Brian Levine - Mind and The Frontal Lobes (2011) (A) PDF

Mind and
the Frontal Lobes

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Mind and
the Frontal Lobes
COG NITION, BE HAVIOR , A ND BRAI N I MAGI NG
EDITED BY
BRIAN LEVINE AND FERGUS I.M. CRAIK
1
1
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Library of Congress Cataloging-in-Publication Data
Mind and the frontal lobes : cognition, behavior, and brain imaging / edited
by Brian Levine and Fergus I.M. Craik.
p. cm.
Includes bibliographical references and index.
ISBN 978-0-19-979156-9 (hardback)
1. Frontal lobes. 2. Frontal lobes—Pathophysiology. I. Levine, Brian,
1963- II. Craik, Fergus I. M.
QP382.F7M56 2011
612.8′2—dc23 2011022189
______________________________________________
987654321
Printed in the United States of America on acid-free paper
For my mother
- BL
In June 2009, 350 attendees gathered for two days at an international conference
to celebrate the career and achievements of Donald T. Stuss, a neuropsychologist
and pioneering researcher on human frontal lobe function. The conference fea-
tured some of the world’s leading researchers on cognitive aging, dementia, brain
injury, functional neuroimaging, memory, rehabilitation, and consciousness. This
volume, a result of the conference, is dedicated to Don with our gratitude, respect,
and affection.
Thanks to Baycrest Centre, Joseph L. Rotman, the Canadian Institutes of Health

Research, and the Departments of Psychology and Medicine (Neurology),
University of Toronto for supporting the conference that resulted in this volume.
Paula Ferreira, Jean Lazarus and the Baycrest Research Division administrative
team are thanked for operational support. Terry Picton is thanked for suggesting
the cover design.
Contents
Contributors xi
1. Unifying Clinical, Experimental, and Neuroimaging Studies

of the Human Frontal Lobes 3
brian levine and fergus i. m. craik
2. Confabulation 16
m i c h a e l p. a l e x a n d e r
3. Reflections on ROBBIA 33
tim shallice
4. Rostral Prefrontal Cortex: What Neuroimaging

Can Learn from Human Neuropsychology 47
pa u l w. b u r g e s s , g i l g o n e n - ya a c o v i , a n d e m m a n u e l l e v o l l e
5. Combining the Insights Derived from Lesion

and fMRI Studies to Understand the
Function of Prefrontal Cortex 93
m a r k d ’ e s p o s i t o a n d dav i d b a d r e
6. Dynamic Communication and Connectivity in

Frontal Networks 109
b r a d l e y v o y t e k a n d r o b e r t t. k n i g h t
7. The Frontal Lobes and Mental State Attribution 123

r . s h ay n a r o s e n b a u m a n d j e n n i f e r s . r a b i n
ix
x Co ntents
8. Monitoring and Alerting: Two Forests Among the Trees 152

ian h. robertson
9. Cognitive Rehabilitation in Old Age: The Rotman Initiative 164

gordon winocur
10. Effects of Aging on Memory and Attention: A Frontal

Lobe Problem? 183
fergus i. m. craik
11. The Aging Brain: An Alternate Perspective

on Age-Related Changes 198
e l i z a b e t h c . l e r i t z , r e g i n a e . m c g l i n c h e y, dav i d h . s a l at,
a n d w i l l i a m p. m i l b e r g
12. Structural Brain Imaging and Cognitive Aging 214

joel ramirez and sandra e. black
13. The Effects of Focal and Diffuse Brain Injury on Behavior:

Assessing “A Slice of Life” with Neuropsychology
and Multimodal Neuroimaging 235
brian levine
14. Does the Future Exist? 248

e n d e l t u lv i n g a n d k a r l k . s z p u n a r
15. The Necessary Narrative 264

t e r e n c e w. p i c t o n
Index 279
Contributors
Michael P. Alexander Gil Gonen-Yaacovi

Harvard Medical School Institute of Cognitive Neuroscience
Beth Israel Deaconess Medical Center University College London
Boston, Massachusetts London, UK
David Badre Robert T. Knight

Brown University University of California, Berkeley
Providence, Rhode Island Department of Psychology &
Helen Wills Neuroscience Institute
Sandra E. Black Berkeley, California
Cognitive Neurology Research Unit
Sunnybrook Health Sciences Centre Elizabeth C. Leritz
Toronto, Ontario, Canada Geriatric Research, Education and
Clinical Center (GRECC)
Paul W. Burgess VA Boston Healthcare System;
Institute of Cognitive Neuroscience Division of Aging,
University College London Brigham & Women’s Hospital;
London, UK Harvard Medical School;
Boston, Massachusetts
Fergus I.M. Craik
Rotman Research Institute at Baycrest Brian Levine
University of Toronto Rotman Research Institute at Baycrest
Toronto, Ontario, Canada University of Toronto
Toronto, Ontario, Canada
Mark D’Esposito
Helen Wills Neuroscience Institute
University of California, Berkeley
Berkeley, California
xi
xii Co ntri b uto rs
Regina E. McGlinchey David H. Salat

Geriatric Research, Education and Neuroimaging Research for Veterans
Clinical Center (GRECC); Center (NeRVe)
VA Boston Healthcare System; VA Boston Healthcare System;
Department of Psychiatry Athinoula A. Martinos Center for
Harvard Medical School Biomedical Imaging;
Boston, Massachusetts Massachusetts General Hospital;
Harvard Medical School
William P. Milberg Boston, Massachusetts
Geriatric Research, Education and
Clinical Center (GRECC); Tim Shallice
VA Boston Healthcare System; Institute of Cognitive Neusocience
Department of Psychiatry University College London;
Harvard Medical School London, UK
Boston, Massachusetts SISSA, Trieste, Italy
Terence W. Picton Karl K. Spunzar

University of Toronto Rotman Research Institute at
Toronto, Ontario, Canada Baycrest Centre
University of Toronto
Jennifer S. Rabin Toronto, Ontario, Canada
York University
Rotman Research Institute Endel Tulving
at Baycrest Rotman Research Institute at
Toronto, Ontario, Canada Baycrest Centre
University of Toronto
Joel Ramirez Toronto, Ontario, Canada
Cognitive Neurology Research Unit
Sunnybrook Health Sciences Centre Emmanuelle Volle
Toronto, Ontario, Canada INSERM
Paris, France
Ian H. Robertson
Institute of Neuroscience and Bradley Voytek
School of Psychology University of California, Berkeley
Trinity College Helen Wills Neuroscience Institute
Dublin, Ireland Berkeley, California
R. Shayna Rosenbaum Gordon Winocur

York University Rotman Research Institute at Baycrest
Rotman Research Institute at Baycrest University of Toronto
Toronto, Ontario, Canada Toronto, Ontario, Canada
Mind and
the Frontal Lobes
1
Unifying Clinical, Experimental, and
Neuroimaging Studies of the
Human Frontal Lobes
BRIAN LEVINE AND FERGUS I. M. CRAIK
The frontal lobes mediate the most advanced forms of human behavior. They
include the main preparatory and effector mechanisms for intentional motor
behavior, including limb movements, eye movements, and speech movements.
Frontal lobe regions are crucial to numerous mnemonic operations, including
the online maintenance and manipulation of information, allowing humans to
“transcend the default mode” of instinctual stimulus–response relationships
(Goldman-Rakic, 1987; Mesulam, 2002), and the organization of information for
encoding and retrieval in long-term memory (Fletcher & Henson, 2001; Wheeler,
Stuss, & Tulving, 1997). They are involved in the determination of abstract rela-
tionships and mental flexibility (Dias, Robbins, & Roberts, 1996; Milner, 1963).
They enable selection, maintenance, and consistency of attention (Stuss &
Alexander, 2007). The ventral and medial frontal sectors are heavily intercon-
nected with the limbic system (Barbas, 1995) and therefore important to emo-
tional processing (Eslinger & Damasio, 1985; Rolls, 2000). Recent research has
pointed to the involvement of the frontal lobes in social cognition (Iacoboni &
Dapretto, 2006) and future-oriented thought (Schacter, Addis, & Buckner, 2007).
Given the key role of the frontal lobes in so many human information-
processing operations, it is not surprising that they are also implicated in practi-
cally every major neurological and psychiatric disorder, the most prevalent being
traumatic brain injury (Stuss & Gow, 1992), dementia (Neary et al., 1998), schizo-
phrenia (Cohen & Servan-Schreiber, 1993), and depression (Mayberg et al., 1999).
They are also central to theories of development in both children (Bunge & Wright,
2007) and older adults (Craik & Grady, 2002).
With over 10,000 citations and an h-index of 54, Don Stuss is arguably the
world’s leading authority on the frontal lobes. In June 2009, 350 scientists and
3
4 MI ND A ND THE FR ON TAL LOBE S
clinicians gathered in Toronto to hear 15 leading researchers in the area of frontal

lobe function, and to celebrate Don’s career and achievements. This introduction
to the volume that arose from this conference provides a brief historical context
to the chapters that follow, with an emphasis on how Don’s research has bridged
time periods, concepts, and methods.
Historical Overview
For our purposes, research on frontal lobe function can be divided into three
broad eras. The first, from the mid-19th to the mid-20th century, was character-
ized by clinical case studies and qualitative observations of animals with experi-
mental frontal lesions. The second era consisted of more organized experimental
group studies of animals and humans with frontal lobe lesions. The third and cur-
rent era, the onset of which coincides with the publication of Stuss and Benson’s
The Frontal Lobes (1986) (see also Stuss & Benson, 1984), is characterized by a
proliferation of detailed anatomical research using multimodal imaging and
sophisticated cognitive science paradigms.
THE FIRST ERA

The case of Phineas Gage (Harlow, 1868), while not the first description of frontal
lobe syndrome (de Nobele, 1835), was seminal because of Harlow’s cogent descrip-
tion of Gage’s personality syndrome: he was “no longer Gage” despite retaining
intact basic perceptual, mnemonic, and motor functions. (For limitations of the
“standard” interpretation of Gage’s history, see Macmillan, 2000.) Other human
lesion studies of the mid- to late 19th century concerned emotional and personal-
ity changes (Jastrowitz, 1888; Oppenheim, 1890; Welt, 1888). Corresponding
deficits were described in experimental lesion studies of animals in this same time
period (Bianchi, 1895; Ferrier, 1886). Interestingly, as in the human case studies,
constructs of “character” and “personality” were invoked to describe behavioral
changes that could not easily be described in objective terminology in use at that
time, although notions of apathy, disinhibition, and social changes foreshadowed
concepts that were operationalized in modern studies. As a result of the numer-
ous localized brain lesions resulting from injuries in World War I, early-20th-
century researchers were able to verify and, to some extent, localize the previous
findings in larger case series of patients (Ackerly, 1937; Feuchtwanger, 1923;
Goldstein, 1944; Kleist, 1934). (For a more comprehensive review of the early
history of frontal lobe function, see Benton, 1991.)
These reports notwithstanding, a predominant view throughout much of
the 20th century was that the frontal lobes are “silent” with respect to damage
effects, a carryover from Flourens’s mass-action model. This view, which likely
contributed to the rise of psychosurgical interventions for psychiatric disorders
U nifying Cl inical , E xper imental , an d N e u roim ag in g S t u die s 5
(Benton, 1991), was most explicitly advanced by Hebb (1945). Even now, it is not
unusual to encounter unenlightened clinicians who regard significant frontal lobe
lesions as inconsequential. Historically, the primary counterargument to the
“silent” point of view (in addition to the case of Phineas Gage) was the localization
of expressive speech to the left inferior frontal gyrus by Broca (complemented by
the contemporaneous extra-frontal localizations by Wernicke and Leipmann).
These findings were accompanied by the increased reliability of gross anatomical
maps, then by cytoarchitectonic maps, and finally by evidence of specific frontal
connectivity to extra-frontal cortical regions as well as to the limbic system, the
thalamus, the striatum, and the cerebellum.
THE SECOND ERA

These developments paved the way for lesion mapping studies that characterized
the second era of research on frontal lobe functions, especially in non-human
primates. Jacobsen’s (1936) studies of deficits on the delayed response task in
monkeys with frontal lobe lesions had already provided the first systematic
description of deficits on an objective cognitive task. Jacobsen was the first to
combine psychological dissociation (e.g., “memory” vs. visual discrimination)
with anatomical dissociation (bifrontal vs. posterior lesions). Although the rela-
tive roles of mnemonic and non-mnemonic processes on delay tasks are actually
still a matter of investigation, Jacobsen’s basic paradigm whereby “the differential
cues must be supplied by the subject from its past experience” (p. 57) remains
fundamental. Possibly inspired by Jacobsen’s reports of resolution of experimen-
tal neurosis following bifrontal lesions in his experimental animals (Valenstein,
1986), E. Moniz developed the procedure of prefrontal leucotomy, to which tens
of thousands of people were subjected through the early 1970s.
Twenty years after Jacobsen’s seminal work, Mishkin and colleagues conducted
a series of studies deconstructing the effects of lesions to specific frontal sectors
in the monkey on a variety of delay-type tasks (see Mishkin, 1964). The pioneer-
ing lesion and intracellular recording studies of Fuster (1985) and Goldman-Rakic
(1987) in monkeys can also be viewed as part of Jacobsen’s legacy (see also
Passingham, 1985; Petrides, 1989), as can contemporary functional neuroimag-
ing studies of working memory function (D’Esposito, Postle, & Rypma, 2000).
Developments in human research in the second era included Halstead’s (1947)
application of psychometric principles to develop a battery to assess frontal lobe
function (later expanded to the Halstead-Reitan Neuropsychological Battery;
Reitan & Wolfson, 1985) and Luria’s (1966) classic analyses of cases with frontal
lobe damage. Yet human research was fundamentally limited by lack of precision
of both psychological processes and neuroanatomy. The most notable exception
to this was Milner’s (1963) study on patients with frontal and temporal lobe
excisions due to intractable epilepsy, through which a psychological test, the
Wisconsin Card Sorting Test (Berg, 1948) became a standard measure of frontal
lobe function (Stuss, Levine, Alexander, et al., 2000). This research was excep-
tional because of the disconnection between experimental psychology and neu-
rology in the 1960s and 1970s. In other words, most experimental psychological
research at that time arose from the behavioral and cognitive revolutions, neither
of which was concerned with the brain. Meanwhile, few neurologists were inter-
ested in behavior and cognition, which meant that few psychologists had access to
high-quality patient samples.
THE THIRD ERA

This state of affairs changed with the rise of the modern behavioral neurology,
pioneered by Norman Geschwind at the Boston Veteran’s Administration (VA)
hospital and Harvard University in the 1960s. Geschwind was interested in the
neurological origins of complex human behavior, especially language, attracting
neurologist trainees who included Marsel Mesulam, Mick Alexander, Kenneth
Heilman, Antonio Damasio, and Frank Benson. Because of the mental and behav-
ioral consequences to veterans of World War II, the VA invested in psychological
services. In the case of the Boston VA, this policy enabled the presence of psy-
chologists such as Edith Kaplan, Harold Goodglass, and Laird Cermak, making it
a fountainhead for neuropsychology as well as behavioral neurology. This was the
environment that Don entered as a postdoctoral fellow in 1976.
This brings us back to prefrontal leucotomy. As part of his postdoctoral fellow-
ship, Don, in collaboration with Frank Benson and Edith Kaplan, collected data on
22 patients who had been institutionalized at the Northampton VA with a diag-
nosis of schizophrenia in the early 1940s, 17 of whom had undergone a prefrontal
leucotomy resulting in bilateral lesions constrained to the ventral sectors of the
frontal lobes. To control for the confound of a diagnosis of chronic schizophrenia,
Don and his colleagues used a comparison group of patients who had also been
hospitalized with schizophrenia at the same institution and at the same time,
but who had not had surgery. Severity of illness was dealt with by stratifying the
leucotomy patients according to their postsurgical recovery.
The patients were administered a comprehensive battery of neuropsychological
tests. By and large, there were no significant effects of leucotomy on standard-
ized measures of intelligence, language, memory, motor, and visuoperceptual/
visuoconstructive functions (Benson & Stuss, 1982; Stuss, Benson, Clermont,
et al., 1986; Stuss, Benson, Kaplan, Malva, & Weir, 1984; Stuss, Benson, Kaplan,
Weir, & Della Malva, 1981; Stuss, Kaplan, Benson, et al., 1981), seemingly support-
ing a view that either the frontal lobes are silent or that leucotomy has no mental
or behavioral side effects. Yet this conclusion was not consistent with clinical obser-
vation of the patients: “What I observed was the daily behavior, during the inter-
ludes from testing. But when I tested them, I used all the tricks of the trade to focus
their attention for those periods of time for testing, and when I could get them
to pay attention, they performed normally” (Don Stuss, personal communication).
It wasn’t until Don administered more advanced experimental tests involving

suppression of interference within memory (Stuss, Kaplan, Benson, et al., 1982),
sustained attention, verbal abstraction, and shifting perceptual sets (Stuss,
Benson, Kaplan, et al., 1983) that the patients’ cognitive deficits were apparent.
Furthermore, decades before affective neuroscience became fashionable, Don
sought empirical concordance for these patients’ emotional deficits by quantifying
their abnormal responses to emotional scenes (Stuss & Benson, 1983).
In retrospect, a major contribution of the Southampton VA leucotomy study
was the empirical demonstration that patients with frontal damage, especially
ventral frontal damage, can appear normal on standard neuropsychological tests
(Stuss & Levine, 2002). Eliciting cognitive deficits requires astute clinical observa-
tion combined with awareness of the psychological instruments optimized to cap-
ture the deficit. However, an even greater practical contribution that emanated
from Don’s collaboration with Frank Benson was a comprehensive review of the
neuropsychology of frontal lobe function (Stuss & Benson, 1984) followed by The
Frontal Lobes monograph (Stuss & Benson, 1986).
It is interesting to reflect on the fact that this was not the only volume on this
topic in existence at the time (Perecman, 1987; Pribram & Luria, 1973; Warren &
Akert, 1964). Why does the Stuss and Benson volume stand out so (with over
1,500 citations)? There are several answers in our view. First, it consolidated all
that was known about the frontal lobes from both animal and human research.
Second, by synthesizing anatomical and psychological data, it anticipated the
modern neuroscience methods in a cogent style that was meaningful to both clini-
cians and researchers. Finally, it had vision, as represented by a hierarchical model
of frontal lobe function that dared to mention consciousness.
The Stuss and Benson volume was also the beneficiary of perfect timing.
Around the time of its publication, advances in physics and high-speed computing
enabled the placement of MRI scanners in clinical settings, making available
structural images of the brain that were exponentially more detailed than those
that were previously available. This was followed shortly by the first H2O positron
emission tomography studies showing correlates of human brain activity in
response to task demands, soon to be supplanted by functional MRI.
As a very gross measure of the exponential increase in frontal lobe research,
PubMed lists 2,707 journal articles containing the words “frontal lobe” or “frontal
cortex” published between 1900 and 1986. In the past 23 years (1987 to present)
10,506 such articles were published, encompassing a huge variety of findings and
observations.
Overview of this Volume

This volume represents work by a group of researchers united by Don’s influence.
It also reflects the breadth that Don continues to cultivate in his research program,
including neuropsychological (focal lesion) studies, traumatic brain injury, aging,

dementia, memory, rehabilitation, imaging, and consciousness. Don’s first publi-
cation in the area of neuropsychology, a case series entitled “An extraordinary
form of confabulation” (Stuss, Alexander, Lieberman, & Levine, 1978), was the
first to relate this syndrome to frontal lobe dysfunction and not just amnesia. This
contention is now received wisdom (e.g., Gilboa et al., 2006; Moscovitch & Melo,
1997). In his review of confabulation (Chapter 2), Don’s longtime (and current)
collaborator, Mick Alexander, asks why we should care about confabulation, a rare
disorder that usually resolves on its own with no implications for prognosis and
treatment. Indeed, few researchers and clinicians did care about confabulation in
1978. Since then, studies of confabulation have revealed its importance to the
understanding of interactions between the medial temporal lobes and the frontal
lobes and the strategic monitoring of mnemonic output.
Many of the thousands of studies referring to the frontal lobes in the past two
decades are functional neuroimaging studies. Don was initially skeptical about
the long-term impact of these studies. Although he engaged with the technology
(e.g., Floden, Vallesi, & Stuss; 2011; Soros et al., 2006; Vallesi, McIntosh, Shallice,
& Stuss, 2009), his main body of work continues to develop from the focal lesion
group method that he started in the Southampton leucotomy series, most recently
in the ROBBIA series in collaboration with Alexander, Shallice, and Picton (e.g.,
Alexander, Stuss, Picton, Shallice, & Gillingham, 2007; Shallice, Stuss, Picton,
Alexander, & Gillingham, 2007, 2008; Stuss, Alexander, Shallice, et al., 2005;
Stuss, Shallice, Alexander, & Picton, 1995). In Chapter 3, Shallice carefully reviews
the strengths and weaknesses of the group focal lesion method, arguing that the
task effects in focal lesions studies are much larger than effect sizes for psy-
chophysiological interactions in fMRI. He also contrasts the ROBBIA method of
comparing focal lesion groups on relatively simple component process tasks of
attention to performance on more complex tasks, showing that convergence
exists between these two approaches.
In their chapter on the rostral prefrontal cortex (Chapter 4), Paul Burgess and
colleagues argue for the use of lesion evidence to constrain functional neuroimag-
ing findings, stressing the classically important method of double dissociation.
They provide a comprehensive summary and synthesis of Don’s work on Brodmann
area 10, a region that Don identified as important in the higher levels of his hier-
archical model of consciousness, but one that did not receive much attention until
it repeatedly lit up in functional neuroimaging studies. Burgess and colleagues
review the literature on strategy application disorder, beginning with Shallice and
Burgess’s (1991) classic case series to the present, where it is embedded in the
Gateway Hypothesis model, which integrates fMRI and lesion data to localize the
relevant cognitive processes.
One of the most advanced approaches to integrating focal lesion and neuro-
imaging data is to actually scan the patients with focal damage to investigate how
their lesions disrupt distributed systems involved in compensation and cognition.
Two contributions to this volume reflect the latest efforts in this direction.
D’Esposito and Badre (Chapter 5) point out that while the patient studies are
necessary for understanding behaviors relevant to frontal lobe function, they are
not sufficient to localize these behaviors to intra-frontal sectors. Moreover, func-
tional imaging studies allow for analysis of dynamic connectivity patterns in dis-
tributed systems that cannot be studied in static images of patients. On the other
hand, imaging studies alone cannot tell you what happens when critical elements
of the system are damaged. By combining lesion and functional imaging methods,
D’Esposito and Badre extend Don’s work on task setting and the left lateral pre-
frontal cortex to a more detailed mechanistic account involving hierarchical pro-
cesses along the rostral–caudal axis.
Voytek and Knight (Chapter 6), using EEG in focal lesion patients, demonstrate
how top-down modulation from the dorsolateral prefrontal cortex affects func-
tioning in posterior visual areas. This is a powerful demonstration of the distrib-
uted nature of perceptual and cognitive functions, with evidence of the critical
role played by frontal processes in neuroplasticity. This in turn informs theories of
frontal compensation following brain damage. Voytek and Knight point out that
such compensatory processes are harder to predict in higher association cortex
than in primary motor and sensory cortex.
Another psychological construct associated with area 10 is theory of mind. In
Chapter 7, Rosenbaum and Rabin expand upon Don’s focal lesion work in theory
of mind (Stuss, Gallup, & Alexander, 2001), personal memory (Wheeler et al.,
1997), and affective processing (Shammi & Stuss, 1999; Stuss & Alexander, 2000).
In an effort to link theory of mind with other self-related and affective processes
they describe a network model with critical nodes in the temporal pole and tem-
poroparietal junction as well as, most importantly, in the medial prefrontal cortex.
As in the chapter by Burgess and colleagues, Rosenbaum and Rabin emphasize
principled combinations of lesion and functional neuroimaging data. This is par-
ticularly important for functional localization in the anterior and medial prefron-
tal sectors, which are rarely selectively damaged in humans.
In his chapter on integrating theories of attention and frontal lobe function
(Chapter 8), Ian Robertson highlights the complementary contributions of Don
and Michael Posner, who share a vision of seeing the “forest,” a massive challenge
given the incredible complexity and volume of research on the topics they tackle.
Such a problem space gives rise to multiple and sometimes incompatible theories
as researchers attempt to work through the data, and this is certainly the case for
frontal lobe function. Robertson stresses the importance of Don’s work for trans-
lating a number of very disparate ideas into a practical, multicomponent frame-
work (i.e., a tripartite model of anterior attention systems; Stuss & Alexander,
2007), for helping people with attention problems.
A direct application of Don’s work to rehabilitation can be found in a series
of papers on cognitive rehabilitation in the elderly in a large-scale project led
by Don, in collaboration with Winocur, Levine, and Craik (Craik et al., 2007;
Levine et al., 2007; Stuss, Robertson, Craik, et al., 2007; Winocur et al., 2007). In
Chapter 9 Winocur reviews the background in the development of interventions
that followed from ideas of strategic deficits in patients with frontal damage.
Although the cognitive neurorehabilitation protocols employed in these studies
made no claims to necessarily rehabilitate frontal lobe function in aging (as dem-
onstrated, for example, by neuroimaging changes), they were successful at the
behavioral level, demonstrating how concepts derived from theories of frontal
lobe function can be useful even when the anatomical underpinnings are not the
target of the intervention.
Don’s research has been important to theories of cognitive aging, which often
implicate frontal lobe function. In Chapter 10 Gus Craik’s review of cognitive
aging research focusing on self-initiation, environmental support, and age-related
resource depletion shows how these linkages can be examined through careful
behavioral manipulations, which in turn can be translated into manipulations
using neuroimaging and other techniques. Craik’s chapter explores the similari-
ties and differences between the effects of normal aging and the consequences of
frontal lobe pathology. In Chapter 11 Leritz and colleagues probe the frontal-
aging hypothesis in more detail, incorporating structural and functional imaging
results. Although Leritz and colleagues hold that the frontal-aging hypothesis is
not validated, it has nonetheless been fruitful from a behavioral perspective in
probing and understanding cognitive decline in aging (e.g., Stuss, Craik, Sayer,
Franchi, & Alexander, 1996). In Chapter 12 Ramirez and Black provide a broader
perspective on brain volume loss and white matter changes in the context of
normal aging and dementia. In particular, they review the literature on white
matter hyperintensities on T2-weighted MRI images, which are ubiquitous in
aging, blurring the distinction between pathological and normal aging.
Traumatic brain injury shares with aging and dementia effects on distributed
systems, which, as Don has pointed out, can mimic frontal lobe damage (Stuss &
Gow, 1992). In Chapter 13 Levine reviews his research on strategy application
disorder in traumatic brain injury, demonstrating both convergence with and
departure from the more classic studies of strategy application disorder in focal
frontal lesions (see Burgess et al.). He reviews both behavioral and imaging stud-
ies designed to deconstruct how real-life behavior is affected in this disorder,
which is among the most common causes of frontal lobe damage.
As mentioned previously, Don was bold enough to write about mechanisms of
human consciousness long before this was popular. Endel Tulving’s later formula-
tions of episodic memory, stressing awareness of the self across time, were devel-
oped in collaboration with Don and Mark Wheeler (Wheeler et al., 1997). Research
on the neural correlates of a person’s ability to imagine the future is now a very
hot topic. In Chapter 14 Tulving and Szpunar review the literature on human con-
sciousness in relation to past and future, concluding that concepts of the future
must be embedded in a mental reality that is intra-personal and distinct from
universally shared physical reality.
The final chapter, by Picton, provides a fitting ending to this volume in that it
integrates Don’s contributions from simple (bottom-up) tasks (as in the ROBBIA
studies) with his broader theorizing concerning human self-awareness, such as
with Capgras syndrome (Alexander, Stuss, & Benson, 1979). Picton explains how
the simple processes such as those delineated in the ROBBIA tasks must combine
prior to the execution of higher-level, more complex tasks. As Picton points out,
there is a spiritual aspect to Don’s work, perhaps fitting with Don’s earlier voca-
tion as a monk. The spiritual component relates to the observation of disturbances
in self-awareness in patients, then asking how these may be relevant for con-
sciousness in healthy adults.
Summary
In reviewing Don Stuss’s career and the contributions to this volume, the courage
of Don’s convictions is clear. Don saw the importance of the frontal lobes when
very few people were actively studying these problems in humans, and he was
one of the first to demonstrate this by applying principled psychological methods
to this study. Don’s impact is compounded when one considers his leadership
in administration, most notably as founding director of the Rotman Research
Institute and VP of Research at Baycrest, where he has created an environment
for intellectual discovery in cognitive neuroscience that has grown from 5 to
20 scientists. This environment is unique not only for its technical resources,
but also—and especially—for its combination of psychological, neurological, and
neuroimaging expertise. This is the same vision seen in his book and his research
program, a vision that allows us to use these resources in a principled and theory-
driven manner. Perhaps most importantly, this environment has provided train-
ing opportunities to hundreds of students and postdoctoral fellows, many of
whom have gone on to become international leaders.
Acknowledgment
Work on this chapter was supported by grants from the Canadian Institutes of
Health Research and the Heart and Stroke Foundation Centre for Stroke Recovery
to BL and a grant from the Natural Sciences and Engineering Research Council of
Canada to FIMC.
References
Ackerly, S. (1937). Instinctive, emotional, and mental changes following prefrontal lobe extirpa-
tion. American Journal of Psychiatry, 92, 717–729.
Alexander, M. P., Stuss, D. T., & Benson, D. F. (1979). Capgras syndrome: A reduplicative phenomenon.
Neurology, 29, 334–339.
Alexander, M. P., Stuss, D. T., Picton, T., Shallice, T., & Gillingham, S. (2007). Regional frontal inju-
ries cause distinct impairments in cognitive control. Neurology, 68(18), 1515–1523.
Barbas, H. (1995). Anatomic basis of cognitive-emotional interactions in the primate prefrontal
cortex. Neuroscience and Biobehavioral Reviews, 19, 499–510.
Benson, D. F., & Stuss, D. T. (1982). Motor abilities after frontal leukotomy. Neurology, 32(12),
1353–1357.
Benton, A . (1991). The prefrontal region: Its early history. In H. S. Levin, H. M. Eisenberg, &
A. L. Benton (Eds.), Frontal lobe function and dysfunction (pp. 256–272). New York: Oxford
University Press.
Berg , E. A . (1948). A simple objective technique for measuring flexibility in thinking. Journal of
General Psychology, 39, 15–22.
Bianchi, L . (1895). The functions of the frontal lobes. Brain, 18, 497–522.
Bunge, S. A., & Wright, S. B. (2007). Neurodevelopmental changes in working memory and cogni-
tive control. Current Opinion in Neurobiology, 17(2), 243–250.
Cohen, J. D., & Servan-Schreiber, D. (1993). A theory of dopamine function and its role in cognitive
deficits in schizophrenia. Schizophrenia Bulletin, 19(1), 85–104.
Craik, F. I. M., & Grady, C. L . (2002). Aging, memory, and frontal lobe functioning. In D. T. Stuss &
R. Knight (Eds.), Principles of frontal lobe function (pp. 528–540). New York: Oxford University
Press.
Craik, F. I. M., Winocur, G., Palmer, H., Binns, M. A., Edwards, M., Bridges, K., et al. (2007). Cognitive
rehabilitation in the elderly: effects on memory. Journal of the International Neuropsychological
Society, 13(1), 132–142.
D’Esposito, M., Postle, B. R., & Rypma, B. (2000). Prefrontal cortical contributions to working
memory: evidence from event-related fMRI studies. Experimental Brain Research, 133(1),
3–11.
deNobele, E. (1835). Annales de Medecine Belge.
Dias, R., Robbins, T. W., & Roberts, A. C. (1996). Dissociation in prefrontal cortex of affective and
attentional shifts. Nature, 380(6569), 69–72.
Eslinger, P. J., & Damasio, A. R . (1985). Severe disturbance of higher cognition after bilateral
frontal lobe ablation: Patient EVR . Neurology, 35, 1731–1741.
Ferrier, D. (1886). The Functions of the Brain (2nd ed.). London: Smith, Elder.
Feuchtwanger, E. (1923).Die Funktionen des Stirnhirns. Berlin: Springer.
Fletcher, P. C., & Henson, R. N. (2001). Frontal lobes and human memory: insights from functional
neuroimaging. Brain, 124(Pt 5), 849–881.
Floden, D., Vallesi, A., & Stuss, D. T. (2011). Task context and frontal lobe activation in the Stroop
Task. Journal of Cognitive Neuroscience, 23(4), 867–879.
Fuster, J. M. (1985). The prefrontal cortex, mediator of cross-temporal contingencies. Human
Neurobiology, 4, 169–179.
Gilboa, A., Alain, C., Stuss, D. T., Melo, B., Miller, S., & Moscovitch, M. (2006). Mechanisms of spon-
taneous confabulations: a strategic retrieval account. Brain, 129(Pt 6), 1399–1414.
Goldman-Rakic, P. S. (1987). Circuitry of primate prefrontal cortex and regulation of behavior by
representational memory. In F. Plum & V. Mountcastle (Eds.), Handbook of physiology: the
nervous system (pp. 373–417). Bethesda, MD: American Physiological Society.
Goldstein, K . (1944). The mental changes due to frontal lobe damage. Journal of Psychology, 17,
187–208.
Halstead, W. C. (1947). Brain and intelligence: a quantitative study of the frontal lobes. Chicago:
University of Chicago Press.
Harlow, J. M. (1868). Recovery after severe injury to the head. Publication of the Massachusetts
Medical Society, 2, 327–346.
Hebb, D. (1945). Man’s frontal lobe: a critical review. Archives of Neurology and Psychiatry, 54, 10–24.
Iacoboni, M., & Dapretto, M. (2006). The mirror neuron system and the consequences of its
dysfunction. Nature Reviews Neuroscience, 7(12), 942–951.
Jacobsen, C. F. (1936). Studies of cerebral function in primates. Comparative Psychology Monographs,
13, 1–68.
Jastrowitz, M. (1888). Beiträge zur Localisation im Grosshirn und über deren praktische
Verwerthung. Deutsche medizinische Wochenschrift, 14, 81–83, 108–112.
Kleist, K . (1934). Gehirnpathologie. Leipzig: Barth.
Levine, B., Stuss, D. T., Winocur, G., Binns, M. A., Fahy, L., Mandic, M., et al. (2007). Cognitive reha-
bilitation in the elderly: effects on strategic behavior in relation to goal management. Journal
of the International Neuropsychological Society, 13(1), 143–152.
Luria, A. R . (1966). Higher cortical functions in man. New York: Basic Books.
Macmillan, M. (2000). An odd kind of fame: stories of Phineas Gage. Cambridge, MA: MIT Press.
Mayberg , H. S., Liotti, M., Brannan, S. K., McGinnis, S., Mahurin, R. K., Jerabek, P. A., et al. (1999).
Reciprocal limbic-cortical function and negative mood: converging PET findings in depression
and normal sadness. American Journal of Psychiatry, 156(5), 675–682.
Mesulam, M. M. (2002). The human frontal lobes: transcending the default mode through contin-
gent encoding. In D. T. Stuss & R. Knight (Eds.), Principles of frontal lobe function (pp. 8–30).
New York: Oxford University Press.
Milner, B. (1963). Effects of different brain lesions on card sorting: the role of the frontal lobes.
Archives of Neurology, 9, 100–110.
Mishkin, M. (1964). Perseveration of central sets after frontal lesions in monkeys. In J. M.
Warren & K. Akert (Eds.), The frontal granular cortex and behavior (pp. 219–241). New York:
McGraw-Hill.
Moscovitch, M., & Melo, B. (1997). Strategic retrieval and the frontal lobes: evidence from confabu-
lation and amnesia. Neuropsychologia, 35(7), 1017–1034.
Neary, D., Snowden, J. S., Gustafson, L., Passant, U., Stuss, D. T., Black, S., et al. (1998). Fronto-
temporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology, 51(6),
1546–1554.
Oppenheim, H. (1890). Zur Pathologie der Gehirngeschwulste. Archiv fur Psychiatrie und
Nervenkrankheiten, 21, 560–87.
Passingham, R. E. (1985). Cortical mechanisms and cues for action. Philosophical Transactions of the
Royal Society London B, 308, 101–111.
Perecman, E. (Ed.). (1987). The frontal lobes revisited. New York: The IRBN Press.
Petrides, M. (1989). Frontal lobes and memory. In F. Boller & J. Grafman (Eds.), Handbook of
neuropsychology (Vol. 3, pp. 75–90). Amsterdam: Elsevier.
Pribram, K. H., & Luria, A. R . (1973). Psychophysiology of the frontal lobes. New York: Academic
Press.
Reitan, R., & Wolfson, D. (1985). The Halstead-Reitan Neuropsychological Test Battery. Tucson, AZ:
The Neuropsychological Press.
Rolls, E. T. (2000).The orbitofrontal cortex and reward. Cerebral Cortex, 10(3), 284–294.
Schacter, D. L., Addis, D. R., & Buckner, R. L . (2007). Remembering the past to imagine the future:
the prospective brain. Nature Reviews Neuroscience, 8(9), 657–661.
Shallice, T., & Burgess, P. W. (1991). Deficits in strategy application following frontal lobe damage
in man. Brain, 114, 727–741.
Shallice, T., Stuss, D. T., Picton, T. W., Alexander, M. P., & Gillingham, S. (2007). Multiple effects of
prefrontal lesions on task-switching. Frontiers in Human Neuroscience, 1, 2.
Shallice, T., Stuss, D. T., Picton, T. W., Alexander, M. P., & Gillingham, S. (2008). Mapping task switch-
ing in frontal cortex through neuropsychological group studies. Frontiers in Neuroscience, 2(1),
79–85.
Shammi, P., & Stuss, D. T. (1999). Humour appreciation: a role of the right frontal lobe. Brain,
122(Pt 4), 657–666.
Soros, P., Sokoloff, L. G., Bose, A., McIntosh, A. R., Graham, S. J., & Stuss, D. T. (2006). Clustered
functional MRI of overt speech production. NeuroImage, 32(1), 376–387.
Stuss, D. T., & Alexander, M. P. (2000). Affectively burnt in: a proposed role of the right frontal lobe.
In E. Tulving (Ed.), Memory, consciousness and the brain: the Tallin Conference (pp. 215–227).
Philadelphia: Psychology Press.
Stuss, D. T., & Alexander, M. P. (2007). Is there a dysexecutive syndrome? Philosophical Transactions
of the Royal Society of London, Series B: Biological Sciences, 362(1481), 901–915.
Stuss, D. T., Alexander, M. P., Lieberman, A., & Levine, H. (1978). An extraordinary form of
confabulation. Neurology, 28, 1166–1172.
Stuss, D. T., Alexander, M. P., Shallice, T., Picton, T. W., Binns, M. A., Macdonald, R., et al. (2005).
Multiple frontal systems controlling response speed. Neuropsychologia, 43(3), 396–417.
Stuss, D. T., & Benson, D. F. (1983). Emotional concomitants of psychosurgery. In K. Heilman &
P. Satz (Eds.), Advances in neuropsychology and behavioral neurology (pp. 111–140). New York:
Guilford Press.
Stuss, D. T., & Benson, D. F. (1984). Neuropsychological studies of the frontal lobes. Psychological
Bulletin, 95(1), 3–28.
Stuss, D. T., & Benson, D. F. (1986). The frontal lobes. New York: Raven Press.
Stuss, D. T., Benson, D. F., Clermont, R., Della, M. C., Kaplan, E. F., & Weir, W. S. (1986). Language
functioning after bilateral prefrontal leukotomy. Brain and Language, 28(1), 66–70.
Stuss, D. T., Benson, D. F., Kaplan, E. F., Malva, D. D., & Weir, W. S. (1984). The effects of prefrontal
leucotomy on visuoperceptive and visuoconstructive tests. Bulletin of Clinical Neurosciences,
49, 43–51.
Stuss, D. T., Benson, D. F., Kaplan, E. F., Weir, W. S., & Della Malva, C. (1981). Leucotomized and
nonleucotomized schizophrenics: comparison on tests of attention. Biological Psychiatry,
16(11), 1085–1100.
Stuss, D. T., Benson, D. F., Kaplan, E. F., Weir, W. S., Naeser, M. A., Lieberman, I., et al. (1983).
The involvement of orbitofrontal cerebrum in cognitive tasks. Neuropsychologia, 21(3),
235–248.
Stuss, D. T., Craik, F. I. M., Sayer, L., Franchi, D., & Alexander, M. P. (1996). Comparison of elderly
subjects to patients with frontal lesions: evidence from word list learning. Psychology and
Aging, 11, 387–395.
Stuss, D. T., Gallup, G. G., & Alexander, M. P. (2001). The frontal lobes are necessary for “theory of
mind.” Brain, 124(Pt 2), 279–286.
Stuss, D. T., & Gow, C. A . (1992). “Frontal dysfunction” after traumatic brain injury. Neuropsychiatry,
Neuropsychology, and Behavioral Neurology, 5(4), 272–282.
Stuss, D. T., Kaplan, E. F., Benson, D. F., Weir, W. S., Chiulli, S., & Sarazin, F. F. (1982). Evidence for
the involvement of orbitofrontal cortex in memory functions: an interference effect. Journal
of Comparative and Physiological Psychology, 96(6), 913–925.
Stuss, D. T., Kaplan, E. F., Benson, D. F., Weir, W. S., Naeser, M. A., & Levine, H. L . (1981). Long-
term effects of prefrontal leucotomy: an overview of neuropsychological residuals. Journal of
Clinical Neuropsychology, 3(1), 13–32.
Stuss, D. T., & Levine, B. (2002). Adult clinical neuropsychology: lessons from studies of the frontal
lobes. Annual Review of Psychology, 53, 401–433.
Stuss, D. T., Levine, B., Alexander, M. P., Hong , J., Palumbo, C., Hamer, L., et al. (2000). Wisconsin
Card Sorting Test performance in patients with focal frontal and posterior brain damage:
effects of lesion location and test structure on separable cognitive processes. Neuropsychologia,
38(4), 388–402.
Stuss, D. T., Robertson, I. H., Craik, F. I. M., Levine, B., Alexander, M. P., Black, S., et al. (2007).
Cognitive rehabilitation in the elderly: a randomized trial to evaluate a new protocol. Journal
of the International Neuropsychological Society, 13(1), 120–131.
Stuss, D. T., Shallice, T., Alexander, M. P., & Picton, T. (1995). A multidisciplinary approach to ante-
rior attentional functions. Annals of the New York Academy of Sciences, 769, 191–212.
Valenstein, E. S. (1986). Great and desperate cures. New York: Basic Books.
Vallesi, A., McIntosh, A. R., Shallice, T., & Stuss, D. T. (2009). When time shapes behavior: fMRI
evidence of brain correlates of temporal monitoring. Journal of Cognitive Neuroscience, 21(6),
1116–1126.
Warren, J. M., & Akert, K. (Eds.). (1964). The frontal granular cortex and behavior. New York:
McGraw-Hill.
Welt, L. (1888). Uber charaktervaranderungen des menschen infoldge von lasionen des stirnhirns.
Deutsches Archiv für klinische Medizin, 42, 339–90.
Wheeler, M. A., Stuss, D. T., & Tulving, E. (1997). Toward a theory of episodic memory: the frontal
lobes and autonoetic consciousness. Psychological Bulletin, 121, 331–354.
Winocur, G., Craik, F. I. M., Levine, B., Robertson, I. H., Binns, M. A., Alexander, M., et al. (2007).
Cognitive rehabilitation in the elderly: overview and future directions. Journal of the
International Neuropsychological Society, 13(1), 166–171.
2
Confabulation
M I C H A E L P. A L E X A N D E R
Confabulation is an oddity among cognitive neuropsychological disorders. It is a

