principal postulated
by the Canadian psychologist Donald Hebb (1949) applies: “What fires together
wires together.”
Through Hebbian network plasticity, the extensively cross-wired neurons in the
cerebral cortex also strengthen their connections with their nearest neighbors. When
the brain is engaged behaviorally, inputs that are activated nearly simultaneous in
time strengthen together, increasing their cooperativity to generate more salient
(i.e., more powerful and more reliable) responses. That plasticity-driven growth in
local “teamwork” is a critical aspect of the improvement in selective, specialized
processing of information supporting any learning-based advance in behavior (see
Merzenich, 2013; Merzenich and deCharms, 1996; Merzenich and Jenkins, 1993).
A growing neuronal response coordination is the primary determinant of the feed-
forward power of any plastically strengthening cortical process. Cortical neurons at
all “higher” system levels are integrators operating with very short time constants.
Their plasticity processes are also coincident-input dependent. The greater the coor-
dination of neurons in the lower levels of the network that feeds them, the greater
their selective powers and selectivity, and the greater the power of that input to drive
plastic remodeling at higher system levels. Moreover, at the “top” of our great brain
systems, coordination of activity is a primary determinant of the power with which
cortical networks can sustain the reverberant activities that are selective for behav-
ioral targets or goals (i.e., working memory) (see Wang et al., 2004). The strengths of
these key plasticity-gating processes at the top are critically dependent upon the
strengths of the coordinated inputs that feed them.
Given this relatively recent neurological understanding of the basis of plastically
increasing selectivity and reliability on the path to improving neurobehavioral per-
formance in learning, we routinely emphasize stimulus features in tasking in ways
known to drive more strongly correlated local responses within cortical networks.
We also specifically apply training tools designed to grow the powers of coordinated
actions in simple and serial behaviors. Our goal is to rapidly increase the coordinated
representations of the details of all task-relevant stimuli and actions in ways that
broadly generalize to all behaviors arising from targeted brain systems.
2.4 Progressive Changes Achieved Through Small Learning

Steps Enable Ultimately-Large-Scale Change; Substantial
Repetition and Overlap in Training are Requisites for
Achieving Optimal Change Rates
In the post-critical-period brain, the capacity for change, at any system level, is
limited by the spreads of inputs that are fed to that system level (see Chapter 1).
At any moment in time, in any given cortical area, neurons are most-strongly
engaged—dominated in their responses—by a limited subset of specific, most-
effective inputs that represent a small minority of the total input repertoire anatom-
ically projecting to that cortical locus. Under the control of “top-down biasing,” in
attended learning, normally ineffective inputs are disinhibited. By that change, the
cortex can now change the connection strengths of those inputs, so that these alter-
native, formerly sub-rosa inputs can now come to dominate this cortical zone. That
change in neuronal dominance is the essence of brain plasticity. By its nature, this
process imposes limits on the magnitudes of the steps over which learning-driven
change can be achieved. Those learning steps must necessarily be within the limits
of anatomically available input sources; if they are, plasticity that strengthens behav-
iorally important inputs and that weakens noncontributing inputs is achieved.
Notably, changes are only possible if physical (i.e., anatomical) sources of input
can support them.
In practice, in brain systems, because inputs change through the elaboration of
horizontal inputs when changes in inputs that are predominant change, large-
magnitude changes can be commonly achieved if a system is engaged to change
in a series of small steps (Mahncke et al., 2006; Merzenich et al., 1998; also see
Knudsen, 2002). It might be noted that this principle was earlier discovered in em-
pirical studies in experimental psychology that showed that learning-driven changes
could be achieved for small parametric steps in perceptual learning - ultimately
achieving large-scale changes - but was frustrated when the learning step was too
great, that is, did not “overlap” with the already-mastered ability (Sutton, 1998).
We have extensively studied the parametric dimensions of progressive stepwise
change, and have studied the dose–response (repetitive stimulus-trial) conditions re-
quired for progressively driving enduring change (Merzenich, 2013; Merzenich
et al., 1998). Our training strategies are informed by these studies, in an attempt
to optimize achievable rates and magnitudes of learning-driven change.
2.5 Plastic Changes Link Representations of Serial Events in

Complex Behaviors
Studies have shown that the brain plastically also strengthens connections between
the predicted (serial) events in any learned behavior (Zhou et al., 2010; see
Merzenich, 2013). The processes underlying this successive-signal/successive-
action signaling are a key target for strengthening, in the recovery of almost any com-
plex, real-world neurobehavioral ability.
We extend training to directly exercise the representation of predicted (syntacti-

cally important) serial events in all therapeutic training regimes.
2.6 Plasticity is Controlled by Neuromodulatory Processes

In the adult brain, plasticity is regulated as a function of behavioral state. One set of
processes mediated by the release of acetylcholine from the subcortical nucleus basa-
lis engages excitatory and inhibitory processes to enable plastic change. As noted
earlier, the nucleus basalis is engaged by any significant neural activity generated
in a closely attended behavior (Sarter et al., 2001, 2006). Once engaged, as is de-
scribed by Froemke et al., (2013; see Chapter 3; also see Kilgard and Merzenich,
1998; Wright et al., 2010; Chapter 11), a plasticity-enabling epoch is open for several
following minutes.
A second set of processes, mediated by the modulatory neurotransmitter nor-
adrenaline (norepinephrine), amplify the activity generated by any unexpected event
or by any closely attended input. These effects are rapidly attenuated if that input is
nonvariant (Aston-Jones and Cohen, 2005; Sara, 2009; Sara and Bouret, 2012).
Importantly, if repeatedly engaged under the right conditions (see Chapter 13),
the actions of the primary midbrain source of noradrenaline are enduringly upregu-
lated, to increase the baseline level of excitability (arousal) in the cortex, thereby
positively amplifying plastic change.
A third set of processes mediated by the modulatory neurotransmitter dopamine
selectively controls plasticity for input that has occurred just before that rewarding
stimuli, or via engagement by the same modulatory control machinery after any
event that the brain itself judges to have been positively achieved.
Operating collectively, these (and several other neuromodulatory) enabling
processes could be thought of as “on–off switches” controlling plasticity in
the post-critical-period brain. Each adds its own nuance to cortical plasticity
processes (Merzenich, 2001). Acetylcholine is released when the brain is en-
gaged by unexpected (novel) stimuli, and when attention is focused on a task
at hand. As noted earlier, top-down biasing selectively determines the neurolog-
ical machinery that is enabled to change, through disinhibition driven by this
more general cholinergic input. As is elegantly documented in the studies of
Robert Froemke and colleagues (see Chapter 3; see also Chapter 9), the disin-
hibition, again, results in increase in the local power of excitatory inputs in that
window of attention/working memory. In effect, these processes open up a
window defining which new inputs can come, through plasticity, to dominate.
Noradrenaline is also released when the brain is engaged by unexpected stimuli,
and under conditions of focused attention. It broadly amplifies cortical activities
in ways that promote plastic change. Dopamine release is induced by hedonic
rewards associated with behavioral success, and by processes in the brain that
expressed goal or target achievement (Bao et al., 2001, 2002; Schultz, 2007).
It selectively enables positive change for inputs that contribute to that
immediate-past success, and broadly weakens competitive activities that are

uncorrelated with that success.
Plasticity-related studies (supplemented by a long history of empirical studies
from experimental psychology) have now defined the optimal conditions for evoking
these crucial neuromodulatory activities. In the training programs we develop, we
consistently apply these “rules” to optimize neuromodulation resulting in most en-
during change.
2.7 The Neuromodulatory Machinery of the Brain is Also Plastic

Studies conducted initially in animal models have shown that the processes in the
brain that control fast learning can themselves be upregulated by specific forms
of training. Training in particular forms has been shown to recover the power of
acetylcholine-based processes that enable plasticity. In one variation of the studies
demonstrating the plasticity of neuromodulatory control systems, we used a pharma-
ceutical strategy to grossly dysregulate plasticity in infant animals (Zhou et al., in
review). As a result, they grew into adulthood with grossly impaired modulatory con-
trol processes. Through relatively simple forms of training, nearly-normal processes
controlling the production and release of dopamine, noradrenaline, serotonin, and
acetylcholine were restored in now-adult animals.
With such training in humans, this key contributor to the powerful disinhibition
that underlies learning under conditions of focused attention is restored to high-
normal levels (see Chapter 13). The second contributor, working memory/selective
attention, can also be significantly improved or restored by specific forms of inten-
sive training (see Berry et al., 2010; Smith et al., 2008; Wolinsky et al., 2013; see
Chapter 7). These and other forms of exercises also reinvigorate dopamine and ace-
tylcholine signaling in learning. With their upregulation through training, their pos-
itive modulation of change is significantly increased; learning rates and asymptotic
achievement levels in learning are both elevated, when these strategies are applied in
human models.
Learning rates are also impacted by the processes in the brain that suppress ex-
ternal and internal noise (distractors). When these processes are weak, as is usually
the case in the impaired brain, a trainee responds with more false-positive responses
when they are challenged in learning. Lower learning rates and goal achievement
ceilings are the result. We recently developed learning strategies that resulted in a
recovery of this key distractor-suppression faculty (Mishra and Gazzaley, 2012;
Mishra et al., in review; see also Chapter 14).
We incorporate strategies for renormalizing the learning-control machinery of
the brain in the therapeutic training program that we apply. Targets include the neu-
romodulatory processes mediated through acetylcholine, dopamine, noradrenaline,
and serotonin; the strengthening of working memory and selective attention pro-
cesses contributing so critically to learning; and the suppression of neurological
noise (internal and externally generated “distractors”; noncorrelated process
“noise”) that interferes with learning and memory.
2.8 Plasticity Processes are Bidirectional

By its nature, plasticity engages fundamentally reversible neurological change pro-
cesses. We have conducted a number of studies in which we demonstrated that neu-
roplasticity follows Hebbian principles: the representations of inputs and actions are
competitively sorted on the basis of the temporal distributions of inputs (Merzenich
and DeCharms, 1996; Merzenich and Jenkins, 1993). Following these principles, it is
just as easy to degrade the brain’s processing abilities as it is to strengthen or refine it.
In the designs of therapeutic training regimes, the Hebbian “rule” must be considered
to assure that training-driven changes are always in the positive, strengthening,
recovering, renormalizing direction.
We have recently conducted a number of studies in animals, richly confirmed
by plasticity-based training studies in humans, which show that plasticity processes
are very broadly reversible. For example, we documented many aspects of the
function, anatomy, and chemistry in the brains of aged versus young adult animals,
showing that every measure differed markedly (de Villers-Sidani and Merzenich,
2011; de Villers-Sidani et al., 2010; Mishra et al., in review). In the aged rats’
auditory cortices, time and space constants were longer and greater; response
selectivity was poorer; reliability of sound feature representation was poorer;
response correlation was weaker; the neuron populations representing sensory in-
puts were more weakly coupled, operating with far weaker cooperativity; inhibitory
processes controlling “top-down” modulation were dramatically weaker; local and
long range (with other cortical areas; to the frontal cortex, dorsal thalamus) connec-
tions were poorly myelinated; level-to-level (system) coordination expressed in
gamma and theta frequency ranges was less sharply localized and more ephemeral;
representational topographies were degraded; trophic factors contributing to phys-
ical brain remodeling were only weakly expressed; the normal strong adaptation to
repeated identical stimuli and the responses to unexpected stimuli against a contin-
uous or repeated background were sharply reduced; the strong suppression of non-
attended distractors was reduced; receptor subunits for inhibitory and excitatory
processes were altered in a degrading direction; and the modulatory control pro-
cesses controlling plasticity itself were all more weakly operating in very old versus
prime-of-life animals (see Fig. 1 for a summary). After finding these striking
differences between aged and young rats’ brains, we then asked which of these
operational characteristics of the brain can be “rejuvenated” by appropriate behav-
ioral training. Somewhat to our surprise, with training limited in these aged rats to
approximately 1 h/day for about 1 month, the answer was: all of them (de Villers-
Sidani and Merzenich, 2011; de Villers-Sidani et al., 2010; Mishra et al., in review).
In fact, most were driven to the functional and physical state that applied for rats
studied in the prime-of-life.
Interestingly, the fundamental reversibility of plasticity processes works in the
other direction as well, as is demonstrated in studies in which we increased levels
of noncorrelated noise (chatter) in the processing machinery of the brain in young,
vigorous adults. That manipulation resulted in highly accelerated brain “aging,” as
Reversal of age-related changes in neocortical structure

and function resulting from training
A Strength of B Coordination C Strength of D Index of E Parvalbumin-
local response vs. distance post-excitatory topographic labeled
correlation inhibition representational inhibitory
order neurons
Response coordination
Number/unit volume
Old trained
Old trained
Old trained
Young
Young
Young
Young
Trained
Old
Old
Old
Old
Trans-cortical distance
F Response G Fidelity of H Response I Oddball minus J Myelination

difference: represention selectivity adapted (myelin basic
target minus of rapidly (receptive field size) standard protein)
distractor successive response
stimuli
Old trained
Old trained
Old trained
Old trained
Old trained
Young
Young
Young
Young
Young
Old
Old
Old
Old
Old
FIGURE 1
Ten of the more than 40 specific measures of neocortical structure, chemistry, and function
shown to differ in the aged versus the young Norway rat brain (A–J). As with these
examples, all indices manifested a degraded physical and functional status of the cerebral
cortex in the aged versus the young adult animal; and all indices were substantially or
completely reversed in aged rats by training them (a) to respond to variant stimuli against
a repeated background of standard stimuli, with a staircase adaptation of variant-to-standard
disparities, or (b) to respond to a target presented in a background of “distractors,” with the
disparities between distractors and targets again adapted in a staircase progression. Note that
many of these same measures (all that were measured) were seen to very rapidly change
to the aged-rat status in healthy normal young adult rats by applying strategies that increased
cortical process noise (uncorrelated neuronal “chatter”) over a 3-week-long young adult
epoch (Zhou et al., 2011).
Illustration adapted from de Villers-Sidani et al. (2010); and Mishra et al. (in review).
indexed by degrading changes in the functional and physical characteristics of the

machinery of the brain as noted above (Zhou et al., 2011).
Because these reversible change processes can drive neurological changes in an
advancing or degrading direction, driving the processing and physical characteristics
of the brain backward to simulate aging is also equivalent to driving the animal back-
ward in age: The physical and functional properties of the brain near the end of life
closely corresponds to those same characteristics in the brain near the beginning of
life. That conclusion is supported by documenting the operational and physical char-
acteristics of the machinery of the brain in very old and very young animals: they
closely match one another. It is also manifested by the fact that accelerated changes
leading to “premature aging,” carried forward far enough, similarly result in the
reopening of the “critical period” (Zhou et al., 2011; and see Chapter 1).
Because chronic neurological or psychiatric illness and brain injury invariably
leads to “negative plasticity” attributable to an increase in background “chatter”
(noise that is not correlated with the behavior in play), the fundamental reversal
of these functional characteristics of the neurological machinery of the brain is a tar-
get of every training program that we have developed, on the path to renormalizing
neurological processing and the physical brains of individuals with various clinical
indications.
2.9 Our Overall Goal is to Restore - Insofar as Possible - Normal

Neurological Function
Neurorehabilitation strategies addressing many human problems have been based on
the premise that the distorted or damaged brain is irreparable in adults. Empirically
based rehabilitation strategies have focused on “getting the most out of” the brain,
substantially through finding alternative ways to work around lost or failing abilities.
By contrast, our goal is to engage the resources of the brain itself to restore its weak-
ened or lost abilities to their natural, healthy state. The brain is everywhere plastic,
throughout our lifetimes. When the brain is intact, we believe that large-scale resto-
ration “in place” necessary for overcoming almost any distortion or limitation is usu-
ally achievable. To the extent to which that is true, the medical outcome is no longer
palliative; it is, by definition, curative.
3 PART 2: DESIGNING PROGRAMS TARGETING SPECIFIC

CLINICAL INDICATIONS
With these premises for designing neuroplasticity-based therapeutic training pro-
grams in mind, we now turn to describe how, guided by this perspective, we attempt
to address the neurological weaknesses and distortions that describe specific clinical
indications in neurological or psychiatric patient populations. In general:
3.1 Our Starting Point is an Understanding of the Nature and

Origins of the Neurological Expressions of the Specific
Targeted Disorder
Our training programs are specifically designed to target the major aspects of the
patients’ neurology. We assume that plasticity-driven changes, if appropriately
implemented, will significantly renormalize brain systems in ways that can be
expected to reestablish generalized neurobehavioral recovery. Two examples of
the development of specific programs on this basis are described in Part 4
below: (a) training to establish more competent social cognition and social control
3 Part 2: Designing Programs Targeting Specific Clinical Indications 151
in psychotic and autistic patients and (b) achieving functional rejuvenation and
resilience training in aging. For other examples of therapeutic programs that are
based on this approach, see Chapters 7, 12, and 13.
3.2 Common Features Implemented in Our Therapeutic Programs

All training modules are designed to be continuously adaptive, following “staircase”
procedures (Levitt, 1971) or other training progressions assuring success in training
on about 75% of exercise trials. By that strategy, every trainee quickly establishes a
challenge level in training that matches their capabilities, adjusting automatically to
continuously sustain that difficulty level as their abilities advance. This is important
since studies have shown that learning does not occur if the task is too easy or too
difficult (see Engineer et al., 2012). Training can usually be sustained in rewarded
manner at this level with high enthusiasm. Importantly, training controlled near the
edge of the trainee’s abilities results in sustained close attention in tasking - an
important state condition for most efficiently driving plastic remodeling. We also
commonly apply behavioral “observing responses” initiating task cycles, to further
assure close attention to the demands of the training challenge.
In implementing these staircase progressions, training always advances through a
series of small challenge steps, constructed to assure neurologically supportable im-
provements. In most of our training programs, we also introduce carefully staged
progressions in task difficulty. In any given module, those advances in difficulty
are implemented as a series of progressively more challenging subtasks arrayed
across two training dimensions - for example, speed of stimulus presentation might
vary across one dimension, while task complexity or cognitive load varies across
a second. Following that design, the trainee might begin the training module with
a subtask that can be achieved (for example) with relatively slow reception, decision,
and action-control processes, solving a task problem presented in an elementary
form. At the highest training level, the brain must operate at high speed in reception,
decision-making, and responding, at a task problem now presented in a very chal-
lenging form. Tasks are also designed with the practice repetition that assures that
training results in the induction of stable, enduring neurological changes.
Performance feedback is also a routine feature of every training program. Ap-
plied trial by trial at an approximately time-optimized way, positive feedback is more
strongly emphasized in training than performance error. This feedback is designed to
directly exercise the reward machinery of the brain to upregulate its actions contrib-
uting to the control of learning and memory. Surprises (unexpected stimuli delivered
under conditions of close attention and controlled expectation) are also systemati-
cally introduced into training exercises because they strongly, directly engage and
train cholinergic, adrenergic, dopaminergic, and serotonergic neurons in subcortical
neuromodulatory control nuclei (see Mahncke et al., 2006; Merzenich, 2013,
for review).
Every task is also designed to provide efficient, repeated measures of perfor-
mance abilities. Adaptive task formats result in the rapid establishment of a
performance benchmark (i.e., threshold) in each brain training cycle. That bench-
mark has two values for the trainee. First, it documents the trainee’s abilities at
that task, compared to those of all others who have completed the same task for
the first time. That performance data can be related specifically to the average
ability of others in their (or in other) demographic(s) - for example, to an indi-
vidual of the same gender and age in the normal distribution, or to the distribution
of all other patients also in treatment for the same clinical indication. Second,
these benchmark “scores” provide a standard that the patient is challenged to
improve upon, through repetitive tries. Their goal is to ratchet up training
achievements cycle by cycle in training - documenting, with each try, the growth
of their abilities again referenced to those neurological capabilities in the grand
trainee population.
Finally, we continuously document training gains for the patient as a part of
training task implementation, and across the course of training, in ways designed
to contribute to trainee motivation. For addressing clinical indications using
tools that are prescribed and monitored in use by rehabilitation professionals,
patient compliance and outcomes data can be provided to those clinicians via
an established social network link. This professional monitoring is designed
to help promote patient compliance, inform the clinician about trainee progress,
provide them with insights into how their other treatments might contribute to
more-complete positive recoveries, and provide a continuous line of commu-
nication between patients and the professionals responsible for their treatment
and care.
3.3 There are Common Training Targets in Almost all

Therapeutic Programs
Some aspects of the functionality of an impaired brain are improvable, and are
therefore general targets of our therapeutic training programs (see Mahncke
et al., 2006; Merzenich et al., 1998). These common deficits arise because a com-
promised brain changes its operational characteristics (speed of operations; resolu-
tion of perceptual detail) in predictable ways to sustain control of behavior under
more-challenging conditions, and because the machinery controlling learning itself
is almost always compromised in a chronic disorder, illness, or brain-injury sce-
nario (see Merzenich, 2013). In our initial training in therapeutic applications,
we usually record weaker-than-normal operations of these aspects of brain function
at training outset. One common early goal in training is to recover these basic op-
erational characteristics of the processing machinery in the brain in ways that will
help enable learning success and recovery, at all due speed. These common targets
include: (a) processing speed, (b) processing accuracy, (c) processes controlling
phasic and sustained attention, (d) neuromodulatory control of learning and the sub-
cortical systems that support it, (e) working memory, and (f) noise/distractor
suppression.
3 Part 2: Designing Programs Targeting Specific Clinical Indications 153
3.4 Therapeutic Programs Should be “Localized” to Address

Neurological Distortions Specific to the Targeted
Clinical Condition
While all programs are constructed on the same platform with training modules fol-
lowing the same basic designs, it is necessary to adapt them in detail so that they can
be effectively applied to each specific target population. Each clinical indication
manifests condition-specific neurological impairments and distortions that must
be separately addressed in training. Moreover, patients for any given clinical condi-
tion are on a journey of recovery that specifically applies for that neurological or
psychiatric profile, and our interactions and “conversation” about their journey must
be adapted with an acknowledgment of its specific nature. As an aspect of creating
therapeutic training programs that apply to specific clinical conditions, we also try to
embed education and training in domains that are outside of our Internet/computer-
and pad-delivered training. Some examples of this extension of training to “real life”
are illustrated in the clinical tool examples described in Part 4 below.
3.5 Therapeutic Programs Must Also be “Localized” in

Ways That Assure Effective Application to Specific
Patient-Population Demographics
Training programs should be “localized” to the site (country, subculture, language,
computer/pad/smartphone access) and the population of use. The tools that might
apply for a child or young adult or older adult might need to be sharply differentiated,
both with respect to (a) stimulus sets, training targets, and goals, and (b) the feed-
back, reward, and “gaming” aspects of training. Some of those changes relate to
training content; others relate to “playability” required to assure that trainees in
the targeted subpopulation “take their medicine.” For example, if the goal was to re-
cover individuals suffering from a conduct disorder, the tasking required for improv-
ing social cognition and social control (and related perceptual and cognitive
processing weaknesses) would be very different if applied in a misbehaving 5-year
old, in an incarcerated 30-year old, in an addicted 50-year old parolee, or in a socially
disturbed senior. In each case, the challenge, entertainment, and goal achievement
values of the training program would necessarily be radically different - localized
to each demographic - to achieve wide acceptance of use.
3.6 Embedded Assessments Continuously Document Gains

Achieved Through Training
As noted earlier, every task we apply therapeutically is adaptive, using an algorithm
that quickly advances to quantitatively measure ability for that task. Each time the
trainee reinitiates that specific task, their goal is to advance above their earlier “high-
est score.” In practice, trainees almost always advance their abilities try by try. For an
individual completing a serial, many-part training program addressing a major
psychiatric or neurological impairment, we may derive hundreds or thousands of

these measures of performance ability across the course of rehabilitative training -
thereby richly documenting performance and neurological improvements across
training spectra, throughout the rehabilitation epoch.
Because all of these measures apply for improvements of the many subtasks that
we are directly training the subject on, it is also important to determine whether train-
ing benefits extend to other, nonpracticed but related abilities (near transfer) - and
even more importantly, to untrained abilities that impact everyday quality of life
(far transfer). To assess these near and far-transfer outcomes for training, we can em-
bed similar tasks that have no direct equivalent in training (assessing near transfer), or
that document gains in important measures of real-life abilities that are outside of our
direct training repertoire (evaluating the extents of far transfer). As is argued compel-
lingly by Jacoby and Ahissar in Chapter 5, the establishment of real-life benefits is a
key goal of any therapeutic training program. Many programs applied as “cognitive
therapy” fail to achieve it, in large part because while they may result in “training-to-
the-task” benefits, they fail to recover implicit abilities underlying the general expres-
sive deficits arising from their impaired or dysfunctional brain systems.
3.7 Delivery Platform Enables Self-Administration of Training

and, if Necessary, Supports Clinical Monitoring and Support
One practical goal of our research has been to produce Internet delivery platform that
can enable the rapid delivery of programs with all of the assets described above,
efficiently localized to any clinical condition or demographic. That platform is
now in hand. An online clinician portal, which allows for secure and easy user
enrollment, tracking and monitoring, is also available for use.
4 PART 3: EVALUATING PROGRAM PLAYABILITY

AND EFFICACY
Once a program has been created in its initial form, we progress in an iterative “agile”
development process in which feedback from outcomes and playability reports is
used to further refine program designs. Some of that feedback comes from standard
use measures embedded in modern Internet-delivered software production tools and
formats. Other feedback comes from compliance and training progression data
derived, as described, from every training subtask and module. We also commonly
collect group and individual user responses and invite feedback comments on reward
structures and “meta-game” designs. Our initial goals are (a) to assure that the
demands of the program are willingly (ideally, enthusiastically) achieved by targeted
clinical trainees; and (b) to measure the extents to which a program effectively drives
positive changes in therapeutically targeted brain systems and behaviors. In this
latter case, these preliminary outcomes determinations are usually designed to pro-
vide an initial estimate of dose–response relationships, and of program versions and
5 Part 4: Examples of Practical Therapeutic Tools 155
population sizes required to achieve statistically secure evaluation of program effec-

tiveness in a larger, random-assignment, controlled outcomes trial.
Once playability and usability have been established, a goal is to measure pro-
gram efficacy on the path to validating medical claims via an FDA-quality (real-
world, randomized, appropriately controlled) outcomes trial. Here, the objective is
to create a medical deliverable: A program for which outcomes are assured, to an
FDA-medical device standard of proof.
5 PART 4: EXAMPLES OF PRACTICAL THERAPEUTIC TOOLS

CONSTRUCTED FOLLOWING THESE PRINCIPLES
We have now translated this science to create about 20 different program versions
targeting specific psychiatric and neurological clinical indications. Three are de-
scribed in other chapters in this volume. Paula Tallal has described neuroscience-
based programs designed to improve aural language and reading abilities in
school-age children (Chapter 7). Tom Van Vleet and Joe DeGutis describe a training
approach that has been shown to ameliorate visual reception and related losses at the
heart of hemispatial neglect syndrome following brain damage or stroke
(Chapter 13). Bruno Biagianti and Sophia Vinogradov describe the state of develop-
ment of training tools designed to renormalize the neurological abilities of chronic
and first-onset schizophrenia patients (Chapter 12). It is useful to describe how we
have constructed specific training programs, to understand how we have applied
brain plasticity science to address the deficits of a particular clinical indications.
The first is a social cognition training program which targets social cognition deficits
in schizophrenia; the second is an Alzheimer’s Disease prevention program designed
for healthy aging adults.
5.1 Targeting Developmental and Adult-Acquired Impairments

in Social Cognition
5.1.1 Neurological Basis of Therapeutic Program Design
Social cognition (SC) is defined as the mental operations underlying social interac-
tions: the perception, processing, and interpretation of social information, and the
generation of responses to this information (Augoustinos et al., 2006; Brothers,
1990a,b; Fiske and Taylor, 2008; Kunda, 1999). SC is considered to span five distinct
domains (Adolphs, 1999, 2009): emotion perception (the recognition of facial and
vocal affect), social cue perception (the ability to detect and comprehend cues in
a social context; Augoustinos et al., 2006; Fiske and Taylor, 2008; Kunda, 1999),
theory of mind (the mental capacity to infer one’s own and others’ mental states),
attributional style (attribution of causes of events to the self, to others, or to factors
in the environment), and empathy (the ability to share, understand, and appropriately
react to the emotional states of others; Shamay-Tsoory et al., 2005). Abilities in these
domains, normally acquired early in life, enable the social behaviors that underlie our
function as part of a society.
However, in schizophrenia, in addition to the various positive and negative symp-
toms associated with the illness, as well as persistent cognitive deficits (see Green,
2006), patients exhibit deficits in all five domains of SC (e.g., Addington and
Addington, 1998; Brune et al., 2007; Edwards et al., 2002; Frith and Corcoran,
1996; Harrington et al., 2005; Mandal et al., 1998; Williams et al., 2003; see recent
reviews in Billeke and Aboitiz, 2013; Kohler et al., 2010; Hellewell and Whittaker,
1998). These deficits are considered core in schizophrenia, as they persist throughout
the course of the illness (Green et al., 2012), are expressed very early in the course of
the illness (Edwards et al., 2001; Green et al., 2012; Pinkham et al., 2007), and are
even recorded in prodromal patients (Pinkham et al., 2007) and in unaffected rela-
tives of schizophrenia patients. Moreover, SC deficits are closely linked to functional
ability in schizophrenia (Pinkham et al., 2003; Penn et al., 2008) and affect daily liv-
ing factors including occupational status, community functioning, independent liv-
ing skills, relapse rate, and quality of life (Addington et al., 2006; Bell et al., 2009;
Couture et al., 2006; Fett et al., 2010; Horan et al., 2012; Sergi et al., 2007; Vauth
et al., 2004). In addition, SC deficits have been found to mediate the relationship
between neurocognition and functional outcomes in schizophrenia (Couture et al.,
2006), as well as predict conversion to psychosis in young individuals at risk for psy-
chosis (Vauth et al., 2004). In fact, the degree of SC impairment is a stronger pre-
dictor of the level of everyday functional ability than are cognitive abilities or the
severity of positive symptoms (Horan et al., 2012).
These behavioral deficits have been recently shown to be rooted in anatomical
and functional abnormalities within the complex brain network known as “the social
brain” (Adolphs, 1999, 2009; Botvinick et al., 2005; Lamm et al., 2007; Wicker et al.,
2003). Significant anatomical and functional abnormalities have been localized to
the superior temporal sulcus (STS; Straube et al., 2013), anterior insula (Sheng
et al., 2013), amygdala (Gur et al., 2002; Schneider et al., 1998), medial prefrontal
cortex (mPFC; Russell et al., 2000), and to the cingulate cortex (Pinkham et al.,
2008a,b), all are known to be critically involved in perception and processing of
social information.
Collectively, these behavioral and neurological abnormalities make SC an
important target for neuroplasticity-based intervention in schizophrenia. As the
goal of any effective treatment is to improve life outcomes for patients, the direct
link between SC and functional outcome in schizophrenia makes renormalization
of SC function a clear target. The fact that SC deficits are resistant to pharmaco-
logical treatments including second-generation antipsychotic medications (Green,
2007) or to cognitive training per se (see Sacks et al., 2013 and Chapter 12 for sum-
mary of cognitive training in schizophrenia) further stresses the importance of
targeted SC training for schizophrenia. Indeed, several studies have recently shown
some promising effects of social skills and SC training in chronic patients (see
recent reviews in Bartholomeusz and Allott, 2012; Choi et al., 2009; Kurtz and
Richardson, 2012).
5.1.2 Plasticity-Based Strategies for Treating Social Cognition

in Schizophrenia
We have recently completed the development and feasibility testing of an online SC
training program (SocialVille), which implements the neuroplasticity principles de-
scribed in this chapter. In particular, the SocialVille exercises target processing speed
and accuracy of information representation in the social brain areas that underlie SC
and social function (see Nahum et al., 2013a,b), the same areas that have been shown
to abnormally operate in schizophrenia patients.
The SocialVille program suite is Web-based and browser playable; this allows
training to be completed from any Internet-connected computer or laptop, using
a unique password-protected login. The 23 exercises currently included in the
SocialVille suite collectively target the SC domains listed above, emphasizing speed
of processing, working memory, and attention to social cues. All SocialVille exer-
cises use adaptive algorithms (e.g. up-down, Levitt, 1971) which allow maintaining
about 75–80% success throughout training. The exercises are designed so that a
“block” of trials takes between 5 and 10 min to complete in a given training session.
Feedback is provided for every trial, used both to provide reinforcement and learn-
ing-through-correction. In the course of training, the tasks become more challenging
by either adding more options to the response array, more stimulus types, increased
similarity between stimuli, and more complex social situations. For example, in
“Find that Feeling” exercise, the user is required to find the face that shows emotion
which matches that of the target face. In a single training session, the duration of
presentation of the target face becomes shorter (i.e., more challenging) as the user
succeeds, and longer if the user makes mistakes. In the course of training, across sev-
eral sessions, several parameters gradually change to make the task more challeng-
ing. These include the number of foils in the response array, the depth of emotion, the
number of emotions in the set, the angle of presentation of the face, etc. To allow for
this large variability in the course of training, we have produced a large number of
stimuli for the SocialVille program suite. This stimulus set includes clips featuring
15 types of emotions from 100 actors; a set of neutral faces from various angles; a set
of 900 gaze shifts; a large database of sentences spoken in various emotional pros-
odies; and a set of social stories, scenarios, and vignettes. We use these social stimuli
repeatedly in the course of training, across basic perception tasks, working memory
tasks, social attention tasks, and the like.
5.1.3 Specific SocialVille Delivery Strategies

The exercises described above are delivered in the context of the SocialVille “city”
setting (Fig. 2). This is used to provide a unified context for the various exercises,
which can increase motivation, compliance, and interest. The exercises are embed-
ded within a colorful city setting, and each exercise corresponds to a specific map
location in the city. On a given training session, upon login, the user can explore
the various open locations of the SocialVille city (e.g., the bank, the theater, the park,
the museum) and complete them in any order. The user gains points, awards, and
FIGURE 2
The SocialVille social cognition training program. (A) Upon entering the training (through
a Web browser), the user is prompted with the SocialVille “city” map, which shows the
open locations that should be visited today (1). Upon entering a location on the map, an
introductory screen is shown, explaining the task (2). Then, the exercise starts, comprised
of several (20–70) trials (3); feedback is given following every trial. A “Results” screen is
also accessible, showing the points earned from each location, and the bonus awards and
friends earned (4). (B) An example of the SocialVille “name that feeling” exercise (café
location on the map). On every trial, an image of a person showing emotion is presented on the
screen for a short period of time. The picture is followed by a mask for 500 ms, which is
then followed by a response array with emotion names. The user should select the correct
emotion by clicking on it. A feedback is given after every trial. The presentation time of
the target is adaptively set based on the user’s responses. A block of this task contains
70 trials, which allow calculating the threshold for about 75% correct in the task. The number
of response options in the array, and the number of emotions vary throughout training.
game friends upon completion of game milestones. These meta-game awards and
progress can be reviewed in a separate “Results” screen.
Embedded assessments are included for each of the SocialVille exercises, which
allow measuring progress on this particular exercise in the course of training. Assess-
ments are completed by the user at the beginning, half-way through, and at the end of
training for each exercise, to allow tracking user progress in the course of training.
Data from each training exercise is transferred to a secure clinician Web portal,
which allows the treating clinician to track progress and compliance, derive perfor-
mance thresholds, and enroll new users to training.
We have thus far successfully completed a feasibility study of SocialVille use in
17 early schizophrenia patients (Nahum et al., submitted). We further initially
tested the program in several other clinical populations that show similar SC deficits.
These include children and adolescents with autistic spectrum disorders or Asper-
ger’s Syndrome, and healthy older adults. The program is now being localized to
be applicable to these populations.
5.2 BrainHQ; Targeting Age-Related Impairments and Increasing

Resilience Designed to Delay the Onset of Senile Dementia
5.2.1 Neurological Basis of Therapeutic Program Design
Functional neurological losses associated with normal aging are “the universal
brain disease.” A massive body of evidence describes age-related decline and its
neurological bases (see Merzenich, 2013, for review). Those negative functional
changes marking - to a highly variable extent - every older life, are the primary
targets of the progressive training programs that we have created at BrainHQ.
Those physical and functional changes progress to emergent and visible neuro-
pathology in the brains of about half of individuals in sampled American and
European populations by their mid-60s (Jagust, 2013). In an estimated 5.4 million
Americans, that progressive pathology has resulted in the formal diagnosis of AD.
This large population, surviving for an average of 4.7 years after diagnosis, is rap-
idly rising in world populations (CDC/NIMH, 2013). Our first goal in developing
therapeutic tools for application in adult populations is to broadly strengthen - and
at an older age, rejuvenate - their brains, restoring “more youthful” perceptual,
cognitive, action control, and social control abilities. A second goal is to increase
resilience in the brains of older (and younger at-risk) individuals against that
destructive progression to AD.
We began our consideration of tool development, again, with an analysis of pat-
terns of progressive loss and neurological impairment recorded in normally aging
individuals - and, to meet our second goal, by reviewing how these changes relate
to the onset of AD pathology. AD is a “neurodegenerative disease” marked by
the pathological formation of beta-amyloid within neurons and in extracellular tis-
sues, by the formation of amyloid crystals that, with soluble forms of amyloid, poison
and render dysfunctional brain cells in the immediate areas in which they form, and
by the formation of microfibrillary “tangles” within nerve cells that directly destroy
their functionality and ultimately result in cell death (see Merzenich, 2013; Reitz
et al., 2011). The earliest physical signs of pathology are subcortical, in the limbic
system areas that modulate plasticity processes in the forebrain: the locus coeruleus
(norepinephrine), ventral tegmental area and substantia nigra (dopamine), basal
nucleus of Meynert (acetylcholine), and the dorsal raphe nucleus (serotonin) (see
Braak et al., 2011; Grudzien et al., 2007; Zarow et al., 2003). Because the functional
integrity of these subcortical nuclei is dependent on active behaviorally driven feed-
back connections from the forebrain, their deterioration is greatly contributed to by a
progressive disconnection of highest brain levels - the “default network” (Buckner
et al., 2008) - controlling “highest” brain functions, recorded as a consequence of
aging in numerous human studies (Hahn et al., 2013; Heister et al., 2011; Kenny et al.,
2012; Lo et al., 2011; Weiner et al., 2013). Blood flow and glucose metabolism studies
have repeatedly documented progressive, negative changes in this meso- and neocor-
tical machinery in parallel with losses in cognitive and action-control abilities in nor-
mal aging. Importantly, the degree of this “functional disconnection” resulting in
default system inactivity is strongly, directly correlated with the emergence of patho-
logical markers of AD.
In our own studies, we have shown that “noise” (neuronal “chatter”) grows pro-
gressively in the brain as we age (see de Villers-Sidani et al., 2010; Mishra et al., in
review; Zhou et al., 2011). That growing noise results in natural plastic changes in the
way that the brain represents, by its neural activities, the details of what you see or
hear or feel or smell. Because those striking changes in brain speed, accuracy, and
reliability ultimately degrade the quality of information “fed forward” in our fore-
brain systems to the default-network level of our brain’s operation, these “highest
levels” of brain systems are the first to be functionally disconnected in age-related
decline (see de Villers-Sidani and Merzenich, 2011; Merzenich, 2013, for review).
The emergence of AD pathology adds to this progressive, highest level deactivation
because the pathology amplifies an individual’s “brain noise” and weakens feedback
to lower brain system levels, including the modulatory machinery that enables plas-
ticity itself.
What underlies the poisonous production and release of amyloid and amyloid-
body formation in the first place? What engenders the destructive proliferation of
microtubules in nerve cells? We know that they are both contributed to by com-
promised immune processes. The altered blood perfusion attributable to changes
in neuronal activity is an almost-certain contributor to connectional diselabora-
tion, accumulated cellular debris, and immunological compromise. A recovery
of more normal perfusion resulting from more normal levels of default system
engagement could be expected to result in immune system strengthening. More-
over, the increased brain activity expressed through a functional recovery of the
default system should result in its parallel metabolic recovery. We also know that
there is a substantial downregulation of brain-produced noradrenaline in most
aged individuals (Mufson et al., 2002; Zarow et al., 2003; and see Heneka
et al., 2006), and that the physical (metabolic, neuronal population, noradrenaline
production, transporters) status of its primary brain source, the mid-brain locus
coeruleus, is directly correlated with cognitive performance abilities and with
risks of AD onset in elder populations. Noradrenaline is a key regulator of the
subpopulation of microglial cells that scavenge infectious agents and debris in
brain tissues. Damage to the neurons supplying it results in a rapid increase in
amyloid production and release (Heneka et al., 2006; Jardanhazi-Kurtz et al.,
2009). Increasing circulating levels of noradrenaline in older brains results in a
faster clearance of cellular debris following focal lesions and increases the scav-
enging of soluble amyloid itself (Heneka et al., 2010). A key design goal in cre-
ation of our therapeutic treatment strategy is to reinvigorate this machinery in the
older brain.
The inactivation of the default network in aging results in a diselaboration of syn-

aptic connections and ultimately in cell death. Both of these negative changes pro-
vide rich sources of prions and other amyloid-attracting brain matter debris.
Moreover, the emergent AD pathology leads to more death and destruction, which
exacerbates the problems in sustaining functional integrity by impaired immune sys-
tem machinery. We expect the broad recovery of immune system function contrib-
uted by revascularization and noradrenaline system revitalization to result in a more
efficient scavenging of debris argued to contribute to pathology genesis, neuropil
reduction, and cell death.
Finally, changes in synaptic processes related to neuronal activity levels in AD
models have been argued to lead to a cascade of changes that result in intracellular
amyloid accumulation that plausibly set neuropathological processes (e.g. tau
accumulation; cell death) in motion (Bredesen et al., 2010; Koffie et al., 2011).
These changes arise, again, in forebrain structures that are functionally decoupled.
We hypothesize that the strong reengagement and reactivation of this machinery will
change the course of these destructive intracellular processes that contribute so
strongly to neuropil reduction, microfibrillary tangle formation, and neuron death.
In summary, we hypothesize that the destructive changes that presage AD can be
delayed by forms of training that broadly recover forebrain system functionality, and
enduringly grow and sustain the levels of engagement of the brain’s default-network
and noradrenaline-producing machinery. BrainHQ was created to achieve these
important therapeutic brain health objectives.
5.2.2 Plasticity-Based Strategies for Ameliorating Functional Losses

Associated with Normal Aging, and for Growing Resilience
Against Possible AD Onset
We have created a program called “BrainHQ” (by Posit Science), designed to reju-
venate brain systems known to be progressively functionally impacted by normal
aging (http://brainhq.com). Because losses ultimately impact all brain systems, train-
ing is necessarily extensive in scope. The BrainHQ training tools focus on driving
changes in (1) modulatory system function and control; (2) attention control; (3) au-
ral speech and language; (4) visual perception; (5) memory, syntax, and other dimen-
sions of cognition; (6) executive control; (7) social cognition; and (8) spatial and
temporal scene reconstruction and navigation.
To achieve these broad objectives, trainees are engaged in game-like exercises
targeting different levels of processing in brain systems accounting for these differ-
ent domains of behavior. As described above for the SC training suite (SocialVille),
exercises begin by training subjects in ways that improve the speed, accuracy, and
reliability of the processing of features of inputs or actions that ultimately underlie
explicit neurobehavioral abilities. To cite a specific example, listening training fo-
cuses on making progressively finer acoustic distinctions of features important for
high-accuracy, high-speed aural speech reception, initially exaggerating those fea-
tures to facilitate neuroplastic change. It then advances to improve accurate, high-
speed reception under sparse coding conditions at the phonemic, syllabic, word, and
connected-speech levels. In parallel, other exercises are designed to upregulate

attention, broadly suppress interfering distractors, strengthen the modulatory
control machinery controlling learning rates, and improve working memory - all
major contributors to recovering the high-speed, high-accuracy, high-coherence
operations of this (or any other) great brain system. With its recovered powers,
the ability of this system to effectively engage “highest” (default-network) brain
levels is sustained or, if necessary, recovered - in an organic, comprehensive
way that we believe should grow resilience against AD onset. In BrainHQ, we
provide several hundred hours of brain exercises that, over the course of time,
provide the basis for broad, generalized improvements and protections for the
adult brain.
5.2.3 Specific BrainHQ Delivery Strategies

Exercises on BrainHQ are designed to be playable on an Internet browser on any
connected computer; modified forms of all exercises are playable on Internet-
connected iPads. At BrainHQ, a trainee can choose any program module(s) for that
day’s/week’s exercise, or can follow recommended schedules provided in BrainHQ
“courses.” Work on those courses may be completed independently, or by design,
can be monitored via a “clinician portal” by a supervising medical professional.
All exercises are constructed following earlier-described principles. In general,
the trainee has a series of brief (10–20) subtasks to complete each training day; they
begin each task by “setting a benchmark” at that specific challenge, then must im-
mediately improve on their performance on this progressive exercise before other
subtasks are “unlocked.” In this game-like setting, those now-unlocked boxes
represent the next level of challenge in the specific task domain(s) that they are
working on. The trainee is guided back to the same tasks over a series of successive
days, mastering progressively more-challenging task forms as they advance in
training. Every time a trainee completes a subtask (box), their abilities are defined
relative to every other individual who has ever engaged in this exercise for the
first time. This measured performance ability on that task provides a crucial
reference for documenting training-driven improvements. The trainee can easily
access displays provided at the Website that track their progress in any subtask,
task, or broad cognitive domain, and can evaluate their current abilities compared
to others in their demographic(s). A BrainHQ user can be expected to quickly
derive many of these personalized performance measures to generate an increasingly
in-depth reconstruction of their broader, detailed neurobehavioral status -
and can track, in detail, changes in that status attributable to their efforts spent in
training (Fig. 3).
The Alzheimer’s Prevention Course (TAP) was created at BrainHQ to provide a
more regulated program specifically designed to assure that the kind of broad train-
ing designed to recover functionality in ways believed to be neurologically protec-
tive are assured. Thus, for example, special emphasis is paid to (a) revitalizing the
locus coeruleus, to strengthen noradrenaline signaling of immune response activity
in the brain; and (b) assuring that we effectively restore more normal engagement
FIGURE 3
The BrainHQ training program for AD prevention. (A) The exerice view. For each exercise,
the level (“stage”) that the user is in is presented. The user can complete and unlock
more and more levels and can go back and redo levels that were unlocked. (B) An example
of a BrainHQ training exercise (Useful Field of View, UFOV). In this exercise, participants
must identify a visual stimulus presented in the center of gaze, while simultaneously locating
a target in the peripheral vision. The game is adaptive as the task gets difficult with successful
brain training. In this example, the duration of visual stimulus presentation decreases.
(C) Feedback is given on their relative performance compared to their age cohort.
(connectivity) of the default network, where AD pathology rises with particular ini-
tial virulence. In this course, trainees initially complete extensive survey information
documenting their neurological status, and self-assess their quality of life. They
then complete 12 program-delivered assessments that are specifically designed
to evaluate default-network functionality before - and at periodic benchmarks
after - training. We also collect daily information about lifestyle and other probable
contributors to their improving brain health. Those queries also provide self-reports
of trainees about their neurological and physical status that are very important for
documenting far-transfer training impacts, and for documenting how other changes
in lifestyle contribute to recovered brain health. After approximately 50-training-hour
epochs, self-reports related to brain and physical health and quality of life and the
12 special automated assessment measures are repeated, to determine the improve-
ments in neurobehavioral status and the resilience values of this training course.
In its present form, TAP delivers more than a hundred hours of brain training
designed to be used in 30-min daily training sessions completed over a period of
40–50 weeks. Our goal is to extend training in program participants out into the
future, potential to the end of their lives.
5.2.4 Evidence That This Training is Effective

Nearly 40 controlled outcomes studies have evaluated the effectiveness of use of
different programs delivered at BrainHQ; most of these validated programs are in-
corporated in the AD-resilience training provided by TAP. To briefly summarize:
(1) Training targeting the aural speech/language system have been shown to sub-
stantially improve all measured listening, memory, and related cognitive abilities,
with broad generalization demonstrated by quality of life/everyday life assessments
(Mahncke et al., 2006; Smith et al., 2008; Zelinski et al., 2011; Stevens et al.,
2008). Many additional studies demonstrating the behavioral and neurological
values of this form of training are documented in studies in children and young
adults, described by Tallal in Chapter 7. In studies conducted in individuals of
all ages, recoveries in perceptual abilities in listening repeatedly document im-
proved speed of processing, accuracy, and attention control in processing abilities.
(2) Training targeting visual perception and related cognition abilities result in
sharp improvements in visual processing (e.g., Ball et al., 2007; Berry et al.,
2010; Wolinsky et al., 2013). Improvements in speed and accuracy of processing
and improvements in spatial vision (saccade sampling rates; multitasking; local and
global reconstructions; scene reconstruction; useful field of view) were, again, re-
peatedly recorded in these studies. These aural languages and visual training studies
also extensively document improvements in attention, working memory and imme-
diate and delayed recall, and in associative memory/syntactic abilities. (3) Training
targeting social cognition and social control have been described for other neuro-
logical populations, and the behavioral and physiological evidence supporting their
use has been summarized earlier. (4) Studies document benefits of training for ex-
ecutive control and temporal and spatial navigation processes in training (e.g., see
Ball et al., 2007; Merzenich, 2013; Smith et al., 2008). With working memory and
References 165
with the highest levels of operation in SC, these explicit behaviors normally di-
rectly engage frontal, posterior parietal, anterior and posterior cingulate, medial
ventral and hippocampal zones that undergo disconnection as a preamble to AD
onset. (5) Broad far-transfer effects are recorded - for example, to everyday quality
of life (Ball et al., 2007; Smith et al., 2008), to sustained confident independence
(Edwards et al., 2009; Wolinsky et al., 2010a), to resilience impacts against the on-
set of depression (Wolinsky et al., 2009), to measures documenting improved brain
health (Wolinsky et al., 2006, 2010b), and to sustained (Edwards et al., 2009) and
safer automobile driving (Ball et al., 2010) - among other indices (Wolinsky et al.,
2006, 2007, 2009, 2010a,b; Ball et al., 2010; Edwards et al., 2009). (6) Positive
improvements have been shown to endure for many months to years following
training completion (e.g., Wolinsky et al., 2006, 2009, 2013; Zelinski et al., 2011).
Does this form of training delay AD onset? Does it block, and can it reverse neu-
ropathology progressions? Answering that question is the current goal of a large con-
trolled Internet-delivered trial, led by Dr. Hyunkyu Lee that is now underway. A
growing body of evidence provides increasingly compelling evidence that this is,
indeed, the case. By training thousands of individuals at risk for AD onset at BrainHQ,
we should be able to answer this question, with finality, in the immediate future.
6 CONCLUSIONS
Neuroplasticity-based training strategies are emerging as a new class of therapeutic
tools providing a new level of organic treatment of neurological and psychiatric ill-
ness. Because they can broadly address neurological impairments and disease-driven
neurological distortions, they hold promise of driving more complete and more en-
during changes in the brains of patients with many brain-related clinical indications.
Training programs constructed on these bases are relatively inexpensive to produce
and validate, and can be delivered to patients in need of help at low cost via the In-
ternet. Confirmation of use, compliance, and training benefits are routinely recorded,
with the supervising clinician “in the loop,” as an integral part of program use. Pa-
tient use and outcomes are measured by assessments embedded directly in these pro-
grams. We strongly believe these new therapeutic tools shall be a large part of the
picture of improved medical treatments of developmental and acquired-adult neuro-
logical and psychiatric impairments and disease over the coming decade.
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CHAPTER
Fast ForWord®: The Birth of

the Neurocognitive Training
Revolution
7
Paula Tallal1
Rutgers, The State University of New Jersey, Center for Molecular and Behavioral Neuroscience,
Newark, NJ, USA
1
Corresponding author: Tel.: 619-417-4149; Fax: 973-353-1760,
e-mail address: tallal@andromeda.rutgers.edu
Abstract
In 1996, I cofounded Scientific Learning Corporation (SLC) with Drs Michael Merzenich,
William Jenkins, and Steve Miller. I coined the term “Cogniceutical” to describe the new type
of company we envisioned. SLC was the first company cofounded by academic scientists with
the mission of building neurocognitive interventions. Fast ForWord® is the registered trade
name of the platform SLC built to translate basic neuroplasticity-based training research into
clinical and educational products. Fast ForWord® was the first cognitive neurotherapeutic in-
tervention, the first to be individually adaptive in real time, the first “brain fitness” program
that collected data over the Internet, and the first to use computer gaming technologies to
change brains and enhance human potential. We included lofty goals in our first business plan
for SLC. These included: using neuroplasticity-based training to improve language, literacy,
and other academic skills; helping seniors maintain and recover function; helping people learn
English as a second language; helping patient populations with neurological or mental disor-
ders. SLC’s first focus became improving language and literacy. Mike, Bill, Steve, and I began
this journey together in 1994 with a laboratory-based research study that included seven chil-
dren. To date, over two million children in 46 countries have used Fast ForWord® products. On
any given school day, approximately 60,000 children log in to train on 1 of 10 Fast ForWord
Language, Literacy, or Reading programs. We did not know at the time that we were creating
what became a “disruptive innovation.” This chapter chronicles this transformational journey.
Keywords
neurocognitive training, video games, language, literacy, reading, language-learning impair-
ments, neuroplasticity-based training, dyslexia, autism, Fast ForWord®:, Scientific Learning
Corporation

175
176 CHAPTER 7 Fast ForWord: A Transformational Journey
1 INTRODUCTION
Fast ForWord® grew out of over 25 years of basic and clinical research in two dis-
tinct scientific disciplines. One utilized behavioral, electrophysiological, and neuro-
imaging methods to study individual differences in language development and the
etiology of developmental language-based learning disabilities (including specific
language impairment (SLI), autism, and dyslexia). The other utilized neurophysio-
logical methods in animals to study neuroplasticity, that is, changes at the cellular
level driven by behavioral training techniques. This chapter reviews (1) how these
two lines of research were integrated to form the scientific basis of Fast ForWord®
(and subsequently its sister product Posit Science Corporation’s Brain Fitness
Program®), and (2) the steps taken to translate and instantiate our integrated labo-
ratory research into clinical and classroom interventions that could be scaled up for
distribution around the world, while remaining efficient and effective.
When we began our collaboration in 1993, the now rapidly growing fields of “cog-
nitive neurotherapeutics” and “neuroeducation” did not exist. The concept of using
neuroplasticity-based training to improve “brain fitness” in humans did not exist.
Few clinics or schools had computers and fewer still had Internet access. The methods
we developed which subsequently were the basis of over 50 patents were the first to use
video gaming technologies with the explicit goal of improving human performance.
Over the past 17 years since inception, Scientific Learning Corporation (SLC) has de-
veloped a large series of perceptual, cognitive, language, literacy, and early math train-
ing exercises, “disguised” as interactive, individually adaptive, computer games,
trademarked Fast ForWord®. SLC products, now delivered over the Internet, include
a wide variety of individually adaptive assessment and intervention exercises that pro-
vide real-time feedback and rewards as well as ongoing, electronic data analysis and
detailed reporting to the end user. A sister company, Posit Science Corporation,
cofounded by Dr Michael Merzenich, delivers similar products to aging adults and
adult patient populations. Posit’s first product, The Brain Fitness Program®, adapted
several of the original Fast ForWord® auditory processing, verbal memory, and lan-
guage comprehension exercises, including the use of acoustically modified speech.
2 INTEGRATING RESEARCH ON LANGUAGE DEVELOPMENT

AND DISORDERS WITH NEUROPLASTICITY RESEARCH
It is generally assumed that most children develop language automatically, with no
need for explicit instruction. However, prospective, developmental studies have
shown that there are quite substantial individual differences in language develop-
ment driven by a wide variety of genetic, environmental, and sociocultural factors
(Bates and Tomasello, 2001; Heim and Benasich, 2006). As such, millions of chil-
dren enter school with weak aural receptive and/or expressive language skills. Pro-
spective longitudinal research has shown that entering formal education with weak
language skills, especially poor language comprehension, places a child at increased
2 Integrating Research on Language Development and Disorders 177
risk for a cascade of negative life outcomes (Hart and Risley, 1995). Despite the crit-
ical role aural language plays in academic success, with over 80% of classroom in-
struction presented aurally, it is remarkable that there is little if any formal school
curriculum focused explicitly on receptive (comprehension) and expressive (spoken)
language development. Rather, early education focuses on teaching written language
(reading, writing, spelling). During the preschool years the focus is on “reading read-
iness.” Once formal education begins, if a child begins to struggle, intervention is
focused on reading. Put simply, schools are in the business of teaching a child to learn
to read, not to talk or listen. However, if our ultimate goal is to improve literacy out-
comes, what is needed is a better scientific understanding of how the brain learns to
process and produce language, how language forms the foundation upon which lit-
eracy skills depend, and how to effectively transfer this scientific knowledge to
clinics and classrooms in the form of effective and efficient intervention tools.
The Fast ForWord® series of training programs (there are currently 10 products, in-
cluding Fast ForWord® Language, Literacy, and Reading Levels 1–5) was devel-
oped to address this need.
The most basic unit of any language is the phoneme, the smallest unit of sound
that can change the meaning of a word. For most languages, in order to learn how to
read and become a proficient reader, the child must become aware that words can be
segmented into smaller units of sound (phonemes) and it is these sounds that the let-
ters represent. This is referred to as phonological awareness. Phonemes are the basic
building blocks for both spoken and written language. Not surprisingly, phonological
skills have been shown to correlate both prospectively as well as concurrently with
both aural and written language ability throughout life (Tallal, 2004). To improve
literacy outcomes, we need to understand the language to literacy continuum, and
how at a fundamental level phonemes of a language come to be organized or “repre-
sented” in the brain. As phonemes are, themselves, comprised of smaller, dynami-
cally changing, acoustic spectrotemporal features, the role that complex auditory
processing plays in the development of phonological systems has been a major topic
of research, and one that was fundamental to the design of the series of Fast For-
Word® Language and Literacy products.
As is the case in all other sensory modalities, the acoustic information within the
complex waveform of speech can be broken down into distinct physical features (fre-
quency, duration, amplitude), each of which is represented in fine grained detail in
the auditory system (Kraus et al., 1995, 1996). According to Hebb (1949), when a
complex signal occurs, all of the neurons that are activated by this complex set of
features, per unit time, fire together. The likelihood that a particular pattern will
come to be represented increases with each additional exposure of a firing pattern
ensemble. It has been increasingly documented that phonological systems are devel-
oped through exposure to the native language(s) (Kuhl et al., 1997). Each language
has its own set of phonemes that must be learned from experiencing repeating acous-
tic patterns within the ongoing speech waveform. As infants are exposed to a con-
tinuous speech stream from the environment, they must parse the incoming acoustic
signal into consistent, replicable chunks of time that occur in statistically predictable
sequences (Saffran, et al., 1996). It is hypothesized that when sensory inputs enter the
nervous system differentially in time, the neuronal representation develops as dis-
tinct and separable. However, when information enters the nervous system either si-
multaneously or within a critical window of time (tens of milliseconds) that is too
rapid to separate, the information is “bound” together and thus is neurally coded
as a unit (Wang et al., 1995). It is in this way that the many different physical features
of a complex stimulus, such as speech, are combined (bind together) to form a unified
phonological percepts (Tallal, 2004). For speech, statistically consistent acoustic
patterns occur frequently and consistently within the ongoing acoustic waveform
in chunks of various durations. Chunking within the tens of milliseconds (ms)
time window will allow for the fine grain analysis needed to represent the acoustic
differences between individual phonemes such as /b/ and /d/. Chunking over longer
periods of time (hundreds of milliseconds) will result in firing patterns consistent
with syllable length representations (Hickok and Poeppel, 2007). It is these chunks
of acoustic information, which form the building blocks for language, that can be
infinitely combined to form both spoken and written words. Furthermore, based
on optimal control theory (Todorov, 2006), it is hypothesized that similar unsuper-
vised statistical learning processes are at play for learning how words are combined
to form sentences that are consistent with the specific grammatical rules that govern
how each language is constructed.
While most children develop language without the need for explicit training, a
growing number of children are entering formal education without sufficient lan-
guage skills to support proficient written language and literacy development. Chil-
dren who fall within the lower end of the continuum of individual differences in
language development are diagnosed as having “language-based learning disabil-
ities.” In addition to linguistic studies that focus on describing the differential pattern
of language development in these populations of children (Leonard, 1998), research
has focused on delineating basic domain-general sensory, motor, and cognitive def-
icits that consistently co-occur with language impairments (Tallal et al., 1993). In
1973, I reported for the first time that children with developmental language impair-
ments were significantly impaired in both discriminating and sequencing two brief
(75 ms) complex tones differing in fundamental frequency when they were separated
by an inter-stimulus-interval (ISI) of 150 ms or less, but performed as well as age-
matched controls with longer duration ISIs (Tallal and Piercy, 1973). In a series of
follow-on papers, we showed that this deficit in “rapid auditory processing” (RAP)
extended to verbal stimuli that incorporated similarly brief, rapidly successive acous-
tic cues that are critical for speech identification and discrimination (Tallal and
Piercy, 1974, 1975). For example, the major cue for stop-consonants is the rapidly
changing frequency spectrum of the second and third formant transitions that is not
only transitional but also of short duration (approximately 40 ms). We hypothesized,
and subsequently demonstrated, that rather than being impaired in all aspects of
speech perception, children with developmental language impairments are selec-
tively impaired only in identifying and discriminating between those speech sounds
that depended on the processing of brief, rapidly successive acoustic cues. To further
3 Integrating Neuroplasticity-Based Training Research 179
specify the nature of this deficit, we used computer speech synthesis to control the
exact duration of acoustic cues within speech syllables (intrasyllabically). Specifi-
cally, we extended the duration of the formant transition within the syllables /ba/
and /da/ from 43 to 95 ms. The results of this study showed, for the first time, that
not only were children with SLI selectively impaired in discriminating the brief du-
ration of the discriminable components within speech syllables but that their percep-
tion could be virtually normalized by extending in time these brief duration acoustic
cues. Subsequent studies in our own and many other labs in the ensuing 20 years
showed that there is a highly significant correlation between a language impaired
child’s RAP performance (as measured by the ISI needed between two brief nonver-
bal tones) and (1) their speech perception and production abilities, (2) their language
comprehension abilities, and (3) their phonological awareness abilities as measured
by their nonword reading abilities (Stark and Tallal, 1988; Tallal, 2004). In subse-
quent prospective longitudinal studies beginning in infancy, we showed that the sin-
gle best predictor of verbal IQ in toddlers (36 months old) was their RAP threshold
(as measured by the ISI needed between two brief nonverbal tones) established when
they were infants (Benasich and Tallal, 2002). Importantly, infants’ RAP thresholds
did not predict subsequent nonverbal IQ, demonstrating the specificity of the rela-
tionship between RAP and language development. Remarkably, out of a large battery
of perceptual and cognitive tests, RAP thresholds established at 6 months of age
proved to be the single most powerful variable that, when combined with gender,
predicted 94% correctly those children who would score in the “impaired” range
on the Stanford Binet Verbal IQ test by age 3 years.
3 INTEGRATING NEUROPLASTICITY-BASED TRAINING

RESEARCH WITH RESEARCH ON INDIVIDUAL DIFFERENCES
IN LANGUAGE DEVELOPMENT
Neurophysiologists have mapped the features of the sensory world at the single cell
level. This research has shown that within each sensory modality, the features that
represent the physical world come to be mapped at the cellular level in a highly or-
ganized fashion. For example, in the auditory modality, there is a tonotopic repre-
sentation of frequency such that cells that fire to a specific frequency are located
physically adjacent to cells that fire to the next higher frequency, in a continuous
manner throughout the frequency range (Clopton et al., 1974). In addition to tono-
topic (frequency) representation in A1, there are neurons that code selectively for
temporal features of sound (Eggermont, 1981), as well as “inseparable” temporos-
pectral combinations such as frequency sweeps similar to those occurring within for-
mant transitions of speech (Orduna et al., 2001). That these sensory maps must be
learned from environmental exposure is evidenced by neurophysiological research,
showing the effects of sensory deprivation or alteration (Neville, 1985). Exposure to
altered acoustic input during critical periods of early development, for example
continuous or pulsed noise, significantly disrupts the development of tonotopic

representation in primary auditory cortex, and these developmental changes continue
to be evident into adulthood. Merzenich and colleagues have shown that beyond this
early period, sensorineural maps can no longer be altered by mere exposure. Rather,
alteration of neural maps requires active attention to highly repetitive and explicit
input features in the context of an intensively trained, individually adaptive task, with
timely feedback and reinforcement of correct responses (Chang and Merzenich,
2003; Recanzone et al., 1993; Zhang, et al., 2001). This form of training is referred
to as neuroplasticity-based training.
4 THE BIRTH OF FAST FORWORD®: TRANSLATING THEORY

INTO PRACTICE
Considering the amount of speech directed to the infant, it is easy to understand how
important speech is in shaping the auditory cortex during critical periods of human
development. Furthermore, adult speech to infants (known as “parentese”) has been
shown to exaggerate (extend in time and amplitude enhance) the acoustic changes
that differentiate phonemes within syllables and words (Liu et al., 2003). Three de-
cades of research with children with developmental language and literacy impair-
ments has shown that these children are at high risk for having specific deficits in
processing the brief, rapidly successive, temporospectral cues within ongoing speech
(Tallal, 2004). Furthermore, we demonstrated as early as 1975, using computer-
synthesized speech syllables, that language impaired children’s perception could
be substantially normalized, at least at the single syllable level, by extending in-time
rapid temporospectral, intrasyllabic cues (Tallal and Piercy, 1975). We hypothesized
that this acoustic modification of the temporospectral cues within computer-
synthesized speech may play a similar role as “parentese” in helping children seg-
ment and process the rapid temporospectral cues within ongoing speech, well beyond
the critical period. Unfortunately, it took 20 years before technological advances
made it possible to develop a speech algorithm that could make similar intrasyllabic
acoustic alterations in real time within ongoing speech (Nagarajan et al., 1998). Dur-
ing that same period of time, research demonstrating not only that the brain was
highly plastic well beyond the critical period but also elaborating the precise “scien-
tific learning principles” needed to most efficiently and effectively drive
neuroplasticity-based training, came of age (Jenkins et al.,1990). Cortical plasticity
and learning studies conducted in primate and human models had shown that such
training (1) had to be applied with a heavy schedule of practice trials (repetition, rep-
etition, repetition), (2) spaced across a series of successive training days, (3) had to
individually adapt along easy to harder trajectories to drive continuous performance
improvements, and (4) would have to be conducted under conditions of high moti-
vational drive with timely rewards (Merzenich and Jenkins, 1998).
In 1993, the Tallal lab at Rutgers University, Newark began collaborating
with the Merzenich lab at UCSF. We began with parallel research goals: (1) to
5 Designing Neuroplasticity-Based Training Games 181
determine whether basic nonverbal auditory temporal thresholds could be improved

(decreased) in human children, specifically those with language-learning impair-
ments (LLI) that were characterized by RAP deficits; (2) to develop a speech proces-
sing algorithm that would selectively find, amplitude enhance, and extend in time
(acoustically modify) the most rapidly changing acoustic changes (3–30 Hz) that oc-
curred in real time within ongoing speech (see Nagarajan et al., 1998 for details); and
(3) to determine if training children with LLI to process basic auditory temporospec-
tral cues faster, while simultaneously training speech and language skills using this
acoustically modified speech, would lead to improvements in speech and/or lan-
guage abilities. Specifically, we hypothesized that the “scientific learning princi-
ples,” that had been shown in studies with monkeys to drive neuroplasticity in
sensory maps, might be adapted for use with children with LLI to ameliorate their
rate processing constraints. Simultaneously, we hypothesized that we would be able
to improve aural language skills by training a wide variety of linguistic skills using
acoustically modified speech. However, rather than having children depend on
acoustically modified speech for improved speech processing, our aim was to de-
velop neuroplasticity-based training procedures that would individually adapt, based
on a child’s linguistic performance, from the acoustically modified “slowed down”
speech to natural “fast” speech. Specifically, a hierarchy of training exercises, “dis-
guised” as games (that ultimately evolved into a series of computer/Internet base
training programs marketed under the trade name Fast ForWord® Language) was
developed to (1) attempt to drive neural processing of rapidly successive acoustic
stimuli to faster and faster rates; (2) attempt to improve foundational cognitive skills
such attention, memory, and sequencing; and (3) improve speech perception, phono-
logical analysis and awareness, and language comprehension. We aimed to do this by
providing intensive daily training exercises within various linguistic contexts (pho-
nological, morphological, semantic, and syntactic) that utilize speech stimuli that
have been acoustically modified to amplify and temporally extend the brief, rapidly
successive intrasyllabic cues within ongoing speech.
5 DESIGNING NEUROPLASTICITY-BASED TRAINING GAMES