“positive” sign like seizures or hallucinations, not a negative sign like amnesia or
anomia. It is quite hard to define but is obvious to the informed observer. It is
usually transient, which is fortunate because there are no recognized treatments.
It carries no discrete diagnostic or prognostic significance. No brain lesion site
is sufficient to account for it. The fixed, structural lesion site most commonly
associated with it actually only occasionally produces lasting confabulation.
Confabulation is only one of many cognitive phenomena associated with that
lesion site, but how the others are related to confabulation is either controversial
or has never been examined. For all of the oddities of confabulation as a topic of
scientific investigation, there are a few accepted conclusions:
1. Significant confabulation is seen only in patients who are or recently were

amnesic, but most amnesics do not confabulate.
2. The illnesses in which confabulation is commonly seen usually cause a period
of at least delirium, often preceded by coma: subarachnoid hemorrhage from
ruptured anterior communicating artery aneurysms, traumatic brain injury,
extensive neurosurgical procedures.
3. If there is a focal lesion responsible for confabulation, it will be in frontal sys-
tems; analysis of almost 40 reports on confabulation revealed that when
lesions could be localized, 81% were in prefrontal cortex, left or right, unilat-
eral or bilateral, but most commonly orbital or medial (Gilboa, Alain, Stuss,
et al., 2006).
4. If there are consistently associated deficits, they will be executive.
The last two of these conclusions are, of course, why confabulation has attracted
the attention of Don Stuss for 30 years.
16
C on fabu l at ion 17
Case Description: A Patient who Exemplifies

All of the Accepted Wisdom
The patient is a 29-year-old man who had an acute subarachnoid hemorrhage. He
initially presented deeply comatose. Initial studies demonstrated an anterior com-
municating artery aneurysm (ACommA) and a left frontal intracerebral hemor-
rhage. He underwent immediate evacuation of the hematoma and placement of a
ventriculostomy catheter for increased intracranial pressure. He developed diabe-
tes insipidus and vasopressin was started. The aneurysm re-ruptured during coil-
ing, causing a right frontal hemorrhage. An emergency clipping was performed.
On day 19 a permanent left frontal ventriculoperitoneal shunt was placed.
Emergence from coma was not clearly defined, but a detailed assessment on day 24
revealed akinetic mutism believed secondary to bilateral frontal infarcts. He was
discharged on day 31 to a rehabilitation hospital. Over the next 4 months he made
very slow improvements. Methylphenidate was begun, perhaps increasing his
responsiveness. He was transferred to a chronic hospital, where he still resides.
At 8 months after the hemorrhage, he still requires supervision. He ambulates
independently, although in a restricted ward. He can do all self-care but requires
considerable prompting to initiate. He is doubly incontinent unless prompted and
kept on a regular schedule.
His mother has observed that he has no emotional expression other than a
bland happiness. He never shows any concern about his condition. Although in
general family and staff consider him to have severe amnesia, he occasionally will
spontaneously make a perfectly correct recollection of a recent occurrence. He
initially confabulated spontaneously but seemed too apathetic to act on incorrect
recollections. Now he keeps a journal in which he is supposed to record his daily
experiences to assist his memory, but his “experiences” often incorporate con-
fabulatory content from the day’s TV viewing. He shows no memory for upcom-
ing appointments or home visits.
On examination 8 months after the hemorrhage, he was alert and cooperative
but very apathetic, rarely bothering to participate in the history unless directly
posed a question. He showed no emotional response to the discussion about his
lengthy hospitalization, the double incontinence, or his poor functional progno-
sis. Responses were delayed and sparse, but fluent and grammatical. When asked
about daily activities, he replied, “I go to one of my therapies.” All language testing
is normal.
Attention was variable. Counting backwards and serial subtractions were done
very quickly and without error, but his backward digit span was only 3. He could
name only 10 animals in 60 seconds, but sustaining the task was very difficult and
almost every animal required its own prompt. He was extremely distractible and
stimulus-bound, his attention attracted by my note-taking and, in the context of
observing his balance and gait, he walked by the computer screen, seemed to
forget the task, turned towards the screen, noticed objects like the reflex hammer
on the desk, and reached for them.
He was not oriented. He knew the month and the year, but not season, the
date, the day, the hospital, or the city. He was aware of some odds and ends from
recent news—the previous day’s baseball results, the new president elected at the
time of his hemorrhage, that there were wars in Iraq and Afghanistan—but not
others, such as recent plane crashes or various scandals of prominent politicians.
On a 3-word list with a 20-second interval, he recalled 2 words, but on a 9-word
list, the learning curve was 6–7-7–7, and after a 5-minute delay he recalled only
2 words and had 2 intrusions—words not previously uttered anywhere in
the examination—sometimes considered “evoked confabulation” (Schnider, von
Däniken, & Gutbrod, 1996).
Additional testing was performed at 7 to 8 months after the hemorrhage
(graciously supplied by Paul Spiers, PhD). Estimated pre-illness IQ was 121. Stroop
and Trails tasks were average (all scores 9–11) but card sorting was quite poor:
only 2 sorts with increased perseverative errors.
The elemental neurological examination was not remarkable. CT performed
6 months after the hemorrhage showed very extensive bilateral ventromedial
encephalomalacia (Fig. 2.1).
Extensive bilateral orbital

frontal damage-more
medial than lateral
Complete damage to the

septal forebrain
Severe medial polar injury
Figure 2.1. CT performed 6 months after hemorrhage shows very extensive bilateral
ventromedial encephalomalacia.
The lesion findings can be summarized as follows: (1) comprehensive posterior

medial injury, including the septal portions of the basal forebrain; (2) almost total
loss of Brodmann’s area 10; (3) extensive damage to the white matter under and
anterior to the frontal horns and to the anterior cingulate gyrus; and (4) complete
damage to at least the medial portion of the posterior orbital gyri bilaterally.
This patient is an embodiment of the four conclusions listed above.
Background
So what is confabulation? It is “a falsification of memory occurring in clear con-
sciousness in association with an organically derived amnesia” (Berlyne, 1972).
Spontaneous confabulations are “statements or actions that reflect unintentional
but obvious distortions of memory” (Gilboa et al., 2006). Confabulations are
“erroneous memories, either false in themselves or resulting from true memories
misplaced in context and inappropriately retrieved or interpreted” (Kopelman,
Guinan, & Lewis, 1995). The confabulated content may be subtle and undetect-
able to those who do not know the truth. It may occur only when “provoked” in
response to a memory test or prompted questioning. It may be “spontaneous” and
the patient’s overt behavior may indicate that the patient is acting on the false
belief even when very unlikely or even bizarre (Kopelman, 1987; Schnider,
2003).
Confabulation does not include a conscious attempt to deceive, and it is sup-
posed to be distinguished, somehow, from simple errors or disagreement between
rememberers. In a circular way, confabulations are defined as incorrect memories
that arise from a pathological state of the brain, not just a “normal” memory fail-
ure. When dramatic—spontaneous and behavioral—there is agreement on the
diagnosis of confabulation, but there is no definitive experimental test to define
confabulation.
The earliest published observations about confabulation come from Bonhoeffer
in 1901 and 1904, who distinguished between momentary and spontaneous or
fantastic confabulation (translations not available but cited in Berlyne [Berlyne,
1972]). Pick described confabulation in various disorders as having two necessary
components: suggestibility leading to incorrect recall and the absence of a correc-
tive mechanism (translations also not available but cited in Berlyne [Berlyne,
1972]). Suggestibility might be due to clouded consciousness or to poor judgment,
but the notion that confabulation began with an early misjudgment or misattri-
bution that was not, as it should have been, corrected on further consideration
was clearly established. Van der Horst proposed that an inability to recall the
temporal signposts for a memory might leave memories displaced in time
(Van Der Horst, 1932). Weinstein and Kahn published the seminal clinical descrip-
tions of confabulation (and reduplication and denial of illness) in 1954 (Weinstein
& Kahn, 1954). What is striking about the case descriptions of confabulation
(and reduplication and denial) at the end of the book is the consistency of the
anatomy (large frontal lesions, mostly acute) and the often profound executive
and attentional impairments accompanying confabulation.
Berlyne (1972) brought confabulation into modern consideration with a small
series published in a psychiatry journal. He emphasized the distinction between
momentary and fantastic, based on the plausibility of the connection between
the confabulation to a patient’s personal history or on the grandiosity of the
confabulation, although the case descriptions suggest that this distinction was
not always easily applied, as it still is not. Both types were frequently autobio-
graphical: momentary confabulation was a true memory displaced in time, with
content related to personal, habitual activities, sometimes requiring prompting
to emerge and variable in conviction; fantastical confabulation, while anchored in
personal experience, was more grandiose or invented, spontaneously offered, and
stereotyped.
Stuss and collaborators and other colleagues at the Boston VA waded into this
in the late 1970s. Mercer and colleagues evaluated 11 patients with amnesia due
to mixed etiologies and with a range of severity of confabulation using a confabu-
lation battery (Mercer, Wapner, Gardner, & Benson, 1977). Note that eliciting
confabulated recall in a test setting may not yield the exact same behavior as a
spontaneous confabulated tale. They demonstrated that the severe confabulation
subjects differed from the others by (1) their propensity to confabulate on spe-
cifically recent personal memories, (2) their relative imperviousness to cues—
either to acknowledge the cue or to benefit from it if acknowledged, (3) the
prominence of perseverative answers when confabulating, and (4) a relationship
between response latency and the tendency to confabulate, as though hesitation
in response allowed time to monitor the response. They also described a single
patient with mild confabulation until he developed subacute hydrocephalus. As
hydrocephalus worsened, confabulation became more flagrant. Once a shunt was
placed, confabulation decreased.
Stuss and colleagues described five patients with very prominent and persis-
tent confabulation (Stuss, Alexander, Lieberman, & Levine, 1978). All had signifi-
cant frontal lesions; all had moderate to severe retrograde amnesias, all had been
amnesic, although at the time of evaluation two had normal memory quotients
(93 and 112); all had significant impairments in card sorting and fluency tasks. In
three, prominent misuse of cues appeared to underlie the content of confabula-
tion, which was still personally meaningful much of the time: while testing orien-
tation of a Navy veteran as he sat in a hallway watching food trays be distributed,
he said, “I’m in a Navy kitchen”; while asking an academic psychiatrist how he had
spent the day after he returned from a difficult tracheostomy revision, he said
that he had recently delivered a paper on respiratory diseases. The content of the
confabulation for these patients was quite stimulus and environmentally bound.
Bizarre content based roughly on past personal history characterized the others:
a World War II veteran of European battles would tell everyone that his head
wound (craniotomy scar) was because he had been shot in Germany (not true but
might have been), but then he always added two details: he had been shot by a
teenaged girl and killed but had been brought back to life by surgeons (needless to
say, not true). These patients could repeatedly “recall” the same stories although
they were not true—in fact, preposterous—even when they could never recall
stories in memory tasks that were equally personally untrue.
In 1981 the Boston VA group returned to the question of the effect, positive or
negative, of cuing and the possibility of delaying response as a mechanism to
allow for correction (Shapiro, Alexander, Gardner, & Mercer, 1981). Seven patients
with confabulation (four severe and three mild on a confabulation battery) were
asked to recall story content with graded cuing. With cues, the patients with mild
confabulation slowed their responses and increased “I don’t know” responses
(fewer confabulations)—that is, they showed more attention to responses. The
patients with severe confabulation continued to confabulate. Two other tasks
allowed manipulation of response. On a task requiring a logical shift, no manipu-
lation prevented perseverative responding at the shift point. On an estimation
task when the examiner delayed the patient’s response, errors were reduced. One
patient was followed as he improved from severe to mild to non-confabulating.
The response characteristics—perseverations, response inhibitions, latencies,
etc.—improved in parallel, the opposite course of the single case described in the
earlier paper.
In the mid-1980s there were reports of amnesia and confabulation focusing on
ACommA rupture and surgery. These reports emphasized both the lesion causing
amnesia (assumed to be septal or basal forebrain) and the one causing confabula-
tion. We described the general severity of executive impairments in the cases with
confabulation (Alexander & Freedman, 1984). Damasio, Graff-Radford, Eslinger,
Damasio, and Kassell (1985) proposed a mechanism: an inability to reproduce the
correct context out of all of the multidimensional properties of an experience at
the point of retrieval of the memory of the experience. They also proposed that
this was a specific consequence of the basal forebrain and orbitofrontal lesions.
The proposed mechanism might be relevant, but non-confabulating amnesics
have superficially the same orbitofrontal lesions. Other reports continued to
emphasize variations on defective executive corrective mechanisms underlying
confabulation in patients with amnesia from many causes (trauma, Korsakoff
syndrome, tumors, etc.) (Baddeley & Wilson, 1988; DeLuca & Cicerone, 1991;
Kapur & Coughlan, 1980; Kopelman, 1987).
DeLuca and Cicerone reported the same high prevalence of general executive
impairments, specifically in ACommA patients with or without confabulation
(DeLuca, 1993; DeLuca & Cicerone, 1991), but by the 1990s some reports on con-
fabulation began to suggest that there might be a specific executive or corrective
deficit, not a general one. Fischer and associates reported that only tests with a high
demand on response monitoring such as card sorting or Stroop interference tasks
were associated with confabulation (Fischer, Alexander, D’Esposito, & Otto, 1995).
Among the patients in this report, there were several in whom the distinctions
dating back to Bonhoeffer were apparent. Environmental cues suggesting content
of spontaneous confabulation were very potent among patients who worked in
health care: a nursing home nursing aide who believed that she was working at the
rehabilitation center despite wearing a patient’s gown (her uniform) and that her
memory aid book was her work schedule. Cunningham and associates also empha-
sized a correlation with set shifting and sustained attention but not general prob-
lem-solving or verbal fluency (Cunningham, Pliskin, Cassisi, Tsang, & Rao, 1991).
Johnson and coworkers suggested that a specific impairment in attributing source
and temporality to recollection was the specific executive impairment, as these
aspects of recall are independent of general recall of content (Johnson, O’Connor,
& Cantor, 1997).
Current Views of Mechanisms of Confabulation

In the late 1990s investigation of confabulation began to produce two quite dis-
tinctive accounts of the mechanism. One explanation, best defined by Schnider
and colleagues in Geneva, might be considered the “temporality” account, a fail-
ure to attribute ongoing events to the present time—that is, some type of encod-
ing failure (Schnider, von Däniken, & Gutbrod, 1996). The other explanation, best
defined by Moscovitch and colleagues in Toronto, is a failure to construct and
then check the recollection’s accuracy—that is, a retrieval account (Moscovitch &
Melo, 1997). I will consider these two accounts in turn.
In 1996 Schnider and colleagues began their very productive investigation of
confabulation (Schnider, von Däniken, & Gutbrod, 1996). Sixteen patients with
amnesia due to mixed etiologies, generally early post-acute (1 to 3 months), were
evaluated. For purposes of the study, amnesia was defined as poor performance
on the delayed recall portion of a list-learning task. Schnider and colleagues have
consistently used a very specific, if somewhat idiosyncratic, set of definitions for
confabulation. No specific confabulation battery is administered. True confabula-
tors for purposes of group assignment for experiments were only those patients
who spontaneously confabulated and demonstrated overt behaviors consistent
with the content of the confabulation, such as attempting to leave the hospital to
go to work (n = 6). Patients with “provoked confabulation” simply had increased
false-positive intrusions on the list-learning task (n = 10). Performance on a gap-
filling test (questions whose answers cannot be known and therefore are designed
to permit confabulation) was also not different, yet this task has no personal con-
tent. These results suggest that a tendency to provoked or permitted errors does
not underlie spontaneous confabulation: is not simply a more severe form of con-
fabulation. There was also no relationship of confabulation to executive measures,
although two of the three measures used were only fluency tasks. The investiga-
tors devised a test of temporal context confusion (TCC) that requires subjects to
determine if they have seen a target previously during a long presentation of

objects. These targets then become the single appearance foils of the next block of
the task a short delay later. Only patients with spontaneous confabulation had a
high rate of false endorsements of the foils on the second trial. This was inter-
preted as an inability to “maintain a normal contrast between representations of
ongoing reality and memories that refer to the past because they fail to suppress
activated but presently irrelevant memory traces” (Schnider, 2003, p. 665).
Schnider and colleagues have completed a very comprehensive research
program to demonstrate the explanatory power of this defective temporality
theory for spontaneous confabulation. Recovery from spontaneous confabula-
tion (7/8 patients recovered) is paralleled by normalization of TCC (Schnider,
Ptak, von Däniken, & Remonda, 2000). TCC is the only task that differentiates
spontaneous confabulating from non-confabulating amnesics (Nahum, Ptak,
Leemann, & Schnider, 2009). In an event-related potentials study of the same
protocol in healthy normal controls, they demonstrated a unique marker for rejec-
tion of foils (previous targets) in the second run at about 200 to 250 milliseconds
after presentation, but the marker for recognition of targets is a marker at 400 to
480 milliseconds (Schnider, 2003). A parallel fMRI study in controls demonstrated
activation in the first run in the medial temporal cortex, but in the second run in
the posterior orbitofrontal cortex (OFC). The overall conclusion: the posterior
OFC “filters out those [inputs] that fail to match the cues that represent ongoing
reality. The requirements for such cues are unknown [but] spontaneous confabu-
lators act on the basis of presently inadequate memories; that is, on the basis of
expectations that have no present potential of being satisfied” (Schnider, 2003,
pp. 667–668).
Most recently, using the same general approach, these investigators have
extended the theory (Nahum, Ptak, Leemann, & Schnider, 2009). They tested 25
mixed-etiology rehabilitation inpatients, generally between 30 and 60 days post-
onset, selected for amnesia defined as long delay recall ≤5 on the California Verbal
Learning Test (CVLT; n = 11), a demonstrated imaging lesion of OFC (n = 8), or
both (n = 6). Of the 17 patients with amnesia, 5 were spontaneous confabulators
(1 “limbic encephalitis,” 1 ACommA, 1 traumatic brain injury, 2 hypoxia). They
were tested with the CVLT, verbal fluency, design fluency, Stroop interference, an
orientation questionnaire, and an experimental task requiring associative learn-
ing with unpredictable switch of the stimulus–response mapping. The measures
of interest were errors during learning the association over repeated trials and
perseverative (extinction) errors after response switch. Normal controls were at
ceiling in both tasks, making attribution of dissociations between subjects prob-
lematic. In all patient groups orientation was correlated with learning errors,
extinction errors, and most memory measures. Spontaneous confabulators dif-
fered from other amnesics on extinction errors and orientation measures. They
concluded that the ability to extinguish irrelevant material immediately on expo-
sure before consciously determining content is the mechanism of establishing a
present reality, and that spontaneous confabulation is a failure of “the archaic

faculty of extinction, already available to primitive creatures like aplysia and dros-
ophila, to check the relation of thoughts and upcoming memories with ongoing
reality” (p. 970).
Before considering the retrieval hypothesis for confabulation, consider some
of the larger theories of recall that emerged around the same time. Burgess and
Shallice probed the consistent features of recall in a small group of healthy sub-
jects and devised a “recollection structure” that required three elements: descrip-
tions (the actual elements that recall is supposed to bring forward), editing
(verification, checking, and comparison functions), and mediators (mental rou-
tines to jump-start recall by identifying starting descriptors or to resolve discrep-
ancies detected by the verification between descriptors or final memories)
(Burgess & Shallice, 1996). Extending these notions, Moscovitch and Melo (1997)
summarized a considerable body of work, much of it from Toronto. The key dis-
tinction is between two types of retrieval processes: associative/cue-dependent and
strategic. Associative retrieval is a relatively automatic process representing direct
mapping of hippocampus (specific, immediate cues) to cortical association cortex
(stored knowledge as the targeted memory or the starter descriptor). Strategic
retrievals are problem-solving routines (mediators) required when associative
routine does not succeed or recall is not verified. The Toronto group further
defined the mediators as “framing the memory problem” and drawing on knowl-
edge and related memories to constrain search until associative routines are effec-
tive. Verification was not really defined beyond monitoring. So how might
impaired strategic retrieval lead to confabulation as opposed to just correctable
mistakes?
Moscovitch and Melo reported 17 patients with amnesia, 9 with confabulation
and 8 without (Moscovitch & Melo, 1997). Only one of the nine confabulation
patients had had a ruptured ACommA, but six of the eight patients with confabu-
lation had bilateral ventromedial frontal lesions; none of the non-confabulating
patients had that lesion profile. Time post-onset was not specified and lesions
were described only qualitatively. Confabulation was scored with a cued word and
prompt method rather than just the behavioral observations, and it is unclear if
the subjects would have met the spontaneous confabulation criteria of Schnider’s
group. Moscovitch and Melo devised a task that allowed comparison of confabula-
tion in personal memory and in general semantic memory as well as the sensitiv-
ity to prompts when memory failed. The confabulating patients were equally likely
to confabulate on semantic material as personal. Prompting dramatically increased
the frequency of confabulation in the confabulating group only. Confabulation
more commonly affected the content of recall than the time of the event. They
concluded that confabulation, as defined by their task, occurred when the associa-
tive memory system failed to produce a memory; amnesics had many “I don’t know”
responses, but this was not the case for confabulators. Errors (and confabulation)
might emerge if the strategic search mechanism is faulty, but confabulations are
produced only if monitoring of the search product is impaired. (Unrelated directly

to the question of confabulation, it must be noted that this strategic retrieval
hypothesis also unifies the route to recall of both episodic and semantic memory.)
The Toronto group returned to this issue in 2004 with an investigation of four
subjects with bilateral medial frontal injury (three with ACommA and one with
infarction in the identical territories but without an ACommA) who were all spon-
taneous and behavioral confabulators (Gilboa et al., 2006). Controls were a group
of eight patients with amnesia after ACommA but no confabulation, four patients
with medial temporal damage and amnesia, and nine healthy subjects. Patients
were all very chronic, and the non-confabulating ACommA patients very likely
had a confabulation epoch earlier in their course. The subjects performed the TCC
task as described by Schnider and a parallel task in which the content but not the
time was manipulated. The confabulators had many more errors on the TCC task
than the normal controls and the medial temporal controls, but six of the eight
non-confabulating ACommA controls also had more TCC errors, indicating that
TCC errors were not specific to confabulators in this sample. On the comparison
task of content confusions, the results were identical. The subjects were also asked
to relate very familiar stories (fairy tales or Biblical parables) in as much detail as
possible. Omissions and distortions were uncommon and equally likely to appear
in all groups. Incorporation of material from outside the common story content
and idiosyncratic plot and character references were seen only in the confabulat-
ing patients. The investigators harvested personal stories for the patients from
family members from both before and after the brain injury. These were used to
create a true/false autobiographical recognition task. After answering, patients
were asked to rate their confidence in the answer. A parallel test with familiar tales
was created as well. The confabulating patients had high false-positive scores on
both tests for both plausible and implausible foils, as well as high confidence on
error items. The authors concluded that TCC was present in confabulators, but
not solely in that group (and the text of the report indicates considerable inter-
action with Schnider about certifying that construction and scoring were done as
in Geneva) and not uniquely: content confusion was also apparent for both seman-
tic and historical material as well as autobiographical material.
Gilboa and colleagues identified three potential levels of monitoring at which
failure could occur. The first is a feeling of knowing (FOK) that operates prior to
retrieval, as though setting an intuitive sense of possible need to monitor. We,
among others, have demonstrated impaired FOK with right ventromedial lesions
in patients, several of whom previously confabulated but did not do so at the time
of the study (Schacter, Curran, Galluccio, Milberg, & Bates, 1996; Schnyer et al.,
2004). The second is a feeling of rightness (FOR), a rapid, very-early-post-retrieval,
intuitive sense of accuracy. This level of monitoring appears to arise from the ven-
tromedial cortex, perhaps also more strongly on the right (Gilboa, Alain, He, Stuss,
& Moscovitch, 2009). This is, of course, very close to the argument of Schnider.
The third level is slower and conscious and occurs post-retrieval: a knowledge of
rightness (KOR), involving monitoring of content. This is equivalent to the verifi-

cation or comparison step of other models. It may be very slow, recruited only
strategically, launching problem-solving routines to achieve verification or rejec-
tion. Depending on the complexity of verification, KOR appears perhaps depen-
dent on more lateral/cognitive/frontal operations.
In a subsequent event-related potential study of eight patients with ventrome-
dial lesions after ACommA, this convergence around preconscious processing was
buttressed (Gilboa, Alain, He, Stuss, & Moscovitch, 2009). The patients failed to
show an early (170 milliseconds) posterior cortical response to familiar faces
(personally known or celebrities) that was robust in controls. They also failed to
show normal early (230 to 260 milliseconds) frontopolar modulation of poten-
tials seen in controls, but the closer the patients’ frontal wave forms matched
those of controls, the more accurate their explicit recognition. Thus, the frontal
lesion caused a “top-down” failure of the posterior cortex to do preconscious
familiarity judgments and interfered with the accuracy of the slower conscious
explicit task performance. At the time of this experiment only one of these
patients was confabulating, but three others either were still having difficulty
with verifying memories or had been definitively identified as confabulators
earlier in their course. The group had fairly mild memory and executive impair-
ments, so these findings, although not derived from currently confabulating
patients, represent the residuals of the cognitive deficit that allows the emergence
of confabulation.
Turner, Cipolotti, Yousry, and Shallice (2008) recently took yet another
approach to the question and supported the hypothesis that there is a specific
impairment after orbitomedial injuries that “permits” confabulation in the pres-
ence of amnesia. They studied 38 patients with focal frontal lesions, a mix of
orbital and right or left lateral lesions (mostly tumors) and 12 focal posterior
lesions (all tumors). There was a significant difference in time since surgery, with
medial and left lateral cases in general studied very early and right lateral and
especially orbital lesions much later. There were only three spontaneous confabu-
lators; all had ACommA (out of 12 total ACommA cases), but on a version of Dalla
Barba’s multidimensional confabulation battery there was considerable emergent
confabulation (Dalla Barba, Mantovan, Cappelletti, & Denes, 1998). Patients with
orbital (and very chronic) lesions produced very significantly more confabulatory
responses than controls (p < 0.001), as did patients with medial lesions, although
this effect was borderline significant (p = 0.049). Confabulatory responses were
most common in the personal episodic domain and in orientation for time, par-
ticularly in the patients with orbital or medial lesions. Laterality had less clear
effects. Eight patients of the total of 50 were identified as high confabulators
(comparable to spontaneous); all had frontal lesions. Performance on a memory
composite measure was significantly lower in the high group, yet the executive
composite was only marginally lower (p = 0.06). On the individual executive tests
there was much variability. While the prior claim that specific executive tests
might best correlate with confabulation (Cunningham, Pliskin, Cassisi, Tsang, &
Rao, 1991; Fischer, Alexander, D’Esposito, & Otto, 1995) was not supported,
the patients in these prior studies were spontaneous confabulators. Turner and
colleagues proposed a very likely resolution of this executive deficit and confabu-
lation conundrum: executive deficits are an epiphenomenon, a peripheral indica-
tor of frontal lesions, only some of which may be critical for “permitting”
confabulation.
Much of the work of Stuss and colleagues in the past 10 years has focused on
the specific regional effects of frontal lesions. The traditional executive tasks are
most likely to be affected by lateral lesions, not orbitomedial ones, so a weak
correlation of executive tests with a behavior uniquely due to ventromedial
damage is to be expected (Alexander, Stuss, Shallice, Picton, & Gillingham, 2007;
Picton et al., 2007; Stuss, Floden, Alexander, Levine, & Katz, 2001; Stuss, Toth,
Franchi, et al., 1999). The specific executive pattern in any given study will
vary depending on the mix of lesion sites, etiologies and chronicities, but it is the
rapid preconscious deficit that primes patients to confabulate—perhaps not per-
sonal TCC alone but a less specific FOR response to the content of memory
retrieval. So the conclusion seems to be that faulty automatic associative memory
due to some limbic lesion plus impaired early preconscious FOR due to ventrome-
dial damage produces confabulation, but there are still holes in a full account.
Many operations are implemented in the first second of recollection. An experi-
ment designed to account for encoding pathways—physical enactment versus
cognitive analysis—in a recognition task in normal subjects demonstrated that
early (200+ milliseconds) event-related potential responses seem to reflect only
“retrieval orientation” effects as they are insensitive to the familiarity of the stim-
uli. Later effects (800 to 1300 milliseconds) seen in prefrontal regions represent
the actual attempt to recover source information from memory, after an item has
been recognized as familiar and follows the earlier stage of retrieval orientation,
perhaps reflecting the generation of internal cues to guide source retrieval
(Senkfor, Van Patten, & Kutas, 2008).
Resolution of Current Hypotheses

First, how can we account for implausible content that does not simply disrespect
current time but is occasionally frankly impossible (shot in the head, piloting a
space capsule) or at least very implausible (giving a lecture on pulmonary disease)
or account for the occasionally remarkable environmental capture (“a Navy
kitchen”) that does not occur as a stimulus passes by but slowly unfolds out of a
stable environment? These remarkable errors from observational reports are
paralleled by the implausible distortions of very ingrained semantic knowledge
demonstrated by Gilboa and associates (Gilboa et al., 2006) in an experimental
study. No matter how thematically connected to a pre-illness life, rejecting these
beliefs should not depend on their being preconsciously marked as irrelevant

to current time. The answer is not clear, in part because of the very great range
of confabulation that gets included in different studies. There may be three
factors.
Recall Pick’s observation that confabulation is likely to occur under circum-
stances of clouded consciousness. We suspect that certain implausible notions are
prompted by some idiosyncrasy of the patient’s circumstance as he or she emerges
from coma, delirium, or anesthesia if those specific brain lesions are present.
Stuss suggested that something registers about that circumstance as an accurate
experience and becomes “affectively burned in” (Stuss & Alexander, 1999). That
may be how patients can “recall” a confabulation even though it is not true (more-
over, they could not learn or recall it if it were a neuropsychological task) and why
it is likely to feel correct. Second, as suggested by Burgess and McNeil (1999),
some confabulations may begin as the intrusion of a salient generic memory,
perhaps prompted by some unique early event during recovery that becomes
reinforced by repetition. If the patient cannot recall alternative specific memories
or, as they suggest, if the confabulation has “implications for future action” and
continuously reinforces itself through expectation, it may be unopposed despite
implausibility. But third, there must be, at least on occasion, a failure of the con-
scious post-retrieval verification system. Consider the parallel disorder Capgras
syndrome when it occurs after acute brain injury. As amply demonstrated by
Weinstein and Kahn, confabulation and Capgras syndrome may occur together
(Weinstein & Kahn, 1954). Even when distinct, these two syndromes have several
common properties: similarities of lesion distributions, occurrence after emer-
gence from delirium, during a period of amnesia and while executive function is
impaired. In the patient described by Stuss and colleagues, the idiosyncratic event
occurred when his attention and memory had improved enough to allow a pro-
gram of home passes (Alexander, Stuss, & Benson, 1979). The actual event was
the appearance of his wife when she arrived to take him home on a pass with a
new car and a new hairstyle—almost but not quite what he remembered. At home
he expected his children, and they were there, but not as old and not quite the
same as he remembered. Generic recall, repetition, reinforcement, and expecta-
tion “burned in” the false memory. Unlike most confabulating patients, he was
aware of the implausibility of two families, but a very large right ventral frontal
and temporal lesion so attenuated his capacity for verification that intuition and
emotional connection to the memory overrode it.
Another potential hole for the complete account: if confabulation is caused by
a specifiable lesion set, why does that lesion pattern so infrequently cause perma-
nent confabulation or even at times not cause confabulation at all? The answer is
unknown. For patients who recover, one potential answer is that the conscious
post-retrieval verification system eventually resets that automatic system based
on repeated error signals. This allows the fundamental impairments—amnesia,
TCC, FOR—to be detectable, while one surface manifestation of those deficits,
confabulation, slowly attenuates. For the patients with the same orbital or ven-
tromedial frontal lesions who never confabulate, the answer may be that they
were not amnesic. A brief summary of the remarkable range of cognitive and
behavioral effects associated with activity in this region and of impairments asso-
ciated with lesions in this region may indirectly inform about confabulation:
1. Impaired prospective memory: Many confabulations have implications for

future behaviors, but patient rarely pursue them.
2. Unresponsiveness to negative outcomes: Confabulators are frequently undis-
turbed that what might happen based on the confabulation does not.
3. FOK: exaggerated certainty that a correct target will be recognized
4. Multi-attribute decision-making (Fellows, 2006): critical capacity to recon-
sider contingencies and implications of a decision or, perhaps, a recollection
5. Theory of mind: how other people understand and react to the implausibility
of the confabulation (Floden, Alexander, Kubu, Katz, & Stuss, 2008; Stuss,
Gallup, & Alexander, 2001)
6. Belief versus disbelief: There is at least one study that suggests that when con-
fronted with claims that can be believed or disbelieved, disbelief is the more
active state; it is more difficult to drop a belief than to hold it (Harris, Sheth, &
Cohen, 2008).
Conclusions
For more than 30 years, Don Stuss has been producing hypotheses, experimental
protocols, and data that inform our understanding of frontal lobe injuries and the
nature of executive system disorders. His first publication on confabulation was
in 1978, a clinical report of five patients with epic confabulation. They were inves-
tigated with standard neuropsychological tests and early (very early) CT localiza-
tions to infer the course of cognitive activity over minutes to days. This first study
yielded novel notions about the nature of the additional deficit, beyond amnesia,
that was required for confabulation to emerge. The most recent publication on
confabulation from Toronto (Gilboa et al., 2009) was an analysis of eight patients,
some recovered from confabulation and all with the OFC lesion. This report used
focused experimental tasks, modern MRI lesion localization, and very precise
event-related potentials to chart the course of cognitive activity in the range of
hundreds of milliseconds. The account of confabulation has become more and
more finely grained from generically executive to specifically cognitive, although
it is still not perfectly understood.
Confabulation is an intriguing clinical phenomenon and has generated much
more interest than is warranted by its prevalence. Persistent confabulation is rare;
thus, investigators assemble groups of four or five or eight subjects or evoke con-
fabulation with a task contrived to do just that in the susceptible. Its very defining
features are so slippery, and its presence so often transient, that standardizing
experimental approaches is difficult. It usually disappears without any direct clin-
ical intervention as the underlying disorder improves. There is no evidence that
confabulation has any specific effect on or relationship to prognosis or treatment
of the underlying disorders. Why should we care?
Consider a pleasant, not apparently confused, middle-aged college graduate, a
one-time aerospace engineer, as he tells you the reason he is in the hospital: he is
to be debriefed after his space flight (which he has never done). His capsule came
down in Havana harbor (where he has never been) and there was an international
incident because the U.S. Navy had to go into the harbor to rescue him. He had
jumped into the water to evade the Cuban Coast Guard (nothing similar is likely
to have ever occurred)—oh, and he broke his glasses (no doubt he had done that
once upon a time) when he jumped from the capsule. Each day you interview him
he “remembers” the same story, although he cannot remember anything he was
told about why he was actually in the hospital (severe frontal contusion after a fall
while intoxicated). Trying to recreate his hospital experience, you discover that he
required a tracheostomy and a prolonged weaning in the ICU, emerging from
coma to delirium, day after day lying on his back wearing a humidifying mask with
a monitor beeping above him and many Spanish-speaking staff around him. That
experience could launch a career.
References
Alexander, M. P., & Freedman, M. (1984). Amnesia after anterior communicating artery aneurysm
rupture. Neurology, 34, 752–757.
Alexander, M. P., Stuss, D. T., & Benson, D. F. (1979). Capgras syndrome: A reduplicative phenom-
enon. Neurology, 29, 334–339.
Alexander, M. P., Stuss, D. T., Shallice, T., Picton, T. W., & Gillingham, S. (2007). Regional Frontal
Injuries Cause Distinct Impairments in Cognitive Control. Neurology, 68, 1515–1523.
Baddeley, A. D., & Wilson, B. (1988). Frontal amnesia and the dysexecutive syndrome. Brain and
Cognition, 7, 212–230.
Berlyne, N. (1972). Confabulation. British Journal of Psychiatry, 120, 31–39.
Burgess, P. W., & McNeil, J. E. (1999). Content-specific confabulation. Cortex, 35, 163–182.
Burgess, P. W., & Shallice, T. (1996). Confabulation and the control of recollection. Memory, 4,
359–411.
Cunningham, J. M., Pliskin, N. H., Cassisi, J. E., Tsang , B., & Rao, S. M. (1991). Relationship
between confabulation and measures of memory and executive function. Journal of Clinical
and Experimental Psychology, 19, 867–877.
Dalla Barba, G., Mantovan, M. C., Cappelletti, J. Y., & Denes, G. (1998). Temporal gradient in con-
fabulation. Cortex, 34, 417–426.
Damasio, A. R., Graff-Radford, N. R., Eslinger, P. J., Damasio, H., & Kassell, N. (1985). Amnesia fol-
lowing basal forebrain lesions. Archives of Neurology, 42, 263–271.
DeLuca, J. (1993). Predicting neurobehavioral patterns following anterior communicating artery
aneurysm. Cortex, 29, 639–647.
DeLuca, J., & Cicerone, K . (1991). Confabulation following aneurysm of the anterior communicat-
ing artery. Cortex, 27, 417–423.
Fellows, L. K . (2006). Deciding how to decide: ventromedial frontal lobe damage affects informa-
tion acquisition in multi-attribute decision making. Brain, 129, 944–952.
Fischer, R. S., Alexander, M. P., D’Esposito, M., & Otto, R . (1995). Neuropsychological and neu-
roanatomical correlates of confabulation. Journal of Clinical and Experimental Psychology, 17,
20–28.
Floden, D., Alexander, M. P., Kubu, C. S., Katz, D., & Stuss, D. T. (2008). Impulsivity and risk-taking
behavior in focal frontal lobe lesions. Neuropsychologia, 46, 213–223.
Gilboa, A., Alain, C., He, Y., Stuss, D. T., & Moscovitch, M. (2009). Ventromedial prefrontal cortex
lesions produce early functional alterations during remote memory retrieval. Journal of
Neuroscience, 29, 4871–4881.
Gilboa, A., Alain, C., Stuss, D. T., Melo, B., Miller, S., & Moscovitch, M. (2006). Mechanisms of spon-
taneous confabulations: a strategic retrieval account. Brain, 129, 1399–1414.
Harris, S., Sheth, S. A., & Cohen, M. S. (2008). Functional neuroimaging of belief, disbelief, and
uncertainty. Annals of Neurology, 63, 141–147.
Johnson, M. K., O’Connor, M., & Cantor, J. (1997). Confabulation, memory deficits, and frontal
dysfunction. Brain and Cognition, 34, 189–206.
Kapur, N., & Coughlan, A. K . (1980). Confabulation and frontal lobe dysfunction. Journal of
Neurology, Neurosurgery and Psychiatry, 43, 461–463.
Kopelman, M. D. (1987). Two types of confabulation. Journal of Neurology, Neurosurgery and
Psychiatry, 50, 1482–1487.
Kopelman, M. D., Guinan, E. M., & Lewis, P. D. R . (1995). Delusional memory, confabulation, and
frontal dysfunction: a case study in De Clérambault’s syndrome. Neurocase, 1, 71–77.
Mercer, B., Wapner, W., Gardner, H., & Benson, D. F. (1977). A study of confabulation. Archives of
Neurology, 34, 429–433.
lation and amnesia. Neuropsychologia, 35, 1017–1034.
Nahum, L., Ptak, R., Leemann, B., & Schnider, A . (2009). Disorientation, confabulation, and
extinction capacity: clues on how the brain creates reality. Biologic Psychiatry, 65, 966–972.
Picton, T. W., Stuss, D. T., Alexander, M. P., Shallice, T., Binns, M. A., & Gillingham, S. (2007).
Effects of frontal lesions on response inhibition. Cerebral Cortex, 17, 826–838.
Schacter, D. L., Curran, T., Galluccio, L., Milberg , W. M., & Bates, J. F. (1996). False recognition and
the right frontal lobe. Neuropsychologia, 34, 793–808.
Schnider, A . (2003). Spontaneous confabulation and the adaptation of thought to ongoing reality.
Nature Review Neuroscience, 4, 662–671.
Schnider, A., Ptak, R., von Däniken, C., & Remonda, L . (2000). Recovery from spontaneous con-
fabulations parallels recovery of temporal confusion in memory. Neurology, 55, 74–83.
Schnider, A., von Däniken, C., & Gutbrod, K . (1996). The mechanisms of spontaneous and pro-
voked confabulations. Brain, 119, 1365–1375.
Schnyer, D. M., Verfaellie, M., Alexander, M. P., LaFleche, G., Nicholls, L., & Kasniak, A. W. (2004).
A role for right medial prefrontal cortex in accurate feeling-of-knowing judgments: evidence
from patients with lesions to frontal cortex. Neuropsychologia, 42, 957–966.
Senkfor, A. J., Van Patten, C., & Kutas, M. (2008). Enactment versus conceptual encoding: equiva-
lent item memory but different source memory. Cortex, 44, 649–664.
Shapiro, B., Alexander, M. P., Gardner, H., & Mercer, B. (1981). Mechanisms of confabulation.
Neurology, 31, 1070–1076.
Stuss, D. T., & Alexander, M. P. (1999). Affectively burnt in: a proposed role of the right frontal lobe.
In E. Tulving (Ed.), Memory, consciousness and the brain: the Tallinn Conference (pp. 215–227).
Stuss, D. T., Alexander, M. P., Lieberman, A., & Levine, H. (1978). An extraordinary form of con-
fabulation. Neurology, 28, 1166–1172.
Stuss, D. T., Floden, D., Alexander, M. P., Levine, B., & Katz, D. (2001). Stroop performance in focal
lesion patients: dissociation of processes and frontal lobe lesion location. Neuropsychologia,
39, 771–786.
mind.” Brain, 124, 279–286.
Stuss, D. T., Toth, J. P., Franchi, D., Alexander, M. P., Tipper, S., & Craik, F. I. M. (1999). Dissociation
of attentional processes in patients with focal frontal and posterior lesions. Neuropsychologia,
37, 1005–1027.
Turner, M. S., Cipolotti, L., Yousry, T. A., & Shallice, T. (2008). Confabulation: damage to a specific
inferior medial prefrontal system. Cortex, 44, 637–648.
Van Der Horst, L . (1932). Ueber die Psychologie des Korsakowsyndroms. Msschr Psychiatrie
Neurologie, 83, 65–84.
Weinstein, E., & Kahn, R. L . (1954). Denial of illness. Springfield, IL: Charles Thomas.
3
Reflections on ROBBIA
TIM SHALLICE
The ROBBIA Set of Studies

The ROBBIA project was an ambitious enterprise. It took well over 10 years to
complete but in the end led to many findings (see, e.g., Stuss & Alexander, 2007).
It was a splendidly collaborative project, and one that exemplified how science can
be such a deeply personally satisfying activity. However, Don Stuss was undoubt-
edly the prime mover, the intellectual and organizational dynamo at its hub with
his unrivalled knowledge of prefrontal processes in humans. In many ways,
though, the spirit of ROBBIA was contrary to that of the Zeitgeist. It began in the
mid-1990s (Stuss, Shallice, Alexander, & Picton, 1995) with a theoretical perspec-
tive that was not that common at the time: that working memory is not the be-all
and end-all of the functions of the prefrontal cortex. More specifically, it held that
a variety of computationally distinct processes are required to implement the
supervisory functions of the prefrontal cortex, which again was far from generally
agreed (see, e.g., Duncan, 2001, for a very different view). Again not in line with
the more traditional clinical neuropsychological approach to the prefrontal cortex,
the ROBBIA project began by attempting to separate out putative processes, not
by examining complex high-level tasks but by using a battery of simple tasks
designed to have their lower-level characteristics, such as the stimuli and the per-
ceptual and motor processes involved, as similar as possible from one task to
another. Finally, the methodology we employed was not functional imaging or
even single case analysis but rather the most traditional approach as far as the
study of human subjects using behavioral neuroscience methods is concerned—
namely, the anatomically based neuropsychological group study, essentially of the
sort that was widely used in the 1960s, although employed by us with more ana-
tomical precision. The end product too (see, e.g., Shallice, Stuss, Picton, et al.,
2008b; Stuss & Alexander, 2007) is rather orthogonal to the most fashionable per-
spective for conceiving of the prefrontal cortex, namely as a post-Fusterian,
essentially hierarchical set of control systems (e.g., Badre, 2008; Botvinick, 2008;
Koechlin et al, 2003).
33
Why did we use simple tasks? If one carries out an intuitive task analysis of
classical clinical tests of prefrontal function such as Wisconsin Card-Sorting, the
Trail Making test, Proverbs, and to a lesser extent Verbal Fluency, they clearly
involve many different processing components. Don’s work in particular had
shown the variety of subsystems involved, making the standard inference from
the qualitatively different effects on behavior of different lesion sites in the pre-
frontal cortex (Stuss et al., 1998, 2000). Even simple tasks, if they are designed to
investigate the prefrontal cortex, will inevitably involve other processes outside
the prefrontal cortex as well, and will probably load on many more processes than
is the case for, say, a perceptual study or a motor control one. Moreover, we believed
it likely that the functions computed in these processes would be fairly abstract
and not closely related to any single behavioral measure (Shallice & Burgess, 1996;
Stuss et al., 1995). In addition, the effective dependent variables that these tasks
provide tend to be crude by comparison with the accuracy provided by physical or
physiological variables, being frequently little more than an ordinal relation across
conditions. Thus, we believed that there was relatively little likelihood of making
major progress in fractionating prefrontal functions and characterizing their com-
ponents using the types of task that had been relatively effective in clinically diag-
nosing prefrontal deficits in the past, in other words by using complex clinical
tasks. There will be too many degrees of freedom in moving between task perfor-
mance—both normal and impaired—and conceptions of the organization of the
underlying system. Of course, one danger in using simple tasks is that we might
not have found selective deficits following prefrontal lesions. But we did.
The Anatomically Based Neuropsychological

Group Study and its Vicissitudes
Why did we use neuropsychological methods? There were two main reasons and
two subsidiary ones. Given what we have just said about tasks involving prefrontal
cortex tending to require the operation of multiple subsystems, it is still possible
to study these processes in a functional imaging experiment employing, say, a sub-
traction, factorial, or cognitive conjunction design, but one needs great skill or
good fortune in selecting the appropriate experimental conditions to tap the par-
ticular function effectively. It can be done, but successful paradigms are in my view
rather rare (excellent examples are Badre & D’Esposito, 2007; Braver et al., 2003;
and Burgess et al., 2001). One can of course add a psychophysiological interaction
component to the fMRI analyses. Yet as far as the absolutely critical behavioral
aspects of the results are concerned, the differences between normal subjects in
the control group are much less than those between subjects in a neuropsycho-
logical experiment (i.e., comparing patients and controls or comparing patients),
so behaviorally one would expect psychophysiological interaction analyses and
functional imaging data to be much less sensitive than neuropsychological data.
R e fl e ct ion s on R OBBI A 35
The second reason is that when we began the project in 1995 we had no clear
agreed-upon conception of how the prefrontal cortex was organized, only specu-
lations. With the possible exceptions of Patricia Goldman-Rakic, Michael Petrides,
Jordan Grafman, and John Duncan—who between themselves did not see eye to
eye—no one else did, either. The type of fMRI experiment referred to in the previ-
ous paragraph depends upon a well-worked-out theory of the relevant processes
and then attempts to test the theory. Our belief based on the history of neuropsy-
chology was that neuropsychology provided more potential for serendipity than
did functional imaging, and serendipity is what we thought the field needed at the
time. Why should neuropsychological data have a greater potential for serendipity
than functional imaging? The principal reason, apart from the sheer magnitude of
the behavioral effects, is that the method provides more than just the probability
of the patient being correct or making an error across conditions. When they are
wrong, patients make errors that provide positive diagnostic information on the
function of the relevant subsystem. Given the paucity of the behavioral data pro-
vided by accuracy alone and the relative lack of informativeness of reaction times
in many tests of executive functions, additional behavioral evidence in the form
of the nature of the errors is extremely valuable.
This was demonstrated, for instance, in the ROBBIA study by Shallice, Stuss,
Alexander, Picton, and Derkzen (2008a). In this study subjects must say how
many beeps occurred in stimulus trains of between 8 and 22 beeps presented at a
3-per-second rate. Two prefrontal groups, the superior medial and the right lat-
eral, were impaired in the task. But the two groups differed on the nature of their
errors: the superior medial group underestimated the number in the train; the
right lateral group was just inaccurate without consistently underestimating.
Somewhat related contrasts between these two groups were also found in gener-
ating a sequence of taps at a particular preset rate (Picton et al., 2006). The error
analysis allows one to use a cognitive neuropsychology style of theorizing on
group data, presupposing that the impairments within any one subgroup are
functionally unitary. It points to qualitatively different underlying processes being
impaired in the two groups.
Thirdly, we have a fairly clear conception of how to relate neuropsychological
evidence to a theory of how the cognitive system operates. We see brain damage
as resulting in loss of cognitive resource in one or more functional subsystems.
Of course, we cannot specify in any particular case for a specific subsystem how
much resource is lost and how it is damaged. However, the presupposition that a
subsystem is not functioning adequately is sufficient to allow theoretical prog-
ress, if only by falsifying certain positions (Caramazza, 1986; Shallice, 1988). As
far as functional imaging is concerned, what we know about the BOLD signal is
that its physiological underpinnings are very complex (Logothetis, 2008). We do
not have any model on the functional level of what is implied that the region is
more activated in one condition than another, or even whether this is the same
for all significant differences in activation across tasks and across brain regions.
Thus, drawing functional conclusions from an fMRI experiment requires an

unsupported act of faith that activation levels correspond in some well-behaved
way to the amount of some cognitive resource employed (Shallice, 2003; but see
Henson, 2005, for a more positive view).
Even though conceptually one can draw inferences from an empirical pattern
of deficits in a patient or patients to the theoretical organization of an underlying
cognitive system, there are many problems in putting the inference into practice.
First, there is the choice between a patient and the average performance of a
group of patients. The arguments for the inferential preference for using only
individual case data to draw inferences about the theoretical organization of cog-
nition, and not using group data, were never very convincing (Shallice, 1988) and
have somewhat rarely been put effectively into practice as far as frontal lobe func-
tion is concerned. Exceptions involve a few highly specific syndromes, such as
dynamic aphasia (e.g., Robinson et al., 1998, 2005), confabulation (Moscovitch &
Melo, 1997; Schnider, 2007) and other memory disorders (Levine et al., 1998),
and two more core frontal syndromes: lesions of the anterior cingulate (e.g.,
Critchley et al., 2003; Milea et al., 2003) and of frontopolar regions (Shallice &
Burgess, 1991). However, in general the lack of the ability to create paradigms
with many equivalent trials and the potential lack of stationarity of the manifes-
tations of prefrontal damage have tended to make the group study the preferred
methodological neuropsychological option for studying frontal lobe function.
Moreover, recent developments in the language domain have shown individual
differences to be a much more severe problem in the logic of inferences from
impaired performance to normal function in single case designs than was previ-
ously realized (Woollams et al., 2007).
The group study approach, though, is faced by a number of methodological
problems. I will consider three. First, what anatomical basis is used to combine
patients into a group? Second, how does one deal with the possible confounding
effects of other variables, such as etiology, age, and lesion size, which may differ
according to the particular location of each group? Third, does one prefer the
Scylla of the short-term acute effects of lesion creation after operation or the
Charybdis of potential reorganization of function in choosing between the use of
acute or chronic cases?
In the ROBBIA series of studies we used both a coarse-grained and a fine-
grained approach in the allocation of patients to groups. Our large-grained
approach was to divide the two frontal cortices into four regions—left lateral,
right lateral, superior medial, and inferior medial. In a recent study of memory
problems of prefrontal patients we replaced the superior medial/inferior medial
division by a medial/orbital one (Turner et al., 2007). I see no principled difference
between these two approaches, although most other recent developments in
neuropsychological group procedures have used a finer-grained approach. Such
finer-grained approaches include voxel-based morphometry, voxel-based lesion-
symptom mapping (Bates et al., 2003: Rorden, Karnath, & Bonhila, 2007),
and the ROBBIA one of using regions analogous to Brodmann areas—in our case,
the areas of frontal cortex specified by Petrides and Pandya (1994). The choice of
fine-grained regions is made because it is generally held to be more appropriate to
reduce the anatomical grain of the approach, much as it is held to be preferable to
use 3T fMRI rather than 1.5T. Intermediate between the two approaches is the
use of five regions of interest within each frontal cortex (superior frontal gyrus,
medial frontal gyrus, inferior frontal gyrus, medial, and orbital)—the approach
employed by Aron and coworkers (2004). In addition, it is held, for instance by
Rorden and Karnath (2004), that it is preferable not to determine the possible
anatomically critical areas a priori, which is a necessary consequence of determin-
ing the anatomical groupings prior to analysis.
There are two major methodological problems with a finer-grained approach
alone. First, anatomical location can correlate with another critical variable, such as
lesion size, etiology, education, or age. Thus, in the ROBBIA studies the superior
medial group had the largest average lesion size; their lesions were on average over
three times larger than those of, say, the left lateral group. Interestingly, in the Aron
and associates (2004) study of task-switching, the right frontal group had more than
double the average lesion size of the left frontal group, showing a rather analogous
left–right difference to the ROBBIA studies. It is possible that left lateral prefrontal
patients may have smaller lesions because they present with clinical symptoms more
evidently than do right-hemisphere patients with similar-size lesions and so are
more likely to reach the attention of the research team. If this is the case, then a
sample biased with respect to lesion site might well result. This would be less likely
with samples where the presenting symptom is, for instance, an epileptic seizure, as
with many tumor patients. Moreover, in practice differences in etiology will inevita-
bly influence a contrast between different frontal lobe subregions, even if the con-
found concerns, say, the relative proportions of different types of tumors.
If one has a fairly coarse-grained approach, then one can partially cope with at
least the first, third, and fourth of these potential confounding factors by
approaches like partialling out the effects of the confounding factor. More criti-
cally, given a whole set of related studies as in the ROBBIA studies, the use of a
double dissociation type of logic across studies at least allows one to limit the
effect of potential confounding factors to one region per confounding factor.
Thus, specific impairments in a ROBBIA type of study that are specific to only one
of the three frontal groups and not the superior medial group cannot be attrib-
uted to lesion size. The same logic cannot be as easily used where fine-grained
analysis is carried out, and especially when the groupings are analysis based and
therefore differ from one study to another. Correlations between the amount of a
particular area damaged with a behavioral variable (e.g., Aron et al., 2004) are just
as susceptible to this problem as the more standard procedure of comparing
patients with damage to an area with patients without damage to that area.
As far as functional inferences about the processing undertaken in different
frontal lobe subregions are concerned, the greater reliability of the coarse-grained
rather than the fine-grained averaging of performance does not necessarily extend
to the anatomical localization of the different processing components that are
isolated. For instance, if a right lateral group and a left lateral prefrontal group
were to contain very different proportions of ventrolateral and dorsolateral
lesions, then a functional distinction that was actually between systems localized
in the ventrolateral and dorsolateral regions could masquerade as one between
the left and right lateral regions.
There is, however, a second and probably more serious problem for the finer-
grained approach that is much less apparent. There is a great difference in the
potential for detecting an impairment across different main areas, as the sensitiv-
ity is strongly dependent on the number of cases with a lesion in a particular area.
Thus, in the ROBBIA series of studies, the finer-grained analysis subdivided the
two frontal cortices, together with subcortical structures, particularly in the basal
ganglia, into 69 different areas. Thus, left Brodmann area 45 was divided in two.
Patients of course tended to have lesions that covered a number of these areas, in
some cases a lot of them. However, glossing over the problem of lesion size,
patients with lesions in each of these areas were compared with patients who did
not have a lesion in the area.
Using 69 subgroups raises a Bonferroni correction problem, which was not
confronted; however, a worse problem is area representation. There was only one
patient whose lesion involved more than 25% of the area in each of seven areas,
including, for instance, the left global pallidus and the two parts of left area 8. By
contrast, 14 areas were represented in 10 cases or more, culminating in 3 areas
with 14 cases each (right area 14 orbital, right area 14 ventral, right area 32i). The
criterion of at least 3 cases was used as the minimum for an effect to be detected.
Thus, for about 20% of the areas no effect could be detected, however strong, and
even in areas that did satisfy the criterion, there was a five-fold difference in the
number of patients in the more critical positive group. For a given effect size there
is an enormous difference in the probability of it being detected if the lesion is in
one area than in another. For the coarse-grained analyses the numbers of patients
in each group varied from 15 in the inferior medial group to 6 in the right lateral
group, a considerable difference between group sizes (150%), but this is a mere
nothing by comparison with the 1300% for the finer-grained analysis! Moreover,
replacing, say, our sub-Brodmann area procedure by, say, lesion behavior mapping
(LBM) would not in any way reduce the problem of the natural history of lesion
representation in particular areas.
Converging Evidence on Inferences

from the ROBBIA Studies
The ROBBIA set of studies has the major methodological advantage of using the
same set of patients. This allows the method of making inferences from differing
selective deficits across tasks to be used optimally. It also has the problem, how-
ever, that the results are potentially biased by idiosyncratic characteristics of this
patient group. In my view the best way to deal with this problem and problems of
lesion size, of other correlated variable artifacts, of the need for major Bonferroni
corrections (if the finer-grained procedure is used), and of differential representa-
tions of lesion locations discussed earlier is by means of converging operations.
This approach is possible within neuropsychology itself. Thus, instead of using
chronic lesions, as in the ROBBIA studies, one can work with acute tumor patients
postoperatively.
Since in the ROBBIA studies only about 20% of the patients were tumor
patients, with the remaining 80% having suffered strokes (including infarcts) and
trauma, and since those patients were in the chronic stage, the tumor group
essentially consists of a different type of patient population with a different natu-
ral history of lesion locations. However, drawing inferences to normal cognition
from the performance of acute tumor patients has a very bad reputation within
neuropsychology. Some gliomas, such as oligodendrogliomas and some astrocy-
tomas, can grow diffusely throughout one or both hemispheres. With MR imag-
ing, unenhanced T1 images can underestimate tumor extent, while T2 images
cannot distinguish tumor from edema. Even when the border of the tumor appears
sharp on a scan, it is likely to have invaded apparently healthy tissue. However, it
should be noted that even for gliomas, Mikkelsen and Rosenblum (1999) argue,
“Regional and remote recurrences are less frequent because of rapid fall-off in
tumor cells” (p. 77), with 75% of recurrences starting within 2 cm of the apparent
position of the original tumor. Complementarily, prior to surgery, it may be
unclear whether the nervous tissue within a glioma is operative or not. Low-grade
gliomas, too, being slow-growing, may lead to reorganization of function (Duffau,
2006). Following the operation, there may be more or less edema, and again how
this affects nervous tissue can be unclear. Thus, even if tumor patients are included
in a study, it is routinely assumed that it is better to leave a period of a few weeks
to allow the edema to subside before testing the patient.
However, it is now standard practice in tumor neurosurgery to use functional
imaging of functions held to be located near to the tumor before surgery to estab-
lish precisely where they are localized in the patient as rapidly possible. One can
frequently activate regions very close to the seen location of the tumor, suggest-
ing that the area is functional. Thus, the area close to the seen location is in these
cases functional. Moreover, in three recent studies we have found that using
VLSM produces a localization of function very close to that obtained by other
methods. Thus, in Shallice and coworkers (2010) we have found that optic ataxia,
an impairment in reaching accurately to a position in contralesional space,
can be localized in an acute tumor population in the medial superior posterior
parietal cortex, just where one would expect given fMRI studies of the parietal
reach region, where there is a hotspot in this region (Connolly, Anderson, &
Goodale, 2003). The location also fits with that for optic ataxia using patient
populations with other etiologies, such as stroke (Battaglia-Mayer & Caminiti,