For our first study, we designed and developed a series of verbal training exercises
ranging from speech discrimination to grammatical comprehension, disguised as
“games.” Some of these games were implemented on computers, while trained pro-
fessionals using tape-recorded stimuli presented others. In addition to explicitly
training perceptual and linguistic skills, all were developed in a training format that
also aimed to simultaneously increase foundational cognitive skills including audi-
tory attention, speed of processing, sequencing, and memory span. For example, as
seen in Fig. 1A, one of the speech processing exercises was designed in the format of
a “concentration game.” In this game, a series of squares were laid out on the com-
puter screen in a visual grid. When each square was clicked, a syllable was presented
acoustically. The goal of this game was to find two syllables that matched. When
FIGURE 1
Screenshots from two Fast ForWord® Language V1 games are shown. (A) One of the speech
processing exercises (phonic match) that was designed in the format of a “concentration game.”
5 Designing Neuroplasticity-Based Training Games 183
clicked sequentially they would disappear. To enhance attention, memory, and

motivation, bonus points were given when the screen was cleared with the fewest
number of clicks. The task began at an easy level, with only four squares and two
pairs of syllables that were acoustically easy to discriminate. As each player pro-
gressed, the number of squares in the grid increased (memory training) while the
acoustic difference between syllables decreased (speech discrimination training).
Thus, both speech discrimination and memory skills were simultaneously being
trained and individually adapted. Another exercise was presented as a board game
with colored circles and squares. Children pressed an orienting button to receive a
command. Commands, initially presented with the highest degree of acoustic modifi-
cation, began at a very easy level such as “touch the red square.” As a child progressed
through the game, the number and size of circles and squares presented, as well as
the difficulty of the commands, increased based on each participant’s trial-by-trial re-
sponse. The goal was to present commands of increasing length and grammatical com-
plexity, such as “Before touching the large blue circle, put the small red square
between the large white square and the large blue square.” As participants advanced,
the degree of acoustic modification decreased back to normal, fast speech. This exer-
cise “cross-trained” sustained attention, sequencing, serial memory, and grammar in
FIGURE 1—Cont’d In this game, a series of squares with the same picture on them are laid out
on the computer screen in a visual grid. When each square is clicked, a syllable is presented
acoustically. The goal of this game is to find two syllables that match. When clicked
sequentially these two squares disappear. Bonus points, as indicated by the point counter
bottom right of the screen, are given when the screen is cleared with the fewest number of
clicks. To indicate this, the “progress creature” on the left begins at the top of the screen and
moves toward the chair with each successive click. The task begins at an easy level, with only
four squares and two pairs of syllables that were acoustically easy to discriminate. As each
player progresses, the number of squares in the grid increases (this screenshot shows nine
squares) while the acoustic difference between syllables decreases. (B) The game Language
Comprehension Builder adapted from Curtiss and Yamada Comprehensive Evaluation of
Language (CYCLE®, 2013) to train each role of English grammar. To initiate a trial, a
participant clicks on the hand on the ear button to indicate that they are ready to listen.
A command is presented acoustically, in this example, “Point to, the cup is broken.” One
correct picture and two or three foils were carefully designed to assure that comprehension of
a specific grammatical rule, not just vocabulary, is required to answer each command
correctly. Correct responses are rewarded by a “ding” sound and winning of a sticker along
the bottom and a point is added to the point counter. Incorrect responses are indicated by a
“clunk” sound, the command is repeated, and the correct picture is highlighted. After each
row of 10 stickers at the bottom is completed, additional reward in the form of bonus points
and an equivalent number of “ding” sounds are given. To assure that memorization of
commands does not occur, the same set of picture is also used for the command, “The cup is
not broken.” From Scientific Learning Corporation.
the context of listening comprehension. Yet another exercise (shown in Fig. 1B) was
designed to train English grammatical rules. The commands used in this game were
licensed from the Curtiss and Yamada Comprehensive Evaluation of Language
(CYCLE #). We adapted this comprehension assessment that was based on years
of laboratory research on the progression of normal and delayed language development
(Curtiss and Yamada, 2013) into a training exercise designed to train the rules of En-
glish grammar. These speech discrimination and language exercises were developed to
be individually adaptive; the goal being to find for each child a level of cognitive and
linguistic functioning that could be responded to at a high rate of accuracy (approxi-
mately 80% correct). As the exercise progressed, the goal was to move toward more
rapid and less amplified, natural speech following correct linguistic responses or back
to easier (more acoustically modified speech) following incorrect responses.
In addition to the speech discrimination and language comprehension exercises,
one game was designed to increase the speed of auditory processing. This computer
game used adaptive training with the goal of driving more efficient (shorter) tempor-
ospectral integration thresholds for rapidly successive acoustic sweep tones
(computer-generated tones that sweep from either high frequency to low frequency,
or low to high). To increase generalization across the entire frequency range of
speech, three different frequency ranges were selected that covered the frequency
range of human speech. As a child progressed in this game, the sweep tone stimuli
were individually adapted to decrease in the duration of the tones, the ISI between
tones, and the slope of the sweeps, based on each child’s trial-by-trial performance.
The overarching goal of these combined verbal and nonverbal training exercises was
to drive, through adaptive training, each child into the normal processing rate of tens
of milliseconds (the range important for phoneme perception) while simultaneously
increasing each child’s ability to process more complex linguistic structures.
6 THE FIRST LABORATORY STUDIES: RUTGERS SUMMER

CAMPS 1994–1995
Two initial laboratory studies were conducted with children who each met the cri-
teria for LLI. These children had normal nonverbal intelligence (85 or above), with
language ability at least 1 year behind (see Merzenich et al., 1996 for subject details).
The goal of these first studies was to determine (1) if training in rapid tone sequenc-
ing would result in increased speed of auditory processing, and (2) if speech discrim-
ination and language comprehension abilities improved more when they were
presented with acoustically modified speech than with normal speech. The first study
was a feasibility study with seven LLI children. The second study, run as a summer
camp, included 22 children with SLI who were quasi-randomly assigned (match on
age, nonverbal IQ, and degree of language impairment) to either an Experimental
(N ¼ 11) or Control (N ¼ 11) group. The Experimental group received the language
training exercises with acoustically modified speech, while the Control group
6 The First Laboratory Studies: Rutgers Summer Camps 1994–1995 185
received the exact same language training, but with natural speech. As such, this
study allowed a direct evaluation of whether or not there was added value of provid-
ing speech language training with the acoustically modified speech. Furthermore, the
Experimental group played the computer game designed to improve RAP skills,
while the Control group played a visual computer game for an equivalent period
of time that did not require rapid processing and was not temporally adaptive.
The camp ran for 6 weeks. In weeks 1 and 6, all subjects received a battery of stan-
dardized tests (pre- and post-training measures, respectively). They then received
training 5 days a week for 4 weeks. Training sessions were intermixed with breaks
for snacks, outdoor games, and art activities. Both groups participated together in the
same “computer camp” and received the same amount of training, reinforcement,
homework (listening to an audio storybook either with or without acoustically mod-
ified speech), and rewards for performance. This allowed a direct control for other
potential variables that could have an effect on performance such as test–retest ef-
fects, Matthew effects, regression to the mean, etc.
The results of these experiments were published in two back-to-back papers in
Science in 1996. The language results are reported in Tallal et al. (1996). Tradition-
ally, few children with language-learning impairments receive more than one or two
short (30–60 min) sessions of individual or group speech therapy per week and little
progress is expected to occur within only 4 weeks of clinical intervention. In contrast,
results from this study demonstrated that the rigor, scope, and consistency of the
training (100 min, 5 days per week for 4 weeks) resulted in highly significant im-
provements in speech discrimination, language processing, and grammatical under-
standing for both groups of children. This result has important clinical implications
for the intensity of speech therapy that needs to be provided for children with
language-based learning disabilities. However, in addition to showing the benefit
of more intensive language intervention, this controlled laboratory study also dem-
onstrated the added benefit of providing language instruction using acoustically
modified speech. Results showed that the Experimental group who received language
intervention training with acoustically modified speech demonstrated significantly
better outcomes in speech discrimination, language processing, and grammatical un-
derstanding than the Control group who received the same language intervention, but
with natural (unmodified) speech.
An accompanying paper published in the same issue of Science reported the re-
sults of the nonverbal rapid auditory sequencing training that the Experimental group
received for 20 min a day, 5 days a week for 4 weeks (Merzenich et al., 1996). This
study showed for the first time that basic auditory thresholds are highly modifiable in
human children by behavioral training. Importantly, this study also showed that the
measured improvement in a child’s auditory temporal threshold for correctly seg-
menting and sequencing successive nonverbal auditory sweep tones was signifi-
cantly correlated with post-training outcomes in real-time language processing
(r ¼ 0.81, p < 0.05). That is, the amount of improvement a child made in nonverbal
auditory processing speed was highly correlated with the amount of improvement
that child made in language comprehension.
These controlled laboratory studies demonstrated the immediate efficacy of this

novel training approach. However, it was also important to determine the longer
term effectiveness of this brief, but intensive, training. To address this question,
the LLI children were assessed again at 6 weeks as well as 6 months after training
had concluded (Bedi et al., 1999). Results of these follow-up studies showed that all
children continued to make progress relative to their performance after 4 weeks of
training. Furthermore, the children with LLI who received the experimental training
protocol continued to perform significantly better than children who received
the treatment control conditions. The Experimental group not only maintained their
initial gains but also continued to improve at an accelerated pace compared to the
control group during the 6 weeks following the conclusion of the program. These
significant improvements and group difference were maintained out to 6 months.
These results provide strong evidence for the longer term efficacy of this new train-
ing approach.
As might be expected, these early reports of highly positive increases in language
scores in children with language-learning deficits led to considerable excitement in
both the scientific and clinical communities as well as the general public. We had
thousands of requests to “send the CD.” Of course, there was no CD to send at this
stage! However, our results did suggest that what we had developed had considerable
practical applications. Our Universities’ Technology Transfer Offices, which owned
our intellectual property and had submitted patents disclosures based on it, guided us
as to how to proceed to translate our research out of our labs and into public use. It
quickly became clear that what we had begun to develop was something completely
new. If we aimed to translate our research into the public domain, we would need to
start our own company. And so, in 1996, together with my research collaborators,
Drs Michael Merzenich, William Jenkins, and Steve Miller, we cofounded Scientific
Learning Corporation. Our goal was to figure out how to scale up and deliver cog-
nitive, neuroplasticity-based, individually adaptive training programs to individuals
around the world, while still maintaining efficacy.
7 SCALING UP: THE “NEUROTHERAPEUTIC REVOLUTION”

FAST FORWORD ® LANGUAGE VERSION 1 (V1)
7.1 First Multisite Clinical Field Trial (1996–1997)
It is one thing to obtain results in well-controlled studies in a research laboratory un-
der the direct supervision of skilled research scientists. It is quite another to demon-
strate that efficacy can be achieved in real-world clinics and classrooms where
children most commonly receive intervention. Soon after founding SLC, our first
goal was to convert the games used in our laboratory studies into a fully computer-
ized training program and then to conduct large-scale field trials in clinical and ed-
ucational settings to assess its efficacy. The purpose of this trial was to determine
whether the efficacy that was demonstrated in the laboratory could be replicated
7 Scaling up: The “Neurotherapeutic Revolution” Fast 187
in clinics and classrooms with fully computerized exercises, under the supervision of
clinicians and teachers (rather than trained researchers). In addition, in order to as-
sure consistency in program delivery, data collection and analysis, and quality con-
trol across multiple sites and long distances, the computerized adaptive training
programs were created in the form of a CD-Rom. Our next hurdle was to figure
out how to monitor the implementation of the program remotely, and interact with
the professionals delivering it to children at many different sites simultaneously
across days, weeks, and months. In this first version of what became Fast ForWord®
Language, trial-by-trial responses for each of the seven exercises in the program
were recorded on the hard drive of the computer each child used to play the games.
These responses were sent daily, protected by individual client ID numbers, over
the Internet to SLC where they are analyzed, tabulated, and immediately returned
electronically to the professional supervising the training. We recruited licensed
speech language pathologists (SLPs) who were interested in collaborating with us
to provide this novel intervention in their clinic or classroom to children who met
the criteria as LLI. We developed a 2-day, hands-on training workshop for SLPs that
covered the study design, subject selection inclusionary and exclusionary criteria,
how to set up the training on their own computer, how to upload and download
the data they were going to collect over the Internet, how to help children who might
be struggling to progress in the various exercises, and how to keep children moti-
vated throughout the daily exercises that were to be delivered for 100 min a day,
5 days a week for 4–8 weeks. What we had not anticipated, and what turned out to be
the most difficult early barrier to translating Fast ForWord® Language to real-world
settings, was that few SLPs in 1996 had a computer in their clinic or classroom, and
virtually none had an Internet connection! Thus, for many of our collaborating
schools and clinics, Fast ForWord® was their first experience using computer/
Internet technology.
Clinicians who volunteered to participate in this field trial were encouraged to
select a battery of standardized central auditory processing, speech, and language
tests that they used most commonly in their own clinical practice to assess children
with LLI. Children who were receiving speech therapy and scored at least one or
more standard deviations below the mean in the area of central auditory processing,
speech discrimination, and/or language comprehension were eligible for inclusion.
Case history records indicated that children who met these study criteria had one or
more of the following diagnostic classifications: SLI, attention deficit disorder, per-
vasive developmental disability, autism, central auditory processing disorder
(CAPD), dyslexia, or learning disability.
The first field trial included over 500 children aged 4–14 identified by 60 profes-
sionals at 35 clinical or educational sites. At each site, these independent speech lan-
guage professionals collected all of the pre- and poststandardized test data as well as
administered the Fast ForWord® Language training program to students who met the
study criteria. The goals of this first field trial were to determine (1) whether or not the
results obtained in the laboratory could be replicated by clinicians who most often treat
children with language-based learning problems; (2) whether the result would
generalize to a broader population of children with a variety of speech, oral, and writ-
ten language and/or CAPDs; and (3) whether efficacy would generalize to the wide
variety of standardized tests that are most commonly used clinically. This first field
trial was not designed to be a controlled study, but rather a “proof of concept” for scal-
ing up this novel approach for clinical and education settings while still maintaining
efficacy in terms of improved language functions. This is important because if the
training failed to improve language outcomes in the hands of clinicians in the field,
this would have indicated that the basic methods we were planning to use to scale
up our research were not effective in field settings. However, if the results did replicate
those found in the controlled laboratory studies, we could proceed to further scale up in
the field, as a randomized control trial had already demonstrated that the method was
effective in the laboratory. A summary of results from this first field trial are presented
in Miller et al. (1999), comparing pre-Fast ForWord training standardized test scores to
post-test standard scores. On average, the 35 sites reported convincing evidence that
clinicians can be trained to provide Fast ForWord® Language in their clinics and class-
rooms according to the prescribed protocol. Specifically, 90% of the children experi-
enced significant gains in one or more tested areas. Most children made significant
gains in multiple areas, including central auditory processing, phonemic awareness,
listening, speaking, attention, language fundamentals, grammar, and ability to follow
directions. On average, children advanced 1–2 years, based on standardized tests, fol-
lowing 4–8 weeks of Fast ForWord® Language participation. Significant improve-
ment was obtained in areas targeted by Fast ForWord® Language training. In
addition, results showed that efficacy generalized beyond areas directly trained to in-
clude improved expressive (spoken) language abilities as well as some early reading
(phonological awareness) abilities, despite the fact that no letters were included in any
of the Fast ForWord® Language exercises. Importantly, this finding demonstrated that
these methods not only improved skills that were directly trained but also generalized
to related skills that were not directly trained.
There was considerable variability across children as to the degree and pattern of
improvements they made across domains, as would be expected, based on the variety
of symptomatology and clinical classifications of this large heterogeneous group of
children with language-learning problems. Figure 2 shows that significant efficacy
was obtained for a much broader group of children than had been included in the
initial laboratory studies. Further analysis showed that differences in the degree of
efficacy were not based on the child’s clinical diagnostic classification, age, gender,
or degree of impairment. That is, this intervention method was shown to improve
language skills in both male and female children between the ages of 4 and 14 years
with a variety of clinical diagnoses and across a broad range of language functioning.
These results are significant not only in magnitude of improvement but specifically
in light of the very brief period of time (weeks rather than years) over which the in-
tervention (training) was provided. Thus, this first multisite, field trial, which was
conducted entirely by professional licensed SLPs in their own clinics or classrooms,
showed that the results that we initially found in our controlled laboratory studies
were broadly replicable in clinics and classrooms.
FIGURE 2
Comprehensive language quotients (Test of Language Development and Comprehensive
Evaluation of Language Function) for all children pre- and post-Fast ForWord® training.
Scores are shown for all children with language impairment (LI) combined, as well as for LI
children diagnosed clinically as having pervasive developmental disorder (PDD), or with
comorbid attention deficit disorder (ADD), or central auditory processing disorder (CAPD).
Although the degree of language deficit differed at pretest among these groups of children
(with children diagnosed as PDD having the most severe language disorder and CAPD having
the least severe), there were no significant differences in the magnitude of improvement
across groups achieved with training. All groups were 1 or more SD below the mean at pretest
and showed significant improvement (p < 0.0001) from pre- to posttraining. Although the
PDD group improved significantly following training, they still remained more than 1 SD below
the mean following training, based on these test batteries. The children with LIs comorbid for
ADD or CAPD entered the study with pretest scores more than 1 SD below the mean, while
their average test scores approached the normal median posttraining.
Adapted from Tallal et al. (1998).
7.2 Second Field Trial: School-Based Randomized Control Trial

(1997)
The second field trial was conducted in collaboration with 19 schools in 9 districts
in California, Texas, Illinois, Indiana, and Nebraska. While the first field trial was
focused on children receiving speech and language services in clinics and special
schools, the purpose of the second field trial was to evaluate the effectiveness of
Fast ForWord® Language in typical public schools. This randomized controlled
trial included over 400 kindergarten through 3rd grades who were selected by their
teachers as “at-risk” for academic failure. Once students were selected by their
teachers as being “at risk,” they were randomly assigned to either receive Fast
ForWord® Language training or to receive the traditional educational services
being provided in their school for “at-risk” students. Students in the Comparison
group were matched by age and gender to the Experimental group. All participants
also received a battery of standardized tests both at the beginning and end of
the study.
One of the most striking findings from this field trial of school children se-
lected by their classroom teacher as being “academically at risk” was the finding
that, based on standardized test scores obtained prior to training, low receptive
language comprehension test scores proved to be these children’s most common
problem. Recall that these teachers were not instructed or encouraged to select
children for this trial based on language impairment, but rather based on their in-
tuition that a child was “at risk for academic failure.” As part of this study, we
asked teachers to complete a checklist indicating why they thought the child was
“at risk.” Most frequently checked were reading problems, attention deficits, im-
maturity, and behavioral problems. Least frequently checked were language com-
prehension deficits. This suggests that classroom teachers are not aware that it
may be weak receptive language skills that they are actually recognizing in “ac-
ademically at risk” students. Rather, once a child begins to fail in formal educa-
tion, it is assumed they are having difficulty learning to read and any special
services they receive generally focus on improving reading and other literacy
skills. This is compatible with results from an epidemiological study showing that
only 29% of children meeting the criteria for SLI in kindergarten had ever been
previously identified as language impaired (Tomblin, et al., 1997).
The results of this field study showed that before training, over half of the sub-
jects identified by their teachers as “academically at risk” scored one or more
standard deviations below the mean in oral language comprehension. As pre-
sented in Fig. 3, after Fast ForWord® Language, post-training results showed that
the oral language comprehension performance of these “academically at risk”
children significantly improved, shifting substantially to within the normal distri-
bution. These data confirmed the earlier findings from our laboratory-based con-
trol trial (Tallal et al., 1996). Consistent with the laboratory results, average gains
in this school-based randomized trial were 1–2 years on standardized measures of
language comprehension or phoneme awareness following 4–6 weeks of Fast
ForWord® Language participation. Furthermore, improvements were signifi-
cantly greater in children receiving Fast ForWord® Language, as compared to
the control group receiving standard intervention strategies (see Miller et al.,
1999; Tallal et al., 1998 for details).
Much of the data from these large-scale field trials have been published in
book chapters rather than peer-reviewed journals (Merzenich et al., 1998,1999;
Miller et al., 1999; Tallal et al., 1999). When we attempted to submit these data
for publication in peer-reviewed academic journals, we encounter a surprising
FIGURE 3
Pre- and post-Fast ForWord® Language v1 training frequency histograms for “at-risk”
students using z-scores of language comprehension performance (TACL-R) for the speech
and language training group (N-288). The bold lines superimpose a bell curve on the
histogram to represent the standard normal distribution of scores on this test. The change
from pre training (top) to posttraining (bottom) indicates a large positive shift in the
distribution of performance following 4–8 weeks of training. Prior to training, the language
comprehension performance for both groups was well-below average, approximately at
the 12.5 percentile for the normal distribution (−1.14 z-scores), a finding consistent with the
“at-risk” status assigned by their classroom teachers. At posttesting, control group
performance (not shown) had improved (21st percentile or −0.8 z-scores), but was still well-
below age-expected performance levels and lower than the performance of the training group
(38th percentile or −0.3 z-scores). The number of subjects performing at or above the median
in age-corrected language comprehension performance improved for the trained subjects
from 11.4% to 39.0% as compared to 12.0% to 16.2% for the control group (w2 ¼ 22.06,
p < 0.0001) for posttesting difference between experimental and control subjects. Scientific
Learning Corporation MAPS for Learning: Product Report 3 (1)1:13. http://www.scilearn.
com/alldocs/rsrch/sbr/30052ffwlanguageprodrpt.pdf.
setback to our translational efforts as scientists. Our papers were rejected, in some
cases even from being considered for peer-review because they now pertained to a
commercial product that we were helping to develop. When we raised the issue as
to how research data being translated out of the lab into clinics and classrooms
were supposed to be disseminated throughout the translational process, we were
told by one journal editor that this kind of data generally was published in product
manuals and on company websites, not in scientific journals.
7.3 Fast ForWord® Language version 1 (v1): University-Based

Studies
After our first studies were published in Science, there was a flurry of university-
based studies that followed. Most of these studies focused on investigating the
effectiveness of Fast ForWord® Language v1 for children with SLI or dyslexia using
behavioral, electrophysiological, and/or neuroimaging outcome measures.
7.3.1 Studies Using Behavioral Outcome Measures Only

Several of the early attempts to study Fast ForWord® Language v1 were, unfor-
tunately, premature as they were conducted soon after this first product was re-
leased and the software as well as the protocol for implementing it effectively in
school settings was still undergoing substantial improvement. Also, because the
results of the field trials had not been published in peer-reviewed journal, re-
searchers could not take advantage of how these programs were evolving and
how to implement them with fidelity. To the contrary, many researchers indi-
cated that they explicitly wanted to evaluate the efficacy of Fast ForWord® Lan-
guage v1 as stand-alone software, without any input from SLC. However, Fast
ForWord® products were designed as “blended” approaches that require ongoing
interaction between a child and their professional provider. They were not
designed to be used in the way they were implemented in many of the
university-based studies that ended up getting published in peer-reviewed aca-
demic journals. As a result, many of these early studies suffered from very poor
or nonstandard implementations. Five of these early studies constitute the only
data used in an influential meta-analysis published by Strong et al. (2011). Un-
fortunately, there were many flaws in this publication. These authors adopted an
unusually stringent set of criteria for accepting a study into their meta-analysis;
only randomized control trials that included equivalent groups at study onset and
had been published in a peer-reviewed academic journal were considered. Of the
over 200 studies on Fast ForWord® Language that Strong et al. reviewed, only
six studies met their strict criteria and one was dropped for lack of available
data. It should be pointed out that several studies published in excellent peer-
reviewed scientific journals, that had positive results, were excluded for uncon-
ventional reasons. Of the five studies that made the cut for this meta-analysis,
three acknowledged having very poor compliance; one stated that nearly 40%
of the posttest outcome data were either missing or unreliable. Another study
used parents rather than the trained professionals to deliver the program to their
own impaired child at home. It is also important to emphasize that regardless of
when the study was actually published, all of the data included in this meta-
analysis were collected prior to 2005 using two very early, and now discontin-
ued, versions of Fast ForWord® Language v1.
Of the five studies included in the Strong et al. (2011) meta-analysis, the Gillam
et al. (2008) NIH-funded trial had by far the best implementation. The results from
this study demonstrated that students who used the Fast ForWord® Language prod-
ucts for 50 h achieved statistically significant improvements in language and reading
skills—improvements comparable to an active control group receiving 50 h of
one-on-one therapy with a licensed SLP. In this trial, 74% of the language impaired
children who received Fast ForWord® Language had follow-up scores that were
significantly higher than their pretest scores 6 months after treatment ended. In
addition, those children who received the computer-based interventions significantly
outperformed the active control groups in early reading skills, specifically phonolog-
ical awareness. It is confounding, considering these positive data on the efficacy of
Fast ForWord® Language reported in this NIH-funded trial, which is clearly the best
of the five studies included in this meta-analysis, that Strong et al. (2011) published
the following conclusion: “There is no evidence from the analysis carried out
that Fast ForWord is effective as a treatment for children’s oral language or reading
difficulties.” This statement is blatantly incorrect and in direct conflict with the
actual data.
In the years since these early studies were conducted, SLC has significantly al-
tered and improved the Fast ForWord® software, created improved protocols, and
provided better training and support to schools and clinics. In addition, nine new
products including a series of six products explicitly designed for reading interven-
tion have been released. It is important to emphasize that none of the data included in
this meta-analysis was derived from any of the currently used Fast ForWord® prod-
ucts. We encourage scientists and educators to consider the entire corpus of more
than 200 studies on Fast ForWord® products that are available or summarized on
the Scientific Learning website (http://www.scientificlearning.com/results). These
studies demonstrate the efficacy that has been achieved using more current versions
of Fast ForWord® Language (v2 and Literacy) and the Reading series (Readiness
and Levels 1–5), as well as the benefits that accrue when these products are imple-
mented with fidelity by experienced Fast ForWord® professionals in the educational
and clinical settings for which they were designed.
7.3.2 Neurophysiological and Neuroimaging Studies

of Fast ForWord® Language
Several laboratory studies on Fast ForWord® Language included physiological out-
come measures. The first of these studies was conducted at Stanford University in John
Gabrieli’s lab in collaboration with a school that specialized in educating children di-
agnosed with developmental dyslexia (Temple et al., 2003). Children in this study
received Fast ForWord® Language training in their school under the supervision of an
experienced Fast ForWord® provider. Functional MRI was performed on 20 children
with dyslexia (8–12 years old), while they performed a phonological processing task in
the scanner, both before and after remediation with Fast ForWord® Language. Results
showed significantly improved oral language and reading performance after training.
After training, the children with dyslexia also showed increased metabolic activity in
the left temporoparietal cortex and left inferior frontal gyrus, brain regions associated
with phonological processing, bringing brain activation in these regions closer to that
seen in typical readers. Increased activity was also observed in right-hemisphere
frontal and temporal regions and in the anterior cingulate gyrus. Finally, a significant
correlation was found between the magnitude of increased activation in left tempor-
oparietal cortex and improvement in oral language ability.
In Gaab et al. (2007), whole brain fMRI was performed on 22 children with devel-
opmental dyslexia and 23 typical-reading children. In this study, nonspeech analogue
stimuli that differed in the duration of onset and offset were used as stimuli. As had
been found in adults, fMRI results with these nonspeech stimuli demonstrated that
the typical-reading children showed activation for rapid (20 ms) compared to slow
(200 ms) transitions in left prefrontal cortex. Children with developmental dyslexia
failed to show any differential metabolic response in these regions to rapid versus slow
transitions. Remarkably, after only 8 weeks of training with Fast ForWord® Language,
the children with developmental dyslexia not only showed significant improvements in
language and reading skills but also exhibited substantially “normalized” activation for
rapid relative to slow transitions in left prefrontal cortex. Gaab et al. (2007) concluded
that the presence of a disruption in the neural response to rapid versus slow acoustic
transitions in children with developmental dyslexia prior to remediation, coupled with
significant improvement in language and reading scores and increased brain activation
after remediation, gives further support to the inclusion of training aimed at increasing
RAP in interventions for reading disabilities.
A study done in Helen Neville’s lab examined whether 6 weeks of high-intensity
(100 min/day 5 days per week) training with Fast ForWord® Language would influ-
ence neural mechanisms of selective auditory attention previously shown to be de-
ficient in children with SLI (Stevens et al., 2008). Twenty children, 8 diagnosed with
SLI and 12 with typically developing language received training in the lab. An ad-
ditional 13 children with typically developing language received no specialized
training (NoTx control group) but were tested and retested after a comparable time
period to control for maturational and test–retest effects. Before and after training,
children completed standardized language assessments and an event-related brain
potential measure of selective auditory attention. Relative to the NoTx control group,
both the dyslexic and typical children who received training showed significant in-
creases in standardized measures of receptive language as well as larger increases in
the effects of attention on neural processing. The enhanced effect of attention on neu-
ral processing represented a large effect size (Cohen’s d ¼ 0.8) and was specific to
changes in signal enhancement of attended stimuli. These findings indicate that the
neural mechanisms of selective auditory attention, previously shown to be deficient

in children with SLI, can be remediated through training and can accompany im-
provements on standardized measures of language. This was also the first study to
show that significant enhancement of language and attention could be achieved after
Fast ForWord® Language training not only in children with language impairments
but also in typically developing children. That is, this form of training generalized to
enhancing language skills in typical as well as impaired children.
In a recent study, Heim et al. (2011) used combined source modeling and time-
frequency analysis of the human electroencephalogram (EEG) to examine the effects
of Fast ForWord® Language training on early oscillatory responses in auditory cor-
tex. Twenty-one elementary school students diagnosed with LLI received this train-
ing for an average of 32 days in a clinical setting under the supervision of an SLP
experienced in delivering this program. Pre- and post-training assessments per-
formed in the laboratory included standardized language/literacy tests and EEG re-
cordings in response to fast-rate tone doublets. Twelve children with typical
language development were tested and retested after a comparable time period to
control for maturational and test–retest effects. As had been found in other studies
using Fast ForWord® Language training, the LLI children made significant gains in
receptive language skills post-training. Furthermore, during the first EEG assessment
(pre-training), LLI children showed reduced amplitude and phase locking of early
(45–75 ms) oscillations in the gamma-band range (29–52 Hz) for the second stimu-
lus of the tone doublet. After Fast ForWord® Language training, amplitude reduc-
tion for the second tone in the sequence was no longer evident for the LLI children,
although these children still exhibited attenuated phase locking.
Russo et al. (2010) also reported physiological improvements in auditory func-
tion in a study with children with autism spectrum disorders (ASD). Children with
ASD share many common deficits to children diagnosed with SLI, including re-
ceptive language and auditory processing deficits. While these children have been
included in field studies previously, and shown to benefit from Fast ForWord®
Language training (see Fig. 2), this is the first laboratory-based study to address
whether the language impairments that characterize children with ASD may po-
tentially be alleviated through training-induced improvements in auditory proces-
sing. To assess the impact of Fast ForWord® Language training on auditory
function in children with ASD, brainstem and cortical responses to speech sounds
presented in quiet and noise were recorded from five children with ASD. These
children received training by their clinician who had extensive experience provid-
ing Fast ForWord® Language to children with ASD. The results showed that rel-
ative to six control children with ASD, who did not receive Fast ForWord®
Language, post-training-related changes were found in brainstem response timing
in three of the five children with ASD, while pitch-tracking was found in only one
ASD child. Impressively, all five of the trained children with ASD showed
improvement in cortical response timing after Fast ForWord® Language
intervention.
8 THE FAST FORWORD® READING SERIES

While the Fast ForWord® Language series was inspired by laboratory-based scientific
research, which was then translated and scaled for use in clinics and classrooms, the Fast
ForWord® Reading series was inspired by educators’ need to improve the literacy skills
of their students. Despite an increasing understanding by educators of the essential role
of phonological awareness in early reading development, and despite the research show-
ing the essential role of aural language development as the foundation on which profi-
cient reading depends (Hart and Risley, 1995; Tallal, 1980), it soon became clear that the
majority of educators were not particularly motivated to improve language proficiency
in their students. The No Child Left Behind Act of 2001 (P.L.107–110 (H.R.1) Title I)
gave educators a clear mandate—increase reading proficiency, as measured by state-
wide, “high stakes” achievement tests. In turn, educators gave SLC a mandate—make
research informed products that will help us achieve this goals. The Fast ForWord® Lan-
guage games focused on improving auditory processing, phonological processing, and
language comprehension skills. There were no letters in any of these games. It soon be-
came clear that if we wanted to make products that schools would use, they had better
have letters in them!
Informed by decades of research on reading development (Mann, 2002, 2003) and
with the help of some leading reading research scientists, SLC began to expand the
original Fast ForWord® Language programs into a series of Fast ForWord® Reading
programs. These programs moved systematically through the language to literacy con-
tinuum, and from reading readiness to middle and high school level reading. The Fast
ForWord® Reading series is an intensive, computer-based series of six different pro-
grams that rapidly and systematically build reading skills from the ground up, while
individually adapting to each student’s ability level and knowledge base. Fast For-
Word® Reading was designed to intensively train fundamental cognitive skills (includ-
ing working memory, focused and sustained attention, and sequencing) while
simultaneously building reading decoding, spelling, sentence comprehension, and pas-
sage comprehension. Each skill involves a number of other skills, such as phoneme
awareness, sensitivity to letter-sound correspondences, understanding of morpholog-
ical word changes, and knowledge of Standard American English grammar. Unlike the
Fast ForWord® Language programs, which were originally designed for children with
language-learning impairments, the Fast ForWord® Reading series is designed for any
student who is working on learning to read and becoming a better reader, at any level
from K-12th grade. The reading series does not use acoustically modified speech. It
does, however, adhere to the same “scientific learning principals,” as well as focus
on training basic cognitive and linguistic skills, that underlie the Fast For Word® Lan-
guage series. The major scientific advisors involved with developing the Fast For-
Word® Reading series were Drs Virginia Mann, Steve Miller, and William Jenkins.
These scientists worked from the onset in close collaboration with a dedicated team
of educators, computer game designers, programmers, artists, animators, and writers
at SLC over many years to develop the Fast ForWord® Reading series.
8 The Fast ForWord Reading Series 197
The Fast ForWord® Reading series currently includes the following six products;
each product includes five to seven exercises “disguised” as computer games:
Fast ForWord® Reading Readiness builds prereading skills, with a focus on letter
recognition and naming, phonological awareness, and letter-sound associations.
Fast ForWord® Reading Level 1 builds critical early reading skills, with an
emphasis on phonemic awareness, early decoding skills, vocabulary knowledge
and skills, and motivation for reading.
Fast ForWord® Reading Level 2 consolidates early reading skills, with a focus on
applying phonics and decoding strategies, improving word recognition, and
understanding the rules for reading comprehension.
Fast ForWord® Reading Level 3 builds on the Fast ForWord® Reading Level 2
product by concentrating on reading knowledge and fluency, with a focus on
phonology and spelling, morphological properties and complexity, syntactic
complexity, vocabulary and comprehension.
Fast ForWord® Reading Level 4 builds reading skills in school by applying
knowledge of word origins, word forms, sentence structures, and punctuation
rules to improve comprehension.
Fast ForWord® Reading Level 5 is appropriate for students in upper elementary,
middle, and high school. It concentrates on enhancing advanced reading
comprehension skills and expanding vocabulary skills.
Details pertaining to the science behind the development of each exercise within the
Fast ForWord® Reading series, school-based research studies evaluating their effi-
cacy, and descriptions and screen shots of each exercise can be found at: http://www.
scilearn.com/products/fast-forword-reading-series/.
8.1 Independent School-Based Studies of the Fast ForWord®

Language and Reading Series
Whereas Fast ForWord® Language grew out of laboratory-based basic research
that was initially designed to address theoretical and experimental questions per-
taining to the causes and determinants underlying individual differences in lan-
guage development and disorders, and subsequently translated into products
that could be used in clinics and classrooms, Fast ForWord® Reading products
were developed based on educators’ expressed need for more effective and effi-
cient products for improving the literacy proficiency of their students. As such,
the vast majority of research on Fast ForWord® Reading products comes from
school-based studies initiated and conducted by educators trained to provide Fast
ForWord® products within their own schools. Several research designs have been
used in the assessment of efficacy of the Fast ForWord® Reading series. Many of
the schools primarily wanted to see if they could get reading improvements in
their struggling readers who, despite more traditional interventions, were continu-
ing to fail to meet proficiency standards for their age and grade. Other studies
used a repeated measures design that was based on tracking literacy scores on
statewide standardized achievement tests over a number of years before and sub-
sequently after the school introduced Fast ForWord® products. The goal of this
design was to determine if the slope of the trajectory of students’ scores was sig-
nificantly increased after Fast ForWord® use. Figure 4 shows the highly signif-
icant results one district achieved using this design, both in literacy and math.
Although it is very difficult to do in a regular school setting, some school-based
studies conducted randomized control trials (RTC). Two were conducted by
teachers in their own schools for their doctoral research (Rogowsky, 2010;
Slattery, 2003). Both of these studies found significantly greater literacy improve-
ments in the students who had been randomly assigned to receive Fast ForWord®
training as compared to the students in the control groups who participated in an-
other school program. For example, for her thesis research, Rogowsky (2010)
conducted an RTC of Fast ForWord® Literacy and Fast ForWord® Reading Level
2 products with middle school students. As a middle school writing instructor, she
was particularly interested in whether these products would lead to improvements
in Standardized Edited American English (SEAE) writing skills, as measured by a
standardized writing assessment. After 6 weeks of training, her results showed
that the children who had received Fast ForWord® training improved in authentic
writing skills significantly more than those that had been randomly assigned to
the active control groups. Rogowsky et al. (2013) followed up this middle school
study with a college population. Twenty-five college students (12 native English
language; 13 English Second Language), who demonstrated poor writing skills,
received daily training during the spring semester (11 weeks) with Fast For-
Word® Literacy and upper levels of Fast ForWord® Reading (Levels 3–5). A
comparison groups of students (N ¼ 28) attending the same university did not re-
ceive training. All students took the Gates MacGinitie Reading Test (GMRT) and
the Oral and Written Language Scales (OWLS) at the beginning (Time 1) and end
(Time 2) of the spring college semester. Results from this study showed that the
training group made a statistically greater improvement from Time 1 to Time 2 in
both their reading skills and their writing skills than the comparison group. As can
be seen in Fig. 5, the group who received training began with statistically lower
writing skills before training, but exceeded the writing skills of the comparison
group after training (Rogowsky et al., 2013).
Studies on the effectiveness of educational interventions are inherently
difficult, in part because of the many skill sets required to conduct these studies
in real-world clinics and school settings. Before introducing a new method,
curriculum, or product, schools have to answer a practical question: does the
new approach lead to better outcomes for their students than whatever interven-
tion strategies they currently have in place? In translating research from the lab-
oratory to classrooms, we have found that most schools’ administrators and
curriculum directors are only willing to make important decisions for their school
after they have conducted their own, internal, independent study. As a result, hun-
dreds of independent school-based studies, some of them RTC, of one or more
FIGURE 4
District-wide longitudinal trends of 4th-grade Louisiana Education Assessment Program (LEAP)
achievement levels of the St. Mary Parish district in 2003 (3 years before Fast ForWord®
implementation began in 2006) and extending through 2011, as compared to Louisiana state-
wide LEAP scores. In the 2006–2007 school year, the St. Mary Parish Public School System
started school-wide use of the Fast ForWord® Language and Reading products at eight
elementary schools that were in Academic Assistance (a designation for schools that fail to
improve sufficiently). During the 2008–2009 school year, the remaining elementary schools
began using the Fast ForWord® products as well. Top: Percentage of students at or above Basic
Level on initial LEAP English Language Arts (ELA). Bottom: Percentage of students at or above
Basic Level on initial LEAP Math. Solid line: St. Mary’s Parish School district, dashed line: state-
wide average from 2006 to 2011, 4th grade English Language Arts proficiency levels rose from
55% to 81%; Math proficiency levels rose from 59% to 80%. Learning: Research Reports 16(2):
1–9. http://www.scilearn.com/alldocs/rsrch/sbr/30530stmaryparishedurpt.pdf.
FIGURE 5
College students’ Written Expression Scale standard scores of the Oral and Written
Language Scales (OWLS) for struggling and average writers. Mean values for the struggling
writers (N ¼ 25) who participated in the training group (filled squares) and N ¼ 28
comparison participants (open circles) are shown at Time 1 compared to Time 2, 11
weeks later. Vertical bars indicate standard errors of mean. While the comparison group
outperformed the training group students on the OWLS Writing Expression Scale at Time
1, the trained group’s considerable spurt in writing following Fast ForWord® Language v2
and Reading (Levels 3–5) intervention led to a reversed performance pattern at Time 2,
with higher standard writing scores achieved by the trained students. From Rogowsky
et al. (2013).
levels of Fast ForWord® Language and/or Reading, have been conducted by

educators in their own schools. Unfortunately, K-12 educators do not write up their
results for publication or read peer-reviewed academic journals, while scientists are
generally only willing to accept data that have been vetted and published in peer-
reviewed academic journals. This makes it exceedingly difficult for research scien-
tists interested in educational translation and K-12 educators interested in research to
find ways to communicate their findings and ideas to each other. In an attempt to
bridge this gap, several independent agencies such as the US Department of Educa-
tion’s Office of Special Education Programs (OSEP), the National Center on Re-
sponse to Intervention (NCRTI), and The What Works Clearinghouse (WWC)
have developed stringent metrics for evaluating both study designs and outcome data
from education research studies, based on the quality of a study rather than whether
or not it has been published in a peer-reviewed journal.
9 Independent Agency Evaluations of Fast ForWord Products 201
9 INDEPENDENT AGENCY EVALUATIONS OF

FAST FORWORD® PRODUCTS
The National Center on Intensive Intervention (NCII) is funded by the US Depart-
ment of Education and housed at the American Institutes for Research. As part of
their mission to help educators implement data-based individualized instruction,
NCII reviews studies on various educational interventions used with struggling stu-
dents, and publishes their analyses. According to their website, the NCII reviews fo-
cus on the degree to which intervention studies meet the following criteria:
Participants: at-risk students in Grades K-12; Study design: two group study, pref-
erably with random assignment, comparable initial skills and demographics between
the two groups, and no attrition bias; Fidelity of implementation: data showing the
program was used as designed; Study measures: accurate (psychometrically reliable)
and important (relevant to the program’s instructional content). Targeted measures
assess skills targeted by the intervention. Broader measures assess related aspects of
competence. NCII reviews also report the effect size found in each study. The effect
size quantifies the impact of the intervention by comparing the post-intervention
skills of the two groups (a medium effect size is around 0.5, while a large effect size
is around 0.8). NCII reviewed three studies on the Fast ForWord® Language prod-
ucts: (1) Miller et al. (1999). This RTC study included 388 students. Result demon-
strated positive efficacy with a Medium (0.59) effect size; (2) Scientific Learning
Corporation (2004). This study used a matched group design and included 50 stu-
dents. Result demonstrated positive efficacy with a Medium (0.44) effect size;
and (3) Slattery (2003). This RTC included 60 students. Result demonstrated highly
positive improvements with a Large (1.44) effect size. For full report, see http://
www.intensiveintervention.org/chart/instructional-intervention-tools.
Using funding from the US Department of Education’s Office of Special Education
Programs (OSEP), the National Center on Response to Intervention (NCRTI) was estab-
lished by the American Institutes for Research and researchers from Vanderbilt Univer-
sity and the University of Kansas. According to their website, the Center provides
guidance to educators on implementing proven models for Response to Intervention
(RTI) and Early Intervening Services (EIS). NCRTI reviews studies evaluating the
impact of various products on struggling students. The reviews focus on the following
components of the study: Participants: students in 5th grade and below; students below
the 30th percentile or groups that average below the 25th percentile; Study design: two
group, preferably random assignment. Analysis showing comparable initial skills be-
tween the two groups, demographic breakdown showing similar demographics between
the two groups; Fidelity of implementation: data showing the product was used as
designed; Study measures: accurate and relevant (psychometrically valid). Proximal
measures assess skills directly targeted by the intervention; distal measures assess as-
pects of competence that are related to the targeted skills. In addition to reporting on
the four components of interest, NCRTI reports the effect size. NCRTI reviewed the
same three studies on the Fast ForWord® Language products as cited above (N ¼ 498
students), breaking out results further into Proximal and Distal effect sizes. The two RCT
studies (Miller et al., 1999; Slattery, 2003) showed large proximal effect sizes (7.45 and
1.46, respectively), while the Slattery study also showed a Large Distal effect size (1.05).
For full report, see http://www.rti4success.org/instructionTools.
Nevada Senate Bill 185 (SB 185) funded districts to purchase and implement in-
novative and remedial educational programs, materials, and strategies specific to their
academic needs. The Nevada Department of Education commissioned the Colorado-
based Leadership and Learning Center (LLC) to conduct an in-depth evaluation of the
programs that were purchased with SB 185 grants. Their 2010 Interim Report includes
a review of the performance of Fast ForWord® products, which were used at three
schools. The Leadership and Learning Center used multivariate analysis to determine
the impact of programs on student achievement: “Emphasis was placed on measuring
student growth toward academic proficiency and mastery using state and local
assessments. . .. The analyses were completed as a result of extensive site visits, phone
interviews, and an examination of two-year sets of school cohort achievement data for
Criterion- Referenced Tests (CRT) for grades three through eight and High School
Proficiency Exams (HSPE) for grades nine through twelve.” The advantage of this re-
port is that it compares many of the currently available commercial products. This re-
port concludes that Fast ForWord® products increased student reading achievement
scores by an average of 22.2 percentage points. Fast ForWord® was found to have
the largest average impact of all programs reviewed in the report and it qualified Fast
ForWord® to be classified as a “High-Gain Program.”
The What Works Clearing House (WWC) was created by the NSF Institute for Ed-
ucation Sciences (IES) to review and give ratings to products and programs aimed at
teaching and improving academic skills. According to their website the WWC has de-
veloped and standardized a stringent rating scale both for the quality of a research study
as well as the effectiveness of a product or program. WWC selects specific topics of
most concern to educators, strictly defines the scope for each topic area, and specifies
the grade range that each review will include. Fast ForWord® products have been
reviewed and received positive rating in three areas: Early Reading K-3rd grade, Ad-
olescent Literacy 3rd–10th grade, and English Language Development K-6th grade.
WWC: Early Reading Effectiveness Rating K-3rd Grade. The WWC identified
nine studies of Fast ForWord® that both fell within the scope of the Beginning Read-
ing topic area and met WWC evidence standards. Seven studies met standards with-
out reservations and two studies meet WWC evidence standards with reservations.
Together, these studies included 1390 students from several areas of the United
States and Western Australia. Results show that WWC considers the extent of evi-
dence for Fast ForWord® on the reading skills of beginning readers to be medium to
large for two outcome domains—alphabetics and comprehension—and small for one
outcome domain—reading fluency.
WWC: Adolescent Literacy Effectiveness Rating Grades 3-10. The WWC identi-
fied two studies of Fast ForWord® that fell within the scope of the Adolescent Literacy
review protocol that met evidence standards, and six studies that met WWC evidence
10 Cognitive Neurotherapeutics: The Challenges of Translation 203
standards with reservations. The eight studies included approximately 2000 students,
ranging in age from 5 to 17 years, who attended elementary, middle, and high schools
in Indiana, Maryland, North Carolina, Ohio, Pennsylvania, Virginia, an urban district
in the northeastern United States, and Australia. Based on these eight studies, the
WWC considered the extent of evidence for Fast ForWord® on adolescent learners
to be small for the alphabetics and reading fluency domains and medium to large
for the comprehension and general literacy achievement domains.
WWC: English Language Development Grades K-6. The WWC identified one study
of Fast ForWord® Language that met evidence standards and a second study that met
standards with reservations. The two studies included a total of 250 K—6th grade En-
glish Language Learners (ELL) from 16 school districts. The studies examined English
language development and reading achievement. For some unspecified reason, for this
topic area phonological and phoneme awareness, which are the most important early
reading skills for elementary ELL and those that Fast ForWord® Language has been
shown to most significantly improve, were considered to be outside the scope of this
review and were not included in measures of reading achievement. Given that none
of the Fast ForWord® Reading products were evaluated, improvement in higher levels
of reading would not be expected. On the other hand, Fast ForWord® Language re-
ceived a positive rating for improvement of English language development, raising
the English language scores of ELL students by an average of þ31 percentile points.
This was one of the highest ratings given by WWC for English Language Development
for ELL K-6 students.
10 COGNITIVE NEUROTHERAPEUTICS: THE CHALLENGES

OF TRANSLATION
The biggest challenge we have faced along our journey to translate our laboratory
research into real-world settings has been negotiating the torturous path between
the world of scientists, as compared to the very different world of K-12 educators
and clinicians who make the decisions about whether our products will be offered
to the children who could benefit from them. Nowhere have these different worlds
collided more directly than when it comes to assessing and reporting the efficacy of
Fast ForWord® products. Our university-based colleagues have primarily used a
combination of behavioral, physiological, and neuroimaging technologies to address
questions about neuroplasticity-based training that have the potential to advance sci-
entific knowledge and theory. Scientists are experts at designing elegant studies in
which we can manipulate one variable at a time, within a well-controlled environ-
ment. These studies generally include “active control” methods designed to assess
not only efficacy but also specificity. Many “active controls,” designed for research
purposes, are not scalable and would be prohibitively expensive to implement in a
real-world settings. For example, the NIH-funded Fast ForWord® trial used 50 h of
one-on-one therapy provided by a licensed SLP as an “active control” in order to

match the 50-h training protocol for Fast ForWord® (Gillam et al., 2008). Finding
that these two methods were highly successful in increasing language scores, albeit
equivalent, was interpreted as a failure to demonstrate specificity for Fast For-
Word®. However, providing the intensity of therapy used as the active control in this
study to the majority of students who need it is cost prohibitive in the real world.
What schools, clinics, and parents need to know is how a new method, like Fast For-
Word®, compares to the actual alternatives that are available to their students, not
hypothetical ones that are not. As such, these same results have an entirely different
valence to educators, clinicians, and parents searching for cost-effective methods to
serve their students and view them as strongly positive scientific evidence supporting
their own experience using Fast ForWord®.
Regardless of whether research scientists studying the science of learning are
involved directly in translating research from their lab to clinics and/or classrooms,
most state in their grant applications that a primary goal of their research is to
improve educational and/or clinical outcomes. However, the reality is that we face
considerable challenges should we actually attempt to make good on this promise.
The catch 22 is that many scientists are eager to translate our research ideas and in-
novations into practical, clinical, and educational applications. However, once these
innovations are translated, they take on a life of their own to meet the needs of the
intended end users. The reality is that most clinicians and K-12 educators neither
read nor publish their work in peer-reviewed academic journals. Conversely,
university-based scientists are either unaware of or have been reluctant to value
data collected by educators and clinicians in school-based and/or clinical studies.
Despite the best of intentions, scientists, clinicians, and educators continue to be akin
to the proverbial ships passing in the night. The work being done by independent agen-
cies such as the WWC, NCRTI, and NCII to bridge this gap is certainly a step in the
right direction. However, if we as scientists are serious about translating our research
into practical applications, which have the potential to change brains and enhance hu-
man potential, we need to develop more effective, bidirectional ways to collaborate,
communicate, and learn from the consumers of our research and engage with them as
equal partners throughout the ongoing, iterative, translational process.
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CHAPTER
Music Training for the

Development of Reading
Skills
*
Adam Tierney*,{, Nina Kraus*,{,{,},},1
8
Auditory Neuroscience Laboratory, Northwestern University, Evanston, IL, USA
{
Communication Sciences, Evanston, IL, USA
{
Institute for Neuroscience, Evanston, IL, USA
}
Neurobiology and Physiology, Evanston, IL, USA
}
Otolaryngology, Evanston, IL, USA
1
Corresponding author: Phone: þ847-491-3181,
e-mail address: nkraus@northwestern.edu
Abstract
The beneficial effects of musical training are not limited to enhancement of musical skills, but
extend to language skills. Here, we review evidence that musical training can enhance reading
ability. First, we discuss five subskills underlying reading acquisition—phonological aware-
ness, speech-in-noise perception, rhythm perception, auditory working memory, and the abil-
ity to learn sound patterns—and show that each is linked to music experience. We link these
five subskills through a unifying biological framework, positing that they share a reliance on
auditory neural synchrony. After laying this theoretical groundwork for why musical training
might be expected to enhance reading skills, we review the results of longitudinal studies pro-
viding evidence for a role for musical training in enhancing language abilities. Taken as a
whole, these findings suggest that musical training can provide an effective developmental
educational strategy for all children, including those with language learning impairments.
Keywords
music, reading, phonological, speech, brain, rhythm
Decades of research have established that musical training has profound effects on the
development of the brain. Lifelong musicians show reliable differences in brain structure
when compared to nonmusicians, including white matter organization within the corpus
callosum (Lee et al., 2003; Schmithorst and Wilke, 2002; Steele et al., 2013) and the ar-
cuate fasciculus (Bengtsson et al., 2005) and thicker gray matter in motor and auditory
cortices (Bangert and Schlaug, 2006; Bermudez et al., 2009; Elmer et al., 2013; Gaser and
Schlaug, 2003a,b; Hyde et al., 2009; Keenan et al., 2001; Schlaug, 2001; Schlaug et al.,
209
210 CHAPTER 8 Music Training and Reading
1995, 2005; Schneider et al., 2002, 2005; Sluming et al., 2002). Musical training’s ability
to alter the structure of the brain is an impressive demonstration that neural development
is shaped by a complex interaction between genes and environment and can be, therefore,
dramatically changed by experience throughout life.
That musical training shapes the brain is not in question. However, the limits of
the influence of musical training are still being established. Are the benefits of mu-
sical experience limited to musical abilities, or do they extend to language abilities as
well? Here, we review evidence that musical training can enhance language skills
underlying reading ability. One of the ingredients necessary for transfer of learning
from musical experience to language skills is overlap between the processes under-
lying the perception and production of language and music (Patel, 2010, 2011, 2013).
The first section of this review, therefore, is structured around abilities and neural
functions that have been shown to be vital for reading: phonological awareness,
speech-in-noise perception, rhythm perception, auditory working memory, and
sound pattern learning. All of these processes have also been shown to be enhanced
by musical training. These links between musical and linguistic abilities, and evi-
dence for an overlapping biological basis for performance in the two domains, dem-
onstrate the close relationship between these two systems. Moreover, these findings
suggest that musical training might provide an effective developmental educational
strategy for all children, including those with language learning impairments. After
laying this theoretical groundwork for why musical training might be expected to
enhance reading skills, we review the results of longitudinal experimental studies
providing evidence for a role for musical training in enhancing language abilities.
1 PHONOLOGICAL AWARENESS
Many language skills, from reading to speech perception and production, rely upon
phonological awareness, the explicit knowledge of the components of speech and
how they can be combined (Ramus, 2003; Ramus et al., 2003; Rvachew and
Grawburg, 2006; Siegel, 2006). Phonological awareness, in turn, relies upon the abil-
ity to categorize speech sounds (Berent et al., 2012; Boets et al., 2008, 2011; King
et al., 2002; Kraus et al., 1996; Reed, 1989; Richardson et al., 2003; Serniclaes et al.,
2004; Sharma et al., 2006; Tsao et al., 2004; Vandermosten et al., 2011), which are
distinguished by small differences in timing and frequency content. The syllable
[da], for example, can be distinguished from [ta] by as little as 10 ms voice onset
time. The auditory system’s hallmark ability to represent timing and frequency with
high degrees of precision is, therefore, vital to language acquisition and use, and chil-
dren who display deficits in auditory temporal and frequency resolution also exhibit
problems with language skills. For example, children with language learning impair-
ments have difficulty detecting a sound when it is followed immediately by a noise
burst, a phenomenon known as backward masking (Gibson et al., 2006; Griffiths
et al., 2003; Marler et al., 2001, 2002; McArthur and Hogben, 2001; Montgomery
et al., 2005; Tierney and Kraus, 2013a; Wright et al., 1997). These children do
not perform poorly when the noise is presented simultaneously with the tone
1 Phonological Awareness 211
(Montgomery et al., 2005), suggesting that the problem does not stem from a global
auditory deficit but that language skills are specifically tied to the precision of tem-
poral encoding in the auditory system. Further evidence for a link between reading
ability and auditory temporal encoding comes from research showing that reading
skill is linked to the ability to tap consistently to a beat and the ability to discriminate
rhythmic patterns (reviewed below).
Not only is precise temporal encoding necessary for speech discrimination, but
precise frequency representation is crucial as well, as many speech sounds can be
differentiated on the basis of frequency content or changing frequency contours. Ac-
cordingly, the ability to detect sinusoidal changes in frequency is also linked to read-
ing skills and phonological awareness (Boets et al., 2008, 2011; Gibson et al., 2006;
Talcott et al., 2000; Wright and Conlon, 2009). Further evidence for a link between
frequency and pitch perception and reading skill comes from studies of the ability to
discriminate pitch patterns. For example, normal-reading subjects perform better
than learning-disabled readers on tests of tonal pattern discrimination (Atterbury,
1983, 1985). Other researchers (Barwick et al., 1989) found that reading ability cor-
related with tonal memory and chord discrimination in a group of 9-year-olds. Lamb
and Gregory (1993) found that pitch discrimination was significantly related to read-
ing ability in 5-year-olds. Anvari et al. (2002) found that melody and chord discrim-
ination correlated with phonemic awareness and reading. Forgeard et al. (2008)
found that children with dyslexia showed deficits on melody discrimination.
Speech sounds are brief in natural speech. As a result, detecting and discriminat-
ing speech sounds not only requires precise representations of time and frequency
information; the listener must also be able to make rapid auditory judgments, which
may therefore be particularly important for the development of phonological aware-
ness. Certain perceptual judgments are only difficult for children with language
learning problems if they must be completed rapidly, in a brief amount of time
(Tallal and Gaab, 2006); these skills include detection of the order of stimuli
(Breier et al., 2003; Griffiths et al., 2003; Rey et al., 2002; Tallal, 1980; Tallal
and Piercy, 1973a,b), detection of tone pairs (Choudhury et al., 2007), and speech
sound discrimination (Tallal, 2004; Tallal and Piercy, 1974, 1975). Moreover, rapid
auditory processing ability in infants and toddlers can predict the acquisition of lan-
guage skills later in life (Benasich and Tallal, 2002). Consistent with this relationship
between reading and temporal processing, there is also, as discussed in detail below,
a strong relationship between reading and the perception of rhythm.
Reading ability, therefore, relates to temporal and frequency resolution, rapid au-
ditory processing, and phonological awareness. These four skills may in turn rely
upon a common neural foundation—neural synchrony in the auditory system—which
may be crucial for the acquisition of reading. Supporting this Neural Synchrony
Hypothesis, the electrophysiological responses to sound of children with language
impairments differ from those of normally developing peers in a number of ways,
all indicative of reduced neural synchrony on time scales ranging from microseconds
to seconds. For example, both rapid subcortical and cortical neural responses to sound
are delayed in language-impaired children (Banai et al., 2005, 2009; Basu et al., 2010;
Benasich et al., 2006; Billiet and Bellis, 2011; Hayes et al., 2003; Hornickel et al.,
2009, 2011; King et al., 2002; Rocha-Muniz et al., 2012; Song et al., 2008).
Language-impaired children also tend to have subcortical responses to speech sounds
with diminished representations of the higher frequencies (300 Hz and above) critical
for speech sound discrimination (Banai et al., 2009; Hornickel et al., 2011, 2012;
Rocha-Muniz et al., 2012; Wible et al., 2004), indicating decreased phase-locking that
may underlie diminished behavioral frequency tracking. Language-impaired chil-
dren’s diminished neural synchrony may hinder their ability to discriminate speech
sounds, as children with poor phonological awareness have subcortical responses that
distinguish to a lesser degree between different speech sounds (Hornickel et al., 2009,
2011). Reading ability is also linked to trial-by-trial consistency in the subcortical re-
sponse to sound (Hornickel and Kraus, 2013). Similarly, trial-by-trial response consis-
tency in the cortex is diminished in rats with allelic variations in a gene associated with
dyslexia (Centanni et al., 2013).
Many of these same indices of auditory neural synchrony are enhanced by musical
training. For example, musicians have faster neural responses (on the scale of tenths of
milliseconds) to both musical and speech sounds (Musacchia et al., 2007, 2008;
Parbery-Clark et al., 2009b, 2012a,b,c; Strait et al., 2009, 2012, 2013a,b). Musicians
also show enhanced encoding of the same frequencies of speech stimuli (above
300 Hz) which are less robustly represented in language-impaired children. Further-
more, just like the neural responses of good readers, the neural responses of musicians
better encode the differences between speech sounds. See Fig. 1 for an illustration of
how neural differentiation of speech sounds is impaired in participants with poor pho-
nological awareness and enhanced in musicians. The trial-by-trial consistency of the
neural response to sound has also been linked to the ability to move to a beat
(Tierney and Kraus, 2013b) and is enhanced in older musicians compared to nonmu-
sicians (Parbery-Clark et al., 2012b). See Fig. 2 for an illustration of how trial-by-trial
response consistency relates systematically to reading ability (Hornickel and Kraus,
2013) and is enhanced in musicians (Skoe and Kraus, 2013). Cortical responses have
been shown to be enhanced in musicians as well (Schneider et al., 2002, 2005; Shahin
et al., 2003, 2004; Tervaniemi et al., 2006, 2009).
2 SPEECH IN BACKGROUND NOISE

According to the Neural Synchrony Hypothesis, children who have difficulty acquir-
ing language skills have impaired auditory neural synchrony. If so, this impairment
is likely to be more severe when stimuli are presented in conditions that tax the
auditory system’s ability to robustly represent the characteristics of sound. In fact,
children with language impairments have particular difficulty perceiving speech
when it is presented in background noise (Boets et al., 2007, 2011; Bradlow and
Kraus, 2003; Cunningham et al., 2001; Geiger et al., 2008; Sharma et al., 2006;
Ziegler et al., 2009). Background noise disrupts the neural responses to sound in chil-
dren with language impairment, with enlarged effects of noise including diminished
FIGURE 1
Neural differentiation of speech sounds underlies phonological awareness ability and is
enhanced in musicians. Differences in high-frequency spectral content that acoustically
differentiate consonants are converted to neural timing differences. These timing differences
can be examined by analyzing phase shifts at particular frequencies between neural
responses to different consonant–vowel syllables. (Left) Children with good phonological
awareness as measured by the Comprehensive Test of Phonological Processing show larger
phase shifts between responses to the speech syllables /ba/ and /ga/ (White-Schwoch and
Kraus, submitted). (Right) In young adults, musicians (began practicing by age 7, at least
12 years of training) also show larger phase shifts between responses to /ba/ and /ga/
(replotted with permission from Parbery-Clark et al., 2012c). These phase shifts are limited
to the response to the consonant–vowel transition, and are absent in the representation
of the steady-state vowel, during which period the two syllables are identical.
FIGURE 2
Trial-by-trial neural response consistency varies systematically with reading ability (left panel)
(modified from Hornickel and Kraus, 2013) and is enhanced in musicians (right panel)
(modified from Skoe and Kraus, 2013). Musicians were trained on a wide variety of
instruments beginning by age 12. These data span a wide variety of ages, combined across
several studies, and thus the number of years of training varied depending on the age of the
population studied. Response consistency is measured by dividing all the neural responses to
a sound collected in a given subject into two halves, averaging these trials to form two different
waveforms, and then correlating the two waveforms.
correlations between the stimulus and the response, delayed responses, and smaller
amplitudes (Anderson et al., 2010; Cunningham et al., 2001; Warrier et al., 2004;
Wible et al., 2005).
Musical training, on the other hand, increases the auditory system’s resilience to
noise and other sources of signal degradation, decreasing the effects of background
noise and reverberation on response amplitude, timing, and encoding of speech har-
monics (Bidelman and Krishnan, 2010; Parbery-Clark et al., 2009b, 2012a; Strait
et al., 2012, 2013b; Tierney et al., 2013 reviewed in Strait and Kraus, 2013). Musicians
also are better able to perceive speech degraded by noise or reverberation across the
life span, from infancy through old age (Bidelman and Krishnan, 2010; Parbery-Clark
et al., 2009a, 2011a, 2012a; Zendel and Alain, 2012, 2013; Tierney et al., 2013;
reviewed in Kraus et al., 2012). See Fig. 3 for a demonstration of the musician advan-
tage for speech-in-noise perception, the excessive noise-induced delay in reading im-
paired children (Anderson et al., 2010), and the smaller noise-induced delay in the
musician neural response to sound (Strait et al., 2012). See Table 1 for an overview
of the neural “signatures” to speech syllables linked to both reading ability and musical
experience (Kraus and Nicol, in press).
3 RHYTHM
Correctly perceiving the structure of music requires the perception and maintenance
in memory of patterns in time extending over several seconds. Rhythmic structure in
music does not consist solely of durational patterns, however; notes are also given
different levels of prominence based on how they align with a metrical framework
that operates on multiple levels (Palmer and Krumhansl, 1990). The presence of met-
ric structure helps guide beat perception: When tapping to the beat of rhythmic pat-
terns, participants tend to tap close to beats that fall at the beginning of a measure
rather than in the middle (Patel et al., 2005). Similarly, when perceiving speech,
the listener can take advantage of durational regularities such as the slowing that
tends to occur as speakers approach the ends of sentences (Fant et al., 1991; Klatt
and Cooper, 1975; Vaissière, 1991; Venditti and van Santen, 1998) and the some-
what predictable occurrence of syllables with different degrees of stress, one corre-
late of which is duration (Lieberman, 1960). These temporal regularities can be
useful cues for speech segmentation (Cutler and Butterfield, 1992; Nakatani and
Schaffer, 1978; Smith et al., 1989), which is necessary for the development of pho-
nological awareness. Supporting the role of speech rhythm in the development of
phonological awareness and reading ability, good readers show a greater sensitivity
to speech rhythm as measured by tasks such as distinguishing between compound
nouns and noun phrases (i.e., “lighthouse” vs. “light house”) and matching a low-
pass-filtered spoken phrase with one of two nonfiltered phrases (Gutiérrez-Palma
and Palma Reyes, 2007; Holliman et al., 2010; Whalley and Hansen, 2006;
Wood, 2006; Wood and Terrell, 1998).
3 Rhythm 215
School-age
Speech-in-noise perception
-5 -5
70 children Young adults Older adults
60
*** -4 ** -4
50 **
-3 -3
40
30 -2 -2
20
-1 -1
10
0 0 0
Musicians Nonmusicians Musicians Nonmusicians Musicians Nonmusicians
Neural timing (ms)
Poor readers Nonmusicians

*
**
Good readers
Musicians
Quiet Noise Quiet Noise

FIGURE 3
Speech-in-noise perception is linked to both reading ability and musical training. (Top)
Musicians benefit from enhanced speech-in-noise perception across the lifespan. Left,
standardized scores; center and right, signal-to-noise threshold in dB (modified from Kraus
et al., 2012). School-age children musicians (n ¼ 15) began training by age 5 and trained for
at least 4 years (nonmusician, n ¼ 16); young adult musicians (n ¼ 16) began training by age
7 and trained for at least 10 years (nonmusician, n ¼ 15); older adult musicians (n ¼ 18)
began training by age 9 and trained for at least 40 years (nonmusician, n ¼ 19). (Bottom left)
Background noise has a less disruptive effect on the timing of the neural response to sound in
good readers (blue) than poor readers (black) (participants divided into top vs. bottom halves
based on performance on the Test of Word Reading Efficiency; modified from Anderson et al.,
2010). (Bottom right) Background noise has less of a disruptive effect on the timing of the
subcortical electrophysiological response to sound in children with musical experience (red)
compared to children with no musical experience (black) (modified from Strait et al., 2012).
(*p < 0.05;**p < 0.01;***p < 0.001).
Tracking rhythmic patterns is, therefore, vital for both music and speech percep-
tion, which in turn is important for the acquisition of reading skills. Moreover, it has
been suggested that the same neural mechanism is responsible for tracking rhythm in
music and speech. An influential theory of musical rhythm perception, Dynamic
Attending Theory, proposes a set of neural oscillators that phase-lock and resonate
to the temporal structure of music, resulting in an attentional focus that waxes and
wanes, following the rhythmic structure of a piece or song (Large, 2000, 2008;
Large and Jones, 1999; McAuley and Jones, 2003; Velasco and Large, 2011). As
evidence in support of this theory, listeners are faster at performing a variety of per-
ceptual tasks if stimuli are presented aligned with an expected beat (Barnes and
Jones, 2000; Bolger et al., 2013; Escoffier et al., 2010; Grube and Griffiths, 2009;
Table 1 Musicians and good readers show enhancements in similar neural measures in response to speech syllables, suggesting
overlapping biological bases for musical expertise and reading ability
F0 syllable Speech formant Onset Syllable Response Response disruption by
representation representation timing harmonics consistency background noise
Musicians No relationship Enhanced, earlier Earlier Enhanced Enhanced Lessened

Good No relationship Enhanced, earlier Earlier Enhanced Enhanced Lessened
readers
In particular, reading acquisition may rely on neural synchrony, which musical training enhances.
3 Rhythm 217
Jones et al., 2002; Ladinig et al., 2009; Miller et al., 2013). Stimuli aligned with
stronger metrical positions also give rise to larger electrophysiological potentials
(Abecasis et al., 2005, 2009; Brochard et al., 2003; Geiser et al., 2009, 2010;
Ladinig et al., 2009; Pablos Martin et al., 2007; Potter et al., 2009; Schaefer
et al., 2011; Vlek et al., 2011; Winkler et al., 2009) and greater oscillatory activity
in the beta and gamma range (Iversen et al., 2009; Snyder and Large, 2005). More-
over, neural oscillations have been recorded which reproduce the perceived rhythmic
structure of abstract rhythmic patterns (Nozaradan et al., 2011, 2012).
A similar neural mechanism has been proposed for the tracking of the rise and fall
of speech amplitude over time (Goswami, 2011; Poeppel et al., 2008): phase-locking
of slow neural oscillations in the delta and theta range (2–7 Hz). This Temporal Sam-
pling Hypothesis proposes that delta/theta oscillatory phase-locking selectively
“samples” the low-frequency information in the amplitude envelope, which is crucial
for the segmentation of speech and discrimination of speech sounds (Drullman,
1994). Supporting this hypothesis, electrophysiologic recordings from auditory cor-
tex can reflect the speech envelope (Abrams et al., 2008; Aiken and Picton, 2008;
Doelling et al., 2013), and the phase of slow oscillations in neural responses can
be used to discriminate spoken sentences (Luo and Poeppel, 2007). That this enve-
lope tracking is important for the development of language skills rather than a mere
epiphenomenon is demonstrated by the fact that while good readers show right-
lateralized envelope tracking, poor readers show envelope tracking that is distributed
symmetrically across the two hemispheres (Abrams et al., 2009). Similarly, while
normally developing subjects show right-lateralized phase-locking to low-frequency
(2 Hz) amplitude modulation, subjects with dyslexia show symmetrically distributed
phase-locking (Hämäläinen et al., 2012).
If the Dynamic Attending Theory and the Temporal Sampling Hypothesis are
both correct, rhythm in music and the envelope of speech may be tracked biologi-
cally via the same mechanism—phase-locking of low-frequency neural oscillators
to slow rises and falls of amplitude, a mechanism that (like the fine temporal and
frequency representation discussed in the first section of this chapter) relies upon ro-
bust neural synchrony. Thus, strengthening this mechanism through training in one
domain could lead to benefits for the other. This shared mechanism could explain
why reading ability and phonological awareness relate to a variety of rhythm-
tracking abilities, including discrimination of stimuli based on amplitude rise times
(Goswami et al., 2002, 2011; Hämäläinen et al., 2005; Leong et al., 2011; Muneaux
et al., 2004; Surányi et al., 2008; Thomson and Goswami, 2008; Thomson et al.,
2006) and temporal patterns (Anvari et al., 2002; Atterbury, 1983, 1985; Douglas
and Willatts, 1994; Forgeard et al., 2008; Huss et al., 2011; McGivern et al.,
1991; Overy, 2000, 2003; Strait et al., 2011), reproduction of rhythmic patterns
(Atterbury, 1983, 1985; Creak, 1936; Dellatolas et al., 2009; Peynircioglu et al.,
2002; Rautenberg, 2013), tempo reproduction (Moritz et al., 2012), and tapping to
the beat of music (David et al., 2007). Children with language learning impairment
have been shown to tap more variably to a beat (Corriveau and Goswami, 2009;
Thomson and Goswami, 2008; Thomson et al., 2006; Wolff, 2002), and this
60 60
Tapping variability (ms)
Tapping variability (ms)

50 50
40 40
30 30
20 20
10 10
80 90 100 110 80 90 100 110 120
Nonword reading Word reading
Rhythm
Neural response
Reading
consistency
FIGURE 4
The ability to tap to a beat is linked to reading ability and is strengthened with musical training
(Slater et al., 2013). (Top) Good readers (according to score on the Woodcock-Johnson III
standardized tests Word Attack and Letter-Word ID) tap less variably to the beat of a
metronome (replotted with permission from Tierney and Kraus, 2013a). Word reading,
r ¼ 0.38, p ¼ 0.0036; nonword reading, r ¼ 0.35, p ¼ 0.0067. (Bottom) The relationship
between reading and rhythm may in part be driven by a shared reliance on precise auditory
encoding, as both reading and beat synchronization ability relate to the consistency of the
neural response to sound.
relationship between beat synchronization and reading ability holds in a typically

developing population as well (Tierney and Kraus, 2013a). Musical training leads
to increased rhythmic skills: for example, compared to nonmusicians, musicians pro-
duce less variable taps when drumming to a metronome (Krause et al., 2010a,b;
Repp, 2010; Repp and Doggett, 2007), and a single year of music training in elemen-
tary school leads to an enhanced ability to keep a constant tempo when tapping out a
beat (Slater et al., 2013). Given potential overlap between rhythm-tracking mecha-
nisms in speech and music, rhythmic musical training may be particularly beneficial
for enhancing reading acquisition. In fact, training in beat synchronization has indeed
been shown to lead to improved reading fluency (Taub and Lazarus, 2012). See Fig. 4
for an illustration of how reading relates to rhythm skills such as beat synchronization
(Tierney and Kraus, 2013a).
5 Learning Sound Patterns 219
4 AUDITORY WORKING MEMORY

As described above, reading acquisition depends heavily upon auditory perceptual
skills such as the ability to perceive and neurally represent differences in timing.
Acquiring language and learning to read also depend on auditory working memory,
however; conversing with a partner requires the ability to remember and act upon
what was just said, and the development of phonological awareness relies upon
the ability to keep an auditory sequence in mind long enough to decode it into its
component sounds. Poor readers show low performance on verbal short-term mem-
ory tests including recall of word lists (Brady et al., 1983; Gathercole and Baddeley,
1990), letter lists (Siegel, 1994), and sequences of digits (Strait et al., 2010). Poor
readers also have difficulty with verbal working memory tests such as backwards
recall of digit sequences (Gathercole et al., 2006) and word list recall during simul-
taneous semantic comprehension (Brady et al., 1983; Gathercole et al., 2006).
In the course of learning to perform music, students must learn to memorize long
auditory passages and sequences of movements, pick out and focus attention on a
single sound out of a surrounding cacophony, and take in a complex auditory passage
at a glance. In particular, auditory working memory is relevant to almost all musical
tasks, from tuning an instrument to learning a passage by ear to improvising. Over
time, experience with the challenges of music performance confers cognitive bene-
fits: verbal short-term memory, for example, is enhanced in musicians (Chan et al.,
1998; Ho et al., 2003; Jakobson et al., 2008; Tierney et al., 2008). Musicians also
show superior performance on tests of auditory working memory (Parbery-Clark
et al., 2009a, 2011a; Strait et al., 2013b; reviewed in Kraus et al., 2012). These results
suggest that the same cognitive resources underlying auditory working memory,
which is impaired in poor readers, may be enhanced by musical training. Figure 5
illustrates that both good readers and musicians perform better on tests of auditory
working memory (Kraus et al., 2012).
5 LEARNING SOUND PATTERNS

To acquire the phonemic knowledge necessary for the acquisition of reading skills, it
is not enough to be able to represent sound precisely, discriminate between sounds,
and hold sequences of sounds in memory. To learn the locations of the boundaries
between words and between syllables, budding readers must also be able to pick up
on sound patterns and adjust their expectations accordingly—that is, they must be
able to learn about sound. Typically developing children, when presented with a
stream of speech syllables in which certain syllables tend to be followed by certain
other syllables (i.e., /du/ always precedes /ta/), are able to extract the underlying tran-
sitional probabilities governing the formation of words (Saffran et al., 1996, 1999),
and their ability to do so relates to their expressive vocabulary. Learning-impaired
children, however, are less successful at detecting these regularities, showing perfor-
mance no different from chance (Evans et al., 2009).
School-age
children
130
Auditory working memory

120
110
100
90
80
Good Poor
readers readers
School-age
Young adults children Older adults
Auditory working memory
130 130
130
120 120 120
110 110 110
100 100 100

Musicians Nonmusicians Musicians Nonmusicians Musicians Nonmusicians
FIGURE 5
Auditory working memory is linked to both reading ability and musical training. (Top) School-
age good readers (divided into halves based on performance on the Test of Silent Word
Reading Fluency) perform better (standardized scores) than poor readers on the Woodcock-
Johnson III test of auditory working memory (unpublished data). (Bottom) Musical
experience is linked to an enhancement of auditory working memory across the lifespan.
Modified from Kraus et al. (2012).
Musicians, on the other hand, show an enhanced ability to lock onto regularities
in sound. Francois and Schön (2011) demonstrated that musicians were better able to
learn both musical and linguistic regularities in a sung language: the degree to which
stimuli followed an underlying musical or linguistic rule modulated electrophysio-
logical responses to a greater extent in musicians compared to nonmusicians. In a
follow-up longitudinal study, François et al. (2013) studied 8-year-old children
for 2 years as they were trained in either music or painting. At pretest, after 1 year,
and after 2 years of training, the painting group was unable to learn the transitional
probabilities between stimuli. The music group performed at chance at pretest, but
performed above chance after 1 year and again after 2 years of training, demonstrat-
ing an enhanced ability to extract the rules underlying word segmentation. Further-
more, whether or not stimuli followed the learned rule modulated
electrophysiological responses to a greater extent in the music group after 2 years
of training. Similarly, Skoe et al. (2013) found that subjects with musical training
were better able to detect the transitional probabilities within tone sequences and
6 Summary and Limitations of Cross-Sectional Studies 221
the number of years of training correlated with the extent to which the presence of
statistical patterns in tone sequences affected the subcortical response to sound.
Another, simpler way to examine the neural tracking of stimulus regularities is to
present a speech sound in one of two contexts: either within a stream consisting of
only that same sound or among a set of other sounds. In good readers, the sound pre-
sented in the consistent, predictable context elicits a larger electrophysiological re-
sponse compared to the unpredictable condition. In poor readers, however, the
response is more similar in the two conditions (Chandrasekaran et al., 2009; Strait
et al., 2011), suggesting that reading is tied to the ability to track patterns in sound.
This predictability enhancement is also tied to musical aptitude (Strait et al., 2011)
and is larger in musicians than in nonmusicians (Parbery-Clark et al., 2011b). Mu-
sical training may, therefore, exercise mechanisms for the detection of patterns in
sound that are also critical for reading acquisition.
6 SUMMARY AND LIMITATIONS OF CROSS-SECTIONAL

STUDIES
The preceding sections have laid the theoretical groundwork for why one might
expect musical training to enhance the ability to read. Although the processes
involved in playing an instrument and connecting printed letters to speech sounds
and meaning may at first seem quite different, when music and reading are broken
down to their components there is quite a bit of overlap in the resources upon which
the two abilities draw. Precise temporal and frequency representation, rapid auditory
processing, perceiving a signal in noise, auditory working memory, and auditory
pattern learning are all abilities called upon in the process of learning music and read-
ing. Moreover, overlap has been reported in the biological foundations of reading and
music: rhythmic patterns in both speech and music may be tracked by phase-locking
of slow oscillations and precise neural synchrony may be vital for both the develop-
ment of phonological awareness and rhythmic ability.
There is ample reason to believe, therefore, that musical training could have a
positive impact on children learning to read. The previously discussed links between
reading and music have, however, come largely from cross-sectional and correla-
tional studies, indicating that proficient reading ability and musical training are
linked to similar perceptual and neural mechanisms. These results suggest that mu-
sical training could improve reading ability, but cannot be taken as strong evidence
for this claim. Certain other factors could conceivably account for relationships be-
tween musical and reading skills. Although the majority of these studies attempted to
control for factors such as general intelligence and socioeconomic background, less
tangible factors such as parental involvement in education may be playing a role as
well and are more difficult to control for. Somewhat stronger evidence in support of a
causative influence of musical training on language skills comes from correlations
between extent of musical training and performance; a study by Corrigall and
Trainor (2011), for example, reported positive correlations between length of music
training and reading comprehension performance, even after controlling for age, so-
cioeconomic status, IQ, and number of hours that children spent reading per week.
Length of music training has also been reported to correlate with speech-in-noise
perception (Parbery-Clark et al., 2009a) and auditory working memory (Strait
et al., 2012; reviewed in Skoe and Kraus, 2013). Nevertheless, it remains possible
that participants with certain personality characteristics are more likely, a priori,
to continue with musical training rather than stopping after a few years (Corrigall
et al., 2013). Longitudinal experimental studies, therefore, provide the most ironclad
evidence for a causative relationship between musical experience and reading
ability. In the past few decades, there have been numerous attempts to design lon-
gitudinal experiments to investigate the question of how undergoing musical training
affects linguistic ability, including the acquisition of reading and precursor skills
such as phonological awareness. In this section, we review the literature on musical
Table 2 Summary of longitudinal studies of the effect of music training on reading

ability and phonological awareness
Improvements
Control relative to
Study Subjects Music training group control group
Without random assignment
Hurwitz et al. 20 7-year-olds Experimenter- No training Reading

(1975) designed
Standley 32 4–5-year- Experimenter- No training Pre-reading
(1997) olds designed skills
Overy (2000, 9 dyslexic Experimenter- None Phonological
2003) 9-year-olds designed awareness and
spelling
Register 86 5–7-year- Experimenter- Literacy- None
(2004) olds designed to training
teach language television show
skills
Gromko 103 5-year- Experimenter- No training Phoneme
(2005) olds designed segmentation
fluency
Rauscher 75 5-year-olds Private Suzuki Swimming Word naming
and Hinton violin instruction lessons or no and phonemic
(2011) training awareness
Moritz et al. 30 5-year-olds Preexisting Less frequent Phonological
(2012) school music music classes awareness
classes
Tierney et al. 43 Preexisting Fitness training Earlier neural
(2013) adolescents school music timing
classes
6 Summary and Limitations of Cross-Sectional Studies 223
With random assignment
Roskam 36 learning- Experimenter- Learning None

(1979) disabled designed disability
6–9-year-olds rehabilitation
Douglas and 12 reading- Experimenter- No training Reading
Willatts disabled designed
(1994) 9-year-olds
Fisher (2001) 80 5-year-olds Experimenter- Language skill Phoneme
designed to teaching segmentation
teach language without music and oral skills
skills
Costa-Giomi 80 fourth- Private piano No training None
(2004) graders instruction
Register et al. 33 second- Experimenter- No training Word
(2007) graders, 6 designed to knowledge
reading- teach reading
disabled skills
Forgeard 44 6-year-olds Unclear No training Word reading
et al. (2008)
Moreno et al. 32 8-year-olds Computer- Painting or no Reading
(2009) based training
Degé and 41 5–6-year- Experimenter- Phonological Phonological
Schwarzer olds designed skill training awareness
(2011)
Herrera et al. 97 4-year-olds Experimenter- Phonological Phonological
(2010) designed to skill training or awareness
teach no training
phonological
skills
Taub and 280 students, Synchronization No training Reading
Lazarus age unclear to metronome
(2012)
Bhide et al. 19 poor Computer- Reading None
(2013) readers, 6–7 based rhythm intervention
years old training
Cogo- 240 poor Experimenter- No training Reading and
Moreira et al. readers, 9 designed phonological
(2013) years old awareness
Rautenberg 159 7-year- Experimenter- Visual arts Word reading
(2013) olds designed training or no
training
Slater et al. 42 6–9-year- Previously No training Reading
(2013) olds existing music
program
training and reading. See Table 2 for a summary of the experimental design and
results of these studies.
7 LONGITUDINAL MUSIC TRAINING STUDIES

The gold standard experimental model for learning/training studies is random assign-
ment to an experimental group with two control groups: an active control and a pas-
sive control, with a unified course of training. If children are not randomly assigned
to either a musical training group or a control group, the possibility remains that any
differences which emerge between the two groups are due to some preexisting dif-
ference in motivation or ability which caused some of the children to pursue music in
the first place. Not using an active control group leaves open the possibility that
trained children are improving relative to control children simply due to the extra
attention they are receiving from instructors. And ideally, assessments will also
be made before training, just after training, and long after training has stopped, to
determine whether any training-related benefits are retained after training ceases.
In practice, few if any fully controlled studies of musical training can hew to these
stringent criteria because of challenges inherent in assessment of training in a real-
world setting. It can, for example, be very difficult to conduct a study on the effects of
musical training with random assignment, as subjects who are interested in musical
training may be unwilling to postpone the start of their training until after the com-
pletion of the study. Furthermore, finding an active control training regimen that
matches musical training in intensity and motivation can be logistically difficult.
Finally, if children are engaged in musical training as part of a music class or other
structured program that briefly brings these children together, it can be quite difficult
to continue to track them for months after instruction ceases. There is often, there-
fore, a tradeoff between the ecological validity of the musical instruction presented to
subjects and the extent to which study designs can meet these criteria. On the one
hand, using training programs or lesson plans developed by the experimenter can
enable more rigorously controlled studies, but the results of such studies will be
somewhat difficult to generalize to the effects of real world music learning condi-
tions. On the other hand, by studying existing programs that have been demonstra-
tively successful in teaching children musical skills, researchers can maximize the
applicability of their research to educators, at the cost of certain limitations in study
design. The body of knowledge about the effects of musical training on reading abil-
ity has been contributed to by a broad variety of study designs which, as a whole,
support the notion that musical training can enhance reading acquisition.
To date, studies on the effects of musical training on language skills and the neu-
ral encoding of sound have used a variety of behavioral and neural assessments. This
approach has revealed a variety of advantages linked to musical training, but com-
parisons among studies have been difficult, as difference in outcomes could be either
due to differences in the extent, type, or age of onset of training or due to differences
in the outcome measures themselves. The use of a uniform biological assessment of
8 Experimental Studies without Random Assignment 225
the neural encoding of sound—that is, using the same measure irrespective of age or
species—would enable cross-study comparison, allowing researchers to determine
how musical training affects different populations or how the effects of different
kinds of musical training vary. We have pioneered the use of a neural, scalp-
electrode recorded measure with several unique attributes, the complex auditory
brainstem response (cABR). This electrophysiological response closely mirrors
the acoustic characteristics of the evoking stimulus (Skoe and Kraus, 2010), and
can be modified by experience (Kraus and Chandrasekaran, 2010). Moreover, while
the cABR shows a high degree of test–retest reliability (Hornickel et al., 2012;
Krishnan et al., 2012), there are large individual differences in aspects of the cABR
between participants which have been linked to a variety of communication skills,
including speech-in-noise perception and reading (Anderson et al., 2010). Under-
standing the source of these individual differences and how they underlie differences
in communication skills is an important direction for future neuroeducational work.
This neural response represents a snapshot into a neural hub of hearing—depicting a
cohesive sensory-cognitive-reward system. More widespread adoption of this mea-
sure would, therefore, both enable researchers to study the effects of music on the
biological basis of speech perception and language skills and facilitate the synthesis
of music training research into an integrated whole. To facilitate the cABR’s adoption
as a widely used measure across studies future work should focus on the improvement
of the efficiency and ease-of-use of the collection of this biological metric.
8 EXPERIMENTAL STUDIES WITHOUT RANDOM ASSIGNMENT

In the first longitudinal study ever conducted on the question of whether musical
training enhances reading ability, Hurwitz et al. (1975) gave children from one
school system musical training from the Kodaly curriculum, a standard music edu-
cation approach in use since the mid-twentieth century; children from a second
school system were given no special training. The two groups were matched on read-
ing ability at pretest, but after 1 and 2 years of training the experimental group had
better reading scores than the control group. Standley (1997) gave prekindergarten
children either musical training designed by the experimenter or no training, and
found that the music training group, compared to the control group, showed gains
in performance on tests of language knowledge necessary for reading acquisition.
However, the musical training included focus on pre-reading and writing skills,
and thus it is difficult to know whether the experimental group’s gains can be attrib-
uted to the musical aspects of the training per se. Overy (2000, 2003) gave rhythm-
based musical training designed by the experimenter to a group of children and found
gains in phonological awareness and spelling; given the lack of a control group, how-
ever, these results are difficult to interpret. Register (2004) taught early literacy skills
to children via either a television show or a musical curriculum designed by the re-
searcher and administered by a music therapist and found that the two approaches
led to equivalent gains in preliteracy skills. Gromko (2005) gave music instruction
designed by the experimenter to children at a treatment school, while children at a

control school were given no special training; children at the treatment school, but
not control children, showed gains in phoneme segmentation fluency. Rauscher and
Hinton (2011) gave 5-year-old children private, one-on-one Suzuki violin instruc-
tion, swimming lessons, or no training. The three groups did not differ at pretest,
but at posttest, the violin group’s performance on Letter-Word Calling and Phonemic
Awareness tests had improved relative to the other two groups. Moritz et al. (2012)
compared kindergartners from two different charter schools, one of which provided
daily music lessons, and another which provided only one music lesson per week.
Children from the school with more frequent music lessons showed greater gains
in phonological awareness than children who were exposed to less musical training.
Finally, longitudinal work in progress in our laboratory is examining reading ability
over time in adolescents in charter schools who have elected to participate in either
in-school music classes, ROTC training, or no special training. The musical training
being studied has been used successfully for years at these schools to teach children
musical skills. Preliminary data suggest that neural responses to a speech sound pre-
sented in noise are becoming less delayed in the musically trained group compared to
the other two groups, supporting previous findings of a link between musical training
and a lessening of the noise-induced delay in neural responses to sound (Tierney
et al., 2013).
9 EXPERIMENTAL STUDIES WITH RANDOM ASSIGNMENT

Taken as a whole, the results reported in the previous section suggest that musical
training in childhood may lead to increased phonological awareness and reading abil-
ity. However, without the use of random assignment, one cannot entirely reject the
possibility that any gains made in the experimental group versus the control group
are due either to a preexisting difference in personality (Corrigall et al., 2013), mo-
tivation, or ability (driving the experimental group to take up music lessons in the
first place) or to preexisting differences in the classes or schools to which the two
groups of subjects belonged. The strongest evidence for an effect of musical training
on reading ability comes from experimental studies that have randomly assigned sub-
jects to either a musical training group or a control group.
In the first study of musical training and reading to use random assignment,
Roskam (1979) divided learning-disabled 6-9-year-old children into a control and
two experimental groups, one of which was rehabilitated using standard techniques
and the other of which received music therapy designed by the experimenter. No sig-
nificant effects of training were found. In a small pilot study, Douglas and Willatts
(1994) studied 12 reading-disabled children, half of which were given musical train-
ing designed by the experimenters. Reading scores for the musical training group
increased from pretest to posttest, while scores for the control group did not change.
Fisher (2001) compared children in kindergarten who learned language skills
through lessons which incorporated music, compared to children who took more
9 Experimental Studies with Random Assignment 227
traditional nonmusical classes. The music group showed greater gains in phoneme
segmentation ability and oral skills. Costa-Giomi (2004) randomly assigned children
to either a training group who received private, one-on-one piano instruction
designed by individual piano teachers for 3 years or a control group that received
no instruction and found no effects on academic achievement in either language
or math. Register et al. (2007) compared second-grade students engaged in a music
curriculum designed by the experimenters to students receiving no musical training
and found that the music group experienced greater gains pre- to posttest in word
knowledge. However, given that the music curriculum included instruction in read-
ing strategies it is difficult to know whether the increased reading skill was driven by
the musical aspects of the training. In a pilot study, Forgeard et al. (2008) found that
six children given musical training improved more than children who received no
training on word reading. (The exact nature of the musical training—in particular,
whether it was classroom training or a program designed by the experimenter—is
difficult to determine from the manuscript.)
Early work on musical training and reading skill using random assignment, there-
fore, did not provide strong evidence for the effectiveness of musical training; the
studies cited above all either reported null results, used extremely small numbers
of subjects, or presented musical training which included linguistic training. How-
ever, more recent work has used larger subject populations and reported much more
promising results. Moreno et al. (2009), for example, gave children computer-based
training designed by the experimenter to enhance either painting skills or musical
skills. Only the children in the music group showed improvement in a reading task
after training. Herrera et al. (2010) examined the development of phonological abil-
ities in children in a control group, a group receiving phonological training, and a
group receiving phonological training featuring additional musical elements. The
training programs were designed by the authors. At posttest, the musical training
group outperformed the other two groups on phonological awareness. Degé and
Schwarzer (2011) compared the effects of a music program and a phonological skills
program (both created by the authors) in preschoolers and found that the two training
groups led to similar gains in phonological awareness. Taub and Lazarus (2013) gave
children either training in synchronizing movements to a metronome or no training
and found at posttest that the experimental group’s reading scores were higher than
the control groups’ scores. Bhide et al. (2013) gave a group of 6–7-year-old children
either a computer-assisted reading intervention or rhythm training designed by the
experimenters including both musical and linguistic elements; both groups improved
in reading ability by similar amounts. However, given that the rhythm training con-
tained both musical and linguistic elements, it is difficult to determine whether the
gains shown by the children in the rhythm group could be elicited by the musical
elements alone. Cogo-Moreira et al. (2013), in a large-scale clinical study, found that
musical training designed by the experimenters (compared to no training) led to in-
creases in reading ability and phonological awareness in young poor readers when
compliance was taken into account. Rautenberg (2013) found that music classes
designed by the experimenter led to an improvement in word reading compared
to either visual arts classes or no classes. Finally, a longitudinal study from our re-
search group is currently examining the development of reading skills over time in
two groups of children, one of whom was assigned musical training as part of the
Harmony Project, a nonprofit organization which for years has provided musical
training to underserved children in gang-reduction zones of Los Angeles. All partic-
ipants requested to participate in the Project; these participants were pseudo-
randomly assigned to two groups. In the first year of the study, one group received
musical training while a matched control group did not. The control group began
music classes the following year. Preliminary results suggest that musical training
led to increases in reading ability, speech in noise, and rhythm skills (Slater et al.,
2013).
10 WHY MUSIC?
In summary, there is a theoretical basis for a link between musical training and read-
ing ability, as the neural and cognitive resources necessary for reading acquisition
and those resources drawn upon in the course of learning to play music overlap.
Moreover, extensive empirical evidence collected over several decades indicates that
musical training can enhance reading ability. Noteworthy is that some of the same
aspects of neural encoding of speech that are deficient in individuals with commu-
nication difficulties such as dyslexia, reflecting decreased neural synchrony, are
strengthened in musicians compared to their nonmusician peers, suggesting overlap-
ping biological bases for musical expertise and reading ability (Kraus and
Chandrasekaran, 2010; Strait and Kraus, 2011). These results may indicate that mu-
sical training can lead to increased neural synchrony throughout the auditory system,
suggesting that music could be an effective way to boost reading skills in children.
Nevertheless, the question remains: why not simply train reading itself? Would that
not be a more direct, and potentially more effective, way of enhancing reading abil-
ity? Certainly, we do not mean to suggest that musical training should supplant read-
ing training. Instead, we would argue for the inclusion of musical training as a part of
a balanced school curriculum, including reading, foreign language instruction, math-
ematics, science, athletics, etc. Difficulties with reading can stem from a variety of
sources. Some children are likely to draw the greatest benefit from musical training,
while other children may respond better to other forms of instruction.
One of the reasons musical training can be such a powerful educational tool is that
music is inherently rewarding, emotion-inducing, and attention-grabbing (Menon
and Levitin, 2005; Patel, 2011, 2013). Neural plasticity can be enhanced by attention
(Fritz et al., 2013) and motivation (David et al., 2012; Rutkowski and Weinberger,
2005), and neural plasticity can enhance perceptual learning (Reed et al., 2011). The
rewarding nature of music listening and music performance (Salimpoor et al., 2013)
makes it ideal for getting children interested in school and giving them the auditory,
motor, and cognitive skills they need to learn to read and succeed, both in school and
later in life. In fact, active training in early life can lead to benefits in task
References 229
performance in adulthood (Sarro and Sanes, 2011), but passive exposure to stimuli in
juveniles does not have long-term benefits (Engineer et al., 2004; Sarro and Sanes,
2011). As music is one of the most active, absorbing ways that children can interact
with sound, even a few years of music instruction early in life can have profound
effects on the functioning of the nervous system years later (Skoe and Kraus, 2012;
White-Schwoch et al., 2013). And of course, even if a given child receives no
extramusical benefit from his or her instruction, at worst they will have gained an
aesthetic appreciation with the potential to last a lifetime.
Acknowledgments
This research is supported by NSF BCS-1057556 and BCS-0921275, NIH R01-HD069414,
and the Knowles Hearing Center. We would also like to thank Samira Anderson, Travis
White-Schwoch, Jessica Slater, and Elaine Thompson for comments on a previous version
of this Chapter.
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CHAPTER
Mechanisms of Plasticity in
the Developing and Adult
Visual Cortex
Mriganka Sur1, Ikue Nagakura, Naiyan Chen, Hiroki Sugihara
9
Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences,
Massachusetts Institute of Technology, Cambridge, MA, USA
1
Corresponding author: Tel.: þ1-617-253-8784; Fax: þ1-617-253-9829
e-mail address: msur@mit.edu
Abstract
The visual cortex provides powerful evidence for experience-dependent plasticity during de-
velopment, and for stimulus and reinforcement-dependent plasticity in adulthood. The synap-
tic and circuit mechanisms underlying such plasticity are being progressively understood.
Increasing evidence supports the hypothesis that plasticity in both the developing and adult
visual cortex is initiated by a transient reduction of inhibitory drive, and implemented by per-
sistent changes at excitatory synapses. Developmental plasticity may be induced by alterations
in the balance of activity from the two eyes and is implemented by a cascade of signals that
lead to feedforward and feedback changes at synapses. Adult plasticity is imposed on mature
synapses and requires additional neurotransmitter-dependent mechanisms that alter inhibition
and subsequently response gain.
Keywords
circuits, sensory cortex, ocular dominance plasticity, reinforcement learning, inhibition,
excitatory synapses, glutamate receptors, parvalbumin neurons
The visual system is a powerful model system for analyzing how sensory experience
and electrical activity regulate the development of synapses and neuronal circuits in a
processing pathway. In particular, the primary visual cortex, or V1, has been a prov-
ing ground for revealing both the phenomena and mechanisms of developmental
plasticity in the mammalian cerebral cortex. The visual cortex exhibits profound
plasticity during development: for example, an alteration in visual drive induced
by even a brief eyelid closure of one eye, which induces unbalanced inputs from
the two eyes, results in weakening of V1 neuron responses to the deprived (closed)
eye while strengthening the responses to the nondeprived (open) eye (Gordon and
Stryker, 1996; Hubel and Wiesel, 1970). The mechanisms underlying developmental
243
244 CHAPTER 9 Mechanisms of Plasticity
plasticity in the visual cortex have been the subject of intense study (Espinosa and
Stryker, 2012; Nagakura et al., 2013).
The visual cortex also exhibits prominent plasticity in adulthood, as revealed by
systematic changes in neuronal responses due to prolonged visual stimulation
(Dragoi et al., 2000) or by pairing visual stimuli with neuromodulatory inputs
(Chen et al., 2012). While it is generally accepted that adult V1 is less susceptible
to passive experience-driven changes and therefore exhibits less plasticity than dur-
ing the critical period, considerable plasticity can be induced in V1 and other sensory
cortex by reinforcement-dependent associative learning; however, the mechanisms
of adult plasticity are less understood. In this review, we suggest that both develop-
mental and adult plasticity share common features related to initiating and maintain-
ing changes in neuronal responses. Specific mechanisms by which response
plasticity is maintained may differ in the developing and adult cortex, as would spe-
cific mechanisms by which plasticity is initiated, but the conceptual similarities point
to important principles underlying experience and stimulation-dependent plasticity
of neuronal responses and representations in cortical circuits.
1 VISUAL CORTEX PLASTICITY DURING DEVELOPMENT

One of the most extensively studied forms of plasticity in the developing brain relates
to changes induced in V1 by brief closure of one eye, or monocular deprivation
(MD). Whereas neuronal responses in V1 are normally driven by each of the two
eyes in some combination, responses after MD are dominated by the open eye. Such
ocular dominance plasticity (ODP) is prominent during a developmental “critical pe-
riod” (Gordon and Stryker, 1996; but see Frenkel and Bear, 2004), which refers to a
particularly sensitive phase of development during which even a brief alteration in
visual experience induces significant changes in cortical circuits.
Considerable attention has been devoted to excitatory glutamatergic synapses in
V1 and their downstream signaling mechanisms as sites for implementing and main-
taining ODP. Glutamate receptors include N-methyl-D-aspartate receptors
(NMDARs), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
(AMPARs), and metabotropic glutamate receptors (mGluRs). Several lines of evi-
dence suggest that the composition of NR2A subunits (which have reduced calcium
influx, and thus reduce plasticity) and NR2B subunits (which have high calcium per-
meability, and thus enhance plasticity) of NMDARs changes through visual experi-
ence during postnatal development (Flint et al., 1997). The NR2A/NR2B ratio
increases during normal development, allowing less plasticity toward adulthood
(Quinlan et al., 1999). Rearing rodents in the dark from birth, however, leads to re-
duction in the ratio of NR2A/NR2B subunits (Chen and Bear, 2007), which likely
allows ODP to take place even during adulthood (He et al., 2006). MD also induces
dephosphorylation and internalization of the GluA1 subunit of AMPARs, which cor-
responds to synaptic depression induced by MD (Heynen et al., 2003). The mGluRs
1 Visual Cortex Plasticity During Development 245
are known to be required for plasticity in the visual cortex layer 6, but it appears not
in the layer 2/3 nor 5 (Daw et al., 1999; Rao and Daw, 2004).
The signaling initiated by glutamate and its receptors is conveyed inside a neuron
into a cascade of downstream signaling. The cAMP-dependent protein kinase (pro-
tein kinase A or PKA) regulates glutamate receptor-mediated synaptic plasticity by
phosphorylating GluA1 and regulating glutamate receptor complexes (Heynen et al.,
2003; Kameyama et al., 1998). Moreover, PKA translocates into the nucleus for
downstream cAMP response element (CRE)-mediated gene expression together with
extracellular signal-regulated kinase 1,2 (ERK) (Cancedda et al., 2003). Both PKA
and ERK are required for ODP (Beaver et al., 2001; Di Cristo et al., 2001), likely
through CRE-mediated gene expression (Fig. 1).
Gene expression analysis in the primary visual cortex during the critical period
and following visual deprivation provides a comprehensive view of cortical changes
during normal development and experience-dependent plasticity. The critical period
in mice is accompanied by a distinct transcriptional profile that includes genes
Ca2+
Presynaptic excit neuron NMDAR/AMPAR
GABAR
ACh
Presynaptic inhib neuron
mGluR
Pyramidal neuron
Glutamatergic synapse
Astrocyte process mAChR

Implementing/
maintaining plasticity K+ channels
Glutamate
GABA
Intracellular
signals
ACh
0
Ca2+
Gene transcription
G
A
B
A
er
gi
c
sy
Initiating/activating plasticity
na
ps
e
FIGURE 1
Schematic of a cortical pyramidal neuron with an excitatory synapse (top left) and inhibitory
synapse (bottom right). Symbols are explained in the key (top right). Increasing evidence
supports the hypothesis that plasticity in the developing and adult cortex is initiated by a
transient reduction of inhibitory drive, and implemented by persistent changes at excitatory
synapses. See text for details.
related to the actin cytoskeleton, G protein signaling, transcription and myelination,

and MD during the critical period reverses the expression pattern of the majority of
these genes (Lyckman et al., 2008). In particular, MD activates sets of genes that
comprise molecular pathways related to growth factors and neuronal degeneration
(Tropea et al., 2006). Expression of a binding protein of insulin-like growth
factor-1 (IGF1) is highly upregulated after MD, which downregulates IGF1 and
its downstream phosphatidylinositol 3-kinase/Akt signaling pathway; exogenous
application of IGF1 upregulates these signals and prevents ODP (Tropea et al.,
2006). Taken together, signaling initiated by the release of glutamate leads to signif-
icant changes in the postsynaptic response, which leads to subsequent physiological
changes that are important components of implementing ODP.
ODP was described as arising from “binocular competition” (Hubel and Wiesel,
1970), which is now considered to involve two separable processes: a feedforward or
Hebbian component in which closed eye responses are reduced, and a feedback or
homeostatic component in which open eye responses are enhanced (Sato and
Stryker, 2008; Tropea et al., 2009). In mice, these two processes are sequential
in time: short-term MD, of 1–4 days duration, leads to reduction of closed eye
responses, whereas longer MD, of 5 or more days, reveals open eye enhancement.
In ferrets, however, the enhancement of open eye responses is evident nearly syn-
chronously with reduction of closed eye responses (Yu et al., 2011), suggesting that
the mechanisms of feedforward and feedback changes may themselves be dynami-
cally regulated. Distinct mechanisms have been proposed for these changes. In ad-
dition to the molecules mentioned previously, most of which affect the reduction of
closed eye responses after MD and hence the feedforward component of ODP, many
microRNAs are abundantly expressed in V1 and are affected by MD (Mellios et al.,
2011). Expression of miR-132 is significantly reduced by short-term MD, and inhi-
bition of miR-132 prevents the reduction of closed eye responses after brief MD.
Other molecules affect the feedback component of MD. Tumor necrosis factor
alpha (TNF-a) is a proinflammatory cytokine that is released by glial cells and acts
on neurons through its receptor TNFR1 (Stellwagen and Malenka, 2006; Stellwagen
et al., 2005). In mice lacking TNF-a, no homeostatic increase is observed in open eye
responses while closed eye responses are left intact (Kaneko et al., 2008). These mice
show normal LTP in the visual cortex but lack synaptic amplitude regulation induced
by activity blockade, suggesting a role for synaptic scaling in this component of plas-
ticity. Separate molecules negatively regulate feedback plasticity. In mice lacking
STAT1 (a member of the Signal Transducers and Activators of Transcription family
of transcription factors), there is an accelerated increase of open eye responses after
short-term MD along with normal decrease of closed eye responses (Nagakura et al.,
2011). Interestingly, the accelerated enhancement of open eye responses is accom-
panied by increased AMPAR expression and function. A single molecule that ap-
pears to coregulate both feedforward and feedback plasticity is the immediately-
early gene Arc (Arg3.1). Arc has a role in synaptic plasticity through regulation
of AMPAR trafficking (Shepherd and Bear, 2011), and mice lacking Arc show im-
pairments in both closed and open eye responses after MD (McCurry et al., 2010).
2 Plasticity in the Adult Visual Cortex 247
Arc is coexpressed with the synaptic molecule CaMKIIa in pyramidal neurons; a

novel FRET probe reveals that activated CaMKIIa is upregulated in individual
closed eye synapses/spines of ferret V1 after brief MD and thus has a role in preserv-
ing spines from being lost (Mower et al., 2011).
While changes in glutamatergic, excitatory synaptic transmission are crucial for
implementing ODP, growing evidence points to the role of gamma-aminobutyric
acid (GABA) receptor-mediated inhibition in initiating ODP and regulating the crit-
ical period (Fig. 1). Mice with genetic deletion of the GABA-synthetic enzyme
GAD65 show lack of ODP induced by MD (Hensch et al., 1998), while accelerating
GABA circuit function triggers premature plasticity prior to the critical period (Di
Cristo et al., 2007; Sugiyama et al., 2008). Brain-derived neurotrophic factor
(BDNF) is a key neurotrophin that triggers maturation of inhibitory circuits, and
overexpression of BDNF leads to a precocious termination of the critical period
for ODP (Huang et al., 1999). Parvalbumin (PV)-expressing basket cells, which com-
prise the largest class (up to 50%) of inhibitory interneurons in the mouse visual cor-
tex (Gonchar et al., 2007), appear to regulate ODP via synaptic inputs to GABAA
receptor-a1 subunits in excitatory neurons (Fagiolini et al., 2004). Maturation of
PV cells is controlled by molecules such as BDNF and the embryonic homeoprotein
Otx2 (Huang et al., 1999; Sugiyama et al., 2008). Additional mechanisms of regu-
lating inhibition include Lynx1, which binds to the nicotinic acetylcholine (ACh)
receptor and maintains the balance between excitation and inhibition through cho-
linergic inhibition; without Lynx1, plasticity is extended into adulthood
(Morishita et al., 2010). Transient reduction of PV-mediated inhibition appears to
have a crucial role in triggering ODP (Kuhlman et al., 2013): direct recordings from
PV interneurons in mouse V1 reveal a reduction in their closed eye (and even open
eye) responses after 1 day of MD, which leads to a rapid restoration of visual drive to
pyramidal neurons. Enhancing GABAergic inhibition blocks ODP, while reducing
the spike activity of PV neurons extends the critical period.
2 PLASTICITY IN THE ADULT VISUAL CORTEX

V1 neuron responses in the adult brain can be modified by previous visual experi-
ence, on timescales ranging from seconds to days. In particular, the orientation tun-
ing curves of neurons can be altered by selective experience with particular
orientations. Practicing orientation discrimination for weeks or months can lead to
an overrepresentation of the practiced orientation at the expense of other orientations
(Schoups et al., 2001). Specific temporal patterns of rapidly presented pairs of stim-
uli, for tens of minutes, can shift the tuning curve of V1 neurons toward the condi-
tioned orientation (Felsen et al., 2002; Yao and Dan, 2001; Yao et al., 2004). Paired
electrical and visual stimulation can induce a similar effect after prolonged pairing
(Godde et al., 2002). Physiologically, continuous presentation of a single orientation
for several seconds to minutes leads to a reduction of responses to the adapting
orientation, and a shift in the tuning curve away from the adapting orientation
(Dragoi et al., 2000, 2001, 2002). Perceptually, the “tilt aftereffect” demonstrates
that viewing a tilted contour even briefly causes the perceived orientation of a sub-
sequently viewed contour to be tilted away from the adapting contour (Gibson, 1937;
Paradiso et al., 1989; Wenderoth and Johnstone, 1988). These forms of visual plas-
ticity induced by passive exposure are often of short duration, and persistent training-
induced plasticity in the adult brain often requires prolonged practice coupled with
reinforcement.
Adult plasticity on long time scales induced by reinforced associative learning
importantly involves neuromodulatory systems including ACh, norepinephrine, se-
rotonin, dopamine, and histamine. These neuromodulators can alter cellular excit-
ability and induce plasticity through presynaptic and/or postsynaptic mechanisms
(Gu, 2002). Among the neuromodulators, the role of ACh in the sensory cortex, in-
cluding the visual cortex, is best understood. The cortex receives its main source of
ACh from cholinergic axons that originates in the nucleus basalis of the basal fore-
brain (Metherate et al., 1992). When cholinergic activation of the adult cortex is
paired with both intracellular depolarization of neurons (Woody et al., 1978) and ap-
plication of glutamate (Lin and Phillis, 1991; Metherate et al., 1987), prolonged fa-
cilitation of neuronal responses is observed. Pairing cholinergic and sensory
stimulation in the adult cortex can induce both neuronal and representational plas-
ticity in the adult somatosensory cortex (Donoghue and Carroll, 1987; Howard
and Simons, 1994; Lamour et al., 1988; Metherate et al., 1987; Rasmusson and
Dykes, 1988; Tremblay et al., 1990a,b), auditory cortex (Bakin and Weinberger,
1996; Dimyan and Weinberger, 1999; Edeline et al., 1994; Kilgard and
Merzenich, 1998a,b; Kilgard et al., 2001), and visual cortex (Chen et al., 2012).
ACh-induced changes can occur at both single cell and cortical map levels. The for-
mer involves neuronal plasticity characterized by potentiation of glutamatergic syn-
apses at pyramidal neurons, while the latter involves representational plasticity as
characterized by reorganization of sensory maps that represent and encode specific
parameters of sensory stimuli (Bakin and Weinberger, 1996; Bao et al., 2003;
Froemke et al., 2007; Kilgard and Merzenich, 1998a; Puckett et al., 2007).
The mechanisms underlying ACh-induced plasticity include direct and indirect
pathways, and appear to involve mechanisms for both initiating and implementing
plasticity. Activation of M1 muscarinic receptors by ACh can directly potentiate re-
sponses in pyramidal neurons through inhibition of postsynaptic SK channels
(Buchanan et al., 2011; Giessel and Sabatini, 2010). ACh leads to prolonged but
prominent calcium responses in astrocytes in vitro (Perea and Araque, 2005), and
in vivo (Navarrete et al., 2012; Takata et al., 2011), making astrocytes a potential
mediator of nucleus basalis-mediated plasticity of cortical responses. Indeed, stim-
ulation of the nucleus basalis directly and strongly activates calcium responses in V1
astrocytes via muscarinic receptors, and mice with conditional knockout of
astrocyte-specific IP3R2 receptors do not have ACh-induced calcium elevation
and fail to show neuronal plasticity induced by paired visual and nucleus basalis
stimulation (Chen et al., 2012). Astrocytes can induce release of gliotransmitters
or regulate extracellular glutamate (Schummers et al., 2008) and potassium
3 Common Principles of Developmental and Adult Plasticity 249
(Seigneur et al., 2006); these mechanisms can lead to increased levels of extracellular
glutamate (Fellin et al., 2004) or D-serine (Henneberger et al., 2010) that can activate
neuronal NMDARs to implement plasticity at excitatory synapses (Fig. 1).
ACh stimulation also elicits rapid responses in inhibitory neurons (Alitto and
Dan, 2012; Kawaguchi, 1997; McCormick and Prince, 1986), including excitatory
responses from subsets of inhibitory neurons and inhibitory responses from other
subsets (Arroyo et al., 2012). An important correlate of basalis-induced plasticity
in the auditory cortex is a transient reduction of inhibition to pyramidal neurons
(Froemke et al., 2007), and reinforcement learning in the adult auditory cortex is ac-
companied by a reduction of PV neuron firing by cholinergic inputs (Letzkus et al.,
2011). Since PV neurons provide divisive inhibition and regulate the response
gain of their target neurons (Wilson et al., 2012), a reduction in PV neuron firing
provides a powerful way to enhance the influence of inputs to pyramidal neurons.
Thus, the rapid reduction of PV-mediated inhibition to pyramidal neurons, together
with sensory drive, may be a necessary condition for initiating plasticity in the adult
sensory cortex.
3 COMMON PRINCIPLES OF DEVELOPMENTAL AND

ADULT PLASTICITY
Certain common principles seem to anchor neuronal and circuit plasticity in both the
developing and adult sensory cortex. The initiation or activation of plasticity appears
to involve a transient reduction of inhibition on pyramidal neurons, likely mediated
via a reduction of activity of PV interneurons. This reduction of PV activity is in-
duced by simple and passive manipulations such as MD during the critical period
in the developing visual cortex, but in the adult cortex, after excitatory synapses
on cortical neurons along with intracortical inhibition have matured, MD no longer
suffices to initiate ODP and additional mechanisms are required to affect PV activity.
We hypothesize that neuromodulatory inputs have this role; by their selective action
on inhibitory neuron types, they transiently reduce PV activity in order to initiate
plasticity. A minimal level of excitatory drive to PV neurons seems to be required
when the critical period starts, so that these neurons can reflect reduced closed
eye responses and thus trigger plasticity. Mature levels of drive to PV neurons appear
to close off the critical period for MD-driven changes (via mechanisms that remain to
be elucidated), and neuromodulatory systems related to reinforcement or reward are
required in conjunction with sensory training signals to activate response changes.
An important element of this hypothesis is that neuromodulatory signals should spe-
cifically target PV neurons and thus affect PV-pyramidal neuron circuits that also
receive feedforward sensory drive. The powerful regulation of response gain in
pyramidal neurons by PV input is consistent with the proposal that a reduction of
PV activity significantly impacts responses due to correlated (or uncorrelated)
sensory inputs. Indeed, methods for reactivating ODP in the adult visual cortex
uniformly require a prominent reduction of intracortical inhibition (reviewed in

Espinosa and Stryker, 2012; Nagakura et al., 2013).
The implementation and maintenance of neuronal and circuit plasticity appears to
rely importantly on changes at glutamatergic synapses (Fig. 1), though we cannot
rule out plasticity at inhibitory synapses as well. Plasticity of glutamatergic synapses
is implemented by a host of mechanisms that eventually lead to increased or de-
creased insertion and function of AMPA (and other) receptors. These changes must
be synapse-specific, since closed and open eye inputs, which target separate synap-
ses, seem to be separately regulated, as revealed by feedforward and feedback
changes after MD. Whether or not similar mechanisms are also involved in imple-
menting and maintaining adult plasticity remains to be discovered. Regardless
of specific details, however, these hypotheses provide a conceptual framework for
understanding cortical plasticity that can motivate future experiments.
Acknowledgments
Supported by grants from the NIH and the Simons Foundation (M. S.), and a fellowship from
A*STAR, Singapore (N. C.).
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CHAPTER
Brain Mechanisms of
Plasticity in Response to
Treatments for Core
Deficits in Autism
10
Pamela E. Ventola1, Devon Oosting, Laura C. Anderson, Kevin A. Pelphrey
Yale Center for Translational Developmental Neuroscience, Yale Child Study Center,
New Haven, CT, USA
1
Corresponding author: Tel.: þ203-785-5657, e-mail address: pamela.ventola@yale.edu
Abstract
Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by social
communication impairments and repetitive behaviors. Although the prevalence of ASD is es-
timated at 1 in 88, understanding of the neural mechanisms underlying the disorder is still
emerging. Regions including the amygdala, superior temporal sulcus, orbitofrontal cortex,
fusiform gyrus, medial prefrontal cortex, and insula have been implicated in social processing.
Neuroimaging studies have demonstrated both anatomical and functional differences in these
areas of the brain in individuals with ASD when compared to controls; however, research on
the neural basis for response to treatment in ASD is limited. Results of the three studies that
have examined the neural mechanisms underlying treatment response are promising; follow-
ing treatment, the brains of individuals with ASD seem to “normalize,” responding more sim-
ilarly to those of typically developing individuals. The research in this area is in its early stages,
and thus a focused effort examining the neural basis of treatment response in ASD is crucial.
Keywords
autism, ASD, treatment, social brain, social cognition, neuroimaging, treatment response
1 INTRODUCTION
Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized
by deficits in social communication and the presence of repetitive behaviors and re-
stricted interests. Social and communicative deficits include impaired peer relation-
ships, a paucity of nonverbal communication, difficulty engaging in reciprocal social
interactions/conversations, and an impairment in theory of mind (ToM: the ability to
ascribe emotional and mental states to other people) (American Psychiatric
Association, 2000). Restricted and repetitive behaviors and interests range from
255
256 CHAPTER 10 Neural Basis of Treatment Response in ASD
preoccupations with ordering or categorizing (i.e., reciting numbers and letters in se-
quence or grouping objects based on physical properties), to the self-stimulatory
mouthing of objects, to an intense interest in a particular topic (e.g., a certain tele-
vision show or parts of the human body) (American Psychiatric Association, 2000).
As a spectrum disorder, ASD is heterogeneous in its presentation and impacts indi-
vidual competencies in the domains described above in different ways. Some lower-
functioning children are unable to communicate and present with a more severe
symptom profile, whereas those with high-functioning ASD are typically verbally flu-
ent but have difficulty understanding the nuances of social interactions (Geschwind
and Levitt, 2007). According to the Centers for Disease Control (CDC) 2008 estimate,
ASD affects 1 in every 88 children in the United States and is disproportionately repre-
sented in males, occurring at a rate nearly five times that of females (Centers for
Disease Control [CDC], 2012). The National Center for Health Statistics’ recent study
on parent-reported ASD identified a prevalence rate of 1 in 50 children (Blumberg
et al., 2013). These prevalence estimates support the relevance and necessity of a better
understanding of the etiological mechanisms underlying this disorder.
While behavioral symptoms typically become a concern for parents around
2 years of age, the average age at which a child receives a professional diagnosis
ranges from 4 to 6 years old depending on symptom severity (CDC, 2012). This delay
in diagnosis eclipses a crucial time span in which intervention services have been
shown to be particularly effective at ameliorating ASD symptoms (Dawson,
2008; Princiotta and Goldstein, 2013). During early childhood, the brain is especially
able to adapt and change in response to new experiences (Dawson, 2008). This plas-
ticity makes this period an important target for the implementation of interventions
whose methods have been shown to mediate the abnormalities in brain structure and
function commonly seen in individuals with ASD (Dawson, 2008). In this chapter,
we will outline the current findings on the atypical development of the social brain in
ASD, the different types of treatment options for individuals with ASD, and then
finally summarize the current, yet early stage research on neural plasticity in
response to empirically validated interventions in this population.
2 THE TYPICAL AND ATYPICAL SOCIAL BRAIN

Beginning in the late 1930s, researchers have used a variety of methods to identify
and explore the neural networks that contribute to social cognition, the ability to per-
ceive the temperaments and intentions of others (Brothers, 1990). Neurologists Hein-
rich Kluver and Paul Clancy Bucy first discovered that social behavior had a brain
basis when they observed inappropriate socialization and emotional responses in rhe-
sus monkeys after performing bilateral lesions in brain regions including the amyg-
dala and temporal lobes (Kluver and Bucy, 1939). Several years later, other lesion
studies in both humans and nonhuman primates confirmed that brain regions
including the amygdala and orbitofrontal cortex are necessary for appropriate
social cognition including emotional reactivity and approach and avoidance behavior
2 The Typical and Atypical Social Brain 257
(e.g., Butter et al., 1968; Damasio et al., 1990; Dicks et al., 1969; Eslinger and
Damasio, 1985; Kling and Steklis, 1976). Studies investigating brain responsivity
at the level of single neurons have identified particular neurons in the monkey tem-
poral cortex that process facial expressions (Hasselmo et al., 1989; Perrett et al.,
1984) and the gaze of other animals (Perrett et al., 1984), two important components
of social cognition.
These findings from lesion and single-cell studies led Brothers (1990) to propose
a model for a “social brain” network composed of regions of the primate brain that
are critically involved in social processing. This model of the social brain included
the following regions: amygdala, superior temporal sulcus (STS), orbitofrontal
cortex, and fusiform gyrus (FG). In the decades since, many neuroimaging studies
have confirmed the importance of these brain regions in social cognition and have
added other regions to the list such as medial prefrontal cortex (mPFC) and insula,
among others (Allison et al., 2000; Amodio and Frith, 2006; Decety and Grezes,
1999; Lamm and Singer, 2010).
One of the regions of the social brain that continues to be implicated in various
aspects of social and emotional processing in typical development is the amygdala, a
subcortical structure in the anterior medial temporal lobe. Amygdala lesions lead to
impaired fixation to the eyes, emphasizing the role of the amygdala in attention
modulation and the evaluation of emotional expressions (Adolphs and Spezio,
2006; Gamer and Buchel, 2009; Kennedy and Adolphs, 2010; Whalen, 2007).
Although the amygdala has often been studied in the context of fear processing,
evidence suggests that the amygdala plays a broader role in the detection of a variety
of salient stimuli including biological motion (Davis and Whalen, 2001; Morris et al.,
1998; Pelphrey et al., 2003a,b) and codes for the motivational significance of
environmental stimuli (Nishijo et al., 1988).
The STS is another brain region that has been continually implicated in a variety
of social tasks. Single-cell studies in monkeys have shown that the STS is critical
for following the gaze of others (Campbell et al., 1990; Perrett et al., 1990,
1992). Similarly, in humans, the STS is involved in perceiving the movement of con-
specifics including whole-body motion (see Allison et al., 2000 and Decety and
Grezes, 1999 for reviews) as well as eye movements (Pelphrey et al., 2003a,b,
2004a,b; Puce et al., 1998; Wicker et al., 1998). The ability to perceive the motion
of other humans and to predict their future behaviors may be a precursor to ToM
abilities (Pelphrey and Carter, 2008).
The orbitofrontal cortex, including ventral medial prefrontal cortex (vmPFC), has
also been associated with social processes. The first evidence that this brain region
plays an important role in social cognition came in 1848, when Phineas Gage en-
dured a frontal lobe lesion after being impaled by a tamping rod and soon afterwards
became uncaring and socially inappropriate (Damasio et al., 1994). Since then, other
studies investigating the effects of frontal lobe lesions have concluded that patients
with vmPFC damage maintain normal intellectual abilities but they lack the ability to
plan and organize, they behave in socially inappropriate ways, and they have little
concern for others (Ackerly and Benton, 1948; Brickner, 1932), suggesting that
vmPFC is involved in executive functioning, appropriate social regulation, and

empathy.
The FG has been most commonly implicated in face processing (Kanwisher et al.,
1997). One study found that patients with schizophrenia, who have difficulties with
face recognition, have reduced FG grey matter compared to healthy controls
(Onitsuka et al., 2003). The FG is also part of a network of social brain regions that
activates during the Heider and Simmel paradigm, a task during which geometric
shapes interact in socially relevant ways (Castelli et al., 2002). Additionally, the
FG shows activation during the visual perception of point-light displays (PLDs)
of biological motion (Pelphrey et al., 2003a,b; Vaina et al., 2001).
The mPFC has more recently been added to the list of “social brain” regions. Pri-
marily, the mPFC is involved during tasks that involve mentalizing, or thinking about
other peoples’ mental states (i.e., ToM) (Amodio and Frith, 2006; Fletcher et al.,
1995; Goel et al., 1995). This region has also been implicated in self-reflection
(e.g., Kelley et al., 2002; Northoff et al., 2006; Saxe and Powell, 2006) and activates
during tasks that require participants to recall past events in their lives (Shannon and
Buckner, 2004).
Most recently, several studies have shown insula activation in a variety of social
tasks. This region activates when participants are asked to label facial expressions
(Adolphs et al., 1996a,b) and when participants experience soft, gentle touch
(Björnsdotter and Olausson, 2011; Gordon et al., 2011; Löken et al., 2009;
McGlone et al., 2012). Other studies have shown anterior insula activation, while
participants experience empathy and compassion, emphasizing the role of this region
in the interpretation of other peoples’ bodily states (for a review see Lamm and
Singer, 2010).
To better understand the role of the aforementioned social brain regions in typical
development, researchers have begun investigating social brain dysfunction in pa-
tients with ASD, which is characterized by core deficits related to social cognition.
Neuroimaging studies of people with ASD have consistently shown hypoactivation
in several social brain regions including amygdala, FG, and STS during a variety of
tasks. For example, while healthy adults show amygdala activation while viewing the
eyes of other people, adults with ASD do not (Baron-Cohen et al., 1999). Other stud-
ies have shown that in addition to functional differences, the amygdala of patients
with ASD also shows structural abnormalities (Schumann et al., 2004; Sparks
et al., 2002). Additionally, adults with ASD show STS hypoactivation while listening
to human voices (Boddaert et al., 2003; Gervais et al., 2004), watching goal-directed
actions (Pelphrey et al., 2005), and attributing intentions to geometric shapes within a
social context (Castelli et al., 2002).
Functional differences in brain activation between typically developing individ-
uals and those with ASD emerge relatively early in development; children and
adolescents with ASD show hypoactivation in FG while viewing faces (Schultz
et al., 2000) and hypoactivation in a network of social brain regions (including
FG, vmPFC, amygdala, and STS) while viewing biological motion (Kaiser et al.,
2010; Pelphrey et al., 2005). Recent studies (Elsabbagh et al., 2012; Lloyd-Fox
3 Treatment Overview 259
et al., 2013) have even evidenced differential neural patterns in infants at risk for
developing ASD (by virtue of having an older sibling with the disorder), suggesting
that social brain abnormalities in those with a family history of ASD may serve as an
early-emerging endophenotype of the disorder. Although it is unclear whether social
brain dysfunction in ASD is a cause or a consequence of the disorder, prospective,
longitudinal studies including high-risk infants are beginning to disambiguate cause
and effect by elucidating the development of the social brain in both typical and atyp-
ical development (e.g., Elsabbagh et al., 2012; Lloyd-Fox et al., 2013).
3 TREATMENT OVERVIEW
Since autism was first identified in the early 1940s (Kanner, 1943), multiple theories on
its origins have been examined. Twin studies and DNA analysis of individuals with ASD
have provided strong support for the contribution of genetics to the development of the
disorder, though reliable genetic markers of ASD have yet to be established (Meek et al.,
2013). Environmental exposure to toxic substances, abnormal immune responses, and
adverse prenatal experiences, especially those during critical periods such as the first
trimester and parturition, have also been implicated (Gregory et al., 2013; Landrigan,
2010; Rossignol and Frye, 2012). Furthermore, some purport that deficits in specific
cognitive processes, such as executive functioning and ToM, that are often present in
individuals with ASD may stem from neurological abnormalities in connectivity and
structure and may underlie some of the social impairment and restricted behaviors
characteristic of the disorder (Frith, 1997, 2012; Minshew and Williams, 2007).
Though in the past decades, there have been a plethora of theories about the
origins of ASD and specific brain regions have been consistently implicated, we have
yet to pinpoint the primary underlying neurobiological causes of the disorder. There-
fore, many current interventions target the secondary behavioral symptoms of ASD.
Using behavior modification techniques, these treatments aim to reduce or redirect
socially inappropriate behaviors and restricted interests while also teaching social
strategies, language, and daily living skills (Koegel and Koegel, 2012; Lovaas
et al., 1973). In addition, psychopharmacological treatments that seek both to alle-
viate often comorbid aberrant behavioral issues (e.g., hyperactivity, aggression, self-
injurious behavior) as well as to ameliorate core ASD symptoms are emergent
(Hollander et al., 2007; Tsai, 1999). In what follows, the predominant treatments
in each category are discussed.
3.1 Behavioral Treatments

3.1.1 Applied Behavioral Analysis (ABA)
Applied behavior analysis (ABA; Lovaas et al., 1973) is a systematic approach to
skill acquisition for children with ASD that relies on discrete trial training, a method
whereby specific skills are broken down and learned in a highly structured stepwise
fashion (Vismara et al., 2010). ABA approaches identify the situational antecedents
and consequences of behaviors and then modify these parameters using tools, such as
reinforcement or environmental restructuring, in order to encourage the child to learn
the desired behavior or response (Vismara et al., 2010). ABA can be implemented in
the home or at school, and programs are often intensive, with children receiving 20 or
more hours per week of direct therapy (Harris and Delmolino, 2002). Early work by
Lovaas et al. (1973) showed that children who were treated intensively with ABA
(40 þ hours per week) made significant cognitive gains compared to controls, with
nearly half of the sample achieving intellectual functioning typical of their chrono-
logical age (Lovaas et al., 1973). Subsequent studies demonstrated intellectual func-
tioning improvement after intensive therapy as well, though the magnitude of
improvement and study conditions varied (Harris and Delmolino, 2002; Smith
et al., 2000). Findings regarding the effect of ABA on adaptive behavior (i.e., daily
living skills) are mixed (Peters-Scheffer et al., 2011).
3.1.2 Pivotal Response Treatment (PRT)

Pivotal response treatment (PRT; Koegel and Koegel, 2012) builds upon the foundations
of ABA but is implemented in a naturalistic manner. Rather than structuring discrete tri-
als focused specifically on obtaining desired responses, as is commonly seen in ABA, the
therapist utilizes the motivations of the child to direct and structure play activities in ways
that promote naturalistic skill acquisition in domains pivotal to broader areas of function-
ing (Koegel and Koegel, 2012; Koegel et al., 1999a,b). Techniques such as offering the
child choices about activities, reinforcing attempts at target skills (such as rewarding a
child for a vocal approximation of a word in addition to the full production of the word),
and the inclusion of previously mastered activities to avoid continuous placement of
novel demands, and resulting child frustration, are used (Koegel et al., 1987a,b). Overall,
PRT aims to address the child’s social motivation, or the desire to engage in social in-
teractions, and identifies this area as a particularly important target for improvement of
social and communicative abilities (Koegel and Koegel, 2012).
Multiple studies with young children with ASD have reported language gains
after parental administration of PRT (Coolican et al., 2010; Minjarez et al., 2011).
PRT has also been shown to increase symbolic play behavior (Stahmer, 1995),
child-initiated social interactions (Koegel et al., 1999a), and positive parent–child
interactions (Koegel et al., 1996), and to decrease ASD symptomology, especially
in cognitively-able children with ASD (Koegel et al., 1999b). One notable common-
ality across many of the studies examining PRT is that children receiving PRT were
able to generalize and maintain the skills learned during therapy in nonclinical set-
tings, albeit to varying degrees (Koegel et al., 1987a,b, 1999a,b; Pierce and
Schreibman, 1997; Stahmer, 1995). The generalizability and maintenance of learned
skills are some of the most important goals of this intervention design.
3.1.3 Early Start Denver Model (ESDM)

The Early Start Denver Model (ESDM), developed by Rogers and Dawson (2010), is
an empirically supported intervention program intended specifically for infants, tod-
dlers, and preschoolers diagnosed with, or at risk for, ASD. ESDM is similar to PRT
3 Treatment Overview 261
in its naturalistic approach to skill acquisition, utilizing ABA strategies to teach spe-
cific behavioral lessons during developmentally appropriate time periods (Dawson
et al., 2010). ESDM can be administered in either group or individualized settings
and heavily emphasizes positive reciprocal relationships and parental involvement,
in addition to direct contact with therapists. A randomized controlled trial of ESDM
implemented with toddlers with ASD reported significant gains in cognitive ability,
receptive and expressive language, and adaptive behavior after completion of a
2-year program executed primarily by parents with therapist guidance (Dawson
et al., 2010; Rogers et al., 2012). Other studies and reviews have supported the trial
described above, showing improvements in intellectual functioning, language, adap-
tive behavior, and ASD symptomology (Princiotta and Goldstein, 2013; Vismara
et al., 2010; Warren et al., 2011).
3.2 Psychopharmacological Treatments

3.2.1 Oxytocin Therapy
In addition to its well-established roles in parturition and lactation, the neuropeptide
oxytocin is known to be involved in social attachment and bond formation (Insel,
1997). The deficits in social interaction and communication characteristic of ASD
suggest possible abnormalities in oxytocin production and/or oxytocin receptor sen-
sitivity (Insel et al., 1999). Studies on the behavior of prairie voles and mice found
that blockage or lack of oxytocin receptors inhibited bond formation between prairie
voles and promoted “social amnesia,” or the inability to recognize familiar individ-
uals, in mice (Carter et al., 2008; Kuehn, 2011). Several studies have demonstrated
atypical levels of blood plasma oxytocin levels in individuals with ASD as compared
to controls, though the direction of change (higher or lower levels) varied with the
age of the population (Jansen et al., 2006; Modahl et al., 1998). Supplemental oxy-
tocin administration has been found to facilitate the processing and retention of
social information (i.e., assignment of emotion to speech intonation), improve the
ability to identify affect based on facial expression, and to reduce repetitive behav-
iors in older children with ASD (Hollander et al., 2003, 2007). Other studies have
found an increased ability to perceive emotion in faces and increased attention
to faces, especially the eyes, in adults with ASD after a single administration of
intranasal oxytocin (Andari et al., 2010; Guastella et al., 2010; Kuehn, 2011).
3.2.2 Risperidone Therapy

The dopamine and serotonin agonist Risperidone is an atypical antipsychotic
whose effectiveness in tempering the aggressive and self-injurious behaviors that
sometimes accompany ASD has been studied extensively (Malone et al., 2002;
McDougle et al, 1998; Pandina et al., 2007; McCracken et al., 2002; Shea et al.,
2004). The Autism Network of the Research Units on Pediatric Psychopharmacology
(RUPP) conducted an 8-week, double-blind, randomized, placebo-controlled trial
of Risperidone use in school-age children and adolescents with ASD and found
a significant decrease in irritability, aggressive behavior, and self-injury
(McCracken et al., 2002). Other studies support these results, reporting decreased
hyperactivity and conduct problems in both children and adults with ASD as well
as a decrease in internalizing symptoms in adults (Malone et al., 2002; McDougle
et al., 1998; Pandina et al., 2007; Shea et al., 2004). These results may be of particular
importance because the aggressive and self-injurious behaviors shown to decline
upon treatment with Risperidone are often some of the most concerning for parents
and caregivers (McCracken et al., 2002).
4 NEURAL RESPONSE TO ASD TREATMENT

Although there are now several efficacious treatments for ASD, the field as a whole is
just beginning to identify the neural mechanisms of ASD treatment; just three recent
studies have investigated the neural response to treatment in ASD (Dawson et al.,
2012; Gordon et al., 2013; Voos et al., 2013). All three studies to date have demon-
strated the remarkable plasticity of the brain in response to treatment. After treatment,
the children with ASD processed social information more similarly to typically devel-
oping children, suggesting that the extent of the plasticity is such that their brains were
able to move toward “normalizing” the processing of social information.
The first study (Voos et al., 2013) directly addressing the question of potential
biological markers (biomarkers) and treatment response at the neural circuitry level
in ASD was a case study on the neural mechanisms of response to PRT (Koegel et al.,
1987a,b; Koegel and Koegel, 2012). The case study included two preschool-aged
children. The children received 4 months of intensive intervention using principles
of PRT. Both before and after treatment, the children completed a functional mag-
netic resonance imaging (fMRI) task that probed neural processing of biological
motion, a basic form of social information. The participants saw either coherent
or scrambled PLDs of biological motion created from motion capture data. Outcome
data included activity in prespecified, independently identified regions of interest in-
cluding what the authors termed in prior work, “State Regions”: areas of dysfunction
unique to children with ASD in comparison to their unaffected siblings and typically
developing children (left ventrolateral prefrontal cortex (vlPFC), right amygdala,
right posterior STS (pSTS), vmPFC, and bilateral fusiform gyri); “Trait Regions”:
areas of dysfunction shared between children with ASD and their unaffected siblings
in comparison to typically developing children (bilateral FG, left dorsolateral pre-
frontal cortex, and right inferior temporal gyrus); and “Compensatory Regions”:
areas of increased activation in unaffected siblings as compared to children with
ASD and typically developing children (right pSTS and vmPFC) as identified by
Kaiser and colleagues (2010).
As illustrated in the table and figure (Table 1/Fig. 1) (Voos et al., 2013), the re-
sults from this case study were promising; the neural systems supporting social per-
ception were malleable with treatment for ASD. As shown in Table 1, both children
made clinically significant gains in skills related to core vulnerabilities in ASD. They
made the most substantial improvements in adaptive skills, but they also made gains
4 Neural Response to ASD Treatment 263
Table 1 Case-study results: Social communication and adaptive skills following PRT
treatment
Pre (t1) Post (t2)
ADOS Algorithm Total Score (Autism Total Score cut-off ¼ 9; Higher score indicates higher
level of impairment)
Child 1 (age 5:5 at start of treatment) 12 6
Child 2 (age 5:1 at start of treatment) 14 16
Pragmatics Profile Subtest Score (Typical range > 120)
Child 1 86 132
Child 2 49 74
Vineland age equivalent (months) Child 1 Child 2
Pre (t1) Post (t2) Pre (t1) Post (t2)
Receptive 78 90 26 59
Expressive 66 53 38 67
Written 73 82 68 84
Personal 90 78 38 42
Domestic 66 91 18 35
Community 74 71 47 56
Interpersonal relationships 54 31 46 46
Play and leisure time 70 78 46 67
Coping skills 27 55 29 47
in social communication skills. Furthermore, when comparing the fMRI results pre-
and posttreatment, the children showed increased activation in portions of State and
Trait regions after treatment, meaning, after treatment, the children showed in-
creased activation in areas of the brain responsible for processing social information.
This is exemplified in Fig. 1, which illustrates the differential response between
pre- and posttreatment. The colored areas of the figure reflect brain regions with
increased activation following treatment.
Thus, PRT resulted in increased activation in regions recruited by typically de-
veloping children during social perception. Specifically, one child demonstrated
greater activation in three regions after treatment; two distinct regions of the
State-defined left FG and a portion of the Trait-defined left dorsolateral prefrontal
cortex (dlPFC). The other child demonstrated greater activation in four regions after
treatment; a portion of the State-defined right pSTS, State-defined left vlPFC,
State-defined right FG, and State/Trait-defined left FG. Therefore, the results suggest
that the social brain is not irretrievably “broken” in children with ASD; instead, it is
simply not being effectively recruited in the processing of biological motion. Impor-
tantly, although these results are promising, they are very preliminary, and additional
work with a larger sample is needed to make firm conclusions.
Another recent study (Dawson et al., 2012) investigating the plasticity of the so-
cial brain in response to intervention in ASD examined the ESDM (Rogers and
FIGURE 1
Case-Study fMRI results following PRT treatment. Results of t2–t1 beta maps
(Biological > Scrambled) (beta difference >0.5, k ¼ 4) limited to state, trait, and
compensatory regions as defined by Kaiser and colleagues (2010). The colored areas reflect
brain regions with increased activation following treatment (differences between pre- and
posttreatment). After treatment, Child 1 demonstrated greater activation in a portion of the
state-defined right posterior superior temporal sulcus (pSTS), state-defined left ventrolateral
prefrontal cortex (vlPFC), state-defined right fusiform gyrus (FG), and state/trait-defined left
FG. Child 2 demonstrated increased activation to biological motion in trait-defined left
dorsolateral prefrontal cortex (dlPFC) and two distinct regions of the state-defined left FG.
Dawson, 2010). This study used electroencephalography (EEG) as a measure of neu-

ral systems level change. The study included a large sample of young children with
ASD. At the start of treatment, the children were between 18 and 30 months of age.
One group received ESDM treatment for 2 years and the other received community-
based intervention provided by Birth to Three/early intervention agencies for the
same duration. After the intervention, EEG activity (ERPs and spectral power)
was measured during the presentation of faces versus objects. Age-matched typical
children were also assessed.
Compared to the community intervention group, the ESDM group exhibited
greater improvements in ASD symptoms, IQ, language, and adaptive and social be-
haviors as measured by a number of standardized assessments: the Mullen Scales of
4 Neural Response to ASD Treatment 265
Early Learning (Mullen; Mullen, 1990), Pervasive Developmental Disorder-