2002; Himmelbach, Karnath, & Perenin, 2007; Pisella et al., 2009). A second study
concerns the localization of impairments on a clinical subtest in the Visual Object
and Spatial Perception (VOSP) battery, Fragmented Letters (Warrington & James,
1991). In Fragmented Letters a solid capital letter is presented to the subject,
broken up into separated black areas. The tendency is to view the figure as a set of
black regions rather than a whole letter-form. The test loads on global processing.
When global processing is impaired it is impossible for the patient to see the let-
ter-form. Using a large sample of acute tumor patients we found that the critical
lesion site was in the left temporo-occipital white matter, almost identical to the
area that Fink and colleagues (1999) had found to be activated when identifying
the global component of Navon figures by comparison with identifying the local
component of the same figures (Shallice et al., 2010). Finally, Campanella and
associates (2010), using a similar patient population, have found that when sub-
jects have to name living things and manipulable artifacts matched on a variety
of nuisance variables, there is a region where subjects perform significantly worse
with artifacts than with living things. This is in the left posterior superior tempo-
ral gyrus, extending down into the middle temporal gyrus and up into the inferior
parietal cortex. Brambati and associates (2006), working with a sample of 152
patients with a variety of dementing conditions, also examined naming of differ-
ent semantic categories. They used a somewhat wider set of artifact categories,
including vehicles and large household objects, as well as tools and small house-
hold objects. Using this wider set they also found a selective deficit, by compari-
son with domestic animals and fruits, in a virtually identical region. Thus, in three
different studies, localization of a processing component in an acute tumor group
gave a very similar result to the localization of the same processing component
using another methodology or a patient population with a different etiology.
We have carried out three studies that should test for the localization of pro-
cessing components that were held to be isolated by the ROBBIA in acute popula-
tions, two composed entirely of tumor patients and the other composed of 50%
tumor patients and nearly 50% vascular patients. The most directly relevant study
was an attempt to replicate the variable foreperiod temporal preparation para-
digm of Stuss and coworkers (2005). The variable foreperiod paradigm involves a
standard simple choice reaction time experiment in which the stimulus is pre-
ceded by a warning signal, with the interval drawn from a rectangle distribution.
It has been known since Woodrow (1914) that in this situation, reaction time
decreases as the preparation interval increases. In the Stuss and coworkers study
we found that three of the four frontal groups had a completely normal foreperiod
effect, with its magnitude being just the same as in the normal control group. The
exception was the right lateral group, who instead of quickening their response by
30 milliseconds or more for the longer compared with the shorter foreperiods,
were slightly slower at the longer foreperiod. It was argued that for the longer
foreperiods control subjects must realize some way into the foreperiod that
no stimulus had yet occurred and so increase their degree of preparation. If the
right lateral group had a problem of active checking, then they would fail to appre-
ciate that no stimulus had yet occurred and so fail to increase their degree of prep-
aration. One alternative account that temporal preparation is linked to an
automatic conditioning process (Los, Knol, & Boers, 2001) can be rejected because
this conflates the foreperiod effect with sequential effects on the previous trial.
However, this account can be ruled out as the two effects have quite different
developmental trajectories (Vallesi & Shallice, 2007). In a second neuropsycho-
logical study of the paradigm we assessed it in acute tumor patients (Vallesi,
Mussoni, Mondani, et al., 2007). Patients were tested both just before (1 to
3 days) and just after (3 to 6 days) the operation. The 58 patients had tumors
involving the left or right hemispheres and either the prefrontal, premotor, or
parietal cortices. The results strongly supported the frontal origin of an impair-
ment. There was a significant interaction in the effect of surgery on the size of the
foreperiod effect across group. In one group it was significantly reduced as an
effect of surgery from 57 milliseconds to 12 milliseconds. This was in the right
prefrontal group. However, the result is not that clear: if one considers just the
postoperative results alone, then both the right frontal and the left frontal groups
show reduced foreperiod effects (left frontals, 18 milliseconds; right frontals,
12 milliseconds; controls, 50 milliseconds).
It remains to be determined which of those two types of measure is the more
important. Thus, for optic ataxia, for instance, there is a selectively increased
impairment due to the operation in the critical region, but this is not found for
the fragmented letters test (Shallice et al., 2010). Using other methodologies,
Vallesi, Shallice, and Walsh (2007) found a selective effect of repetitive transcra-
nial magnetic stimulation on foreperiod in the right lateral prefrontal cortex but
not in the left. On the other hand, Vallesi, McIntosh, Shallice, and Stuss (2009)
obtained both left and right frontal effects when comparing variable-foreperiod
with fixed-foreperiod paradigms using fMRI. However, only the degree of right
dorsolateral activation correlated across subjects with the size of the variable fore-
period effect (but see Vallesi, Stuss, McIntosh, & Picton, 2009). Overall, the addi-
tional analyses give some support to the localization of the variable-foreperiod
effect made by Stuss and colleagues (2005).
Reverberi and coworkers (2005) used a problem-solving task designed to pro-
vide a different way of investigating the potential separability of active monitor-
ing and task-setting. Ten years before, Burgess and I (1996) had developed a
visuospatial task to assess the ability of patients to abstract rules: the Brixton
task. Subjects were presented, one at a time, with a pack of cards on each of which
was a 2 × 5 set of circles, one of which was colored blue. The blue circle moved from
one card to the next according to a simple rule that changed once every five to
nine cards; an example of a simple rule would be an alternation between two posi-
tions. Subjects had to guess where on the next card the circle would be colored
blue, which required them to abstract the currently active rule.
In the Reverberi and coworkers study, two cards before the end of any particu-
lar rule, a set of four cards, each with one red circle, were presented one at a time.
The subjects were told these cards were irrelevant and all they had to do with each
was to touch the red circle. The red circles, however, obeyed a different rule, and
when the color of the circle on the card changed back to blue, the subject had to
revert to obeying the blue rule active just before the current red circle cards
occurred. What was found was that the left lateral group was impaired at abstract-
ing the “blue rules” even when they had intact working memory for this type of
material. They did not show adequate task-setting, although at a more abstract
level than in the ROBBIA studies. It was, however, the right lateral patients who
were captured by the red rules: They failed to actively monitor which rule should
have been active when the red rule switched back to a blue one.
Turner and associates (2007) used another paradigm that should involve active
monitoring and checking. This was a free recall paradigm in which subjects were
presented with a series of 16-word lists, each composed of four words in each of
four categories. For each list, two of the categories were new and two were in the
preceding list. This was done because we considered it would impose extra pres-
sure on an active checking system, since prior-list intrusion errors will be likely to
occur from proactive interference. When subjects had recalled all that they could
in free recall, they were prompted with the category labels. There was a second
important aspect to the study: when subjects could recall no further items at
retrieval, they were presented with the labels of the categories occurring in the
list. Prior to prompting, the right lateral group, like the medial group, recalled
significantly fewer words than controls. However, no group produced a signifi-
cantly higher rate of intrusion errors compared to the controls. The situation was
quite different after prompting. One group differed from controls only in the
number of words recalled after the prompts; this was the right lateral group. In
addition, there was a significant difference in the number of prior-list intrusion
errors across the patient groups. The right lateral group, again, was the only group
to produce a significantly higher number of such errors than controls. Thus, the
right lateral group of patients appeared to fail to recall unprompted as many words
as they could, given that the potential number can be estimated from the addi-
tional words recalled following the prompt. In addition, it failed to detect errors
that arose from words presented in a different list from the one that was actively
being recalled. This is a very similar problem to that that seen in the Reverberi and
colleagues study, where a primed alternative had to be rejected. We argued that
the impairment of the right lateral group was somewhat wider than the active
monitoring deficit proposed by the ROBBIA studies (e.g., Stuss et al, 2005). We
suggested, instead, that the deficits in performance of the right lateral group
arose from a failure to initiate supervisory operations, when no external cue was
available that a problem had arisen. Such a process could explain a failure to search
for extra items at the end of retrieval in a free recall paradigm, as well as a failure
of active monitoring per se.
These studies were carried out in parallel to ROBBIA. In general they provide
converging evidence for the theoretical inferences drawn from the ROBBIA group
of studies, and therefore indirectly support the methodology that Don Stuss and
colleagues developed. Thus, the Reverberi and associates study (2005) supports
the left lateral prefrontal localization of the task-setting supervisory function, if
at a much more abstract level than ROBBIA studies such as Alexander and col-
leagues (2007). Three different studies by Vallesi and collaborators—one with
tumor patients (Vallesi, Mussoni, Mondani, et al., 2007), one with transcranial
magnetic stimulation (Vallesi, Shallice, & Walsh, 2007), and one with functional
imaging (Vallesi, McIntosh, Shallice, & Stuss, 2009)—support the right lateral
prefrontal localization of a critical component of the variable foreperiod effect as
originally found by Stuss and colleagues (2005) in ROBBIA. This in turn provided
key evidence for the right lateral localization proposed in ROBBIA (Shallice et al.,
2008b; Stuss & Alexander, 2007) of the conscious checking and active monitoring
supervisory function. Such an active checking function also receives support from
the free recall study by Turner and coworkers (2007). This study, however, also
suggests a possible broadening of the ascribed functions of the right lateral system
isolated in ROBBIA, namely from active monitoring to the initiating of all non-
externally triggered supervisory operations. Overall, though, the outcome of
ROBBIA was the proposal of a set of component processes of an overall supervi-
sory system that differ qualitatively, not just in terms of their levels in a process-
ing hierarchy. The neuropsychological studies just described fit well with this basic
framework.
Acknowledgments
I would like to thank Fergus Craik for most helpful comments on an initial version
of the paper.
References
Alexander, M.P., Stuss, D.T., Picton, T.W., Shallice, T., & Gillingham, S.M.E. (2007). Regional frontal
injuries cause distinct impairments in cognitive control. Neurology, 68, 1515–1523.
Aron, A. R., Monsell, S., Sahakian, B. J., & Robbins, T. W. (2004). A componential analysis of
task-switching deficits associated with lesions of left and right frontal cortex. Brain, 127,
1561–1573.
Badre, D., & D’Esposito, M. (2007). Functional magnetic resonance imaging evidence for a hierarchi-
cal organization of the prefrontal cortex. Journal of Cognitive Neuroscience, 19, 2082–2099.
Badre, D. (2008). Cognitive control, hierarchy, and the rostro-caudal organization of the frontal
lobes. Trends in Cognitive Science, 12, 193–200.
Bates, E., Wilson, S. M., Saygin, A. P., Dick, F., Sereno, M. I., Knight, R. T., et al. (2003). Voxel-based
lesion-symptom mapping. Nature Neuroscience, 6, 448–450.
Battaglia-Mayer, A., & Caminiti, R . (2002). Optic ataxia as a result of the breakdown of the global
tuning fields of parietal neurones. Brain, 125, 225–237.
Botvinick, M. M. (2008). Hierarchical models of behavior and prefrontal function. Trends in

Cognitive Science, 12, 201–208.
Brambati, S. M., Myers, D., Wilson, A., Rankin, K. P., Allison, S. C., Rosen, H. J., et al. (2006).
The anatomy of category-specific object naming in neurodegenerative diseases. Journal of
Cognitive Neuroscience, 18, 1644–1653.
Braver, T. S., Reynolds, J. R., & Donaldson, D. I. (2003). Neural mechanisms of transient and sus-
tained cognitive control during task switching. Neuron, 39, 713–726.
Burgess, P. W., & Shallice, T. (1996). Bizarre responses, rule detection and frontal lobe lesions.
Cortex, 32, 241–259.
Burgess, P. W., Quayle, A., & Frith, C. D. (2001). Brain regions involved in prospective memory as
determined by positron emission tomography. Neuropsychologia, 39, 545–555.
Campanella, F., D’Agostini, S., Skrap, M., & Shallice, T. (2010). Naming manipulable objects:
anatomy of a category specific effect in left temporal tumours. Neuropsychologia, 48,
1583–1597.
Caramazza, A . (1986). On drawing inferences about the structure of normal cognitive systems
from the analysis of patterns of impaired performance: The case for single-patient studies.
Brain and Cognition, 5, 41–66.
Connolly, J. D., Andersen, R. A., & Goodale, M. A . (2003). fMRI evidence for a “parietal reach region”
in the human brain. Experimental Brain Research, 153, 140–145.
Critchley, H. D., Mathias, C. J., Josephs, O., O’Doherty, J., Zanini, S., Dewar, B. K., et al. (2003).
Human cingulate cortex and autonomic control: converging neuroimaging and clinical evidence.
Brain, 126, 2139–2152.
Duffau, H. (2006). Brain plasticity: from pathophysiological mechanisms to therapeutic applica-
tions. Journal of Clinical Neuroscience, 13, 885–897.
Duncan, J. (2001). An adaptive coding model of neural function in prefrontal cortex. Nature Reviews
Fink, G. R., Marshall, J. C., Halligan, P. W., & Dolan, R. J. (1999). Hemispheric asymmetries
in global/local processing are modulated by perceptual salience. Neuropsychologia, 37,
31–40.
Henson, R . (2005). What can functional neuroimaging tell the experimental psychologist?
Quarterly Journal of Experimental Psychology Section A-Human Experimental Psychology, 58,
193–233.
Himmelbach, M., Karnath, H. O., & Perenin, M. T. (2007). Action control is not affected by spatial
neglect: A comment on Coulthard et al. Neuropsychologia, 45, 1979–1981.
Koechlin, E., Ody, C., & Kouneiher, F. (2003). The architecture of cognitive control in the human
prefrontal cortex. Science, 302, 1181–1185.
Levine, B., Black, S. E., Cabeza, R., Sinden, M., McIntosh, A. R., Toth, J. P., et al. (1998). Episodic
memory and the self in a case of isolated retrograde amnesia. Brain, 121, 1951–1973.
Logothetis, N. K . (2008). What we can do and what we cannot do with fMRI. Nature, 453,
869–878.
Los, S. A., Knol, D. L., & Boers, R. M. (2001). The foreperiod effect revisited: conditioning as a basis
for nonspecific preparation. Acta Psychologia, 106, 121–145.
Mikkelsen, T., & Rosenblum, M. L . (1999). Tumour invasiveness. In M. S. Berger & C. B. Wilson.
(Eds.), The gliomas. Philadelphia: Saunders.
Milea, D., Lehericy, S., Rivaud-Pechoux, S., Duffau, H., Lobel, E., Capelle, L., et al. (2003). Antisaccade
deficit after anterior cingulate cortex resection. Neuroreport, 14, 283–287.
lation and amnesia. Neuropsychologia, 35, 1017–1034.
Petrides, M., & Pandya, D. N. (1994). Comparative architectonic analysis of the human and
macaque frontal cortex. In F. Boller & J. Grafman (Eds.), Handbook of neuropsychology
(pp. 17–57). Amsterdam: Elsevier.
Picton, T. W., Stuss, D. T., Shallice, T., Alexander, M. P., & Gillingham, S. (2006). Keeping time:
effects of focal frontal lesions. Neuropsychologia, 44, 1195–1209.
Pisella, L., Sergio, L., Blangero, A., Torchin, H., Vighetto, A., & Rossetti, Y. (2009). Optic ataxia and
the function of the dorsal stream: contributions to perception and action. Neuropsychologia,
47, 3033–3044.
Reverberi, C., Lavarone, A., Gigli, G. L., Skrap, M., & Shallice, T. (2005). Specific impairments of
rule induction in different frontal lobe subgroups. Neuropsychologia, 43, 460–472.
Robinson, G., Blair, J., & Cipolotti, L . (1998). Dynamic aphasia: an inability to select between
competing verbal responses? Brain, 121(Pt 1), 77–89.
Robinson, G., Shallice, T., & Cipolotti, L . (2005). A failure of high-level verbal response selection in
progressive dynamic aphasia. Cognitive Neuropsychology, 22(6), 661–694.
Rorden, C., & Karnath, H. O. (2004). Using human brain lesions to infer function: a relic from a past
era in the fMRI age? Nature Reviews Neuroscience, 5, 813–819.
Rorden, C., Karnath, H. O., & Bonilha, L . (2007). Improving lesion-symptom mapping. Journal of
Cognitive Neuroscience, 19, 1081–1088.
Schnider, A . (2007). The confabulating mind: how the brain creates reality. Oxford: Oxford University
Press.
Shallice, T. (1988). From neuropsychology to mental structure. Cambridge, UK: Cambridge University
Press.
Shallice, T. (2003). Functional imaging and neuropsychology findings: how can they be linked?
Neuroimage, 20, S146–S154.
Shallice, T. & Burgess, P. (1996). The domain of supervisory processes and temporal organization
of behaviour. Philosophical Transactions of the Royal Society of London B Biological Sciences, 351,
1405–1411.
in man. Brain, 11, 727–741.
Shallice, T., Stuss, D. T., Alexander, M. P., Picton, T. W., & Derkzen, D. (2008a). The multiple dimen-
sions of sustained attention. Cortex, 44, 794–805.
Shallice, T., Stuss, D. T., Picton, T. W., Alexander, M. P., & Gillingham, S. (2008b). Mapping task
switching in frontal cortex through neuropsychological group studies. Frontiers in Neuroscience,
2, 79–85.
Stuss, D. T. & Alexander, M. P. (2007). Is there a dysexecutive syndrome? Philosophical Transactions
of the Royal Society of London, B, 362, 901–915.
Stuss, D. T., Alexander, M. P., Hamer, L., Palumbo, C., Dempster, R., Binns, M., et al. (1998). The
effects of focal anterior and posterior brain lesions on verbal fluency. Journal of the International
Neuropsychological Society, 4, 265–278.
Multiple frontal systems controlling response speed. Neuropsychologia, 43, 396–417.
38, 388–402.
Stuss, D. T., Shallice, T., Alexander, M. P., & Picton, T. W. (1995). A multidisciplinary approach to
anterior attentional functions. Annals of the New York Academy of Sciences, 769, 191–211.
Turner, M. S., Cipolotti, L., Yousry, T., & Shallice, T. (2007). Qualitatively different memory impair-
ments across frontal lobe subgroups. Neuropsychologia, 45, 1540–1552.
Vallesi, A., McIntosh, A. R., Shallice, T., & Stuss, D. T. (2009). When time shapes behavior: fMRI
evidence of brain correlates of temporal monitoring. Journal of Cognitive Neuroscience, 21,
1116–1126.
Vallesi, A., Mussoni, A., Mondani, M., Budai, R., Skrap, M., & Shallice, T. (2007). The neural
basis of temporal preparation: insights from brain tumor patients. Neuropsychologia, 45,
2755–2763.
Vallesi, A., & Shallice, T. (2007). Developmental dissociations of preparation over time: deconstruct-
ing the variable foreperiod phenomena. Journal of Experimental Psychology: Human Perception
and Performance, 33, 1377–1388.
Vallesi, A., Shallice, T., & Walsh, V. (2007). Role of the prefrontal cortex in the foreperiod
effect: TMS evidence for dual mechanisms in temporal preparation. Cerebral Cortex, 17,
466–474.
Vallesi, A., Stuss, D. T., McIntosh, A. R., & Picton, T. W. (2009b). Age-related differences in processing
irrelevant information: evidence from event-related potentials. Neuropsychologia, 47, 577–586.
Warrington, E. K., & James, M. (1991). VOSP: Visual Object and Space Perception Battery.
Bury St. Edmunds, UK: Thames Valley Test Company.
Woodrow, H. (1914). The measurement of attention. Psychological Monographs, 17, 1–158.
Woollams, A. M., Lambon Ralph, M. A., Plaut, D. C., & Patterson, K . (2007). SD-squared: on the asso-
ciation between semantic dementia and surface dyslexia. Psychological Review, 114, 316–339.
4
Rostral Prefrontal Cortex
What Neuroimaging Can Learn from
Human Neuropsychology
PA U L W. B U R G E S S , G I L G O N E N - YA A C O V I , A N D E M M A N U E L L E V O L L E
Rostral prefrontal cortex (PFC) approximates area 10 of the human brain and is
variously referred to as “anterior PFC” or “frontopolar cortex.” It is a very large
brain region in humans, covering approximately 25 to 30 cubic centimeters, and
it is a large area in humans relative to other animals (Holloway, 2002; Semendeferi
et al., 2001). In volumetric terms it is probably the largest single architectonic
region of the frontal lobes (Christoff et al., 2001), which themselves represent
approximately one third of the total cortical mass. Rostral PFC has many other
features that suggest that it might play a highly important role in human cogni-
tion, especially higher-order capacities. For instance, the supragranular layers of
area 10 in humans have more space available for connections with other higher-
order association areas than in other animals (Semendeferi et al., 2001). It
also follows a complex and protracted course of development, with suggestions
that full maturity might not be achieved even as late as early adulthood (see
Dumontheil et al., 2008, for review). This process of change may continue through-
out life: specific volume reductions (relative to total brain volume) have been
found in frontopolar cortex between early adulthood and middle age (John et al.,
2009).
Until approximately 15 years ago, virtually nothing was known about the func-
tions of this region. There were two principal reasons for this situation. First, the
large difference in rostral PFC structure and relative volumes between animals
and humans cast doubt on the transferability of findings derived from the former
to the latter. Thus, the study of this region was less attractive to scientists con-
ducting animal lesion studies than other prefrontal regions. Second, lesions to
this region in humans typically cause impairments that are not as easily demon-
strable in the clinic as those that cause basic impairments in language, motor,
47
or perceptual systems (Burgess et al., 2009). This meant that researchers have
tended to focus on the functional characteristics of other frontal lobe regions
(e.g., dorsolateral PFC), especially those where comparison with animal studies
might be more straightforward. Consequently, the relatively small, but neverthe-
less striking, body of evidence from human neuropsychology that could have been
used as the basis for theorizing about rostral PFC lay largely unconsidered.
The Advent of Neuroimaging: From Famine to Feast?

In the 1990s, the relatively new technique of functional neuroimaging began to
exert real influence within the field. With this method, the question of what ros-
tral PFC “is for,” in terms of cognition, was thrust to the forefront of cognitive
neuroscience. This was because the evidence from neuroimaging seemed to indi-
cate that structures within rostral PFC support processing that may be used
in a very wide variety of situations (e.g., Grady, 1999). Indeed, incidental (i.e.,
unplanned) findings of activations in rostral PFC were found during the perfor-
mance of just about any kind of cognitive task, ranging from the simplest (e.g.,
conditioning paradigms; Blaxton et al., 1996) to highly complex tests involving
memory and judgment (e.g., Burgess et al., 2001, 2003; Frith & Frith, 2003;
Koechlin et al., 1999) or problem-solving (e.g., Christoff et al., 2001; for review,
see Ramnani & Owen, 2004).
Perhaps unsurprisingly, given the plethora of data, a range of theories emerged
(see Burgess et al, 2006, for review). For instance, rostral PFC was associated with
episodic memory functions (e.g., Rugg et al., 1996; Tulving et al., 1996), with
Buckner (1996, p. 156) suggesting that “the common activation during episodic
retrieval is highly localised, falling at or near Brodmann area 10.” It was also asso-
ciated with what might be termed “metacognition,” such as reflecting on one’s
own thoughts, or thinking in a very controlled, conscious, or goal-directed mode
(e.g., Johnson et al., 2002). For instance, Christoff and Gabrieli (2000, p. 183)
described the role of this region as of “evaluation, monitoring, or manipulation of
internally generated information,” and “theory of mind” researchers suggested a
role for medial rostral PFC “when we attend to our own mental states as well as
the mental states of others” (Frith & Frith, 2003, p. 467). Further, there was a set
of theories that Burgess and colleagues (2006) term the “Sum Process” accounts.
These, broadly, maintain that rostral PFC supports processing involved in the
coordination of otherwise independent processing resources (e.g., Dreher,
Koechlin, Ali, & Grafman, 2002; Koechlin et al., 1999; Koechlin, Ody, & Kouneiher,
2003; Ramnani & Owen, 2004). Lending broad support to this type of account
was the identification of a consistent association between BOLD signal changes in
rostral PFC and the performance of prospective memory tasks (e.g., Burgess et al.,
2001, 2003), where performance of an ongoing task has to be dovetailed with the
detection of, and response to, a prospective memory cue.
R os t ral P re fron t al C ort ex 49
The proliferation of these theories was perhaps an improvement upon the

complete dearth beforehand. But because of the inherent nature of neuroimaging
data, these accounts have, in the main, been allowed to all stand side by side.
Indeed, they are continuing to proliferate, with little or no revision or dismissal of
any existing accounts. It is possible that neuroimaging data (from one study alone,
at least) cannot provide sufficient evidence to effect the dismissal of a cognitive
model. There are a range of views on this matter, and a full debate is beyond the
scope of this chapter (for review see, e.g., Coltheart, 2006; Henson et al., 2006).
However, whether or not it is possible in theory, it is not currently happening in
practice, except perhaps by the process of “natural selection” to which Henson
(2006) refers (where, presumably, the randomness of science politics and chance
forces sit alongside logical argument and data as influences). A potential serious
contributor to this situation is that, as Chambers and Mattingly (2005) have
noted, neuroimaging analyses may detect activation in regions of the brain that
are not actually involved in performance of the experimental paradigm under
investigation. This is especially significant for the study of rostral PFC: there is
good evidence for hemodynamic changes in this region during “mind-wandering”
and other task-irrelevant processing (see Gilbert et al., 2007, for review).
On these grounds, theorizing about the cognitive functions supported by ros-
tral PFC based on neuroimaging data will be particularly convincing where it is
constrained by findings from lesion studies. In time, transcranial magnetic stimu-
lation (and related methods) may also provide useful data in this respect (although
there are technical issues to be overcome, especially with respect to rostral PFC
structures deeper within the brain [e.g., caudal medial rostral PFC]). However,
data from human lesion studies are both directly relevant and already available.
This chapter aims to outline the key aspects of these data and to show the ways in
which they can be potentially of great use to the neuroimaging community.
Rostral PFC and “Intelligence”

A key example of the way in which data from human lesion studies might con-
strain theorizing that has arisen out of neuroimaging studies is the issue of the
role of rostral PFC in “intelligence.”
It could be argued that over the past 50 years the majority of theorists within
the field of the psychology of individual differences have moved towards the view
that there may be no single construct that best represents “intelligence.” Instead,
they have concentrated more on what Spearman would have considered second-
order or specific factors—those that Thomson (1939) pointed out may (on math-
ematical grounds) be sufficient to explain “intelligence.” On this view, seeking
stable patterns of activation in the brain that relate to a single “intelligence” con-
struct might be fruitless. Congruent with this view, and predating most, is
the application of the most commonly used intelligence test in neuropsychology,
the Wechsler intelligence scales (and variants; Wechsler, 1939). On this concep-
tion of intelligence, the construct can encompass a wide range of abilities and
aptitudes, and an IQ score is a simple average of a sample of them, most com-
monly used as a form of baseline against which other test scores might be com-
pared. The scores on any two subtests themselves, or between the larger groupings
(e.g., Verbal IQ vs. “Performance,” mainly non-verbal IQ), can show considerable
variation in any one individual, even within the healthy population (see, e.g.,
Spreen & Strauss, 1988, p. 121). The alternative common conception of IQ in cog-
nitive neuroscience is in the sense of “g,” as typified, for example, in the works of
John Duncan (e.g., Duncan et al., 2000).
Using the construct “intelligence” perhaps more in the former way than the
latter, Jung, Haier, and colleagues claim that “central psychological constructs
[such as general intelligence (g) and working memory capacity] . . . share common
neural systems . . . a common anatomic framework for these constructs implicates
Brodmann area 10” (Colom, Jung, & Haier, 2007; see also Jung & Haier, 2007).
More specifically, the hypothesis is that the contribution to cognition made by
processes supported by rostral PFC is “to hypothesis test various solutions to a
given problem” (Jung & Haier, 2007, p. 138). Although the specifics of this claim
are not outlined in great depth in information-processing terms, it seems likely
that a decrement in such an ability might affect performance on a very wide range
of tasks. Thus, lesions to this region should cause marked decrements on a wide
range of tasks, including IQ tests.
This prediction unites this latter conception of intelligence with the “g” view.
The notion of “g” originally came from Charles Spearman’s examination of the
performance of many individuals across lots of cognitive tests, using correlation
matrices. He noticed an effect he called “positive manifold” (Spearman, 1904) in
these matrices. This is the tendency for any correlation matrix of this kind to have
more positive correlations than negative ones. In other words, there is a tendency,
across lots of people, and across lots of tests, for those who are better at one test
to also be better at another. Spearman’s interpretation was that this positive
manifold was evidence of a hypothetical ability that is required to perform many
types of test, which he called “g” (short for “general intelligence”). Since that time,
various psychometric tests have been designed to measure this construct, often
now referred to as “fluid intelligence” (following Cattell, 1963).
The key idea here is that there is a particular cognitive resource, or process,
that underpins performance on a wide range of tasks. This distinguishes the
notion of fluid intelligence from the one outlined above, where IQ is just an aver-
age of a range of different abilities. As Roca and colleagues (2010) note, functional
imaging studies of tasks that supposedly measure fluid intelligence tend to find
extensive activity on the lateral surface of the frontal cortex, especially around
the inferior frontal sulcus and anterior insula/frontal operculum. Additionally,
fluid intelligence tasks also regularly activate the dorsal anterior cingulate/pre-
supplementary motor area and the intraparietal sulcus. Accordingly, Duncan and
colleagues have proposed that these activations reflect the neural operation of a
cognitive system that supports fluid intelligence (e.g., Duncan, 2001, 2005;
Duncan et al., 2000; Duncan & Owen, 2000).
One way in which this latter conception of intelligence is similar to the previous
one considered here is in the prediction it makes for human lesion studies. If rostral
PFC supports some processing that corresponds in some way to fluid intelligence
(or Spearman’s “g”), then this hypothesis also predicts that lesions to this region
should cause decrements across a wide range of tasks. The extent of the decrement
on any one task might reflect the degree to which that task loads upon “g.” However,
unless the hypothesis applied to rostral PFC makes the prediction that lesions to
this region should cause a wide range of decrement across many tasks (and more so
than at least some other brain regions), then it is essentially unfalsifiable.
Rostral PFC Lesions Need Not Cause Substantial

Impairment on Traditional Tests of Intelligence
The problem for many of the functional neuroimaging-based accounts of rostral
PFC function is that lesions to rostral PFC do not typically cause substantial dec-
rements on IQ tests. Nor do they cause impairment on a wide range of other tasks,
while simultaneously causing impairment on a quite restricted range of others.
Moreover, this has been known for many years.
Probably the first group human lesion study of rostral PFC functions was car-
ried out by Petrie (1952), although this was not its principal aim. Petrie compared
the effects of two different leucotomy procedures on cognition in participants
with “neurotic” symptoms. The standard procedure at that time made an incision
at a rostral–caudal plane that, if extended to the outer surface of the brain, would
have bisected Brodmann areas (BAs) 45, 47, 46, 9, and 8. This was compared with
the effects of a rostral incision, where the cut was made more anteriorly, falling
just behind area 10.
The rostral operation led to improvements in a range of tasks, notably manual
dexterity and concentration, fewer perseverations, and better performance on
WAIS (Wechsler Adult Intelligence Scale) Digit Symbol and Similarities subtests.
There was no change, relative to preoperative levels, on many further tests (Porteus
Mazes, WAIS Verbal IQ, Performance IQ, Full Scale IQ (FSIQ), Cattell Fluency,
Proverb Interpretation). However, there were decrements on just two tests: there
was a varied response to distraction, and the sense that time passes more quickly
(unfilled estimation of the passage of 60 seconds). In this study, Petrie (1952)
provided compelling evidence that lesions affecting rostral PFC lesions do not
cause significant IQ decrement, although they may cause impairments in some
mental capacities that, to this day, are not particularly well understood.
Since Petrie’s study, a substantial body of further evidence from human lesion
studies has accumulated, also demonstrating that patients with rostral PFC
damage are not typically impaired on traditional tests of intelligence. Many single
cases reported have scored in the superior range on such tests, with little or no
discernable change from estimates of premorbid functioning, despite extensive
rostral PFC involvement (e.g., Goel & Grafman, 2000; Goldstein et al., 1993;
Shallice & Burgess, 1991; see Burgess, 2000, for review). Indeed, Uretzky and
Gilboa’s (2010) case, Z.P. (WAIS-III Verbal IQ 121, Performance IQ 104, FSIQ
113), who has circumscribed right front-polar atrophy following a traffic accident,
gained degrees in civil engineering and business administration after his injury,
which hardly suggests a marked IQ deficit.
Of course one might object that there may be something unusual about these
single cases, or that the estimates of premorbid functioning might be inaccurate.
However, group studies have also shown no difference in IQs between patients
with rostral PFC lesions and those elsewhere. For instance, in Dreher and cowork-
ers’ (2008) study, patients with rostral PFC lesions (n = 7; called frontopolar
lesions by Dreher and coworkers) had a mean number of years of education of
14.71 (SD 3.4), and the patients whose lesions affected the frontal lobes but not
the rostral aspects of it (n = 5) had a very similar number (mean 14.2, SD 2.5).
Likewise, there was no significant difference in the performance of the two groups
in terms of WAIS-III Full-Scale IQ scores (rostrals’ mean = 110.43, SD = 20.4; non-
rostrals = 103.20, SD = 8.35).
Another way to look at this issue would be to start with the intelligence test
rather than the lesion: in other words, to gather data on many patients with vari-
ous lesions and to ask which lesion location shows the strongest relationship with
IQ decrement. Warrington, James, and Maciejewski (1986) provided by far the
largest study of this kind to our knowledge, examining 656 patients with unilat-
eral cerebral lesions on a shortened version of the WAIS. They found that Verbal
IQ was impaired following left hemisphere lesions, regardless of where the lesion
was located within the hemisphere. Performance IQ was impaired only following
lesions affecting the right parietal lobe. In an analysis by individual subtest, the
only finding was a relationship between Block Design and Picture Arrangement
decrement and right parietal involvement. More than 20 years later, Gläscher and
associates (2009) carried out a similar kind of study, using the more sophisticated
lesion imaging methods now available, and examining 241 patients with focal
brain damage on the WAIS-III. They found a statistically significant lesion–deficit
relationship in left inferior frontal cortex for verbal comprehension scores, with
an association between lesions in left lateral frontal and parietal cortex for the
working memory index, and in right parietal cortex for perceptual organization.
They found no single localization for processing speed.
From these studies we can conclude that there is little evidence for a preferen-
tial link between rostral PFC lesions and WAIS IQ decrements. But is this some
artifact of the particular definition of intelligence encapsulated by the Wechsler
Intelligence scales, or the way they measure them? Apparently not. Roca and col-
leagues (2010) studied the relationship between measures of fluid intelligence
(e.g., Cattell’s Culture Fair Test) and performance on a range of measures of execu-
tive functions. In their first experiment, the sample comprised 44 patients with
chronic lesions affecting a variety of subregions within the frontal lobes (note: not
just affecting rostral PFC). For two of the most commonly used executive function
tasks (Wisconsin Card Sorting Test [Nelson version] and Verbal Fluency), they
found that although the patients were significantly poorer than a group of matched
healthy controls in terms of raw performance on all three tests, once the variance
attributable to fluid intelligence was accounted for by covariance, this difference
disappeared. In other words, for some executive tasks there seems to be an overlap
in the processing demands with fluid intelligence measures. But there was no
apparent relation between where within the frontal lobes the lesion was located
and deficits on the fluid intelligence measure (the Culture Fair Test). In other
words, Roca and associates did not find a stronger relationship between fluid
intelligence deficits and lesions that affected rostral PFC than for other parts of
the frontal lobes.
However, in a second experiment, they did make a discovery that informs us of
the nature of the mental abilities that rostral PFC might support. Here, they
administered a different, and wider, range of executive and social function tasks
to 21 patients. Most of these were performed more poorly by the patient group
than controls. This time, however, the investigators found that for some of the
executive tasks, adjusting for fluid intelligence did not remove the group differ-
ence. These tests were go/no go (Dubois et al., 2000; Luria, 1966); proverb inter-
pretation (Hodges, 1994); Hayling Sentence Completion Task (Burgess & Shallice,
1996, 1997); Hotel Task (Manly et al., 2002; a version of Shallice & Burgess’s
[1991] Six Element Task); and the Faux Pas test (Stone et al., 1998). Roca and
coworkers (2010) then devised a score that represented the mean residual from
these tests (i.e., a score that represented the degree of impairment on the tests
that could not be explained by fluid intelligence). When they examined the lesion
overlaps for the six patients who showed the greatest negative value, they found
that the location of the overlap was in rostral PFC, especially in the right hemi-
sphere. In other words, the rostral PFC lesions caused an impairment that was
well measured by a number of executive tasks, but that could not be explained by
changes in fluid intelligence. This study, together with the evidence above, there-
fore provides good evidence that rostral PFC lesions do not typically affect perfor-
mance substantially on tests of intelligence any more than lesions elsewhere
within the brain. This finding holds whether IQ is conceived of as an average across
different domains, or as some homogeneous process, or set of them, operating
across all cognitive domains.
A recent study, however, seems prima facie to run against the findings by Roca
and coworkers. Gläscher and associates (2010) reported a Schmid-Leiman factor
transformation analysis of WAIS subtests in their group of 241 patients with
brain damage of various etiologies (principally stroke). This analysis specified a
higher-order factor common to three lower-order constructs (Verbal, Spatial,
Working Memory). The investigators found that the factor scores for this higher-
order construct related to the presence of lesions in the left frontal pole, and con-
cluded that this region plays some part in supporting “g.” This is an interesting
finding. However, there may be many other possible interpretations of these data
(as indeed, Thomson [1939] pointed out that there were for the positive manifold
in correlation matrices that Spearman took as primary evidence of “g”). Gläscher
and associates did not use control or comparison tasks, so this limits an interpre-
tation in information-processing terms. Linked to this, there may be influences
that do not act equally as regards the possibility of general decrement in rostral
PFC patients: damage to this region tends to be neurologically “silent,” so it is often
not detected until the lesions are large or have affected particular pathways or
other PFC or subcortical regions, causing multiple deficits. Nevertheless, although
these limitations make interpretation difficult, they do raise the intriguing possi-
bility of some form of higher-order construct supported by a rostral PFC region.
The Challenge that Rostral PFC Presents

to Neuroimaging
In light of all the data above, especially findings from single cases, the unequivocal
assertion that there is a special role for rostral PFC in “intelligence” (as tradition-
ally defined) seems plausible only if the theorizing that led to that conclusion had
considered data from neuroimaging alone. If this is what has occurred, it may
turn out to be a useful example to historians of science. It is already widely
accepted in the neuroimaging community that, as Poldrack and Wagner (2004)
put it: “Neuroimaging can demonstrate that brain activity is correlated with a
cognitive task or process, but cannot demonstrate that the region is necessary for
that task or process: This requires showing that disruption of the region results in
impairment of the function” (p. 180). It would seem that the issue of intelligence
and rostral PFC is likely to be a test of the degree to which “involved in, but not
necessary for” will prove useful in characterizing brain–behavior relations—or at
least, of the difficulty in devising contrast conditions or other experimental
manipulations that control for all possible non-relevant cognitive processing (see,
e.g., Friston et al., 1996)
Another problem for neuroimaging inferences in reference to theorizing about
rostral PFC function concerns the specificity of findings; in other words, the
degree to which neural activation in a particular region is specific to a particular
task. For some more “informationally encapsulated,” routine-type processing,
such as basic visual processing, there may be such a close correspondence between
a particular local pattern of activation and a particular stimulus (or thought) that
one is able with some accuracy to predict the latter from the former, at least within
a highly constrained experimental situation. However, this seems less likely for
more “central processes” and perhaps most problematic of all for systems sup-
ported by frontal lobe structures, which deal with novelty (Burgess, 1997), and
may have “adaptive coding”-type characteristics (Duncan, 2001). Where a consis-
tent relationship is found between performance of task type A and activation in
region X, it may be relatively easy to base one’s theorizing about the functions of
that region around information-processing models relating to task type A.
However, if region X is also active in a wide range of tasks other than A, this may
prove unproductive.
It may be that this kind of situation has already occurred in relation to rostral
PFC theorizing. One of the earliest observations in relation to rostral PFC activa-
tions from neuroimaging was the large number of studies of episodic memory in
which activations in BA 10 were found (e.g., Buckner et al., 1996). Grady (1999)
provided an excellent review of the relevant findings available at the end of the
1990s. She reviewed 90 PET studies demonstrating regional cerebral blood flow
(rCBF) changes within the frontal lobes, and concluded that the most heavily rep-
resented function of BA 10 is episodic memory. The basis for this conclusion was
that most of the experiments reporting BA 10 activation were using episodic
memory paradigms. This was an understandable conclusion, but may have been
misleading since it did not take into account the predominance of episodic memory
investigations in the literature at that time. If one adjusts for the different pro-
portions of studies across different cognitive domains, a different picture emerges.
Thus, 37/90 (41%) of the studies that Grady considered in her review investigated
episodic memory, and 47/90 (52%) of the studies she considered reported rCBF
changes in BA 10. However, only 68% of the episodic memory studies reported
BA 10 activations, and only 25 (53%) of the paradigms that caused BA 10 activa-
tions were episodic memory ones. Furthermore, 7/90 of the studies that Grady
considered were investigations of “working memory,” and 6 of these (86%) showed
BA 10 activation. Finally, 6/90 studies investigated conditioning or motor learn-
ing, and all 6 (100%) reported BA 10 activation. Thus, on the basis of these data it
is doubtful that, whatever role BA 10 functions play in cognition, they are any
more active when people are involved in episodic memory tasks than when they
are engaged in other sorts of tasks. As MacLeod, Buckner, Miezin, Petersen, and
Raichle (1998) put it, “although . . . BA 10 is routinely activated by episodic
memory tasks, it is not uniquely activated by episodic memory tasks” (p. 41).
As with the “intelligence hypothesis” of rostral PFC function, caution might have
been indicated by the human lesion evidence. The data from both single-case stud-
ies and group studies (see, e.g., Burgess et al., 2000; Petrie, 1952) show that uncom-
plicated lesions to rostral PFC do not cause pervasive problems with episodic recall
and recognition. Indeed, many patients with even extensive rostral PFC lesions
may be completely normal on a wide range of clinical neuropsychological tests of
episodic memory (e.g., Case A.P. from Shallice & Burgess, 1991). This is not, of course,
to say that rostral PFC is not involved in some aspects of memory functioning—
it probably is, as we shall see below—the point instead is that constraining the
theorizing based on neuroimaging data by requiring the accounts to be in agree-

ment simultaneously with the human lesion evidence might have greatly acceler-
ated the advance of our understanding. The question then might have been
something like “what kind of processing might regularly be prompted by episodic
memory tests (and other tests) but which, when damaged, would not cause a def-
icit on, e.g., a forced-choice recognition memory test?” Notably, those few authors
who did pursue a line of reasoning of this type alighted upon accounts that now
seem remarkably prescient (e.g., Wheeler, Stuss, & Tulving, 1997).
Other Ways in which Lesion Evidence