Behavior Inventory (PDD-BI; Cohen et al., 2003), Vineland Adaptive Behavior
Scales (Vineland; Sparrow et al., 2005), Autism Diagnostic Interview-Revised
(ADI-R; Rutter et al., 2003), and Autism Diagnostic Observation Schedule (ADOS;
Lord et al., 2002). Following the treatment, the ESDM group and the typically de-
veloping children showed faster neural response and increased cortical activation
(decreased a power and increased y power) when viewing faces, in comparison to
the community intervention group, who showed the opposite pattern (shorter latency
and greater cortical activation when viewing objects). Greater cortical activation
while viewing faces was associated with improved social behavior in the ASD group.
This was the first large-scale trial to demonstrate that early behavioral intervention is
associated with normalized patterns of brain activity in young children with ASD.
While groundbreaking, this study did not include a baseline time point, however.
Thus, it is not possible to evaluate whether and/or how the groups differed prior
to the onset of treatment nor can we determine the degree to which the observed
results reflect placebo effects.
In addition to research on the neural systems level response to behavioral treat-
ment, one recent study (Gordon et al., 2013) investigated the neural mechanisms of
response to a psychopharmacological intervention, intranasal oxytocin. The neuro-
peptide oxytocin plays a critical role in social functioning. Behavioral studies dem-
onstrate that in children and adults with ASD, a single administration of intranasal
oxytocin leads to improved social motivation (Andari et al., 2010), social cognition
(Bartz and Hollander, 2008), and reduced repetitive behaviors (Anagnostou et al.,
2012; Hollander et al., 2003; Miller, 2013).
Gordon and colleagues (2013) completed the first study examining the impact of
oxytocin on brain function in children with ASD. Their groundbreaking research
investigated the neural systems level mechanisms by which oxytocin may enhance
social functioning in children with ASD. They completed a randomized, double-
blind, crossover, an fMRI study in 17 children and adolescents (aged 8–16.5 years)
with ASD. Participants were randomized to oxytocin and placebo nasal sprays on
two consecutive visits. Forty-five minutes following administration, brain function
was assessed using the “Reading the Mind in the Eyes Test” (RMET; Baron-Cohen
et al., 1997, 2001), a well-validated fMRI social cognition task in a block design with
a nonsocial condition (vehicles).
Similar to the behavioral studies, these results also revealed that the neural sys-
tems supporting social cognition are malleable in children with ASD. A single ad-
ministration of oxytocin enhanced activity in key neural circuits supporting social
reward, social motivation, social recognition, and ToM, such as the dorsal and ven-
tral striatum, premotor cortex, posterior cingulate, inferior parietal lobule, and pSTS.
These same areas have been implicated in the neural phenotype of ASD (Iacoboni
and Dapretto, 2006; Seghier, 2012). The results from this neuroimaging study sug-
gest that oxytocin may make social stimuli more rewarding and socially salient to
children with ASD. The authors emphasize the potential for treatment approaches
that utilize oxytocin to enhance salience within social contexts. They specifically
predict that the most successful therapeutic use of oxytocin will be by administering
the compound prior to evidence-based behavioral treatments that provide opportu-
nities for feedback and learning in supportive social contexts.
5 SUMMARY AND FUTURE DIRECTIONS

In conclusion, the field as a whole is just beginning to understand the neural mech-
anisms of ASD and how they relate to treatment of the disorder. Understanding the
neural underpinnings of ASD treatment will guide the refinement of existing treat-
ments, inform the development of novel interventions, and lead to the development
of algorithms that predict which treatment is likely to benefit a given patient. Without
knowing how therapy works, it is impossible to determine what treatment ingredients
and at what doses are necessary for therapeutic change. Elucidating neural mecha-
nisms through which change takes place during proven efficacious treatments for
ASD could also have applications to a broader range of currently experimental ther-
apeutic interventions as well. Therefore, we, as a field, need to continue to focus our
efforts on studying the neural basis of and response to treatment in ASD.
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CHAPTER
Targeting Plasticity with

Vagus Nerve Stimulation to
Treat Neurological Disease
*
Seth A. Hays*,{, Robert L. Rennaker*,{,{, Michael P. Kilgard*,{,1
11
The University of Texas at Dallas, School of Behavioral Brain Sciences, Richardson, TX, USA
{
The University of Texas at Dallas, Texas Biomedical Device Center, Richardson, TX, USA
{
The University of Texas at Dallas, Erik Jonsson School of Engineering and Computer Science,
Richardson, TX, USA
1
e-mail address: kilgard@utdallas.edu
Abstract
Pathological neural activity in a variety of neurological disorders could be treated by directing
plasticity to specifically renormalize aberrant neural circuits, thereby restoring normal func-
tion. Brief bursts of acetylcholine and norepinephrine can enhance the neural plasticity asso-
ciated with coincident events. Vagus nerve stimulation (VNS) represents a safe and effective
means to trigger the release of these neuromodulators with a high degree of temporal control.
VNS-event pairing can generate highly specific and long-lasting plasticity in sensory and mo-
tor cortex. Based on the capacity to drive specific changes in neural circuitry, VNS paired with
experience has been successful in effectively ameliorating animal models of chronic tinnitus,
stroke, and posttraumatic stress disorder. Targeted plasticity therapy utilizing VNS is currently
being translated to humans to treat chronic tinnitus and improve motor recovery after stroke.
This chapter will discuss the current progress of VNS paired with experience to drive specific
plasticity to treat these neurological disorders and will evaluate additional future applications
of targeted plasticity therapy.
Keywords
vagus nerve stimulation (VNS), cortical plasticity, recovery, neuromodulators, acetylcholine,
norepinephrine, targeted plasticity

275
276 CHAPTER 11 Targeting Plasticity with Vagus Nerve Stimulation
1 NEURAL PLASTICITY IN THE CONTEXT OF NEUROLOGICAL

DYSFUNCTION
Plasticity provides an organism with the ability to adapt to a changing environment.
Under normal physiological conditions, plasticity promotes acquisition of new
knowledge and skills. In response to a pathological disturbance, insufficient or mal-
adaptive plasticity prevents full recovery. After a stroke, reorganization of cortical
motor representations occurs in the surrounding undamaged tissue and in the con-
tralesional hemisphere (Calautti and Baron, 2003; Nudo, 1999). Reorganization of
motor circuitry is observed after other types of brain lesions, such as traumatic brain
injury (Axelson et al., 2013). Plasticity induced by rehabilitative training is thought
to be the substrate for partial recovery; therefore, appropriately directed plasticity
that enhances the robustness and specificity of reorganization could improve recov-
ery. Similarly, targeted plasticity could be applied to specifically renormalize cir-
cuitry that exhibits maladaptive activity (Kilgard, 2012). One such instance of
maladaptive plasticity is phantom limb pain. Following loss of a digit, deafferenta-
tion results in increased cortical representation of the remaining skin areas
(Merzenich et al., 1984). In amputees, this cortical reorganization can often be
accompanied by pain, which is correlated with the degree of overrepresentation
(Flor et al., 1995). Some forms of chronic pain unrelated to limb loss display a similar
manifestation, suggesting that aberrant plasticity in the central nervous system may
underlie this percept of pain (Flor, 2003; Flor et al., 1997). Cochlear damage can
produce changes in the tonotopy of the auditory cortex (Robertson and Irvine,
1989). This cortical reorganization and other accompanying changes in neuronal
properties may produce tinnitus, a condition characterized by the perception of sound
when no sound is present (Eggermont and Roberts, 2004). New methods are needed
to drive specific circuit changes that can renormalize neuronal activity and thereby
ameliorate a range of neurological disorders.
2 NEUROMODULATORY CONTROL OF PLASTICITY AND

MEMORY
It is clear that neuromodulators strongly influence the expression of plasticity; there-
fore, control of neuromodulatory release during experience may serve as one method
to direct plasticity. Cortical neuromodulatory systems, including acetylcholine and
norepinephrine, all participate in cortical plasticity to varying degrees and have been
the subject of extensive study (Gu, 2002). The cell bodies of neurons responsible for
cholinergic innervation throughout the central nervous system are located in struc-
tures within the basal forebrain (Mesulam et al., 1983). These neurons release ace-
tylcholine widely throughout the brain, which acts on ionotropic nicotinic receptors
and metabotropic muscarinic receptors. Noradrenergic innervation originates in neu-
rons in the locus coeruleus of the brain stem and projects throughout the central ner-
vous system (Freedman et al., 1975). Norepinephrine released from these neurons
2 Neuromodulatory Control of Plasticity and Memory 277
stimulates a-adrenergic and b-adrenergic receptors, which fall in the metabotropic G

protein-coupled receptor superfamily. The downstream effectors engaged by activa-
tion of both cholinergic and noradrenergic receptors (Gilman, 1987) enable these
neuromodulators to have broad cellular effects that may be needed to drive the mul-
tifaceted mechanics of plasticity. Three primary lines of evidence that support the
role of the cholinergic and noradrenergic systems in the expression of plasticity
are discussed in the succeeding text.
2.1 Reduction of neuromodulatory transmission diminishes

plasticity
Reduction of neuromodulatory transmission results in impaired experience-
dependent plasticity. Lesions of the cholinergic system diminish topographical reor-
ganization in motor, somatosensory, and auditory cortices (Baskerville et al., 1997;
Conner et al., 2003; Kamke et al., 2005; Sachdev et al., 1998). Transient inhibition of
neuromodulatory transmission with pharmacological antagonists of cholinergic
receptors similarly reduces plasticity in both motor and somatosensory cortices
(Maalouf et al., 1998; Meintzschel and Ziemann, 2006; Sawaki et al., 2002). Lesions
of the nucleus basalis and cholinergic antagonists also interfere with learning
(Dunnett, 1985; Murray and Fibiger, 1985). Reduction of noradrenergic signaling
by lesions or antagonism also diminishes experience-dependent plasticity in the vi-
sual system (Kasamatsu and Pettigrew, 1976; Kasamatsu and Shirokawa, 1985) and
in the motor cortex (Meintzschel and Ziemann, 2006; Sawaki et al., 2003). Lesions of
the locus coeruleus and adrenergic antagonists impair some forms of learning
(Anlezark et al., 1973; Ögren et al., 1980). Together, these studies indicate that ro-
bust expression of experience-dependent plasticity requires cholinergic and norad-
renergic transmission.
2.2 Enhancement of neuromodulatory transmission facilitates

plasticity
Manipulations that enhance cholinergic and noradrenergic transmission facilitate
plasticity. Direct exogenous application of acetylcholine to the auditory cortex dur-
ing tone presentation promotes spectral plasticity (Ma and Suga, 2005) and applica-
tion during presentation of visual stimuli induces receptive field plasticity in the
visual cortex (Greuel et al., 1988). More indirect manipulations that also increase
cholinergic transmission enhance plasticity, for example, electrical stimulation of
the nucleus basalis paired with tones drives robust spectral and temporal plasticity
in neurons of the auditory cortex (Kilgard and Merzenich, 1998a,b). Stimulation
of the nucleus basalis paired with visual training increases visual acuity and improves
performance on a visual task (Kang et al., 2013). Furthermore, cholinergic agonists
enhance plasticity within the circuitry of the motor cortex when applied with motor
training (Meintzschel and Ziemann, 2006). Similarly, local infusion of norepineph-
rine into the visual cortex and electrical stimulation of the locus coeruleus support
ocular dominance plasticity (Kasamatsu et al., 1985; Pettigrew and Kasamatsu,

1978), and pharmacological manipulations that increase noradrenergic transmission
increase training-dependent plasticity within the motor cortex (Meintzschel and
Ziemann, 2006). Direct norepinephrine infusion into the visual cortex during visual
stimulation promotes receptive field reorganization (Greuel et al., 1988). Synthesis
of the results from these studies indicates that, when paired with experience, in-
creased function of the cholinergic and noradrenergic systems can enhance neural
plasticity.
2.3 Engagement of neuromodulatory systems during learning

and attention
Neuromodulatory systems are engaged during the acquisition of a new task and dur-
ing attentional processing. Participation in a new behavioral task triggers release of
neuromodulators. Increases in acetylcholine levels are observed during the acquisi-
tion phase, but not the consolidation phase, of learning an operant task (Orsetti et al.,
1996). Norepinephrine levels are transiently increased in the amygdala following in-
hibitory avoidance training, and the magnitude of increase correlates with memory
retention (McIntyre et al., 2002). These temporally restricted increases suggest that
neuromodulatory release supports learning. Attention is known to facilitate behav-
iorally specific plasticity and learning (Moucha and Kilgard, 2006). Neuromodula-
tory systems are involved in attention, as disruption of the cholinergic or the
noradrenergic systems impairs attentional processing (Muir et al., 1993, 1994). As
such, attentional engagement of neuromodulatory systems would be expected to fa-
cilitate plasticity. Indeed, behavioral tasks that require attending to sensory stimuli
drive plasticity within the relevant cortical circuitry. Adult owl monkeys trained on a
tone discrimination task that required attention resulted in enhanced responses to be-
haviorally relevant tones, which correlated with task performance (Recanzone et al.,
1993). Similar tone exposure in nonattending animals was insufficient to engender
plasticity, demonstrating that sensory exposure alone is typically insufficient to drive
plasticity. These studies suggest that release of neuromodulators during attentional
processing facilitates plasticity.
Electrophysiological and computational modeling studies implicate high levels
of acetylcholine in enhancing the effects of efferent inputs to cortical circuitry while
minimizing the transmission through local connections (Hasselmo and McGaughy,
2004). In contrast, low levels of acetylcholine facilitate local circuit function and
reduce the effects of extracortical inputs. Norepinephrine can control the state of cor-
tical networks and can affect information processing (Constantinople and Bruno,
2011). This provides a theoretical framework for enhanced plasticity and learning
whereby heightened neuromodulatory transmission makes cortical circuitry more
receptive to inputs. While neuromodulatory input may facilitate plasticity, it is
not sufficient by itself to drive neuronal changes. The expression of plasticity
requires experience coincident with the release of neuromodulators. The broad
innervation patterns of both the acetylcholine and norepinephrine result in diffuse
3 Harnessing Plasticity with Vagus Nerve Stimulation 279
neuromodulatory release (Eckenstein et al., 1988; Levitt and Moore, 1978); there-
fore, the effects acetylcholine and norepinephrine are restricted by the coincident
network activity in the local circuitry. Temporal specificity is a product of the rel-
ative timing of neuromodulatory release and coincident neuronal activity. The tem-
poral requirements for synaptic plasticity are well described, and small changes in
timing of neuronal firing can have major impacts on spike-timing-dependent plastic-
ity (STDP) (Dan and Poo, 2004). Neuromodulators influence the temporal rules that
define STDP (Pawlak et al., 2010). The presence of acetylcholine or norepinephrine
dictates the polarity of synaptic plasticity, and the ratio of these neuromodulators
determines the temporal requirements for STDP (Seol et al., 2007). Studies using
lesions and pharmacological antagonism have demonstrated that these neuromodu-
latory systems interact to facilitate plasticity and learning (Bear and Singer, 1986;
Decker and Gallagher, 1987; Decker et al., 1990). As these neuromodulatory
systems cooperate during processes that drive plasticity and learning, concurrent
control of both acetylcholine and norepinephrine release would be useful to direct
plasticity.
3 HARNESSING PLASTICITY WITH VAGUS NERVE

STIMULATION
Targeted neural plasticity has potential to transform the ways in which neurological
diseases are treated, but the complex dynamics of plasticity processes make it chal-
lenging to control. Under normal conditions, plasticity is fine-tuned to promote
learning. However, in pathological conditions, the physiological processes driving
plasticity are insufficient to restore function. Therefore, new techniques to direct ro-
bust and specific plasticity may overcome this insufficiency and provide clinically
significant benefits.
A technique developed as a targeted plasticity therapy should exhibit four key
characteristics. First, it should engage multiple neuromodulatory systems in a phys-
iological or near physiological manner. Because neuromodulators act synergistically
and the relative concentration of each is crucial for the expression of plasticity (Bear
and Singer, 1986; Seol et al., 2007), the ability to engage multiple neuromodulatory
systems through physiological pathways will likely produce the most robust plastic-
ity. Second, it must be able to be delivered in a safe, tolerable way. Fear-inducing or
stressful stimuli can be potent modulators of plasticity (Joëls et al., 2006; Maren and
Quirk, 2004; McIntyre et al., 2012), but clearly, their harmful effects limit their use-
fulness. Instead, a method would be effective if it could engage the same plasticity-
promoting systems as aversive stimuli without the unfavorable sensory percepts to
promote plasticity. Third, it should be able to be applied with a high degree of tem-
poral precision, as timing is a critical regulator of plasticity and restricts plasticity to
relevant events. Fourth, its plasticity-inducing properties should not decay or saturate
during the course of therapy. Pharmacological manipulations can strongly effect
neuromodulatory transmission but are unlikely to be successful as a method to target
plasticity due to saturation and poor temporal control. It would be valuable for a tar-
geted plasticity therapy to remain constant over time, thus permitting repeated expo-
sures until the desired benefits are achieved.
Several manipulations that fit some or all of these criteria may be successful at
specifically targeting plasticity to treat neurological disease. Deep brain stimulation,
transcranial magnetic stimulation, optogenetic stimulation, or intensive repeated
training could potentially trigger sufficient neuromodulatory release during experi-
ence to induce therapeutic plasticity. In this chapter, we will focus on one particular
technique to drive targeted plasticity. This method uses stimulation of the vagus
nerve paired with behavioral experience to drive specific forms of neural plasticity.
Vagus nerve stimulation (VNS) engages multiple neuromodulatory systems and can
be precisely temporally controlled. Additionally, VNS is a safe and approved method
currently being used in over 60,000 patients for management of intractable epilepsy
and depression (Ben-Menachem, 2002; Englot et al., 2011; Sackeim et al., 2001).
Recent studies have demonstrated that VNS paired with sensory, motor, or cognitive
training can drive specific forms of cortical plasticity that result in behaviorally rel-
evant changes. As a result, VNS applied as a targeted plasticity therapy offers the
potential to treat sensory, motor, and cognitive dysfunction.
3.1 Control of memory and neuromodulatory release

by the vagus nerve
The vagus nerve is most widely recognized for its activation of parasympathetic
“rest-and-digest” responses; however, it also acts as a conduit to relay ascending in-
formation from the periphery to the central nervous system. The vagus nerve com-
municates arousing information from the periphery regarding both favorable events,
including a meal or deep breaths (Schwartz et al., 2000; Zagon, 2001), and aversive
events, such as stress or inflammation (Maier et al., 1998). This information on pe-
ripheral status can enhance memory in the central nervous system, and a variety of
studies have demonstrated that the vagus nerve is required for memory-enhancing
influences of peripheral stimulation (Jensen, 1996). Vagotomy impairs the
memory-enhancing effects of several substances that stimulate receptors in the pe-
riphery, including cholecystokinin (Flood et al., 1987), bombesin (Flood and Morley,
1988), gastrin-releasing peptide (Flood and Morley, 1988), 4-OH amphetamine
(Williams and Jensen, 1991), substance P (Nogueira et al., 1994), and L-glucose
(Talley et al., 2002). The variety of substances that influence memory suggests that
the vagus nerve relays diverse peripheral information. Transmission of information
by the vagus nerve is not painful, stressful, or rewarding, but powerfully controls
memory. Based on this memory-enhancing influence, the ability to precisely control
the vagus nerve provides a potential method to selectively drive plasticity.
The vagus nerve regulates memory by exerting control over multiple neuromo-
dulatory systems responsible for plasticity. Eighty to ninety percent of the left
cervical branch of the vagus nerve is composed of afferent sensory fibers that
project upward from the viscera into the medulla in the central nervous system
(Berthoud and Neuhuber, 2000; Foley and DuBois, 1937; George et al., 2000; Leslie
et al., 1982). These fibers synapse bilaterally on neurons within the nucleus tractus
solitarius, which then project to the noradrenergic locus coeruleus and the choliner-
gic basal forebrain (Berntson et al., 1998; George et al., 2000; Henry, 2002; Semba
et al., 1988; Van Bockstaele et al., 1999). Electrical stimulation of the vagus nerve
drives neuronal activity within these regions and consequently induces release of
neuromodulators throughout the cortex (Detari et al., 1983; Dorr and Debonnel,
2006; Follesa et al., 2007; Groves et al., 2005; Roosevelt et al., 2006). A reduction
in either noradrenergic or cholinergic transmission reduces the effects of VNS in the
central nervous system (Krahl et al., 1998; Nichols et al., 2011), suggesting that VNS
is exerting its effects through both the locus coeruleus and basal forebrain.
3.2 Stimulation of the vagus nerve paired with tones drives

reorganization in the auditory cortex
Because stimulation of the nucleus basalis or locus coeruleus paired with tones drives
plasticity, it is reasonable to predict that stimulation of the vagus nerve paired with
tones could engage the same neuromodulatory systems and subsequently enhance
experience-dependent plasticity without the need for deep brain stimulation. Engi-
neer and colleagues sought to investigate whether VNS paired with the presentation
of tones could drive reorganization of the tonotopic map in the primary auditory cor-
tex (Fig. 1A) (Engineer et al., 2011). Rats were presented with three hundred 9 kHz
tones per day for 20 days either with or without paired VNS, followed by auditory
mapping to derive the frequency map in the auditory cortex. As predicted from pre-
vious studies, repeated presentation of tones without VNS did not induce map reor-
ganization. However, presentation of the same number of tones paired with VNS
significantly increased the proportion of neurons that responded to frequencies near
9 kHz. A second cohort of rats was presented with 19 kHz tones, and a similar map
expansion was observed corresponding to 19 kHz in rats that received VNS, suggest-
ing that the observed reorganization is due to the specific event paired with VNS
rather than a generalized effect in the auditory cortex. Interleaved 4 kHz tones that
were not paired with VNS did not exhibit an increased response, suggesting that the
transient burst of neuromodulators driven by VNS can label temporally specific stim-
uli. In addition to the robust changes in spectral properties, VNS can also enhance
temporal response characteristics of neurons in the primary auditory cortex
(Shetake et al., 2011). Presentation of rapid (15 pulses per second) trains of tones
paired with VNS increased the maximal following rate of neurons within the primary
auditory cortex compared to naı̈ve controls. Alternatively, presentation of slow
(5 pulses per second) trains of tones paired with VNS decreased maximal following
rate compared to naı̈ve controls. These findings indicate that VNS can enhance the
temporal plasticity of neurons in the primary auditory cortex. In summary, VNS re-
peatedly paired with specific auditory experiences can drive specific, long-lasting
plasticity to change multiple characteristics of neuronal responses in the auditory
cortex.
FIGURE 1
Model of targeted plasticity therapy driving specific changes in neural circuits and not in other
areas. (A) (i) Presentation of an 8 kHz tone drives circuit activity in the auditory cortex (green).
(ii) Temporally precise release of neuromodulators (blue), such as that induced by VNS,
paired with this activity drives plasticity. (iii) After targeted plasticity, the map reorganization
results in an increase in representation of the paired tone (Engineer et al., 2011). Previously
subthreshold inputs (yellow) drive activity (green) after pairing with VNS. (B) (i) Activity within
neurons of the motor cortex results in movement of the shoulder. (ii) Diffuse release of
neuromodulators paired with movement drives plasticity in the motor cortex. (iii) After
targeted plasticity, the number of circuits representing the shoulder movement is increased
(Porter et al., 2011). The large rectangles represent topographical organization of the auditory
and motor cortices, and the activity of neurons is represented within each individual box.
Green denotes suprathreshold action potential firing, yellow denotes subthreshold
depolarization, and gray denotes no response.
3.3 Stimulation of the vagus nerve paired with forelimb training

drives reorganization in the motor cortex
Based on the robust enhancement of sensory experience-dependent plasticity
conferred by VNS, Porter and colleagues sought to determine whether VNS was
capable of enhancing event-specific plasticity within the motor system (Fig. 1B)
(Porter et al., 2011). To this end, rats were trained to perform one of two skilled
motor tasks. The first task was designed to primarily engage the shoulder and re-
quired the rat to rapidly press a lever located outside the cage twice within 500 ms.
The second task was designed to primarily engage the forepaw and required the rat
to reach through a small slot in the floor of the cage and spin a wheel 145 within
2 s. After reaching proficiency on one of the tasks, rats underwent an additional 5
days of training with or without stimulation of the vagus nerve delivered on the
successful trials. Intracortical microstimulation mapping was then used to derive
the area of motor cortex controlling specific movements. Rats that received re-
peated VNS paired with training on the lever press task demonstrated a major in-
crease in areal representation of the shoulder, but no increase in forepaw compared
to rats that did not receive VNS. Similarly, rats that receive VNS paired with train-
ing on the wheel spin task exhibited a significant increase in the area of motor cor-
tex representing the forepaw with no expansion of the shoulder. Therefore, VNS
facilitated robust expansion of the motor cortex representation of the specific move-
ment that was paired with stimulation. Both tasks were designed such that reward
pellets were delivered on successful trials and were typically consumed 1–2 s after
the delivery of VNS. Despite the relatively close timing of pellet consumption and
mastication with VNS, no increase was observed in the jaw representation, suggest-
ing VNS must be precisely timed with an event to drive specific plasticity. These
findings closely parallel the results observed in the auditory cortex and demonstrate
that VNS paired with events can induce robust plasticity specific to the event with
which stimulation is paired.
3.4 Stimulation of the vagus nerve during a cognitive task enhances

memory retention
In addition to the topographical manifestations of plasticity, delivery of VNS after
behavioral experience can enhance memory retention. Early studies provided evi-
dence that a vagotomy impaired the enhancement of memory retention caused by
peripheral pharmacological manipulations (Williams and Jensen, 1991). Based on
this, Clark and colleagues investigated whether stimulation of the vagus nerve after
inhibitory avoidance training would improve consolidation of avoidance memories
(Clark et al., 1995). Rats were trained on a single-trial inhibitory avoidance task,
followed immediately afterward by 30 s of VNS or no stimulation. Upon retest
24 h later, rats that had received VNS demonstrated a remarkable increase in reten-
tion compared to rats that did not receive stimulation. A similar increase in memory
retention was observed in humans on a word recognition memory task. Clark and
colleagues conducted a study in which subjects read paragraphs with some
highlighted words and did or did not receive VNS immediately after reading
(Clark et al., 1999). VNS immediately after reading significantly improved sub-
jects’ ability to recognize highlighted words in a list of distracters. These findings
provide support for the ability of VNS paired with experience to enhance memory
retention.
4 APPLYING TARGETED PLASTICITY TO TREAT DISEASE

Because VNS paired with experience can drive event-specific plasticity, this tech-
nique may hold promise to direct beneficial plasticity in order to treat many
manifestations of neurological disorders. A number of studies have provided
proof-of-concept validity for the use of VNS paired with specific experience to treat
an array of plasticity-related neurological disorders.
4.1 Chronic tinnitus

Chronic tinnitus is an alarmingly common disorder that causes minor to highly dev-
astating reduction in quality of life (Davis and El Rafaie, 2000). Current treatments
are largely ineffective, with great variability in patient response and adverse effects
(Parnes, 1997). While the exact mechanism is still under debate, it is generally
accepted that maladaptive plasticity within the central nervous system underlies
the pathophysiology in many cases (Eggermont and Roberts, 2004). In the case of
noise-induced hearing loss, the central nervous system fails to receive input from
a region of the damaged cochlea. This loss of input causes destabilization of the nor-
mal excitatory and inhibitory balance within central auditory circuits that can lead to
map distortion, increased receptive field size, and increased synchronous activity in
quiet, which appears to be responsible for the tinnitus percept (Engineer et al., 2011).
As detailed previously, VNS paired with tones can drive specific plasticity to alter
spectral and temporal response characteristics of the central auditory neurons
(Engineer et al., 2011; Shetake et al., 2011). If map distortion and receptive field size
lead to tinnitus, in principle, VNS paired with the appropriate presentation of tones
could drive plasticity to restore the normal characteristics of the circuitry and alleviate
the percept of tinnitus (Fig. 2A). Engineer and colleagues sought to evaluate the
capacity of VNS to eliminate the behavioral correlate of chronic tinnitus in rats
(Engineer et al., 2011). The rationale for the study was based on increasing the number
of cortical neurons tuned to frequencies other than the tinnitus frequency to reduce the
overrepresented tinnitus frequency. Noise trauma was induced to damage the high-
frequency region of the cochlea, causing a large increase in the proportion of neurons
tuned to middle frequency tones, a reduction in the proportion of neurons responding
to high-frequency tones, and an increase in overall synchrony, all reflective of
changes proposed to be responsible for tinnitus. Rats displaying a tinnitus percept cen-
tered on middle frequency tones were assigned to receive either VNS-tone therapy or
sham therapy. The VNS-tone therapy consisted of VNS paired with randomly inter-
leaved tones that spanned the rat hearing range but excluded the tinnitus frequencies.
Sham therapy consisted of the same tone exposure without VNS. The VNS-tone
therapy fully ameliorated the tinnitus percept 10 days after the therapy began. The
behavioral improvements were observed for up to 3 months after the end of VNS-tone
therapy, demonstrating that the effects of the therapy were long-lasting. Sham therapy
did not improve the tinnitus percept at any of time points tested. Paralleling the be-
havioral improvements, VNS-tone therapy restored most electrophysiological
FIGURE 2
Model of VNS paired with experience driving therapeutic plasticity in neural circuits. (A) (i) In
tinnitus, the auditory neurons are hyperactive and the map of sound frequency is distorted.
(ii) Presentation of high and low tones (black arrows) is insufficient to drive plasticity.
(iii) However, high and low tones paired with VNS (blue) drive plasticity within the auditory
system. (iv) After targeted plasticity therapy, activity within the auditory system is
renormalized, demonstrating that VNS paired with experience can reverse maladaptive
plasticity (Engineer et al., 2011). (B) (i) Following a stroke, circuits previously controlling the
forelimb are destroyed (black), resulting in impaired function. (ii) Physical rehabilitation
(black arrows) drives some reorganization and partially restores function. (iii) Physical
rehabilitation paired with VNS drives robust and specific neural plasticity by increasing
subthreshold activity (yellow). (iv) VNS paired with physical rehabilitation can drive robust and
specific changes to enhance recovery limited by insufficient plasticity (Khodaparast et al.,
2013; Khodaparast et al., submitted).
correlates of tinnitus, including map distortion and elevated synchrony. This study
provides evidence that VNS paired with tones can reverse pathological plasticity
and ameliorate chronic tinnitus. A clinical trial utilizing this implementation of
VNS paired with tones was conducted to treat chronic tinnitus in patients and dem-
onstrated promising results (Arns and De Ridder, 2011; Microtransponder, 2010).
4.2 Stroke
Stroke is a common cause of disability, affecting 795,000 people in the United States
each year, with as many as 85% of cases leading to impairments in upper limb func-
tion (Dobkin, 2004; Roger et al., 2012). A stroke typically causes a unilateral disrup-
tion of blood flow to the brain, and because of the anatomy of the neurovasculature,
the motor cortex is susceptible to cell death. The death of neurons in the motor cortex
interferes with the circuitry responsible for controlling muscle groups, leading to a
loss of coordinated motor function. The most common poststroke intervention, phys-
ical rehabilitation, leads to some functional gains, but in the majority of cases, the
improvement is incomplete, leaving patients with chronic disability (Dobkin,
2004, 2005; Lai et al., 2002).
Notable reorganization of motor maps occurs after stroke, in both the surviving
peri-infarct region and the undamaged contralateral motor cortex (Calautti and
Baron, 2003; Nudo and Friel, 1999). Plasticity in these areas is believed to be the sub-
strate for functional recovery (Hallett, 2001). As detailed earlier, a study from Porter
and colleagues demonstrated that VNS paired with physical training can enhance
plasticity within the motor cortex (Porter et al., 2011). Therefore, VNS paired with
physical training after a stroke may enhance reorganization within spared circuitry
of the motor cortex and improve function outcomes (Fig. 2B). Khodaparast and col-
leagues tested this hypothesis in two studies using a rat model of ischemic stroke
(Khodaparast et al., submitted). In the first study, rats were trained on the bradykinesia
assessment task, a skilled forelimb task that provides unbiased, quantitative measure-
ments of multiple parameters of forelimb movement speed (Hays et al., 2013). All rats
became highly proficient at the task. After induction of ischemic damage in the motor
cortex contralateral to the trained limb, performance dropped significantly. Rats were
then assigned to receive rehabilitative training with or without the delivery of VNS.
VNS paired with rehabilitative training fully restored task performance by the second
week of treatment and significantly improved performance compared to rehabilitative
training without VNS. VNS paired with rehabilitative training also improved fore-
limb movement speed compared to rehabilitative training alone. These findings dem-
onstrate that VNS paired with physical rehabilitation can improve recovery of
forelimb speed after stroke compared to rehabilitative training without VNS.
A second study by the same group extended these findings to recovery of fore-
limb strength after stroke (Khodaparast et al., 2013). Rats were trained to proficiency
on the isometric force task, an automated method to quantify forelimb strength (Hays
et al., 2012). After induction of ischemic lesion, performance on the task and fore-
limb strength were significantly reduced. VNS paired with rehabilitative training
resulted in significantly better performance and stronger maximal pull force over
5 Mechanisms of Targeted Plasticity Directed by VNS 287
the course of therapy compared to rehabilitative training without VNS. These ben-
efits persisted after the cessation of VNS, suggesting a long-term improvement.
Highlighting the benefits of VNS, 100% of subjects that received VNS paired with
rehabilitative training demonstrated a full recovery of forelimb strength, while only
22% of subjects that received rehabilitative training without VNS demonstrated a full
recovery. In both studies, no difference in lesion size was observed, suggesting that
VNS is not conferring a neuroprotective effect but rather improving recovery by en-
hancing plasticity. These findings provide initial evidence that VNS paired with re-
habilitative training can restore clinically relevant parameters of forelimb function
after a stroke. Based on these findings, a clinical trial applying VNS paired with
physical rehabilitation in stroke patients is ongoing (Microtransponder, 2012).
4.3 Cognitive dysfunction

Aberrant plasticity is believed to underlie the hypersensitivity and abnormal memory
retention that accompanies posttraumatic stress disorder (PTSD) (Bremner et al.,
2007; Peña et al., 2012), and reversal of this maladaptive plasticity may erase fear
memory (Sandkühler and Lee, 2013). As such, the ability to apply VNS to normalize
the hypersensitive responses to stimuli may improve the symptoms of PTSD. A proof
of principle study conducted by Peña and colleagues in a rat model of PTSD lends
credence to this hypothesis. Rats were trained on an auditory fear conditioning task
followed by extinction training with or without VNS (Peña et al., 2012). Testing was
conducted 1 day later to assess conditioned fear retention. VNS paired with extinc-
tion training resulted in a significant reduction of conditioned fear retention com-
pared to extinction training without VNS. Unpaired VNS delivered shortly after
training failed to reduce conditioned fear retention, suggesting that VNS must be
temporally aligned with the behavioral experience. The beneficial effects of VNS
are long-lasting, as conditioned fear remains reduced 2 weeks after the cessation
of treatment. Additionally, VNS paired with extinction training was similarly effec-
tive at reducing a remote fear memory compared to extinction training without VNS.
Although chronic VNS is known to confer anxiolytic effects (Furmaga et al., 2011;
George et al., 2008), this effect is not dependent on temporal specificity. Therefore, if
VNS is exerting anxiolytic effects to reduce conditioned fear response, unpaired
VNS delivery should be effective. However, because unpaired VNS fails to reduce
the conditioned fear response, VNS is most likely acting through modulation of plas-
ticity and memory rather than providing a generalized, nonspecific reduction in anx-
iety. Although much development remains, this study provides initial support that
VNS paired with behavioral experience can improve extinction training.
5 MECHANISMS OF TARGETED PLASTICITY DIRECTED BY VNS

Anatomical, electrophysiological, and biochemical findings indicate that VNS en-
gages the cholinergic and noradrenergic neuromodulatory systems (Detari et al.,
1983; Dorr and Debonnel, 2006; Follesa et al., 2007; Groves et al., 2005;
Naritoku et al., 1995; Nichols et al., 2011; Roosevelt et al., 2006). There is a high
degree of similarity in the auditory plasticity evoked by VNS paired with tones
(Engineer et al., 2011; Shetake et al., 2011) compared with direct stimulation of
the nucleus basalis paired with tones (Kilgard and Merzenich, 1998a,b), indicating
that these pathways may share a common mechanism. Several studies demonstrate
that disruption of neuromodulatory transmission occludes the effects of VNS. Nor-
epinephrine is necessary, as lesions of the locus coeruleus prevent the antiepileptic
effects of VNS (Krahl et al., 1998). Cholinergic antagonists abrogate the electrophys-
iological effects of VNS in the auditory cortex, implicating acetylcholine in the ef-
fects of VNS in the central nervous system (Nichols et al., 2011). These findings
suggest that both the cholinergic and noradrenergic systems contribute to the ability
of VNS to specifically direct plasticity.
VNS promotes several downstream changes in molecular signaling cascades that
are known to underlie plasticity. VNS drives expression of brain-derived neuro-
trophic factor (BDNF), an important regulator of plasticity (Follesa et al., 2007).
BDNF engages a variety of downstream effectors, including activation of cAMP re-
sponse element-binding protein, that drive synaptic plasticity (Ernfors and
Bramham, 2003; Mattson et al., 2004). Activity-regulated cytoskeletal protein
(Arc) is regulated by BDNF and is strongly associated with plasticity (Bramham
and Messaoudi, 2005; Bramham et al., 2008). Other downstream pathways affected
by BDNF, such as Nogo receptor signaling, are known to contribute to recovery after
motor cortex damage, suggesting a possible mechanism for VNS-dependent en-
hancement of recovery after stroke (Fang et al., 2010; Takei, 2009; Tsai et al.,
2011). Consistent with increased BDNF expression, VNS increases phosphorylation
of multiple sites in the BDNF receptor, TrkB (Furmaga et al., 2012). A compound
that inhibits Trk autophosphorylation prevents the VNS-dependent increases in TrkB
phosphorylation, indicating that VNS is driving activation of TrkB through the ca-
nonical mechanism. These phosphorylated sites on TrkB are associated with broad
downstream effects, such as activation of mitogen-associated protein kinase,
phosphatidylinositol-3 kinase, and phospholipase C-g, which are linked to plasticity
(Gottschalk et al., 1999; Thomas and Huganir, 2004). Additionally, VNS induces
expression of interleukin-1b (Hosoi et al., 2000), which is associated with plasticity
and memory (Avital et al., 2003). VNS also increases expression of the trophic factor
basic fibroblast growth factor (Follesa et al., 2007), which is believed to promote
recovery after motor cortex lesion (Rowntree and Kolb, 1997). VNS may even
directly alter the expression of NMDAR and GABAAR expression levels, thereby
influencing neuronal excitability (Zhang and Zhang, 2002). The extensive activation
of signaling cascades demonstrates that VNS engages many molecular mechanisms
that are known to enhance plasticity and memory.
The molecular changes induced by VNS translate into changes in neuronal and
network properties. Low-intensity stimulation of the vagus nerve results in the acti-
vation of a slow hyperpolarizing current in the cortical neurons, suggesting that in-
trinsic neuronal properties may be modified by VNS (Zagon and Kemeny, 2000).
Synaptic properties are also altered by VNS, as stimulation causes long-lasting
6 Targeted Plasticity Requires Less VNS than Approved Protocols 289
strengthening of excitatory postsynaptic potentials in the hippocampal neurons (Ura

et al., 2012). Additionally, VNS followed by weak tetanic electrical stimulation of
the hippocampus enhances long-term potentiation (Zuo et al., 2007). The enhance-
ment of hippocampal synaptic plasticity clearly provides a potential mechanism for
VNS-directed targeted plasticity. Stimulation of the vagus nerve also causes large-
scale changes in network activity. VNS rapidly induces desynchronization that can
be observed in the EEG and in multiunit cortical recordings (Chase et al., 1967;
Nichols et al., 2011). This desynchronization is dependent on cholinergic transmis-
sion (Nichols et al., 2011). Chronic VNS induces long-term changes in the EEG
power spectrum, increasing the power of low-frequency bands (Valdés-Cruz
et al., 2008). Together, the findings suggest that VNS may promote neural plasticity
by altering network state.
6 TARGETED PLASTICITY REQUIRES LESS VNS THAN

APPROVED PROTOCOLS
VNS induces a variety of cellular- and circuit-level changes and effectively drives
specific plasticity, but in order to be useful as a targeted plasticity therapy, it must
be able to be delivered in a safe, tolerable manner. Standard FDA-approved protocols
to treat epilepsy and depression using continuously delivered VNS are well tolerated
with few adverse effects (Sackeim et al., 2001). VNS applied for targeted plasticity
uses 100 times less current than these protocols and would be expected to have fewer
adverse effects (Engineer et al., 2011). Continuously applied VNS for epilepsy and
depression typically employs a 30 s “on” period every 5 min for 24 h per day
(Handforth et al., 1998; Sackeim et al., 2001). The “on” cycle consists of 500 ms
pulses delivered at 30 Hz at an intensity that is set at a tolerable level for each indi-
vidual patient but does not exceed 3.5 mA. Variations on these parameters have been
found to be safe and effective (Heck et al., 2002). The studies applying VNS with
paired experience to drive plasticity use significantly less total current per day than
the FDA-approved protocols. Stimulation parameters used to drive map reorganiza-
tion in auditory cortex consisted of 300 daily stimulations of a 500 ms train at 30 Hz
0.8 mA of 100 ms pulses (Engineer et al., 2011). Similar amounts of stimulation were
found to drive motor cortex reorganization and enhance recovery after stroke
(Khodaparast et al., 2013; Khodaparast et al., submitted; Porter et al., 2011). The en-
hancing effects of VNS on extinction training and memory retention use even less
stimulation, with one to four stimulation trains of 30 s consisting of 500 ms
0.4 mA pulses delivered at 20 Hz (Clark et al., 1995, 1998; Peña et al., 2012). In sum-
mary, the low levels of VNS current that effectively enhance plasticity and memory
would be expected to be safe and tolerable.
The effectiveness of different parameters of VNS for continuously delivered and
paired protocols likely arises from the different desired outcomes. For seizure sup-
pression or antidepressant effects, a sustained, tonic increase in neurotransmitter
levels may be desirable and could be achieved using the consistent 5 min off/30 s
on stimulation cycle (Handforth et al., 1998; Sackeim et al., 2001). The antiepileptic
effects of VNS are mediated by the locus coeruleus (Krahl et al., 1998), so a sustained
increase in the level of norepinephrine may drive EEG desynchronization and seizure
suppression. Consistent with this, lower amounts of current are less effective at pre-
venting seizures (Handforth et al., 1998). The requirement of sustained neuromodu-
lator levels for seizure suppression is further supported by the finding that treatment of
epilepsy with VNS becomes more effective over time (Heck et al., 2002). Alterna-
tively, for the plasticity-enhancing effects of paired VNS, a discrete, phasic release
of neurotransmitter release is required to drive specific plasticity. Only events occur-
ring coincident with VNS are reinforced while surrounding events are not (Engineer
et al., 2011; Porter et al., 2011). Temporally precise release of acetylcholine and nor-
epinephrine triggered by VNS coincident with an event may serve to “label” its im-
portance and reinforce this event in comparison with other unlabelled events. Because
of the temporal requirements, a continuous delivery of VNS would not be expected to
be effective in driving specific plasticity. The benefits of targeted plasticity using
VNS persist for weeks or months after discontinuation of stimulation because targeted
plasticity therapy drives long-lasting changes in neural circuits (Arns and De Ridder,
2011; Engineer et al., 2011; Khodaparast et al., 2013). In summary, the effectiveness
of VNS is likely dependent on the temporal requirements for changes in neuromodu-
latory levels; therefore, sustained increases are efficacious for epilepsy and depres-
sion, and discrete, phasic increases are required for the enhancement of plasticity.
7 FUTURE APPLICATIONS
The low levels of current delivered for VNS-directed plasticity suggest that targeted
plasticity therapy using VNS can be safely implemented into patients. The proof-of-
concept experiments discussed in the preceding text demonstrate the efficacy of tar-
geted plasticity therapy and suggest that it holds promise for treating tinnitus, stroke,
and PTSD. In principle, the ability to specifically manipulate plasticity represents
considerable potential for treating a variety of neurological disorders.
Pain disorders can be extremely debilitating and have massive economic, social,
and personal consequences. Pain is typically treated with drugs that carry a signif-
icant risk of tolerance and dependency (Martell et al., 2007; Schnoll and Weaver,
2003), highlighting the significant clinical need for a safe, effective therapy. Tar-
geted plasticity therapy may be effective in treating disorders related to sensory dys-
function, such as chronic pain, in the same manner as tinnitus. As chronic pain is
thought to be related to an increased somatosensory cortical representation
(Birbaumer et al., 1997; Flor, 2003; Flor et al., 1995, 1997), sensory input of non-
painful areas paired with VNS may be effective in renormalizing the cortical repre-
sentations and thereby reducing the percept of pain. A similar implementation may
be effective for phantom limb pain.
The proof-of-concept evidence demonstrating the effectiveness of VNS paired
with rehabilitative training to improve motor function after ischemic stroke opens
8 Concluding Remarks 291
the possibility that targeted plasticity therapy may drive plastic changes that are ben-
eficial in other disorders of motor function (Khodaparast et al., 2013; submitted).
Hemorrhagic stroke is a devastating subtype that has a mechanistically distinct path-
ophysiology compared to ischemic stroke and typically affects subcortical structures
and white matter. It is not clear whether VNS will be effective after white matter
damage, but VNS paired with rehabilitative training may be amenable for restoring
function by driving plasticity in spared circuitry. Neuronal death from the initial im-
pact of a traumatic brain injury or the resulting sequelae can impair motor function
and may benefit from targeted plasticity therapy. Despite significantly different un-
derlying pathologies, VNS paired with rehabilitation could be tested in models of
spinal cord injury and Parkinson’s disease. Significant development is still required,
but targeted plasticity therapy could potentially promote plasticity within intact
motor circuitry to confer therapeutic benefits.
The memory-enhancing effects of VNS paired with training indicate that targeted
plasticity therapy could potentially be applied to treat a range of cognitive disorders.
Based on the VNS-dependent enhancement of cued fear extinction in rats (Peña
et al., 2012), it has been suggested that VNS may improve exposure therapy. Exposure
therapy is beneficial for some patients experiencing generalized anxiety disorder and
PTSD. The therapy aims to reduce the response to fear-inducing stimuli through habit-
uation (Frueh et al., 1995). As VNS sped the reversal of a fearful memory in rats, similar
principles may allow VNS to enhance the effects of exposure therapy in patients. Paired
with the appropriate exposure, VNS may bolster the effects of the therapy and provide a
more robust, rapid reversal of the fear response. Maladaptive plasticity is associated
with a variety of other cognitive disorders, including anxiety, bipolar disorder, schizo-
phrenia, depression, drug addiction, and attention-deficit hyperactivity disorder
(Brunoni et al., 2008; Lozano, 2011). The complex cognitive aspects of these disorders
have left them undermanaged, emphasizing the need for effective, flexible treatments
that can address the underlying pathophysiology. VNS, if paired with the appropriate
behavioral exposure, may be able to improve these disorders.
8 CONCLUDING REMARKS
The remarkable capacity for experience-dependent plasticity in the sensory, motor,
and cognitive systems is a testament to its importance. In many neurological disor-
ders, insufficient and maladaptive plasticity can hinder recovery. The ability to har-
ness and specifically direct plasticity may reduce the suffering caused by these
disorders. Targeted plasticity therapies, including VNS paired with relevant events,
may represent such an intervention. While proof-of-concept studies have provided
encouraging results, continuing studies should be directed at defining the optimal
parameters to maximize benefit, delineating the factors that affect outcomes, and
identifying other disorders that may respond to targeted plasticity therapy.
VNS is one of many potential tools that can drive specific plasticity and subse-
quently treat neurological disorders. Mirroring aspects of the development of
FIGURE 3
Vaccination and targeted plasticity therapy are based on similar principles. (A) Injection of an
antigen alone causes a generally weak immunologic response. Injection of an adjuvant alone
causes a nonspecific inflammatory response. Many different compounds can act as
adjuvants, including aluminum salts, virosomes, or saponins (Cox and Coulter, 1997).
Concurrent presentation of the antigen and adjuvant results in a significantly enhanced
immunologic response beyond that evoked by either element alone, resulting in specific and
long-lasting immunity. (B) Targeted plasticity therapy is based on similar principles of
synergism. Experience alone drives activity within circuitry but does not result in plasticity.
Neuromodulators alone have generalized neuronal effects, but do not drive lasting changes. A
variety of factors can cause release of neuromodulators, including attention, pain, or VNS.
When bursts of neuromodulators correspond with experience, specific and long-lasting
plasticity results.
vaccines, VNS acts as an adjuvant, while experience mimics the antigen (Fig. 3).
Together, these elements synergistically provoke a significant biological response
that surpasses the typical physiological response to the antigen alone. As such,
VNS paired with experience enhances the brain’s response to experience and, when
targeted appropriately in a disease state, can promote recovery or reversal of neuro-
logical disease. The development of other tools that can act as an adjuvant to rein-
force the response to experience could also be applied as targeted plasticity therapies.
Considering the transformative potential of targeted plasticity therapies, efforts
should be focused on the development and translation of VNS and other methods
for targeting plasticity to treat neurological disease and improve human health.
Acknowledgments
We would like to thank Dr. Andrew Sloan, Navid Khodaparast, and Daniel Hulsey for insight-
ful comments and discussion about the chapter. This work was supported by grants from the
Michael J. Fox Foundation, the US National Institute for Deafness and Other Communicative
Disorders, Texas Biomedical Device Center, and Vulintus.
Conflict of interest: M. P. K. is a consultant for and has a financial interest in MicroTran-
sponder, Inc.
References 293
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CHAPTER
Computerized Cognitive
Training Targeting Brain
Plasticity in Schizophrenia
*
12
Bruno Biagianti*,{, Sophia Vinogradov*,{,1
San Francisco Department of Veterans Affairs Medical Center, San Francisco, CA, USA
{
Department of Psychiatry, University of California, San Francisco, CA, USA
1
Corresponding author: Tel.: (415) 750-2073; Fax: (415) 750-6996
e-mail address: Sophia.vinogradov@ucsf.edu
Abstract
Two important paradigm shifts have occurred recently in the field of schizophrenia research.
First, we now understand schizophrenia to be a neurodevelopmental disorder, one that is char-
acterized by aberrant patterns of activation and connectivity in cortical and subcortical neural
networks that are present before illness onset and that worsen as an individual progresses into
later stages of the disease. Second, we now understand that these abnormalities are not immu-
table and fixed, but instead can respond to interventions targeting brain plasticity, particularly
when delivered in the prodromal and early phases of schizophrenia.
In this chapter, we will first describe some of the neurocognitive impairments that charac-
terize schizophrenia, highlighting the developmental course of the illness. We will then briefly
review salient features of currently available computerized cognitive training programs that
target these impairments. Next, we will present an overview of current research findings re-
garding neurobiological effects of computerized cognitive training in schizophrenia and how
these results shed light on the critical neuroplasticity mechanisms that support successful train-
ing. Finally, we will present recommendations for future research to optimize computerized
cognitive training programs, with an aim to promoting functional recovery.
Keywords
schizophrenia, neurocognition, neurodevelopmental, cognitive training, neural system
impairments
Schizophrenia is a serious psychiatric illness characterized by hallucinations, delu-

sions, disorganized behavior, cognitive impairments, and poor psychosocial out-
comes. Genetic liability factors interact with environmental insults, many of them
occurring during the pre- and perinatal period, with the result that at-risk individuals
are vulnerable to a range of environmental stressors (Fig. 1). This interaction of genes
and environment leads to aberrations in brain development and neural network

301
302 CHAPTER 12 Computerized Cognitive Training
FIGURE 1
Neurodevelopmental model of schizophrenia, highlighting the pre-emptive period and
intervention targets discussed in this review (adapted and modified by permission of Tyrone
Cannon, PhD). DA, dopamine; HPA, hypothalamic-pituitary-adrenal.
functioning, which are not typically evident until adolescence or very early adult-
hood, when brain maturation is nearing completion (Andreasen, 2010; Hoffman
and McGlashan, 1997). At that point, usually as a response to environmental
stressors, the individual (who may until then have had no observable symptoms
or only mild nonspecific symptoms), experiences “psychosis,” or a break with real-
ity—often initially in mild or attenuated form, which if left untreated then progress
into a full-blown psychotic episode. Schizophrenia must thus be understood as a neu-
rodevelopmental neurocognitive disorder characterized by decreased efficiency and
abnormal connectivity in cortical and subcortical neural networks—rendering young
individuals particularly vulnerable to the deleterious effects of stress.
1 NEUROCOGNITIVE IMPAIRMENTS IN SCHIZOPHRENIA

Abundant evidence indicates that, in addition to increased stress responsivity, indi-
viduals who are destined to develop schizophrenia show a range of neurocognitive
impairments well before illness onset. Deficits in vigilance, speed of processing,
2 Shifting the View of Schizophrenia from Neurodegeneration 303
working memory, verbal learning and memory, executive functioning, global cog-
nition, and IQ are observed prior to the first psychotic episode (Becker et al.,
2010; Brewer et al., 2005; Eastvold et al., 2007; Jahshan et al., 2010; Keefe et al.,
2006; Kim et al., 2011a,b; Lencz et al., 2006; Niendam et al., 2006; Seidman
et al., 2006; Simon et al., 2007). From high risk status to first psychotic episode, in-
dividuals show continued cognitive impairment (Becker et al., 2010; Hawkins et al.,
2008), or further cognitive decline (Jahshan et al., 2010; Keefe et al., 2006; Simon
et al., 2007; Wood et al., 2007). A recent longitudinal study in a population-
representative sample indicated that a decline in processing speed was particularly
characteristic, occurring gradually from childhood to beyond the early teen years
(Meier et al., 2013). Cognitive deficits are not surprisingly associated with poorer
functional outcome (Green, 1996; Green et al., 2000): in young individuals who have
just experienced their first episode of psychosis, verbal memory, speed of processing,
and attention have been shown to predict psychosocial and vocational functioning 7
years later (Milev et al., 2005).
Interestingly, in both recent onset and chronic schizophrenia, cognitive functioning
and symptom severity are for the most part independent of one another: cognitive def-
icits are present in the absence of florid symptoms, and while antipsychotic medications
are effective in ameliorating some of the clinical symptoms, they have little effect on
cognitive impairment or long-term outcome (Goldberg et al., 2007; Keefe et al., 2007).
Given the relative independence of cognitive dysfunction and symptoms, as well as the
deleterious effects of cognitive impairment on social and occupational outcomes and
quality of life, it is clear that cognitive enhancement is a critical treatment goal in
schizophrenia. Moreover, cognitive enhancement is likely to be a key means for inter-
vening preemptively to ameliorate the course of illness, or perhaps even to inoculate the
at-risk individual against the onset of a first psychotic episode.
2 SHIFTING THE VIEW OF SCHIZOPHRENIA FROM

NEURODEGENERATION TO NEUROPLASTICITY AND
RECOVERY
The current picture in schizophrenia is one of a brain that has undergone aberrant
patterns of neurodevelopment, with reduced functional (and possibly structural) con-
nectivity among key higher-order neural systems and impaired cognitive and socio-
affective operations. For most of the past century, the illness has been conceptualized
as a neurodegenerative disease associated with progressive functional decline, a ni-
hilistic perspective first embodied by Kraepelin’s original nomenclature of dementia
praecox. In the past decade, however, it has become clear that with early detection
and well-designed interventions, intact brain plasticity mechanisms can be harnessed
to promote healthier neural system functioning, increased resiliency to stressors,
symptom reduction, and functional recovery. Indeed, if applied early enough in
the course of illness, it should be possible to harness these mechanisms to induce true
pre-emption of the usual illness trajectory.
Previously, there was a great deal of skepticism about the possibility of adaptive
plasticity and neural system improvement in serious neuropsychiatric disorders such
as schizophrenia. This was due in part to the fact that these illnesses are characterized
by long-standing and fairly serious impairments in behavior and in multiple distrib-
uted limbic, prefrontal and frontostriatal neural circuits. Further, recent findings by
Balu and Coyle (2011) indicate that many schizophrenia-risk genes are involved in
regulating neuroplasticity, perhaps contributing to abnormal patterns of synapse for-
mation and cortical connectivity. It is thus possible that there are some inherent lim-
itations in the “brain plasticity” mechanisms of certain individuals with
schizophrenia.
Despite this skepticism, emerging data over the past 5 years suggest that it is pos-
sible to develop intensive computerized cognitive training methods that successfully
harness the brain-learning machinery in schizophrenia to generate widespread adap-
tive behavioral and neural responses (Dale et al., 2010; Eack et al., 2009, 2010a;
Fisher et al., 2009; Subramaniam et al., 2012). These adaptive improvements include
better cognition and functioning as well as increases in gray matter volume and plas-
tic changes in cortical activation patterns (e.g., Adcock et al., 2009; Eack et al.,
2010b; Subramaniam et al., 2012). Positive results in younger individuals are partic-
ularly promising (Eack et al., 2010a; Fisher et al., 2013).
3 COMPUTERIZED COGNITIVE TRAINING IN SCHIZOPHRENIA:

BEHAVIORAL RESULTS
In this section, we briefly review the three most frequently studied computerized
cognitive training programs in order to identify key components that appear to con-
tribute to behavioral improvement in patients. Neuropsychological tests are catego-
rized into the cognitive domains recommended by the Measurement and Treatment
Research to Improve Cognition in Schizophrenia (MATRICS) committee
(Nuechterlein and Dawson, 1984). Table 1 presents a summary of the rationale
and key features for each of the programs.
3.1 CogPack (Marker Software)

Designed in Germany, CogPack (Marker, 1987–2007) contains multiple exercises
in: Visuomotor Skills, Vigilance/Comprehension/Reaction, Language Material,
Memory, Numbers/Logic, Knowledge/Orientation/Everyday Skills, and Special
Elements (e.g., executive functioning and tone and pitch discrimination). If a specific
task is solved, the program goes on to another type of task, but if unsolved, a similar
task is given. Training exercises cover a range of cognitive domains within the first
six sessions, with subsequent sessions focusing on repeated practice of exercises
across each domain (McGurk et al., 2005, 2007).
Sartory et al. (2005) tested CogPack exercises which targeted attention, verbal abil-
ity, spatial ability, numerical ability, memory and processing speed. Inpatients with
Table 1 Scientific rationale and key features of commonly used computerized cognitive training programs in schizophrenia
Program Rationale Key features
CogPack, Marker Information on rationale and approach not • 64 programs for testing and training, each with several
Software available variants for visuomotor, comprehension, reaction, vigilance,
memory, language, intellectual, and professional skills
• Exercises can be edited and expanded
• Difficulty level and the sequence of exercises can be modified
CogRehab, Originally developed for traumatic brain injury. • Hierarchical approach: training of fundamental cognitive
Psychological Based on the rationale that diffuse traumatic functions followed by more complex functions
Software Services lesions rarely have just one behavioral effect, • 8 modules target 4 domains: simple attention and executive
and the degree to which a single behavior skills, visuospatial skills, memory, and problem solving
will be normal (or pathological) may depend • 2 modules of increasing complexity within each domain
on its interactions with other functional systems • Exercises follow a standard sequence and progression of
(Chen et al., 1997) difficulty. Subjects graduate to new tasks after reaching a
prescribed performance level
Brain Fitness Originally developed for children with learning • Exercises are grounded in basic principles of learning-
Program Auditory disabilities but has been subsequently heavily induced neuroplasticity
Module, Posit modified and adapted for adults, with an emphasis • Intensive—many thousands of learning trials are performed
Science Inc. on both individuals with schizophrenia and the for each specific exercise
cognitive decline associated with aging. Applied to • Neuroadaptive—the dimensions of each exercise (e.g.,
patients with schizophrenia based on the known speed, working memory load) are parametrically and
impairments in auditory processing and frontally continuously modified on a trial-by-trial basis for each
mediated verbal memory operations individual user during the course of each exercise in order to
maintain performance at 80% accuracy
• Attentionally engaging—each trial is gated by a “ready” signal
from the user to indicate and require directed attention
• Rewarding—correct responses are continuously rewarded by
amusing auditory and visual stimuli in order to drive high
levels of training compliance and to engage reward and
novelty detection systems for successful learning
schizophrenia (N ¼ 21) completed fifteen, 45 min daily sessions over 3 weeks and
showed significant gains on immediate and delayed verbal memory as well as proces-
sing speed relative to 21 inpatients on a waitlist. Wölwer et al. (2005) used CogPack
tasks of attention, memory, and executive functioning, in combination with desk work
and training of compensatory strategies (verbalization and self-instruction) among in-
patients and outpatients (N ¼ 24) and also found gains on measures of verbal learning
and memory compared to a “treatment as usual” group (N ¼ 25).
McGurk et al. (2005, 2007b) tested the effects of 3 months of a combination of
CogPack exercises (attention, psychomotor speed, learning and memory, and exec-
utive functions), therapist-guided compensatory strategies (“Thinking Skills for
Work”), and supported employment among 23 schizophrenia outpatients versus
participation in supported employment only (N ¼ 21). Similar to Sartory et al.
(2005) and Wölwer et al. (2005), subjects who completed the cognitive training
showed gains on measures of verbal learning and processing speed. Importantly,
over a 2–3-year period post-treatment, subjects who received cognitive training
were more likely to work, held more jobs, worked more weeks and total hours,
and earned more wages compared to subjects receiving supported employment
alone. In a second study, the authors combined the training with vocational
rehabilitation (N ¼ 18) and found similar cognitive effects and better work outcomes
over a 2-year follow-up period relative to vocational rehabilitation alone (N ¼ 16)
(McGurk et al., 2009).
Lindenmayer et al. (2008) provided 45 inpatients with 24 h of CogPack exercises
(attention and concentration, psychomotor speed, learning and memory, and execu-
tive functions) in conjunction with a work program in a psychiatric center. Relative
to a computer games (CG) control group (N ¼ 40), subjects who completed the
cognitive training showed gains on measures of verbal learning, processing speed,
and global cognition. Further, over a 12-month follow-up, subjects who completed
cognitive training worked more total weeks relative to subjects in the control group.
CogPack showed positive effects on both cognition and quality of life in 50
outpatients in a rehabilitation program who completed 36 h of exercises in verbal
memory, verbal fluency, psychomotor speed and coordination, executive function-
ing, working memory, attention, culture, language, and simple calculation skills
(Cavallaro et al., 2009). Relative to subjects who completed computer-assisted
non-domain-specific activities (N ¼ 36), subjects who completed CogPack showed
gains on measures of attention, reasoning and problem solving, and the Quality of
Life Scale, as well as durability of gains at 6- and 12-month follow-up (Poletti
et al., 2010).
CogPack appears to have consistent positive effects on verbal learning and mem-
ory and processing speed in schizophrenia (Table 2), and substantially improves vo-
cational outcomes when combined with supported employment or vocational
training programs (Table 3). Sample sizes studied have been relatively small, how-
ever, and control groups have varied widely. Additional research is required to de-
termine the specificity of CogPack’s effects and to replicate the findings of improved
quality of life.
3 Computerized Cognitive Training in Schizophrenia: Behavioral Results 307
Table 2 The effects of computerized cognitive training on cognition in schizophrenia

Improvements
Computerized in cognition
Cognitive (significant
Training Authors and Experimental and group time
Program sample size control conditions interactions)
CogPack, Sartory et al., CogPack þ inpatient Verbal learning,

Marker 2005 (N ¼ 42) treatment versus verbal memory,
Software occupational processing
therapy þ inpatient speed
treatment
Wölwer et al., CogPack þ inpatient or Verbal learning,
2005 (N ¼ 77) outpatient treatment versus verbal memory
inpatient or outpatient
treatment
McGurk et al., CogPack þ supported Verbal learning,
2005, 2007b employment þ outpatient processing
(N ¼ 44) treatment versus speed
supported
employment þ outpatient
treatment
Lindenmayer CogPak þ inpatient Verbal learning,
et al., 2008 treatment versus computer verbal memory,
(N ¼ 85) games or typing processing
skills þ inpatient treatment speed
McGurk et al., CogPack þ vocational Verbal learning,
2009 (N ¼ 34) rehab versus vocational verbal memory,
rehab processing
speed
Cavallaro et al., CogPack þ outpatient Attention,
2009 (N ¼ 86); rehabilitation treatment executive
Poletti et al., versus outpatient functioning
2010 (N ¼ 100) rehabilitation treatment
CogRehab, Hogarty et al., CET (CogRehab þ attention Global cognition,
Psychological 2004 (N ¼ 121), exercises þ social cognitive speed of
Software 2006 (N ¼ 106) group exercises) versus processing at 12
Services Enriched Supportive and 24 months
Therapy of treatment
Eack et al., CET (CogRehab þ attention No cognitive
2009 (N ¼ 58), exercises þ social cognitive gains at 12
Eack et al., group exercises) versus months of
2010a (N ¼ 58) Enriched Supportive treatment
Therapy Global cognition
at 24 months of
treatment
Bell et al., 2001 CogRehab þ work therapy Working
(N ¼ 65), 2003 versus work therapy memory,
(N ¼ 102), 2007 executive
(N ¼ 116); functioning
Fiszdon et al.,
2004 (N ¼ 94)
Continued
Table 2 The effects of computerized cognitive training on cognition

in schizophrenia—cont’d
Improvements
Computerized in cognition
Cognitive (significant
Training Authors and Experimental and group time
Program sample size control conditions interactions)
Wexler and Bell CogRehab þ vocational Working
2005 (N ¼ 54); program versus vocational memory,
Greig et al., program executive
2007 (N ¼ 62); functioning
Bell et al., 2008
(N ¼ 72)
Kurtz et al., CogRehab þ day treatment Working
2007 (N ¼ 42) versus computer skills memory
training þ day treatment
Benedict et al., CogRehab þ day treatment No significant
1994 (N ¼ 33) versus day treatment group time
interactions
Brain Fitness Fisher et al., BFP auditory Verbal working
Program 2009 (N ¼ 55); module þ outpatient status memory, verbal
Auditory 2010 (N ¼ 32) versus computer learning, verbal
Module, Posit games þ outpatient status memory, global
Science Inc cognition
Popov et al., BFP auditory Verbal working
2011 (N ¼ 39) module þ inpatient memory, verbal
treatment versus learning
CogPack þ inpatient
treatment
Keefe et al., Brain Fitness Program Verbal learning,
2013 Auditory Training þ weekly global cognition,
(N ¼ 53) group adapted from auditory
NEAR þ outpatient status frequency
versus Computer discrimination
games þ weekly healthy
lifestyles
groups þ outpatient status
3.2 CogRehab (Psychological Software Services)

The Psychological Software Services CogRehab software (Bracy, 1995), originally
designed for patients with traumatic brain injury, has been used in a number of stud-
ies in schizophrenia. The exercises emphasize simple attention, executive skills, vi-
suospatial skills, memory, and problem solving. Program parameters, such as
difficulty level, are adjusted based on each individual’s progress through the
program.
Table 3 The effects of computerized cognitive training on symptoms and functioning

and durability of cognitive gains in schizophrenia
Computerized
Cognitive The effect of training on
Training symptoms and functioning
Program Authors and sample size and durability of cognitive gains
CogPack, Sartory et al., 2005 (N ¼ 42) • None reported

Marker Software Wölwer et al., 2005 (N ¼ 77) • None reported
McGurk et al., 2005, 2007a • Greater number of hours worked,
(N ¼ 44) wages earned, and more jobs
worked at 1-year and 2–3-year
follow-ups
• Improvement in PANSS
Depression and Autistic
Preoccupation at post-training
Lindenmayer et al., 2008 • Greater number of weeks worked
(N ¼ 85) at 12-month follow-up
McGurk et al., 2009 (N ¼ 34) • Greater number of weeks worked
at 12-month follow-up; greater
number of internship hours and
internship wages at 12-month
follow-up
Cavallaro et al., 2009 • Improved quality of life scores at
(N ¼ 86); Poletti et al., 2010 post-training; durability of effects
(N ¼ 100) on cognition and quality of life at
6- and 12-month follow-up
CogRehab, Hogarty et al., 2004 • Improvement on clinician ratings
Psychological (N ¼ 121), 2006 (N ¼ 106) of social adjustment at 12
Software months
Services • Improvement on clinician ratings
of cognitive style, social
cognition, and social adjustment
at 24 months
• Durability of gains in speed of
processing, cognitive style, social
cognition, and social adjustment
at 12-month follow-up
Eack et al., 2009 (N ¼ 58), • Improvement on clinician ratings
Eack et al., 2010a (N ¼ 58) of cognitive style, social
cognition, social adjustment, and
symptoms at 12 and 24 months
of treatment
• Greater proportion of CET
subjects were employed at 24
months of treatment. Effect on
employment was no longer
significant at 12-month follow-up
Continued
Table 3 The effects of computerized cognitive training on symptoms and

functioning and durability of cognitive gains in schizophrenia—cont’d
Computerized
Cognitive The effect of training on
Training symptoms and functioning
Program Authors and sample size and durability of cognitive gains
Bell et al., 2001 (N ¼ 65), • Greater number of hours worked
2003 (N ¼ 102), 2007 at 6-month follow-up
(N ¼ 116); Fiszdon et al., • Durability of cognitive gains at
2004 (N ¼ 94) 6- and 12-month follow-up
Wexler and Bell 2005 • Greater number of hours worked
(N ¼ 54); Greig et al., 2007 at 12-month follow-up; higher
(N ¼ 62); Bell et al., 2008 quarterly employment rates and
(N ¼ 72) higher cumulative rates of
competitive employment over 3
quarters
• Improvement on the PANSS
Cognitive Component, Vocational
Cognitive Rating Scale and Work
Behavior Inventory at 12-month
follow-up
Kurtz et al., 2007 (N ¼ 42) • None reported
Benedict et al., 1994 (N ¼ 33) • None reported
Brain Fitness Fisher et al., 2009 (N ¼ 55); • No significant group time
Program 2010 (N ¼ 32) interactions at post-training or
Auditory 6-month follow-up
Module, Posit • Improvements in cognition were
Science Inc. significantly associated with
improvements in functional
outcome (QLS) at 6-month
follow-up in cognitive training
subjects
Popov et al., 2011 (N ¼ 39) • No significant group time
interactions at post-training
Keefe et al., 2013 • No significant group time
(N ¼ 53) interactions at post-training
Cognitive enhancement therapy (CET) (Hogarty and Flesher, 1999, 2004, 2006)
is a small-group approach for the treatment of social cognitive and neurocognitive
deficits in schizophrenia. Subjects work in pairs and complete approximately 75 h
of computerized cognitive training exercises, which also included attention exercises
from the Orientation Remediation Module (Ben-Yishay et al., 1987), and CogRehab
exercises of memory and problem solving. Four to six months cognitive training,
subjects begin 1.5 h per week of social cognitive group therapy, with treatment de-
livered over a 2-year period. Hogarty et al. (2004) tested the effects of CET (N ¼ 67)
relative to Enriched Supportive Therapy (EST, N ¼ 54) in outpatients with schizo-
phrenia. At 12 months of treatment, the CET group showed significant gains in speed
of processing, global cognition, and social adjustment, while at 24 months of treat-

ment, the CET group showed significant improvement across all measures relative to
the EST group, with the exception of symptoms. EST participants also showed clin-
ically meaningful change at 2 years of treatment on many of the outcome measures,
including neurocognition. Although cognitive testing was performed by staff blind to
group assignment, unblinded staff conducted clinical ratings, and the CET and EST
conditions were not matched in terms of staff contact. Follow-up evaluation 1 year
after the completion of treatment found durability of all effects with the exception of
neurocognition, and a significant relationship between early improvements in speed
of processing and the long-term effects of CET on social cognition and social
adjustment.
Eack et al. (2009) also examined the effects of CET (N ¼ 31) relative to EST
(N ¼ 27) in individuals with recent-onset schizophrenia. After 1 year of CET treat-
ment, improvements on the cognitive measures (speed of processing and global cog-
nition) were not evident, but global cognition showed moderate improvement after 2
years of treatment. At both 1 and 2 years of treatment, CET subjects showed signif-
icant gains on measures of social cognition, and a significantly greater proportion of
CET subjects were engaged in competitive employment at 2 years. A follow-up
study 1 year later (Eack et al., 2010a) showed that the gains on social and symptom
measures were broadly maintained, while the effect on employment was no longer
significant. Cognitive assessments were not conducted at the follow-up.
Neurocognitive Enhancement Therapy (NET) (Bell et al., 2001, 2003; Wexler
and Bell, 2005) utilized CogRehab exercises of attention, memory, language, and
executive functioning, some of which were modified for use with schizophrenia.
Bell et al. (2001, 2003) compared the effects of NET þ work therapy (N ¼ 47) to
the effects of work therapy alone (N ¼ 55). Subjects in the NET þ work therapy con-
dition completed 26 weeks of 3–6 h of cognitive training, a feedback support group,
and a weekly social information processing group and showed greater gains on mea-
sures of working memory and executive functioning compared to subjects receiving
work therapy only. At 6-month follow-up, the gains in working memory were dura-
ble, with effect sizes ranging from 0.45 to 0.73 (Bell et al., 2003). At follow-up, the
NET þ work therapy subjects worked significantly more hours compared to subjects
who completed work therapy alone (Wexler and Bell, 2005). In a second study, the
authors tested the effects of NET in combination with a vocational program
(NET þ VOC ¼ 38) for 1 year relative to subjects receiving VOC only (N ¼ 34).
NET þ VOC subjects showed greater gains on measures of working memory and ex-
ecutive functioning, markedly better vocational outcomes at 12-month follow-up
(Wexler and Bell, 2005; Greig et al., 2007), and a significantly higher rate of employ-
ment at 24-month follow-up (Bell et al., 2008).
Kurtz et al. (2007) used CogRehab tasks of attention and memory, two tasks of
attention from Loong (1988), and a speed-reading task designed to increase
language-processing speed. The cognitive training condition (N ¼ 23) was compared
to a computer skills training condition (N ¼ 19), with 100 h of training over 1 year.
Subjects in the cognitive training group showed greater gains in working memory
compared to the computer skills training group. In this study, both groups received
equivalent computer time and equivalent staff interaction. Interestingly, both groups
showed improvements in processing speed, working memory, episodic memory
(verbal and visual), and executive functioning, indicating that nonspecific engage-
ment and stimulation has a salutary effect on neurocognition.
In summary, in studies where CogRehab training exercises of attention and
working memory have been used in sufficient doses, gains in working memory
have been consistently reported (Table 2). Further, the addition of CogRehab
has provided significant benefits on work outcomes in studies that added cognitive
training to work therapy or vocational programs (Table 3). Again, sample sizes
have been small, control groups have varied widely, and the specificity of the ef-
fects is not yet clear.
3.3 Brain Fitness Program—Auditory Training Module (BFP,

PositScience, Inc.)
Brain Fitness Program (BFP) is an auditory/verbal learning training program that is
designed to restore and enhance auditory perceptual and working memory processes,
with the goal of increasing the accuracy and temporal resolution of auditory inputs
feeding working memory and long-term verbal memory processes. Unlike the Cog-
Pack and CogREhab, which have their origins in neuropsychological models of cog-
nitive dysfunction, the design of BFP was explicitly rooted in experimental
principles of maximizing neuroplastic changes in targeted distributed neural systems
(in this case, the auditory/verbal learning system). BFP was originally designed to
address the verbal memory impairments associated with aging, but has been applied
to patients with schizophrenia based on the known impairments in auditory proces-
sing and frontally mediated verbal memory operations in the illness (Foucher et al.,
2005; Friston and Frith, 1995; Javitt et al., 2000; Kasai, 2002; Kawakubo et al., 2006;
Light and Braff, 2005; Ragland et al., 2004, 2007; Wible et al., 2001). Though many
of the exercises have a heavy emphasis on perceptual processing, they also explicitly
require sustained attention and working memory and repeatedly engage cognitive
control and response-selection mechanisms.
The exercises have the following features: (1) intensive—many thousands of
learning trials are performed for each specific exercise; (2) neuroadaptive—the di-
mensions of each exercise (e.g., speed, working memory load) are parametrically and
continuously modified on a trial-by-trial basis for each individual user during the
course of each exercise in order to maintain performance at 80% accuracy; (3)
attentionally engaging—each trial is gated by a “‘ready” signal from the user to in-
dicate and require directed attention; (4) rewarding—correct responses are continu-
ously rewarded by amusing auditory and visual stimuli in order to drive high levels of
training compliance and to engage reward and novelty detection systems for success-
ful learning.
Our group has previously reported the effects of BFP delivered as a stand-alone
treatment (Fisher et al., 2009). Twenty-nine schizophrenia outpatients completed
50 h of the training over a 10-week period and were compared to an active CG con-
trol condition (N ¼ 26) designed to control for the effects of computer exposure, con-
tact with research personnel, and monetary payments. Relative to the control group,
using a per protocol analysis, the auditory training showed positive effects on mea-
sures of verbal working memory, verbal learning and memory, and global cognition.
Effect sizes in verbal learning and memory, and in global cognition, were large
(Cohen’s d 0.86–0.89). At a 6-month no-contact follow-up, improved cognition
was significantly associated with improved functional outcome.
Popov et al. (2011) tested the effects of BFP compared to CogPack among inpa-
tients in Germany. Patients in the BFP condition (N ¼ 20) completed 20 one-hour
sessions over 4 weeks, while patients in the CogPack condition (N ¼ 19) followed
the standard protocol recommended by the developers of 60–90 min sessions, three
times per week, for 4 weeks. Both subject groups showed improvement in verbal
learning and verbal memory; however, the BFP group showed significantly greater
gains in verbal working memory and verbal learning. Patients who completed BFP
also showed normalization of auditory sensory gating deficits not seen in the Cog-
Pack group (described in the next section).
In a multisite feasibility study (Keefe et al., 2013), 25 outpatients were random-
ized to BFP plus weekly support groups, or to a CG control condition plus weekly
healthy lifestyles groups (N ¼ 22). Subjects completed 3–5 one-hour sessions per
week for 40 sessions or 12 weeks, whichever came first. After 20 sessions, in an in-
tent-to-treat-analysis, the BFP group showed significant gains in verbal learning
(d ¼ 0.69), auditory frequency discrimination (d ¼ 0.84), and global cognition
(d ¼ 0.28) relative to the control group. However, at the endpoint of the study, the
effects on verbal learning and global cognition did not reach significance. The au-
thors suggest this is likely due to the study completion deadline—that 9 out of the
25 auditory training subjects did not complete the entire 40 sessions within the
12-week period, which may have reduced the efficacy of the training.
A single-arm, open-label, multisite, trial of 40 training sessions, using a repeated
baseline assessment design, found no overall gain in a cognition summary score in
stable outpatients, but did find that participants with greater improvement in auditory
processing speed (evidence of target engagement in auditory system) showed larger
gains in cognition (Murthy et al., 2012). Finally, a pilot study of 10 weeks of an
unspecified number of hours of auditory training combined with visual training ex-
ercises found no significant effects on cognitive or event-related potential measures
compared to a TV watching control group or a treatment-as-usual group; however,
methodological issues make interpretation/comparison difficult (e.g., interleaving
training across visual and auditory domains, unequal baseline cognitive performance
in subject groups, combining of raw scores across tests into a summary score; Rass
et al., 2012).
Once again, sample sizes have been small and study methods have varied, though
three of the five studies have used an active control group that permitted maintenance
of a double-blind. These early data suggest some specificity of BFP for verbal pro-
cesses and global cognition.
3.4 Comparative Effects of Computerized Cognitive Training

in Schizophrenia
The computerized programs reviewed above show some consistent patterns in terms
of their benefits on specific cognitive domains. CogPack shows consistent patterns of
improvement in measures of verbal learning, verbal memory, and processing speed,
and also improves work outcomes when combined with vocational rehabilitation.
CogRehab improved working memory in three out of six studies, executive function-
ing in two out of six studies (Table 2), and significantly improved work outcomes
when combined with vocational rehabilitation (Table 3). These discrepancies are
likely the result of differences in the exercises and assessment measures used, and
in treatment intensity. For example, in studies where significant gains in working
memory were found, subjects completed 3–6 h of cognitive training per week over
a 5-month period (Bell et al., 2001, 2003) versus studies that used 1 h per week of
training over a 1–2-year period (e.g. Hogarty et al., 2004; Eack et al., 2009). Finally,
BFP shows consistent improvement on measures of verbal working memory, verbal
learning, and global cognition in three double-blind studies with an active computer
control condition, and greater improvement than CogPack in one study.
4 COMPUTERIZED COGNITIVE TRAINING IN SCHIZOPHRENIA:

NEUROBIOLOGICAL RESULTS
In this section, we examine what is currently known about the neurobiological effects
of computerized cognitive training in schizophrenia. These findings point the way
for research that will determine the critical physiological mechanisms that support
successful neuroplastic changes in order to inform development of optimally effi-
cient intervention strategies.
4.1 Serum Biomarker and Genetic Findings

Serum compounds can serve as peripheral biomarkers of training-induced physiolog-
ical changes and have the potential to increase our understanding of neurophysiolog-
ical processes that are recruited by different types of training. In our clinical trial of
BFP auditory training, we measured two compounds in the serum of participants be-
fore and after 50 h of training: brain-derived neurotrophic factor (BDNF) (Vinogradov
et al., 2009a) and D-serine (Panizzutti et al., 2013). BDNF plays a key role to neuro-
plasticity, neurodevelopment and neuronal function, and decreases in normal BDNF
levels are found in schizophrenia (Buckley et al., 2007). Consistent with these re-
ports, we found significantly lower baseline serum BDNF levels in patients with
schizophrenia relative to healthy control subjects; however, subjects who received
BFP showed a significant increase in serum BDNF compared with subjects who were
in the CG control group, and after training, achieved mean serum BDNF comparable
to healthy subjects (Vinogradov et al., 2009a). While intriguing, the interpretation of
4 Computerized Cognitive Training in Schizophrenia 315
this finding is limited by the fact that the relationship between serum BDNF and
brain processes is unknown.
Dysfunction of glutamatergic neurotransmission mediated by the N-methyl-D-as-
partate (NMDA) receptors and D-serine (an endogenous receptor agonist) may also
be involved in the pathophysiology of schizophrenia (reviewed in Labrie et al.,
2012). Since animal studies indicate that learning and memory can affect the levels
of D-serine (Vargas-Lopes et al., 2011), we predicted that training-induced cognitive
gains would be associated with changes in serum D-serine levels. At baseline, we
found reduced serum D-serine in schizophrenia subjects compared to healthy control
subjects, consistent with previous findings in both serum and cerebrospinal fluid
(Bendikov et al., 2007; Hashimoto et al., 2003; Panizzutti et al., 2013). We also found
a significant positive correlation between cognitive improvement, and increases in
serum D-serine, in subjects who underwent 50 h of the BFP exercises, but not in
subjects who were in the CG control condition. These results raise the possibility that
D-serine and/or the NMDA receptor is involved in the neurophysiological changes
induced by BFP cognitive training in schizophrenia.
During this trial, we also determined the anticholinergic activity of medications
taken by participants, as measured via serum radioimmunoassay. We found that im-
provements in global cognition after training were negatively correlated with serum
anticholinergic burden; in fact, serum anticholinergic activity accounted for 20% of
the variance in the change in global cognition independent of the effects of IQ, age, or
symptom severity (Vinogradov et al., 2009b). These findings have implications
for the design and evaluation of neuroplasticity-based cognitive treatments for
schizophrenia in situations where participants are administered medications with an-
ticholinergic burden.
Finally, it is possible that common variants in genes known to influence cognition
affect an individual’s response to cognitive training. One small study investigated the
association between the COMT Val158Met polymorphism and neuropsychological
improvement after 36 h of Cogpack exercises in 27 patients with schizophrenia
(Bosia et al., 2007). Patients with the COMT Met allele made greater gains in cog-
nitive flexibility than patients without the Met allele. In contrast, another study failed
to observe a significant association between the COMT Val158Met polymorphism
and cognitive improvement following therapist-led pencil-and-paper cognitive re-
mediation therapy (Greenwood et al., 2011). In a recent small study, we genotyped
48 schizophrenia outpatients who had participated in our cognitive training studies
using BFP. We analyzed the association between the training-induced improvement
in global cognition, and DNA variants in three genes known to show a relationship
with cognitive performance—DISC1, COMT, and BDNF. Changes in global cogni-
tion after training were nominally associated with single nucleotide polymorphisms
in the COMT and DISC1 genes. The strongest association was with COMT
rs165599, a SNP previously associated with neurocognition in healthy subjects
(Panizzutti et al., 2013). It is probable that a wide number of gene variants that affect
aspects of cognition or learning potential will play a significant role in determining
the magnitude of patients’ response to cognitive training interventions.
4.2 Psychophysical Findings

What aspects of cognitive training are fundamental for optimal treatment response?
Thus far, treatment duration, type of training, and participant characteristics do not
show a significant moderating effect on outcomes (Grynszpan et al., 2011; McGurk
et al., 2007; Wykes et al., 2011). However, we have found a significant association be-
tween gains on an auditory discrimination training exercise and gains in verbal working
memory and global cognition, but not visual cognition (Fisher et al., 2009). We have
replicated these data in a second subject sample, using a measure of auditory processing
speed as an index of improvement in psychophysical processing (Fisher et al., 2010).
These findings are consistent with data reported in Murthy et al. (2012) and suggest that
generalized training to better global cognition only occurs when subjects can success-
fully engage basic perceptual learning processes.
In a related study, 14 participants with schizophrenia were studied who com-
pleted a range of BFP computerized training modules in auditory, visual, and cog-
nitive control processes. The gains in visual processing speed strongly predicted
improvement in visual memory but not in auditory or verbal measures; however,
the amount of time spent in visual training was not associated with these improve-
ments (Surti et al., 2011). Taken together, these results indicate that the ability to
show target engagement (learning) when exposed to targeted training is more ro-
bustly associated with cognitive improvement than is the amount of time spent doing
exercises. The results also suggest that progress in this form of training is domain-
specific. It is highly likely that there is individual variation in psychophysical com-
ponents of learning potential and/or cortical plasticity responses and that this will be
a fruitful avenue for further investigation.
4.3 Magnetoencephalography (MEG): Improvements in Neural

Operations During Early Auditory Processes
Using magnetoencephalography (MEG), we have shown that patients with schizo-
phrenia demonstrate hemispheric asymmetry abnormalities in early neural response
dynamics in auditory cortex during discrimination of syllable pairs. After 50 h (10
weeks) of BFP auditory training, schizophrenia subjects showed a trend toward nor-
malization of the asymmetry, which was positively associated with gains in both task
accuracy and verbal learning after training (Adcock et al., 2009). We have also
shown that training enhances the M100 response in auditory cortex during syllable
identification, as well as high gamma band activity in left dorsolateral prefrontal cor-
tex (Dale et al., 2010). Training-related changes in neural activity in both auditory
and prefrontal cortical regions correlated with training-related improvements in neu-
ropsychological measures of executive function, primarily driven by enhancement of
the M100. These results suggest that BFP training of auditory processing enhances
both representational fidelity in auditory cortex and early engagement of prefrontal
regions, and that this increased efficiency in the distributed neural system is associ-
ated with better executive function.
In another MEG study, Miller and collaborators used measures of auditory sen-
sory gating, a finding related to early auditory processing abnormalities in schizo-
phrenia, to explore the effects of BFP auditory training and CogPack training
(Popov et al., 2011). Four weeks (approximately 20 h) of BFP normalized sensory
gating in patients with schizophrenia, while this effect was not evident in subjects
who completed CogPack. These results indicate that exercises that specifically target
perceptual discrimination ability in the auditory system—as opposed to providing
more generalized cognitive training—may normalize early auditory gating impair-
ments in schizophrenia.
Weiss et al. (2011) also investigated the effects of this form of cognitive training
on early perceptual operations. Two MEG recordings were acquired during perfor-
mance of an FM sweep discrimination task used to improve the acuity of auditory
processing, before and after 2.5 h of task practice. Practice increased power and mu-
tual information, an index of communication between brain regions, in temporal-
parietal regions. Participants showed improved accuracy after practice, and these
improvements correlated with the increase in power and mutual information.
Overall, the emerging MEG data suggest that carefully designed computerized
training of auditory processes can increase the fidelity, precision, and signal-to-noise
ratio of early auditory representations in the brain, with important downstream be-
havioral effects.
4.4 Functional Magnetic Resonance Imaging (fMRI): Improvements

in Neural Activation Patterns During Higher-Order Processes
4.4.1 Verbal Working Memory
In 2000, Wexler, Anderson, Fulbright, and Gore showed that training-induced im-
provements in verbal working memory were associated with increased activation
of the left inferior frontal cortex. Of the eight patients in this uncontrolled study, three
made substantial gains in verbal working memory performance after 25 h of training
on the task, and these subjects also showed increased task-related functional Mag-
netic Resonance Imaging (fMRI) activation in left inferior frontal cortex. A signif-
icant association between performance improvement and activation increase of the
left inferior frontal cortex was observed across all eight patients (Wexler et al., 2000),
indicating that task-related performance gains are related to increased recruitment of
relevant cortical regions.
More recently, nine patients who completed 25 h of CogPack exercises of atten-
tion and working memory plus training on a word N-back working memory task
showed increased brain activation in several regions during both a word and a picture
N-back task—including the dorsolateral prefrontal cortex, frontopolar cortex and an-
terior cingulate gyrus—as compared to nine patients who received social skills group
therapy (Haut et al., 2010). There were significant activity-behavioral associations
between improved working memory performance and increased activation within
the regions of activity overlap for the word and picture N-back tasks (i.e., left fron-
topolar cortex and left dorsolateral prefrontal cortex). These findings suggest
generalization of neurobehavioral improvements in verbal working memory to vi-

sual working memory.
Bor et al. (2011) compared eight patients receiving 28 h of cognitive training,
facilitated by a psychologist, of Rehacom software exercises in attention, working
memory, logical thinking, and executive functions versus eight patients who did
not receive training (single-blind randomized trial design). The between-group con-
trast of session 2 versus session 1 revealed increased activation in the training group
in the left inferior/middle frontal gyrus, cingulate gyrus, and inferior parietal lobe
during an untrained n-back working memory task. Increased activation in the left
inferior/middle frontal gyrus was associated with improvements in attention and rea-
soning abilities, indicating some possible generalization of training effects.
4.4.2 Reality Monitoring

In a double-blind randomized controlled trial, our group investigated the behavioral
and neural effects of intensive computerized cognitive training in schizophrenia on
an untrained meta-cognitive reality-monitoring task (Subramaniam et al., 2012). Re-
ality monitoring—the ability to distinguish self-generated information from
externally-presented information—is impaired in patients with schizophrenia; unlike
healthy subjects, patients with schizophrenia do not show activation of the medial
prefrontal cortex (mPFC) when performing reality-monitoring decisions
(Subramaniam et al., 2012; Vinogradov et al., 2008). Thirty-one patients with
schizophrenia were randomized to 80 h of either cognitive training (50 h of BFP au-
ditory training plus 30 h of visual processing training combined with social cognition
training (SCT)) or a CG control condition. At baseline, patients showed no signifi-
cant recruitment of mPFC during the reality-monitoring task (Fig. 2B), in contrast to
15 healthy comparison subjects, in which activation of mPFC was significantly as-
sociated with accurate reality-monitoring performance (Fig. 2A). After cognitive
training, patients showed improved reality monitoring, which was associated with
increased task-related activation of the mPFC, similar to the brain-behavior associ-
ations observed at baseline in the healthy subjects (Fig. 2C).
These behavioral and neural improvements were not observed in control patients
who completed 80 h of CG. Remarkably, patients who showed larger training-
induced increases in mPFC activation during the reality-monitoring task also dem-
onstrated better real-world social functioning 6 months later. Results of this study
indicate that intensive cognitive training of basic cognitive processes can normalize
brain-behavior associations during a non-trained higher-order reality-monitoring
task, so that they more closely resemble what is observed in healthy subjects.
4.4.3 Social Cognition

Habel et al. (2010) used fMRI to examine 10 patients who completed 9 h of comput-
erized training of affect recognition (TAR); these patients showed increased activa-
tion in several regions—including the left middle and superior occipital lobe, the
right inferior and superior parietal cortex, and bilateral inferior frontal cortices—
as compared to 10 patients who did not receive TAR. Furthermore, activation
FIGURE 2
Whole brain fMRI analysis during reality-monitoring task performance reveals signal increase
within: (A) the medial prefrontal cortex (mPFC) in 15 Healthy Comparison Subjects (HC),
(B) the posterior cingulate cortex, rather than the mPFC, in patients with schizophrenia
(SZ) prior to computerized cognitive training, and (C) the mPFC in only the group of
schizophrenia patients who completed 80 h of Active Training (SZ-AT) but not those who
completed the Computer Games control condition (SZ-CG). From Subramaniam et al. (2012).
changes in patients after TAR exercises correlated with their behavioral improve-
ment in emotion identification.
More recently, in a double-blind randomized controlled trial, our group investi-
gated the behavioral and neural effects of intensive computerized cognitive and so-
cial cognitive training in schizophrenia on a facial emotion recognition task (Hooker
et al., 2013). Twenty-two schizophrenia participants were randomly assigned to ei-
ther 50 h of auditory-based cognitive training plus SCT which consisted of exercises
from the Microexpressions and Subtle Expressions Training Tool (METT/SETT,
Eckman, 2003) and MindReading (Baron-Cohen et al., 2003) or to 50 h of a placebo
CG condition. We found a group by session interaction which was driven by the SCT
subjects who showed greater neural increases in two emotion-processing regions—
including the superior temporal cortex and somatosensory-related cortex—as com-
pared to the CG subjects. Furthermore, neural increases in these regions were
correlated with behavioral improvement on an independent emotion perception mea-
sure (MSCEIT: Perceiving Emotions). Together, these findings suggest that com-
bined cognitive and social cognitive training increased neural activation of the
systems that supported better emotion recognition. Because facial emotion recogni-
tion has been shown to predict functional outcome even after accounting for the con-
tribution of general cognition (Hooker and Park, 2002; Poole et al., 2000), these
findings indicate that a combination of computerized basic cognitive and social cog-
nitive training interventions has the highest likelihood of improving quality of life for
people with schizophrenia.
Overall, it appears unequivocally that the higher-order behavioral and neural im-
pairments in schizophrenia are not fixed and that, even during complex operations
such as verbal working memory, reality monitoring, and social cognition, they
can demonstrate significant plasticity in response to well-designed cognitive training
interventions.
4.5 Voxel-Based Morphometry: Sustaining Gray Matter Volume

In a recent study, Eack et al. (2010a) showed that CET (60 h of CogRehab integrated
with approximately 70 h of social cognitive group sessions and individual coaching
over a 2-year period) was protective against gray matter loss in 30 outpatients with
recent-onset schizophrenia. Patients who received CET showed preservation of gray
matter volume over the 2 years of the study within the left hippocampus, parahippo-
campal gyrus, fusiform gyrus, and amygdala compared to the 23 outpatients who re-
ceived enriched supportive individual therapy for the same period. Within the CET
group, less gray matter decline in the left parahippocampal gyrus and fusiform gyrus
and greater gray matter increases in left amygdala were all associated with greater
2-year improvement in social cognition/social behavior. Additionally, in the CET
group, less loss of left parahippocampal gyrus and fusiform gyrus volumes were cor-
related with improvements in neurocognitive function. However, it is not clear
whether these effects were mediated by the computerized cognitive training
per se, or by the rich social skills group therapy and enhanced therapeutic contacts
of the psychosocial components of CET, as might be suggested by the gray matter
preservation in neural structures critically important for social-emotional functions.
Nonetheless, these findings demonstrate that well-designed interventions can halt, or
potentially reverse, the usual declines in gray matter volume that are observed in
early phases of the illness.
5 FUTURE DIRECTIONS
There is now a consensus in the field that cognitive training offers a number of
significant advantages as we seek to develop meaningful approaches to not only
treat, but to pre-empt schizophrenia. Over 10 years ago, Bentall and Morrison
(2002) noted that, as compared to pharmacological treatments, behavioral interven-
tions for schizophrenia have fewer deleterious side effects, are less stigmatizing,
and target the presenting nonspecific symptoms through a normalizing approach.
In addition, they are generally more tolerable and acceptable than medications
References 321
(Morrison et al., 2004). We posit that, in at least some forms, they are also more
scalable, and can be delivered via web-based technology to remote or under-
resourced clinical sites. More importantly, if we are able to achieve the goal of en-
gendering adaptive plastic changes in impaired neural systems, then such methods
can halt or reverse the pathological neural system changes that characterize
schizophrenia.
While the emerging data are promising, much important work remains to be
done. A strong and rigorous approach to methodological issues such as sample size
and sample characteristics, assessment criteria, clinical staging, and optimal trial
design and data analytic approaches must be implemented in order to build a con-
vincing evidence base. With the current rapid advances in the development of
cognitive-enhancing medications, we must also be prepared to explore the most ad-
vantageous ways in which these agents can—and probably should—be combined
with behavioral treatments in order to optimize patients’ outcomes (Keefe et al.,
2011). Indeed, some agents may be of no value when given alone, but may substan-
tially facilitate the effects of cognitive training in schizophrenia.
Medications are not the only possible approaches to enhance the brain’s response
to behavioral interventions. Exercise is a potent, safe, and highly valuable “neuro-
trophic agent” that should become a significant part of the treatment armamentarium
for schizophrenia (see Pajonk et al., 2010). Neuromodulatory techniques such as di-
rect current stimulation are known inducers of cortical plasticity (Celnik et al., 2009;
Khedr et al., 2010). All of these areas are under active investigation at present in
combination with cognitive training.
Finally, advances in information technology and in interactive and entertainment
software indicate that web-based treatment delivery methods can be developed that
will generate the same interest, engagement, perceived value, and social acceptabil-
ity as web-based games. Indeed, novel collaborative efforts are already underway to
develop socially-networked browser-based cognitive therapy for schizophrenia as
well as highly engaging game-like cognitive training tools for early psychosis pa-
tients. We are only a few steps away from the development of web-deliverable brain
plasticity-based treatments for impaired neural systems that can be delivered on a
scale never before imagined for any other behavioral intervention. We are at a con-
ceptual threshold that could not have been imagined even a decade ago, facing the
real possibility that we may be able to move beyond pre-emption in schizophrenia, to
inoculation against its cognitive and psychosocial ravages.
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CHAPTER
The Nonspatial Side of

Spatial Neglect and
Related Approaches to
Treatment
13
Thomas M. Van Vleet*,{,1, Joseph M. DeGutis{,}
*
{
Department of Veteran Affairs, Martinez, CA, USA
{
Department of Veteran Affairs, MA, USA
}
Department of Medicine, Brigham and Women’s Hospital,
Harvard Medical School, Boston, MA, USA
1
Corresponding author: Tel.: (415) 394-3100 ext. 119
e-mail address: tomvanvleet@gmail.com
Abstract
In addition to deficits in spatial attention, individuals with persistent spatial neglect almost uni-
versally exhibit nonspatially lateralized deficits in sustained and selective attention, and working
memory. However, nonspatially lateralized deficits in neglect have received considerably less
attention in the literature than deficits in spatial attention. This is in spite of the fact that non-
spatially lateralized deficits better predict the chronicity and functional disability associated with
neglect than spatially lateralized deficits. Furthermore, only a few treatment studies have spe-
cifically targeted nonspatially lateralized deficits as a means to improve spatial neglect. In this
chapter, we will briefly review several models of spatial attention bias in neglect before focusing
on nonspatial deficits and the mechanisms of nonspatial–spatial interactions and implications for
treatment. Treatment approaches that more completely address nonspatial deficits and better ac-
count for their interactions with spatial attention will likely produce better outcomes.
Keywords
spatial neglect, hemineglect, neglect, spatial attention, sustained attention, rehabilitation
1 INTRODUCTION
Approximately one-third of all individuals suffering unilateral brain injury exhibit a
complex, debilitating array of neurological deficits known as the neglect syndrome
(Halligan et al., 2003; Heilman et al., 1987, 1993; Mesulam, 1990). This collection of

327
328 CHAPTER 13 Nonspatial Side of Spatial Neglect and Related Approaches
spatial and nonspatially lateralized attention deficits vary greatly in presentation and
severity (Appelros et al., 2002; Buxbaum et al., 2004; Pedersen et al., 1997), and
endure more often following right hemisphere damage (Ringman et al., 2004;
Stone et al., 1993). The most apparent problem is failure, or dramatic slowing, of
response to stimulation presented to the side of space opposite the lesion (Azouvi
et al., 2003; Driver and Vuilleumier, 2001; Heilman et al., 1985; Hornak, 1992;
Ishiai et al., 2006; Mattingley et al., 1998). Although less obvious, deficits that
are not spatially lateralized (Danckert and Ferber, 2006; Husain et al., 1997;
Robertson et al., 1997a; Van Vleet and Robertson, 2006) are also fundamental to
persistent neglect. In fact, the severity of nonspatial deficits is a stronger predictor
of the chronicity of spatial neglect in the post-acute phase of recovery than the spatial
deficits themselves (Duncan et al., 1999; Hjaltason et al., 1996; Husain et al., 1997;
Peers et al., 2006; Robertson et al., 1997a).
In this chapter, we will briefly review several models of spatial attention bias in
neglect before focusing on nonspatial deficits and the mechanisms of nonspatial/spa-
tial interactions and implications for treatment. We contend that treatment ap-
proaches that more completely address nonspatial deficits and account for
nonspatial/spatial interactions will produce better outcomes and may eventually lead
to effective, practical treatments for this debilitating disorder that currently has no
widely accepted standard of care.
2 SPATIAL DEFICITS IN NEGLECT

In the acute phase of recovery, patients suffering from neglect commonly present
with a bias in spontaneous orienting and motor initiation toward the side of their le-
sion (ipsilesional), neglecting the side opposite their lesion (contralesional). Perfor-
mance on tasks requiring volitional or goal-directed spatial attention reveal a graded
contralesional bias centered on direction of gaze, head, or body (egocentric neglect),
with the most contralesional locations showing the worst performance.
Individuals with neglect may also present with spatial deficits that manifest
within object-centered reference frames, known as allocentric neglect (List et al.,
2008, 2011). Some reports suggest that ego- and allocentric neglect rarely co-occur
clinically and may be dissociated anatomically (Medina, 2009; Verdon et al., 2010).
However, more recent findings (Rorden et al., 2012) suggest a strong association be-
tween egocentric and allocentric neglect (see also Yue et al., 2012). In particular,
allocentric behavioral deficits were only observed in conjunction with egocentric
deficits and both deficits were shown to have considerable functional anatomical
overlap.
In the post-acute phase of recovery (>3 months), pronounced biases in sponta-
neous orienting and motor initiation typically resolve, especially in patients with ne-
glect caused by left hemisphere lesions. However, spatially lateralized deficits in
goal-directed spatial attention typically persist after neglect caused by right
hemisphere lesions. For example, several studies report deficits in components
of goal-directed attention such as visual search and disengagement of attention
3 Theoretical Accounts of Lateralized Spatial Deficits in Neglect 329
(e.g., disengaging from rightward stimuli to attend to leftward stimuli) several years
post-insult (Johnston and Diller, 1986; List et al., 2008; Posner et al., 1984). Over the
last 40 years, several theories have been proposed to account for these goal-directed
spatial attention deficits in neglect, many of which are not mutually exclusive. While
a review of these theories is beyond the scope of this chapter, we briefly describe
several popular theories below.
3 THEORETICAL ACCOUNTS OF LATERALIZED SPATIAL

DEFICITS IN NEGLECT
3.1 Anatomical Models
3.1.1 Hemispheric Rivalry and Synchrony
One classic theory of neglect emphasizes the importance of balanced interhemi-
spheric activation in goal-directed spatial attention. According to Kinsbourne, spatial
neglect may best reflect the influence of disrupted interhemispheric activity on spa-
tial attention (He et al., 2007; Kinsbourne, 1977; Kinsbourne and Bruce, 1987). The
resulting imbalance in attention is thought to result from relative hyperexcitation of
the intact hemisphere due to release of inhibition from the damaged, hypoactive
hemisphere (Corbetta and Shulman, 2002; Corbetta et al., 2005; Koch et al.,
2008a). Interestingly, additional damage to the intact hemisphere can sometimes re-
mediate hemispatial neglect, perhaps through rebalancing interhemispheric compe-
tition (Vuilleumier et al., 1996). Likewise, recent studies employing transcranial
magnetic stimulation (TMS) to functionally deactivate the intact hemisphere can sig-
nificantly reduce neglect (Brighina et al., 2003; Koch et al., 2008b, 2012; Oliveri
et al., 2001) (see more on this below). Recent studies of resting state network activity
have also shown that interhemispheric connectivity, particularly in posterior parietal
cortex, is disrupted in the acute phase of recovery but in recovered patients is fully
restored. This further confirms the importance of interhemispheric communication
and balance in successful goal-directed spatial attention (Carter et al., 2010;
He et al., 2007).
3.1.2 Right Hemisphere Pays Attention to Both Sides of Space, Left Pays
Attention to the Right Side of Space
Another traditional and popular theory of neglect postulates that the right hemisphere
controls goal-directed attention to both sides of space, while the left hemisphere only
controls attention to the right side of space (Mesulam, 1981). According to this the-
ory, damage to the right hemisphere is associated with more severe spatial attention
impairments (as the left cannot compensate), whereas after left hemisphere damage
the right hemisphere is able to successfully compensate (i.e., attend to both sides of
space). There has not been a wealth of neuroimaging support for this theory; in fact,
studies in healthy controls generally show that brain regions involved in goal-
directed spatial attention (e.g., intraparietal sulcus, IPS) are sensitive to the opposing
side of space in an equal and opposite fashion (Silver et al., 2005; Snyder and
Chatterjee, 2004). However, a recent report has shown that with increasing visual
short-term memory load, an asymmetry does in fact emerge: left IPS regions show
load effects for the right side of space whereas right IPS regions show load effects for
both sides of space (Swisher et al., 2007). This suggests that asymmetries in attention
may only be pronounced during demanding tasks (e.g., searching for items in a clut-
tered array) and further suggests a crucial link between spatial attention and the cog-
nitive load of a task, which we will expand upon below.
3.2 Cognitive Models of Attention in Neglect

3.2.1 Hyperattention/Increased Salience Detection to Ipsilesional Stimuli
Lateralized failure in detection of stimuli is often discussed with regard to salience,
the sensory distinctiveness and behavioral relevance of an object relative to other
objects. Hyperattention (Bartolomeo and Chokron, 1999) accounts of neglect con-
tend that events occurring in ipsilesional space “override” co-occurring events in
contralesional space. This abnormally high salience of ipsilesional stimuli may pre-
vent them from being filtered when they are task-irrelevant (Bays et al., 2010;
Shomstein et al., 2010; Snow and Mattingley, 2006) or lead to repeated re-fixations
during search tasks (Husain et al., 2001). Allowing individuals with neglect to erase
targets rather than marking them in a cancellation paradigm so that they are no longer
salient or no longer compete for attention improves search performance. However,
some individuals continue to neglect the remaining items (Ishiai et al., 2006).
3.2.2 Feature Integration

Distinct from detection of salient items, accurate discrimination of more complex stim-
uli (i.e., searching for your car in a parking lot full of cars) may rely on the proper in-
tegration of elementary features such as color and shape (Eglin et al., 1989; Robertson
et al., 1988; Treisman and Gelade, 1980; Van Vleet and Robertson, 2009). Thus,
according to feature integration theory, spatial neglect may result from a failure to prop-
erly bind or conjoin features of an object located in contralesional space. This theory is
bolstered by the fact that early visual mechanisms such as contrast sensitivity (Spinelli
et al., 1990), image segmentation based on low-level features (Driver and Mattingley,
1998), and visually evoked responses in occipital cortex are typically intact in neglected
space (Di Russo et al., 2008; Rees et al., 2000; Watson et al., 1977). For example, Pisella
et al. (2004) demonstrated that individuals with neglect could detect of color and shape
changes in the neglected field but were impaired in detecting more complicated location
changes in a matrix of four objects. Further, a study examining implicit attention in ne-
glect showed that feature priming in neglected space does not appear dependent on ex-
plicit attention, as feature primes presented at undetectable levels in neglected space
influenced speeded detection on subsequent probe trials (Van Vleet and Robertson,
2009). Priming dependent on the combination of two features (i.e., conjunction) in
neglected space was only effective if explicitly attended, suggesting that individuals
with neglect require spatial attention to bind elementary aspects of complex objects
(Eglin et al., 1989; Kristjánsson et al., 2005; Treisman and Gelade, 1980; Van Vleet
and Robertson, 2009).
4 Nonspatially Lateralized Deficits 331
In addition to these popular models, other models contribute to explaining the

lateralized spatial deficits in neglect. For example, Posner and colleagues character-
ize neglect as an impairment in the ability to disengage attention from ipsilesional
events (i.e., deficit in reorienting to contralesional events) (Posner et al., 1984). Still
others argue that local processing bias (Robertson et al., 1988) is an important com-
ponent of neglect, as hemispheric specialty for attention to global or local aspects of
an object or scene have shown that the right hemisphere is biased toward global pro-
cessing and the left toward local processing (Delis et al., 1986; Eglin et al., 1989;
Robertson et al., 1988). While this deficit is not strictly lateralized (i.e., can occur
in intact space), patients’ resulting local bias following right hemisphere lesion could
increase the tendency to search near the current focus of attention, exacerbating a
bias to attend to ipsilesional locations.
Characterizing the mechanisms of all the component spatial deficits, the hetero-
geneity in presentation of these deficits across patients (e.g., intentional neglect, allo-
centric neglect, egocentric neglect), and the brain regions that cause these deficits has
been the major objective of neglect research over the last 40 years. In spite of this
robust body of research, better understanding of nonspatial deficits and their inter-
action with spatial deficits may hold more promise to improving functional outcomes
in patients suffering from neglect.
4 NONSPATIALLY LATERALIZED DEFICITS IN NEGLECT

AND NONSPATIAL/SPATIAL INTERACTIONS
In addition to deficits in spatial attention, individuals with persistent neglect almost
universally exhibit nonspatially lateralized deficits in sustained attention, selective
attention/attention to transient events, and spatial working memory (Battelli et al.,
2001; Duncan et al., 1999; Malhotra et al., 2005, 2009; Robertson et al., 1997a).
As mentioned, nonspatial deficits are stronger predictors of chronic spatial neglect
and related functional disability than are the spatially lateralized deficits themselves
(Duncan et al., 1999; Hjaltason et al., 1996; Husain et al., 1997; Peers et al., 2006;
Robertson et al., 1997a). This is likely because lesions that produce persistent neglect
typically damage brain regions that support nonspatially lateralized attention. Con-
sidering the conspicuous spatial biases typical of neglect, this pattern of neglect le-
sions presents a paradox: brain areas associated with goal-directed lateralized spatial
attention are typically spared (Corbetta and Shulman, 2002) while brain mechanisms
that support nonspatially lateralized attention are much more commonly damaged.
Although it has been suggested that nonspatially lateralized deficits are not es-
sential to the neglect disorder and simply exacerbate neglect symptoms (Husain
and Rorden, 2003), we contend that because neglect producing lesions implicate
nonspatial regions and because nonspatial deficits predict the functional outcomes
of neglect as well as or better than spatial deficits that nonspatial deficits should
be considered a core feature of the disorder. Below we review several component
nonspatially lateralized deficits common to neglect and consider models that account
for the interaction of spatial and nonspatial deficits.
4.1 Arousal and Alertness

One critical nonspatial deficit accompanying neglect is difficulty maintaining
focused engagement. This impairment manifests as decreased physiological arousal
(Heilman et al., 1978) and/or poor sustained attention (Bartolomeo and Chokron,
1999) and may also be related to slowed updating of visual working memory
(Husain et al., 1997; Van Vleet and Robertson, 2006), poor temporal resolution
(Battelli et al., 2001), and slow response times (Samuelsson et al., 1998).
Diminished physiological arousal is particularly evident in individuals with right
hemisphere lesion-induced neglect (Hjaltason et al., 1996; Robertson, 2001;
Samuelsson et al., 1998), who commonly present as disengaged. Consistent with this
presentation, neglect resulting from right hemisphere damage has shown to result in
reduced galvanic skin responses to electrical stimulation (Heilman et al., 1978) and
a failure to show normative heart rate fluctuation following a target-related cue
(Yokoyama et al., 1987). More persistent deficits in cognitive alertness have shown
to significantly affect spatially lateralized attention (Robertson et al., 1995, 1998).
In two seminal studies, Robertson and colleagues demonstrated that increases in either
phasic (Robertson et al., 1998) (moment-to-moment) or tonic (sustained) alertness
(Robertson et al., 1995) decreased or transiently eliminated neglect (see additional dis-
cussion below). Further supporting the association between alertness and spatial bias, a
recent report demonstrated that reducing alertness via administration of a sedative re-
sults in the immediate re-emergence of spatial neglect symptoms in recovered patients
(Lazar et al., 2002). Additionally, increased alertness via implementation of time pres-
sure during the performance of standard measures of spatial bias (e.g., cancellation
task) has shown to significantly improve performance in detecting leftward targets
(George et al., 2008).
4.2 Sustained Attention

Distinct from physiological arousal or alertness (Heilman et al., 1978), which may be
more sensitive to manipulations of novelty or unexpected events (i.e., effects driven
from the bottom-up), deficits in sustained attention to a goal (i.e., from the top-down)
may better account for chronic difficulties in neglect patients (Singh-Curry and
Husain, 2009; Van Vleet et al., 2011). For example, deficits in sustained attention
have been shown to undermine more complex cognitive functions such as short-term
memory and executive control functions, which may particularly impair everyday
functioning.
Sustained attention to spatial location may be particularly impaired in neglect. A
series of experiments that examined the ability of right hemisphere patients with ne-
glect to sustain attention found deficits even for simple detection of stimuli presented
at central fixation (Malhotra et al., 2009). Follow-up experiments demonstrated even
more pronounced deficits when neglect patients were required to attend to spatial
location over time, showing a much steeper vigilance decrement (decrement in per-
formance over time) than when sustaining attention to letters. Thus, sustaining atten-
tion to spatial locations appears to be particularly affected in neglect.
4 Nonspatially Lateralized Deficits 333
4.3 Selective Attention/Attention to Transient Events

Deficits in speeded selective attention in neglect have been shown in studies examining
the processing limits of the visual system. For example, performance on the attentional
blink task provides a measure of the temporal dynamics of selective attention—the time
taken by the visual system to identify two visual stimuli occurring closely in time.
Patients with neglect have shown to have a significantly protracted attentional blink
(>1000 ms) compared to controls (400 ms) and the length of the attentional blink
has shown to correlate with the severity of spatial neglect (Husain et al., 1997). Recent
studies by Battelli et al. (2001) also show deficits in temporal resolution in neglect, as
reflected in performance in apparent motion paradigms. Unlike low-level motion de-
tection, apparent motion is the perception of illusory motion such as when two lights
are flashed sequentially at separate locations producing a clear impression of motion.
The deficit in apparent motion in neglect is likely due to a bilateral deficit in the tem-
poral resolution of attention to transient events. Additional evidence that neglect pa-
tients have particular deficits in attending to transient events is from studies that
show sub-second and multisecond time perception deficits (Basso et al., 1996;
Danckert et al., 2007; Harrington et al., 1998).
4.4 Spatial Working Memory

In addition to difficulties in sustaining attention and detecting transient events, neglect
has also been associated with deficits in holding spatial information in working mem-
ory (for a comprehensive review, see Striemer et al., 2013). Spatial working memory
deficits may explain why patients with neglect revisit previously attended (marked)
ipsilesional locations during cancellation tasks (Husain et al., 2001). Follow-up studies
demonstrate that revisiting behavior may be at least partially due to patients’ difficulty
updating spatial locations across successive eye movements (i.e., saccadic remapping)
(Husain et al., 2001). Additionally, patients with neglect may show spatial span deficits
(Malhotra et al., 2005). For example, patients with neglect exhibited poor spatial short-
term memory for stimuli presented centrally along the vertical meridian. These deficits
in short-term memory increased with increasing span and correlated with severity of
neglect on cancellation tasks (particularly neglect resulting from damage to parietal
cortex and/or insula) (Malhotra et al., 2005).
4.5 Attentional Capacity

Some researchers have interpreted the nonspatial deficits above as reflecting a gen-
eral reduction in the capacity of their attention and working memory (Driver and
Vuilleumier, 2001). An influential study by Peers et al. (2006) showed that dual
tasks, which significantly tax attention and working memory capacity, cause a gen-
eral biasing of attention to the right, similar to effects of low arousal (Peers et al.,
2006). A recent study suggests that this rightward bias during dual-tasks particularly
affects neglect patients, possibly due to their reduced attention/working memory
capacity (Bellgrove et al., 2013).
5 THEORETICAL ACCOUNTS OF NONSPATIAL DEFICITS AND

NONSPATIAL/SPATIAL INTERACTIONS
Compared to the numerous models accounting for the spatial deficits in neglect, there
are far fewer models of nonspatial deficits that account for nonspatial/spatial inter-
actions, likely because these deficits have only been discovered or re-examined in the
last 20 years. We briefly review two models, one that proposes that neglect damages
alertness and sustained attention mechanisms that are largely unique to the right
hemisphere, and another that proposes that patients with neglect have a reduced at-
tentional capacity. Like models of spatial deficits, it should be noted that these
models of nonspatial deficits are not mutually exclusive.
5.1 Right Hemisphere Is Specialized for Alertness and Sustained

Attention
Though patients’ nonspatial symptoms are apparent on a variety of tasks, one aspect
that they all have in common is they require maintenance of adequate levels of alert-
ness and task engagement. One of the key neurotransmitters involved in arousal and
alertness is norepinephrine, which is primarily synthesized in the locus coeruleus in
the brainstem and has projections throughout the cortex. Damage to the right hemi-
sphere may be particularly detrimental to alertness because the right hemisphere has
shown to have a higher number of noradrenergic receptors (particularly in inferior
parietal regions) compared to the left hemisphere (Foote et al., 1983).
Regarding the interaction of nonspatial and spatial deficits, this model contends
that reductions in alertness are associated with decreased activity in right inferior
frontoparietal regions (alertness network). This alertness network has shown to par-
tially overlap/interact with more dorsal frontoparietal regions involved in goal-
directed spatial attention (e.g., frontal eye fields, IPS), particularly overlapping in
lateral frontal regions (He et al., 2007). The mechanism of this interaction and rea-
sons why these networks interact is currently unknown and a key question for future
neglect research. The result of this decreased interaction between the alertness net-
work and the spatial attention network is an imbalance favoring the left hemisphere,
resulting in a rightward spatial bias (for a more in-depth review of these mechanisms,
see Corbetta and Shulman, 2011).
Right hemisphere dominance in the regulation of alertness and the interaction be-
tween alertness and spatial bias has also been demonstrated in healthy individuals as
well as those with attention deficit hyperactivity disorder (ADHD, see Klingberg
et al., 2005). This suggests that the alertness–spatial attention interaction is a general
characteristic of the brain rather than a neglect-specific phenomenon. For example,
studies in healthy individuals show a slight tendency to attend to the left side of an
object (Nicholls et al., 1999) and that this slight leftward bias is reduced or shifted to
the right under conditions of low arousal (Bellgrove et al., 2004; Manly et al., 2005;
Matthias et al., 2009) or when taxing sustained attention (Newman et al., 2013;
6 Treatments for Neglect 335
Russell et al., 2004). Further, recent studies suggest that children with ADHD exhibit
lateralized attention deficits similar to neglect (though typically smaller in magni-
tude) and that this is ameliorated by ADHD-targeted medications that boost the abil-
ity to sustain attention (Bellgrove et al., 2013).
5.2 Attentional Capacity

This model suggests that patients suffering from persistent spatial neglect have sig-
nificantly reduced attentional capacity (Driver and Vuilleumier, 2001) (i.e., limited
resources to perform attention-demanding tasks), which may underlie many of their
nonspatial deficits such as a protracted attentional blink (Battelli et al., 2001; Husain
et al., 1997; Robertson et al., 1998). This limited attentional capacity may affect
goal-directed spatial attention mechanisms in an analogous manner as diminished
alertness, however, with important differences. In particular, evidence suggests that
attentional resources may be lateralized to right ventral frontoparietal regions that, as
Corbetta and Shulman (2011) have recently demonstrated, interact with dorsal
frontoparietal regions involved in spatial attention. Reduction in available atten-
tional resources, as required in dual-task paradigms, may decrease right ventral
frontoparietal (network subserving attentional resources) and dorsal frontoparietal
(spatial attention) network interactions, producing increased rightward spatial bias.
A key difference is that the attentional capacity model better accounts for the exac-
erbation of lateralized attention biases in patients during dual-task performance. In
contrast, the alertness model would suggest that dual-task performance, which is sig-
nificantly more stressful/arousing than single-task performance, would be associated
with lesser rather than greater rightward spatial bias (George et al., 2008).
Though future work is imperative to better characterize these models, particularly
with regard to the mechanisms of the interactions between nonspatial and spatial at-
tention, even in their current form they highlight the importance of nonspatial–spatial
interactions in understanding and treating neglect.
6 TREATMENTS FOR NEGLECT

Because of the disability associated with persistent neglect, there is a pressing need to
develop effective treatments. In particular, neglect is associated with poor motor re-
covery, higher disability and poor response to rehabilitation in general (Buxbaum
et al., 2004; Cherney et al., 2001; Katz et al., 1999; Paolucci et al., 2001). Compared
to other patient groups with similar lesion extent, patients with neglect consistently
score lower at both admission and discharge on established measures of functional
ability, and activities of daily living (Denes et al., 1982; Jehkonen et al., 2001; Kalra
et al., 1997). Patients with neglect represent a considerable challenge to rehabilita-
tion efforts as, compared to others with acquired brain injury, they demonstrate sig-
nificantly more denial (anosagnosia; Adair et al., 1995) or apathy toward their
deficits.
Though several treatment approaches have been developed over the last 30-years
(for a review, see Luauté, 2006), these approaches have collectively shown limited
success. Furthermore, the majority of treatment studies have judged treatment suc-
cess as the amelioration of spatial deficits only, largely ignoring nonspatial deficits.
Because nonspatial deficits are a fundamental aspect of chronic neglect and may
underlie (and perpetuate) spatial deficits, we argue and provide evidence that
addressing these deficits first or in concert with spatial deficits may produce better
treatment outcomes. Below we review several neglect spatial and nonspatial treat-
ments and suggest ways that these treatments can be developed and intelligently
combined to produce better outcomes in patients suffering from neglect.
6.1 Treatments That Target Spatially Lateralized Cognitive

Mechanisms
The most effective neglect therapies to emerge that have targeted spatially lateralized
mechanisms have been visual scanning training (Pizzamiglio et al., 1990; Weinberg
et al., 1977) and prism adaptation (Rossetti et al., 1998). Some have argued that treat-
ments such as vestibular stimulation, contralesional limb activation, optokinetic
stimulation, and neck muscle vibration also directly shift lateralized spatial aware-
ness, though it could be argued that their improvements simply stem from enhanced
alertness or general engagement of the right hemisphere. Furthermore, the evidence
of the long-term effectiveness of these treatments is less clear.
Visual scanning training is one of the oldest and most commonly used approaches
to treat neglect. The aim of visual scanning training is to have patients actively and
consciously pay attention to stimuli on the contralesional side during various detec-
tion, reading, writing, and copying tasks. The advantages of this training are that it
has shown significant improvements when used for an extended period (e.g., 28 h
over 4 weeks) (Weinberg et al., 1979). However, its therapeutic effects have shown
quite a bit of individual variation and may not be appropriate with patients with more
severe issues with deficit awareness (Adair et al., 1995). Further, others have ques-
tioned the ability of scanning training to generalize outside the training environment
(Robertson and Halligan, 1999).
Compared to visual scanning training, prism adaptation training sessions are
much shorter (20 min session) and rely more on a “bottom-up” mechanism. Prism
adaptation treatments involve the patient learning to accurately point to targets
(50 trials or more) while wearing right-deviating prisms (which feels like one is
reaching to the left side to hit a right target). The therapeutic effect (e.g., improved
ability to move to contralesional space) occurs after the prisms are removed and can
accumulate after performing many sessions over a period of weeks. Though prism
adaptation has shown to consistently improve spatial aiming in contralesional space,
it may not affect perceptual or representational aspects of neglect (Barrett et al.,
2012). Together, these treatments targeting spatially lateralized deficits offer some
relief for patients suffering from neglect. However, on their own, they are relatively
incomplete and offer only limited prospects for recovery of function.
6.2 Treatments That Target Hemispheric Asymmetry

Over the last 15-years, several studies have utilized noninvasive brain stimulation
(e.g., TMS) in attempts to re-balance hemispheric asymmetries in excitability and
improve symptoms of neglect. One of the first reported studies by Oliveri and
colleagues (1999) used TMS to temporarily deactivate left posterior parietal regions
and found that this lessened the neglect symptom of extinction, the phenomenon
where patients with unilateral brain damage fail to report a stimulus delivered to
the side contralateral to the lesion when an ipsilateral stimulus is delivered simulta-
neously (Oliveri et al., 2001). More recent TMS studies targeting similar regions in
patients with neglect have utilized higher frequency trains of pulses (continuous theta
burst TMS) over multiple sessions in an attempt to create longer-lasting deactivation
of the intact posterior parietal regions (Koch et al., 2012). Indeed, these studies have
shown both significant improvements in standard neglect batteries (which assess
spatially lateralized deficits) and in daily functioning. Though promising, it is still
unclear if these effects can be sustained and if this approach can also ameliorate
patients’ nonspatially lateralized deficits.
6.3 Treatments That Target Nonspatially Lateralized Mechanisms

At this point it should be clear that there are several reasons to specifically target
nonspatially lateralized deficits in the treatment of neglect. First, treatments that
target nonspatially lateralized mechanisms, such as sustained attention would po-
tentially benefit most patients, as these deficits affect nearly all patients suffering
from persistent neglect (DeGutis and Van Vleet, 2010). Also, treating sustained at-
tention deficits may enable patients to be more alert, fully engaged, and derive
greater benefit from other treatments and therapies (e.g., occupational therapy).
Second, treating nonspatial attention deficits may guard against the re-emergence
of neglect symptoms, such as when a recovered patient is experiencing low arousal
or decreased attentional capacity. Finally, training to improve nonspatial deficits
may help re-balance spatially lateralized attention mechanisms, which may make
subsequent training of spatial attention (e.g., prism adaptation training) more effec-
tive. Below we briefly review current treatments that target nonspatial deficits and
suggest future directions for the development of more effective treatments for
neglect.
6.3.1 Pharmacological Interventions

Pharmacological interventions for neglect have shown some success in treating
deficits in alertness, although results have been generally less successful than
behavioral treatments (e.g., prisms, sustained attention training). These studies have
examined the effects of these interventions to improve alertness and/or spatial
attention (Buxbaum et al., 2004; Danckert et al., 2007).
Despite mixed results in prior studies examining the effects of dopaminergic

agonists to treat neglect (Barrett et al., 1999; Fleet et al., 1987; Geminiani et al.,
1998; Grujic et al., 1998), a recent study examining rotigotine, a complete dopamine
agonist, was associated with a significant increase in the number of contralesional tar-
gets identified in the Mesulam shape cancellation task, as well as a decrease in the path-
ological rightward spatial bias (Danckert et al., 2007). However, rotigotine did not
affect performance on measures of working memory, sustained attention or motor per-
formance. Analogous results obtained in a rodent model of neglect suggest that bene-
ficial effects of dopaminergic agonists in neglect are brain-location-specific (Van Vleet
et al., 2003), therefore systemic administration may produce mixed results.
Similarly, administration of the noradrenergic agonist, guanfacine, a selective
alpha 2A receptor agonist has been shown to be useful for treating alertness impair-
ments in patients with neglect (Buxbaum et al., 2004). In two patients with spared
right prefrontal cortex, guanfacine extended the time spent searching for relevant
targets resulting and an increase in the number of targets found. A third patient with
damage to the right prefrontal/inferior frontal cortex and neglect did not benefit
from the drug. In general, while drug therapies have shown promise, their effects
may be too nonspecific with the goal of treatment to simply increase the baseline
level of alertness rather than promoting greater intrinsic regulation (i.e., do not
specifically address the core mechanisms of neglect dysfunction). Further, drug
therapies may be dependent on the functional integrity of remaining brain areas
and may not be suitable for a large number of patients with neglect. Finally, drug
therapies often produce unwanted side effects and may negatively interact with
other medications.
6.3.2 Behavioral Treatments

One of the first reported therapist-administered behavioral treatments to target non-
spatial deficits in neglect employed strategies that teach patients to increase alertness
through periodic self instruction (e.g., “attend”) (Gorgoraptis et al., 2012; Robertson
et al., 1995). While these methods produced improvements in spatial attention, they
rely on adequate recall of the behavioral strategy, which may not be conducive for
patients with deficit awareness issues, and may not generalize beyond the training
environment (Robertson and Halligan, 1999).
As a result of these concerns, computerized behavioral training methods have
largely eclipsed top-down, therapist-administered treatments. Computerized treat-
ments that target nonspatial deficits in neglect have taken a distinctly different ap-
proach, providing systematic and adaptive challenges tailored to individual patient’s
specific level of deficit. This bottom-up approach to treatment (i.e., no explicit strat-
egy required) provides many hundreds to several thousands of learning trials pre-
sented within multiple (albeit virtual) contexts to more fully engage natural
mechanisms of plasticity. In general, computerized treatments to improve nonspatial
deficits have targeted sustained attention or intrinsic alertness and have exploited
two well-characterized properties of the brain’s alertness-control machinery: tonic
and phasic alertness. As mentioned previously, Tonic alertness refers to the ongoing
state of intrinsic readiness that fluctuates on the order of minutes to hours, and is
intimately involved with sustaining attention and also provides the cognitive tone
necessary for performing more complicated functions such as working memory
and executive control (Harvey et al., 1995; Matthias et al., 2010). In contrast, phasic
alertness is the rapid modulation in alertness due to any briefly engaging event, and is
vital for operations such as orienting and selective attention (Matthias et al., 2010).
To improve tonic alertness, computerized interventions for neglect have required
patients to maintain attentional engagement over prolonged time periods. For exam-
ple, an intervention referred to as AIXTENT (Sturm et al., 2006; Thimm et al., 2006)
challenges individuals with neglect to continuously drive a virtual car while
responding to cues to slow down (e.g., virtual traffic lights). Studies of AIXTENT
in individuals with neglect have shown benefit. In one study, six out of seven
neglect patients improved on at least one spatial neglect test (e.g., line bisection,
cancellation tasks, visual search tasks, drawing tasks); improvements persisted
for 4 weeks after training was terminated in two patients. Further, for those patients
showing behavioral improvement, neuroimaging revealed partial restoration of
the right hemisphere functional network known to subserve intrinsic alertness in
healthy individuals, especially in the right dorsolateral or medial frontal cortex.
Individuals that did not improve showed an increase of activation only in the left
hemisphere, suggesting that training did not fully re-engage the damaged hemisphere
in some patients.
In contrast to attempts to enhance tonic alertness, experimental interventions
aimed at improving the efficiency of phasic alertness in neglect have utilized extrin-
sic, unexpected alerting events (e.g., unexpected tone) (Robertson et al., 1998). How-
ever, due to the short-acting effect of extrinsic alerting and the close relationship
between phasic and tonic alertness, recent studies have examined phasic alertness
in the context of tonic alertness, and thus utilize paradigms that require continual
monitoring of successive stimuli for behaviorally relevant events (e.g., phasic spike
in alertness to infrequent and unexpected appearance of a target stimulus) (DeGutis
and Van Vleet, 2010a; Sturm et al., 2006; Thimm et al., 2006; Van Vleet and
DeGutis, 2013). This top-down approach to phasic alertness may engage similar
but distinct mechanisms (Singh-Curry and Husain, 2009) from bottom-up ap-
proaches. Electrophysiological studies have shown that bottom-up approaches
may have a frontal source (Comerchero and Polich, 1999), whereas top-down ap-
proaches may have a more posterior, parietal source (Herrmann and Knight, 2001).
A recent series of treatment studies from our lab using a computer-based task that
targets both tonic and phasic alertness (tonic and phasic alertness training, TAPAT)
has shown promising results (DeGutis and Van Vleet, 2010a; Van Vleet and
DeGutis, 2013). TAPAT was designed to challenge patients to better intrinsically
sustain attention via prolonged training epochs (3 12-min blocks per session).
TAPAT training involves performing visual and auditory continuous performance
tasks with key elements to foster sustained attention. First, the tasks employed jit-
tered interstimulus intervals, shown to improve response control in other clinical
populations, such as ADHD (Bouret and Sara, 2005; Wodka et al., 2009). The train-
ing also included numerous rich, novel and colorful stimuli (particularly in the visual
TAPAT) to further engage attention (Schultz et al., 1997). Further, participants were
required to respond via button press to frequent and centrally presented images or
tones while trying to inhibit their response to an infrequent and randomly presented
target stimulus (a unique target image or target tone was committed to memory prior
to each 12-min training epoch), similar to other go-no-go paradigms (Comerchero
and Polich, 1999; Robertson et al., 1997a,b). The unexpected presentation of the
target image (or tone), which informed participants to inhibit the execution of the
pre-potent motor response, was particularly salient (i.e., producing a strong phasic
modulation in alertness) (Aston-Jones and Cohen, 2005). Finally, all stimuli in
TAPAT were presented at central fixation, which ensured that patients with visual
field deficits could also benefit.
Following only limited training (5 h over 9 days), patients with neglect improved
their intrinsic alertness as reflected in improvements in accuracy on go and/or no-go
trials in all but 2 of 20 patients. Further, improvements in target accuracy (i.e., in-
hibitory control/phasic alertness) across TAPAT training was significantly corre-
lated with improvements on sensitive measures of spatial attention following only
limited training (5 h over 9 days) (DeGutis and Van Vleet, 2010a; Van Vleet and
DeGutis, 2013). Specifically, individuals with neglect that trained on TAPAT versus
a spatial search training task (utilizing the same stimuli used in TAPAT) showed
group-level performance improvements on a sensitive conjunction search task
(List et al., 2008); post-training, the time required to locate targets on the left versus
the right side of the search array was not different. Benefits in spatial attention (i.e.,
absence of spatial bias) were also evident on an alternate, novel conjunction search
array and an adaptive landmark task in patients that completed TAPAT training ver-
sus spatial search training. These effects are notable as it clearly demonstrates that
patients with neglect are capable of re-regulating intrinsic alertness, thereby normal-
izing spatial attention. Figure 1 shows performance from a representative patient on
the conjunction search task, delivered at the end of each TAPAT training session and
daily for several weeks post-training in this case. The distribution shows a clear evo-
lution of the treatment effect over several sessions and its impact following 2 weeks
without additional training.
Finally, as mentioned, all training was conducted at central fixation; thus, the re-
sults show a clear transfer of training-related benefit (i.e., greater intrinsic alertness)
to untrained tasks of spatial attention. In addition, TAPAT training versus control
resulted in normative performance (i.e., performance was not different from an
age-matched healthy control group) on a nonspatially lateralized, visual working
memory updating task (attentional blink) (Husain et al., 1997; Pattyn et al., 2008;
Van Vleet and Robertson, 2006). Outcomes on all measures examined were most
improved in those patients with worse neglect at baseline.
Taken together, these results support models of neglect that advance the critical
role of alertness and sustained attention to affect not only spatial attention, but also
other nonspatial functions such as selective attention/attention to transient events.
7 Future Directions 341
FIGURE 1
Daily performance on a sensitive conjunction search task (List et al., 2008) for a
representative patient with neglect following right parietal damage (DW). Figures show
performance pre, during and post TAPAT training. Differences in threshold presentation
times (TPT) for right targets–left targets are shown. A score of zero represents symmetrical
target detection, positive values represent a rightward bias and negative values leftward bias.
The results from behavioral treatment studies that target nonspatial deficits clearly
show the influence of plasticity, as these nonspatial mechanisms are shown to be re-
mediable rather than permanently damaged (even in very chronic patients; Van Vleet
and DeGutis, 2013).
7 FUTURE DIRECTIONS
As the other chapters in this volume detail, many studies now show that the proces-
sing machinery of the brain is plastic, remodeled throughout life by learning and
experience, enabling the strengthening of skills or abilities or the acquisition of
new skills, at any age. These studies show that continual engagement in goal-directed
and rewarded behaviors is advantageous to sustaining efficient brain operations, en-
gaging targeted brain structures and causing the release of specific neurotransmitters
that enable, amplify, and shape plasticity in the adult brain. This rich body of liter-
ature offers numerous insights that can be applied to the proper development of treat-
ment methods to more efficiently drive the extensive, requisite, and generalized
changes required for significantly improving neurological syndromes such as neglect
(see Chapter 9).
As discussed throughout this chapter, recent advances in knowledge regarding
the influence of nonspatially lateralized deficits on spatial attention in neglect
require future rehabilitation efforts to consider novel approaches that directly address
these functions. The successes of such simple nonspatial treatments such as TAPAT
are promising, but represent only the beginning of this exciting area of rehabilitation
research. For example, a number of studies have shown that task complexity and spa-
tial working memory load contribute to the magnitude of spatial deficits in neglect.
Thus, intervention strategies that target spatial working memory capacity for exam-
ple, shown effective in other clinical populations (Klingberg et al., 2005), may be
beneficial for patients suffering from neglect (see Striemer et al., 2013 for expanded
discussion). Additionally, first person action video game training has shown to sig-
nificantly enhance selective attention and detection of transient events in healthy in-
dividuals. By modifying these games for patients suffering from neglect (e.g.,
slowing down the action and making adjustments for contralesional hypokinesia),
it may be possible to boost arousal and potentially improve nonspatial and spatial
symptoms. In addition, future research on the nature of spatial–nonspatial attention
interactions will enable the development of more effective and targeted treatments
for neglect.
Finally, two additional considerations for future development of treatments for ne-
glect. First, treatments that more comprehensively and completely engage nonspatial
mechanisms may prove more useful or longer lasting if combined with spatial thera-
pies (e.g., prism adaptation to also improve directional hypokinesia). Combined ther-
apies may also prove synergistic. As discussed, a number of recent studies have shown
benefits in spatial attention following TMS of the intact hemisphere. Combined com-
puterized training targeting nonspatially lateralized deficits (e.g., sustained attention)
may bolster these TMS effects, driving behaviorally specific alterations in the under-
lying neural mechanisms. Alternatively, computer-based training paired with transcra-
nial direct current stimulation that excites peri-lesional right-sided regions and
dampens homologous regions in the left hemisphere may produce more pronounced
and longer-lasting improvements in neglect symptoms.
Second, future rehabilitation efforts should also consider the “real-world” impli-
cations of treatment. For example, “statistical learning” deficits, (Shaqiri et al., 2013)
or poor ability to implicitly ascertain properties of a particular environment (i.e., ap-
preciate elements that occur more often than others), can affect decision making ca-
pacity in neglect. The statistical learning model suggests that neglect is a breakdown
in the accurate construction of mental models of the environment, in which future
predictions or decisions are based. This multilevel conceptualization of neglect takes
into account a number of nonspatially lateralized deficits (e.g., temporal mispercep-
tions, spatial working memory deficits) that contribute to functional disability. Con-
sideration of the cumulative effects of nonspatially lateralized dysfunctions in
neglect can inspire the development of more comprehensive rehabilitation interven-
tions designed to improve functional abilities. For example, treatments that target
deficits in temporal perception and spatial working memory may also improve
patient’s future predictions about the location of relevant events. Ultimately, im-
provements in functional ability or transfer of training-related benefits to untrained
real-word functions, is the most important aim of neglect rehabilitation. A multi-
modal, cognitive neuropsychological approach, which capitalizes on known proper-
ties of neuroplasticity is the best method to achieve this goal.
References 343
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CHAPTER
A Cognitive Framework
for Understanding
and Improving Interference
Resolution in the Brain
14
Jyoti Mishra1, Joaquin A. Anguera, David A. Ziegler, Adam Gazzaley1
Departments of Neurology, Physiology and Psychiatry, University of California, San Francisco,
CA, USA
1
Corresponding authors: Tel.: þ1-415-502-7322; Fax: þ1-415-502-7538,
e-mail address: jyoti@gazzaleylab.ucsf.edu; adam.gazzaley@ucsf.edu
Abstract
All of us are familiar with the negative impact of interference on achieving our task goals. We
are referring to interference by information, which either impinges on our senses from an ex-
ternal environmental source or is internally generated by our thoughts. Informed by more than
a decade of research on the cognitive and neural processing of interference, we have developed
a framework for understanding how interference impacts our neural systems and especially
how it is regulated and suppressed during efficient on-task performance. Importantly, exter-
nally and internally generated interferences have distinct neural signatures, and further, dis-
tinct neural processing emerges depending on whether individuals must ignore and
suppress the interference, as for distractions, or engage with them in a secondary task, as dur-
ing multitasking. Here, we elaborate on this cognitive framework and how it changes through-
out the human lifespan, focusing mostly on research evidence from younger adults and
comparing these findings to data from older adults, children, and cognitively impaired popu-
lations. With insights gleaned from our growing understanding, we then describe three novel
translational efforts in our lab directed at improving distinct aspects of interference resolution
using cognitive training. Critically, these training approaches were specifically developed to
target improved interference resolution based on neuroplasticity principles and have shown
much success in randomized controlled first version evaluations in healthy aging. Our results
show not only on-task training improvements but also robust generalization of benefit to other
cognitive control abilities. This research showcases how an in-depth understanding of neural
mechanisms can then inform the development of effective deficit-targeted interventions,
which can in turn benefit both healthy and cognitively impaired populations.
Keywords
interference, distraction, multitasking, attention, cognitive control, cognitive training, neuro-
plasticity, aging
351
352 CHAPTER 14 Cognitive Framework for Interference Resolution
1 INTRODUCTION
In our modern-day environment, we are immersed in digital media and related mo-
bile technologies that constantly barrage us with an overload of sensory information.
More than ever before, there are constant cognitive demands on our neural systems to
selectively attend to sensory inputs that are relevant to immediate goals and critically
to ignore or minimize the priority of other interfering sources of information. Those
individuals who can successfully identify and prioritize relevant information over
interference are able to achieve planned goals and function efficiently in demanding
cognitive settings. Understanding cognitive functions that allow us to integrate
with our complex world in a goal-directed way is the domain of top-down cognitive
control research (Bar, 2003; Corbetta and Shulman, 2002; Frith, 2001).
More than a decade of research in the Gazzaley laboratory has revealed that the
two sides of top-down control, enhancement of goal-relevant inputs versus suppres-
sion of interference, are both equally important and notably are distinct in their un-
derlying neural mechanisms (Clapp et al., 2010, 2011; Gazzaley et al., 2005a, 2008;
Zanto et al., 2010). This emerging research recently inspired a new framework for the
characterization of interference (Fig. 1, Clapp and Gazzaley, 2012). Per this frame-
work, interference can be generated from either external or internal information
sources. External interference occurs from environmental sensory stimuli and can
be further classified into “distractions” and “interruptions.” Distractions are to-be-
ignored sensory information, like the background chatter when working at a café.
Interruptions are external stimuli that need to be attended but are of secondary
priority in our top-down goal sets. Interaction with interruptions while attending
to primary goal-relevant stimuli qualifies as multitasking, such as may occur when
conversing with a copassenger while driving a car. Indeed, research described in the
following sections has shown that distractions and interruptions have distinct neural
processing. Importantly, this framework has helped clarify prior research in the field
that had generated confusing results when both types of external interference were
interchangeably employed in cognitive paradigms.
Similar to external interference, internal interference can also be classified either
as irrelevant internal distractions termed “intrusions,” as may occur during mind-
wandering or daydreaming, or as internal interruptions (i.e., “diversions”) that
FIGURE 1
The conceptual framework for classification of different types of interference.
Adapted from Clapp and Gazzaley (2012).
2 External Interference Resolution Across the Lifespan 353
engage cognitive systems while another primary goal-relevant task is being per-
formed. Planning today’s dinner while reading this chapter is an example of an in-
ternal diversion, which like external interruptions involves attempts at multitasking.
Note that an understanding of the neural mechanisms that subserve internal interfer-
ence processing is still a nascent field. While many new studies suggest that internal
interference engages a known default mode network (DMN) in the brain (i.e., spe-
cific brain regions that are more active during non-task-oriented behaviors;
Andrews-Hanna, 2012; Buckner et al., 2008), the exact neural signatures that distin-
guish internal intrusions versus diversions require sophisticated methodologies such
as predictive pattern classification algorithms and are yet to be fully determined.
The following sections serve as an introduction to the basis of the impact of dif-
ferent kinds of interference on human performance. Note that either external or in-
ternal interference can occur while one is engaged in either an external or internal
goal-relevant primary task. For example, the primary task could be an immediate
discrimination task in which individuals must accurately and rapidly respond to rel-
evant stimuli that occur sequentially or simultaneously intermixed with irrelevant
inputs, such as taking possession of the ball in a soccer game and making a speedy
sensorimotor decision that leads to a goal score in the face of interference from the
opponent team. Or the primary task could be a working memory (WM) task that re-
quires maintenance and manipulation of information in mind for short time periods,
such as remembering a phone number until the end of a conversation. Alternatively,
the primary task could even stretch over longer time scales, drawing on long-term
memory (LTM), where stimulus information is maintained over several minutes
to hours, while other tasks occur in the interim. Here, we review evidence for inter-
ference during each of these multi-time scale cognitive operations: discrimination,
WM, and LTM. Note that the research reviewed here is from the standpoint of
behavioral and underlying neural performance, that is, neural mechanisms that en-
able the observed behavioral outcomes. Considering young healthy 20–30-year-old
adults as a reference point, we review evidence for modified interference resolution
abilities in older age and in children. The second portion of the chapter focuses on
novel cognitive training strategies that we have developed as guided by our under-
standing of interference processing in the brain and the first set of evidence of the
effectiveness of these novel approaches.
2 EXTERNAL INTERFERENCE RESOLUTION ACROSS