Is Critical for Theorizing
In this way (and others), one of the great utilities of lesion evidence is that a nega-
tive finding can be as significant for theorizing as a positive one. This is, of course,
demonstrated by perhaps the most significant pattern of behavior as regards the-
orizing in cognitive neuropsychology: the double dissociation. This is where, in its
classic example, one patient shows a marked decrement in one domain of cogni-
tion but unimpaired performance in another. Then another patient shows the
opposite pattern. Here, the decrements in each case are noteworthy only because
they are accompanied by a normal-level contrast.
In this respect, one might ask for the broadest evidence we have of the patterns
both of impairment and preservation following rostral PFC lesions. The wonder-
ful set of group human lesion studies carried out over many years by Donald T.
Stuss and Michael Alexander and their colleagues in Toronto provide probably the
best such database for the purpose, since similar methods were applied to the
analysis of the data over a long period of time. Moreover, some of the cases were
shared across studies, which for this purpose is useful.
What we are trying to address in this analysis is whether lesions affecting ros-
tral PFC cause a breadth of deficits comparable with lesions elsewhere within the
frontal cortex. In this way, the aim is to answer the question of whether (a) theo-
rizing should start by considering that rostral PFC supports processing that oper-
ates across a very wide range of tasks, or (b) whether one might instead consider
performance on a more specific subset of them as particularly good indicators of
a “rostral PFC-supported” cognitive substrate. One might imagine that this is per-
haps not much more than a formalized version of what occurred in the early days
of research into the functions of the primary visual cortex, for example, where a
particular relation between deficit on a subset of tasks (i.e., those involving visual
processing) and lesions to this region was noted. Fortunately, however, the proce-
dures of Stuss and Alexander take into account what is already known about fron-
tal lobe function, in that they do not consider as experimental tasks sets of them
that have been shown not to be relevant, and indeed, they go to some lengths to
exclude patients with complicating presentations.
Details about the precise population contributing to these analyses are of

course available in the original research papers. Broadly, however, Stuss and
Alexander followed the following procedures.
They tested patients whose lesions involved the frontal lobes (and sometimes
outside the frontal lobes) and collected sets of non-patient control subjects
matched as closely as possible to the patients for sex, age, and education. The
lesions included infarction, hemorrhage (including ruptured aneurysms), trauma,
and tumors. Most patients with tumors had resection of meningiomas or low-
grade gliomas and had not been treated with radiation. Stuss and Alexander
avoided patients in the very acute phase of their illness (e.g., less than 2 months
after onset), and also excluded people with significant aphasia, visual neglect,
motor control, or any other significant neurological or psychiatric disorders.
Further, the patients tended to have IQ scores within the normal range.
Incidentally, it should be mentioned that in these studies, and comparable ones
where rigorous neuropsychological screening is used to remove potential con-
founds (e.g., Burgess et al., 2000), no simple link between etiology and cognitive
results is found: it is the location of the lesion that is the principal determining
factor.
The results shown in Tables 4.1 and 4.2 and summarized in Figure 4.1 demon-
strate the number of variables, out of the total of 44 under consideration (see
Table 4.1 for a list of them), where impairments were documented by the Stuss/
Alexander group for each broad architectonic subdivision of the frontal lobes. Not
all the group lesion studies conducted by Stuss and Alexander over this period are
included because of technical differences in their analysis method; the figure
shows only those where comparability is sufficient for this purpose.
This simple meta-analysis of the Stuss/Alexander series of studies shows two
results quite clearly. The first of these is that rostral PFC lesions do not cause defi-
cits on a more widespread set of tasks than lesions elsewhere within the frontal
lobes. For both left and right hemispheres, lateral and medial surfaces, deficits
were noted on the range of variables examined by Stuss and Alexander (see Table
4.2 for a list) less frequently than for some other frontal lobe regions. Although
right medial aspects of superior area 10 were implicated (alongside others) in
groups of patients who performed poorly on some variables, for the other regions,
with the possible exception of some aspects of ventral PFC, cognitive deficits
associated with area 10 lesions, regardless of hemisphere or surface, were consis-
tently amongst the least frequent findings in this series of studies stretching over
10 years. Indeed, even considering the most frequently implicated subregion of
area 10 (right medial superior), the equivalent region within area 9 (i.e., right
superior medial) was implicated more than twice as frequently. This evidence
would seem to suggest that if “intelligence” is a construct that determines perfor-
mance across a range of tasks, it would be most appropriate on this evidence to
start first by considering area 9, not area 10 as the most likely supporting brain
region.
6A 8B 6A
5 8B 5
4 8Ad 8Ad 4
9 9/46d 7
7 1/2/3 8Av 9/46d 9 8Av 1/2/3
9/46v
40 9/46v 40
46 46
39 39
41/4 6B 44 45B 10s 10s 45B 44 6B 42
17 18 19
2 45A 41/ 19 18 17
22 45A 22
10i 10i 37
37 47/12 47/12
21 21
11 11 38
38
20
20
6A 1/2/3 1/2/3 4 6A
4
8B 5 5 8B
7
9 31 7 31 9
32s 23 23
24s 19 19 24s
32s
10s 18 18
30 10s
30
17 17
18 18 24i 32i
32i 24i 35 19 19 35 10i
10i
25 34 34 25
14 37 37 14
28 28
11 11
36 36
38 20 20 38
1 condition 2 conditions 3 conditions 4–11 conditions
12–19 conditions 20 conditions or above
Figure 4.1. A visual illustration of the findings from a selection of Stuss and
colleagues’ studies involving patients with frontal lobe lesions, between 1998 and
2008. Test results are compared to patients with non-frontal lesions and/or controls.
The figure shows the frequency of a reported impairment for each Brodmann area
based on the results from 44 behavioral variables described in Table 4.1. These
frequencies are divided into six ranges, represented by different colors. Dark blue = the
region was found to be impaired, to a statistically significant degree, on 1 of the 44
behavioral variables (relative to either controls or at least one other patient group).
Light blue = 2/44 variables impaired. Green = 3/44 variables impaired. Yellow = 4 to 11
variables impaired. Orange = 12 to 19 variables impaired. Red = 20 or more variables
impaired. The results show that rostral PFC regions (area 10) are not impaired on a
larger number of these behavioral indicators than other PFC regions. These
results provide a constraint for theorizing about the functions of rostral PFC.
(See Color Plate Section for a color version of this figure.)
Of course, the selection of tasks that Stuss, Alexander, and colleagues used in
this series of studies was not random. They were chosen largely because of their
putative sensitivity to frontal lobe lesions, or were discovered to be so during the
course of the experiment. However, this adds in extremely useful ways to the
results already outlined above. We can ignore any suggestion that rostral PFC
lesions usually cause serious deficits in primary sensory functions, or in the “rou-
tinized” learned skills such as basic aspects of language processing, motor or visuo-
perceptual abilities, reading, writing, or simple aspects of memory (e.g., knowledge;
Table 4.1. Summary of the Findings from Stuss and Colleagues Testing Patients with Lesions in Frontal Lobes, 1998–2008
Study Condition Variables Right Medial Left Medial Right Lateral Left Lateral
1. The effect of focal anterior 1A. Letter-based Making errors (compared to 9/46, 46, 44,
and posterior brain lesions fluency task controls) 45, 47/12
on verbal fluency (Stuss
et al., 1998)
1B. Letter-based Produced fewer (compared 6A, 8B, 9, 24 6A, 8B, 9/46, 46, 44,
fluency task to controls) 9, 24 45, 47/12
1C. Semantic Produced fewer words 9/46, 46, 44,
fluency task (compared to controls) 45,
47/12, 5, 7,
40
2. Humor appreciation: a role 2A. Verbal Humor Impairment in distinguishing 8B, 9, 10s 8B, 9, 10s
of the right frontal lobe Statements test between humorous and neutral
(Shammi & Stuss, 1999) verbal stimuli (compared to
controls)
2B. Verbal Humor Impairment in choosing correct, 8B, 9, 10s 8B, 9, 10s
Statements test funny punchlines to incomplete
verbal joke items (compared to
controls)
(Continued)
Table 4.1. (cont’d)
3. Wisconsin Card Sorting 3A. WCST 128 Number of correct categories 6A, 8B, 9, 24, 6A, 8B, 9/46, 46, 44, 9/46, 46, 44,
Test performance in patients (compared to controls and 10s 9, 24, 45, 47/12 45, 47/12
with focal frontal and patients with non-frontal 10s
posterior brain damage: lesions)
effect of lesion location and
test structure on separable
cognitive processes
(Stuss et al., 2000)
3B. WCST 128 Perseverations of the preceding 6A, 8B, 9, 24, 6A, 8B, 9/46, 46, 44, 9/46, 46, 44,
criterion (compared to controls) 10s 9, 24, 45, 47/12 45, 47/12
10s
3C. WCST 128 Perseverations of the preceding 6A, 8B, 9, 24, 6A, 8B, 9/46, 46, 44, 9/46, 46, 44,
response (compared to controls) 10s 9, 24, 45, 47/12 45, 47/12
10s
3D. WCST 64A Number of correct categories 6A, 8B, 9, 24, 6A, 8B, 9/46, 46, 44, 9/46, 46, 44,
(compared to controls and 10s, 10i, 11, 9, 24, 45, 47/12 45, 47/12
patients with non-frontal lesions) 25, 32 10s, 10i,
11, 25, 32
3E. WCST 64A Perseverations of the preceding 6A, 8B, 9, 24, 6A, 8B, 9/46, 46, 44, 9/46, 46, 44,
criterion (compared to controls) 10s 9, 24, 45, 47/12 45, 47/12
10s
3F. WCST 64A Perseverations of the preceding 6A, 8B, 9, 24, 6A, 8B, 9/46, 46, 44, 9/46, 46, 44,
response (compared to controls, 10s 9, 24, 45, 47/12 45, 47/12
patients with frontal and 10s
non-frontal lesions)
3G. WCST 64A Set loss (compared to controls) 10i, 11, 10i, 11,
25, 32 25, 32
3H. WCST 64B Number of correct categories 6A, 8B, 9, 24, 6A, 8B, 9/46, 46, 44, 9/46, 46, 44,
(compared to patients with 10s 9, 24, 45, 47/12 45, 47/12
frontal and non-frontal lesions) 10s
3I. WCST 64B Perseverations of the preceding 6A, 8B, 9, 24, 6A, 8B,
criterion (compared to patients 10s 9, 24,
with frontal and non-frontal 10s
lesions)
3J. WCST 64B Perseverations of the preceding 6A, 8B, 9, 24, 6A, 8B, 9/46, 46, 44,
response (compared to patients 10s 9, 24, 45, 47/12
with frontal and non-frontal 10s
lesions)
4. Stroop performance in 4A. Color naming Color errors (compared to 44, 45A,
focal lesion patients: condition patients with frontal lesions) 45B, 46,
dissociation of processes and 9/46, 8A,
frontal lobe lesion location 6A, 6B
4B. Incongruent Incongruent errors (compared to 8B, 9, 32s 8B, 9, 32s
condition patients with frontal lesions)
(Continued)
5. Dissociation within the 5A. Simple task Slowing down in reaction time 6A, 8B, 9, 24 6A, 8B,
anterior attentional system: (compared to controls) 9, 24
effects of task complexity
and irrelevant information
on reaction time and
accuracy
5B. Easy task Slowing down from simple to easy 44, 45A, 45,
task (compared to controls) 47/12, 11,
10, 46, 9/46,
9, 8B, 8A
5C. Easy task Number of omissions (compared 6A, 8B, 9, 24 6A, 8B, 44, 45A, 45B,
to controls) 9, 24 47/12, 11,
10, 46, 9/46,
9, 8B, 8A
5D. Complex task Less proportional increase 6A, 8B, 9, 24, 6A, 8B, 9, 44, 45A, 45,
(compared to controls) 10, 11, 25, 32 24, 10, 11, 47/12, 11,
25, 32 10, 46, 9/46,
9, 8B, 8A
5E. Complex task Number of omissions (compared 6A, 8B, 9, 24 6A, 8B,
to controls) 9, 24
5F. Complex task Number of false-positive 44, 45A, 45,
responses (compared to controls) 47/12, 11,
10, 46, 9/46,
9, 8B, 8A
5G. Redundant Less proportional increase 6A, 8B, 9, 24 6A, 8B, 44, 45A, 45,
task (compared to controls) 9, 24 47/12, 11,
10, 46, 9/46,
9, 8B, 8A
5H. Redundant Number of omissions (compared 6A, 8B, 9, 24 6A, 8B, 44, 45A, 45,
task to controls) 9, 24 47/12, 11,
10, 46, 9/46,
9, 8B, 8A
5I. Second Number of omissions (compared 6A, 8B, 9, 24 6A, 8B,
simple task to controls) 9, 24
6. Impaired concentration 6A. Slowing in 9, 24, 32s 9 9/46
due to frontal lobe damage reaction time
from two distinct lesion sites (compared to
(Alexander et al., 2005) controls and
patients with
frontal lesions)
(Continued)
6B. Number of 45A, 45B, 44,

errors (compared 47/12
to controls [in the
first 100 trials]
and patients with
frontal lesions)
7. Multiple frontal systems 7A. Choice Slowing in reaction time 9, 24, 32s 9/46v, 46
controlling response speed reaction time test (compared to controls)
7B. Prepare First and forth replications of 9, 24, 32s
reaction time prepare reaction time with 1
second of warning (compared to
controls)
7C. Prepare Second and third replications of 9, 24, 32s 6A, 9/46d,
reaction time prepare reaction time with 3 9/46v, 46,
seconds of warning (compared to 45A
controls)
8. Effects of focal frontal 8A. Go/No Go Slowing in reaction time 9, 32s, 24s,
lesions on response (compared to controls) 25
inhibition
(Picton et al., 2006)
8B. Go/No Go Variability in reaction time 9, 32s, 44, 45A,
(compared to controls) 24s, 24i 47/12
8C. Go/No Go False alarms in no-go blocks 6A, 8B 6A, 8B
(compared to controls)
9. Inhibitory control is 9A. Stop Signal Slowing in reaction time 6A, 8B, 9
slowed in patients with right Task (compared to controls)
superior frontal damage
(Floden & Stuss, 2006)
10. Keeping time: effects of 10A. Tone paced Variability to inter-response 44, 45B
focal frontal lesions condition interval (compared to controls
(Picton et al., 2006) and patients with frontal lesions)
10B. Self-paced Variability to inter-response 45A, 8Ad
condition interval (compared to controls
and patients with frontal lesions)
10C. Accuracy and Deterioration in performance 9, 10s, 32s 6A, 8B, 9/46d, 10s 9, 8B, 8Ad,
variability of (compared to controls) 24s, 9/46d, 45B
timing 32s
11. Regional frontal injuries 11A. Modified Slowing in reaction time 6A, 9, 32s, 9, 25 8Av, 9/46d, 9
cause distinct impairments Stroop test (compared to controls and 24s, 25
in cognitive control patients with frontal lesions)
(Alexander et al., 2007)
(Continued)
11B. Modified False-positive errors 9/46v, 47/12,

Stroop test (compared to controls and 45B
patients with frontal lesions)
12. Multiple effects of 12A. Single task Number of errors (compared to 6A 9/46v
performance lesions on condition controls)
task-switching
(Shallice et al., 2008)
12B. Long Cue Number of errors (compared to 9, 14
and Short Cue controls)
conditions
combined
13. The multiple dimensions 13A. Slow Deterioration of performance 10s, 9, 32s, 9, 24s 10s
of sustained attention condition (compared to patients with 24s
(Shallice et al., 2008) frontal lesions)
13B. Fast Deterioration from low number of 9, 32s, 24s 6A, 8Av, 6B,
condition targets to high number of targets 44, 45A, 46
in the fast condition
(compared to patients with
frontal lesions)
Notes: The first column specifies the paper names. The second column specifies 44 conditions in which patients with frontal lobe lesions were found to be impaired. The
third column specifies the variables measured for each of the conditions.
The remaining four columns specify Brodmann areas that represent the localization of the lesions in the impaired conditions in respect to two brain surfaces (i.e., lateral
and medial) and the two hemispheres (i.e., left and right). Typically, lesions encompassed more than one region in any one patient. In all conditions the significance level
was p < 0.05.
Abbreviations: v = ventral, d = dorsal, I = inferior, s = superior.
Technical note: In most of the papers there was no specific classification of the lesion localization in terms of Brodmann areas. To include as many conditions as possible
but at the same time include conditions where the localization is accurate and specific, we used different criteria for the lesion localization across the papers as follows:
1. In papers 1 and 5 lesion localization were not specified in terms of Brodmann areas. As suggested to us by Prof. Stuss and Dr. Alexander, the classification of the
lesion localization was as follows:
Lesions in “inferior medial PFC” were referred to in this analysis as BA 10, 11, 25, and 32 on the medial surface, while lesions in the “superior medial” region were
classified as BA 6A, 8B, 9, and 24 on the medial surface. This procedure was adopted from Levine et al. (1998). Lesions on the left or right lateral surface were clas-
sified as BA 44, 45A, 45, 47/12, 11, 10, 46, 9/46, 9, 8B and 8A, lesions involving dorsolateral PFC were classified as BA 9/46, 46, 44, 45, 47/12 on the lateral surface,
and lesions in the parietal lobe were classified as BA 5, 7, 40 on the lateral surface.
2. In paper 2 for the two conditions reported, a specific classification of the patients’ lesions in terms of Brodmann areas was given (BA 8B, 9, 10s in the right hemi-
sphere).
4. For paper 3 a classification in terms of Brodmann areas was given to two groups of patients: “Superior Medial” (BA 6, 8, 9, 10s, and 24) and “Inferior Medial” (BA
10i, 11, 12, 25, and 32). For the other groups of patients (i.e., right and left dorsolateral PFC) the classification was similar to those in papers 1 and 5.
5. In paper 4 a specific classification in terms of Brodmann areas was reported, in accordance with the cytoarchitectonic areas adopted by Petrides and Pandya (1994),
to the following groups: the left or right lateral surfaces (BA 9/46, 44, 45, 46, 6A, 6B, 8A), “Superior Medial” (BA 8B, 9, 32s), and “Inferior Medial” (BA 10, 11, 14).
6. In papers 6–13 there was no classification in terms of Brodmann areas for the groups of patients. Thus, for these papers only conditions in which lesion localizations
were specified in terms of Brodmann areas (e.g., usually in a figure) could be included in the analysis.
7. In all papers brain areas representing localization of lesions were illustrated in the figure in the following way: BA 24, 10, and 32 were divided into the inferior and
superior subregions, and BA 9/46, and 8A were divided into the ventral and dorsal subregions.
episodic recognition memory), and so forth: all the studies so far reviewed here
detail patients with rostral PFC damage but whose abilities in these kinds of
domains is unaffected. Nor does it seem likely that the screening procedure used
by Stuss, Alexander, and their colleagues led to an abnormal degree of rejection of
rostral PFC patients: the clinical wisdom of many years is that rostral PFC is rela-
tively silent in terms of neurological symptoms (indeed, this was one of the rea-
sons for the relative lack of progress made in this area until recent times).
We can also dismiss the suggestion that rostral PFC supports some kind of
processing related to “intelligence” as defined as a “g”-type processing resource.
Such a construct must surely have a strong general influence upon behaviors such
as choice reaction time and other “hard” tasks. Neither would rostral PFC be well
characterized as relating to some processing reflected in some “average” of intel-
ligence tasks. Further, what the Stuss/Alexander findings show is that there
appears to be no special relation between rostral PFC lesions and deficits on a
range of traditional “executive” tasks either.
From this, we can learn that explanations in terms of the macro-level con-
structs traditionally used in the field (but rarely with detailed formulation in
information-processing theory), such as “planning” or “problem-solving” or “cog-
nitive control,” may be inadequate starting points for theorizing about rostral
PFC function (see also Burgess, 2000; Burgess et al., 2000). While it may be that
rostral PFC supports processing that plays a role in the performance of tasks that
have been labeled as, for example, “analogical reasoning,” it is doubtful that this
construct adequately defines the characteristics of the task that particularly
require that processing (Volle et al., 2010). Indeed, in many cases it may be a
matter of identifying the common processing across tasks that prima facie look
quite different (i.e., use different stimuli, largely different instructions, different
responses, etc.) rather than the defining features of a particular task (for neuro-
imaging evidence see the studies of Burgess and colleagues. who have made exten-
sive use of “cognitive conjunction”-type designs; e.g., Burgess et al., 2001, 2003;
Gilbert et al., 2005; Simons et al., 2005).
The second finding from the Stuss/Alexander meta-analysis is that the deficits
that can most precisely be attributed to rostral PFC lesions seem to relate to quite
specific situations. None of the Stuss/Alexander studies implicated only area 10
as critical to performance of a particular variable: instead, they identified brain
regions where area 10 was one of the regions that, when impaired, caused impair-
ment. However, this makes the results even more remarkable. If one considers
just those variables where lesions that included rostral PFC (area 10) caused an
impairment that was significantly worse than in patients with lesions elsewhere,
the result is a very restricted subset of the 44 variables indeed. Patients with
lesions that included rostral PFC showed impairments in humor judgment, in
2 (only) of the 10 Wisconsin Card Sorting Test (WCST) variables considered by
Stuss and Alexander, and in maintaining performance in time-keeping tasks, and
were worst during slow conditions of sustained attention tasks. With this latter
finding, there is an interesting concordance with the findings of Petrie (1952),

more than 50 years earlier, which suggested that rostral PFC lesions can lead to a
variable response to distraction, and the sense that time passes more quickly, but
leaving other cognitive abilities intact.
Towards a Theory of Rostral PFC Function,

Integrating Human Lesion Data with
Functional Neuroimaging
So, if the wide array of cognitive constructs relating to IQ and many traditional
executive abilities are to be dismissed as a starting point for theorizing about ros-
tral PFC function, where instead might one start? Burgess and colleagues (2009)
argue that the most telling finding is that many people with rostral PFC pass tra-
ditional tests but show handicaps in everyday behavior. We argue that the reason
for this is that there are many skills required by everyday life activities that are
not captured by traditional neuropsychological (and IQ) tests, and it may be these
skills that are principally affected by rostral PFC lesions.
So what might these abilities be? In fact, when one starts to analyze the
demands of what makes a human effective in real-life situations, it quickly
becomes apparent that there are very many mental abilities that might not be well
estimated by traditional neuropsychological tests. The most obvious are those
relating to social and emotional behavior. But other important abilities relate to
insight and introspective ability, and mentalizing more generally (including
“theory of mind”). To this we might add source and context memory, and a whole
raft of capacities relating to one’s ability to organize behavior over long periods of
time, and in the absence of external cues (e.g., multitasking, prospective memory).
No doubt there are also many additional mental capacities that exist that we have
not even yet identified.
Impairments in Everyday Life in the Context

of High IQ: A Common Occurrence Following
Rostral PFC Lesions
Perhaps unsurprisingly, therefore, impairments in the ability to cope with the
demands of everyday life following frontal lobe involvement are not uncommon.
They also can occur in the context of preserved IQ (for review, see Burgess et al.,
2009).
Probably the first case of this kind for which good neurological documentation
exists was reported by Penfield and Evans (1935). They described the symptoms
Table 4.2. Comparisons of Number of Variables Involved Across
Brain Regions
Table 1. Frontal
Condition 10s 10i 11 14 47/12 25 46 32i 32s 45A 45B

1A. Letter-based Ll Ll Ll Ll
fluency task
1B. Letter -based Ll Ll Ll Ll
fluency task
Lm
1C. Semantic Ll Ll Ll Ll
fluency task
2A. Verbal Humour Rm
Statement
test * Rl
2B. Verbal Humour Rm
Statements
test * Rl
3A. WCST variants: Rm Rl Rl Rl Rl
3A. WCST 128 Lm Ll Ll Ll Ll
3B. WCST 128 Rm Rl Rl Rl Rl
Lm Ll Ll Ll Ll
3C. WCST 128 Rm Rl Rl Rl Rl
Lm Ll Ll Ll Ll
3D. WCST 64A Rm Rm Rm Rl Rm Rl Rm Rm Rl Rl
Lm Lm Lm Ll Lm Ll Lm Lm Ll Ll
3E. WCST 64A Rm Rl Rl Rl Rl
Lm Ll Ll Ll Ll
3F. WCST 64A Rm Rl Rl Rl Rl
Lm Ll Ll Ll Ll
3G. WCST 64A * Rm Rm Rm Rm Rm
Lm Lm Lm Lm Lm
70
Parietal
9 9/46v 9/46d 24i 24s 44 8B 8Av 8Ab 6A 6B 5 7 40

Ll Ll Ll
Rm Ll Ll Rm Rm Ll Rm Rm
Lm Lm Lm Lm
Ll Ll Ll Ll Ll Ll
Rm Rm
Rl Rl
Rm Rm
Rl Rl
Rm Rl Rl Rm Rm Rl Rm Rm
Lm Ll Ll Lm Lm Ll Lm Lm
(Continued)
71
Table 1. Frontal

3H. WCST 64B Rm Rl Rl Rl Rl
Lm Ll Ll Ll Ll
3I. WCST 64B * Rm
Lm
3J. WCST 64B Rm Rl Rl Rl Rl
Lm
4A. Color naming Ll Ll Ll
condition
4B. Incongruent Rm
condition
Lm
5A. Simple task
5B. Easy Ll Ll Ll Ll Ll Ll Ll
task *
5C. Easy task
Rl Rl Rl Rl Rl Rl Rl
5D. Complex Rm Rm Rm Rm Rm Rm
task
Lm Lm Lm Lm
Ll Ll Ll Ll Ll Ll Ll
5E. Complex task
5F. Complex task * Rl Rl Rl Rl Rl Rl Rl

5G. Redundant
task
72
Parietal
9 9/46v 9/46d 24i 24s 44 8B 8Av 8Ab 6A 6B 5 7 40

Rm Rm Rm Rm Rm
Lm Lm Lm Lm Lm
Lm Lm Lm Lm Lm
Rm Rm
Lm Lm
Rm Rm Rm Rm Rm
Lm Lm Lm Lm Lm
Rm Rm Rm Rm Rm
Lm Lm Lm Lm Lm
Rm Rm Rm Rm Rm
Lm Lm Lm Lm Lm
Rm Rm Rm Rm Rm
Lm Lm Lm Lm Lm
Rm Rm Rm Rm Rm
Lm Lm Lm Lm Lm
(Continued)
73
Table 1. Frontal

5H. Redundant
task
5I. Second
simple task
6A. Slowing Rm
in RT
6B. Number of Ll Ll Ll
Errors
7A. Choice Rl Rm
RT test
7B. Prepare RT Rm
7C. Prepare RT Rl Rm Rl
8A. Go-no Go Rm Rm
8B. Go-no Go Rl Rm Rl
8C. Go-no Go
9A. Stop
Signal Task
10A. Tone paced Rl
10B. Self-paced Rl
condition
10C. Accuracy Rm Rm
and variability of
timing Rl Lm
Ll
74
Parietal
9 9/46v 9/46d 24i 24s 44 8B 8Av 8Ab 6A 6B 5 7 40

Rm Rm Rm Rm Rm
Lm Lm Lm Lm Lm
Rm Rm Rm Rm Rm
Lm Lm Lm Lm Lm
Rm Rl Rl Rm Rm
Lm
Ll
Rm Rl Rm Rm
Rm Rm Rm
Rm Rl Rl Rm Rm Rl
Rm Rm
Rm Rm Rm Rl
Lm Lm
Ll Ll
Rm Rm Rm
Rl
Rl
Rm
Rl Lm Lm Lm
Ll Ll Ll Ll
(Continued)
75
Table 1. Frontal

11A. Modified Rm Rm
Stroop
Lm
11B. Modified Ll Ll
Stroop test
12A. Single task
12B. Long Cue + Lm

Short Cue
13A. Slow Rm Rm
condition *
Rl
13B. Fast Rl Rm Rl
condition
Notes: Data are from the Stuss/Alexander series (see Table 4.1 for details of studies and variables).
Each patient may have involvement of multiple brain regions. Each subregion is split into hemisphere
(R or L), and lateral or medial surface (l or m). These studies identified, in group comparisons, an
aspect of area 10 as being part of some larger region specifically involved in 7/44 variables (marked in
italics, and with an asterisk). For variables 2A, 2B, 3G, 5B, and 5F, the comparison was made between
patients whose damage may well have (according to the Stuss/Alexander method of lesion localiza-
tion; see footnote to Table 4.1 for details) included area 10 and controls (with no other patient group
being impaired). For variable 3I the comparison was made between patients whose damage may have
included area 10 and other patient groups (the control group was not tested on this condition). Finally,
for variable 13A the comparison was made between patients whose damage included (but was not
restricted to) area 10 and other patient groups (with no other patient group being impaired relative to
controls).
76
Parietal
9 9/46v 9/46d 24i 24s 44 8B 8Av 8Ab 6A 6B 5 7 40