THE LIFESPAN
2.1 Healthy young adults
Almost a decade ago, Gazzaley et al. (2005a,b, 2008) introduced a novel WM par-
adigm involving delayed recognition, which was used to assess behavioral perfor-
mance and neural processing of goal-irrelevant distracting images presented in an
intermixed sequence with relevant stimuli. An important component of this
paradigm was a passive viewing condition, which allowed comparison of neural

modulations elicited to attended and ignored stimuli relative to a baseline. These
studies showed that healthy young adults enhance sensory neural processing when
encoding goal-relevant stimuli relative to passive viewing and further suppress neu-
ral activity to irrelevant stimuli. Further, both the magnitude of neural activity and
the speed of neural processing were modulated by top-down influences (Gazzaley
et al., 2005b). These findings were consistent in fMRI-based BOLD (blood oxygen
level-dependent) neural activity in visual cortex and in early sensory ERPs (event-
related potentials) and in frontal theta oscillations, which mark top-down engage-
ment with relevant versus irrelevant information.
A more recent study investigated fMRI functional connectivity during a modified
version of this experimental paradigm, which used overlapping relevant and irrele-
vant stimuli presented simultaneously (Chadick and Gazzaley, 2011). This study
showed distinct and dynamic cortical connectivity between sensory and prefrontal
cortices based on task goals. Relevant stimuli engaged neural connections between
sensory and frontoparietal networks, while irrelevant stimuli simultaneously coupled
sensory and DMNs. Zanto and Gazzaley (2009) further demonstrated the ecological
importance of the neural findings, as optimal WM performance within individuals
was related to the extent of neural interference suppression. Finally, Zanto et al.
(2011) tightened this neurobehavioral relationship by showing a causal link between
prefrontal-mediated modulation of the visual cortex activity during stimulus encod-
ing and WM accuracy, as revealed by a TMS (transcranial magnetic stimulation)-
induced perturbation of the inferior frontal junction (IFJ). Note that prior research
also found IFJ to be a critical site for cognitive control of interference (Brass and
von Cramon, 2004; Brass et al., 2005; Bunge, 2004).
Clapp et al. (2010, 2011) used a different experimental design to probe both types
of external interference, distractions and interruptions, introduced during the delay
period of a WM task. Again, comparisons to a passive baseline were integral to the
study. Performance measures revealed that WM accuracy was significantly reduced
in the setting of distraction and even worse when interrupted by another task. Neural
data showed suppressed early visual processing of ignored distractions in young
adults. In contrast, neural activity to interruptions, which served as stimuli for a sec-
ondary discrimination task, was enhanced. Recently, we replicated these findings for
intrasensory interference during auditory WM (Mishra et al., 2013). Using fMRI-
based functional connectivity analyses, Clapp et al. (2011) further revealed that at
the onset of interruptions, connectivity in a visual (visual association cortex,
VAC)–prefrontal (middle frontal gyrus, MFG) memory maintenance network was
disrupted and dynamically reallocated to the attended interruptor. The memory
maintenance network was then reengaged at interruptor offset. Further, the extent
of attention-related enhancement to the interruptor directly correlated with reduced
WM performance accuracy, revealing how neural network dynamics shape cognitive
operations in the face of interference.
Finally, Wais et al. (2010) demonstrated the negative impact of distractions on
LTM. Participants encoded a study list of items and were later probed regarding
recognition of these items. Visual distractors during the recall phase significantly re-
duced LTM accuracy. Neurally, diminished recollection was associated with the dis-
ruption of functional connectivity in a network involving the left IFG, hippocampus,
and VAC. The authors concluded that bottom-up influences from visual distractions
interfere with the top-down selection of episodic details mediated by a capacity-
limited frontal control region, resulting in impaired recollection. Subsequently,
Wais and Gazzaley (2011) showed a similar impact of auditory distractions on LTM.
Overall, these studies characterize the impact of external interference on cognition
in young adults. To put this research in context of everyday function, there is growing
concern that the constant presence of media in our daily lives is distracting and dimin-
ishing task productivity. Indeed, a recent study investigated cognition in young adults
as a factor of their media-multitasking index (MMI; Ophir et al., 2009). The MMI
probed how often individuals engaged with more than one form of media simulta-
neously including print media, television, online videos, music, nonmusical audio,
video games, phone calls, instant and text messaging, email, web-surfing, and other
computer-based applications. Individuals with high MMIs were significantly more sus-
ceptible to interference from irrelevant stimuli in cognitive tasks and could not filter out
interference in memory, relative to those with low MMIs. Note that while these findings
show that high media multitasking is associated with poor interference resolution as
also recently shown by Sanbonmatsu et al. (2013), this evidence is not causal.
In contrast to media multitasking, engagement with a single form of media for ex-
tended periods of time and its impact on cognitive control abilities have been exten-
sively studied for action video games (AVGs). Young adults who are AVG experts
(i.e., engage in AVGs for >5 h per week) have been consistently shown to have su-
perior attention capacities (Dye et al., 2009; Green and Bavelier, 2003). Interestingly,
the neural basis of this superior performance was shown to be enhanced suppression of
distracting sensory information compared to neural activity in nongamers (Mishra
et al., 2011). Of course, from these findings alone, one must not infer that in order
to develop superior interference suppression capacities, one must play AVGs. This
is especially the case as commercial AVGs have much violent content that has raised
popular concern about the negative impact on social affect. Such concern, however, is
not completely based on research. In fact, increasing video-game play over the last few
years has been associated with declining crime rates, speculated to be due to availabil-
ity of a safe alternate avenue to vent real-life frustration in action game play
(Puzzanchera et al., 2011). While it was serendipitous that commercial AVGs were
found to benefit attention, they are likely unsuitable as therapeutics because game dy-
namics are developed to maximally immerse the user, but are not targeted to specif-
ically influence or improve neural function. Targeted therapeutics that can selectively
address neural, cognitive, and behavioral deficits are an urgent need; we discuss our
first interventions that address interference suppression in the second half of this chap-
ter. The next subsection describes alterations in interference processing in healthy
aging, which has been a focus area in the Gazzaley laboratory. We then review a
few related studies in this field in healthy child populations and briefly describe the
status of interference suppression in diverse neuropsychiatric populations.
2.2 Healthy older adults

Several studies from the Gazzaley lab have now supported deficits in interference res-
olution as a neural processing impairment in healthy aging (Gazzaley, 2013). In fact,
poor suppression of irrelevant information is postulated to underlie the diverse cogni-
tive deficits observed in aging spanning multiple functional domains, including
perception, attention, WM, LTM, and action (Hasher et al., 1999). For example, older
adults do not suppress sensory neural processing of irrelevant information during WM
encoding (Gazzaley et al., 2005a, 2008; Zanto et al., 2010) and are susceptible to
distractions during WM retention periods (Clapp and Gazzaley, 2012). Clapp et al.
(2011) showed that similar to younger adults, older adults also engage active
sensory–prefrontal memory maintenance networks that disengage when an interruptor
is presented. Notably, however, these networks in older adults fail to reengage post-
interruption, with prefrontal control regions remaining functionally connected to the
interruptor, even though it is no longer relevant. Cashdollar et al. (2013) behaviorally
characterized a prolonged association with distractors to be several hundreds of mil-
liseconds longer in aging, negatively impacting the processing of postinterference-
relevant inputs. Finally, our lab has also characterized selective age-related deficits
in motor inhibition processes and showed that they seem to be distinct from the sensory
inhibition deficits (Anguera and Gazzaley, 2011). A recent placebo-controlled study of
a cholinergic enhancer (Donepezil) showed that older adults with mild cognitive im-
pairments regain interference suppression function and neural network connectivity
with boosted cholinergic transmission (Pa et al., 2013), suggesting a neurochemical
basis of the suppression deficits.
Of note, not all external interference processing seems to be impaired in aging.
For example, we did not find a greater impact of distractions and interruptions in the
auditory modality in older relative to younger adults (Mishra et al., 2013). Older
adults also perform equivalently to younger adults in a multisensory setting, even
when the audiovisual stimulus content is incongruent/conflicting across the two sen-
sory domains (Mishra and Gazzaley, 2013). Neural data in the audiovisual paradigm,
however, suggest that while older adults on average perform as well as younger
adults, only high-performing older adults exhibit preserved neural signatures with
aging. An audiovisual WM task version with irrelevant stimuli from the auditory mo-
dality interleaved between relevant visual stimuli or vice versa also did not reveal an
age-related cross-modal suppression deficit (Guerreiro et al., submitted for
publication). In general, evidence from these studies agrees with prior cross-modal
research in aging, which consistently demonstrates preserved multisensory perfor-
mance in aging in the face of unisensory cognitive decline, notably in the visual
domain (Hugenschmidt et al., 2009a, 2009b; Laurienti et al., 2006). This body of work
suggests that older adults may benefit most when functioning within multisensory than
unisensory environments.
We have now started to apply targeted and innovative cognitive training ap-
proaches in an effort to remediate deficits in interference resolution observed in older
adults. These are reviewed in the second half of this chapter. The next section focuses
on our current knowledge of interference processing in children.
2.3 Children
Managing sources of external interference during childhood is an emerging societal
concern, especially given the tremendous influx of diverse media technologies in
modern times that can present pernicious sources of goal-irrelevant interference
(Bavelier et al., 2010; Healy, 1998; Jordan, 2004; Schmidt and Vandewater,
2008). Some research even suggests associations between diagnoses of attention-
deficit hyperactivity disorder (ADHD) and media use, although this evidence is
far from certain (Acevedo-Polakovich et al., 2006; Chan and Rabinowitz, 2006;
Milich and Lorch, 1994). The American Academy of Pediatrics recommends limit-
ing media exposure in children to 2 h per day or less based on findings that elevated
media use is associated with poor physical, cognitive, and social development and
academic underperformance in children (Johnson et al., 2007; Junco, 2011; Junco
and Cotten, 2011, 2012; Ozmert et al., 2002). From a neurodevelopmental stand-
point, the cortex does not attain full capacity to manage interference until late ado-
lescence/young adulthood (Giedd, 2012; Hagen and Hale, 1974; Harnishfeger and
Bjorklund, 1994; Leon-Carrion et al., 2004; Spronk and Jonkman, 2012), which
makes neural systems all the more prone to the negative impacts of heightened ex-
posure to interference. Indeed, a recent study showed that teenagers intentionally en-
gage with sources of interference, such as texting and Facebook, even in an observed
study environment, which ultimately was associated with poor outcomes on their
academic learning (Rosen et al., 2013).
The interference framework that was recently proposed in adults (Clapp et al.,
2010) still remains to be neurophysiologically investigated in children. In a first
replication of the WM paradigm introduced by Gazzaley et al. (2005a),
Wendelken et al. (2011) showed enhanced fMRI-based BOLD activations for
task-relevant stimuli in stimulus-selective visual cortex and in dorsolateral pre-
frontal cortex (DLPFC). The strength of these activations increased with age from
8 to 14 years, as did improvements in WM accuracy. In contrast to the young and
older adult studies, however, this study did not show modulations in irrelevant-
stimulus processing, suggesting this critical cognitive operation may be underde-
veloped in children. This is not too surprising as top-down control regions, such as
the DLPFC, demonstrate particularly delayed maturation in terms of cortical thick-
ness (Gogtay et al., 2004). Further myelination processes, white matter tract devel-
opment, and increases in tract coherence progressively advance throughout middle
childhood and young adulthood (Barnea-Goraly et al., 2005; Giedd, 2004). Putting
these significant developmental structural changes in perspective, much future
work is needed to understand interference processing and suppression abilities
in developing brains. Finally, we note that future research on neural interference
suppression during development is even more imperative from the standpoint of
crucial deficits in this ability in various young special needs populations such as
ADHD (Minear and Shah, 2006) and autism (Adams and Jarrold, 2012; Allen
and Courchesne, 2001; Marco et al., 2011). An understanding of the underlying
neural correlates and processing deficits in these neural systems would become im-
portant targets for future therapeutic remediation.
3 INTERNAL INTERFERENCE RESOLUTION ACROSS

THE LIFESPAN
3.1 Healthy young adults
Just as goal-directed activities can be derailed by interference from irrelevant stimuli
in the external environment, interference can also arise from the internal milieu in the
form of intrusive thoughts, emotions, and urges (Beauregard et al., 2001; Christoff
et al., 2009; Dolcos and McCarthy, 2006; Kane et al., 2007; Mason et al., 2007). Fol-
lowing our framework for categorizing different types of external interference, in-
ternal interference can also be categorized in a similar manner as either intrusions
that parallel external distractions or diversions that parallel external interruptions.
Again, the fundamental distinction between intrusions and diversions is the degree
of intentionality: intrusions occur spontaneously, often without awareness, while di-
versions represent volitional thoughts that we entertain while also attempting to com-
plete another task or behavior.
The vast majority of research on internal interference has focused on what we
refer to as internal distractions or intrusions. The terminology that appears in the lit-
erature, however, is far from standardized. Intrusions have been conceptualized as
“mind-wandering” (Mason et al., 2007; Smallwood and Schooler, 2006), “stimu-
lus-independent thought” (Teasdale et al., 1995), “self-generated thought”
(Callard et al., 2012), “task-unrelated thought” (Fransson, 2006), “spontaneous cog-
nition” (Andrews-Hanna et al., 2010), “self-focused attention” (Gentili et al., 2009),
“introspectively oriented thought” (Fransson, 2005), and more indirectly as “spon-
taneous fluctuations of attention” (Cohen and Maunsell, 2011). Semantic differences
aside, the fundamental characteristic of internal interference is that attention is
derailed from an original task or goal and instead becomes focused on internal
thoughts. This shift in attentional focus may be either intentional (i.e., diversions)
or unintentional (i.e., intrusions) and can occur with or without awareness.
Studies of the frequency of “mind-wandering” show that between 30% and 50%
of our waking thoughts are “stimulus-independent” or not related to the primary task
or goal at hand (Killingsworth and Gilbert, 2010; McVay et al., 2009; Smilek et al.,
2010). These off-task thoughts occur during almost every type of behavior and task
that has been monitored (Killingsworth and Gilbert, 2010; McVay et al., 2009), and
they result in demonstrable costs in task performance (Smallwood et al., 2007). In-
ternal distractions tend to be overwhelmingly negative with respect to emotional
content (Killingsworth and Gilbert, 2010) and the frequency of mind-wandering
is inversely associated to telomere length, a molecular marker of severe stress and
biological aging (Epel et al., 2013).
There is evidence that “mind-wandering” reflects both state-dependent changes in
cognitive status, varying inversely with both task difficulty and arousal (Braboszcz
and Delorme, 2011; Smallwood and Schooler, 2006), and trait-level individual differ-
ences in executive function (McVay and Kane, 2010). In general, the frequency of
reporting internal distractions is inversely correlated with executive processes. Mind-
wandering increases as tasks become well practiced (Cunningham et al., 2000;
3 Internal Interference Resolution Across the Lifespan 359
Smallwood et al., 2004); it does not affect performance on easy, mundane tasks, but
negatively impacts tasks that involve cognitive control such as WM (Teasdale et al.,
1995). Further, the frequency of internal distractions correlates negatively with WM
capacity (Kane et al., 2007; Mason et al., 2007; McVay and Kane, 2009). Finally, in-
dividuals with ADHD report more internal distractions under a variety of conditions
(Shaw and Giambra, 1993).
Neuroimaging research has begun to demonstrate some of the neural correlates of
internal distractions, with correlations between mind-wandering and activity in the
DMN network as a primary focus. DMN activity is increased during episodes of
mind-wandering (Andrews-Hanna et al., 2010; Christoff et al., 2009; Preminger
et al., 2011) and the general predilection of participants to mind-wander correlates
with increased DMN activity during cognitive tasks (Christoff et al., 2009; Mason
et al., 2007). A recent study further showed that DMN activity was high during ep-
isodes of mind-wandering when the participants were unaware of the internal distrac-
tion but dropped off once the mind-wandering event entered awareness, at which
time activity in frontal cognitive control circuits increased (Christoff et al., 2009).
A subsequent study of functional connectivity showed positive correlations between
DMN activity and cognitive control regions, but a negative correlation with primary
sensory and motor areas (Christoff, 2012). This pattern suggests a decoupling of sen-
sory and cognitive control cortices during internal distractions—a finding that is also
supported by converging encephalography (EEG) evidence showing attenuated sen-
sory ERPs during episodes of mind-wandering (Kam et al., 2011).
As internal interference is detrimental to on-task performance, it is an imperative
target for regulation and suppression. In fact, failure to adequately regulate the im-
pact of internal interference can lead to significant impairments in cognition, social
conduct, and affect regulation (Beauregard et al., 2001; Dolcos and McCarthy, 2006;
Killingsworth and Gilbert, 2010). Pathological failure to regulate this interference
likely plays an important role in a range of mental illnesses (Broyd et al., 2009;
Buckner et al., 2008), including ADHD (both inattentive and hyperactive behaviors,
Fassbender et al., 2009), posttraumatic stress disorder (intrusive recollections trig-
gered by external cues, Pitman et al., 2012; Yehuda and LeDoux, 2007), major de-
pressive disorder (ruminations and impairments in cognition and attention),
traumatic brain injury (executive function deficits), obsessive compulsive disorder
(uncontrollable anxieties/obsessions and compulsive behaviors), and substance de-
pendence disorders (uncontrollable cravings and contextual triggers for relapse;
Sayette et al., 2010). Because of this vulnerability to disease or trauma, there is much
future research needed to understand the capacity and plasticity of internal interfer-
ence regulation systems, especially for developing targeted interventions that reme-
diate deficits in these regulation processes.
3.2 Healthy older adults

Healthy older adults represent one nonclinical population that has been somewhat
better characterized in terms of their susceptibility to internal distractions
(Giambra, 1989; Jackson and Balota, 2012; McVay et al., 2013). It is well
documented that healthy older adults show decreased WM capacity and deficits in
executive control (Braver and Barch, 2002; Gazzaley and D’Esposito, 2007;
Salthouse, 1994; Ziegler et al., 2010) and in external distractor suppression
(Gazzaley, 2013). Thus, if mind-wandering is inversely related to executive function,
we might predict an increased susceptibility of older adults to internal distractions.
Surprisingly, several studies have shown that older adults report significantly fewer
internal distractions on a variety of tasks (Giambra, 1989; Jackson and Balota, 2012;
McVay et al., 2013). One interpretation of these findings is that older adults have
insufficient resources to maintain both task-relevant and task-irrelevant thoughts;
this notion is consistent with the view that mind-wandering results from failures
of cognitive control.
3.3 Children
Very few studies have explored the frequency and nature of internal interference in
children. A major hurdle to studying this phenomenon is the potential lack of meta-
cognitive insight in children about the target of their attentional focus, although
children do appear to have some intuition about the concept of mind-wandering
as early as 5½ years of age (Flavell and Flavell, 2004). Early studies that used
the Imaginal Processes Inventory to assess mind-wandering and daydreaming
found that high school students reported more daydreaming (i.e., intentional diver-
sions as per our framework) but less uncontrolled mind-wandering, when com-
pared to older college students (Taylor et al., 1978). Further, emergence of
“constructive daydreaming” and a more positive attitude toward daydreaming oc-
curs between the ages of 5 and 10 (Gold and Henderson, 1990; Henderson and
Gold, 1983). More recent studies have sought to assess internal interference by ex-
amining relative activity within the DMN during development (Immordino-Yang
et al., 2012). In children between 8 and 14 years of age, DMN activity decreased as
task demands increased; further, children with ADHD failed to show this deacti-
vation (Fassbender et al., 2009). Children with ADHD showed significantly greater
levels of behavioral variability, and this variability was inversely correlated with
the degree of DMN deactivation. Converging evidence comes from a study that
found that children with ADHD had reduced resting state functional connectivity
between DMN regions (Fair et al., 2010). These studies demonstrate the critical
importance of the DMN for the regulation of internal interference and again point
to a potential neural target for the remediation of deficient interference control in
clinical populations such as ADHD.
Having described the recently developed cognitive framework for interference
resolution and the impact of interference across the lifespan, we now transition to
reviewing novel intervention strategies in this domain. We recently developed these
interventions in an attempt to remediate deficits in interference resolution in a tar-
geted manner.
4 Neuroplasticity-Targeted Interventions for Interference Resolution 361
4 NEUROPLASTICITY-TARGETED INTERVENTIONS FOR THE

RECOVERY OF DEFICITS IN INTERFERENCE RESOLUTION
It is evident from the research reviewed in the prior section that interference control
is a vital component of cognition at every level of cognitive engagement. Also as
noted, poor interference control is a common deficit in many neuropsychiatrically
impaired populations. Further, the negative impacts of interference seem to be in-
creasing in healthy individuals living in modern environments that are burgeoning
with media and mobile technology. Currently, no therapeutics exist that selectively
and effectively address the problem of poor interference resolution abilities. Devel-
opment and scientific evaluation of such interventions, especially in the form of com-
puterized cognitive training that is accessible to many people, is a major research
emphasis at the Gazzaley laboratory.
Brain plasticity research has shown that it is possible to develop cognitive train-
ing approaches that powerfully drive plasticity of specific neural circuits and can be
used to achieve behavioral and neurological remediation (Anguera et al., 2013;
Merzenich and deCharms, 1996; Merzenich et al., 1991). Such neuroplasticity-
targeted training is built on two important principles: (1) continuous performance
feedback and (2) performance-adaptive modulations of task challenge. Punctuated
rewarding feedback is provided to the trainee throughout training at multiple time
scales: on every behavioral trial that lasts a few seconds, summary feedback at
end of every training session block that occurs every few minutes, daily summary
feedback provided at end of each day of training, and finally feedback related to
training progress over multiple days. This elaborate scheme of performance feed-
back has been empirically found to be vital for engaging the trainee and providing
them insight into their specific cognitive impairments, which can then be recovered
through performance-adaptive training. Per the second principle, the training is con-
tinuously adaptive to each trainee’s performance capacities. Adaptive mechanics
scale up task challenge when performance is accurate and at reasonably fast response
times, while task challenge is reduced when poor performance is encountered. Im-
portantly, the adaptive staircase algorithms are set such that on average, the training
generates 75–85% correct performance; at these performance levels, it has been
observed that the trainee is optimally engaged, enjoys training, and has high compli-
ance. Thus, continuous performance feedback and adaptive task challenge uniquely
customize the training to the cognitive status of each individual. These training prin-
ciples have been previously applied in successful language learning programs for
dyslexic children in over 3.5 million children worldwide by Scientific Learning®
(Hayes et al., 2003; Tallal et al., 1996; Temple et al., 2003), in more than
200,000 elderly adults to ameliorate declining cognitive function in old age by Posit
Science® (Anderson et al., 2013; Ball et al., 2010; Mahncke et al., 2006; Smith et al.,
2009; Wolinsky et al., 2013), and in WM training for children with attention deficits
developed by CogMed® (Klingberg, 2010; Rutledge et al., 2012), to name a few. Im-
portantly, however, cognitive training for interference regulation and suppression
has not been directly targeted in past efforts. Notably, there is a need for training that
is specifically targeted to the interference regulation deficit given that nonspecific
brain training programs show little or no transfer of benefit to these critical cognitive
functions, especially in the setting of daily life cognitive tasks (Owen et al., 2010;
Zelinski, 2009).
4.1 Adaptive training to remediate external distractibility

in older adults
In a recently completed study, we developed a novel cognitive training approach to
specifically address the issue of heightened distractibility—an impactful cognitive
deficit in aging and in many neuropsychiatric populations (Mishra et al.,
submitted for publication). A need for a targeted intervention was evident, since de-
spite previous efforts, no training approach had resulted in reduced distractibility in
aging (Berry et al., 2010; Buitenweg et al., 2012; van Muijden et al., 2012; Wilkinson
and Yang, 2012) or in child populations (Stevens et al., 2008; Thorell et al., 2009). Of
note, Berry et al. (2010) did demonstrate successful cognitive and neurophysiolog-
ical improvements as a result of visual perceptual training in aging. Ten hours of
training to discriminate simple visual Gabor patches, which expanded or contracted
within short 50–200 ms display durations, not only improved on-task perception but
also benefitted delayed-recognition WM of untrained dot motion kinematogram
stimuli. Moreover, this transfer of benefit was not just confined to WM behavioral
accuracy, neural evidence showed functional plasticity of early sensory processing of
the encoded WM stimuli within the visual N1 ERP component, which correlated
with the performance gains. Thus, this study was unique in showing robust transfer
of benefit in both cognitive performance and underlying neurophysiology. However,
an assay of WM in the presence of distractions conducted in the study did not yield
any transfer effects.
We recently approached the problem of heightened distractibility in aging from a
neural perspective with the goal of training participants to suppress the neural pro-
cessing of distracting stimuli via engagement in an environment of progressively in-
creasing distractor challenge. The way to succeed in such training is to discriminate
relevant informative targets amidst irrelevant distractor nontargets, which resemble
the target to a greater and greater extent as performance improves. The degree of
distractor challenge is thus adaptively determined by the discrimination performance
of the trainee on each trial. This adaptive distractor training was conceptualized in
collaboration with Merzenich and colleagues, who had recently shown that aging rats
also exhibit a distractor suppression deficit (de Villers-Sidani et al., 2010). Intrigu-
ingly, this rat study revealed that when aging rats are subjected to adaptive target
training (i.e., progressively increased target challenge amidst a fixed background
of distractors), many age-related cortical processing deficits were recovered, but
with the exception of the distraction suppression deficit, again stressing the need
for a targeted intervention approach.
We thus embarked on adaptive distractor training in parallel experiments on older

rats and older humans. Training was implemented in the auditory modality, given its
greater feasibility in rats. Thirty-six training sessions were undertaken in both spe-
cies over a 1-month training period: 1 h per session in rats and 10 min per session in
humans. In each training session block, the rat or human discriminated a new target
tone frequency chosen pseudorandomly in the 0.4–2 kHz frequency range amidst
distractor tones that spanned a 0.2–4 kHz range. A triplet tone sequence was pre-
sented on each trial and the trainees discriminated whether the target tone was pre-
sent within that sequence. Success was rewarded by a game score increase in humans
and a food reward in rats. Critically, each trial’s performance led to adaptive mod-
ification of the distractor frequency range on the next trial, which was progressively
moved within a 2 to 0.1 octave range relative to the target.
At the end of the adaptive distractor training, we observed a 43% and 50% im-
provement in target discrimination amidst distractors in rats and human, respec-
tively. This translated to improvements in octave resolution of large effect sizes
(Cohen’s d) of 1.06 in rats and 1.48 in humans. A hits versus false alarms analysis
showed that training-related discrimination improvements were specifically driven
by diminished distractor-related false-positive errors, which reduced by 53% and
36% from onset of training in rats and humans, respectively, while target hit rate
remained constant through training.
The neural plasticity underlying these behavioral effects was analyzed in single-
and multiunit neuronal recordings in anesthetized rats and high-density EEG
recordings in awake humans. Neurons in the rat auditory cortex consistently showed
suppression of distractor responses in the trained but not untrained animals, while
target responses measured to “oddball” deviant stimuli were unaffected. Concomi-
tantly, the tonotopic organization of the rat auditory cortex was improved in its
spectral and spatial response sensitivity as revealed by sharper neuronal tuning
bandwidth measures and reduced spatial receptive field overlap, respectively. Based
on prior literature, it is most likely that the improvements in the organization of the
aging auditory tonotopic map are a direct outcome of the improved distractor
response inhibition at the single neuron level (Zheng and Knudsen, 1999).
In parallel, the neural population recordings in awake humans analyzed using
ERPs showed that early sensory auditory processing of distractors was selectively
attenuated in trained, but not untrained individuals. Moreover, this sensory modula-
tion (i.e., reduced distractor processing) directly correlated with improved on-task
behavioral performance. In humans, we had the opportunity to probe top-down
engagement with distracting information using frontal theta oscillations. Early
50–150 ms frontal theta power was indiscriminately enhanced in repeat assessments
in untrained individuals suggesting increased overall, but non-stimulus-selective en-
gagement in the second versus first assessment. In contrast, trained individuals
showed selective enhancement of target-linked theta while distractor-related theta
remained near pretraining levels. These data suggested selectively restrained top-
down engagement with distractors. In fact, individuals with reduced post- versus pre-
training distractor-related frontal theta also showed the most improved sensory
signal-to-noise contrasts in post- versus pretraining ERPs. This early frontal theta
localized to known cognitive control sites that have been shown to be involved in
interference regulation in the region of the IFJ (Brass et al., 2005; Zanto et al.,
2011). Finally, a close link between the frontal and sensory regions was revealed
by theta phase coherence modulations between frontal and temporal (auditory sen-
sory) regions at peak activity electrode sites. This phase coherence was exclusively
diminished for distractors posttraining and selectively in trained older humans. This
reduced frontosensory phase coherence for trained distractors was interpreted as re-
duced distractor encoding in a functional network that represents task-relevant tar-
gets. These coherence effects are in line with recent research from the lab showing
that sensory cortices encoding task-relevant versus distracting information preferen-
tially connect with different cognitive control networks, the frontoparietal network
and the DMN, respectively (Chadick and Gazzaley, 2011).
Overall, the neural data demonstrated converging and multiple scales of neural
plasticity exhibited in both rats and humans as a result of adaptive distractor training.
The investigation in anesthetized rats provided insight into pure bottom-up sensory
plasticity in the absence of top-down cognitive control influences. This can be rarely
achieved in humans. The neural findings in humans complemented the results in rat
data, showing evidence for improved sensory distractor suppression posttraining.
Human neurophysiology further highlighted that distractor suppression is a dynamic
network process, such that top-down frontal regulation is intimately modulated along
with the observed sensory changes. Finally, in this study, we evaluated transfer of
benefit of the tone-based distractor training in humans on standard measures of cog-
nitive control, which assayed WM span, delayed WM recognition accuracy in the
presence of interference and sustained attention. WM span was exclusively benefit-
ted in the training group at an effect size of 0.94; it was notable that these gains were
observed for sequence span of letter and number stimuli despite the fact that the train-
ing used elementary tone stimuli. While the other two cognitive tests did not show
group-level improvements, individual-level benefits were observed such that indi-
viduals who improved most in adaptive distractor training also showed the most
gains in sustained attention and in WM recognition in the presence of interference,
thus offering some evidence of improved interference regulation with training. Over-
all, this training study showed how adaptive training can be used to selectively tune
deficient neural circuits by focusing the adaptive task challenge on the deficient neu-
robehavioral process, here distractor suppression. This critical insight paves the way
for the effective development of future cognitive training and neurotherapeutic
approaches that are selectively targeted to specific neural dysfunctions.
4.2 A multitasking video game to enhance cognitive control

in older adults
In our interference framework, external interruptions are induced by multitasking
behavior that demands the performance of a secondary task concurrently with a pri-
mary task. In a recent study of 174 individuals using a custom-designed, targeted 3D
video game, “NeuroRacer,” we showed a rapid decline in multitasking abilities from

ages 20 to 79 (Anguera et al., 2013). “NeuroRacer,” developed in the lab in collab-
oration with professional game designers, assessed perceptual discrimination abili-
ties (“Sign” task) with and without concurrent visuomotor tracking (“Drive” task).
The “Sign” task required discrimination of a specific colored shape target (e.g., a
green circle) amidst a rapid sequential stream of eight other colored shapes that
had either one or no common features with the target shape. During “Sign and
Drive,” the “Sign” task had to be performed concurrently with the “Drive” task to
maintain a car in the center of a winding road using a joystick (Fig. 2). Concurrent
“Sign and Drive” performance was compared to “Sign Only” performance to gen-
erate a multitasking cost index. Multitasking performance was observed to steadily
deteriorate in a linear fashion across the lifespan, with an average cost of 26% in
the second decade of life declining to 65% in the seventh decade.
We then used “NeuroRacer” to investigate if multitasking abilities on the game
can be improved through training. In a randomized controlled trial design, 46 older
adults (60–85 years) were assigned to one of three groups: multitasking training
(MTT; n ¼ 16), single-task training (STT; n ¼ 15) as an active control, or no-contact
control (NCC; n ¼ 15). Training involved playing an assigned version of “Neuro-
Racer” on a laptop at home for 1 h a day, three times a week for 4 weeks (12 total
hours of training), with all groups returning for 1 month posttraining and 6-month
follow-up assessments. The MTT group exclusively engaged in the “Sign and Drive”
condition during the training period, while the STT group divided their time between
a “Sign Only” and a “Drive Only” condition trained separately on each training day.
Thus, MTT and STT groups were matched for all factors except for the presence of
simultaneous interference that only occurred for the MTT group. Training results
showed that multitasking performance costs on the game were significantly reduced
exclusively in the MTT group (64.2% to 16.2% pre- vs. posttraining cost); inter-
estingly, these improvements reached levels that were superior to performance of a
20-year-old cohort that performed a single session of “NeuroRacer” (36.7% cost,
p < 0.001). Of note, training-driven multitasking performance improvements on the
FIGURE 2
“NeuroRacer” experimental conditions shown as screenshot captures from the training task.
Adapted from Anguera et al. (2013).
game remained stable at a follow-up assessment 6-month after the completion of

training (21.2% cost at follow-up).
Following the training period, we assessed for generalized improvements in cog-
nitive control abilities that are known to be impaired in aging on untrained tasks of
sustained attention, divided attention, and WM. We found improvements were ex-
clusively present for the MTT group for both WM (Clapp et al., 2011) and sustained
attention (TOVA; Greenberg, 1996). These important transfer of benefits from
“NeuroRacer” to untrained cognitive control tasks suggested that a common, under-
lying mechanism of cognitive control was challenged and enhanced in the MTT
group. Of note, these transfer of benefits brought about by multitasking in an engag-
ing and immersive 3D video game were of larger scale than observed for prior
dual-task training approaches, which have been implemented in more sparse envi-
ronments (Erickson et al., 2007; Lussier et al., 2012).
To assess the neural basis of the performance improvements, we quantified
event-related spectral perturbations (ERSPs) and long-range phase coherence
time-locked to the occurrence of “Signs” in an assessment version of “NeuroRacer”
at pre- and posttraining. We specifically assessed ERSP and frontal–occipital coher-
ence measures in midline frontal theta (4–7 Hz) oscillations that are a known marker
of top-down engagement as shown in previous studies of WM (Onton et al., 2005)
and sustained attention (Sauseng et al., 2007). Separate analyses for theta band power
and coherence each revealed significant 3-way interactions of condition (“Sign and
Drive” and “Sign Only”), X session (pre and post), and X group (MTT, STT, and
NCC), with follow-up analyses indicating that only the MTT group demonstrated
a significant increase from pre- to posttraining in both neural measures and exclu-
sively for the “Sign and Drive” condition. Notably, midline frontal theta power,
which was deficient relative to theta observed in a younger cohort (20–29 years),
was enhanced to levels comparable to younger adults selectively in the MTT group.
These data clearly demonstrated that selective neuroplastic changes stemmed from
the cognitively demanding interference between the “Sign” and “Drive” tasks when
participants were motivated to engage in them simultaneously. Coupled with previ-
ous findings of increased midline frontal theta on a variety of cognitive control tasks
(Mitchell et al., 2008), our results support a common neural basis for cognitive con-
trol processes, which can be enhanced by immersion in an adaptive, high-
interference environment. This interpretation is bolstered by evidence indicating that
MTT-induced increases in midline frontal theta power during “Sign and Drive” were
positively correlated with improvements in the sustained attention transfer task
(Fig. 3). Thus, MTT-induced enhancement of midline frontal theta power was asso-
ciated with generalized benefits on an untrained cognitive control task, reflecting its
utility as a neural signature of plasticity in cognitive control processes.
Parallel research has shown that midline frontal theta power is inversely corre-
lated with activity in medial prefrontal cortex related to the DMN (Scheeringa
et al., 2008). Thus, it can be hypothesized that “NeuroRacer” may benefit cognitive
control by improving the ability of older adults to suppress the DMN during task en-
gagement, a process known to be compromised in aging (Damoiseaux et al., 2008).
A Midline frontal theta

Initial
B
* 90
3.40
3.05 67.5
Pre–post TOVA RT
2.70
2.35 Older adults Younger adults
Power (dB)
2.00
1.65 45
1.30
0.95
Older adult post-training
0.60
0.25 22.5
–0.10
–0.45
–0.80
–1.15 0
–1.50
–22.5
–1 0 1 2 3 4 5
Post–pre mfTheta power (dB)
Multitask Single task No-contact
training training contact
FIGURE 3
Midline frontal theta activity modulation in “NeuroRacer,” adapted from Anguera et al.
(2013). (A) Theta power 1-month after training improved significantly only for the multitask
training group; and increased power was observed for younger versus older adults. (B)
Correlation in the multitask training group between the change in midline frontal theta power
and behavioral improvement on the TOVA (a test of sustained attention). {p < 0.05 within
group improvement from pre to post, *p < 0.05 between groups.
Future neurophysiological and neurochemical studies are imperative to clarify the

causal relation between medial prefrontal activity and the robust performance gains
observed here. Overall, the large and sustained reduction in multitasking costs and
the generalization of benefits to untrained cognitive control abilities evidenced in our
immersive, interference-laden video-game training emphasize the importance of
deficit- and circuit-targeted neurotherapeutic approaches to treat clinical populations
with deficient cognitive control (e.g., ADHD, depression, and dementia).
4.3 Enhancing self-regulation of internal distractions

Very few studies have examined the potential for training humans to improve their
ability to self-regulate against the negative impact of internal interference. A recent
study examined the efficacy of a 2-week mindfulness training course in improving
on-task performance and reducing episodes of mind-wandering (Mrazek et al.,
2013). Compared to a control group that completed a nutrition education program,
participants in the training group showed a significant decline in the number of
task-unrelated thoughts measured using both self-report and thought probe methods.
This decrease in mind-wandering was associated with an increase in reading com-
prehension scores and WM capacity, a finding consistent with an earlier study that
showed a negative association between scores on a mindfulness inventory and the
frequency of mind-wandering and attentional lapses on a sustained attention task

(Mrazek et al., 2012). Interestingly, a study of long-term meditators found a dynamic
relationship between time spent practicing concentration meditation and DMN ac-
tivity: meditators with a moderate amount of training showed greater DMN activity,
compared to novice controls, while expert meditators showed a decrease in DMN
activity (Brefczynski-Lewis et al., 2007). These findings suggest common processes
may underlie self-regulation of internal distractions and some aspects of meditation
or mindfulness and support the notion that such practices may influence plasticity of
internal distractor suppression networks. A more detailed understanding of the neural
underpinnings of internal interference is bound to inform future training approaches,
allowing them to target and drive remediative plasticity within the specific neural
networks that generate aberrant and unregulated levels of internal interference.
We have recently developed an original meditation-inspired, plasticity-based
cognitive training program for improving self-regulation of attention, metacognitive
awareness, and suppression of internal distractions. Our training paradigm consists
of a portable application deployed on an iPod, which is designed to integrate aspects
of meditation training, specifically, attention to breath and monitoring quality of at-
tention. In addition to incorporating meditation-based practices, our training appli-
cation integrates plasticity-based cognitive training methods, including quantifiable
goals, performance feedback, and performance-driven adaptivity of task challenge.
Our approach to studying internal distraction regulation training is not intended to
replace the many physiological benefits that meditation engenders, including stress
reduction, body awareness, and compassion. Instead, by focusing on a constrained
aspect of meditation (i.e., focused attention and awareness of internal distractions),
we reduce the variability involved in standard meditation practice, thus allowing us
to study the effects of directed training on self-regulation of internal distractions.
We are currently assessing the efficacy of our new internal distraction training
paradigm (Ziegler et al., 2013). In a pilot study, participants completed a 1-week,
daily, at-home training study in which they used our novel interactive iPod applica-
tion designed to adaptively increase their ability to sustain attention to their breath
while minimizing internal distractions. Before and after training, healthy younger
adults performed a mental rotation task with and without auditory noise delivered
through headphones. After each trial, participants reported if they were distracted
by internal thoughts or by some external factor. Analyses of baseline behavioral data
revealed an interesting pattern whereby internal distractions were more frequent than
external distractions in the no-noise condition, while presence of external auditory
noise led to an increase in external distractions and a decrease in internal distractions.
Focused training was associated with significant increases in the total distraction-free
time over the course of the 1-week training. Following training, we found a signif-
icant decrease in reports of internal distractions during the noise-absent mental rota-
tion task, while reports of external distractions did not differ significantly between
pre- and posttraining sessions (Fig. 4). These results suggest that internal and external
distractions interact dynamically depending on the stimulus environment. These pilot
data provide additional evidence supporting the idea that regulation of internal
5 Conclusions 369
50%
% of trials with distraction 25%

(pre–post)
0% Internal thoughts,
no distraction
Internal thoughts,
–25%
with distraction
External thoughts,
–50% no distraction
* External thoughts,
with distraction
–75%
FIGURE 4
Difference in reports of internal and external thoughts between pre- and posttraining cognitive
sessions during performance of a mental rotation task either with auditory background noise
(distraction) or without background noise (no distraction). Errors bars are standard errors of
mean, *p < 0.02, one sample t-test.
distractions can be modified by a training application that integrates meditation prin-

ciples with plasticity-based cognitive training methods. A randomized controlled
evaluation of this novel training paradigm is currently underway.
5 CONCLUSIONS
In this chapter, we describe our recently developed framework for interference in
cognitive processing. Much research from our lab laid the groundwork for the devel-
opment of the interference framework, which divides cognitive interference as either
externally or internally generated. Each of these divisions can then be further sub-
divided into two levels based on the extent of required top-down engagement with
the external/internal interference. External and internal distractions imply irrelevant
information that must be ignored, while external and internal interruptions set up
multitasking scenarios where the individual must engage in two simultaneous tasks.
Notably, this multilevel classification has helped resolve much debate in the litera-
ture regarding interference processing, as research from our lab has shown that dis-
tractions versus interruptions have distinct underlying neural mechanisms and neural
network dynamics. Critically, we have further elucidated that older adults exhibit
aberrant neural dynamics of both types of interference processing relative to young
adults, which impacts their performance on a variety of cognitive tasks. We are now
in the process of characterizing interference processing in the developing child brain,
which notably has much real-world relevance in our media and technology-heavy,
interference-laden modern environments.
Finally, we describe three novel cognitive training approaches that we recently de-
veloped to selectively target and improve processing of external distractions, external
interruptions/multitasking, and internal distractions. The need for distinct training ap-
proaches for each of these forms of interference follows logically from neuroscientific
evidence for distinct underlying neural networks subserving these interference pro-
cesses. We principally demonstrate that neuroplasticity-based training strategies,
which provide continuous performance feedback and adaptively modify interference
challenge during training, are highly successful in the remediation of interference res-
olution abilities. Thus, we envisage that our approaches can be potentially applied to
benefit clinical populations that have significant deficits in interference resolution and
thus inform the future of targeted neurotherapeutic interventions.
Acknowledgments
This work was supported by the National Institutes of Health grants 5R01AG030395 (AG),
5RO1AG0403333 (AG), 5R21AG041071 (AG), and 5R24TW007988-05 subaward
VUMC38412 (JM); the UCSF Institutional Research and Career Development Award
(JAA); the Robert Wood Johnson Foundation; and the Posit Science Corporation.
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CHAPTER
Constraint-Induced
Movement Therapy: A
Method for Harnessing
Neuroplasticity to Treat
15
Motor Disorders
Gitendra Uswatte*,{, Edward Taub*,1
*
Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
{
Department of Physical Therapy, University of Alabama at Birmingham, Birmingham, AL, USA
1
Corresponding author: Tel.: þ1 205 934-2471; Fax: þ205 975-6140
e-mail address: etaub@uab.edu
Abstract
Constraint-Induced Movement therapy or CI therapy is an approach to physical rehabilitation
elaborated from basic neuroscience and behavioral research with primates. The application of
the CI therapy protocol to humans began with the upper extremity after stroke and was then
modified and extended to cerebral palsy in young children, traumatic brain injury, and multiple
sclerosis. A form of CI therapy was developed for the lower extremities and has been used
effectively after stroke, spinal cord injury, fractured hip, multiple sclerosis, and cerebral palsy.
Adaptations of the CI therapy paradigm have also been developed for aphasia, focal hand dys-
tonia in musicians, and phantom limb pain. Human and animal studies using a variety of
methods provide evidence that CI therapy produces marked neuroplastic changes in the struc-
ture and function of the CNS. Moreover, these changes appear to be important for the inter-
vention’s therapeutic effect.
Keywords
Constraint-Induced Movement therapy, rehabilitation, hemiparesis, aphasia, stroke, cerebral
palsy, multiple sclerosis, traumatic brain injury, spinal cord injury
Although neuroscience produced important advances in our understanding of motor

learning in the last half century (e.g., see reviews by Censor et al., 2012; Wolpert
et al., 2011), there were few successful translations of neuroscience research to in-
terventions that rehabilitate motor function after people suffer nervous system

379
380 CHAPTER 15 CI Therapy
injuries (Cramer et al., 2011). One exception is Constraint-Induced Movement ther-

apy, or CI therapy (Taub et al., 1993, 2006a). It is an approach to physical rehabil-
itation, based on basic neuroscience and behavior studies with primates, for which
there is robust evidence of efficacy for rehabilitating motor function after stroke
(Langhorne et al., 2009), cerebral palsy (Brady and Garcia, 2009; Huang et al.,
2009), and other types of central nervous system (CNS) injury. This chapter intro-
duces the primate research that was the basis for CI therapy, highlights some of the
evidence for its efficacy, analyzes the components of the intervention, and discusses
the two mechanisms thought to be responsible for its therapeutic effect, one of which
is CNS neuroplasticity. Principles derived from this work for neurorehabilitation in-
terventions that seek to take advantage of what is now recognized as the striking plas-
ticity present even in the damaged and aged brain are presented last (Uswatte and
Taub, 2010).
1 RECOVERY OF FUNCTION AFTER UNILATERAL FORELIMB

DEAFFERENTATION IN PRIMATES
When somatic sensation is surgically abolished from a single forelimb in monkeys by
severing all dorsal spinal nerve roots innervating that limb, the animal does not make
use of it in the free situation (Knapp et al., 1958, 1963; Lassek, 1953; Mott and
Sherrington, 1895; Twitchell, 1954). This is the case even though the motor outflow
over the ventral roots remains uninterrupted. However, monkeys can be induced to
use the deafferented extremity by restricting movement of the intact limb (Knapp
et al., 1963; Taub and Berman, 1963, 1968). The monkey may not have used the
affected extremity for several years, but the application of this simple technique
results in a striking conversion of the useless forelimb into a limb that is used for
a wide variety of purposes (Taub, 1977, 1980). The movements are clumsy since
somatic sensation has been abolished, but they are extensive and effective. This
may be characterized as a substantial rehabilitation of movement, though the term
is not usually applied to monkeys. If the restraint device is left in place for a period
of 1 week or more, the newly developed ability to use the limb continues when the
restrain device is removed and permanent, persisting for the animal’s lifetime.
Training procedures are another means of overcoming the inability to use a single
deafferented forelimb in primates (Knapp et al., 1958, 1963; Taub, 1976, 1977, 1980;
Taub and Berman, 1963, 1968; Taub et al., 1965, 1966, 1975a, 1978). Transfer from
the experimental to the life situation was never observed when using discrete trial
conditioned response techniques to train limb use. However, when shaping was
employed, there was substantial improvement in the motor ability of the deafferented
limb in the life situation (Taub, 1976, 1977; Taub and Berman, 1968; Taub et al.,
1975a). Shaping is an operant training method in which a desired motor or behavioral
objective is approached in small steps, by “successive approximations,” so that the
improvement required for successful performance at any one point in the training is
small (Morgan, 1974; Panyan, 1980; Risley and Baer, 1973; Skinner, 1938, 1968;
2 Initial Applications of Primate Model to Rehabilitation 381
Taub et al., 1994). The actions shaped included (a) pointing at visual targets (Taub
et al., 1975a) and (b) thumb-forefinger prehension in juveniles deafferented on day of
birth (Taub et al., 1973) and prenatally by intra-uterine surgery (Taub et al., 1975b)
who had not exhibited any prehension previously. In both cases, shaping produced an
almost complete reversal of the prior motor disability, which progressed from total
absence of the target behavior to good (although not normal) performance.
During the course of this century, several other investigators have found that a
behavioral technique could be employed in animals to substantially improve a motor
deficit resulting from neurological damage (Chambers et al., 1972; Lashley, 1924;
Ogden and Franz, 1917; Tower, 1940). However, none of these observations was em-
bedded in a formal theoretical context that permitted prediction nor was the gener-
ality of the mechanisms recognized. Consequently, these findings remained a set of
disconnected observations that received little attention.
2 INITIAL APPLICATIONS OF PRIMATE MODEL TO

REHABILITATION OF PARETIC ARM USE AFTER
STROKE IN HUMANS
The initial studies of the application of CI therapy to humans were carried out by Ince
(1969) and Halberstam et al. (1971). Ince transferred the conditioned response tech-
niques used with the deafferented monkeys that he had observed in Taub’s laboratory
(Taub and Berman, 1963; Taub et al., 1965) directly to the rehabilitation of move-
ment of the paretic upper extremity of three patients with chronic stroke. He secured
the less-affected upper extremity of the patients to the arm of a chair, while asking the
patients to flex their more-affected arm at the sound of a buzzer to avoid a mild elec-
tric shock, as in the primate experiment he observed. The motor status of two of the
patients did not change; the third patient, however improved substantially in the
training and life situations (Ince, 1969). Halberstam and colleagues, from a nearby
institution, used a similar treatment protocol with a sample of 20 elderly patients with
stroke and 20 age-matched controls. The treatment group was asked to either flex
their more-affected arm or to make a lateral movement at the elbow at the onset
of a tone to avoid electric shock; the less-affected arm was not tied down. Most
of the patients in the treatment group increased the amplitude of their movements
in the two conditioned response tasks; some showed very large improvements
(Halberstam et al., 1971). There was no report of whether this improvement trans-
ferred to the life situation.
Steven Wolf and coworkers (Ostendorf and Wolf, 1981; Wolf et al., 1989) ap-
plied the less-affected limb restraint portion, but not the more-affected limb training
component, of the CI therapy protocol described by Taub (1980) to the rehabilitation
of movement in persons with a chronic upper mild/moderate extremity hemiparesis.
The patients were asked to wear a sling on the less-affected arm all day for 2 weeks,
except during a half-hour exercise period and sleeping hours. The patients demon-
strated significant but small improvements in speed or force of movement on 19 of 21
tasks on the Wolf Motor Function Test (WMFT), a laboratory test involving simple
upper-extremity movements and performance of some tasks. There was no report of
whether the improvements transferred to the life situation. Though the effect size was
small (d0 ¼ 0.2), it was reliable. The results appeared promising, especially since
training had not been used and there was some question of compliance by some
patients with the instruction to wear the sling for most of waking hours during the
intervention period. This type of intervention involving only use of a restraint device
is termed Forced Use therapy; it is not CI therapy since it consists of only one of
the four primary components of CI therapy.
3 DEMONSTRATION OF EFFICACY OF CI THERAPY AT

UNIVERSITY OF ALABAMA AT BIRMINGHAM
Taub et al. (1993) applied both the affected arm training and contralateral arm re-
straint portions of the CI therapy protocol and also a set of behavioral techniques
termed the transfer package (TP) (Morris et al., 2006; Taub et al., 2006a,b,
2013b) to the rehabilitation of persons with a chronic upper-extremity hemiparesis
in a study that employed an attention-placebo control group and emphasized transfer
of therapeutic gains in the laboratory to the life situation. Patients with chronic stroke
were selected as subjects for this study because according to the research literature at
the time (Bard and Hirschberg, 1965; Parker et al., 1986; Twitchell, 1951), and clin-
ical experience, spontaneous motor recovery was thought to reach a plateau within
1 year after stroke. There was no evidence that any treatment could produce further
recovery of function after that time. Therefore, any marked improvement in the mo-
tor function of individuals with chronic stroke would be of particular therapeutic sig-
nificance. After a long-standing plateau, the probability would be very low that an
abrupt, large improvement in motor ability could be due to spontaneous recovery.
Four treatment subjects signed a behavioral contract in which they agreed to wear
a sling on their less-affected arm for 90% of waking hours for 14 days. On the
10 weekdays during that period, the treatment subjects received 6 h (later reduced
to three) of supervised task practice using their more-affected arm (e.g., eating lunch,
throwing a ball, playing dominoes, Chinese checkers or card games, writing, pushing
a broom, using the Purdue Pegboard and Minnesota Rate of Manipulation Test) in-
terspersed with 1 h of rest. Five control subjects were told they had much greater
movement in their more-affected limb than they were exhibiting, were led through
a series of passive movement exercises in the treatment center, and were given pas-
sive movement exercises to perform at home. All experimental and control subjects
were at least 1 year poststroke (mean ¼ 4.4 years). Their motor deficit could be char-
acterized as mild/moderate or Grade 2 in the University of Alabama at Birmingham
(UAB) system of classifying motor deficit based on active range of motion at each of
the upper-extremity joints (see Table 1). Treatment efficacy was evaluated by the
WMFT (Morris et al., 2001; Taub et al., 1993; Wolf et al., 1989, 2005), the Arm
Motor Ability Test (AMAT) (Kopp et al., 1997; McCulloch et al., 1988), and the
3 Demonstration of Efficacy of CI Therapy 383
Table 1 Stratification of severity of impairment: Active range of motion and mean

MAL score criteria
Impairment Shoulder Elbow Wrist Fingers Thumb
Grade 2 Flexion 45 Extension Extension Extension of Extension or

(MAL < 2.5 and abduction 20 from 20 from all MCP and abduction of
for AS and 45 a 90 flexed a fully flexed
IP (either PIP thumb 10
HW scales) starting starting or DIP) joints
position position 10 a
Grade 3 Flexion 45 Extension Extension Extension 10 Extension or
(MAL < 2.5 and abduction 20 from 10 from MCP and IP abduction of
for AS and 45 a 90 flexed a fully flexed
(either PIP or thumb 10
HW scales) starting starting DIP) joints of
position position at least two
fingersb

Grade 4 Flexion 45 Extension Extension Extension of Extension or
(MAL < 2.5 and abduction 20 from a 10 from a at least two abduction of
for AS and 45 90 flexed fully flexed fingers >0 thumb 10
b
HW scales) starting starting and <10
position position
Grade 5 (LF- At least one Initiationc of Must be able to either initiatec extension of
MAL < 2.5 of the following: both flexion the wrist or initiate extension of one digit
for AS and Flexion 30 and
HW scales) Abduction extension
30
Scaption
30
MAL, motor activity log; AS and HW scales, amount and how well scales of the MAL; MCP,
metacarpophalangeal joints; IP, interphalangeal joints; PIP, proximal interphalangeal joints; DIP, distal
interphalangeal joints; LF-MAL, lower functioning motor activity log.
Each movement must be repeated three times in 1 min. Grade 6 patients would fall below the minimum
Grade 5 criteria.
a
Informally assessed when picking up and dropping a tennis ball.
b
Informally assessed when picking up and dropping a washcloth.
c
Initiation is defined for the purposes of criteria as minimal movement (i.e., below the level that can be
measured reliably by goniometer).
Motor Activity Log (MAL) (Taub et al., 1993), which is a structured scripted inter-
view tracking arm use in a number of important activities of daily living (ADL) with
an established reliability and validity (Uswatte et al., 2005, 2006; van der Lee et al.,
2004). On the MAL, the treatment group showed a large increase in real-world arm
use over the 2-week period and no decrease in retention of the treatment gain in real-
world use when tested 2 years after treatment. In other experiments, we have found a
20% decrement in retention over a 2-year posttreatment period in patients with a sim-
ilar (mild/moderate) deficit as the patients in this experiment. The control subjects
exhibited no change or a decline in real-world arm use over the 2-week treatment
period. The treatment group also demonstrated a significant increase in motor ability
as measured by both laboratory motor tests (WMFT, AMAT) over the treatment pe-
riod, whereas the control subjects showed no change or a decline in arm motor ability.
These results have since been confirmed in an experiment using shaping (Taub et al.,
1994) of more-affected arm movements instead of task practice and less-affected arm
constraint (Taub et al., 2006a). This experiment also had a larger sample (N ¼ 41) and a
more credible control procedure than in the first study. The shaping procedure involved
requiring that improvements in performance be made in small steps (successive approx-
imations), providing explicit feedback and verbal reinforcement for small improve-
ments in task performance, and selecting tasks that were tailored to address the
motor deficits of the individual patient (Taub et al., 1994, 1996). Modeling, prompting,
and cuing of task performance were also used. The control group was designed to con-
trol for the duration and intensity of the therapist–patient interaction and the duration
and intensity of the therapeutic activities. The control procedure was a general fitness
program in which subjects performed strength, balance, and stamina training exercises,
engaged in games that stimulated cognitive activity, and practiced relaxation skills for
10 days. Both experimental and control subjects were at least 1-year poststroke
(mean ¼ 4.5 years) and exceeded the minimum motor criterion used in the first exper-
iment prior to entry into the study. In addition, all subjects exhibited a substantial lack of
spontaneous use of their more-affected arm in their daily life, as defined by a score of
less than 2.5 on the MAL (less than half as much use of the more impaired arm compared
to before the stroke in the life situation). The motor deficit and amount of arm use of
subjects in the two groups prior to treatment was not significantly different. As in the
first experiment, the treatment group demonstrated a significant increase in motor abil-
ity on the WMFT and a large increase in real-world arm use over the course of the in-
tervention, whereas the control subjects did not. Control subjects’ answers to an
expectancy and self-efficacy questionnaire about their expectations for rehabilitation
prior to the control intervention and their reported increase in quality of life after the
intervention, as measured by the SF-36 (Ware and Sherbourne, 1992), suggested that
they found the control intervention to be credible.
4 COMPONENTS OF CI THERAPY
The upper-extremity CI therapy protocol, as practiced in the UAB laboratory, con-
sists of four basic components (Taub, 2004; Taub et al., 2006a,b): (1) intensive train-
ing of the more-affected arm for multiple days; (2) training with a behavioral
technique termed shaping; (3) the TP, a set of behavioral techniques designed to fa-
cilitate transfer of therapeutic gains from the treatment setting to daily life; and (4)
discouraging compensatory use of the less-affected arm for a target of 90% of waking
hours for the entire treatment period by using a restraining device, originally a sling
and more recently a heavily padded protective safety mitt; the amount of time the
device is worn is recorded by a timer inserted in the device.
Shaping is a training method in which a motor or behavioral objective is
approached in small steps by “successive approximations” (i.e., a task is gradually
4 Components of CI Therapy 385
made more difficult with respect to a participant’s motor capabilities). Its principles
were explicitly formulated by Skinner (1938, 1968) and they have been applied to the
rehabilitation of movement in this laboratory (Taub et al., 1993, 1994). For rehabil-
itation, shaping involves (a) providing immediate and very frequent feedback con-
cerning improvements in the quality of movement, (b) selecting tasks that are
tailored to address the motor deficits of individual participants, (c) modeling,
prompting, and cuing of task performance, and (d) systematically increasing the dif-
ficulty level of the task performed in small steps when improvement is present for a
period of time. The CI therapy shaping protocol is described in greater detail than
here in Taub et al. (1994, 2013b) and Morris et al. (2006).
The TP consists of a set of techniques in common use in the behavior analysis
field for the treatment of a variety of conditions for such problems as medication
adherence, adherence to an at-home exercise regimen for low back pain, drug addic-
tion treatment, addiction relapse prevention, and alteration of autism spectrum be-
haviors; but they have not been used systematically in rehabilitation. The TP
techniques used here are: behavioral contracts, daily home diary, daily administra-
tion of the MAL to track amount and quality of use of the more-affected arm in 30
important ADL, problem solving to overcome perceived barriers to more-affected
arm use in ADL performance, written assignment during treatment of practice at
home both of tasks carried out in the laboratory and use of the more-affected arm
in specified ADL, posttreatment home skill practice assignments, weekly telephone
calls for the first month after laboratory treatment in which the MAL is given and
problem solving carried out. These techniques are described in detail in Taub
et al. (2013b).
A 2 2 factorial experimental components analysis of CI therapy was carried out
to assess the relative contribution made by the TP and shaping to the magnitude of the
treatment effect (Taub et al., 2013b). The two factors were TP (presence, absence)
and Type of Training (shaping, repetitive practice). Each of the four groups in the
study received the same amount of treatment: 3.5 h per day for 10 weekdays. Partic-
ipants (N ¼ 40) were outpatients 1-year poststroke with mild/moderate hemiparesis
(Grade 2). Presence of the TP, regardless of the type of training received, resulted in
pre- to posttreatment gains in use of the more-affected arm in daily life, as measured
by the MAL, that were 2.4 times as large as the gains in its absence (p < 0.01). Pres-
ence of the TP, regardless of Type of Training, also enhanced gains in more-affected
arm motor capacity, as measured by the WMFT in the laboratory. Although type of
training did not influence everyday use of the more-affected arm, groups that re-
ceived shaping had larger gains than groups that received repetitive practice in
more-affected arm motor capacity.
The TP, thus, would appear to be a method for enhancing spontaneous use of a
more-affected arm in everyday life. In most rehabilitation regimens, the participant is
required to carry out exercises guided by a therapist primarily during treatment ses-
sions. The TP makes the patient a more active participant in their own improvement,
not only during the treatment sessions but also at home. The TP provides a systematic
means of specifying explicitly what the participant is expected to do when outside the
treatment setting, monitoring what in fact is done, and providing a structure within
which to solve apparent barriers to carrying out treatment goals. Thus, the TP permits
participants to be immersed in a therapeutic environment for a meaningful portion of
their day. Therapy is not confined to the limited period that the current system per-
mits (Taub and Uswatte, 2013).
5 CI THERAPY IN OTHER LABORATORIES

At UAB, over 600 adults with stroke have been given one variant or another of CI
therapy and all but four of these patients have demonstrated meaningful improve-
ment in motor ability, that is, improvement greater than a Minimum Clinically Im-
portant Difference (Lang et al., 2008; Lum et al., 2004; Uswatte and Taub, 2005; van
der Lee et al., 2004). There have also been approximately 600 papers from other lab-
oratories published to date. To our knowledge all but two of the studies have reported
positive results. A widely cited review of rehabilitation studies in stroke by
Langhorne et al. (2009) concluded that CI therapy has the most robust evidence
of efficacy for rehabilitating hemiparetic arm function. In particular, CI therapy
was the subject of a multisite randomized controlled trial, that is, the Extremity
Constraint-Induced Therapy Evaluation (EXCITE), for which the results were pos-
itive (Wolf et al., 2006).
With respect to magnitude of the treatment effect, this laboratory’s results with
patients with chronic stroke have been replicated in studies from four German lab-
oratories in which the therapists were trained at UAB (Dettmers et al., 2005; Kunkel
et al., 1999; Miltner et al., 1999; Sterr et al., 2002). In the latter three studies, CI ther-
apy was set up with the collaboration of the present author and then monitored twice
yearly. In these studies some but not all elements of the TP were employed. However,
in each case some TP elements were used and attention was focused on the transfer of
therapeutic gains in the laboratory to spontaneous use of the more-affected arm in the
life situation.
Some of the papers on CI therapy from elsewhere report outcomes as large as
those obtained in this and the German laboratories just noted. However, most of these
studies report real-world outcomes that are significant, but only one-third to one-half
as large as those obtained here. There are two likely reasons for the reduced treatment
effect in these studies. One, there was incomplete or complete lack of use of the TP,
which, though reported in the papers from this laboratory, had been largely ignored.
As noted above, we have replicated the reduced treatment effect obtained by others
by duplicating everything that is normally done in treatment here except implemen-
tation of the TP (Gauthier et al., 2008; Taub et al., 2013b). Two, a protocol with
attenuated intensity (tasks or movements per unit time) was used, such as in a study
by van der Lee et al. (1999).
In this regard, a comment is necessary on the multi-site EXCITE trial, which had
real-world outcomes half as large as reported by this laboratory and some others. An
important component of the TP, namely, daily administration of the MAL, was
6 Severity of Impairment, Chronicity, and CI Therapy 387
omitted by vote (six vs. one) of the site principal investigators over the recommen-
dation of one of the authors (E. T.). Moreover, the TP procedures as a whole were not
emphasized in the EXCITE trial because the components analysis study described
previously had not been done (Taub and Uswatte, 2013).
6 SEVERITY OF IMPAIRMENT, TIME SINCE STROKE,

AND LOWER EXTREMITY CI THERAPY
6.1 Lower Functioning Patients
Most of the patients treated at UAB could be characterized as having deficits that were
mild/moderate, defined primarily as having the ability to extend 20 at the wrist and
10 at each of the fingers (Grade 2; see Table 1 for full active range of motor criteria).
Experiments have also been carried out with patients with moderate and moderately
severe deficits (Grades 3 and 4) (Taub et al., 1999). Their treatment change was some-
what less than for higher functioning patients, for example, increases of approximately
400% and 350% for patients with moderate and moderately severe deficits, respec-
tively, compared to approximately 500% for patients with mild/moderate deficits,
but the treatment changes were nevertheless very large. Most recently, work has been
carried out with patients with useless, plegic hands that were initially fisted (Taub
et al., 2013a; Uswatte et al., 2008). Conventional physical rehabilitation procedures,
including some from neurodevelopmental treatment, and functional electrical stimu-
lation were used to maintain the fingers in a sufficiently extended and aligned position
so that CI therapy training procedures could be carried out. At the end of treatment, the
patients exhibited a 186% improvement in the real-world use of the more-affected arm.
It had been converted into a useful “helper” in the life situation (e.g., keeping a piece of
paper in place while writing with the less-affected hand, holding a toothpaste tube
while unscrewing the cap, bearing body weight for bed mobility).
We estimate that CI therapy is applicable to at least 50% of the chronic stroke pop-
ulation with motor deficit, perhaps more. CI therapy would also be appropriate for a
sizable percentage of individuals who had traumatic brain injury in previous years.
6.2 Time Since Stroke

A large majority of previous CI therapy studies were with chronic and subacute
patients with stroke. Several studies with acute patients beginning CI therapy
7–14 days postevent reported little (Boake et al., 2007; Dromerick et al., 2000) or
no (Dromerick et al., 2009) treatment effect. However, a number of other studies
have obtained results as good as those obtained with chronic and subacute patients
(Nijland et al., 2011). The reasons for the weak early results may be related to the
interference in American hospitals of the ward routine with adequate administration
of CI therapy. In any case, the preponderance of evidence now is that that CI therapy
is also efficacious in the acute phase.
6.3 Lower Extremity

CI therapy techniques were developed for the rehabilitation of the upper extremity.
An obvious target for transfer of this approach was to the more-affected lower ex-
tremity of stroke patients. The 38 patients with chronic stroke treated in studies from
our laboratory to date have had a wide range of disability extending from being close
to nonambulatory to having moderately impaired coordination (Taub et al., 1999).
The treatment (lower-extremity-CI therapy or LE-CI therapy) consists of massed
or repetitive practice of lower-extremity tasks for 3 h per day with interspersed rest
intervals as needed over 3 weeks with an additional 0.5 h per day devoted to TP pro-
cedures. Examples of the lower-extremity tasks are, over-ground walking, treadmill
walking with and without a partial body weight support harness, sit-to-stand, lie-to-
sit, stair climbing, walking over obstacles, and various balance and support exercises.
Task performance is shaped as in the upper-extremity protocol. Training is enhanced
through the use of force feedback (limb load monitor) and limb displacement (joint
angle/electric goniometer) feedback devices. No restraining device is placed on the
less-affected leg. The lower-extremity procedure is considered to be a form of CI
therapy because of the use of the TP, the strong massed practice/shaping element,
and because the reward of adaptive patterns of ambulation over maladaptive patterns
in our training procedure constitutes a significant general form of constraint. Com-
parison data were provided by a general fitness control group that received the same
battery of lower-extremity tests as the treatment subjects. The effect size of the
change in real-world performance due to the treatment was large, but not quite as
large as for the upper extremity. The improved lower extremity use was retained
without any decrement for the 2 years that were tested.
7 OTHER CONDITIONS
The CI therapy protocols, that is, upper- and lower-extremity interventions, for adults
with stroke have been applied with similar success to the upper extremity in traumatic
brain injury (Shaw et al., 2003) and to the upper and lower extremity in multiple scle-
rosis (Mark et al., 2008, 2013). Results as good as or better than with adults after stroke
have also been obtained for the upper extremity in children with cerebral palsy and
other pediatric motor disorders of neurological origin across the full range of childhood
years, that is, from 1 year through the teens (Taub et al., 2004, 2007, 2011). Since the
initial study from our laboratory (Taub et al., 2004), over 25 studies of pediatric upper-
extremity CI therapy have been published; two reviews of this literature conclude that
the intervention is efficacious (Brady and Garcia, 2009; Huang et al., 2009). For young
children, the adult upper-extremity protocol is modified to render the intervention suit-
able for this age range, for example, the shaping activities are embedded within games.
CI therapy principles have also been used to devise successful interventions for focal
hand dystonia in musicians (Candia et al., 1999, 2002), phantom limb pain after
amputation (Weiss et al., 1999), and aphasia after stroke.
8 Mechanisms Responsible for CI Therapy Treatment Effect 389
The intervention for aphasia is named Constraint-Induced Aphasia therapy

(CIAT). The initial study was carried out by Pulvermüller, Taub, and coworkers
(Pulvermüller et al., 2001; Taub, 2002), and reported a significant improvement
in everyday speech for what is now termed CIAT I relative to conventional aphasia
therapy. Following a positive evaluation of this study and subsequent ones from other
laboratories by a committee appointed by the American Speech and Hearing Asso-
ciation (Raymer et al., 2008), CIAT I is now beginning to be adopted in clinical prac-
tice (Taub and Uswatte, 2013).
Although the results of the CIAT I protocol have been positive, the intervention
was only an incomplete translation of CI therapy. CIMT produces an improvement of
approximately 500% in real-world use of the more-affected extremity of chronic
stroke patients with mild to moderate motor deficit in the UAB laboratory (Taub
et al., 2006a). Aphasic patients given CIAT I showed an improvement of 30% in
real-world verbal behavior. This is a large treatment effect compared to conventional
speech-language therapies, but it is very small compared to the results produced by
CIMT. Consequently, in order to determine whether the large difference was the re-
sult of an incomplete translation of the CI therapy protocol employed in the UAB
laboratory with motor deficits to the treatment of language impairment, the initial
aphasia treatment protocol (CIAT I) was modified to more closely resemble the
CIMT protocol. A case series study (n ¼ 4) of the enhanced protocol, that is, CIAT
II, reported a mean improvement in real-world speech of approximately 200%
(Johnson et al., 2013).
8 MECHANISMS RESPONSIBLE FOR CI THERAPY

TREATMENT EFFECT
Evidence suggests that there are at least two mechanisms that underlie the treatment
effect of CI therapy: (1) Overcoming learned nonuse (LNU) and (2) use-dependent
plastic brain reorganization.
8.1 Learned Nonuse

The LNU mechanism was proposed in the context of the primate somatosensory
deafferentation studies referred to at the beginning of this article (Taub, 1977,
1980). It was formulated as a means of resolving a central enigma posed by the Mott
and Sherrington experiment of 1895 (Mott and Sherrington, 1895). Why did mon-
keys not use a single deafferented limb? Sherrington’s reasonable answer had been
that extremity deafferentation interrupted the afferent limb of spinal reflexes, and it
was this that abolished use of the extremity even though motor innervation remained
intact. Hence the idea emerged that spinal reflexes were the basic building blocks
from which behavior was elaborated, which was the fundamental tenet of Sherring-
tonian reflexology. This was a pervasive view in neurology for the first 70 years of
the twentieth century. However, the two simple behavioral techniques noted above
enabled very extensive and purposive use of a deafferented limb from which all myo-
tatic reflex activated had been abolished. This demonstration and later control exper-
iments showed that the Sherringtonian reflexological explanation of the primate
unilateral deafferentation experiments in this formulation could not be correct. What
then could account for the absence of purposive movement after unilateral forelimb
deafferentation? The need to address that salient question led to the formulation of
the concept of LNU.
Several converging lines of evidence suggested that nonuse of a single deaffer-
ented forelimb is a learning phenomenon involving a conditioned suppression of
movement termed LNU. The restraint and training techniques appear to be effective
because they overcome LNU. We offer the following explanation for further empir-
ical test and hypothesis formation, though several central predications stemming
from this formulation have been experimentally verified (Taub, 1977, 1980).
Substantial neurological injury usually leads to a depression in motor and/or per-
ceptual function that is considerably worse than the level of function that will be
attained after spontaneous recovery has taken place. The processes responsible for
the initial depression of function and the later gradual recovery that occurs at the
level of both the spinal cord and the brain is, at present, incompletely understood.
Whatever the mechanism, however, recovery processes come into operation follow-
ing deafferentation so that after a period of time movements can once again, at least
potentially, be expressed. In monkeys, the initial period of depressed function lasts
from 2 to 6 months following forelimb deafferentation (Taub, 1977, 1980).
Thus, immediately after surgical deafferentation of a forelimb, monkeys cannot
use that extremity; recovery from the initial depression of function requires consid-
erable time. Animals with one deafferented forelimb are unsuccessful in attempts to
use that extremity during this period. Efforts to use the deafferented limb often lead
to painful and otherwise aversive consequences, such as incoordination and falling,
loss of food objects, and in general, failure of any activity attempted with the deaf-
ferented limb. Many learning experiments have demonstrated that punishment has
the effect of suppressing the behavior associated with it (Azrin and Holz, 1966;
Catania, 1998; Estes, 1944). The monkeys, meanwhile, get along quite well in the
laboratory environment on three limbs and are therefore positively reinforced for this
pattern of behavior which, as a result, is strengthened. Thus, the response tendency to
not use the affected limb persists and, consequently, monkeys never learn that the
limb has become potentially useful several months after surgery.
When the movements of the intact limb are restricted several months after uni-
lateral deafferentation, the situation is changed dramatically. Animals either use the
deafferented limb, or cannot with any degree of efficiency feed themselves, loco-
mote, or carry out large portions of their daily activities. This new constraint on be-
havior increases the drive to use the deafferented limb, thereby inducing monkeys to
use it and overcoming the LNU. However, current ongoing environmental contin-
gencies, such as the relative inefficiency of the affected upper extremity compared
with the unaffected arm, continue to strengthen use of the affected extremity. How-
ever, if a movement-restriction device is placed on the intact forelimb and left on for
several days or longer, use of the deafferented limb acquires strength and then when
the device is removed can compete successfully with the strongly overlearned non-
use of that limb.
The conditioned response and shaping conditions described above, just like the
restriction of the intact limb, place major constraints on the animals’ behavior. In
conditioned response situations, if the monkeys do not perform the required response
with the deafferented limb, they are either punished or do not receive food pellets or
liquid when hungry or thirsty, respectively. Similarly, during shaping, reward is con-
tingent on making an improved movement with the deafferented limb. The monkeys
cannot get by using just the intact forelimb as they can in the colony environment.
These new sets of conditions, just as the movement-restriction device, constrain the
animals to use their deafferented limb to avoid punishment or obtain reward and
thereby induce the animals to use their deafferented limb and overcome the LNU.
8.2 Learned Nonuse Formulation as the Origin of CI Therapy

and its Multiple Applications
The concept of LNU was developed in the context of primate deafferentation exper-
iments. It was proposed as an alternate to the reflexological explanation of the results
of unilateral forelimb deafferentation, which our early experiments showed could not
be correct. However, the formulation of LNU was not specific to somatosensory
deafferentation. The central tenet was based on the regional loss of neuronal excit-
ability observed to follow any substantial damage to the CNS. Thus, if the LNU for-
mulation was correct, as the experimental tests of two counterintuitive predications
(Taub, 1977, 1980; Taub et al., 2006b) seemed to indicate, then it ought to apply to
other types of CNS damage. This line of reasoning led directly to the attempt to im-
prove motor deficit after stroke in humans by the same two techniques that had been
employed with unilaterally deafferented monkeys: intensive training of the more-
affected arm and restraint of the less-affected arm.
The applicability of LNU to humans after stroke was considered reasonable
(Taub, 1980), but initially we were not completely confident that it was correct.
There was the interspecies difference, and the fact that the initial tests of the
LNU formulation were with respect to somatosensory deafferentation and not with
any other type of CNS lesion. However, once the LNU formulation and the tech-
niques used to overcome LNU after deafferentation in monkeys were shown to be
applicable to humans after stroke (Taub et al., 1993), the extension of these tech-
niques to motor deficits resulting from other types of damage to the CNS in humans
was straightforward. These have included to date, as noted above, traumatic brain
injury, cerebral palsy and other types of injury to the immature nervous system, mul-
tiple sclerosis, and spinal cord injury. Extension of the basic CI therapy protocol from
the upper extremity to the lower extremity was equally straightforward. All of these
applications of the CI therapy protocol involved remediation of motor deficits. Thus,
some question arose concerning whether the principles of CI therapy would be ap-
plicable to poststroke aphasia. LNU has been demonstrated to occur in poststroke
aphasia (Croteau et al., 2004) and it is a phenomenon generally recognized to be

common by many speech-language pathologists. However, while speech clearly
consists of a series of motor acts, it diverges from movements of the extremities
in that it is intimately associated with comprehension and the elaboration of linguis-
tic structures that have no obvious counterparts in extremity movement. Now that the
principles of CI therapy have been successfully applied to poststroke aphasia, its rel-
evance seems straightforward. However, it was not clear that this would be the case
at the outset.
A final point to be made is that the use of the CI therapy protocol to improve the
motor deficit after stroke stems primarily from the LNU formulation, as does each of
its subsequent applications to other pathological conditions. The fact that these pre-
dicted applications have been successful constitutes an additional source of evidence
in support of the LNU formulation (Taub and Uswatte, 2013).
8.3 Use-Dependent Brain Reorganization

In a seminal series of studies, Merzenich and coworkers showed that increased use of
a limb and the resulting increase in afferent inflow leads to an expansion of the cor-
tical representation zone of that body part in new-world monkeys (Jenkins et al.,
1990; Recanzone et al., 1992a,b,c). Elbert, Taub, and coworkers (Braun et al.,
2000; Elbert et al., 1995, 1997) reported that the same phenomenon occurs in
humans. It was next found that CI therapy-type interventions involving training of
extremity use after a CNS injury results in both improved extremity function and
reorganization of brain activity. Nudo and coworkers demonstrated this first in
new-world monkeys, showing that the area surrounding a motor cortex infarct that
would not normally be involved in control of the hand came to participate in that
function at the same time that performance on an experimental task involving manual
dexterity improved (Nudo et al., 1996). In humans whose upper-extremity function
had been enhanced by CI therapy, Liepert and coworkers used focal transcranial
magnetic stimulation to show that the cortical representation of an important muscle
of the hand (abductor pollicis brevis) was greatly enlarged (Liepert et al., 1998,
2000). CI therapy had led to an increase in the excitability and recruitment of a large
number of neurons in the innervation of movements of the more-affected limb
adjacent to those originally involved in control of that extremity prior to treatment.
At about the same time, Kopp and coworkers, using EEG source imaging, found that
after CI therapy the motor cortex ipsilateral to the more-affected arm, which nor-
mally controls movements of the less-affected arm, had been recruited to generate
movements of the more-affected arm (Kopp et al., 1999). The finding that CI therapy
is associated with substantial changes in brain activity was confirmed in other early
studies in which the author collaborated involving the Bereitschafts Potential
(Bauder et al., 1999) and positron emission tomography (Wittenberg et al., 2003).
To date, there have been more than 20 studies, many involving functional magnetic
resonance imaging, that have obtained similar results (see review of literature up to
2006 in Mark et al., 2006).
The studies just described employed functional brain imaging and brain mapping
techniques to demonstrate that CI therapy could alter the function of specific brain
regions. The question remained whether CI therapy could measurably alter brain
structure in humans. Starting at the beginning of the first decade of this century it
was shown that experienced taxi drivers have significantly expanded hippocampi
(Maguire et al., 2000), jugglers acquire significantly increased temporal lobe density
(Draganski et al., 2004), and thalamic density significantly declines after limb am-
putation (Draganski et al., 2006). Moreover, in an animal model of stroke, CI therapy
combined with exercise reduced tissue loss associated with stroke (DeBow et al.,
2003). Accordingly, structural imaging studies became a logical initial step toward
understanding whether there are anatomical changes following the administration of
CI therapy and whether these are correlated with clinical improvements.
Longitudinal voxel-based morphometry (pre- vs. posttreatment) was performed
on subjects enrolled in our study of the contribution made by the TP to CI therapy
outcome (Gauthier et al., 2008). It was found that structural brain changes paralleled
changes in amount of use of the impaired extremity for ADL. Groups receiving the
TP showed profuse increases in gray matter tissue in sensorimotor cortices both con-
tralateral and ipsilateral to the more-affected arm, as well as in bilateral hippocampi.
The aforementioned sensorimotor clusters were bilaterally symmetrical and encom-
passed the hand/arm regions of primary sensory and motor cortices as well as the
supplementary motor area and portions of Brodmann’s area 6 (Fig. 1, right side).
It was of importance that increases in gray matter were correlated with increases
on the MAL for the sensorimotor clusters on both sides of the brain and the prede-
fined hippocampus region of interest (r’s > 0.45, p’s < 0.05). Thus, this change in the
brain’s morphology is directly related to administration of the TP which in turn sub-
stantially increases the amount of real-world use of the affected arm. In contrast, the
groups that did not receive the TP showed relatively small improvements in real-
world arm use and failed to demonstrate gray matter increases. In addition, the in-
crease in gray matter from pre-to posttreatment differed significantly between
groups. The fact that the anatomical change is directly related to the TP both lends
increased credibility to the importance of the TP.
In another study (Sterling et al., 2013), children with hemiparetic cerebral palsy
also showed increases in gray matter in the bilateral sensorimotor cortices (Fig. 1, left
side). These changes showed a strong correlation with improvements in spontaneous
real-world arm use as recorded on the pediatric version of the MAL. More focal in-
creases occur in children. This finding is consistent with previous research, which
has shown that, compared to children, adults show significantly more widespread
cortical activation when a manual task is performed including not only bilateral sen-
sorimotor cortices as in children but parietal and supplementary motor areas as well
(Mall et al., 2005).
It is not possible to make a causal attribution regarding the observed cortical
structural changes and improvement in motor function. The gray matter increase
could be either a cause or an effect of increased motor ability and behavioral change,
or it could simply be an independent accompaniment. However, the trend observed
FIGURE 1
Cortical surface-rendered image of gray matter change after CI therapy in (A) children with
hemiparetic cerebral palsy and (B) adults with chronic stroke for comparison. Gray matter
increases displayed on a standard brain. Surface rendering was performed with a depth of
20 mm. Color bar values indicate t statistics ranging from 2.0 to 6.7. For the black and white
version of the figure, cross-hatched areas indicate t statistics in the same range.
This figure is reproduced with permission from: Taub, E., & Uswatte, G. (2013). Constraint-Induced Movement
therapy: a family of neurorehabilitation treatments that harnesses the plasticity of the central nervous system.
Neurologie & Rehabilitation, 19, 161–175.
for a correlation between increases in gray matter volume and magnitude of motor
improvement raises the possibility of a causal relationship. Future research with ei-
ther animals or humans in which CI therapy is administered and cortical structural
change is suppressed may resolve this issue (Taub and Uswatte, 2013).
In both studies increases were also observed in the gray matter of the hippocampus,
which may have included the adjacent subventricular zone. The hippocampus is known
to be involved in learning and memory and these two processes are associated with the
improved limb use that occurs with CI therapy. Evidence also indicates that stem cells
are located at this site in the adult mammalian brain (Eriksson et al., 1998; Yamashima
et al., 2004) and simulated stroke in animals can increase the quantity of these cells
(Yamashima et al., 2004). One might speculate that the increases in gray matter observed
in the hippocampal region and sensory and motor areas of the brain are mediated in part
by increased production of neuronal or glial stem cells that might participate in the
References 395
migratory repair of an infracted area (Kolb et al., 2007). Alternatively, or in addition,

gray matter increases may result from rehabilitation-induced increases in dendritic ar-
borization and synaptic density (Briones et al., 2006), and possibly gliosis or angiogen-
esis. Determination of which of these processes or combination of processes responsible
for the observed increase in gray matter following CI therapy awaits future research.
9 PRINCIPLES FOR EXPLOITING CNS NEUROPLASTICITY

TO ENHANCE REHABILITATION
The work on CI therapy provides guidelines for how clinical researchers and practitioners
can therapeutically harness neuroplastic processes to enhance rehabilitation outcomes for
both adults and children with damage to their CNS. Four general principles are proposed.
Theyare(a)providingextendedandconcentratedpracticeinusingtheimpairedfunctionby
scheduling intensive training; (b) increasing use of the impaired function in the treatment
andhomesettingbyprovidingreinforcementforitsuse,forcingitsusebypreventingtheuse
of compensatory functions, or both; (c) emphasizing training on tasks rather than small
components of the task such as individual movements; and (d) implementing methods
for transferring gains made in the treatment setting to daily life (Uswatte and Taub, 2010).
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CHAPTER
Novelty Interventions to
Enhance Broad Cognitive
Abilities and Prevent
Dementia: Synergistic
16
Approaches for the
Facilitation of Positive
Plastic Change
Patrick Fissler1, Olivia Küster, Winfried Schlee, Iris-Tatjana Kolassa
1
Corresponding author: Tel.: þ49-7531-5026588; Fax: þ49-7531-5026599,
e-mail address: patrick.fissler@uni-ulm.de
Abstract
Process-based cognitive trainings (PCTs) and novelty interventions are two traditional ap-
proaches aiming to prevent cognitive decline and dementia. However, both have their limita-
tions. PCTs improve performance only in cognitive tests similar to the training tasks with
inconsistent transfer effects on dissimilar tests. We argue that this learning specificity is
due to a low training task variability. Novelty interventions are characterized by a high task
variability but do not target specific processing demands affected in aging and dementia. To
overcome the limitations of both approaches, we developed a process-based novelty interven-
tion using a card and board game-based training approach. Here, we use highly variable tasks,
which overlap in targeted processing demands (“overlapping variability” framework). An-
other nontraditional training approach combines cognitively with physically challenging tasks
to induce multimechanistic effects, which might even interact positively. Initial results of both
synergistic approaches indicate their potential to enhance broad cognitive abilities and prevent
dementia.
Keywords
challenging mental activity, novelty intervention, process-based cognitive training, process-
based novelty intervention, physically demanding novelty intervention, learning specificity,
variability of practice, executive control, dementia

403
404 CHAPTER 16 Novelty Interventions for Brain Health
1 INTRODUCTION
As the world population ages, costs of dementia are expected to double within the
next 40 years (Hurd et al., 2013). Effective interventions to prevent dementia are ur-
gently sought after. Currently, no preventive or curative pharmacological therapy for
dementia exists (Daviglus et al., 2011; Plassman et al., 2010); however, a vast and
steadily growing literature suggests cognitive health benefits from engaging in
mentally challenging activities (see, e.g., Verghese et al., 2003; Wang et al.,
2013) and physical activities (see, e.g., Smith et al., 2010; Sofi et al., 2011;
Weuve et al., 2004). Here, we review interventional studies on mentally challenging
activities, excluding studies on pure physical activities such as aerobic (Kramer et al.,
1999; Smith et al., 2010) and resistance exercise (Nagamatsu et al., 2012). We con-
clude that currently used cognitive interventions, namely, novelty interventions and
process-based cognitive trainings (PCTs), did not tap specific processes or showed
only inconsistent transfer effects on cognitive tests dissimilar to the training tasks,
respectively. Addressing these limitations, the rationale for a synergistic process-
based novelty intervention is presented, followed by initial results that indicate
improvement in executive control. Finally, the rationale and cognitive effects of
physically demanding novelty interventions are depicted.
2 EFFECTS OF CHALLENGING MENTAL ACTIVITIES

Evidence from prospective observational studies suggests that the risk for dementia
is reduced in individuals who engaged in challenging mental activities over the
whole lifespan (see Stern and Munn, 2010, and Valenzuela and Sachdev, 2006,
for a meta-analysis and a systematic review). Individuals who were raised with mul-
tiple languages (Bialystok et al., 2007; Craik et al., 2010; Perquin et al., 2013), ac-
quired a high educational level and a high occupational status (Valenzuela and
Sachdev, 2006), or engaged in mentally challenging leisure activities (e.g., playing
board games and musical instruments, Verghese et al., 2003) showed a better cog-
nitive development (see Wang et al., 2012, for a recent review).
At the same time, observational studies have the downside that causal attributions
cannot be made, as attribution of effects to nonmeasured confounding variables and
reverse causality (cognitive impairments lead to reduced activities) cannot be ex-
cluded (see Eriksson Sörman et al., 2013). Experimental studies, on the other hand,
allow for the causal interpretation of effects. Furthermore, their interventional nature
enables the evaluation of theory-driven interventions, for example, cognitive training
instead of unspecific mental activities.
Two approaches within cognitive interventions seem most promising and will be
outlined in more detail in the succeeding text: novelty intervention and process-
based cognitive training (PCT).
Novelty intervention is defined as a program which enables participants to en-
gage in difficult, novel tasks offering a high variability but generally not targeting
2 Effects of Challenging Mental Activities 405
specific processes. Thus, it induces a mismatch of functional organismic supply and

task demands (see Lövdén et al., 2010) in multiple unspecific processes. Often, these
interventions are intrinsically motivating, related to real life and implemented in a
social context (e.g., Carlson et al., 2008; Cheng et al., 2013; Klusmann et al.,
2010; Mortimer et al., 2012). Cognitive leisure activity (Stern and Munn, 2010),
complex mental activity (Valenzuela et al., 2007; Wilson, 2011), and engagement
intervention (Park et al., 2007) depict similar concepts.
Based on Gates and Valenzuela (2010), we define PCT as a repeated practice on
standardized and theory-driven tasks. Similar to novelty interventions, PCTs induce
a supply–demand mismatch but not in unspecific but in specifically targeted pro-
cesses. This mismatch is not maintained by introducing novel tasks but by the adap-
tation of difficulty to participants’ performance in repeatedly practiced tasks. Similar
concepts include cognitive exercise (Gates and Valenzuela, 2010) or process training
(Lustig et al., 2009).
2.1 Novelty interventions

Experimental animal studies on the effect of environmental enrichment (see van
Praag et al., 2000, for a review and Li et al., 2013 and observational studies in
humans suggest the importance of novelty for brain health (Angevaren et al.,
2007; Eskes et al., 2010; Fritsch et al., 2005). For example, Fritsch et al. (2005) tested
the role of novelty-seeking activities from ages 20 to 60 in predicting Alzheimer’s
disease (AD) using a case-control study design. By running a factor analysis on 16
activities, a novelty-seeking factor was extracted, composed of indicators such as the
frequency of learning new skills, taking up new hobbies or learning about a new sub-
ject. More frequent engagement in novelty-seeking activities significantly reduced
the odds ratio for AD even after adjusting for other predictive factors such as age,
education, and occupational status (odds ratio ¼ 0.25; 97.5% CI: 0.139–0.443;
p < 0.001).
These studies stimulated interventional studies on beneficial cognitive effects of
exposure to novelty. For example, Klusmann et al. (2010) compared healthy older
adults—unfamiliar with computers—who were randomized to a 6-month computer
course (75 sessions; 90 min each) or to a passive control group. The computer course
was composed of novel tasks such as writing, playing, calculating, e-mailing, draw-
ing, image editing, or videotaping, to name just a few. Participants who attended the
computer course significantly improved in tests of episodic memory and executive
function, compared with the control group. Various other interventions exposing par-
ticipants to novel, multifaceted mental tasks such as playing strategy video games
(Basak et al., 2008; Glass et al., 2013) and multiple other kinds of video games
(Oei and Patterson, 2013); a diverse range of cognitive and perceptual–motor activ-
ities (Tranter and Koutstaal, 2008); convergent and divergent problem solving in
groups (Stine-Morrow et al., 2008); volunteering to help children with reading
achievement, classroom behavior, and library support (Carlson et al., 2008); partic-
ipating in individualized piano instruction (Bugos et al., 2007); and engaging in
group discussion (Mortimer et al., 2012) showed beneficial effects on cognitive out-
comes. On the contrary, there are also a few studies failing to find any effect from
action and strategy video gaming (Boot et al., 2008, 2013). In contrast to the studies
mentioned earlier, Cheng et al. (2013) investigated the potential to improve cogni-
tion in people with dementia rather than in healthy individuals. Participants in the
intervention group played the Chinese tile-based game mahjong for 1 h, 3 days a
week for 3 months, while the active control group was engaged in simple handicraft
for the same duration. Six months after treatment completion, the mahjong group
differed by 4.5 points (95% confidence interval: 2.0–6.9; d ¼ 0.48) on the Mini-
Mental State Examination from the active control group. To our knowledge, no
experimental study investigated the effects of a pure novelty intervention on
incidence of dementia. Thus, conclusions as to whether these cognitive benefits
translate to a delay of dementia onset cannot be drawn. Taken together, novelty in-
terventions showed promising and rather consistent effects on cognitive outcomes,
indicating enhancement of cognitive ability. Nevertheless, the tasks used in novelty
interventions did not tackle specific processes affected in aging and dementia, such
as executive control processes (see Fig. 1). PCT addresses this issue.
2.2 Process-based cognitive trainings

A recent meta-analysis from Hindin and Zelinski (2012) reliably showed improve-
ments of PCTs on untrained cognitive test performance. These beneficial effects
were found for different types of PCT such as visual (Wolinsky et al., 2013) and au-
ditory processes (Zelinski et al., 2011) and higher-order process training such as task
switching (Karbach and Kray, 2009) and working memory training (Jaeggi et al.,
2008; Klingberg et al., 2005). However, the crucial question is whether those im-
provements in assessed outcomes represented improvements in a broad cognitive
ability or only the acquisition of task-specific skills (e.g., stimulus–response map-
pings or strategies). There is an ongoing debate on this decisive question without
consensus as of yet (see, e.g., Hulme and Melby-Lervåg, 2012; Li et al., 2008;
Lövdén et al., 2013; Melby-Lervåg and Hulme, 2012; Redick et al., 2013;
Schmiedek et al., 2010; Shipstead et al., 2010, 2012). In the following, we explain
why this question is still open to debate despite a vast amount of studies.
Conclusively answering the ability/skill question is hindered because of method-
ological aspects. In the following, these aspects are shortly addressed before study
results are reviewed. Next to the lack of appropriate control conditions (e.g.,
Schmiedek et al., 2010), outcome abilities were frequently not assessed by multiple
tests of the targeted cognitive ability (e.g., Jaeggi et al., 2008, and see, e.g., Shipstead
et al., 2012, for the same argument). Maybe the most important methodological as-
pect is that the cognitive tests shared peripheral task characteristics with the training
tasks (e.g., Dahlin et al., 2008a). Thus, not only improvements in the targeted pro-
cesses may have contributed to the effects but also lower-order processes not repre-
senting the broad cognitive ability (see, e.g., Shipstead et al., 2012). The similarity
between training and transfer measure is rather subjective, and judgments are
2 Effects of Challenging Mental Activities 407
FIGURE 1
Traditional cognitive intervention approaches. Novelty interventions or PCTs depict the most
promising traditional cognitive interventions. Novelty interventions are challenging through
difficult novel tasks, include a high variability of tasks, but target only unspecific cognitive
processes, thus leading to broad transfer but only small improvements in unspecific abilities.
PCT is challenging primarily through task difficulty adaptation to participants’ performance,
targets specific processes, but traditionally implements only a small variability of training
tasks, thus leading to large effects on trained tasks but only very limited transfer on the
cognitive ability level. Limitations of traditional approaches are depicted in italic and bold
letters.
difficult as a thorough description of the training tasks as well as an analysis of the

relation between the training and transfer tasks was often missing (e.g., Shatil, 2013,
and see Lövdén et al., 2013, for the same argument). Finally, the measurement of
neurofunctional and neurostructural outcomes could reveal whether the perfor-
mance improvements in cognitive tests were mediated by the targeted processes.
This field is still in its infancy and does not show consistent patterns which allow
conclusive interpretations (see Buschkuehl et al., 2012, for a review).
Several studies addressed at least some of the mentioned methodological aspects.

While some results suggested cognitive ability enhancement by improvements in
multiple outcomes tapping the same cognitive ability (Smith et al., 2009;
Wolinsky et al., 2013), others did not (Borness et al., 2013; Colom et al., 2010;
Li et al., 2008; Redick et al., 2013; Schneiders et al., 2011, 2012; Stephenson and
Halpern, 2013; Thompson et al., 2013). A similar mixed picture arises from studies
that assessed cognitive tests substantially dissimilar to the training task. While some
studies found positive effects (Brehmer et al., 2011; Jaeggi et al., 2008, 2010;
Karbach and Kray, 2009; Klingberg et al., 2002, 2005; Schweizer et al., 2011,
2013; Zhao et al., 2011), others did not (Ball et al., 2002; Barnes et al., 2013;
Bergman Nutley et al., 2011; Borness et al., 2013; Brehmer et al., 2012;
Buschkuehl et al., 2008; Dahlin et al., 2008b; Jaeggi et al., 2011; Li et al., 2008;
Redick et al., 2013; Thompson et al., 2013).
A study by Schmiedek et al. (2010) used both multiple tests for a single cognitive
ability and outcomes with task characteristics substantially different to the training
tasks. The large sample size even allowed the use of latent difference score models
to extract latent factors representing broad cognitive abilities. Only the lack of an
active control group hindered interpretation of results. The intervention group, in
contrast to a passive control group, engaged in 100 days of processing speed,
episodic memory, and working memory training and showed small improvements
on broad cognitive abilities such as fluid intelligence and episodic memory in youn-
ger adults. In older adults, however, improvements were only found on a latent
factor, which was based on tests with a high overlap of training and test task charac-
teristics. Improvements in latent factors, which were based on dissimilar tests, were
not significant, indicating that in older adults, improvements were limited to task-
specific skills (see Dahlin et al. (2008a) for similar differential age-related transfer
effects). Even a more pessimistic view arises with respect to a recent working memory
training study, which used appropriate control groups, multiple assessments for
each cognitive ability, and cognitive tests dissimilar to the training tasks (Redick
et al., 2013). No differential effect was found as a function of treatment group.
A strategy avoiding the earlier-mentioned methodological problems with regard
to the ability/skill debate is the direct measurement of incidents of dementia. To our
knowledge, only one recent study published results regarding this outcome
(Unverzagt et al., 2012). In this study, which comprised more than 2,800 participants,
none of the three short-term cognitive interventions (including one PCT) were able to
reduce the hazard ratio (HR) for dementia during the 5 years of follow-up, compared
to a passive control group (nonadjusted HR: 0.9; 95% CI: 0.65–1.24 and adjusted
HR: 1.00; 95% CI: 0.71–1.40 of all interventions combined).
2.3 Conclusion
Overall, observational (e.g., Fritsch et al., 2005) and experimental studies (e.g.,
Klusmann et al., 2010) have shown beneficial effects of exposure to novelty on cog-
nitive functions with only a few exceptions (e.g., Boot et al., 2013). In contrast to
3 Rationale and Evidence for Synergistic Approaches 409
PCT, the training tasks applied in novelty interventions have no obvious similarity to
cognitive outcome tests, allowing a straightforward interpretation of results. How-
ever, to our knowledge, no study investigated the effect of novelty interventions
on the incidence of dementia. Furthermore, novelty interventions provided rather
unspecific processing demands, thus not tackling specific processes, which are par-
ticularly prone to deterioration in aging and dementia (see Fig. 1). It seems reason-
able that interventions targeting these specific processes might be more effective.
PCT aims to address this issue by targeting perceptual (e.g., Mahncke et al.,
2006a) and higher-order cognitive abilities such as working memory (e.g.,
Buschkuehl et al., 2008) or task switching (e.g., Karbach and Kray, 2009). Regarding
the efficacy of PCTs, we conclude that several methodological issues leave room for
different interpretations of observed effects (see also Shipstead et al., 2012). There
is abundant evidence that PCTs improve task-specific skills, but most decisively, it
seems that the potential for improvement exists even on the level of broad cognitive
abilities (e.g., Jaeggi et al., 2010; Wolinsky et al., 2013). However, this potential
seems to be exploited only to a very limited degree with current training programs,
especially in older adults (see Fig. 1, Schmiedek et al., 2010, and Dahlin et al.,
2008a). Therefore, new synergistic training approaches are needed, which
enable both the targeting of specific processes shown to deteriorate in aging and
dementia and a generalization to the level of broad cognitive abilities rather than
task-specific skills.
3 RATIONALE AND EVIDENCE FOR SYNERGISTIC APPROACHES

Beneficial effects of traditional interventions such as novelty interventions and PCTs
may be improved by two synergistic approaches: the combination of novelty inter-
ventions with (1) a process-based or (2) a physically demanding element. First, the
process-based novelty interventions aim to overcome limited effects on broad
cognitive abilities while enabling process specificity. Second, the previously dis-
cussed generalization effects of novelty interventions might be enhanced by additive
or synergistic effects of an integrated physical activity component.
3.1 Process-based novelty interventions

In the following, we propose a new cognitive intervention approach, which targets
specific processes while overcoming learning specificity, that is, only cognitive tests
that were similar to the training tasks improved consistently (see Fig. 2). After we
discuss the processes that are worth targeting to delay the onset of dementia, we point
to the overarching phenomenon of learning specificity in various fields of learning.
Furthermore, we present results demonstrating that high task variability counteracted
this phenomenon. The differential neuronal underpinning of learning effects induced
by variable and constant practice protocols will be outlined before we review how the
concept of task variability is implemented in currently used PCTs. Finally, we
FIGURE 2
Process-based novelty interventions. In contrast to previous process-based approaches, the
new approach targets a specific process, for example, executive control, by using a high
variability of training tasks with overlapping processing demands (“overlapping variability”
framework). It thus enables broad transfer on specific cognitive abilities. Strengths of this
synergistic approach are depicted in bold letters.
present the “overlapping variability” framework of effective cognitive interventions

and its implementation in our newly developed process-based novelty intervention
using card and board games.
3.1.1 Tackling specific processes

Executive control (Park et al., 2002) on the behavioral level and the dorsolateral pre-
frontal cortex (dlPFC) on the neuronal level are particularly affected by the aging
process (Raz et al., 2005). Next to memory impairment, decline in executive control
is a core symptom of dementia. In line, synaptic integrity is affected in the frontal
lobe of individuals with high AD pathology (Arnold et al., 2013). Interestingly, dis-
rupted synapse integrity was only found in individuals suffering from dementia
symptoms but not in those with resilient cognition despite high AD pathology
(Arnold et al., 2013). Furthermore, increased neural density and cortical thickness
in the dlPFC seem to mediate the mental activity-induced protective effect on de-
mentia (Valenzuela et al., 2011). Those studies indicate that improving executive
control and its underlying neural substrate can delay the onset of dementia even
in the presence of AD pathology. We want to stress that other processes such as
visual (Unverzagt et al., 2012; Willis et al., 2006; Wolinsky et al., 2013), auditory
(Mahncke et al., 2006a,b; Smith et al., 2009; Zelinski et al., 2011), and memory pro-
cesses (Jennings and Jacoby, 2003; Lustig and Flegal, 2008) might be additional
potential targets for the prevention of dementia.
3.1.2 Overcoming learning specificity

As reviewed in the previous section, PCT not only addressed the issue of process
specificity but also led to learning specificity. This indicated that improvement in
an underlying ability did not or only to a limited extent occur. In line with Green
and Bavelier (2012), we propose an “overlapping variability” framework (see
Fig. 2) to induce changes on the cognitive ability level. According to that framework,
plastic changes can be induced in broad cognitive abilities by variable practice re-
gimes, which overlap in the targeted processing demands while excluding overlap
in demands on lower-order processes. That means that the targeted processing level
on which the different tasks overlap is the one where plastic changes take place but
only if all lower-order processes are varied. The framework that we outline in the
following section can be applied to a wide range of processes including perceptual
and motor processes.
3.1.2.1 Learning specificity as an overarching learning principle

The phenomenon of learning specificity is encountered beyond PCT. Examples
range from auditory learning (Lively et al., 1993), visual learning (Ahissar and
Hochstein, 1997), motor learning (Proteau, 1992), avoidance learning (Adolph,
2000), and knowledge acquisition (Barnett and Ceci, 2002). Interestingly, learning
specificity is so strong that even contextual factors that normally go along with im-
paired cognitive performance, for example, alcohol intoxication, can improve mem-
ory performance, if learning and recall occur in the same intoxicated state (Goodwin
et al., 1969): intoxicated participants who drank 270 ml of 80-proof vodka showed
better performance in recalling items in contrast to sober participants, when both had
learned those in an intoxicated state. Taken together, specific task characteristics,
states, and contexts in which learning occurs have a strong impact on transfer tasks
(see also Green and Bavelier, 2012).
3.1.2.2 Variability of practice enhances generalization

Beginning already in the 1970s, research in motor, verbal, and perceptual learning
revealed that learning specificity can be overcome by using a variable practice pro-
tocol (see Schmidt and Bjork, 1992, for a review). Although variable practice, in con-
trast to constant practice, generally decreased the rate of training task improvements,
it increased performance on transfer tasks.
Regarding perceptual learning, for example, Lively et al. (1993) demonstrated
that Japanese listeners were able to improve in an identification task between the
English consonants /r/ and /1/ presented by a single speaker. However, if an unfamil-
iar speaker presented the words, they performed significantly worse, indicating
learning specificity for the single speaker. In another experiment, words were pre-
sented not by a single but by five different speakers during learning. Participants suc-
cessfully learned to differentiate /r/ and /1/ words. Decisively, if the words were
produced by yet another novel speaker, a decline in identification performance
was not evident at all.
Further evidence for transfer after variable practice comes from observational
studies (Angevaren et al., 2007; Eskes et al., 2010). For example, Eskes et al.
(2010) found that a higher amount of different mental activities, but not a higher
frequency of engagement in activities, was associated with better overall cogni-
tive function. We might speculate that different mental activities have shared pro-
cessing demands, which are improved by these activities and allow transfer to
novel tasks.
What is the differential neuronal underpinning between these specific and gen-
eralizing effects?
3.1.2.3 Neural underpinning of variable and constant practice effects

It is logical that improvement in higher-order processes induces transfer on other
tasks, while improvement in lower-order processes is very specific to the task
(see psycho-anatomy logic, Ahissar and Hochstein, 2004). As variable practice leads
to enhanced transfer of learning, higher-order processes should be responsible.
Decades after the first findings on variable practice effects on transfer tasks
(Schmidt, 1975), neural mechanisms underlying this phenomenon were revealed
(Ahissar and Hochstein, 2004; Kantak et al., 2010). Indeed, results suggest that
plastic brain changes of variable and constant practice occur at different hierarchical
processing levels. Kantak et al. (2010) discovered in a motor learning paradigm
that retention performance after variable practice was affected by repetitive transcra-
nial magnetic stimulation (rTMS)-induced interference in the dlPFC, but not by
rTMS interference in the primary motor cortex. This indicates that effects of variable
practice were attributable to higher-order processing, which are assumed to be de-
pendent on the dlPFC. In contrast, interference in the primary motor cortex was ex-
clusively detrimental for retention performance after constant practice, indicating
reliance on lower-order processes in constant practice learning. This finding fits well
with behavioral and physiological studies in the visual domain, suggesting that initial
training involves high-order brain areas (Ahissar and Hochstein, 1997, 2004); with
increased expertise and task difficulty, neural substrates of learning shift to lower-
order areas, even including the primary visual cortex (Schoups et al., 2001).
Furthermore, we argue that investigations of the neural processing in multilin-
gualism shed some light on the role of task-overlapping higher-order processes as
a function of the variability of practice. Speech acquisition in early and late bilin-
guals might be regarded as a model for variable and constant training regimes, re-
spectively. Technically speaking, early bilinguals were exposed to a variable
training protocol in early childhood, while late bilinguals initially learned only a sin-
gle language (constant practice protocol) before they learned the second language
later in life. According to transfer and higher-order effects of variable practice, early
bilinguals should create an overlapping higher-order processing system for multiple
languages enabling them to integrate and learn novel languages faster. Late bilin-
guals should develop a network that processes language information on a lower
order and should thus not be able to integrate a newly learned language. In fact, a
functional magnetic resonance imaging study demonstrated that early bilinguals
represented both languages in a shared, overlapping brain area (Kim et al., 1997),
while in late bilinguals, the two languages were represented by adjacent but distinct
areas (see also Bloch et al., 2009, for further evidence supporting this notion). Fur-
thermore, the organization of the shared network seemed to facilitate transfer to
novel languages, as it was repeatedly shown that bilinguals learn a novel language
faster than monolinguals (see Cenoz, 2003, for a review). Taken together, variable
practice with shared processing demands seems not only to induce plastic changes in
higher rather than lower processing networks but also to induce task-invariant
higher-order processing capabilities. These processing networks could then be uti-
lized also by subsequent novel tasks. On the behavioral level, this seems to be
reflected by transfer effects on tasks never encountered before. On the other hand,
constant or repeated practice on the same task appears to redistribute the involved
processes from higher- to lower-order networks (e.g., Kantak et al., 2010), thus en-
abling fast learning and highly efficient processing of these tasks but without transfer
to dissimilar ones (Schmidt and Bjork, 1992). What can be deduced from these stud-
ies to the training of executive control?
As mentioned earlier, we conclude that the training of a variety of tasks rather
than the constant practice of a single task yielded better transfer to subsequent
untrained tasks. This seems to be accompanied by higher-order processing networks
able to efficiently process demands of a wide variety of tasks. With regard to exec-
utive control, we propose that training of variable tasks tapping overlapping execu-
tive control processes enhances a shared frontoparietal control network, thus leading
to an improvement even in dissimilar tasks, which tap these task-invariant processing
capabilities (see Duncan, 2010, proposing the existence of such a common fronto-
parietal processing network). On the other hand, repeated practice on a single or a
limited amount of executive control tasks will induce initial plastic changes in
higher-order processes followed by a shift to plastic changes in increasingly
lower-order processing levels. This may be reflected by fast improvements on the
training task but with only very limited transfer to dissimilar tasks.
3.1.3 Variability in process-based cognitive trainings

But how is variability of practice implemented in current training programs targeting
executive control processes? With regard to the phenomena of learning specificity in
repeated practice of the same task, it is astonishing that current PCT studies used
interventions that included only a very limited amount of task paradigms. For exam-
ple, some studies used only a single task paradigm (Jaeggi et al., 2008, 2010;
Schweizer et al., 2011, 2013) or two task paradigms only varying in task content
(Dahlin et al., 2008b). Others used three task paradigms (Buschkuehl et al., 2008;
Olesen et al., 2003; Schmiedek et al., 2010), four task paradigms (Brehmer et al.,
2012; Klingberg et al., 2005), or five task paradigms (Thorell et al., 2009). Further-
more, not only the limited amount of tasks but also the similarity of them may limit
generalization of effects. For example, in the study by Thorell et al. (2009)—which
found strong effects on near-transfer outcomes with mixed effects and generally
smaller effect sizes on far-transfer measures—the training program focused on
visuospatial working memory trained with five different exercises. However, for
all exercises, stimuli were presented with constant presentation times and interstimu-
lus intervals and the participant had to accomplish the same general task, namely, to
remember location and order of the stimuli.
Two studies mentioned explicitly to have used variable tasks to increase general-
ization of the effects (Dahlin et al., 2008a; Karbach and Kray, 2009). Karbach and
Kray (2009) even manipulated variability systematically. Conditions included a
task-switching training with and without task variability. However, Karbach and Kray
(2009) did not induce variability by novel task-switching paradigms but by novel di-
mensions between which participants had to switch. That is, the constant task-
switching group had to switch only between the dimensions “transportation” and
“number,” while the variable training group also needed to switch between several
additional dimensions such as “plant” and “color” or “animal” and “direction.”
The variable training group outperformed the nonvariable conditions in the near-
transfer outcome. In this outcome test, exactly the same task as during the training
sessions was administered but with novel, untrained switching dimensions. There
was no differential group effect between the variable and constant task-switching con-
ditions in far-transfer measures of intelligence, working memory, or interference. We
assume that variability of task paradigms rather than of stimulus dimensions is deci-
sive for far transfer. A rule of thumb may be that the variation level must be equal to
the transfer level. For example, varying speakers in an identification task may induce
transfer on new speakers in this identification task. Varying stimuli dimensions in a
task paradigm may induce transfer on new stimuli dimensions in this paradigm. That
means that a variation in task paradigms within a specific ability is needed to induce a
“farer” transfer on a new paradigm within this specific ability.
A study by Dahlin et al. (2008a) supports this idea: their 5-week training inter-
vention (45 min, three sessions/week) consisted of a single running span paradigm
with five different kinds of stimuli and a keep-track task. A numerical n-back task
and a Stroop task were assessed as a near- and far-transfer measure, respectively.
fMRI served to investigate neuroplastic changes mediating transfer effects. Despite
the fact that the Stroop and the training task activated a shared frontoparietal network
at the baseline assessment, no transfer effect was found. Only the similar near-
transfer n-back task improved as a function of training group. Strikingly, this
near-transfer effect was only evident in young adults, while no improvement was
found in older adults. As a number running span task was part of the training, the
training and the near-transfer task were identical regarding the kind of stimuli used
and differed slightly only by the response format (recalling the last four numbers as
soon as the presentation list ended vs. indicating whether each presented item
matched an item that appeared three items back). The similarity of training and
near-transfer task and the absence of transfer effects to the far-transfer Stroop task
suggest that plastic brain changes occurred at a lower-order level only. Indeed, pre–
post changes in the fMRI revealed a pattern of activation redistribution from higher-
to lower-order brain areas during the training task: while the activation in striatal,
temporal, and occipital areas increased, frontal and parietal activation decreased.
The striatal activation also increased during the near-transfer n-back task and was
interpreted as the mediating area for the transfer effect. Those results allow different
interpretations, but clearly, the higher-order frontoparietal network did not mediate
the near-transfer effects.
Taken together, the variation of stimulus dimensions improved performance on
the near-transfer but not the far-transfer outcome measures, indicating some gener-
alization effect, however only on that level where variation took place. This inter-
pretation is in line with the shift from higher- to lower-order processing in a
training task after 5 weeks of a repeated practice protocol (see Buschkuehl et al.,
2012, for a comprehensive review of training-induced neuronal effects).
In conclusion, repeated practice of a single task leads to a shift from higher-order
to lower-order processing (see Ahissar and Hochstein, 2004, concluding the same in
the perceptual domain), whereas generalization seems to be promoted by high task
variability (see Schmidt and Bjork, 1992, concluding the same for motor and verbal
learning). On that background, it seems surprising that pervious training programs
aiming to improve working memory, shifting, or inhibition applied only a very lim-
ited amount of tasks, which shared most task characteristics. We suggest that enhanc-
ing variability of training tasks (not only of stimuli material but also of task
paradigms) while targeting specific executive control processes enhances generali-
zation on the cognitive ability level (see Fig. 2).
3.1.4 “Overlapping variability” framework

Process-based novelty interventions implement three components necessary to in-
duce far-transfer effects on broad cognitive abilities (see Fig. 2). According to the
framework by Lövdén et al. (2010), a prolonged mismatch between functional sup-
ply and environmental demands is a prerequisite to induce plastic change. This com-
ponent is part of almost all PCTs. In contrast to the common procedure to induce
challenge by difficulty adaptation in repeated tasks, we suggest to use primarily
novel tasks of appropriate difficulty to achieve this aim. This method enables the
application of the “overlapping variability” framework, which comprises the other
two training components of this approach: First, high task variability represents a
prerequisite for generalization and improvements on the ability level (see also
Green and Bavelier, 2012). This component is usually not found in current PCTs,
but implemented in novelty interventions. Second, specific processes should be tar-
geted based on knowledge regarding their neuronal basis and their age- and
dementia-related changes. Novelty interventions are currently not emphasizing this
component, in contrast to PCTs. Hence, the combination of variable tasks with a tar-
geted approach, which makes use of overlapping processing demands of superfi-
cially dissimilar tasks, is the main difference of this new approach from
traditional PCTs and novelty interventions (see Figs. 1 and 2). We want to stress that
the “overlapping variability” framework contrasts with multidomain trainings (see,
e.g., Cheng et al., 2012) as in process-based novelty interventions, only a common
processing demand is targeted and not several independent processes such as epi-
sodic memory, reasoning, and visuospatial ability. Though we focused on executive
control processes, this framework can be applied to several other ones ranging from
perceptual to motor and language processes.
3.1.5 Nourishing intrinsic motivation

As detailed earlier, challenge and task variability seem to be two decisive factors for
healthy brain development and prevention of dementia. Exposure to novelty inher-
ently goes along with both. Interestingly, the same concepts are a key point in
Ryan and Deci’s (2000: p. 70) definition of one of the most influential concepts
in psychology: intrinsic motivation—“the inherent tendency to seek out novelty
and challenges, to extend and exercise one’s capacities, to explore, and to learn [. . .].
From the time of birth, children, in their healthiest states, are active, inquisitive, cu-
rious, and playful.” From an evolutionary perspective, there should be an uncondi-
tional predisposition to strive for factors that increase fitness. Moreover, Ryan and
Deci (2000) not only stressed the natural tendency of humans to strive for challenge
and variability but also proposed its value for cognitive development and psycho-
logical well-being.
Therefore, novelty interventions seem to fit well to nourish intrinsic motivation
by providing an environment which comprises the basic ingredients to elicit feelings
of interest and curiosity. In which way is intrinsic motivation functional for interven-
tions? First, intrinsic motivation determines the environment people choose (guiding
function), allowing long-term adherence to interventions. Second, the motivation-
associated psychological states such as interest and curiosity have been shown to
go hand in hand with the activation of the neuromodulatory control system—a cen-
tral regulatory system for the facilitation of plastic brain changes (plasticity facili-
tation function; see, e.g., Bao et al., 2001, for the role of dopamine). For
example, it has been shown that curiosity is associated with activation of caudate
regions, which are innervated by dopaminergic neurons and part of the neuromodu-
latory control system. Curiosity during learning was associated with improved recall
one to two weeks later, indicating its plasticity facilitating effect (Kang et al., 2009).
3.1.6 Implementation in a novel game-based intervention: Results

from a pilot study
This novel intervention aimed to implement the “overlapping variability” frame-
work, which was embedded in a socially meaningful context. We used card and
board games as the vehicle for the development of variable and challenging tasks
while tapping shared executive control processes based on the unity/diversity frame-
work of Miyake et al. (2000).
After thorough cognitive task analyses, we included a total of 15 games including
self-developed and off-the-shelf games tapping all components of executive control.
While some games stressed a single executive control component, others involved all
components to a similar degree. We selected games with a minimal amount of rules,
allowing for a quick start of the game and restricting the amount of strategies which
can be used to accomplish the task. For optimally nourishing intrinsic motivation, not
only challenge and novelty were provided but also a socially meaningful context,
which allows the fulfillment of the need for relatedness (Ryan and Deci, 2000).
In a single-blinded randomized controlled pilot study, we tested this intervention
to enhance cognitive functions in community-dwelling older adults. Participants
(N ¼ 17) were randomized to a gaming group (n ¼ 9; 7 females; mean age ¼ 70.4)
and a control group (n ¼ 8; 6 females; mean age ¼ 69.8). The groups did not differ
significantly in age, gender, or years of higher education, ps > 0.80. The 5-week
training protocol (three times per week) emphasized variability of practice by play-
ing three games in every 2 h training session. In every other session, two already-
introduced games (30 min each) and one game never played before (1 h) were
applied. That means every game was played not more than three times and 2 h in
total. Overall, participants completed 30 training hours within 15 sessions.
Outcome measures were selected on the basis of the methodological prerequisites
for the assessment of broad abilities rather than task-specific skills (see Section 2.2).
Aiming to assess multiple measures of executive control dissimilar to the training
tasks, three computerized tests assessing inhibition (flanker task, Stahl et al.,
2013), switching (Stahl et al., 2013), and updating (Oberauer et al., 2000) were ap-
plied. Additionally, two complex executive control tests, namely, the Standard Pro-
gressive Matrices (Raven et al., 1990) and the Culture Fair Test 20-R (Weiß, 2006),
were used. The primary outcome operationalizing executive control was calculated
by averaging the standardized single-test scores. Despite the small sample size, linear
mixed effect modeling revealed a marginally significant Group Session interaction
effect, F(1,15) ¼ 4.39, p ¼ 0.054, net effect size, 0.53 SD (see Fig. 3), indicating per-
formance improvement in the intervention group compared to the passive control
group. While the gaming group improved performance in executive control
(0.46 SD, p ¼ 0.04), performance in the passive control group did not change
(0.06 SD; p ¼ 0.70). The use of a passive rather than an active control group limits
the interpretation of effects. Nevertheless, a marginally significant improvement of
the gaming group, in contrast to the control group, in a broad measure of executive
control composed of tests dissimilar to the training tasks was revealed. The result
indicates improvement in executive control, that is, a broad cognitive ability, over-
coming often observed learning specificity.
1.0 Gaming group

Executive control (standardized)
Control group
0.5 *
0.0
−0.5
Pretest Posttest
FIGURE 3
Intervention effect. Change of executive control (standardized) from pre- to posttraining as a
function of intervention group in a pilot study of a process-based novelty intervention using
card and board games. While the waiting-list control group (dark triangles) remained stable,
the intervention group (white squares) significantly improved, resulting in a marginally
significant group time interaction. Arrows represent standard errors. Statistically significant
effects are marked by asterisks: * p < 0.05.
3.2 Physically demanding novelty interventions

In the following, we present a rationale for the combination of novelty interventions
with a physical activity component, which is based on two arguments: First, the
combination might induce multimechanistic effects appropriate for a multicausal
disease such as dementia. Second, both components may interact in a way that
we term “guided plasticity facilitation”. Thus, this extended novelty interventions
might induce additive or synergistic effects by the integration of a physical activity
component.
3.2.1 Tackling multiple mechanisms

Dementia is a multicausal disease (see Olde Rikkert et al., 2006, for a review). For
optimal prevention, it is plausible to tackle different pathological mechanisms by mul-
tiple approaches (Gillette-Guyonnet et al., 2009). Physical and cognitive activities
have shown differential effects on disease progression in animal models (e.g., Wolf
et al., 2006). Furthermore, these multiple pathogenic mechanisms and, hence, the pre-
ventive interventions may be dependent upon person-specific characteristics. Indeed,
there is evidence that cognitive effects of physical, social, or cognitive activity interact
with such characteristics, including genetic polymorphisms such as APOE genotype
(Head et al., 2012; Luck et al., 2013; Niti et al., 2008), brain-derived neurotrophic fac-
tor (BDNF) Val66Met polymorphism (Erickson et al., 2013; Kim et al., 2011) and
dopamine-related genes (Bellander et al., 2011; Brehmer et al., 2009; Pieramico
et al., 2012) as well as baseline levels of growth factors such as VEGF (Voss et al.,
2013), gender (see, e.g., Baker et al., 2010; Kåreholt et al., 2011), or personality traits
such as neuroticism (Wang et al., 2009). If, for example, one population profits most
from physical activity due to a certain BDNF polymorphism (Erickson et al., 2013;
Kim et al., 2011), APOE genotype (Head et al., 2012; Luck et al., 2013; Niti et al.,
2008), or gender (Baker et al., 2010; Kåreholt et al., 2011), a second population profits
most from social activity due to personality traits (see Wang et al., 2009) or gender
(Wang et al., 2013) and a third population benefits most from cognitive activity
due to dopamine-related polymorphisms (Bellander et al., 2011; Brehmer et al.,
2009), the averaged effect across all populations would be best in a combined inter-
vention of all the three types of activity. Such a combination of activity types is given
in certain leisure activities such as dancing or Tai Chi.
3.2.2 Guided plasticity facilitation

In addition to addressing various potential mechanisms by a combination of physical
and cognitive activity, there is increasing evidence that the combination of both ex-
ercise types may have synergistic effects (see Kraft, 2012, for a review). While phys-
ical exercise may “facilitate plasticity,” cognitive activity may “guide” the plastic
changes (see Fig. 4). Exercise-induced plasticity facilitation was shown by enhanced
precursor cell proliferation in the hippocampus (Fabel et al., 2009) and increased
synaptic plasticity such as long-term potentiation (Van Praag et al., 1999). BDNF
FIGURE 4
Guided plasticity facilitation framework.
seems to be one potential mediator of plasticity facilitation effects of exercise as ex-

ercise induces BDNF production (e.g., Neeper et al., 1995; Rasmussen et al., 2009).
BDNF, in turn, is known for its potential to increase synaptic transmission, synaptic
plasticity, and synaptic growth (see Lu et al., 2013, for a recent review). Indeed, the
learning and memory-enhancing effects of exercise were shown to disappear after
blockage of the BDNF-binding receptor TrkB (Vaynman et al., 2004).
Cognitive activity, on the other hand, may “guide” this facilitated plastic poten-
tial by (1) a survival-promoting effect on exercise-induced newborn cells (Fabel
et al., 2009) and (2) the regulation of synaptic change by time-dependent neural ac-
tivity (see Hebb, 1949). For example, Trachtenberg et al. (2002) demonstrated
experience-dependent synaptic plasticity. Experience-induced neural activity seems
to guide elimination and formation of synapses. Neurofunctional plastic changes
were induced after PCT (see Buschkuehl et al., 2012, for a review), which may
be partly attributable to the experience-dependent synaptic turnover. Cognitive
activity-induced plasticity was shown on not only the neurofunctional (see also
Elbert et al., 1995) but also the neurostructural level (see, e.g., Draganski et al.,
2004, 2006; Maguire et al., 2000; Takeuchi et al., 2011; Woollett and Maguire,
2011). Overall, cognitive activity has consistently revealed plasticity-inducing
effects by synaptic change and neurofunctional and neurostructural change.
Kempermann et al. (2010) argued that these “guiding” and “facilitation” effects
of cognitive and physical activity would be beneficial from an evolutionary point of
view given the frequent coincidence of the necessity for learning and physical activ-
ity. For example, acquisition of new spatial representations is inherently bound to
physical activity (disregarding video gaming).
Not only plasticity but also stability of the central nervous system is crucial for its
function (Koleske, 2013). It thus seems apparent that effects of physical activity on
plasticity facilitation would be dysfunctional if they were not restricted to a certain
time frame. In line with this notion, studies repeatedly reported an increase of periph-
eral BDNF during and within one hour after an acute bout of physical exercise fol-
lowed by a reduction below baseline, indicating increased BDNF production and
utilization after exercise (see Knaepen et al., 2010, for a review). Therefore, facilita-
tion of plastic mechanisms, for example, mediated by BDNF, might be most pro-
nounced during or right after physical exercise. Indeed, Winter et al. (2007)
demonstrated in humans that verbal learning and memory were improved after an
acute bout of physical exercise, compared to a period of rest. Performance parameters
of learning and memory were associated with peripheral BDNF and various
catecholamine levels supporting their effect-mediating role. In line with this result,
Roig et al. (2012) found that an acute bout of 20 min intense cycling immediately be-
fore and after a motor task, compared with a period of rest, improved retention of a
learned motor skill 24 h and 7 days after practice. Interestingly, the effect of an acute
bout of exercise after the motor task, in contrast to before practice, had even larger
effect on retention 7 days after motor practice. Taken together, the timing of physical
activity in relation to cognitive activity seems to be crucial in the “guided plasticity
facilitation” framework (see Fig. 4).
3.2.3 Evidence
There is a growing evidence from observational studies indicating that engaging in a
number of different types of activities ranging from cognitive to physical and social
activities is able to reduce cognitive decline (Chan et al., 2005; Lee et al., 2009;
Wang et al., 2013) or dementia incidence (Karp et al., 2006; Paillard-Borg et al.,
2009; Verghese et al., 2003; Wang et al., 2002). Interestingly, beneficial effects
of leisure activity types on cognition follow a dose–response relationship (Wang
et al., 2013). For example, cognition declined over a 2-year period in participants
engaged in low levels in all three activity types, while cognition was stable in par-
ticipants who engaged in high levels in one activity type, and engagement in multiple
activities even predicted cognitive improvement. In this, the different types of activ-
ities had differential effects on several cognitive domains. This result supports the
rationale that multidomain interventions induce multimechanistic effects; thus, they
may be best suited to address a multicausal disease. Karp et al. (2006) demonstrated
that even dementia risk could be reduced by engaging in physical, social, or cognitive
leisure activities and that the strongest effect was present in individuals who engaged
in more than one type of activity. A dose–response pattern of the number of different
activity types—including physical, cognitive, and social activity—for dementia risk
was also found in a study by Paillard-Borg et al. (2009): high engagement in no or
only one type of activity served as the reference group. High engagement in two
types of activities reduced the risk by 34%, and high engagement in all three types
of activities reduced the risk even by 49%. The combination of multiple lifestyle ac-
tivities is decisive for prevention of cognitive decline and dementia and should be
further investigated (see also Lee et al., 2009). One leisure activity that is a good
model for an integrative physical, cognitive, social, and emotional approach is danc-
ing. In an observational study, Kattenstroth et al. (2010) demonstrated that long-time
amateur dancers outperformed age-, education-, and gender-matched controls in re-
action times, motor behavior, and cognitive performance, exhibiting the potential of
this challenging, multicomponent activity.
However, as mentioned earlier, observational studies cannot exclude other inter-
pretations of effects. So what does experimental evidence tell us about the effective-
ness of a combined physical and cognitive approach?
Several interventional studies investigated the effect of combined physical and
cognitive interventions on cognition (Barnes et al., 2013; Fabre et al., 2002;
Legault et al., 2011; Oswald et al., 2006; Shatil, 2013). Apart from the first two studies,
which showed better effects of the combined approach (Fabre et al., 2002; Oswald
et al., 2006), the more recent studies could not show additional or synergistic effects
of the combination of both interventions (Barnes et al., 2013; Legault et al., 2011;
Shatil, 2013). Those studies investigated the effect of combined interventions, but each
component was separated in time from each other. As depicted in the rationale for the
guided plasticity facilitation framework, simultaneous cognitive and physical activi-
ties might be crucial for interaction effects, explaining the negative findings.
Physically demanding novelty interventions provide simultaneous cognitive and
physical activity (see Fig. 5). Indeed, there are several interventional studies which
found beneficial effects on cognition for such a multimodal approach. For example,
consistent and large improvements in cognitive outcomes were found in older adults
allocated to a dancing intervention (Kattenstroth, Kalisch, Holt, Tegenthoff, and
Dinse, 2013), mind–body exercises like Tai Chi (Mortimer et al., 2012), theater play
(Noice and Noice, 2009; Noice et al., 2004), or “exergaming” (Anderson-Hanley
et al., 2012; Maillot et al., 2012), that is, physical exercise carried out in a mentally
stimulating and motivating virtual reality environment. Mixed results, showing im-
provements in some cognitive tests but not others, were found by Pieramico et al.
(2012) for a 1-year multimodal training program consisting of various activities
and by Coubard et al. (2011) for a dancing intervention.
After a 6-month dancing intervention, elderly adults significantly improved in
cognitive outcomes, such as attention and memory functions, compared to partici-
pants of an inactive control group (Kattenstroth, Kalisch, Holt, Tegenthoff, and
Dinse, 2013). Noice et al. (2004) compared the outcome of a 7-session theater course
for healthy older adults not only to the one of an inactive control group but also to an
active visual arts control group. The mentally and physically challenging theater
course resulted in an enhancement in problem solving compared to both control
groups and an improvement in episodic memory when compared to the inactive
FIGURE 5
Physically demanding novelty interventions. Dancing, Tai Chi, cybercycling, and theater arts
depict examples of this combined physical–cognitive approach. In contrast to traditional
novelty interventions, they include physical demands in addition to highly variable, novel tasks
and thus enhance the transfer to unspecific cognitive based abilities.
control group. Similar effects were found for the same intervention with older adults
in retirement homes (Noice and Noice, 2009). Compared to physical training only,
greater improvements were yielded by cybercycling, that is, cycling within a men-
tally challenging virtual reality environment (Anderson-Hanley et al., 2012), and by
Tai Chi (Mortimer et al., 2012).
Finally, there is even initial experimental evidence that long-term Tai Chi train-
ing decreases the incidence of dementia, evaluated with the Clinical Dementia Rat-
ing (Lam et al., 2011, 2012). However, this study had some limitations with respect
to dropout rates, operationalization of dementia incidence, and baseline differences
between groups. Therefore, caution is necessary in the interpretation of results.
To sum up, the evidence for physically demanding novelty interventions such as
dancing, Tai Chi, theater play, or exergaming is promising. To elucidate whether the
combination of activities is decisive, further research is needed comparing physically
demanding novelty interventions with pure physical and novelty interventions. Also,
more research investigating the potential for dementia prevention must follow.
4 CONCLUSIONS
Observational and experimental studies suggest that novelty interventions are effec-
tive behavioral means to delay cognitive decline (e.g., Eskes et al., 2010; Klusmann
et al., 2010) and the onset of dementia (e.g., Fritsch et al., 2005). However, this ap-
proach is rather unspecific, that is, it does not tackle specific processes shown to de-
teriorate in aging and dementia (see Fig. 1). PCT addresses this problem and has
shown transfer effects on untrained cognitive tests. Crucially, however, consistent ef-
fects were only shown for cognitive tests sharing superficial training task character-
istics, suggesting learning specificity with only limited transfer to broad cognitive
abilities (see Fig. 1, e.g., Redick et al., 2013; Barnes et al., 2013). Based on a growing
literature on biological and behavioral effects of variable practice, in contrast to con-
stant practice, we propose in line with Green and Bavelier (2012) that low task var-
iability of currently available PCTs is partly responsible for limited transfer (compare
Figs. 1 and 2). A process-based novelty intervention, using variable card and board
games in a socially meaningful context, addressed this issue and showed initial evi-
dence for an enhancement in the broad cognitive ability of executive control (see
Fig. 3). Furthermore, rather small transfer effects of novelty interventions might be
enhanced by engaging in novel challenging mental activities which also comprise
physical demands such as dancing or Tai Chi (see Fig. 5). A mechanism of action
of this multimodal approach may be guided plasticity facilitation (see Fig. 4).
With respect to current evidence, we suggest four principles that behavioral
interventions for the prevention of dementia should implement:
• Challenge: The training tasks should induce a mismatch of supply and demand
(see Lövdén et al., 2010).
• “Overlapping variability”: The training tasks should have a high task variability
but a low variability in targeted processes. In other words, tasks should overlap in
4 Conclusions 423
the targeted processing demands while relying on a diverse set of nontargeted

lower-order processing demands (see Fig. 2 and Green and Bavelier, 2012).
• Multimodality: The training tasks should implement cognitive and physical
demands (see, e.g., Kempermann et al., 2010; Kraft, 2012) in temporal proximity
(see Roig et al., 2012).
• Meaningfulness: The training tasks and setting should provide elements that
match the human tendency to seek for novelty while fulfilling basic needs of
autonomy, relatedness, and competence (Ryan and Deci, 2000). Thus, an
engaging and personally meaningful environment necessary for long-term
adherence should be provided (see, e.g., Carlson et al., 2008; Park et al., 2007;
Lautenschlager and Cox, 2013).
Novelty interventions are specifically powerful with regard to these four principles
as they induce a mismatch of supply and demand, go along with high variability, and
provoke interest and curiosity, that is, nourish intrinsic motivation (see Fig. 1). For
even more beneficial effects, this approach may be implemented in a process-based
or a physically demanding approach (see Figs. 2 and 5).
According to a recent National Institute of Health consensus and state-of-the-
science statement prepared by independent panels of public representatives and
health professionals, no intervention can be recommended to delay dementia, as
“the evidence is inadequate to conclude that any are effective” (Daviglus et al.,
2010, p. 12). We propose that no single type of activity such as cognitive or physical
activity should be considered as a prevention technique. The focus should rather lie
on a style of activity engagement, a composition of activities, or underlying effective
factors such as novelty, variability, process overlap, and challenge. This is crucial as
activities interact to produce their beneficial effects, which is clearly demonstrated
by variable and constant practice protocols. Therefore, we propose that recommen-
dations for single-activity types are inherently flawed. We come to an alternate con-
clusion for dementia prevention in recommending a lifestyle composed of both
physical demands and novel challenging mental activities integrated in a socially
meaningful context. This conclusion is based on the earlier-mentioned findings of
novelty interventions and on the ratio of their potential costs and benefits: (1) poten-
tial emotional and financial benefits through dementia prevention are high on both a
personal and a societal level, and (2) costs for engagement in such activities are with
exceptions rather low.
For future interventional studies, we suggest that they should assess the most im-
portant outcome of interventions, which is the incidence of dementia. To accomplish
this aim with clinically meaningful results, we are convinced that long-term interven-
tion with high adherence is key (see Unverzagt et al., 2012). Therefore, interventions
should be personally meaningful to participants (see, e.g., Carlson et al., 2008;
Lautenschlager and Cox, 2013) while nourishing intrinsic motivation. Thus, in the
coming years, structured programs for the prevention of dementia might be exper-
imentally validated allowing for widespread public recommendations and imple-
mentation in the health-care system (see Dehnel, 2013).
Acknowledgments
We thank Lisa Dommes for her ideas and her engagement in the development of the game-
based novelty intervention; Julia Günzer, Manuela Rappel, and Sarah Köhler for their contri-
bution in the organization and execution of the earlier-mentioned game-based pilot study;
Andreas Fritz, Johannes Moog, Alexandra König, Friedrich Meixner, Ferdinand Pittino,
and Tanja Dolpp for administering the training sessions; Dana Fischer, Julia Berger, and Susan
Leutloff for their contributions in data collection and data analysis; Lisa Gabriel, Isabell
Ehrmann, Anna Gässler, Christa Selig, and Julia Fischerkeller for selecting the outcome tests
and administering the test sessions; and Florian Schmitz for providing expert advice regarding
the assessment of executive control and for providing the computerized inhibition and swit-
ching tasks. We also thank Steven Jaeger for proofreading and Laura Loy for her ideas and
helpful comments on the chapter.
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CHAPTER
Decoding Speech for