Rm Rm Rm
Lm
Rl Rl Rl
Ll
Ll Rl
Lm
Rm Rm
Lm Lm
Rm Rm Rl Rl Rl Rl
77
that Penfield’s sister was experiencing after the removal of a right frontal oligoden-
droglioma: “She had planned to get a simple supper for one guest (Wilder Penfield)
and four members of her own family. She looked forward to it with pleasure and
had the whole day for preparation. This was a thing she could have done with
ease . . . before. When the appointed hour arrived she was in the kitchen, the food
was all there, one or two things were on the stove, but the salad was not ready,
the meat had not been started and she was distressed and confused by her long
continued effort alone. It seemed evident that she would never be able to get
everything ready at once” (p. 131).
Penfield’s sister was not suffering from a marked and generalized cognitive
decline, and did not have serious disabilities in basic cognitive systems (e.g., clas-
sic dense amnesia, visuo-spatial/perceptual or agnosic problems, disorders of
motor control and so forth). Similar cases were soon reported (e.g., Ackerly &
Benton, 1947; Brickner, 1936). These established, at least on the grounds of clini-
cal observation alone, that behavioral disorganization can be seen in the absence
of gross cognitive decline, harking back to the most famous case of frontal lobe
damage: Harlow’s Phineas Gage.
However, it was not until the mid-1980s that an attempt was made to charac-
terize the nature of the critical cognitive deficit underpinning this type of disor-
der. Eslinger and Damasio (1985) described the case of E.V.R., who had undergone
surgical removal of a large bilateral frontal meningioma. At the time of his opera-
tion E.V.R. was a financial officer with a small company and a respected member
of his community. He was married and the father of two children; his brothers and
sisters considered him a role model and a natural leader. After the operation, how-
ever, E.V.R. lost his job, went bankrupt, was divorced by his wife, and moved in
with his parents. He subsequently married a prostitute and was divorced again
within 2 years. Extensive psychological evaluations demonstrated that he was
superior or above average on most intelligence tests (e.g., Verbal IQ of 125;
Performance IQ of 124) and, indeed, on most other kinds of cognitive test as well.
Despite these normal findings, however, E.V.R. was often unable to make simple
everyday decisions, such as which toothpaste to buy, what restaurant to go to, or
what to wear. He would instead make endless comparisons and contrasts, often
being completely unable to come to a decision at all. Further, Eslinger and Damasio
report prospective memory problems: “it was as if he forgot to remember short-
and intermediate- term goals” (1985, p. 1737).
Eslinger and Damasio’s paper was important because it was the first to present
a formal neuropsychological examination of this kind of presentation, thus adding
in an important way to Penfield and Evans, and the others who had presented
only formal neurological data. However, Eslinger and Damasio’s study still did not
quantify the most critical aspect of the presentation: the nature of the cognitive
impairment.
A study by Shallice and Burgess (1991) addressed this lacuna. They pre-
sented three cases who had all suffered frontal lobe damage following traumatic
brain injury. None had any significant impairment on formal tests of perception,
language, and intelligence, and two performed well on a variety of traditional
tests of executive function. Indeed, one of these cases (A.P.) was probably the best
example of the syndrome so far reported. A.P. sustained an open head injury in a
road traffic accident when he was in his early 20s. The injury caused a virtually
complete removal of the rostral prefrontal cortex bilaterally plus damage to sur-
rounding regions. On standard neuropsychological measures of intellectual func-
tioning, memory, and perception and even traditional tests of executive function,
A.P. performed within the superior range.
But A.P. did show impairment in everyday life. The most obvious was a marked
multitasking and prospective memory problem. This manifested itself as tardi-
ness and disorganization, the severity of which ensured that despite his excellent
intellect and social skills, he never managed to return to work at the level he had
enjoyed premorbidly. Shallice and Burgess (1991) invented two new tests of mul-
titasking to assess these problems. The first, the “Multiple Errands Test,” is a real-
life multitasking test carried out in a shopping mall or similar area. Participants
have to complete a number of tasks, principally involving shopping, while follow-
ing a set of rules (e.g., no shop should be entered other than to buy something).
The tasks vary in terms of complexity (e.g., buy a small brown loaf vs. discover the
exchange rate of the Euro yesterday), and there are a number of “hidden” prob-
lems in the tasks that have to be appreciated and the possible course of action
evaluated. For instance, one item asks that participants write and send a postcard,
yet they are given no pen, and although they cannot use anything not bought on
the street to help them, they are also told that they need to spend as little money
as possible. In this way, the task is quite “open-ended” or “ill-structured” (i.e.,
there are many possible courses of action, and it is up to the individual to decide
which one to choose). (For further studies using versions of this task see, e.g.,
Alderman et al., 2003; Dawson et al., 2009 Knight et al., 2002.)
The second task that Shallice and Burgess invented was a more controlled
experimental task, the “Six Element Test.” This requires participants to swap
efficiently between three simple subtasks, each divided into two sections within
15 minutes, while following some arbitrary rules (e.g., “you cannot do part A of a
subtask followed immediately by part B of the same subtask”). There are no cues
signaling when to switch tasks, and although a clock is present, it is covered, so
that checking it has to be a deliberate action. Thus, this paradigm has a strong
component of voluntary time-based task switching (i.e., one form of prospective
memory). (A version of this task is now part of the Behavioral Assessment of the
Dysexecutive Syndrome [BADS] assessment battery [Wilson et al., 1996].)
Despite their excellent general cognitive skills, A.P. and the other patients
reported by Shallice and Burgess all performed these tasks below the 5th percen-
tile of age- and IQ-matched controls. On the Multiple Errands Task the subjects
made a range of types of error. Many of these could be interpreted as problems
with prospective memory. For instance, they would find themselves having to go
into the same shop more than once to buy items that could all have been bought
at one visit; they forgot to carry out tasks that they had previously learned that
they needed to do, or to follow task rules. They also made a range of social behav-
ior errors (e.g., leaving a shop without paying; offering sexual favors in lieu of
payment). Shallice and Burgess (1991) termed this kind of behavioral disorgani-
zation in the context of preserved intellect and other cognitive functions the
“Strategy Application Disorder.”
Shallice and Burgess’s patients gave little clue as to the anatomical localization
of the lesion critical for this pattern of deficit, since the patients had suffered large
traumatic lesions that invaded many subregions. But 2 years later, Goldstein and
colleagues (1993) described an instructive case. G.N., a 51-year-old right-handed
man, had undergone a left frontal lobectomy 2.5 years earlier following the dis-
covery of a frontal lobe tumor (mixed astrocytoma–oligodendroglioma). A 5-cm
resection of left frontal lobe from the frontal pole was undertaken. This surgery
made little difference to his general cognitive abilities (e.g., WAIS-R Verbal IQ
129, Performance IQ 111; story recall, immediate 75–90th percentile, delayed
50–70th; Rey Osterreith delayed figure recall 80–90th percentile; Trail-making
70–75th percentile). However, it was nevertheless clear from his everyday behav-
ior that something was seriously wrong. He had held a senior management posi-
tion within an international company, but 2 years after surgery he had to take
medical retirement because of increasing lethargy. He worked from home as a free-
lance management consultant but had difficulty making decisions. For instance,
he took 2 weeks to decide which slides to use for a work presentation, but never
actually came to a conclusion. He also experienced anger-control difficulties.
Goldstein and colleagues (1993) administered the Multiple Errands Test. G.N.
made significantly more errors than controls, being less efficient (e.g., having to
return to a shop), breaking rules (e.g., using a stamp that another customer gave
him), misinterpreting tasks (e.g., sticking the stamp on the wrong card), as well as
failing to complete some tasks altogether, reporting that he had known he had to
do them but somehow “forgot” them. He also showed some “social rule” breaks.
For instance, he had omitted to find out the price of tomatoes while earlier in the
greengrocers, and realizing that he should not go back into the shop unless he was
to buy something, he very conspicuously climbed onto the fruit display outside
the shop and peered in the shop window.
This case and others reported in the literature show a remarkably similar pat-
tern of neuropsychological test performance. Burgess (2000) summarized the
performance of eight well-known patients. None of them had any language or
visuo-perceptual impairment, and all scored within the superior range on tests of
current intellectual functions. Four of the seven showed no impairment on any
memory test. But, most remarkably, two showed no impairment on a range of clin-
ical executive function tests known to be sensitive to frontal lobe lesions. Moreover,
no executive test has been failed by more than 2/8 cases. This contrasts with
the observation that all of the reported cases of “strategy application disorder”
who have been given either the Multiple Errands or Six Element Test have failed
at least one of them.
Burgess and colleagues (2009) pointed out that the multitasking situations
presented to a participant by the Multiple Errands and Six Element Tests share a
number of similarities. These are:
1. A number of discrete and different tasks have to be completed.

2. Performance on these tasks needs to be dovetailed in order to be time-
effective.
3. Due to either cognitive or physical constraints, only one task can be performed
at any one time.
4. The times for return to task are not signaled directly by the situation.
5. There is no moment-by-moment performance feedback of the sort that par-
ticipants in many laboratory experiments will receive. Typically, failures are
not signaled at the time they occur.
6. Unforeseen interruptions, sometimes of high priority, will occasionally occur,
and things will not always go as planned.
7. Tasks usually differ in terms of priority, difficulty, and the length of time they
will occupy.
8. People decide for themselves what constitutes adequate performance.
None of these features are characteristic of traditional neuropsychological

tests, nor the types of procedures that are typically used in a neurological exami-
nation. They are, however, very common aspects of everyday situations.
These patients show a single dissociation between performance on traditional
neuropsychological tests and ability to cope with situations requiring complex
behavioral organization. However, some might argue that these everyday situa-
tions are somehow “harder” or “more complex” or simply sample behavior over a
longer time frame (and thus might more easily detect problems that occur only
occasionally). On these grounds one might argue that the dissociation is artifac-
tual. To refute this possibility, Burgess and colleagues (2009) reported two patients
who performed well on the Multiple Errands Test despite showing marked impair-
ment on tests of memory and IQ. The totality of the evidence from single cases
therefore suggests a double dissociation between memory, IQ, and complex
behavioral organization, at least under certain conditions.
Localization of Deficits in Behavioral Organization

that Cannot Be Attributed to IQ Impairment
Stuss and Alexander’s group are not the only ones to have reported group studies
indicating the nature of the impairment caused by rostral PFC lesions. Burgess and
coworkers (2000) examined 60 acute neurological patients from an unselected

series of referrals (approximately three quarters of whom were suffering from
brain tumors). Their performance was compared with a group of 60 age- and
IQ-matched healthy controls. All participants were given a multitasking test called
the Greenwich Test. This is a multitasking test that follows the principles of the
Six Element Test, but in contrast the majority of the variance in performance of
the test comes from rule infractions rather than task-switching problems.
Participants were presented with three different simple tasks and told that they
had to attempt at least some of each of the tasks in 10 minutes, while following a
set of rules. One of these rules relates to all subtests (“in all three tasks, complet-
ing a red item will gain you more points than completing an item of any other
color”) and there are four task-specific rules (e.g., “in the tangled lines test you
must not mark the paper other than to write your answers down”). The task was
administered in a form that allowed consideration of the relative contributions of
task rule learning and remembering, planning, plan-following, and remembering
one’s actions to overall multitasking performance. Specifically, before participants
began the test, their ability to learn the task rules (by both spontaneous and cued
recall) was measured; this measure was called “Learn.” They were then asked how
they intended to do the test, and a measure of the complexity and appropriate-
ness of their plans was gained (a variable called “Plan”). This enabled us to look at
whether their failures could be due to poor planning (see, e.g., Kliegel et al., 2005).
The participants then performed the task itself, and by comparing what they did
with what they had planned to do, a measure of “Plan Following” was made.
Multitasking performance (the number of task switches minus the number of
rule breaks) was referred to as the test “Score.” After these stages were finished,
subjects were asked to recollect their own actions by describing in detail what they
had done (“Recount”). Finally, delayed memory for the task rules was examined
(“Remember”).
Burgess and colleagues (2000) found that lesions in different brain regions
were associated with impairment at different stages in the multitasking proce-
dure. For instance, lesions to a large region of superior posterior medial cortex
including the left posterior cingulate and forceps major gave deficits on all mea-
sures except planning. Remembering task contingencies after a delay was also
affected by lesions in the region of the anterior cingulate. Critically, however,
Burgess and colleagues found that patients with left hemisphere rostral PFC
lesions, compared with patients with lesions elsewhere, showed a significant mul-
titasking impairment (“Score” variable) despite no significant impairment on
remembering task rules (“Remember” variable). Indeed, the left rostral prefrontal
cases showed no significant impairment on any variable except the one reflecting
multitasking performance. In other words, despite being able to learn the task
rules, form a plan, remember their actions, and say what they should have done,
they nevertheless did not do what they said they intended to do. These impair-
ments appeared independently of any IQ decrement.
But perhaps these results were specific to this particular multitasking test
rather than being true of a class of situation with the previously described charac-
teristics? This appears not to be the case. Burgess, Veitch, and Costello (submit-
ted; reported in Burgess et al., 2006) administered a new version of Burgess and
colleagues’ (1996) Six Element Test to 69 acute neurological patients with circum-
scribed focal lesions and 60 healthy individuals using the administration frame-
work of Burgess and colleagues (2000). The Six Element Test differs from the
Greenwich Test in that the multitasking score reflects mainly voluntary time-
based switching rather than rule-following. Compared with other patients, those
whose lesions involved the rostral prefrontal regions of the right hemisphere
made significantly fewer voluntary task switches, attempted fewer subtasks, and
spent far longer on individual subtasks. As with the study by Burgess and col-
leagues (2000), these multitasking deficits could not be attributed to deficits in
general intellectual functioning, rule knowledge, planning, or retrospective
memory. Furthermore, there was no obvious relation between Six Element Test
performance and concomitant failure on several traditional tests of executive
function.
When one considers the earlier case studies reporting relatively isolated defi-
cits of behavioral organization in the light of the results from these group studies,
it seems that that there is a remarkably consistent finding of involvement of ros-
tral PFC. For instance, in the six cases reviewed by Burgess (2000) for whom good
brain scan data were available, all of them had rostral PFC involvement of either
the left or right hemispheres (or both). In addition to these cases, we might also
add the more recent patient reported by Bird and associates (2004) who had suf-
fered a rare form of stroke affecting the medial aspects of area 10 bilaterally, and
who failed the Six Element Test despite passing some other executive tests (e.g.,
the WCST).
From Human Neuropsychology to Neuroimaging:

Constraints for Theorizing
If one uses these results from human neuropsychology to prioritize the potential
functions that one might seek to explore using functional neuroimaging, which
functions, more precisely, might one target?
Burgess and colleagues (2001, 2003) hypothesized that a key cognitive deficit
behind that behavioral organization impairment shown by patients with rostral
PFC damage might concern prospective memory. Prospective memory is the abil-
ity to remember to carry out an intended action (or thought) after a delay period
where one has been occupied with another task. A full review of the conclusions
from these studies is given in Burgess and colleagues (2008) and is beyond the
scope of this chapter. However, in brief, we (and others; see, e.g., Reynolds, West,
& Braver, 2009) have found a consistent relation between hemodynamic changes
in both medial and lateral rostral PFC and performance of prospective memory
tasks. Moreover, recent data from our lab from human group lesion studies of
prospective memory tasks that are very similar to the ones we have used in our
neuroimaging studies are also showing a relation between rostral PFC lesions and
failures on these tasks (Volle, Costello, Gonen-Yaacovi, Gilbert, & Burgess, 2011).
Broadly, we find that lateral rostral PFC activation increases during prospective
memory conditions, with higher medial rostral PFC activation during the ongoing
task only. These activation patterns can occur regardless of the precise form (e.g.,
words, pictures, numbers, etc.) of the stimuli (with the potentially highly impor-
tant caveat that we, and others, have so far used only visual presentation of our
stimuli). Some regions of rostral PFC also appear hemodynamically insensitive to
the demands of the intended action or how difficult it is to spot the prospective
memory target. However, rostral PFC activation patterns do seem highly sensitive
to even very small changes in task instruction (Gilbert et al., 2009).
Here, then, is one example of broad congruence between findings from neu-
roimaging and neuropsychology, and where each method seems to be providing
hypotheses and tests relevant to the other method. Another potential function is
mentalizing, and related functions. “Mentalizing” is a broad term referring to a
range of cognitive processing relating to thinking about one’s own thoughts or
characteristics and those of others (e.g., Theory of Mind and introspection; for
review see Frith & Frith, 2003). There is a consistent relationship in the func-
tional neuroimaging literature between tasks that stress these functions, and
related ones such as deception and moral behavior, and activation of medial ros-
tral PFC (e.g., Eslinger et al., 2009; Gilbert et al., 2007). There is also supportive
evidence from human lesion studies (e.g., Stuss et al., 2001) and transcranial
direct current stimulation (Karim et al., 2010). On these grounds, it seems plau-
sible that the root of at least some of the deficits in social behavior found in the
cases of “strategy application disorder” described previously might also be traced
to impairments in these abilities, although to our knowledge this has not yet been
formally examined.
Another understudied area of human cognition where there may be potential
for fruitful cross-method interaction concerns higher-level memory control, by
which we mean the ability to manipulate and introspect upon episodic memory
traces. Examples include memory for Context (remembering details of an event
that were not central to it at the time of encoding), Source (remembering aspects
of events relating to its provenance, such as when something occurred, where it
occurred, etc.), and Reality Monitoring (distinguishing between imagined and
perceived events). There is a very consistent relation in the literature between
performance of these tasks and activation in rostral PFC (see Burgess et al., 2007,
for review) and elsewhere within the prefrontal cortex (e.g., dorsolateral and
ventrolateral PFC; see Turner et al., 2008). And it has been known for some time
that patients with frontal lobe lesions have difficulties on a range of source moni-
toring tasks (e.g., Duarte et al., 2010; Janowsky, Shimamura, & Squire, 1989;
Kopelman, Stanhope, & Kingsley, 1997; Milner, Petrides, & Smith, 1985;
Shimamura, Janowsky, & Squire, 1990). However, it seems on present evidence
that these kinds of higher-level memory control tasks require the operation of a
network of PFC and extra-PFC regions, and the precise role that rostral PFC may
play within this network is unclear.
The Gateway Hypothesis of Rostral PFC Function

One account that attempts to help, and that seeks to explain simultaneously the
involvement of rostral PFC in a wide range of tasks, is the “gateway hypothesis” of
Burgess and colleagues (Burgess et al., 2005, 2006, 2007). Indeed, the hypothesis
tries to provide a unifying framework for understanding common processing
requirements across the many different types of tasks where rostral PFC involve-
ment has been implicated. It suggests that one important function of rostral PFC
is in enabling a person to effect control over the degree to which he or she attends
to externally available stimuli, or alternatively to stimulus-independent thought
(i.e., self-generated thoughts in our heads).
That we can effect such control can hardly be in doubt: there are many situa-
tions where one needs to exert such control, ranging from preventing mind-wan-
dering (or deliberately engaging in it), to having to attend during boring tasks,
and also including many if not most situations, even if only momentarily, where
one is faced with a novel situation and does not know how to proceed. This type of
attentional control is likely to also be involved where one is dovetailing two or
more activities (so has to “bear something in mind” while performing another
task) or where one has to reflect deeply upon one’s experience in order to choose
a way to respond in an ambiguous or open-ended situation (as may occur in
memory control tasks, or complex social situations), or to view that memory trace
in a new light. Burgess and his colleagues have invented tasks that measure this
“attentional gateway” (i.e., switching between stimulus-oriented and stimulus-
independent attending, or source switching) and have shown a consistent relation
between performance of these tasks and rostral PFC activation, and that that
these patterns of activation seem to overlap and temporally coincide with those
provoked by tasks such as prospective memory tasks (e.g., Benoit et al, submitted;
Dumontheil, Gilbert, Burgess, & Otten, 2010; Dumontheil, Gilbert, Frith, &
Burgess, 2010; Gilbert et al., 2005, 2006).
If rostral PFC supports such a mental ability, then one might expect the follow-
ing: (1) that functional activation in rostral PFC would be found in a wide variety
of tasks, and not restricted to one class; (2) these activations might be quite insen-
sitive to the nature of the stimuli presented (because it is not what the person is
attending to, it is the direction of attending that is crucial), but may be quite sen-
sitive instead to, for example, changes in task instruction (ditto), or to aspects not
often considered by experimenters (e.g., how boring the task is; degree of novelty
within participant); and (3) that IQ would be left relatively unchanged by many
intelligence tests (since they do not typically heavily tap aspects such as prospec-
tive memory, multitasking, high-level memory control, mentalizing and intro-
spection, and so forth. Neither are they typically open-ended, ambiguous,
monotonous, or have any of the other task characteristics mentioned here in rela-
tion to good tests of rostral PFC function. Indeed, when one makes a list, like this,
of the characteristics that IQ tasks do not have, one can begin to see how particu-
lar, perhaps even peculiar, are typical intelligence tests in relation to the demands
made by everyday life.
Conclusion
Cognitive neuroscience must be an inherently multi- or inter-disciplinary enter-
prise because there is no single level at which the instantiation of mental phe-
nomena can be understood. To understand fully how the brain facilitates thought,
we must understand simultaneously how chemical, electrical, hemodynamic, and
other properties and changes occurring within the brain can be related to infor-
mation-processing and phenomenological levels of explanation. It seems likely
therefore that where one particular method does not constrain the inferences it
makes from one level to another by reference to converging evidence from other
methods, the possibility of inferential error increases. This chapter has high-
lighted one such way in which this may be currently occurring. The evidence from
human lesion studies of rostral PFC is hard to reconcile with a sizeable proportion
of the theorizing that is emerging from neuroimaging. Here we have tried to pro-
vide some insights and references that may provide a start towards such recon-
ciliation by constraining neuroimaging evidence with human lesion evidence.
There is little doubt about the enormous increase in our knowledge of the func-
tions and organization of rostral PFC that functional neuroimaging has afforded.
Indeed, as mentioned at the start of this chapter, determined theorizing on this
topic was kick-started by numerous findings of rostral PFC activations in neu-
roimaging experiments, and most of what we currently believe about rostral PFC
comes from this method. However, there is a danger, when a new scientific method
becomes overwhelmingly predominant, that highly relevant material from more
established methods might not maintain the influence that it deserves.
As an investigative method in cognitive neuroscience, functional neuroimag-
ing has many advantages over lesion studies. However, human lesion evidence has
two principal advantages over neuroimaging data. The first is the causal advan-
tage for theorizing that lesion evidence provides: inference is much more straight-
forward. Second, human lesion data often also have an advantage in terms of
understanding the totality of influence that perturbation of a particular cognitive
system evinces. A neurological patient can often be observed in a wide variety of
situations, and performing a wide variety of tasks, so if a particular construct is
impaired, one can see the extent of its influence across them. This is not typically
possible with neuroimaging designs, but may be particularly critical for theoriz-
ing about “central” systems that may operate across many situations and with
many types of stimuli. And indeed, it would appear that some systems supported
by prefrontal cortex have just these characteristics. In this way, the data in par-
ticular from Donald T. Stuss and his colleagues are of critical importance, and they
have provided a database that will serve as a guide to theorists for very many
years to come. For that accomplishment, those of us who study rostral PFC are
extremely grateful.
Acknowledgments
We would like to thank Donald T. Stuss and Michael Alexander for their detailed
and extremely helpful comments on technical matters relating to the meta-
analyses of their results presented in this chapter. We are also very grateful to
Brian Levine and Fergus Craik for their comments on an earlier draft.
References
Ackerly, S. S., & Benton, A. L . (1947). Report of a case of bilateral frontal lobe defect. Research
Publications: Association for Research in Nervous and Mental Disease, 27, 479–504.
Alderman, N., Burgess, P. W., Knight, C., & Henman, C. (2003). Ecological validity of a simplified
version of the Multiple Errands Test. Journal of the International Neuropsychological Society, 9,
31–44.
Alexander, M. P., Stuss, D. T., Picton, T., Shallice, T., & Gillingham, S. (2007). Regional frontal inju-
ries cause distinct impairments in cognitive control. Neurology, 68, 1515–1523.
Alexander, M. P., Stuss, D. T., Shallice, T., Picton, T. W., & Gillingham, S. (2005). Impaired concen-
tration due to frontal lobe damage from two distinct lesion sites. Neurology, 23, 572–579.
Bird, C. M., Castelli, F., Malik, O., Frith, U., & Husain, M. (2004). The impact of extensive medial
frontal lobe damage on “Theory of Mind” and cognition. Brain, 127, 914–928.
Blaxton, T. A., Zeffiro, T. A., Gabrieli, J. D. E., Bookheimer, S. Y., Carrillo, M. C., Theodore, W. H., &
Disterhoft, J. F. (1996). Functional mapping of human learning: a positron emission tomogra-
phy activation study of eyeblink conditioning. Journal of Neuroscience, 16, 4032–4040.
Brickner, R. M. (1936). The intellectual functions of the frontal lobes: a study based upon observation of
a man after partial bilateral frontal lobectomy. New York: Macmillan.
Buckner, R. L . (1996). Beyond HERA: contributions of specific prefrontal brain areas to long-term
memory retrieval. Psychonomic Bulletin and Review, 3, 149–158.
Burgess, P. W. (1997). Theory and methodology in executive function research. In: P. Rabbitt (Ed.),
Theory and methodology of frontal and executive function (pp. 81–116). Hove, U.K.: Psychology
Press.
Burgess, P. W. (2000). Strategy application disorder: the role of the frontal lobes in human multi-
tasking. Psychological Research, 63, 279–288.
Burgess, P. W., Alderman, N., Volle, E., Benoit, R. G., & Gilbert, S. J. (2009). Mesulam’s frontal lobe
mystery re-examined. Restorative Neurology and Neuroscience, 27(5), 493–506.
Burgess, P. W., Dumontheil, I., & Gilbert, S. J. (2007). The gateway hypothesis of rostral prefrontal
cortex (area 10) function. Trends in Cognitive Sciences, 11, 290–298.
Burgess, P. W., Dumontheil, I., Gilbert, S. J., Okuda, J., Schölvinck, M. L., & Simons, J. S. (2008).
On the role of rostral prefrontal cortex (area 10) in prospective memory. In: M. Kliegel, M. A.
McDaniel, & G. O. Einstein (Eds.), Prospective memory: cognitive, neuroscience, developmental,
and applied perspectives (pp. 235–260). Mahwah, NJ: Erlbaum.
Burgess, P. W., Gilbert, S. J., Okuda, J., & Simons, J. S. (2006). Rostral prefrontal brain regions (area
10): a gateway between inner thought and the external world? In: W. Prinz & N. Sebanz (Eds.),
Disorders of volition (pp. 373–396). Cambridge, MA: MIT Press.
Burgess, P. W., Quayle, A., & Frith, C. D. (2001). Brain regions involved in prospective memory as
determined by positron emission tomography. Neuropsychologia, 39, 545–555.
Burgess, P. W., Scott, S. K., & Frith, C. D. (2003). The role of the rostral frontal cortex (area 10) in
prospective memory: a lateral versus medial dissociation. Neuropsychologia, 41, 906–918.
Burgess, P. W., & Shallice, T. (1996). Response suppression, initiation and strategy use following
frontal lobe lesions. Neuropsychologia, 34, 263–273.
Burgess, P. W., & Shallice, T. (1997). The Hayling and Brixton Tests. Thurston, Suffolk: Thames Valley
Test Company.
Burgess, P. W., Simons, J. S., Dumontheil, I., & Gilbert, S. J. (2005). The gateway hypothesis of
rostral PFC function. In: J. Duncan, L. Phillips, & P. McLeod (Eds.), Measuring the mind: speed,
control and age (pp. 215–246). Oxford University Press.
Burgess, P. W., Veitch, E., Costello, A., & Shallice, T. (2000). The cognitive and neuroanatomical cor-
relates of multitasking. Neuropsychologia, 38, 848–863.
Cattell, R. B. (1963). Theory of fluid and crystallized intelligence: a critical experiment. Journal of
Educational Psychology, 54(1), 1–22.
Chambers, C. D., & Mattingley, J. B. (2005). Neurodisruption of selective attention: insights and
implications. Trends in Cognitive Sciences, 9, 542–550.
Christoff, K., & Gabrieli, J. D. E. (2000).The frontopolar cortex and human cognition: evidence for
a rostrocaudal hierarchical organization within the human prefrontal cortex. Psychobiology,
28, 168–186.
Christoff, K., Prabhakaran, V., Dorfman, J., Zhao, Z., Kroger, J. K., Holyoak, K. J., & Gabrieli, J. D. E.
(2001). Rostrolateral prefrontal cortex involvement in relational integration during reason-
ing. Neuroimage, 14, 1136–1149.
Colom, R., Jung , R. E., & Haier, R. J. (2007). General intelligence and memory span: evidence for a
common neuroanatomic framework. Cognitive Neuropsychology, 24(8), 867–878.
Coltheart, M. (2006) What has functional neuroimaging told us about the mind (so far)? Cortex
42(3), 323–331.
Dawson, D. R., Anderson, N. D., Burgess, P. W., Cooper, E., Krpan, K. M., & Stuss, D. T. (2009).
Further development of the Multiple Errands Test: standardized scoring, reliability, and eco-
logical validity for the Baycrest version. Archives of Physical Medicine and Rehabilitation, 90,
S1, 41–51.
Dreher, J. C., Koechlin, E., Ali, S. O., & Grafman, J. (2002). The roles of timing and task order during
task switching. Neuroimage, 17, 95–109.
Dreher, J. C., Koechlin, E., Tierney, M., & Grafman, J. (2008). Damage to the fronto-polar cortex is
associated with impaired multitasking. PLoS ONE, 3(9), e3227.
Duarte, A., Henson, R. N., Knight, R.T., Emery, T., & Graham, K. S. (2010). Orbito-frontal cortex is
necessary for temporal context memory. Journal of Cognitive Neuroscience, 22(8), 1819–1831.
Dubois, B., Slachevsky, A., Litvan, I., & Pillon B. (2000). The Fab: a frontal assessment battery at
bedside. Neurology, 55, 1621–1626.
Dumontheil, I., Burgess, P. W., & Blakemore S-J. (2008). Development of rostral prefrontal cortex
and cognitive and behavioural disorders. Developmental Medicine and Child Neurology, 50,
1–14.
Dumontheil, I., Gilbert, S. J., Burgess, P. W., & Otten, L. J. (2010). Neural correlates of task and
source switching: similar or different? Biological Psychology, 83(3), 239–249.
Dumontheil, I., Gilbert, S. J., Frith, C. D., & Burgess, P. W. (2010). Recruitment of lateral rostral
prefrontal cortex in spontaneous and task-related thoughts. Quarterly Journal of Experimental
Psychology, 63(9), 1740–1756.
Duncan, J. (2001). An adaptive coding model of neural function in prefrontal cortex. Nature Reviews
Duncan, J. (2005). Frontal lobe function and general intelligence: why it matters. Cortex, 41(2),
215–217.
Duncan, J., & Owen, A . (2000). Consistent response of the human frontal lobe to diverse cognitive
demands. Trends in Neurosciences, 23, 475–483.
Duncan, J., Rüdiger, J. S., Kolodny, J., Bor, D., Herzog , H., Ahmed, A., Newell, F. N., & Emslie, H.
(2000). A neural basis for general intelligence. Science, 289(5478), 457–460.
Eslinger, P. J., & Damasio, A. R . (1985). Severe disturbance of higher cognition after bilateral fron-
tal lobe ablation: patient E.V.R . Neurology, 35, 1731–1741.
Eslinger, P. J., Robinson-Long , M., Realmuto, J., Moll, J., deOliveira-Souza, R., Tovar-Moll, F.,
Wang , J., & Yang , Q. X. (2009). Developmental frontal lobe imaging in moral judgment:
Arthur Benton’s enduring influence 60 years later. Journal of Clinical and Experimental
Neuropsychology, 31(2), 158–169.
Floden, D., & Stuss, D. T. (2006). Inhibitory control is slowed in patients with right superior medial
frontal damage. Journal of Cognitive Neuroscience, 18, 1843–1849.
Friston, K. J., Price, C. J., Fletcher, P., Moore, C., Frackowiak, R. S. J., & Dolan, R. J. (1996). The
trouble with cognitive subtraction. NeuroImage, 4, 97–104.
Frith, U., & Frith, C. D. (2003). Development and neurophysiology of mentalizing. Philosophical
Transactions of the Royal Society of London B, 358(1431), 459–473.
Gilbert, S. J., Dumontheil, I., Simons, J. S., Frith, C. D., & Burgess, P. W. (2007). Comment on
“Wandering minds: the default network and stimulus-independent thought.” Science,
317(5834), 43.
Gilbert, S. J., Frith, C. D., & Burgess, P. W. (2005). Involvement of rostral prefrontal cortex in selec-
tion between stimulus-oriented and stimulus-independent thought. European Journal of
Gilbert, S. J., Gollwitzer, P. M., Cohen, A. L., Oettingen, G., & Burgess, P. W. (2009). Separable
brain systems supporting cued versus self-initiated realization of delayed intentions. Journal
of Experimental Psychology: Learning, Memory, and Cognition, 35(4), 905–915.
Gilbert, S. J., Simons, J. S., Frith, C. D., & Burgess, P. W. (2006). Performance-related activity in
medial rostral prefrontal cortex (area 10) during low demand tasks. Journal of Experimental
Psychology: Human Perception and Performance, 32, 45–58.
Gilbert, S. J., Williamson, I. D. M., Dumontheil, I., Simons, J.S., Frith, C. D., & Burgess, P. W. (2007).
Distinct regions of medial rostral prefrontal cortex supporting social and nonsocial functions.
Social Cognitive and Affective Neuroscience 2(3), 206–216.
Gläscher, J., Rudrauf, D., Colom, R., Paul, L. K., Tranel, D., Damasio, H., & Adolphs, R . (2010).
Distributed neural system for general intelligence revealed by lesion mapping. Proceedings of
the National Academy of Sciences of the United States of America, 107(10), 4705–4709.
Gläscher, J., Tranel, D., Paul, L. K. Rudrauf, D., Rorden, C., Hornaday, A., Grabowski, T., Damasio,
H., & Adolphs, R . (2009). Lesion mapping of cognitive abilities linked to intelligence. Neuron,
61(5), 681–691.
Goel, V., & Grafman, J. (2000). The role of the right prefrontal cortex in ill-structured problem
solving. Cognitive Neuropsychology, 17(5), 415–436.
Goldstein, L. H., Bernard, S., Fenwick, P. B. C., Burgess, P. W., & McNeil, J. (1993). Unilateral fron-
tal lobectomy can produce strategy application disorder. Journal of Neurology, Neurosurgery &
Psychiatry, 56, 274–276.
Grady, C. L . (1999). Neuroimaging and activation of the frontal lobes. In B. L. Miller & J. L.
Cummings (Eds.), The human frontal lobes: function and disorders (pp. 196–230). New York:
Guilford Press.
Henson, R. N. (2006). What has (neuro)psychology told us about the mind (so far)? A reply to
Coltheart. Cortex, 42, 387–392.
Hodges, J. R . (1994). Cognitive assessment for clinicians. Oxford University Press.
Holloway, R. L . (2002). Brief communication: how much larger is the relative volume of area 10 of
the prefrontal cortex in humans? American Journal of Physical Anthropology, 118, 399–401.
Janowsky, J. S., Shimamura, A. P., & Squire, L. R . (1989). Source memory impairments in patients
with frontal lobe lesions. Neuropsychologia, 27, 1043–1056.
John, J. P., Burgess, P. W., Yashavantha, B. S., Shakeel, M. K., Halahalli, H. N., & Jain, S. (2009).
Differential relationship of frontal pole and whole brain volumetric measures with age in neu-
roleptic-naïve schizophrenia and healthy subjects. Schizophrenia Research, 109(1–3), 148–158.
Johnson, S. C., Baxter, L. C., Wilder, L. S., Pipe, J. G.,Heiserman, J. E., & Prigatano, G. P. (2002).
Neural correlates of self-reflection. Brain, 125, 1808–1814.
Jung , R. E., & Haier, R. J. (2007). The Parieto-Frontal Integration Theory (P-FIT) of intelligence:
converging neuroimaging evidence. Behavioral & Brain Sciences, 30(2), 35–54.
Karim, A. A., Schneider, M., Lotze, M., Veit, R., Sauseng , P., Braun, C., & Birbaumer, N. (2010). The
truth about lying: inhibition of the anterior prefrontal cortex improves deceptive behavior.
Cerebral Cortex, 20(1), 205–213.
Kliegel, M., Phillips, L. H., Lemke, U., & Kopp, U. A . (2005). Planning and realisation of com-
plex intentions in patients with Parkinson’s disease. Journal of Neurology, Neurosurgery &
Psychiatry, 76(11), 1501–1505.
Knight, C., Alderman, N., & Burgess, P. W. (2002). Development of a simplified version of the mul-
tiple errands test for use in hospital settings. Neuropsychological Rehabilitation, 12, 231–255.
Koechlin, E., Basso, G., Pietrini, P., Panzer, S., & Grafman, J. (1999). The role of the anterior pre-
frontal cortex in human cognition. Nature, 399, 148–151.
prefrontal cortex. Science, 302(5648), 1181–1185.
Kopelman, M. D., Stanhope, N., & Kingsley, D. (1997). Memory for temporal and spatial context
in patients with focal diencephalic, temporal lobe and frontal lobe lesions. Neuropsychologia,
35, 1533–1545.
Levine, B., Stuss, D. T., Milberg, W. P., Alexander, M. P., Schwartz, M., & Macdonald, R . (1998). The
effects of focal and diffuse brain damage on strategy application: evidence from focal lesions,
traumatic brain injury, and normal aging. Journal of the International Neuropsychological
Society, 4, 247–264.
Luria, A. R . (1966). Higher cortical function in man. London: Tavistock.
MacLeod, A. K., Buckner, R. L., Miezin, F. M., Petersen, S. E., & Raichle, M. E. (1998). Right anterior
prefrontal cortex activation during semantic monitoring and working memory. Neuroimage,
7, 41–48.
Manly, T., Hawkins, K., Evans, J., Woldt, K., & Robertson, I. H. (2002). Rehabilitation of executive
function: a facilitation of effective goal management on complex tasks using periodic auditory
alerts. Neuropsychologia, 40, 2671–2681.
Milner, B., Petrides, M., & Smith, M. L . (1985). Frontal lobes and the temporal organization of
memory. Human Neurobiology, 4, 137–142.
Penfield, W., & Evans, J. (1935). The frontal lobe in man: a clinical study of maximum removals.
Brain, 58, 115–133.
Petrides, M., & Pandya, D. M. (1994). Comparative architectonic analysis of the human and
macaque frontal cortex. In: F. Boller & J. Grafman (Eds.), Handbook of neuropsychology (vol. 9,
pp. 17–57). Amsterdam: Elsevier.
Petrie, A . (1952). Personality and the frontal lobes. London, UK: Routledge & Kegan Paul.
Picton, T. W., Stuss, D. T., Alexander, M. P., Shallice, T., Binns, M. A. & Gillingham, S. (2006). Effects
of focal frontal lesions on response inhibition. Cerebral Cortex, 17, 826–838.
Picton, T. W., Stuss, D. T., Shallice, T., Alexander, M. P., & Gillingham, S. (2006). Keeping time:
effects of focal frontal lesions. Neuropsychologia, 44, 1195–1209.
Poldrack, R. A., & Wagner, A. D. (2004). What can neuroimaging tell us about the mind? Insights
from prefrontal cortex. Current Directions in Psychological Science 13(5), 177–181.
Ramnani, N., & Owen, A. M. (2004). Anterior prefrontal cortex: Insights into function from anat-
omy and neuroimaging. Nature Reviews Neuroscience, 5, 184–194.
Reynolds, J. R., West, R., & Braver, T. (2009). Distinct neural circuits support transient and
sustained processes in prospective memory and working memory. Cerebral Cortex, 19(5),
1208–1221.
Roca, M., Parr, A., Thompson, R., Woolgar, A., Torralva, T., Antoun, N., Manes, F., & Duncan J.
(2010). Executive function and fluid intelligence after frontal lobe lesions. Brain, 133(1),
234–247.
Rugg , M. D., Fletcher, P. C., Frith, C. D., Frackowiak, R. S. J., & Dolan, R. J.(1996). Differential
activation of the prefrontal cortex in successful and unsuccessful memory retrieval. Brain,
119, 2073–2084.
Semendeferi, K., Armstrong, E., Schleicher, A., Zilles, K., & Van Hoesen, G. W. (2001). Prefrontal
cortex in humans and apes: a comparative study of area 10. American Journal of Physical
Anthropology, 114, 224–241.
in man. Brain, 114, 727–741.
Shallice, T., Stuss, D. T., Alexander, M. P., Picton, T. W., & Derkzen, D. (2008). The multiple dimen-
sions of sustained attention. Cortex, 44, 794–805.
Shallice, T., Stuss, D. T., Picton, T. W., Alexander, M. P., & Gillingham, S. (2008). Multiple effects of
prefrontal lesions on task-switching. Frontier in Human Neuroscience, 1, 1–11.
Shammi, P., & Stuss, D. T. (1999). Humour appreciation: a role of the right frontal lobe. Brain, 122,
657–666.
Shimamura, A. P., Janowsky, J. S., & Squire, L. R . (1990). Memory for the temporal order of events
in patients with frontal lobe lesions and amnesic patients. Neuropsychology, 28, 803–813.
Simons, J. S., Gilbert, S. J., Owen, A. M., Fletcher, P. C., & Burgess, P. W. (2005). Distinct roles
for lateral and medial anterior prefrontal cortex in contextual recollection. Journal of
Neurophysiology, 94, 813–820.
Spearman, C. (1904). “General intelligence” objectively determined and measured. American Journal
of Psychology, 15, 201–293.
Spreen, G., & Strauss, E. (1988). A compendium of neuropsychological tests: administration, norms and
commentary. New York: Oxford University Press.
Stone, V. E., Baron-Cohen, S., & Knight, R. T. (1998). Frontal lobe contributions to theory of mind.
Journal of Cognitive Neuroscience, 10, 640–656.
Stuss, D. T., Alexander, M. P., Hamer, L., Palumbo, C., Dempster, R., Binns, M., Levine, B., &
Izukawa, D. (1998). The effects of focal anterior and posterior brain lesions on verbal fluency.
Journal of International Neuropsychological Society, 4, 265–278.
Stuss, D. T., Alexander, M. P., Shallice, T., Picton, T. W., Binns, M. A., Macdonald, R., Borowiec, A.,
& Katz, D. I. (2005). Multiple frontal systems controlling response speed. Neuropsychologia,
43, 396–417.
Stuss, D. T., Binns, M. A., Murphy, K. J., & Alexander, M. P. (2002). Dissociations within the ante-
rior attentional system: effects of task complexity and irrelevant information on reaction
time speed and accuracy. Neuropsychology, 16, 500–513.
Stuss, D. T., Floden, D., Alexander, M. P., Levine, B., & Katz, D. (2001). Stroop performance in focal
lesion patients: dissociation of processes and frontal lobe lesion location. Neuropsychologia,
39, 771–786.
Stuss, D. T., Gallup, G. G. Jr., & Alexander, M. P. (2001) The frontal lobes are necessary for “theory
of mind.” Brain, 124(Pt 2), 279–286.
Stuss, D. T., Levine, B., Alexander, M. P., Hong , J., Palumbo, C., Hamer, L., Murphy, K. J., & Izukawa,
D. (2000). Wisconsin Card Sorting Test performance in patients with focal frontal and pos-
terior brain damage: effects of lesion location and test structure on separable cognitive pro-
cesses. Neuropsychologia, 38, 388–402.
Thomson, G. H. (1939). The factorial analysis of human ability. London, UK: University of London
Press.
Tulving , E., Markowitsch, H. J., Criak, F. I. M., Habib, R., & Houle, S. (1996). Novelty and
familiarity activations in PET studies of memory encoding and retrieval. Cerebral Cortex, 6,
71–79.
Turner, M. S., Simons, J. S., Gilbert, S. J., Frith, C. D., & Burgess, P. W. (2008). Distinct roles for
lateral and medial rostral prefrontal cortex in source monitoring of perceived and imagined
events. Neuropsychologia, 46, 1442–1453.
Uretzky, S., & Gilboa, A . (2010). Knowing your lines but missing your cue: rostral prefrontal lesions
impair prospective memory cue detection, but not action-intention superiority. Journal of
Cognitive Neuroscience, 22(12), 2745–2757.
Volle, E., Gilbert, S. J., Benoit, R. G., & Burgess, P. W. (2010). Specialization of the rostral prefrontal
cortex for distinct analogy processes. Cerebral Cortex, 20(11), 2647–2659.
Volle E, Gonen-Yaacovi G, de Lacy Costello A , Gilbert SJ, Burgess PW. (2011). The role of ros-
tral prefrontal cortex in prospective memory: A voxel-based lesion study. Neuropsychologia.
Mar 1. [Epub ahead of print]
Warrington, E. K., James, M., & Maciejewski, C. (1986). The WAIS as a lateralizing and localizing diag-
nostic instrument: a study of 656 patients with unilateral cerebral lesions. Neuropsychologia,
24(2), 223–239.
Wechsler, D. (1939). The measurement of adult intelligence. Baltimore: Williams & Wilkins.
Wheeler, M. A., Stuss, D. T., & Tulving, E. (1997). Towards a theory of episodic memory: the frontal
lobes and autonoetic consciousness. Psychological Bulletin, 121(3), 331–354.
Wilson, B. A., Alderman, N., Burgess, P. W., Emslie, H., & Evans, J. (1996). Behavioural assessment of
the dysexecutive syndrome. Bury St. Edmunds, U.K.: Thames Valley Test Company.
5
Combining the Insights Derived from
Lesion and fMRI Studies to Understand
the Function of Prefrontal Cortex
MARK D’ESPOSITO AND DAVID BADRE
Executive function and cognitive control are both terms used to describe our abil-
ity to direct thought and action based on our goals and intentions, rather than
being driven automatically by the environment that surrounds us. Current theo-
ries of executive function and cognitive control propose that the prefrontal cortex
(PFC) is a critical brain region for this ability by providing top-down signals that
modulate incoming sensory information as this information undergoes progres-
sively more elaborative processing within association cortex for incorporation
into our stream of consciousness (Mesulam, 2002, 2008). The PFC is one of two
zones of multimodal association cortex that exist in the brain with extensive pro-
jections to both cortical and subcortical regions (Fig. 5.1A; Petrides & Pandya,
2002). Thus, the PFC is clearly in a privileged position to be one source of top-
down signals that could sculpt behavior. One of the questions we will address in
this chapter is: “What are the mechanisms by which the PFC can provide top-
down signals?” A theory that we support is that the PFC stores the highest levels
of representations such as rules and goals, and it is the active maintenance of
these PFC representations that bias information processing elsewhere in the brain
that influences how we ultimately make decisions and act (Miller & D’Esposito,
2005; Miller & Cohen, 2001).
Based on its cellular makeup and connectivity, the frontal cortex (from pri-
mary motor to premotor to prefrontal cortex) can be considered a very heteroge-
neous region, as illustrated in Figure 5.1B. These regional differences within the
frontal cortex likely reflect functional subdivisions, and these functional subdivi-
sions may be organized by different types of operations performed, different
types of representations stored, or both. A second question we will address in this
chapter is: “What is the functional organization of the PFC?” We believe that any
93
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8
9 7
4
9
46 40
39
10 6
45 44
43 19
41 18
42
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8B 4
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Figure 5.1. (A) General organization of the cerebral cortex. White regions represent
areas of higher-order multimodal cortex, which includes the prefrontal cortex (Fuster,
2004). (B) Cytoarchitectonic division of the human frontal lobe. Each region is labeled
with numbers that represent the update by Petrides and Pandya of the original
Brodmann maps (Petrides & Pandya, 2002). (See Color Plate Section for a color version
of this figure.)
94
Co mbining the Insig hts Der iv ed fr o m L e s ion an d fM R I S t u die s 95
insight gained regarding the functional organization of the PFC will also provide
insight regarding the mechanisms underlying cognitive control.
Frontal lobe function has been extensively researched both through the careful
study of neurologic patients with focal lesions (usually due to stroke) and using
functional MRI (fMRI) with healthy volunteers. However, there has been surpris-
ingly little direct interaction between these two literatures (Fellows et al., 2005).
Thus, rather than producing two lines of evidence that converge on a better under-
standing of frontal lobe function, the two literatures have, in a sense, pursued
divergent evolution, developing distinct sets of terms, hypotheses, and explana-
tions of empirical phenomena that often have little relation to one another and
that are difficult to reconcile or relate in specific ways. However, this divergence
need not be the case. Indeed, lesion and fMRI methodologies can complement
each other in significant ways, and so when combined can be a powerful approach.
In this chapter, we will also discuss the ways that these approaches complement
each other, and as a case in point, we will describe in some detail a recent line of
fMRI and patient work that has provided fundamental insights into frontal lobe
function; these insights would have been unlikely or impossible for either meth-
odology to have uncovered on its own.
Insights from Lesion Studies About