Understanding and
Treating Aphasia
*
17
Brian N. Pasley*,1, Robert T. Knight*,{,{
Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, USA
{
Department of Neurological Surgery, University of California—San Francisco, San Francisco,
CA, USA
{
Department of Psychology, University of California Berkeley, Berkeley, CA, USA
1
Corresponding author: Tel.: þ510-643-9744; Fax: þ510-642-3192,
e-mail address: bpasley@berkeley.edu
Abstract
Aphasia is an acquired language disorder with a diverse set of symptoms that can affect vir-
tually any linguistic modality across both the comprehension and production of spoken lan-
guage. Partial recovery of language function after injury is common but typically
incomplete. Rehabilitation strategies focus on behavioral training to induce plasticity in un-
derlying neural circuits to maximize linguistic recovery. Understanding the different neural
circuits underlying diverse language functions is a key to developing more effective treatment
strategies. This chapter discusses a systems identification analytic approach to the study of
linguistic neural representation. The focus of this framework is a quantitative, model-based
characterization of speech and language neural representations that can be used to decode,
or predict, speech representations from measured brain activity. Recent results of this approach
are discussed in the context of applications to understanding the neural basis of aphasia symp-
toms and the potential to optimize plasticity during the rehabilitation process.
Keywords
aphasia, speech, language, neural encoding, decoding
1 INTRODUCTION
Aphasia is a language disorder resulting from brain damage, often to frontotemporal
cortex, that causes behavioral deficits in the production or comprehension of speech.
Aphasic symptoms affect a diversity of language components, including auditory,
phonological, or lexical function. This diversity represents a challenge for
435
436 CHAPTER 17 Decoding Speech for Understanding and Treating Aphasia
development of effective treatments that must target specific brain circuits underly-
ing the heterogeneity of language abilities.
Treatment of aphasia relies on behavioral interventions that encourage structural
and/or functional brain plasticity for recovery of language ability. The rehabilitation
process may be aided by maximizing neural plasticity in language areas to recover
damaged circuits. Defining the basic neural mechanisms supporting specific lan-
guage functions is an important building block for clinical insights that can help
to identify injured cortical systems and to improve targeted treatments.
2 APHASIA SUBTYPES, SYMPTOMS, AND REHABILITATION

Aphasia is a linguistic disorder and deficits occur in virtually all modalities. For in-
stance, an aphasic patient with inability to speak would also have impaired writing
ability and a patient who cannot comprehend speech would also have deficits in read-
ing capacity. Broca’s aphasia is typically due to damage in the left inferior frontal
gyrus and nearby subcortical structures including the anterior insula. Classic Broca’s
aphasia patients have preserved comprehension and varying degrees of inability to
produce language that are evident in all modalities of language production. Damage
in left posterior temporal lobe including the superior temporal plane, the superior
temporal gyrus (STG), and the middle temporal gyrus results in Wernicke’s aphasia
and problems with speech comprehension. Lesions to the arcuate fasciculus connect-
ing Broca’s and Wernicke’s regions cause problems in repetition of auditory infor-
mation with largely intact production and comprehension of speech. However, it
should be noted that speech output deficits can be observed in posterior temporal
lesions and prominent comprehension deficits can be seen on inferior frontal lesions.
Recovery to some degree is seen in most aphasics. However, patients with exten-
sive recovery of linguistic skills are often left with anomia, which is the inability to
name objects despite knowing what they are and how to use them. Extensive damage
to the left hemisphere perisylvian language cortices including Broca’s and Wer-
nicke’s area causes the devastating syndrome of global aphasia where the patient
cannot speak or understand language. In essence, the global aphasia patient is
completely cut off from linguistic interactions with the world. Age of injury is the
most salient factor in recovery of function. For instance, a 6-year-old with a global
aphasia due to massive perisylvian damage will show massive language improve-
ment and may even look normal at a year postinjury. This recovery is presumed
due to the engagement of the right hemisphere and highlights the remarkable plas-
ticity of the younger brain. Conversely, a 60-year-old with the same extent of injury
and global aphasia will likely remain severely impaired 10–20 years after the injury.
Individual hemispheric organization for language is another critical factor in recov-
ery. Over 95% of males and 90% of females are left hemisphere-dominant for lan-
guage. The remaining right-handed subjects may show bilateral language capacity
and over 30% of left-handed subjects have bilateral language representation. Left-
handed subjects are also more likely to have bilateral speech representation. From
3 A Neural Systems Approach to Language 437
a clinical perspective, patients who have bilateral language representation will have
more rapid recovery from aphasia.
In sum, these observations indicate that the location of brain damage largely de-
termines the type of aphasic symptoms that arise. This is consistent with the view of
the brain’s language system as a modular network, with specific language functions
organized into functionally distinct neural circuits (Friederici, 2011; Hickok and
Poeppel, 2007; Rauschecker and Scott, 2009). However, the complexity and inter-
dependence of language functions, and that of aphasic symptoms, also suggests a
more distributed system where language abilities are supported by multiple, intercon-
nected brain regions (Friederici, 2011; Hickok and Poeppel, 2007; Rauschecker and
Scott, 2009).
To begin to understand the link between brain injury and the variety of aphasic
symptoms, and how function can be recovered through rehabilitation and reorgani-
zation of the underlying circuits, experimental and analytic tools from systems neu-
roscience can be brought to bear. This chapter focuses on a systems identification
approach that, by use of neural encoding and decoding models, characterizes how
neural activity relates to heterogeneous aspects of speech. The advantage of this ap-
proach is it offers a quantitative, model-based description of the speech features
encoded by specific neural circuits, providing insights into the dependence of apha-
sic symptoms on the location of injury and potential treatment avenues.
3 A NEURAL SYSTEMS APPROACH TO LANGUAGE

3.1 Functional Organization of Language
The brain’s language system can be divided broadly into two areas supporting speech
comprehension and speech production. Classically defined as Wernicke’s and Bro-
ca’s areas, as briefly reviewed earlier, damage to these regions can lead to receptive
or expressive aphasic symptoms, respectively. Both speech comprehension and pro-
duction are believed to involve multiple stages of neural representation (Friederici,
2011; Hackett, 2011; Hickok and Poeppel, 2007; Rauschecker and Scott, 2009).
For speech comprehension, t
he brain’s task is to convert “sound to meaning.” The first stages in this process involve
acoustic signal analysis in early auditory cortex. At the highest level of analysis, the
brain computes semantic representations concerned with word meanings. A hierarchy
of cortical areas underlies this complex transformation, which maps incoming low-
level acoustic sounds to intermediate, categorical representations and ultimately to
high-level neural representations of semantic meaning (Friederici, 2011; Hackett,
2011; Hickok and Poeppel, 2007; Rauschecker and Scott, 2009). Anatomically, the
so-called auditory “what” pathway has been reported to extend along an anterolateral
gradient in superior temporal cortex (Rauschecker and Scott, 2009) where stimulus se-
lectivity increases from pure tones in primary auditory cortex to words and sentences in
anterior temporal cortex (Friederici, 2011).
For speech production, articulatory representations are likely coded in the frontal
lobe within motor, premotor, and Broca’s areas (Bouchard et al., 2013; Goense and
Logothetis, 2008; Hickok and Poeppel, 2007; Sahin et al., 2009; Tankus et al., 2013).
At the lowest level, these areas may code the activation of individual muscles within
the vocal tract (Lofqvist, 1999) that control the complex sequence of movements dur-
ing articulation. At a higher level, speech motor control may involve coding of entire
“gestures” or coordinated muscle synergies (Graziano and Aflalo, 2007; Lofqvist,
1999). Higher-level linguistic functions such as lexical, grammatical, and phonolog-
ical information may also be coded in Broca’s area (Sahin et al., 2009).
Within this broad framework, the neural representation of language remains
a difficult experimental question that has resisted precise delineation for over
150 years. Animal models have been widely explored in nonhuman mammals and
avians in the context of lower-level auditory and motor processing (Aertsen and
Johannesma, 1981; De Boer, 1967; deCharms et al., 1998; Depireux et al., 2001;
Georgopoulos et al., 1982; Theunissen et al., 2001; Todorov, 2004). However,
extending these findings to higher-level speech processing in humans has been
impeded because fine-scale, invasive recording opportunities are limited. In general,
this experimental barrier, and the intricacy of human language ability, has made it
difficult to develop effective neural models of language that approach the detail
and predictive accuracy achieved by existing animal models. Speech is unique to
humans, and there are significant specializations that have evolved for speech pro-
cessing in the human brain that cannot be readily studied in animal models.
3.2 Electrocorticography (ECoG)

Recordings in the human brain are generally restricted to noninvasive techniques
such as electroencephalography (EEG), magnetoencephalography (MEG), or func-
tional magnetic resonance imaging (fMRI). These techniques have yielded key in-
sights into large-scale language organization (Formisano et al., 2008; Mitchell
et al., 2008; Schonwiesner and Zatorre, 2009) but have less spatial and temporal res-
olution than traditional invasive microelectrode recordings available in animal
models. In rare cases, direct electrode recordings can also be obtained in human pa-
tients who are undergoing neurosurgical procedures for epilepsy or brain tumor. In
such cases, clinical treatment requires temporary implantation of subdural electrode
arrays onto the cortical surface. These intracranial electrocorticographic (ECoG) re-
cordings represent a unique opportunity to obtain neural recordings from broad areas
of language-related cortex at high spatiotemporal resolution (millimeter and milli-
second scale). The ECoG signal measured by individual electrodes is a neural signal
similar to the cortical local field potential (LFP). In particular, this chapter focuses on
the high-gamma component (70–150 Hz), a population-level signal, which has been
shown, in LFP recordings to correlate with multiunit spike rate of the local neuronal
population (Goense and Logothetis, 2008; Viswanathan and Freeman, 2007). Previ-
ous intracranial studies (Canolty et al., 2007; Crone et al., 2001; Edwards et al., 2009;
Nourski et al., 2009; Pei et al., 2011a,b) have found that speech perception and pro-
duction evoke robust and sustained increases in high-gamma band power in tempo-
ral, frontal, and parietal cortices. This chapter focuses on recent work from
intracranial human recordings that seeks to bridge the gap between detailed animal
models of low-level auditory-motor processing and relatively unexplored models of
intermediate- and higher-level speech processing in humans.
3.3 Neural Encoding and Decoding Models

To study cortical speech representation, an effective analytic approach is the use of
neural encoding predictive models. A neural encoding model characterizes the rela-
tionship between speech function and measured brain activity. It describes the stim-
ulus or behavioral features that account for and accurately predict the neural
response. For example, does neural activity in STG encode acoustic parameters of
speech or does it code entire categories like consonants and vowels? Does Broca’s
area encode muscle movements or higher-level syntactic rules of language? The use
of encoding models to test such hypotheses offers a quantitative answer to how well
observed neural responses are described by each hypothesis (Figs. 1–4).
In this analytic framework, data are assumed to be generated by a black box that
takes as input a set of predictor (independent) variables and outputs a set of response
(dependent) variables. The black box represents nature’s true relationship between
the predictor and response variables, and the goal is to develop statistical models that
emulate nature’s system as closely as possible (Breiman, 2001). Hypothesis testing is
implicit in the ability of the statistical model to predict new data (i.e., emulate na-
ture). Different encoding models encapsulate different hypotheses about speech
function. These hypotheses are tested by comparing the predictive power of the
encoding models, with a “perfect” model yielding perfect predictions. Because pre-
diction is rarely perfect, the model residuals can be examined to identify particular
aspects of the data not accounted for by the model. This in turn provides specific
information to formulate new models and offers a principled and structured approach
to iterative hypothesis testing.
Encoding models characterize the forward transformation from stimulus to re-
sponse. In its basic form, this is a many-to-one transformation that maps multiple
inputs (e.g., stimulus features) onto a single output (e.g., the neural response from
one electrode/sensor). The resulting statistical model describes estimates of neural
tuning—the responsivity of the neural response to different stimulus features. For
example, the spectrotemporal receptive field (STRF) model, ubiquitous in the study
of early auditory cortex (Aertsen and Johannesma, 1981; De Boer, 1967; deCharms
et al., 1998; Depireux et al., 2001; Theunissen et al., 2001), describes the frequency
selectivity of individual neurons, that is, the observation that the responses of single
auditory neurons prefer a narrow range of sound frequencies peaking at low, middle,
or high values in the acoustic spectrum (Figs. 2 and 3).
It is often useful to study stimulus representation encoded by an entire neuro-
nal population, as measured from multiple sensors rather than a single neural
response. A related approach to studying neuronal population responses is the re-
verse transformation, that is, a “decoding” model that maps neural responses
to stimulus. This is a many-to-many mapping that uses the measured neural
FIGURE 1
(A) Example of single-trial ECoG responses in superior temporal gyrus (STG) to four spoken
words. Top panel, spectrogram of four spoken words presented to the subject. Bottom panel,
amplitude envelope of the speech stimuli (green), high-gamma ECoG neural responses at
four different electrodes (gray), and predicted response from the spectrogram model (black).
The ECoG responses are taken from five representative electrodes in STG (shown in yellow
in C). (B) Spectrogram model, represented as h(f,t), where h is the weight matrix as
a function of frequency f and time t. This representation is equivalent to the standard linear
spectrotemporal receptive field (STRF). Positive weights (red) indicate stimulus components
correlated with increased high-gamma activity, negative weights (blue) indicate components
correlated with decreased activity, and nonsignificant weights (green) indicate no
relationship. STRFs for each site in the electrode grid are shown (white curve marks the
sylvian fissure). Anatomical distribution of these sites is shown in (C). Yellow circles indicate
electrodes that are shown in (A).
FIGURE 2
(A) Fitted spectrogram models for 2 STG sites. Right panels; pure-tone frequency
tuning (black curves) matches frequency tuning derived from fitted frequency models
(red curves). Pure tones (375–6000 Hz, logarithmically spaced) were presented for
100 ms at 80 dB. Pure-tone tuning curves were calculated as the amplitudes of the
evoked high-gamma response across tone frequencies. Model-derived tuning curves
were calculated by first setting all inhibitory weights to zero and then summing across the
time dimension (David et al., 2007). At these two sites, frequency tuning is either high-pass
(top) or low-pass (bottom). (Reproduced from Pasley et al., 2012.) (b) Distribution of
sites with significant modulation model predictive accuracy in the temporal, parietal, and
frontal cortex.
responses to predict or decode the stimulus features under study. For example, in
brain–machine interface applications, decoding models have been used to predict
the position of a computer cursor by learning the mapping from a population of
motor neurons to the direction and velocity of the cursor on the screen (Carmena,
2013). Quantifying which stimulus or behavioral features are successfully
decoded or reconstructed from population activity reveals which aspects of the
stimulus are encoded by the neuronal population as a whole.
Neural encoding and decoding models are central to sensory neurophysiology
(Wu et al., 2006) and brain–machine interface (Carmena, 2013). Recent work has
also demonstrated how this approach can be usefully applied to study different as-
pects of speech or language in the human cortex (Brumberg et al., 2010; Tankus
et al., 2013). Multiple levels of speech representation have been successfully
decoded using intracranial neural signals. These include auditory representations
(Guenther et al., 2009; Pasley et al., 2012), consonants and vowels (Pei et al.,
2011a,b; Tankus et al., 2012), and words (Kellis et al., 2010). Later, we will review
a number of these results as applied to three different levels of speech representation:
auditory, phonetic, and articulatory processing.
FIGURE 3
Top panel, spectrogram model. The neural response across time r(t) is modeled as a linear
function h(f,t) of the spectrogram representation of sound S(f,t) where t is time, f is
acoustic frequency, r is high-gamma neural activity, h is the weight matrix (STRF), and S is the
acoustic spectrogram. For a single frequency channel, the instantaneous output may be high
or low and does not directly indicate the modulation rate of the envelope. Bottom panel,
modulation model. The neural response r(t) is modeled as a linear function h(s,r,f,t) of the
modulation representation M(s,r,f,t), where s is spectral modulation (scale) and r is temporal
modulation (rate). The modulation encoding model explicitly estimates the modulation rate
by taking on a constant value for a constant rate (Adelson and Bergen, 1985; Chi et al., 2005).
3.4 Spectrotemporal Encoding in Auditory Cortex

In recent work, we investigated the neural representation of speech by measuring
ECoG responses to natural speech in clinical patients undergoing treatment for
epilepsy (Pasley et al., 2012). We tested the ability of two different auditory
encoding models to explain measured ECoG responses from the STG, a nonprim-
ary auditory area. These models are based on decades of research on the response
properties of neurons in the mammalian auditory system. The emerging frame-
work of early auditory processing consists of two conceptually similar stimulus
transformations (Chi et al., 2005; Dau et al., 1997; Depireux et al., 2001;
Eggermont, 2002; Miller et al., 2002) (Fig. 3). In the first, an auditory filter bank
extracts spectral energy from the one-dimensional sound pressure waveform,
essentially building an auditory spectrogram representation of the sound. The
FIGURE 4
(A) Example stimulus and response predictions from a representative electrode in the STG.
High-gamma field potential responses (gray curve, bottom panel) evoked as the subject
passively listened to a validation set of English sentences (spectrogram, top panel) not used in
model fitting. Neural response predictions are shown for spectrogram (blue) and modulation
models (red). The modulation model provides the highest prediction accuracy (r ¼ 0.44).
(B) Example of fitted encoding models and response prediction procedure at an individual
electrode site (same as in A). Top right panel; spectrogram model. Convolution of the STRF
with the stimulus spectrogram generates a neural response prediction (bottom left panel, blue
curve). Prediction accuracy is assessed by the correlation coefficient between the actual
(bottom left panel, gray curve) and predicted responses. Bottom right panel; an example
modulation energy model in the rate domain (for visualization, the parameters have been
marginalized over frequency and scale axes). The energy model is convolved with the
modulation energy stimulus representation (middle left panel) to generate a predicted neural
response (bottom left panel, red curve). The energy and envelope models capture different
aspects of the stimulus–response relationship and generate different response predictions.
(C) Prediction accuracy of envelope versus modulation energy model across all predictive
sites (n ¼ 199). The modulation energy model has higher prediction accuracy (p < 0.005,
paired t-test).
spectrogram model is based on the spectrotemporal envelope of the speech stim-

ulus. This model assumes that neural responses are a linear function of spectro-
temporal auditory features and are equivalent to the standard STRF (Aertsen and
Johannesma, 1981; De Boer, 1967; deCharms et al., 1998; Depireux et al., 2001;
Theunissen et al., 2001) In the second stage, a modulation-selective filter bank
analyzes the two-dimensional auditory spectrogram and extracts modulation en-
ergy at different temporal rates and spectral scales (Chi et al., 2005). The key
advantage of this representation, referred to here as the “modulation model,” is

that it explicitly represents amplitude envelope modulations that have a funda-
mental relationship with the information-bearing components of speech. This rep-
resentation emphasizes robust features of speech that correspond to, for example,
formants in the spectral axis, syllable rate in the temporal axis, and formant tran-
sitions in the joint spectrotemporal space (Chi et al., 2005). In contrast to fine
spectrotemporal acoustic structure, which may exhibit significant variability un-
der natural conditions, these slow, relatively coarse patterns in modulation space
carry essential phonological information and are correlated with psychophysical
measures of speech intelligibility and are robust under a variety of noise condi-
tions (Chi et al., 1999; Dau et al., 1997; Elliott and Theunissen, 2009).
To investigate the neural representation of speech in STG, we compared the pre-
dictive power of forward encoding models that predicted high-gamma activity from
the auditory stimulus based on either spectrogram or modulation representation
(Fig. 4). Model parameters are fitted directly to cortical responses to natural speech
and predict neural activity to novel stimuli not used in the fitting procedure. The
fitted parameters describe neural tuning to acoustic frequency, spectral modulation
(scale), and temporal modulation (rate).
Across responsive electrodes, predictive power for the modulation model is
slightly better compared to the spectrogram model (Fig. 4). The fitted spectrogram-
based models exhibit a complex tuning pattern with multiple frequency peaks
(Figs. 1 and 4). Linear STRFs of peripheral auditory single neurons exhibit only a sin-
gle “best frequency” (Schreiner et al., 2000), although multipeaked frequency tuning
has been observed in several auditory areas (Kadia and Wang, 2003; Rauschecker
et al., 1997; Sutter and Schreiner, 1991). Multipeaked tuning at surface electrodes
may therefore reflect spatial integration of a range of individual best frequencies in
the underlying neurons or, alternatively, large neuronal populations with higher-order
selectivity for frequency conjunctions.
To quantify how the population of neuronal responses across STG encodes the
spectrogram and modulation speech representations, we also used decoding models
to reconstruct these representations from multielectrode ECoG responses (Bialek
et al., 1991; Mesgarani et al., 2009). We decoded the original stimulus from cortical
activity patterns at multiple electrodes using a regularized linear regression algo-
rithm similar to previous motor brain–machine interface (Carmena et al., 2003) or
sensory experiments (Bialek et al., 1991; Mesgarani et al., 2009). This method
places an upper bound on coding accuracy by quantifying the fidelity with which
specific features are encoded in the cortical population response. Reconstructed
stimuli were compared directly to the original speech representation (Fig. 5).
We found that both the spectrogram-based and modulation-based representations
can be accurately decoded from single-trial brain activity. However, a key differ-
ence is that the modulation-based reconstruction exhibits substantially higher fi-
delity for rapid modulations of the amplitude envelope, while fidelity of the
spectrogram-based reconstruction has a low-pass characteristic (Fig. 5). Rapid
spectral modulations comprising vowel harmonics are clearly isolated by the
FIGURE 5
(A) Top, the spectrogram of four English words presented aurally to the subject. Middle, the
energy-based reconstruction of the same speech segment, which is linearly decoded from a
set of responsive electrodes. Bottom, the envelope-based reconstruction, linearly decoded
from the same set of electrodes. (B) The contours delineate the regions of 80% spectral power
in the original spectrogram (black), energy-based reconstruction (top, red), and envelope-
based reconstruction (bottom, blue). (C) Mean reconstruction accuracy (correlation
coefficient) for the joint spectrotemporal modulation space across all subjects (N ¼ 15).
Energy-based decoding accuracy is significantly higher compared to envelope-based
decoding for temporal rates >2 Hz and spectral scales > 2 cyc/oct (p < 0.05, paired t-tests).
Envelope decoding accuracy is maintained (r 0.3, p < 0.05) for lower rates (<4 Hz rate,
<4 cyc/oct scale), suggesting the possibility of a dual energy and envelope coding scheme
for slower temporal modulations. Shaded gray regions indicate SEM (Pasley et al., 2012).
modulation-based reconstruction but are not fully resolved in the spectrogram-

based reconstruction (Fig. 5). Similarly, the modulation-based reconstruction more
clearly resolves rapid temporal modulations such as those distinguishing syllable
onsets and offsets (Fig. 5). The distinction between spectrogram and modulation
reconstruction is evident when accuracy is assessed component-by-component
across all subjects (Fig. 5). The modulation-based model recovers the full space
of spectrotemporal modulations, while the spectrogram-based model fails to de-
code higher temporal rates (> 4 Hz) and spectral scales (> 2 cyc/oct at rates
>2 Hz) (Fig. 5). The enhanced reconstruction quality in the modulation energy
domain suggests that the energy representation provides a better functional descrip-
tion of the stimulus–response transformation in higher-order auditory cortex.
3.5 Phonetic Encoding in Auditory Cortex

During natural speech, communication requires the extraction of meaning from a
highly variable acoustic signal. Variability in speech sounds arises from many
sources, including differences among speakers (male or female pitch), tempo (slow
vs. fast speaking rates), and dialect (Greenberg, 2006; Greenberg and Ainsworth,
2004). Further variability is introduced by contextual effects (coarticulation) be-
tween adjacent phonemes, the basic units of speech that convey meaning. Consonant
and vowel phonemes may have unique phonetic identities, but individual acoustic
realizations originate from a distribution of speech sounds, the spectral properties
of which may bear little similarity across examples. For instance, in Fig. 6, the vowel
[ux] is spoken twice during the sentence. Acoustically, these two utterances differ in
spectrotemporal content, exhibiting different formant dynamics as a consequence of
the adjacent phones (coarticulation). Utterances from two different speakers would
exhibit even greater spectral differences. Phonetically, however, these two utterances
are considered to represent the identical category (i.e., the vowel [ux]) irrespective of
acoustic differences. This central problem of acoustic variance has led to the sugges-
tion that a precisely accurate representation of the acoustic signal might actually im-
pede intelligibility, particularly in the face of external factors such as background
noise or competing speech (Greenberg, 2006; Greenberg and Ainsworth, 2004).
Given the ease by which humans communicate across diverse and challenging
FIGURE 6
The word and phonetic transcription of a sentence is shown. The vowel [ux] (TIMIT phonetic
alphabet) occurs twice during the sentence. The spectrogram for the two instances differs
as shown. The spectrogram encoding model assumes neural responses are sensitive to
acoustic variation across phone instances. A phonetic model assumes neural responses are
invariant to acoustic variability across phone instances.
environmental conditions, the human auditory system solves the problem of acoustic
variability with remarkable efficiency. How does the human brain build invariant
categorical representations of highly variable acoustic signals in order to extract
meaning? How does brain injury alter this process and lead to language impairments
observed in aphasia?
To investigate phonetic neural representation, we examined the pattern of neural
responses to continuous streams of natural speech, which contain characteristic se-
quences of consonant–vowel (CV) patterns (Greenberg, 2006). In an auditory stream
of speech, words and syllables function as discrete units, yet the sound itself is con-
tinuous. Speech comprehension depends on segmentation cues that allow listeners to
segment continuous speech sounds into meaningful phonetic units, for instance CV
syllables. What do the auditory encoding models described in the previous section
reveal about the neural basis of this segmentation process? To address this question,
we investigated the relationship between patterns of stimulus tuning in the encoding
models and the average cortical response to consonants and vowels embedded in
phonetically transcribed English sentences (Garofolo et al., 1993). First, we found
a number of electrode sites that showed a robust high-gamma response to vowels
compared to consonants (Fig. 7). The distinct spectrotemporal properties of conso-
nants and vowels (Mesgarani and Shamma, 2011; Mesgarani et al., 2008) suggested a
possible basis for this response selectivity. In particular, consonants are transient
sounds with rapid onset/offset, activating high temporal rates (>8 Hz). In contrast,
vowels are characterized by a fast onset of harmonic structure (activating high rates)
that persists at relative steady state for the duration of the vowel, activating interme-
diate rates (2–8 Hz) (Mesgarani and Shamma, 2011; Mesgarani et al., 2008). Nota-
bly, modulation tuning observed across the full electrode ensemble was well
matched to these intermediate rates (2–8 Hz, Fig. 7). This suggests that modulation
tuning might explain the observed sensitivity to consonants versus vowels. To further
examine if neural tuning patterns can account quantitatively for sensitivity to vowels
versus consonants, we used the estimated models to filter a large set of natural speech
stimuli and assessed the average predicted CV response selectivity (David et al.,
2006). For each site, we compared the measured CV response selectivity to that pre-
dicted by the fitted models. The measured high-gamma CV response difference is
strongly correlated with that predicted by estimated modulation models (Fig. 7,
r ¼ 0.77, p < 107). Selectivity for vowellike sounds can therefore be explained in
part by the modulation tuning measured at specific cortical sites. This finding sug-
gests an interesting possibility that vowel-sensitive sites in higher-order auditory cor-
tex may participate in the process of syllable segmentation by detecting the presence
of vowellike structures, which, in many languages, comprise the syllable nucleus
(Greenberg, 2006).
Recent work has also demonstrated that categorical information about CV sylla-
bles can be decoded directly from STG (Chang et al., 2010). Using a classic psycho-
physical paradigm (Liberman et al., 1967), Chang and Rieger et al. (Chang et al.,
2010) measured ECoG activity in the STG during auditory presentation of three
CV syllables, /ba/, /da/, and /ga/. In this paradigm, a series of stimuli are synthesized
FIGURE 7
Vowel-sensitive cortical sites and multisyllable responsivity. (A) The average high-gamma
response difference (vowels, V, minus consonants, C) across all single syllable sites (n ¼ 5).
Gray curves denote SEM over C/V occurrences. (B) The fitted energy models are used to filter
a large set of English sentences and the average predicted response difference for
consonants versus vowels is compared to the measured high-gamma response difference
between the two classes. Across electrodes, the measured high-gamma CV response
difference is highly correlated with that predicted from the energy model (r ¼ 0.77, p < 107).
(C) The average high-gamma response difference (VCV–CCV) across all multisyllable sites
(n ¼ 8). Time from phoneme onset is time-locked to the final vowel in the CCV or VCV
sequence. (D) Left panel; example modulation model in the rate domain at a vowel-sensitive
site. Right panel; average high-gamma response to consonants (C, blue curve) and vowels
(V, red curve) embedded in English sentences. The high-gamma time series was first
normalized by converting to z-scores. Gray curves denote SEM over CV occurrences.
that vary continuously in the starting frequency of the F2 transition (second vocal
tract resonance) such that the listener’s perception varies across three initial conso-
nants from /ba/, to /da/, to /ga/. Although the actual acoustic parameter, the starting
F2 frequency, varies continuously, the perception of the listener is discrete, corre-
sponding to one of the three discrete CV categories. Using this dissociation between
perception and physical stimulus, Chang and Rieger (Chang et al., 2010) identified
neural signals that encoded the categorical perception, as opposed to the continuous
acoustic parameter. A classification algorithm was used to decode CV category from
ECoG signals recorded across STG. The results revealed a distributed representation
FIGURE 8
Distribution of categorical responses to syllable perception in STG (Chang et al., 2010).
Color indicates STG sites that discriminate specific pairs of syllables. Red: discriminates ba
versus da; green: da versus ga; blue: ba versus ga. Mixed colors: electrode discriminates
more than one pair. Phoneme decoding depends on distributed, interwoven networks
with little overlap.
of STG sites that allowed the classifier to accurately decode the subject’s categorical
percept as opposed to the continuous physical stimulus (Fig. 8). The findings reveal
that the use of encoding and decoding models, as described in these examples, can
help identify important stimulus features coded by the neural system and the distri-
bution of cortical sites that support the given function or behavior.
3.6 Articulatory Encoding in Motor Cortex

Encoding and decoding models have also been applied to the neural basis of speech
production. Speech motor control involves steps to select specific articulator mus-
cles, establish the degree of activation in each muscle, and initiate a coordinated ac-
tivation sequence. A central question in motor control is whether neurons in primary
motor cortex represent low-level parameters of movement such as muscle activations
or, alternatively, high-level aspects such as movement goals (Graziano and Aflalo,
2007; Todorov, 2004). This open question, “muscles or movements?,” is important
for investigating the role of motor cortex in speech production. For example, during
the articulation of individual phonemes, a low-level representation would predict to-
pographic cortical activation corresponding to the engaged articulators. A high-level
representation might predict more general building blocks that correspond to groups
of muscles or, at an extreme, distinct neural circuits devoted to articulation of each
phoneme.
For speech production, one possible encoding model is based on the pattern of
muscle activation in a set of speech articulators across time. In this example, we fo-
cus on the major articulators that have robust cortical representations in the motor
homunculus, including the lips, tongue, and larynx. The basic premise of this
articulator-based representation is the observation that different phonemes have dis-
tinct temporal patterns of coordinated articulator movement (Lofqvist, 1999). The
specific temporal sequence for a given utterance is commonly referred to as a “ges-
tural score” (Browman and Goldstein, 1989). Across time, individual articulators be-
come active and inactive in a coordinated fashion to produce specific phonetic
signals. Articulatory phonology makes the key assumption that phonological con-
trast in speech can be defined in terms of different gestural scores. This assumption
is supported by articulatory measurements where, to a large extent, there is a one-to-
one mapping from the physical configuration of the vocal tract’s articulators to the
phoneme (Deng and O’Shaughnessy, 2003). An articulatory-based encoding model
takes advantage of this direct correspondence. Specifically, the model uses one input
feature for each individual articulator, with a simple on/off coding for whether or not
the articulator is active at each time point. This model assumes that motor neural
activity is a linear function of temporal patterns of muscle activation in a set of ar-
ticulators. In a sense, the neural activity serves as a first-order proxy for the under-
lying gestural score, which can then be used to decode individual phonemes.
To determine average gestural scores for individual phonemes, we used the
MOCHA-TIMIT speech corpus (Wrench and Hardcastle, 2000), which includes si-
multaneous acoustic and articulatory measurements obtained from electromagnetic
articulography (Fig. 9). The time-stamped phonetic transcription can be used to de-
rive linear estimates of the various articulator activities during the articulation of
each phone. Figure 9 shows the articulatory impulse response of three different
phones. As expected, the bilabial consonants /b/ and /p/ have similar responses fo-
cused on the upper and lower lips. In contrast, the dental consonant /l/, which is ar-
ticulated with a flat tongue against the alveolar ridge and upper teeth, exhibits a
strong response in the tongue foci.
We next investigated the relationship between motor cortex ECoG activity and
the average gestural scores of speech articulators during phoneme production.
Figure 9 shows, for a single patient, the cortical motor representation of three major
articulators, the lips, tongue, and larynx. These sites are determined by electrical cor-
tical stimulation mapping in which stimulation is applied to evoke movements in or-
der to map out the motor cortex for presurgical evaluation. Figure 9 shows that
individual articulator dynamics are represented in motor cortex ECoG activity as pa-
tients read aloud visually displayed monosyllables, such as /ba/, /pa/, and /la/. Time
zero indicates the acoustic onset of the spoken syllable as determined from the audio
recording. For /ba/ and /pa/, high-gamma activity in the lip electrode (blue curve)
increases prior to acoustic onset, while tongue activity (red curve) is flat. This is qual-
itatively consistent with the gestural score for bilabial consonants. Similarly, for /la/,
activity in the tongue electrode (red) increases prior to acoustic onset, while lip ac-
tivity remains relatively flat. Interestingly, activity in the larynx electrode (green
FIGURE 9
Articulatory-based encoding model. (A) Upper panel, a hypothesized mapping of articulators
to motor cortex. Muscles corresponding to various articulators in the vocal tract likely have
anatomical representations in the motor homunculus. A “gestural score” (Browman and
Goldstein, 1989) describes the temporal sequence of articulator activity during an utterance.
The physical movement illustrated by the gestural score might then be “readout” via neural
activity in the motor cortex. (B) Anatomical sites of three articulators in the motor map for a
representative patient. Sites are determined both by electrical stimulation mapping
performed during presurgical evaluation and by the presence of ECoG activity during
movement of individual articulators. (C) Left panel, high-gamma ECoG activity during the
articulation of three CV monosyllables. Right panel, linear estimates of the articulator
movement response (e.g., “gestural score”) for the same three consonants. The linear
articulator response was derived from electromagnetic articulography measurements
provided by the MOCHA speech corpus. Neural and articulator responses are qualitatively
similar, indicating that motor map neural activity can be used to distinguish individual
phonemes on the basis of articulatory patterns.
curve) is robust and remains elevated for the duration of all three syllables. This is
likely due to the abduction and adduction of the laryngeal muscles during preparation
and maintenance of voicing onset (Hajime, 1999).
To directly evaluate this simple encoding model, the muscle activity of individual
articulators would need to be measured simultaneously with ECoG neural signals, a
difficult experimental setup. Nevertheless, the qualitative comparison offered here
illustrates the general usefulness of an encoding model approach to the neural basis
of speech production. In principle, the predictive power of this first-order articulator
model could be compared directly to alternative encoding models that propose
higher-level movement representations incorporating second- and higher-order in-
teractions between articulators. For example, recent evidence from sensorimotor cor-
tex suggests the existence of a phonetically organized gesture representation during
speech articulation (Bouchard et al., 2013).
4 APPLICATIONS TO APHASIA
A systems identification approach to investigate different representation levels in the
language system provides a principled experimental framework for study of under-
lying neural mechanisms. Encoding and decoding models can be used to identify
speech features or language rules that are represented by distributed neural activity
in language-related cortex. Prediction accuracy of alternative models can be com-
pared to test hypotheses about which representations best explain measured neural
activity.
A better understanding of the neural mechanisms underlying different language
functions will help identify injured neural circuits in aphasic patients and potentially
suggest targeted strategies to induce neural plasticity during rehabilitation. For ex-
ample, recent work (Robson et al., 2013) identified impairments in basic spectrotem-
poral modulation processing of auditory stimuli in Wernicke’s aphasia patients with
lesions to parietal and superior temporal areas. Notably, these same areas, STG and
parietal cortex, have well-defined patterns of modulation tuning, as described earlier
(Fig. 4) and in Pasley et al. (2012). It is possible that disruption to this modulation
tuning underlies the observed auditory impairments. In this case, aphasic symptoms
appear to have a close relationship with the underlying speech representation in the
lesioned cortical areas.
While this example offers a possible functional explanation for specific aphasic
symptoms, a more powerful application of the systems identification approach would
be to directly measure changes in neural representation induced by rehabilitation. For
example, neural encoding models could be estimated continuously during the reha-
bilitation process to characterize changes in modulation tuning induced by treatment
procedures. Lack of change in the underlying neural tuning would indicate an inef-
fective treatment. On the other hand, observed increases to modulation sensitivity
could be used to optimize and guide training-induced plasticity. With accurate
encoding models for each level of cortical speech representation, the same approach
References 453
would be applicable to a variety of aphasic symptoms, such as impairments to pho-

netic, semantic, or articulatory processing.
Although potential clinical insights into aphasia are evident, the use of encoding
and decoding models as a diagnostic or treatment tool has many important experi-
mental challenges that are currently unmet. For example, detailed models of speech
have been estimated primarily using invasive recording methods that are in general
neither available nor appropriate for aphasia patients. Monitoring plasticity in under-
lying neural speech representations using this tool is therefore not currently feasible.
However, recent work demonstrates that detailed encoding and decoding models are
possible with other noninvasive methods including fMRI (Naselaris et al., 2009;
Nishimoto et al., 2011). In the visual system, such models have been extensively ap-
plied to characterize the neural representation of natural images in numerous visual
areas and to decode the visual content of dynamic visual movies (Nishimoto et al.,
2011). This work demonstrates that fMRI has sufficient spatial resolution to provide
detailed characterizations of neural tuning. In the auditory system, fMRI has been
used to detect patterns of frequency and modulation tuning by characterizing tono-
topic maps (Talavage et al., 2004) and modulation sensitivity in different auditory
areas (Schonwiesner and Zatorre, 2009). Models derived from fMRI have also pro-
vided insights into the larger-scale distributed representation of phonemes
(Formisano et al., 2008) and semantic properties of nouns (Mitchell et al., 2008). Im-
portant challenges remain, for example, how to use fMRI, which has a temporal res-
olution on the order of seconds, to capture the rapid temporal dynamics of speech (on
the order of milliseconds). Despite these challenges, ongoing research to improve
temporal resolution in fMRI or to combine it with higher-resolution methods such
as EEG or MEG offers promising avenues for noninvasive application of neural
encoding and decoding models. As these methods improve, opportunities to directly
measure plasticity in aphasia rehabilitation may offer novel insights into effective
treatment strategies.
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Index
Note: Page numbers followed by f indicate figures and t indicate tables.
A articulatory encoding, motor cortex

Action video games (AVGs), 355 ECoG activity, 450–452, 451f
Activities of daily living (ADL), 382–384, 385 MOCHA-TIMIT speech corpus, 450
Adult plasticity muscle activation, 450
vs. developmental plasticity, 77–79, 78f electrocorticography (ECoG), 438–439
MD, 249–250 functional organization of language, 437–438
neuromodulation effects neural encoding and decoding models, 439–441
basal forebrain, 70–74, 72f fitted spectrogram models, 439, 441f
behavioral states, multidimensionality of, hypothesis testing, 439
69–70, 70f sensory neurophysiology and brain–machine
in vitro data, 70 interface, 441
locus coeruleus, 74–75 spectrogram model, 439, 442f
paraventricular and supraoptic nuclei, superior temporal gyrus (STG), single-trial
oxytocinergic system, 76–77 ECoG responses, 439, 440f
raphe nuclei, 75–76 phonetic encoding, auditory cortex
ventral tegmental area, 75 consonant–vowel (CV) patterns, 447
ODP, 249–250 CV response selectivity, 447–449
principles of, 249–250 speech sounds variability, 446–447
PV neurons, 249–250 vowel-sensitive cortical sites and multisyllable
visual cortex (see Visual cortex plasticity) responsivity, 447, 448f
Adult visual cortex. See Visual cortex plasticity word and phonetic transcription, 446–447, 446f
Alpha-amino-3-hydroxy-5-methyl-4-isoxazole spectrotemporal encoding, auditory cortex
propionic acid receptors (AMPARs), ECoG responses, 442–444
244–245, 246–247 modulation model, 442–444
Alzheimer’s disease (AD) stimulus and response predictions, 443f, 444
BrainHQ subtypes, 436
in adult populations, 159 symptoms, 437
altered blood perfusion, 160 Applied behavioral analysis (ABA), 259–260
The Alzheimer’s Prevention Course (TAP), Arm Motor Ability Test (AMAT), 382–384
162–164 ASD. See Autism spectrum disorders (ASD)
ameliorating functional losses, 161–162 Attention-deficit hyperactivity disorder (ADHD),
aural speech/language system, 164–165 357, 360
broad far-transfer effects, 164–165 Autism spectrum disorders (ASD)
growing noise, 160 Asperger’s syndrome, 100–101
neuronal activity levels, 161 behavioral treatments
noradrenaline downregulation, 160 applied behavioral analysis (ABA), 259–260
pathology of, 159–160 Early Start Denver Model (ESDM), 260–261
program module(s), 162 pivotal response treatment (PRT), 260
social cognition and social control, 164–165 cerebellar Purkinje cells, 100
training benefits, 164–165 GABAergic receptors, 97–99
training program for, 162, 163f increased brain volume, 100
visual perception, 164–165 neural response to
clinical manifestation, 102–103 case-study results, 262–263, 263t
Amblyopia, 21–22 ESDM treatment, 263–265
Aphasia intranasal oxytocin, 265–266
age of injury, 436–437 PRT treatment, 262, 264f
applications to, 452–453 state-defined right FG, 263
457
458 Index
Autism spectrum disorders (ASD) (Continued) types of plasticity

parvalbumin (PV)-positive basket cell, 99 experience-dependent plasticity, 39
psychopharmacological treatments experience-expectant plasticity, 39
oxytocin therapy, 261 experience-independent plasticity, 39
risperidone therapy, 261–262 levels of analysis, 38–39, 38t
single gene disorders, 99 unilateral vs. bilateral injury, 52f, 53–54
transcranial magnetic stimulation (TMS), Brain fitness program, 312–313
104–106 BrainHQ
typical and atypical social brain in adult populations, 159
amygdala, 257 altered blood perfusion, 160
fusiform gyrus (FG), 258 The Alzheimer’s Prevention Course (TAP),
hypoactivation, 258–259 162–164
insula activation, 258 ameliorating functional losses, 161–162
mPFC, 258 aural speech/language system, 164–165
neuroimaging studies, 258 broad far-transfer effects, 164–165
superior temporal sulcus (STS), 257 growing noise, 160
ventral medial prefrontal cortex (vmPFC), neuronal activity levels, 161
257–258 noradrenaline downregulation, 160
pathology of, 159–160
program module(s), 162
B social cognition and social control, 164–165
Behavioral therapy, 54–55 training benefits, 164–165
Brain-derived neurotrophic factor (BDNF), 247 training program for, 162, 163f
Brain development visual perception, 164–165
early brain injury Brain plasticity. See also Brain development
age at assessment, 51–52 adolescence and adulthood, 95
age at injury, 48–51, 49f aging, 95–97, 96f
behavior specificity, 51 Alzheimer’s disease, 102–103
recovery of functions, 51 autism spectrum disorders, 97–101
treatments on, 53t characterization of, 92
factors cognitive ability, 96–97, 96f
behavioral therapy, 54–55 cortical structural changes, 95
chemical therapy, 55–56, 55f default mode network (DMN), 93
complex housing, 40–42, 41f HAROLD model, 93
diet, 47–48 molecular mechanisms, 92
frontal cortical injury, effects of, 40, 40t PASA model, 93
gonadal hormones, 46–47 schizophrenia (see Schizophrenia)
hippocampus and frontal cortex, DNA sensory input, 94–95
methylation levels, 41f theta burst stimulation (TBS), 93–94
intestinal flora, 47 transcranial magnetic stimulation (TMS), 93–94
neonatal tactile stimulation, 42f Alzheimer’s disease, 108–110
parent-child relationships, 44 autism spectrum disorders, 104–106
peer relationships, 44 schizophrenia, 106–108
prenatal therapy, 56
psychoactive drugs, 43
sensory and motor experience, 42f, 43 C
stress, 44–46, 45f Chemical therapy, 55–56, 55f
features of, 38 Chronic tinnitus, 284–286
stages of, 36t, 37–38 CI therapy. See Constraint-induced movement
cell migration, 36–37, 37f therapy (CI therapy)
dendrite and axon growth, 37–38 Cognitive processing. See Interference resolution
neural generation, 36–37 Cognitive training
synaptic pruning, 37–38 control group
Index 459
active control group, 124–125 Constraint-Induced Aphasia therapy

rehabilitation-aimed training procedure, (CIAT), 389
125–126 Constraint-induced movement therapy (CI therapy)
single-arm studies, 123 aphasia, 388, 389
within-group control, 123–124 chronic and subacute patients, stroke, 387
working memory, 125 CIAT I protocol, 389
external distractibility, adaptive training, 362–364 components of, 384–386
internal distractions, self-regulation of, 367–369, control procedure, 384
369f efficacy of, 382–384, 383t
multitasking video game, cognitive control EXCITE trial, 386–387
ERSPs, 366 hemiparetic cerebral palsy, 393, 394f
MTT, 365–366 hippocampus, 394–395
NeuroRacer, 364–366, 367f in laboratories, 386–387
STT, 365–366 longitudinal voxel-based morphometry, 393
neural correlates lower extremity, 388
behavioral changes, 129 lower functioning patients, 387
imaging overinterpretation, 129–130 mechanisms
music training, 129 learned nonuse, 389–392
performance gains use-dependent brain reorganization,
analysis of covariance, 128 392–395
ANOVA, 128 multiple sclerosis, 388, 391–392
complex working memory span, 127 rehabilitation
dual-task condition, 127 CNS neuroplasticity, principles for, 395
pre-training scores and higher post-training of paretic arm, 381–382
scores, 126–127 shaping procedure, 384–385
third graders, 127 TP, 384, 385–386
trained task, 126 traumatic brain injury, 387, 388, 391–392
transfer task, 126 at UAB, 382–384, 383t
reverse hierarchy theory (RHT), 122 unilateral forelimb deafferentation, primates,
in untrained conditions 380–381
action video games, 131–132 Cortical plasticity
effect sizes, 130–131 in cortical neural circuits, encoding
musical education, 132 critical periods, 68–69
positive priming cues, 130 excitatory and inhibitory inputs, 67–68
CogPack (Marker Software), 306, 307t in vivo intracellular electrophysiological
CogRehab (Psychological Software Services) recordings, 66–67
cognitive enhancement therapy (CET), 310–311 primary auditory cortex, 67f, 68
language-processing speed, 311–312 synaptic and spiking receptive fields, 67f,
neurocognitive enhancement therapy (NET), 311 68–69
Computerized cognitive training methods, tonotopic map, 67f, 68–69
schizophrenia, 304 neuromodulation effects
brain fitness program, 312–313 basal forebrain, 70–74, 72f
CogPack (Marker Software), 304–307 behavioral states, multidimensionality of,
CogRehab (Psychological Software Services), 69–70, 70f
308–312 in vitro data, 70
comparative effects, 314 locus coeruleus, 74–75
functional magnetic resonance imaging (fMRI) paraventricular and supraoptic nuclei,
(see Functional magnetic resonance imaging oxytocinergic system, 76–77
(fMRI)) raphe nuclei, 75–76
magnetoencephalography (MEG), 316–317 sensory perception, 79–82, 81f
psychophysical findings, 316 ventral tegmental area, 75
serum biomarker and genetic findings, 314–315 rodent auditory perception, 80–81, 81f
voxel-based morphometry, 320 Criterion- Referenced Tests (CRT), 202
460 Index
Critical period plasticity in healthy older adults, 356

binocular interactions, 6 in healthy young adults
controlling onset, 3–5, 4f AVGs, 355
deprived eye axons, 7 distractions and interruptions, 354
excitatory circuit plasticity, 8–9 fMRI functional connectivity, 354
excitatory–inhibitory (E–I), 4 LTM accuracy, 354–355
GABA-synthetic enzyme, 6–7 MMIs, 355
implications passive viewing condition, 353–354
cross-modal plasticity, 20–21 WM accuracy, 354
higher cognition, 21–22 Extremity Constraint-Induced Therapy Evaluation
mental disorders, 20 (EXCITE), 386–387
inhibitory circuit plasticity
cortical inhibitory synapses, 10
deprivation, 10 F ®
loss of activity, 10 Fast Forword software
PV cell pathway, 10–11 behavioral outcome, 192–193
loss of responsiveness, 6 cognitive neurotherapeutics, 203–204
microRNA (miRNAs), 7 first multisite clinical field trial
molecular brakes, 4 2-day, hands-on training workshop, 186–187
PV circuits degree of efficacy, 188, 189f
disynaptic inhibition, 16–17 goals of, 187–188
GABA role, 17 purpose of, 186–187
inhibitory maturation, 17 standardized central auditory processing, 187
LTP protocol, 17 trial-by-trial responses, 186–187
modulation of, 18–20 independent agency
perisomatic inhibition, 16–17 Criterion- Referenced Tests (CRT), 202
tPA elevation, 17 NCII, 201
tPA release, 7 NCRTI, 201–202
triggers and brakes WWC (see What Works Clearinghouse
brain-derived neurotrophic factor, 12 (WWC))
epigenetic regulation, 15–16 intrasyllabic acoustic alterations, 180
inhibitory control of, 11–12 language-learning impairments (LLI), 180–181
myelin and myelin-associated inhibitors, 14–15 neurophysiological and neuroimaging studies
Narp, 14 with autism spectrum disorders (ASD), 195
PNNs and Otx2, 12–14 electroencephalogram (EEG), 195
fMRI, 193–194
D reading series
vs. active control groups, 197–198
Default mode network (DMN), 352–353
cognitive and linguistic skills, 196
in children, 360
GMRT, 197–198
in young adults, 359
K-12 educators, 198–200
Dementia
literacy scores, 197–198
novelty interventions, 405–406
Oral and Written Language Scales (OWLS),
process-based cognitive trainings (see Process-
197–198
based cognitive trainings)
Rutgers summer camps 1994–1995, 184–186
Dorsolateral pre-frontal cortex (DLPFC), 357
school-based randomized control trial
Dynamic attending theory, 215–217
language post-training, 190
low receptive language comprehension test,
E 190
Early Start Denver Model (ESDM), 260–261 at risk students, 189–190
Event-related spectral perturbations (ERSPs), 366 single syllable level, 180
External interference, 352–353 university-based studies, 192–195
in children, 357 verbal training exercises
Index 461
board game, 181–184 L

concentration game, 181–184, 182f Language-learning impairments (LLI), 180–181
CYCLE#, 181–184 Learned nonuse (LNU), 389–392
Fibroblast growth factor-2 (FGF-2), 43 Long-term memory (LTM), 353, 354–355, 356
First multisite clinical field trial
2-day, hands-on training workshop, 186–187
degree of efficacy, 188, 189f M
goals of, 187–188 Magnetoencephalography (MEG), 316–317
purpose of, 186–187 Maternal separation (MS), 45f, 46
standardized central auditory processing, 187 Medial prefrontal cortex (mPFC), 42f, 43
trial-by-trial responses, 186–187 Media-multitasking index (MMI), 355
Functional magnetic resonance imaging (fMRI) Mental disorders, 20
reality monitoring, 318 Metabotropic glutamate receptors (mGluRs),
social cognition, 318–320 244–245
verbal working memory, 317–318 Monocular deprivation (MD), 244–247
Fusiform gyrus (FG), 258 Motor activity log (MAL), 382–384, 383t, 385, 393
Multitasking training (MTT), 365–366
Musical training
G auditory working memory, 219, 220f
Gates MacGinitie Reading Test (GMRT), 197–198 background noise, speech
impaired auditory neural synchrony, 212–214
H speech-in-noise perception, 214, 215f
Hemiparesis, 381–382, 385 cross-sectional studies, 221–224
longitudinal music training studies, 224–225
phonological awareness
I backward masking, 210–211
Imaginal Processes Inventory, 360 frequency representation, 211
Inferior frontal junction (IFJ), 354 neural differentiation of, 212, 213f
Insulin-like growth factor-1 (IGF1), 245–246 neural synchrony hypothesis, 211–212
Interference resolution perceptual judgments, 211
classification of, 352f trial-by-trial neural response, 212, 213f
external interference with random assignment, 226–228
children, 357 rhythm
healthy older adults, 356 beat perception, 214
healthy young adults, 353–355 beat synchronization, 217–218, 218f
internal interference dynamic attending theory, 215–217
children, 360 rhythmic patterns tracking, 215–217
healthy older adults, 359–360 robust neural synchrony, 217–218
healthy young adults, 358–359 temporal regularities, 214
neuroplasticity-targeted interventions temporal sampling hypothesis, 217
(see Neuroplasticity) sound patterns, linguistic regularities, 220–221
Internal interference, 352–353 without random assignment, 225–226
in children, 360
in healthy older adults, 359–360
in healthy young adults
N
National Center on Intensive Intervention (NCII),
DMN activity, 359
201
intrusions, 358
National Center on Response to Intervention
“mind-wandering”, 358–359
(NCRTI), 201–202
pathological failure, 359
NB. See Nucleus basalis (NB)
“stimulus-independent”, 358
Neuromodulation
basal forebrain
K acetylcholine release, 70–71, 74
Kennard Principle, 48 Alzheimer’s disease, 74
462 Index
Neuromodulation (Continued) successive-signal/successive-action signaling,

cholinergic modulation, 73 145
cholinergic neurons, stimulation of, 70–71 top-down biasing, 145
Hebbian plasticity, 71–73, 74 working memory/selective attention, 147
muscarinic receptors, 71, 72f memory and neuromodulatory release, 280–281
nicotinic receptors, 71–73 neurological dysfunction, 276
parvalbumin-positive interneurons, 71–73 neuromodulatory control of, 276–279
piriform cortex, 74 enhancement of, 277–278
somatosensory cortex, 74 during learning and attention, 278–279
synaptic modifications, 72f reduction of, 277
electrophysiological data, 80 social cognition and social control, 150–151
locus coeruleus, 74–75 stimulation
paraventricular and supraoptic nuclei, auditory cortex reorganization, 281
oxytocinergic system, 76–77 cognitive task enhances memory retention, 283
raphe nuclei, 75–76 with forelimb training, 282–283
sensory perception, 79–82, 81f therapeutic programs
ventral tegmental area, 75 BrainHQ (see BrainHQ)
Neuroplasticity common training targets, 152
behaviors, 142–143 document training gains, 152
feedback connections embedded assessments, 153–154
coordinated actions, 144 internet delivery platform, 154
Hebbian network, 144 neurological distortions, 153
RHT, 143 performance abilities measure, 151–152
selective attention process, 143 performance feedback, 151
interference resolution playability and efficacy evaluation, 154–155
adaptive training, external distractibility, practice repetition, 151
362–364 social cognition (see Social cognition (SC))
multitasking video game, cognitive control, specific patient-population demographics, 153
364–367, 365f, 367f staged progressions, tasks difficulty, 151
performance-adaptive modulations, task sustained close attention, 151
challenge, 361–362 NeuroRacer, 364–366, 365f, 367f
performance feedback, 361–362 N-methyl-D-aspartate receptors (NMDARs),
self-regulation, internal distractions, 367–369, 244–245, 248–249
369f Nonspatial deficits
language development and disorders behavioral treatments, 338–341
acoustic information, 177–178 AIXTENT, 339
aural language, 176–177 TAPAT, 339–340
® ®
Fast Forword software (see Fast Forword tonic and phasic alertness, 338–339
software) in neglect
individual differences, 179–180 alertness, 332
inter-stimulus-interval (ISI), 178–179 attentional capacity, 333, 335
phonological awareness, 177 attention deficit hyperactivity disorder
rapid auditory processing (RAP), 178–179 (ADHD), 334–335
written language, 176–177 norepinephrine, 334
learning steps right inferior frontoparietal region, 334
acetylcholine release, 146 selective attention/attention to transient events,
aged vs. young Norway rat brain, 148, 149f 333
dopamine, 146 spatial working memory, 333
external and internal noise, 147 sustained attention, 332
focused attention, 147 treatments for, 335–336
impaired modulatory control processes, 147 pharmacological interventions, 337–338
noradrenaline, 146 Nucleus basalis (NB)
physical and functional properties, 149–150 acetylcholine release, 70–71, 74
Index 463
behavioral performance, 81f practice enhances generalization, 411–412

muscarinic receptor-dependent decorrelation, tackling specific processes, 410
73–74 variability in, 413–415
spiking and bursting activity, 70–71 Protein kinase A (PKA), 245
synaptic modifications, 72f Psychoactive drugs, 43
O R
Ocular dominance plasticity (ODP), 244–246, 247, Rapid auditory processing (RAP), 178–179
249–250 Rehabilitation, 381–382
Orbital prefrontal cortex (OFC), 42f, 43 CNS neuroplasticity to, 395
Oxytocinergic system, 76–77 of paretic arm, 381–382
Oxytocin therapy, 261 shaping procedure, 384–385
Reverse hierarchy theory (RHT), 122, 143
P Risperidone therapy, 261–262
Robust neural synchrony, 217–218
Parvalbumin (PV), 247, 249–250
Phonetic encoding, auditory cortex
consonant–vowel (CV) patterns, 447 S
CV response selectivity, 447–449 SC. See Social cognition (SC)
speech sounds variability, 446–447 Schizophrenia, 101–102
vowel-sensitive cortical sites and multisyllable computerized cognitive training methods, 304
responsivity, 447, 448f brain fitness program, 312–313
word and phonetic transcription, 446–447, 446f CogPack (Marker Software), 304–307
Phonological awareness CogRehab (Psychological Software Services),
backward masking, 210–211 308–312
frequency representation, 211 comparative effects, 314
neural differentiation of, 212, 213f functional magnetic resonance imaging (fMRI)
neural synchrony hypothesis, 211–212 (see Functional magnetic resonance imaging
perceptual judgments, 211 (fMRI))
trial-by-trial neural response, 212, 213f magnetoencephalography (MEG), 316–317
Pivotal response treatment (PRT), 260 psychophysical findings, 316
Prenatal stress (PS), 45f, 46 serum biomarker and genetic findings, 314–315
Prenatal therapy, 56 voxel-based morphometry, 320
Presbycusis, 80 dementia praecox, 303
Primary auditory cortex genes involved, 304
excitatory and inhibitory synaptic tuning curves, neurocognitive impairments in, 302–303
67f neurodevelopmental model of, 301–302, 302f
spiking tuning profile, 67f, 68 Sensory cortex, adult plasticity. See Adult plasticity
tonotopic map, 67f, 68–69 Signal Transducers and Activators of Transcription
Process-based cognitive trainings (STAT1) family, 246–247
neurofunctional and neurostructural outcomes Single-task training (STT), 365–366
measurement, 406–407 Social cognition (SC)
physically demanding novelty interventions anatomical and functional abnormalities, 156
evidence, 420–422 behavioral and neurological abnormalities, 156
guided plasticity facilitation, 418–420 definition, 155–156
tackling multiple mechanisms, 418 in schizophrenia, 156, 157
for synergistic approaches Socialville delivery strategies, 157–159
implementation in, 416–417 Somatosensory cortex, 68, 74, 79
intrinsic motivation, 415–416 Spatial attention
learning specificity, 411 hemispheric asymmetry, 337
neural underpinning of, 412–413 in neglect
overcoming learning specificity, 410–413 allocentric, 328
overlapping variability framework, 415 feature integration, 330–331
464 Index
Spatial attention (Continued) stimulation, cognitive task enhances memory

hemispheric rivalry and synchrony, 329 retention, 283
hyperattention/increased salience detection, stimulation, with forelimb training, 282–283
330 for seizure suppression, 289–290
left hemisphere lesions, 328–329 stroke, 286–287
right hemisphere, attention, 329–330 Ventral medial prefrontal cortex (vmPFC), 257–258
spontaneous orienting and motor initiation, 328 Visual cortex plasticity
prism adaptation training, 336 ACh, 248–249
visual scanning training, 336 cholinergic activation, 248
Spectrotemporal encoding, auditory cortex development
ECoG responses, 442–444 AMPARs, 244–245, 246–247
modulation model, 442–444 BDNF, 247
stimulus and response predictions, 443f, 444 CRE-mediated gene expression, 245, 245f
Stress ERK, 245
gestational stress, 46 excitatory synapse, 245f
maternal separation, 45f, 46 gene expression analysis, 245–246
prenatal stress, 45f, 46 glutamate receptors, 244–245
Stroke, 286–287 IGF1, 245–246
Superior temporal sulcus (STS), 257 inhibitory synapse, 245f
mGluRs, 244–245
T monocular deprivation, 244, 245–246
Temporal sampling hypothesis, 217 nicotinic acetylcholine receptor, 247
Theta burst stimulation (TBS), 93–94 NMDARs, 244–245
Transcranial magnetic stimulation (TMS), 354 NR2A/NR2B ratio, 244–245
Alzheimer’s disease, 108–110 ocular dominance plasticity, 244–245, 246, 247
autism spectrum disorders, 104–106 parvalbumin, 247
schizophrenia, 106–108 PKA, 245
Transfer package (TP), 382, 384, 385–387, 393 STAT1, 246–247
Tumor necrosis factor alpha (TNF-a), 246–247 TNF-a, 246–247
electrical stimulation and visual stimulation,
U 247–248
glutamatergic synapses, 245f, 250
University of Alabama at Birmingham (UAB),
M1 muscarinic receptors, 248–249
382–384
orientation tuning curves, 247–248
reinforcement learning, 249
V Voxel-based morphometry, 320
Vagus nerve stimulation (VNS)
antiepileptic effects, 289–290
cellular-and circuit-level changes, 289 W
chronic tinnitus, 284–286 What Works Clearinghouse (WWC)
cognitive dysfunction, 287 adolescent literacy effectiveness rating grades,
mechanisms of 202–203
brain-derived neurotrophic factor (BDNF), 288 English language development K-6, 203
cholinergic antagonists, 287–288 Wolf Motor Function Test (WMFT),
neural plasticity 381–384, 385
memory and neuromodulatory release, Working memory (WM), 353, 362, 364
280–281 children, 357
neurological dysfunction, 276 internal distractions, 358–359
neuromodulatory control of, 276–279 older adults, 356
stimulation, auditory cortex reorganization, 281 young adults, 354
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In other studies conducted by physiological psychologists in the same era, re-

Fourth, scientists began to document the neurological bases of the modulation of

(1) Excitatory–inhibitory (E–I) circuit balance is a trigger. The classical

is intrinsically plastic, and one of the outcomes of normal development is then to

2 CRITICAL PERIODS: PRUNING CIRCUITS

3 CRITICAL PERIOD PLASTICITY OF EXCITATORY

3.1 Excitatory Circuit Plasticity During Critical Periods

3.2 Inhibitory Circuit Plasticity During Critical Periods

4 CRITICAL PERIOD TRIGGERS AND BRAKES

Only a1-containing GABAA receptors, which are preferentially expressed and

4.2 Brain-derived neurotrophic factor

4.3 Extracellular Matrix: PNNs and Otx2

lattice-like structures surround cell bodies and proximal neurites, preferentially

4.5 Myelin and Myelin-Associated Inhibitors

4.6 Epigenetic Regulation

catalyzed by DNA methyltransferases. DNA methylation represses transcription

5 CRITICAL PERIOD GATING

5.2 Modulation of PV Circuits

also identified the nicotinic acetylcholine receptor (nAChR) as a regulator of cortical

Similar to cholinergic enhancement, SSRIs may act to promote plasticity by reduc-

6.2 Cross-Modal Plasticity

6.3 Higher Cognition

to early exposure to drugs, adversity, sleep, or genetic perturbation predicts that

Insel, T.R., 2010. Rethinking schizophrenia. Nature 468 (7321), 187–193.

DNA demethylation mediates gene-childhood trauma interactions. Nat. Neurosci. 16,

Brain Plasticity in the

Bryan Kolb1, Richelle Mychasiuk, Arif Muhammad, Robbin Gibb

2 STAGES OF BRAIN DEVELOPMENT

Table 1 Stages of brain development

3 GENERAL TYPES OF BRAIN PLASTICITY

Table 2 Levels of analysis of plasticity

imaging is appropriate to study experience-dependent changes in humans but is far

Table 3 Summary of the effects of frontal cortical injury at different ages

4 FACTORS INFLUENCING BRAIN DEVELOPMENT IN THE

4.1 Complex housing

4.2 Sensory and motor experience

4.3 Psychoactive drugs

4.4 Parent–child relationships

4.5 Peer relationships

4.7 Gonadal hormones

4.8 Intestinal flora

5 BRAIN DEVELOPMENT AFTER EARLY BRAIN INJURY

5.1 Age at injury

5.2 Behavior specificity

5.3 Age at assessment

6 UNILATERAL VERSUS BILATERAL INJURY

The extreme form of a unilateral lesion is hemidecortication or hemispherec-

7 FACTORS INFLUENCING BRAIN DEVELOPMENT IN THE

7.1 Behavioral therapy

abilities of tactile stimulation (Gibb, 2004). We note parenthetically that complex

7.2 Chemical therapy

7.3 Prenatal therapy

Hebb, D.O., 1945. Organization of behavior. McGraw-Hill, New York, NY.

Progress in Brain Research, Volume 207, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63327-9.00003-5

2 ENCODING SENSORY ENVIRONMENTS IN CORTICAL NEURAL