Frontal Lobe Function
One of Don Stuss’ many contributions to cognitive neuropsychology and neurol-
ogy has been to champion the notion that there is not an undifferentiated
“frontal lobe syndrome” (Stuss & Benson, 1984). His studies of patients with cir-
cumscribed frontal lesions, on a wide variety of tasks, have, in our opinion,
brought order to the myriad of theories regarding the relationship between execu-
tive function and the frontal lobes. The empirical data derived from numerous
such studies have led to the proposal that there are at least three distinct func-
tions of the PFC (Stuss & Alexander, 2007): task-setting, which he and his col-
leagues attribute to left lateral PFC function; energization, attributed to superior
medial frontal function; and monitoring, attributed to right lateral PFC function.
These are proposed to be domain-general processes that are important for con-
trolling lower-order domain-specific processors in posterior cortical regions. It is
also proposed that goal-directed behavior requires not only setting the task goal,
but also planning, activating, and sustaining the actions required to achieve that
goal (which they term energization), and keeping track of the intention of the goal
(which they term monitoring).
In this chapter, we will focus on one of these core executive or cognitive control
processes: task-setting. Task-setting is defined as the ability to set a stimulus–
response relationship (Stuss & Alexander, 2007). More specifically, Stuss and
colleagues state that “the establishment of the connection between a stimulus

and a response would require formation of a criterion to respond to a defined
target with specific attributes, organization of the schemata necessary to com-
plete a particular task and adjustment of contention scheduling, so that the auto-
matic processes of moving through the steps of a task can work more smoothly”
(Stuss & Alexander, 2007). The lesion approach used by Stuss and colleagues is
well described in their papers (e.g., Stuss et al., 2005). In brief, patients with focal
frontal lesions, from various etiologies (eg, stroke, tumor, trauma) in the chronic
stage of recovery are studied. For each patient, lesions are mapped on the Petrides
and Pandya (Petrides, 1994) architectonic template, and each architectonic region
is identified as significantly damaged or not. Then, for each behavioral condition
of a task, the performance of patients with damage in a particular region is com-
pared to all other patients who do not have damage to that particular region. As
seen in Figure 5.2, task-setting (as measured by six different tasks) is consistently
impaired after damage to the left lateral PFC (Stuss & Alexander, 2007). However,
if one closely examines the lesion diagrams presented in the paper, the precise
location of the lesions within the frontal cortex causing impairment on each task
varies in location. In three tasks, impairment is due to damage restricted to the
inferior frontal gyrus (areas 44, 45, or 47); in two tasks, damage includes both the
inferior and middle frontal gyrus (areas 9/46); and in another task, damage is
restricted to the premotor cortex (areas 8 and 6). It is important to note that this
variability cuts across regions of the frontal cortex that have very different cyto-
architecture and anatomical connectivity (discussed below). Stuss and colleagues
also make note of this variation in location of damage attributed to different tasks
and suggest that it may reflect a more general left frontal function interacting
with more specific task demands. Thus, these lesion data clearly provide solid evi-
dence for the attribution of a general “task-setting” function to the left lateral
frontal cortex. However, given the extremely low spatial resolution of this method,
it is difficult to further distinguish any regional differences in processing (should
any such distinctions exist), locate network dynamics within the system, or test
hypotheses predicated on more elementary component mechanisms that,
together, give rise to task-setting.
Insights from fMRI Studies About

Frontal Lobe Function
Physiological methods such as fMRI provide an opportunity to understand the
variance exhibited in the lesion data. As a complement to lesion studies, fMRI
experiments more readily lend themselves to subtle within-subject manipulations
that can distinguish activation in different, spatially focal brain regions, often
even in the absence of behavioral differences (i.e., differences in reaction time or
A Concentrate (ROBBIA) B Suppress (ROBBIA)

2.0 3
1.5
# of false
# of false
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alarms
alarms
1.0
1
0.5
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LL RL IM SM CTL LL RL IM SM CTL
C Complex condition (FIT) D WCST 128

10 3
false negatives
False alarms–
Set loss
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LL RL Medial CTL LL RL IM SM CTL
Figure 5.2. Behavioral performance on various tasks by patients with focal frontal
lesions (Stuss & Alexander, 2007). For each task, the brain diagrams illustrate the
location of damage (gray color) in which at least three patients had significantly
impaired performance on the particular task compared to all other patients who did
not have damage in those regions.
error rates) across conditions. Moreover, the exquisite spatial resolution afforded
by fMRI means that these activation differences can be detected even in highly
proximate regions of the brain that might be contained within a single lesion or
region of lesion overlap between patients. Consequently, fMRI is often quite
useful in elucidating the elementary component processes of a broad cognitive
function that may be otherwise obscured by exclusive reliance on the coarser
lesion approach. However, once these elementary processes are identified, they
can motivate more precise hypotheses to be tested using the lesion method.
Hence, this interactive process can yield new testable hypotheses. In what follows,
we will provide an example of the power of this approach.
Hundreds of fMRI studies attempting to understand the organization of the
PFC have been performed over the past 15 years (for a review see Curtis &
D’Esposito, 2006). As expected, specific executive or cognitive control processes
such as task-setting have consistently been shown to activate the lateral PFC
(e.g. Banich, Milham, Atchley, & Cohen, 2000; Brass & von Cramon, 2004; Sakai
& Passingham, 2003). Scanning healthy subjects on tasks that have been tested in
patients is a common, but generally unhelpful, attempt to relate fMRI and lesion
approaches. Without a careful task analysis and redesign of the experiment to
distinguish elementary, component operations, it is difficult to see what is learned
beyond what was established in the original lesion study. Put more concretely, if
patients with frontal lobe lesions perform poorly on the Wisconsin Card Sorting
Task (a common clinical measure attributed to frontal lobe function), why do we
need fMRI to inform us that healthy individuals activate the frontal cortex when
performing this task?
Other fMRI studies have attributed numerous other similar control processes
such as selection, switching, maintenance, retrieval, source monitoring, manipu-
lation, inhibition, etc., to various regions of the PFC (e.g., Duncan & Owen, 2000).
Though within each research domain there is a high degree of consistency in the
association of particular functions with particular subregions of the frontal
cortex, trying to reconcile all of these functions with one another across domains
is a daunting task. To do so likely requires recasting many in terms of more basic-
level mechanisms, and consideration of broader organization of processing that
situates a given frontal subregion in the system-level network on which its func-
tion undoubtedly depends. A careful scrutiny of the myriad of fMRI studies exam-
ining frontal cortex function has led to the observation that there are consistent
patterns of activation, suggesting a principled organization of the PFC. Thus, we
firmly believe that data from these fMRI studies have uncovered a potential orga-
nizing scheme of the frontal cortex that did not emerge directly from scrutiny of
published lesion studies of frontal lobe function.
For example, in 2003 Koechlin and colleagues put forth a hypothesis that the
frontal cortex may be organized from anterior to posterior (or rostral to caudal) in
a hierarchical fashion en route to action (Koechlin, Ody, & Kouneiher, 2003; also
see Fuster, 1997 and Fuster, 2001 for earlier formulation of a similar idea).
Specifically, they proposed a “cascade model” (Koechlin & Summerfield, 2007)
that predicts that cognitive control resolves competition among alternative action
representations based on mutual information with various contextual informa-
tion, termed control signals. Crucially, the control signals relate to one another
hierarchically, in that information is inherited from superordinate to subordinate
levels, and separate signals are processed by spatially distinct regions along the
anterior–posterior axis of the frontal cortex. At the lowest level, sensory control
is supported by the premotor cortex and selects a motor response based on a
sensory input. Next, contextual control, supported by the posterior PFC, selects
an action based on an environmental contextual cue. Episodic control, supported
by the anterior PFC, selects an action based on an ongoing temporal context.
Finally, a highest level, branching control, supported by the frontopolar cortex,
selects action representations based on a pending temporal context. Thus, from
posterior to anterior, frontal regions are distinguished based on their reliance on
control signals that differ temporally, from immediate environment (sensory and
context), to current temporal frame (episodic), to a pending frame (branching).
To test these predictions, Koechlin and colleagues have demonstrated in
healthy subjects that as contextual information required to select a response was
more abstract and relevant over a longer temporal interval, fMRI activation pro-
gressed from posterior to more anterior regions of the frontal cortex. This hypoth-
esis derived from imaging data was consistent with a large body of literature from
other imaging studies and neuropsychological studies that suggested that pro-
gressively anterior subregions of the frontal cortex are associated with higher-
order processing requirements of planning and selection of action (Burgess,
Dumontheil, & Gilbert, 2007; Christoff, Ream, Geddes, & Gabrieli, 2003; Ramnani
& Owen, 2004). More recently, we have proposed that an anterior–posterior hier-
archy can be alternatively understood in terms of differences in control demands,
defined based on the form of the representations that compete during action
selection (Badre, 2008; Badre & D’Esposito, 2009). Action representations might
be organized hierarchically, such that more abstract action representations desig-
nate a set of more specific representations. For example, a task-set can be said to
be abstract because it generalizes across a set of specific stimulus–response map-
pings. As representations at progressively more abstract levels compete, distinct
control processors along the anterior–posterior axis of the PFC might resolve the
competition.
We aimed to test the idea that the frontal cortex comprises a representational
hierarchy using fMRI in healthy subjects during the performance of a response
selection task that required more abstract action decisions to be made across
behavioral conditions (Badre & D’Esposito, 2007). In our study, the lowest level of
the task performed during fMRI (Fig. 5.3A) was called the response task, where
subjects learned that a colored square corresponded to a particular finger response.
At the next level, called the feature task, each colored square corresponded to a
particular shape, and then subjects chose their motor response if the colored
square matched the shape. Thus, at this level, there is not enough information in
color alone to determine the correct response. The object shape had to be consid-
ered in conjunction with the color to make a response. The only difference from
the response task was that the colors now mapped to relevant shapes that cued a
correct response, rather than mapping directly to the correct response. In other
words, an action decision must be based on a more abstract action representation.
At the next level, called the dimension task, subjects learned that a particular color
corresponded to a particular dimension of an object (shape or orientation),
A Response experiment
+ + + + + + + + +
“1” “2” “1” “1” “2”

B Feature experiment
+ + +
“Positive” “Negative” “Positive”

C Dimension and context experiments
“Match” “Non-match” “Non-match”
Figure 5.3. The top of this figure illustrates the behavioral task schematics depicting
trial events in the four tasks used to test representational hierarchy from a fMRI study
in healthy young subjects (Badre & D’Esposito, 2007). In the response experiment,
subjects responded with key presses (number in quotes) to colored squares. In the
feature experiment, subjects made positive or negative responses to specific features of
objects, such as a texture of the central object, with a positive response dependent on
the colored square. In both the dimension and context experiments, subjects decided if
two objects matched along a perceptual dimension determined by the colored square.
However, conflict in the context experiment was manipulated by varying the frequency
of sets of color to dimension mappings. The bottom of the figure presents the whole-
brain analysis that shows a clear posterior-to-anterior progression in activation as
conflict was manipulated in the response (blue; PMd), feature (purple; prePMd),
dimension (green; inferior frontal sulcus [IFS]/DLPFC), and context (red; FPC)
experiments.
100
and they were required to compare the two objects along a particular dimension
and indicate with a motor response whether the objects matched or mismatched
along only the relevant dimension. The subject knew which dimension was rele-
vant based on the color of the square bounding the objects. Hence, the design for
the mappings was identical to the feature and response task, except that now color
mapped to dimension rather than feature or response. Again, the action decision
must be based on more abstract representation. The final and highest level was
called the context task. The subject performed the dimension task, but conflict was
manipulated by varying the frequency of the sets of color to dimension mappings.
In this case, the temporal context (akin to the episodic level of control posited by
Koechlin and colleagues) was required to select the appropriate context (the color
cue) for determining the dimension. Thus, selection of the relevant context was
more abstract. Prior to fMRI scanning, subjects had sufficient practice on these
tasks, and during scanning the tasks were performed separately in blocks to avoid
confusion regarding the task instructions.
During the lowest-level response task, activation was found in the posterior fron-
tal cortex within the premotor cortex (PMd, area 6; Fig. 5.3B). At the next-higher-
level feature task, activation was found anterior to the premotor cortex within the
pre-premotor cortex (pre-PMd; area 8). On the next-higher-level dimension task,
activation was noted anterior to this location within the inferior frontal sulcus (IFS)
on the border of areas 45 and 9/46. Finally, activation on the highest-level context
task was found in the most anterior or rostral portion of the frontopolar cortex, or
area 10. Thus, as action representations became more abstract, activation within
the frontal cortex moved anteriorly. Importantly, this progression of activation
from posterior to anterior portions of the frontal cortex was not simply due to the
task becoming more complex or difficult, because we also varied the difficulty within
each individual task (e.g., response, feature, dimension, or context), and we found that
activation within that particular region engaged by each task increased in magni-
tude with difficulty but did not change its location within the frontal cortex. In
contrast to the emphasis of Koechlin and colleagues (2003) on temporal and con-
textual factors in differentiating regions of the frontal cortex, these results suggest
that regions of the PFC may be differentiated by the level of abstraction at which
the action representations must be selected over competition.
These fMRI results, along with the prior results from Koechlin and coworkers
(2003), provide strong empirical support for the hypothesis that neurons in more
anterior portions of the PFC support increasingly abstract cognitive control pro-
cessing. However, there is still some debate as to what form of abstraction best
determines regional distinctions along the anterior–posterior axis of the frontal
cortex (see Badre, 2008). Nevertheless, the overall findings are quite consistent
with Stuss’ notion of a task-setting function for the left lateral PFC. However,
these data also provide this notion with some additional structure and mecha-
nistic depth. In other words, the findings suggest that task-setting can occur at
multiple levels of abstraction and over multiple time scales based on a variety of
contextual inputs. It also suggests that there is a processing architecture by which

task-setting can be achieved, specifically an anterior-to-posterior hierarchical
architecture. With this finer-grained processing architecture in mind, it may be
possible to revisit patients with focal frontal lobe damage in order to identify
distinct patterns of deficits in task-setting that may have been masked without
such an architecture in mind. In the following section, we pursue precisely this
approach.
Functional Organization of the PFC

What is the evidence that this organization of the frontal cortex, as derived from
fMRI data, is hierarchical? Is information processing flowing from anterior (ros-
tral) portions of the PFC to posterior (caudal) portions during these tasks? Badre
and D’Esposito (2009) present an in-depth review of these questions, some of
which can only briefly be presented in this chapter. A processing hierarchy within
the frontal cortex requires that anterior regions influence the processing in poste-
rior regions more than posterior regions influence anterior regions. Essential
clues regarding a rostrocaudal organization of the frontal cortex can be derived
from its anatomical organization. For example, the neuroanatomists Barbas and
Pandya (Barbas & Pandya, 1989) have noted that different frontal regions have
different degrees of differentiation. Progressively more differentiated regions are
more laminated (e.g., aggregation of cells into cortical layers). Increased differen-
tiation proceeds from anterior regions (frontopolar cortex, area 10) to posterior
regions (mid-dorsolateral [area 46] and posterior frontal [area 8]). Importantly,
areas with well-developed laminar differentiation (such as area 8) have restricted
connections mostly to neighboring regions, whereas areas that have less laminar
differentiation (such as area 10) have widespread connections to other areas.
Thus, less differentiated areas such as those in the anterior frontal cortex (areas
10, 9, 46), which have more diffuse projections, are well situated to be the top of
a hierarchy (Petrides & Pandya, 2007). In contrast, more differentiated areas, such
as those in the posterior frontal cortex (area 9/46, 8), have more intrinsic connec-
tions and are well situated to be lower in a hierarchy.
The anatomical connectivity patterns of different frontal regions could also
provide evidence for a hierarchy. For example, if there is a hierarchical arrange-
ment, area 10 (the most anterior frontal region), area 9/46 (a mid-frontal region),
and area 6 (the most posterior frontal region) would all have reciprocal connec-
tions. However, area 10, at the highest level, would have projections back down to
area 6 at the lowest level, but area 6 would not necessarily project back up to area
10. Anatomical tracer studies are consistent with this relationship in the frontal
cortex. In other words, area 10 does project to presumed lower levels such as area
9/46 and area 6, but area 6 does not have direct projections back up to area 10 (for
a review of these anatomical studies see Badre & D’Esposito, 2009). In summary,
considering the anatomical evidence, the proper frontal wiring seems to be in

place for a hierarchy within the frontal cortex.
A New Approach to Motivating Lesion Studies

with fMRI Results
An anterior-to-posterior flow of control processing within the frontal lobes pre-
dicts that performance on tasks involving higher-order control should be impaired
by disruptions to lower-order processors, even when the higher-order processors
are intact. However, the reverse prediction should not hold: performance should
be unaffected for tasks involving lower-order control when higher-order proces-
sors are damaged but lower-order processors are intact. Consider, for example, a
routine behavior like making coffee. An inability to select and maintain appropri-
ate subgoals (like pouring water or putting grounds in the machine) would result
in impaired performance, even if the patient in question were perfectly capable of
deciding he wanted to make coffee and of maintaining this goal in mind. By con-
trast, if there were not a need to maintain the abstract goal of making coffee
(because, for example, in the context of a morning routine making coffee is habit-
ual), a patient with damage to the more rostral region required to decide to make
coffee would be unimpaired on this task. Extended to the task used by Badre and
D’Esposito (2007), then, the hierarchical prediction is straightforward. Damage
to the pre-PMd would impair performance on the feature task, as well as the
higher-level dimension and context tasks, because these all require a “feature” level
of control (see Fig. 5.3 for the task). However, performance on the lower-
level response task should be intact because this task does not require the feature
level of control. Using the same logic, damage to the IFS would impair the dimen-
sion and context tasks but would leave the feature and response tasks intact. Hence,
the basic principle is that damage to a given region will impair control at a level of
abstraction dependent on its location and all tasks requiring higher but not lower
levels of control. This hypothesized asymmetric pattern of deficit cannot be
directly tested with neurophysiological methods such as fMRI, electroencepha-
lography, or single-unit recording. Rather, it requires a lesion method that exam-
ines the causal effect of isolated disruption of specific processors along the
proposed hierarchical gradient. With this particular hypothesis that we are test-
ing, what we consider “new” about this approach using an “old” method is that the
hypothesis being testing was derived from physiological data.
Thus, we tested the hypothesis that there is a hierarchical organization in the
frontal cortex in a behavioral study of patients with focal frontal lesions (Badre,
Hoffman, Cooney, & D’Esposito, 2009). All of our patients had strokes that were
confined to the frontal cortex, but they obviously varied in size and location
(Fig. 5.4A). We tested our hypothesis directly for two hierarchical levels by using
the identical task that we used in our fMRI study of healthy young individuals.
Dimension deficit
fMRI (dimension effect)
Lesion overlap
1 4 7
1 2 3
fMRI (feature effect)
Lesion overlap
Feature deficit
Figure 5.4. Results from a lesions overlap analysis reveal a distinction in the peak of
overlap (red) among patients with a deficit on the dimension task around the inferior
frontal sulcus/dorsolateral prefrontal cortex and the peak of overlap (red) among
patients with a deficit on the feature task in the anterior dorsal premotor cortex
(Badre et al., 2009). Color bar indicates the number of patients contributing to each
colored region. Insets show correspondence between sites of lesion overlap and the
activation associated with the dimension and feature tasks in a fMRI study of young
healthy individuals (Badre & D’Esposito, 2007). Arrows on brain slices are in the same
position for precise comparison.
Specifically, we hypothesized that a lesion to the pre-PMd region of the frontal

cortex (area 8), which would damage a second-level processor, should impair per-
formance on the feature task as well as the dimension and context tasks, which
should require processors that are above this level (third and fourth levels).
However, performance on the response task, which should require a processor at a
first or lower level, should be normal. By contrast, a more anterior IFS lesion
(areas 45, 9/46), which would damage a third-level processor, should impair
performance on the dimension task as well as the context task, which is at the
fourth level. However, damage to this region should not impair performance on
the response and feature tasks, which require processors at lower levels (first and
second levels). This pattern of behavioral results in patients with focal frontal
lesions would be direct evidence for a hierarchy in the frontal lobe.
We found that as a group patients exhibited a greater behavioral deficit com-
pared to age-matched control subjects as the task rules became more abstract
(Fig. 5.4B). There are two possible explanations for this finding. First, higher-
order control demands could increasingly challenge all patients, regardless of the
site of their lesion, and so their performance becomes differentially impaired as
task complexity increases. Alternatively, because of the asymmetric dependencies
predicted by a hierarchy, deficits in higher-level tasks will be more likely across
patients, regardless of the site of their lesion, than deficits at lower-level tasks.
Therefore, the larger behavioral deficits reflect this aggregate likelihood. If the
aggregation account is the case, then the presence of an impairment at any level
should increase the likelihood of an impairment at all higher levels, but should
not increase the odds of an impairment at a lower level.
We observed that the probability of a deficit on any task, p(D), was 62% across
the patients. Critically, however, the probability of a deficit at any level given a
deficit at a lower level, p(D|L), was 91% across patients, a significant change over
p(D), the probability of a deficit on any task. By contrast, the probability of a defi-
cit at any level given a deficit at a higher level, p(D|H), was only 76%, a weak
change over the prior probability of a deficit on any task. This asymmetry provides
initial support for the hierarchical dependencies among behavioral deficits at the
different levels of the task and the aggregation account of the group data.
Next, we used an observer-independent method to assign patients to lesion
groups based on their behavioral performance across the four tasks. Vectors were
created that corresponded to the idealized behavior of a patient with a selective
deficit at a particular hierarchical level. These vectors served as regressors in a
multiple regression on each patient’s performance differences from age-matched
controls across all conditions of all experiments. Depending on which vector cor-
related with a given patient’s data, that patient was assigned to a particular lesion
group. Based on this analysis, two distinct groups of patients were identified. At
the bottom of Figure 5.4C is the lesion overlap of patients who had a behavioral
pattern consistent with a deficit at the feature level (i.e., the second level). We
observed that these patients were impaired on the second-, third-, and fourth-
level tasks (i.e., dimension and context tasks) but not on the first-level task
(i.e., response task). The site of maximal lesion in this group of patients (shown in
dark red) is within area 8, pre-PMD, in an almost identical location to that identi-
fied in our prior fMRI study (shown directly above the lesion overlap). At the top
of Figure 5.4C is the lesion overlap of patients who had a behavioral pattern con-
sistent with a deficit at the dimension level (i.e., third level). We observed that
these patients were impaired on the third- and fourth-level tasks but not at the
lower first- and second-levels (ie, response and feature tasks). The site of maximal
lesion in this group of lesions was within the IFS, area 9/46. Again, this lesion
location is in an almost identical location to that identified in our prior fMRI
study.
In summary, patients with focal frontal lesions are impaired at making action
decisions at a level of abstraction that is dependent on whether their damage is
more anterior (more concrete) or more posterior (more abstract). Importantly,
the sites of damage among patient groups corresponded precisely to the foci iden-
tified for these levels of abstraction in healthy controls undergoing fMRI while
performing this task. This high degree of correspondence between the fMRI and
patient lesion overlap results provides strong convergent support for the partici-
pation of these regions in cognitive control at different levels of abstraction.
Conclusions
The combination of all the results presented in this chapter provides strong
empirical support for the hypothesis that cognitive control, or perhaps task-
setting specifically, is organized in a representational hierarchy along the anterior
(rostral)-to-posterior (caudal) axis of the lateral frontal cortex. Furthermore,
these results suggest that levels of the representational hierarchy, and so sub-
regions of the PFC, may be differentiated by the level of abstraction at which the
representations that guide action must be selected over competition. How we
address novel problems in reasoning, decision-making, economic choice, and con-
ditions of action under uncertainty may very well reflect both the adaptability and
the constraints conferred by this basic structure–function relationship.
One of the simplest, but most powerful, benefits of considering lesion litera-
ture when conducting fMRI research is that it keeps us honest with respect to
conceptual clarity and falsifiability of our theoretical constructs. In other words,
when drawing functional conclusions about activation in a region or network
of regions, one should generally be able to answer the question, “What would
happen to a patient with a lesion to that area?” If the answer is not a clearly test-
able hypothesis, then the proposed account could use some more specification.
However, beyond this simple litmus test, a disrupted system confers much more
information than just what area is necessary for what function—it can also convey
information about the system-level functional architecture.
As demonstrated by data presented in this chapter, lesion and fMRI studies
can be highly mutually informative when each informs the hypotheses tested by
the other. In this case, lesion studies assigned the general cognitive function of
task-setting to the left lateral PFC. It was proposed that task-setting could be
implemented within a hierarchical architecture that was tested using fMRI.
Based on this hypothesis, behavioral deficits could be used to sort patients into
different groups and the precise locus of their lesion overlap could be studied.
Thus, this iterative process gave rise to a more precise theoretical formation of
frontal function that gets us closer to a mechanistic account. These studies have
also demonstrated that physiological methods such as fMRI, and lesion methods
such as studying patients with frontal lesions, have a symbiotic relationship that
should only grow stronger with time as the users of both approaches become com-
fortable with each other. The landmark work with patients by Don Stuss has
clearly motivated many fMRI experiments, and the fMRI data derived from such
studies will undoubtedly motivate new lesion studies.
References
Badre, D. (2008). Cognitive control, hierarchy, and the rostro-caudal organization of the frontal
lobes. Trends Cogn Sci, 12(5), 193–200.
Badre, D., & D’Esposito, M. (2007). Functional magnetic resonance imaging evidence for a hierar-
chical organization of the prefrontal cortex. J Cogn Neurosci, 19(12), 2082–2099.
Badre, D., & D’Esposito, M. (2009). Is the rostro-caudal axis of the frontal lobe hierarchical?
Nat Rev Neurosci, 10(9), 659–669.
Badre, D., Hoffman, J., Cooney, J. W., & D’Esposito, M. (2009). Hierarchical cognitive control defi-
cits following damage to the human frontal lobe. Nat Neurosci, 12(4), 515–522.
Banich, M., Milham, M., Atchley, R., & Cohen, N. (2000). Prefrontal regions play a predominant
role in imposing an attentional “set”: evidence from fMRI. Cogn Brain Res, 10, 1–9.
Barbas, H., & Pandya, D. N. (1989). Architecture and intrinsic connections of the prefrontal cortex
in the rhesus monkey. J Comp Neurol, 286(3), 353–375.
Brass, M., & von Cramon, D. Y. (2004). Decomposing components of task preparation with func-
tional magnetic resonance imaging. J Cogn Neurosci, 16(4), 609–620.
cortex (area 10) function. Trends Cogn Sci, 11(7), 290–298.
Christoff, K., Ream, J. M., Geddes, L. P., & Gabrieli, J. D. (2003). Evaluating self-generated
information: anterior prefrontal contributions to human cognition. Behav Neurosci, 117(6),
1161–1168.
Curtis, C. E., & D’Esposito, M. (2006). Functional neuroimaging of working memory. In R. Cabeza
& A. Kingstone (Eds.), Handbook of Functional Neuroimaging of Cognition (2nd ed., pp. 269–306).
Cambridge, MA: MIT Press.
Duncan, J., & Owen, A. M. (2000). Common regions of the human frontal lobe recruited by diverse
cognitive demands. Trends Neurosci, 23(10), 475–483.
Fellows, L. K., Heberlein, A. S., Morales, D. A., Shivde, G., Waller, S., & Wu, D. H. (2005). Method
matters: an empirical study of impact in cognitive neuroscience. J Cogn Neurosci, 17(6),
850–858.
Fuster, J. (1997). The Prefrontal Cortex: Anatomy, Physiology, and Neuropsychology of the Frontal Lobes
(3rd ed.). Raven Press: New York.
Fuster, J. M. (2001). The prefrontal cortex—an update: time is of the essence. Neuron, 30, 319–333.
Fuster, J. M. (2004). Upper processing stages of the perception-action cycle. Trends Cogn Sci, 8(4),
143–145.
prefrontal cortex. Science, 302(5648), 1181–1185.
Koechlin, E., & Summerfield, C. (2007). An information theoretical approach to prefrontal execu-
tive function. Trends Cogn Sci, 11(6), 229–235.
Mesulam, M.-M. (2002). The human frontal lobes: transcending the default mode through
contigent encoding. In D. T. Stuss & R. T. Knight (Eds.), Principles of Frontal Lobe Function
(pp. 8–31). Oxford: Oxford University Press.
Mesulam, M.-M. (2008). Representation, inference, and transcendent encoding in neurocognitive

networks of the human brain. Ann Neurol, 64(4), 367–378.
Miller, B. T., & D’Esposito, M. (2005). Searching for “the top” in top-down control. Neuron, 48(4),
535–538.
Miller, E. K., & Cohen, J. D. (2001). An integrative theory of prefrontal cortex function. Annu Rev
Neurosci, 24, 167–202.
Petrides, M. (1994). Frontal lobes and working memory: evidence from investigations of the effects
of cortical excisions in nonhuman primates. In F. Boller & J. Grafman (Eds.), Handbook of
Neuropsychology (Vol. 9, pp. 59–84). Amsterdam: Elsevier Science B.V.
Petrides, M., & Pandya, D. N. (2002). Association pathways of the prefrontal cortex and functional
observations. In D. T. Stuss & R. T. Knight (Eds.), Principles of Frontal Lobe Function (pp. 31–50).
Oxford: Oxford University Press.
Petrides, M., & Pandya, D. N. (2007). Efferent association pathways from the rostral prefrontal
cortex in the macaque monkey. J Neurosci, 27(43), 11573–11586.
Ramnani, N., & Owen, A. M. (2004). Anterior prefrontal cortex: insights into function from anat-
omy and neuroimaging. Nat Rev Neurosci, 5(3), 184–194.
Sakai, K., & Passingham, R. E. (2003). Prefrontal interactions reflect future task operations.
Nat Neurosci, 6(1), 75–81.
Stuss, D. T., & Alexander, M. P. (2007). Is there a dysexecutive syndrome? Philos Trans R Soc Lond B
Biol Sci, 362(1481), 901–915.
Multiple frontal systems controlling response speed. Neuropsychologia, 43(3), 396–417.
Bulletin, 95(3–28).
6
Dynamic Communication and
Connectivity in Frontal Networks
B R A D L E Y V OY T E K A N D R O B E R T T. K N IG H T
How do we maintain a stable percept of the world in the face of the powerful drive
of neuroplasticity in both health and disease? This dichotomy forms one of the
most fundamental unanswered questions in neuroscience concerning the balance
between the dynamic, plastic underpinnings of our neurobiology and the relative
stability of our cognition. The brain undergoes massive changes in size, morphol-
ogy, and connectivity during normal development (Fig. 6.1; Gogtay et al., 2004)
and aging (Sowell et al., 2003) as well as in response to brain injury (Alsott et al.,
2009; Carmichael, 2003), yet we can maintain a relatively stable sense of cogni-
tion and self during the lifespan. Human brains, each with over 100 billion neu-
rons, develop similarly despite the wide variations in environment and experience.
However, within the bounds of this stability there exists a wide range of variabil-
ity and capacity for change. Here we will discuss the role of neuroplasticity in
frontal lobe-dependent cognition by examining the localization of attention and
memory functions in the brain and how these seemingly fixed locations may
reflect flexible neural networks that change communication properties as required
by behavior.
Localization of Cognitive Functions

Localization of cognitive functions in the human brain poses a major problem in
modern neuroscience (Brett, Johnsrude, & Owen, 2002; Young, Hilgetag, &
Scannell, 2000). First, there is the problem of comparing localization of function
data across methodologies and across subjects and rectifying findings from vari-
ous neuroimaging and neuropsychological methodologies—each with their own
109
1.0
0.9
Age
0.8
0.7
Gray matter
0.6
20 0.5
0.4
0.3
0.2
0.1
0.0
Figure 6.1. Changes in gray matter volume with normal development (adapted
from Gogtay et al., 2004). This figure illustrates the structural plasticity of the
neocortex in the developing human brain, especially in association cortex, during
childhood. Note the relative stability of primary sensorimotor and visual areas by
puberty, in contrast to the plasticity of the childhood frontal and temporal association
cortices. (See Color Plate Section for a color version of this figure.)
limitations and underlying assumptions—with computational, lesion, and animal

studies. This presents a daunting prospect for any investigator. Second, neurosci-
entists face the inherent morphological variability across subjects; currently, any
claims to cortical functional specificity are probabilistic claims in that—barring
direct cortical stimulation mapping—one cannot guarantee that a specific cortical
region plays a specific functional role. For example, direct cortical stimulation
mapping suggests frontal, temporal, and parietal sites are all involved in language
functions, yet the specific neuroanatomy of these sites differs widely across
subjects (Sanai, Mirzadeh, & Berger, 2008).
These problems are not just theoretical or didactic issues: neurosurgeons
performing surgical tissue resections must use intraoperative cortical stimulation
mapping to ensure that the cortical tissue to be removed is not “eloquent” (lan-
guage or motor) cortex. Such stimulations are performed while the patient is
awake and performing cognitive and behavioral tasks. During this testing period
the surgeon electrically stimulates different brain regions to monitor speech or
motor arrest. This method—although decades old—is still widely employed
because of the known variability in functional localization and cortical morphol-
ogy across subjects.
D y namic Communication and Conne ct iv it y in F ron t al N e t w orks 111
Although the functional localization story appears bleak at the level of a single
individual, cerebral regions of functional localization are clearly observed when aver-
aged across a group of subjects with neuroimaging techniques such as functional
magnetic resonance imaging (fMRI) and positron emission tomography (PET).
Most studies rely upon the principle of cognitive subtraction, originally estab-
lished in reaction time studies by Franciscus Donders (Donders, 1868). The under-
lying assumption in these studies is that activity in brain networks alters in a
task-dependent manner that becomes evident after averaging many event-related
responses and comparing those against a baseline condition. Deviations from this
baseline reflect a change in the neuronal processing demands required to perform
the task of interest.
Although both the cognitive subtraction method (Friston et al., 1996) and
assumptions regarding baseline activity (Gusnard & Raichle, 2001) have their
own problems, these methods provide details of functional localization that can
then be tested and corroborated using other methodologies, including lesion
studies. The interpretation of these localization results is confounded, however,
by a lack of clarity in what is meant for a “function” to be localized. For example,
Young and colleagues (2000) noted that for a given function to be localizable that
function “must be capable of being considered both structurally and functionally
discrete,(p.155)” a property that the brain is incapable of assuming due to the
intricate, large-scale neuronal interconnectivity.
Thus, discussing behavioral functions outside the context of the larger cortical
and subcortical networks involved with that function is a poorly posed problem.
Therefore, the scientific study of cognition requires detailed neuroanatomical and
connectivity information to complement functional activity findings. The current
effort to map a human connectome (Sporns, Tononi, & Kötter, 2005) will provide
researchers with the neuroanatomical roadmap necessary to examine changes in
large-scale cortical network activity during cognition.
The Lesion Method

While functional neuroimaging techniques such as fMRI and PET have advanced
our understanding of regional specificity, the lesion method provides the stron-
gest case in the argument for causality in functional neuroanatomy; that is, brain
region A can be assumed to play an important role in the network supporting
function X if a lesion to A impairs function X. Research on humans with focal
brain lesions (Fig. 6.2) has provided seminal information with regard to our
understanding of which brain regions contribute to specific behavioral, sensory,
and cognitive functions (Rorden & Karnath, 2004). For example, because pre-
frontal cortex (PFC) and basal ganglia lesions lead to working memory deficits
(Müller & Knight, 2006; Tsuchida & Fellows, 2009; Voytek & Knight, 2010), the
6
Prefrontal
5
4
3
2
1
Figure 6.2. Patient lesion reconstructions. These structural MRI slices illustrate the
lesion overlap across six patients with unilateral PFC lesions. All lesions are normalized
to the left hemisphere for comparison, although two patients had right hemisphere
lesions (adapted from Voytek et al., 2010). Examining groups of patients with
stereotyped lesions allows researchers to test the role of specific regions in behavior.
Software reconstructions were performed using MRIcro (Rorden & Brett, 2000).
(See Color Plate Section for a color version of this figure.)
PFC can be said to play an important, if not necessary, role in working memory
networks.
By combining lesion studies with neuroimaging techniques, researchers can
identify other brain regions associated with a certain behavior. For example,
research using scalp electroencephalography (EEG) has shown that unilateral PFC
lesions cause lateralized deficits in top-down modulation of activity in visual
extrastriate cortex during attention (Fig. 6.3; Barceló, Suwazano, & Knight,
2000; Yago et al., 2004) and working memory (Voytek & Knight, 2010), which
makes EEG a powerful tool for investigating the network dynamics subserving
cognition.
While the underlying notion of brain damage disrupting function is fairly obvi-
ous—damaging parts of a machine prevents the machine from working optimal-
ly—the specific effects of brain damage are neither obvious nor always predictable.
There are several factors that prohibit accurate prediction of which deficits will
manifest after a given brain lesion. This is largely due to the fact that we are still
uncertain about the accuracy of regional localization of function and the poorly
posed nature of the functional localization question in general. Because the prob-
ability distribution of functional localization across subjects is broad, especially
across cortical association areas (Sanai, Mirzadeh, & Berger, 2008), the impor-
tance of distributed cortical networks in behavior and subsequent recovery cannot
be ignored.
Nevertheless, working with patients with circumscribed frontal brain lesions
provides us with insight into how frontal cortex interacts with the rest of the
brain to give rise to cognitive functions. When combined with computational
and behavioral methodology and/or neuroimaging, the lesion method allows
researchers to examine exactly which areas are critical for which cognitive func-
tions. For example, recent work by Badre and colleagues took advantage of the
inherent differences in lesion size and extent in their patient populations to
examine the rostral–caudal organization of cognitive and action control in the
A B
+ + Contralesion Ips ilesion

standards at TOi standards at TOc
NI
+ –
** 2 μV
PI TOi TOc +
0 300
– ms
+ +
+ Δ + Δ
+ 2 μV
Frontals
Controls
0 μV
Controls Frontals
Figure 6.3. Examining the effects of unilateral PFC lesions on attention networks. (A) Lateralization of early visual activity modulated by
attention. For healthy control subjects (top), lateralized, attended stimuli lead to early (~150 ms) activity increases in visual extrastriate cortex
(orange region). For patients with unilateral PFC lesions (shaded region, bottom), normal attention-related activity increases are seen for stimuli
presented ipsilesionally (orange); however, when stimuli are presented contralesionally, patients show activity deficits compared to controls (blue).
(B) This effect is seen in scalp EEG (adapted from Barceló, Suwazano, & Knight, 2000). (See Color Plate Section for a color version of this figure.)
A B C
8.5
1.7
C,F
B,E
A,D
D E F
7.6
1.8
Figure 6.4. Example of voxel-based lesion-symptom mapping (adapted from Bates

et al., 2003). These maps show speech fluency (A–C) and language comprehension
(D–F) in 101 aphasic stroke patients. Color represents the effect of lesion on behavior,
with large t-values suggesting a significant relationship between the presence of a
lesion and a behavioral deficit. (See Color Plate Section for a color version of this figure.)
frontal cortex (Badre et al., 2009). While this “messiness” of lesion size, extent,
and location has traditionally been viewed as a major drawback of the lesion
method, it is the cornerstone of voxel-based lesion-symptom mapping (VLSM)
(Fig. 6.4; Bates et al., 2003). This method requires a detailed neuroanatomical
scan of every patient; t-tests are then performed at every voxel on a variable of
interest (e.g., a cognitive task) where the statistical “groups” are defined by
whether the patient has a lesion in that specific voxel or not. This clever technique
allows researchers to map voxel by voxel which regions are most important for a
cognitive function.
Recent work has expanded the lesion method into computational modeling.
Using a cortically plausible network architecture, researchers have shown the
effects of lesions on functional connectivity (Alstott et al., 2009; Young, Hilgetag,
& Scannell, 2000) and on oscillatory dynamics (Honey & Sporns, 2008) demon-
strating activity changes in remote brain areas (Reggia, 2004) not directly con-
nected to the lesioned brain region (Young, Hilgetag, & Scannell, 2000). These
findings suggest that lesions to highly connected critical hubs—including frontal
and parietal regions—result in widespread changes in functional connectivity
and oscillatory communication.
Recovery and Compensation

Predicting the course of recovery from brain damage is confounded by a lack
of understanding about the extent and time course of recovery possible across
different regions of the central nervous system. Neural plasticity is critical
for functional recovery after brain damage, with improvement possible even
20 years after the initial injury (Bach-y-Rita, 1990). There are several theories
of recovery of function (Grafman, 2000), including cortical compensation by
perilesion and intact homologous brain regions (Wundt, 1902) or subcortical
(Van Vleet et al., 2003) structures; diaschisis reversal (von Monakow, 1969);
unmasking (Lytton, Williams, & Sober, 1999); distributed cortical representa-
tions (Jackson, 1958); and axonal sprouting and neurogenesis (Carmichael et al.,
2001). Many of these theories predate neuroimaging and were based on clinical
observations of patients with brain damage. In 1902, Wilhelm Wundt noted
that:
in both simple and complex disturbances, there is usually a gradual restoration

of the functions in the course of time. This is probably effected by the vicarious
functioning of some, generally a neighboring cortical region in place of that
which is disturbed (in disturbances of speech, perhaps it is the opposite, before
untrained, side that comes into play). (p. 206)
This latter point was proved in a recent paper in which Blasi and coworkers
demonstrated that patients who have recovered from Broca’s aphasia due to left
frontal stroke show fMRI activation in the right frontal Broca’s area homologue
(Fig. 6.5A; Blasi et al., 2002).
The fact that the brain is not a static machine, but rather a fluctuating (plastic),
self-repairing organ (Cramer, 2008), provides an important confound to lesion-
based research. For example, most lesion studies that demonstrate behavioral
deficits in humans are performed on patients who have had sudden (acute)
brain damage (e.g., stroke or trauma) precisely because these patients show
the strongest behavioral deficits. In contrast, patients who have undergone surgi-
cal resections to remove cancerous cerebral tissue tend to show fewer deficits
before and after their surgeries (Desmurget, Bonnetblanc, & Duffau, 2007)
compared to a patient with a comparably sized lesion from a stroke. This phenom-
enon is interpreted as recovery processes resulting from compensation by other
brain regions in cases of slow-growing lesions. Because the lesions are slow-
growing rather than rapidly occurring (such as from stroke), the hypothesis
is that the deficits resulting from the lesion are minimized because the incremen-
tally slow rate of growth permits compensatory processes to mask those deficits.
By definition, acute lesions, on the other hand, result in rapid tissue damage
that cannot be (immediately) compensated for. Thus, although patient work is
A R dorsal IFG
L dorsal IFG
2 4 6
Controls > Patients

Patients > Controls
B
ipsi-
+ + Contra-
1 μv
*
Theta amplitude (μv)
Theta amplitude (μv)

Left
0.5 0.5 Right
*
0.0 0.0
–0.5 –0.5
1 2 3 1 2 3
Memory load Memory load
–1 μv
PFC patients Controls
Figure 6.5. Examples of compensatory activity after frontal damage. (A) Compared to healthy control subjects, patients with damage to left
inferior frontal gyrus who have recovered from speech deficits show increased activation in the homologous area in the intact hemisphere (blue
arrow) and decreased activation in the damaged region (red arrows). (Adapted from Blasi et al., 2002.) (B) Using lateralized visual stimulus designs,
Voytek and coworkers (2010) showed that patients with unilateral PFC lesions (shaded regions) show increased activity over the intact PFC only
when the damaged hemisphere was directly challenged with visual stimuli. This activity was not seen in control subjects, and it scaled with
cognitive demands. (See Color Plate Section for a color version of this figure.)
invaluable, the temporality of the lesion (both onset time and time since damage)
should not be discounted.
Given the number of brain regions needed to support cognitive functions, it is
not unreasonable, given the variety of recovery theories, to hypothesize that cogni-
tive recovery could be supported by any part of the cognitive network. The PFC,
however, plays an important role in cognitive networks by biasing information
flow in other regions to favor positive behavioral outcomes (Miller & Cohen, 2001).
Therefore, the PFC may play a privileged role in cognitive compensation. For exam-
ple, although patients with lateral PFC lesions have lasting attention and working
memory deficits (e.g., Voytek & Knight, 2010; Barceló, Suwazano, & Knight, 2000),
cognitive functions can recover somewhat over time (Voytek et al., 2010).
Numerous studies suggest that the PFC plays a diverse role in a wide range of
cognitive functions involved in the allocation and control of visual attention and
working memory. One hypothesis is that the PFC maintains an association
between endogenous elements in working memory while an unknown neuronal
mechanism compares these endogenous representations to exogenous visual
information as it is processed in extrastriate visual areas (Barceló, Suwazano, &
Knight, 2000; Kimberg & Farah, 1993).
It is important to note that neuropsychological testing alone can be misleading
concerning the extent of recovery after PFC damage. For example, if, during an
attention task, visual stimuli are presented full-field (that is, presented in the
center of the visual field and with unrestrained eye movements), patients with
unilateral PFC lesions do not show obvious visual attention deficits. However, if
visual stimuli are lateralized to the left or right visual hemifield by a matter of a
few degrees and central fixation is maintained, then deficits in visual working
memory (Voytek & Knight, 2010) and attention (Barceló, Suwazano, & Knight,
2000) are evident.
Visual stimulus lateralization takes advantage of the neuroanatomy of the
mammalian visual system such that stimuli presented to the right visual hemi-
field preferentially activate the left visual cortex (and vice versa) before that infor-
mation is then transferred to the opposite visual cortex via the corpus callosum.
Such lateralized designs increase statistical power in that patients can serve par-
tially as their own controls (i.e., “good” hemifield vs. “bad” hemifield; see Fig.
6.3A), thus allowing for a within-subjects comparison of the effects of the brain
lesion on a cognitive function for contralesionally versus ipsilesionally presented
stimuli.
Nevertheless, even in lateralized visual attention and working memory
paradigms, patients with unilateral PFC damage—though worse than control
subjects when stimuli are presented contralesionally—still perform well above
chance levels. This finding is somewhat in contrast to what is observed in lesion
and neuroimaging studies of primary cortical functions. Neuroimaging studies
of movement or visual processing localize these processes to motor and visual
cortex, respectively. Lesions to primary motor or primary visual cortex lead to
striking and permanent deficits (hemiparesis or cortical blindness, in these

specific cases). Conversely, while functional neuroimaging studies show task-
dependent PFC activation during attentional control and working memory,
lesions to the PFC lead to an incomplete loss of those functions. This discrepancy
may have any number of underlying causes, including any combination of the
following: (1) Research paradigms used to assess cognitive deficits may be less
sensitive and less specific than those used to examine motor or sensory deficits;
(2) Cognitive processes dependent on association cortex may be more widely
distributed across a broader network than those dependent on primary cortex,
making cognitive processes more resilient to a single focal lesion; and (3)
Compensatory mechanisms may be facilitating damaged cognitive functions more
than primary functions.
For neuronal activity differences to be considered “compensatory,” Davis and
associates (2008) have outlined at least two criteria that must be met. First, novel
activity increases not seen in normal controls (but seen in, e.g., lesion patients)
must be associated with correct behavioral outcomes. Second, deficits in process-
ing by one region must be associated with increases in activity in the putative
compensatory region. These criteria are important because activity increases
interpreted as “compensatory” may in fact more simply reflect a global increase in
cortical activity due to increases in difficulty in performing a task for lesion
patients compared to control subjects (Hillary et al., 2006). In other words,
because of the lesion, more cognitive resources are recruited to correctly perform
the task compared to controls.
In the context of unilateral PFC damage and its effects on attention and
working memory, Voytek and coworkers (2010) hypothesized that the intact,
undamaged PFC compensates for the damaged cortex in a load-dependent manner
as required by task demands. What was observed (Fig. 6.5B), consistent with
the first criterion for compensation, was that increases in activity over the intact
PFC are enhanced on correct trials when the damaged PFC is challenged with
lateralized visual working memory or attention demands. With regards to
the second criterion, their experimental designs preferentially challenged the
damaged hemisphere in patients with unilateral PFC damage, and increases
in activity over the intact PFC were seen in conjunction with top-down deficits in
the visual extrastriate cortex of the damaged hemisphere. It is important to
highlight that the decreased posterior extrastriate responses seen in cognitive
experiments with patients with unilateral PFC damage (Barceló, Suwazano, &
Knight, 2000; Voytek & Knight, 2010) are seen only when stimuli are presented
to the contralesional hemifield. If we are to assume that these posterior
responses normally index behavior and performance—and PFC patients show
attenuated extrastriate responses even when correctly performing the task—then
logically there must be some other brain regions compensating for the lesioned
cortex.
As previously stated, research indicates that the perilesion cortex and the
homologous intact contralateral cortex may both be involved in recovery and that
there is long-range, intracortical reorganization of behaviorally and recovery-
relevant pathways (Dancause, 2006; Nudo, 2007). Thus, Voytek and coworkers
proposed that the visual information delivered to the contralesional hemisphere
is transferred trans-callosally to the intact hemisphere, where the intact PFC then
assumes task control as needed on a trial-by-trial basis. Support for this conten-
tion is provided by studies in non-human primates revealing that top-down PFC
control over visual cortex during memory retrieval relies on callosal information
transfer (Hasegawa et al., 1998; Tomita et al., 1999). Thus, if trans-callosal infor-
mation transfer could be blocked, then behavioral deficits should be enhanced.
As discussed previously, in contrast with cognitive deficits, primary motor and
sensory functions rarely recover in adults who suffer cortical damage, although
other modalities may take over intact sensory cortex deprived of input due to
peripheral damage (Sadato et al., 1996). Unlike adults with primary cortical
damage, children who have had a surgical hemispherectomy, for example, can
regain motor control of the affected limbs (Benecke et al., 1991); such recovery
can be seen even in children with massive and severe cortical damage (e.g.,
Distelmaier et al., 2007). In contrast, others have observed a surprising normality
among patients missing massive amounts of their cortical tissue (Lewin, 1980).
While deficits caused by lesions to PFC are more likely to recover if they occur
later in life—and this recovery may be dependent upon having some amount of
intact PFC (Kolb & Gibb, 1990)—children with PFC damage may have lasting cog-
nitive impairment (Kolb & Gibb, 1990). The interaction between age and location
of lesion with behavioral recovery may reflect a deeper relationship with the evo-
lution of cognitive and sensory functions in primates (Anderson, 2007) wherein
cognitive functions, having evolved more recently, are more distributed across
cortex and thus more resistant to focal brain damage once those functions have
developed in adulthood.
Integrating all of the prior points, it may be that the farther away from primary
cortical areas a region is, the less predictable the function becomes. This phenom-
enon may help explain why we have fairly robust sensory and motor homunculi in
the primary (“lower”) cortical areas, but no reliable mapping in the “higher” sen-
sory and motor association cortices. This is illustrated by example from clinical
observations: a patient with damage to the premotor cortex is more likely to
recover motor functions than a patient with a lesion of primary motor cortex,
who in turn is more likely to naturally recover than a person with a lower motor
neuron lesion in the spinal cord. A network theory view of this phenomenon
would suggest that differences between the focal networks of primary regions and
distributed networks of the functions subserved by association cortex may
account for these differences in recovery. Given the above caveats, to study human
cortical recovery of function one must carefully balance recovery likelihood with
probability of functional localization—that is, in theory, one is more likely to find

a reliable deficit across subjects with damage to primary cortical regions, but less
likely to observe recovery in these patients.
References
Alstott, J., Breakspear, M., Hagmann, P., Cammoun, L., Sporns, O., & Friston, K . (2009). Modeling
the impact of lesions in the human brain. Public Library of Science Computational Biology, 5,
1–12.
Anderson, M. (2007) Evolution of cognitive function via redeployment of brain areas. Neuroscientist,
13, 13–21.
Bach-y-Rita, P. (1990). Brain plasticity as a basis for recovery of function in humans. Neuropsychologia,
28, 547–554.
Badre, D., Hoffman, J., Cooney, J., & D’Esposito, M. (2009). Hierarchical cognitive control deficits
following damage to the human frontal lobe. Nature Neuroscience, 12, 515–522.
Barceló, F., Suwazono, S., & Knight, R. T. (2000). Prefrontal modulation of visual processing in
humans. Nature Neuroscience, 3, 399–403.
Bates, E., Wilson, S., Saygin, A., Dick, F., Sereno, M., Knight, R. T., & Dronkers, N. (2003).
Voxel-based lesion–symptom mapping. Nature Neuroscience, 6, 448–450.
Benecke, R., Meyer, B. U., & Freund, H. J. (1991). Reorganisation of descending motor pathways in
patients after hemispherectomy and severe hemispheric lesions demonstrated by magnetic
brain stimulation. Experimental Brain Research, 83, 419–426.
Blasi, V., Young , A. C., Tansy, A. P., Petersen, S. E., Snyder, A., & Corbetta, M. (2002). Word retrieval
learning modulates right frontal cortex in patients with left frontal damage. Neuron, 36,
159–170.
Brett, M., Johnsrude, I., & Owen, A . (2002). The problem of functional localization in the human
brain. Nature Review Neuroscience, 3, 243–249.
Carmichael, S. (2003). Plasticity of cortical projections after stroke. Neuroscientist, 9, 64–75.
Carmichael, S. T., Wei, L., Rovainen, C. M., & Woolsey, T. A . (2001). New patterns of intracortical
projections after focal cortical stroke. Neurobiology Discussion, 8, 910–922.
Cramer, S. (2008). Repairing the human brain after stroke: I. Mechanisms of spontaneous recovery.
Annals of Neurology, 63, 272–287.
Dancause, N. (2006). Vicarious function of remote cortex following stroke: recent evidence from
human and animal studies. Neuroscientist, 12, 489–499.
Davis, S. W., Dennis, N. A., Daselaar, S. M., Fleck, M. S., & Cabeza, R . (2008). Que PASA? The
posterior-anterior shift in aging. Cerebral Cortex, 18, 1201–1209.
Desmurget, M., Bonnetblanc, F., & Duffau, H. (2007). Contrasting acute and slow-growing lesions:
a new door to brain plasticity. Brain, 130, 898–914.
Distelmaier, F., Richter-Werkle, R., Schaper, J., Messing-Juenger, M., Mayatepek, E., & Rosenbaum,
T. (2007). “How much brain is really necessary?” A case of complex cerebral malformation and
its clinical course. Journal of Child Neurology, 22, 756–760.
Donders, F.C. (1868). Die Schnelligkeit psychischer Prozesse. Archiv für Anatomie und Physiologie
und wissenschaftliche Medizin, 657–681.
Friston, K. J., Price, C. J., Fletcher, P., Moore, C., Frackowiak, R. S., & Dolan, R. J. (1996). The
trouble with cognitive subtraction. NeuroImage, 4, 97–104.
Gogtay, N., Giedd, J. N., Lusk., L., Hayashi, K. M., Greenstein, D., Vaituzis, A. C., Nugent, T. F.,
Herman, D. H., Clasen, L. S., Toga, A., Rapoport, J. L., & Thompson, P. (2004). Dynamic
mapping of human cortical development during childhood through early adulthood.
Proceedings of the National Academy of Sciences, USA, 101, 8174–8179.
Grafman, J. (2000). Conceptualizing functional neuroplasticity. Journal of Communication Disorders,
33, 345–355.
Gusnard, D. A., & Raichle, M. E. (2001). Searching for a baseline: functional imaging and the resting
human brain. Nature Review Neuroscience, 2, 685–694.
Hasegawa, I., Fukushima, T., Ihara, T., & Miyashita, Y. (1998). Callosal window between prefrontal
cortices: cognitive interaction to retrieve long-term memory. Science, 281, 814–818.
Hillary, F., Genova, H., Chiaravalloti, N., Rypma, B., & DeLuca, J. (2006). Prefrontal modulation
of working memory performance in brain injury and disease. Human Brain Mapping, 27,
837–847.
Honey, C., & Sporns, O. (2008). Dynamical consequences of lesions in cortical networks. Human
Brain Mapping, 29, 802–809.
Jackson, J. H. (1958). A study of convulsions. In: J. Taylor (Ed.), Selected writings of John Hughlings
Jackson. London: Staples.
Kimberg , D. Y., & Farah, M. J. (1993). A unified account of cognitive impairments following
frontal lobe damage: the role of working memory in complex, organized behavior. Journal of
Experimental Psychology General, 122, 411–428.
Kolb, B., & Gibb, R . (1990). Anatomical correlates of behavioural change after neonatal prefrontal
lesions in rats. Progress in Brain Research, 85, 241–255.
Lewin, R . (1980). Is your brain really necessary? Science, 210, 1232–1234.
Lytton, W. W., Williams, S. T., & Sober, S. J. (1999). Unmasking unmasked: neural dynamics follow-
ing stroke. Progress in Brain Research, 121, 203–218.
Miller, E. K., & Cohen, J. D. (2001). An integrative theory of prefrontal cortex function. Annual
Review of Neuroscience, 24, 167–202.
Müller, N. G., & Knight R. T. (2006). The functional neuroanatomy of working memory: contribu-
tions of human brain lesion studies. Neuroscience, 139, 51–58.
Nudo, R. J. (2007). Postinfarct cortical plasticity and behavioral recovery. Stroke, 38, 840–845.
Reggia, J. (2004). Neurocomputational models of the remote effects of focal brain damage. Medical
Engineering and Physics, 26, 711–722.
Rorden, C., & Karnath, H.O. (2004). Using human brain lesions to infer function: a relic from a past
era in the fMRI age? Nature Reviews Neuroscience, 5, 813–819.
Sadato, N., Pascual-Leone, A., Grafman, J., Ibañez, V., Deiber, M. P., Dold, G., & Hallett, M. (1996).
Activation of the primary visual cortex by Braille reading in blind subjects. Nature, 380,
526–528.
Sanai, N., Mirzadeh, Z., & Berger, M. (2008). Functional outcome after language mapping for
glioma resection. New England Journal of Medicine, 358, 18–27.
Sowell, E. R., Peterson, B. S., Thompson, P., Welcome, S. E., Henkenius, A. L., & Toga, A . (2003).
Mapping cortical change across the human life span. Nature Neuroscience, 6, 209–215.
Sporns, O., Tononi, G., & Kötter, R . (2005). The human connectome: a structural description of
the human brain. Public Library of Science Computational Biology, 1, e42.
Tomita, H., Ohbayashi, M., Nakahara, K., Hasegawa, I., & Miyashita, Y. (1999). Top-down
signal from prefrontal cortex in executive control of memory retrieval. Nature, 401,
699–703.
Tsuchida, A., & Fellows, L.K . (2009). Lesion evidence that two distinct regions within prefrontal
cortex are critical for n-back performance in humans. Journal of Cognitive Neuroscience, 21,
2263–2275.
Van Vleet, T. M., Heldt, S. A., Pyter, B., Corwin, J. V., & Reep, R. L . (2003). Effects of light
deprivation on recovery from neglect and extinction induced by unilateral lesions of
the medial agranular cortex and dorsocentral striatum. Behavioral Brain Research, 138,
165–178.
von Monakow, C. (1969). Die lokalisation im grosshirn und der abbau der funktion durch kortikale
herde. In: K. H. Pribram (Ed.), Mood, states and mind. London: Penguin Books.
Voytek, B., & Knight, R. T. (2010). Prefrontal cortex and basal ganglia contributions to visual
working memory. Proceedings of the National Academy of Sciences, USA, 107(42),
18167–18172.
Voytek, B., Davis, M., Yago, E., Barceló, F., Vogel, E.K., & Knight, R.T. (2010). Dynamic neuroplas-
ticity after human prefrontal cortex damage. Neuron, 68(3), 401–408.
Wundt, W. (1902). Outlines of psychology (2nd ed.). Leipzig: Engelmann.

Yago, E., Duarte, A., Wong , T., Barceló, F., & Knight, R. T. (2004). Temporal kinetics of prefrontal
modulation of the extrastriate cortex during visual attention. Cognitive, Affective, & Behavioral
Young , M., Hilgetag , C., & Scannell, J. (2000). On imputing function to structure from the behav-
ioural effects of brain lesions. Philosophical Transactions of the Royal Society B: Biological
Sciences, 355, 147–161.
7
The Frontal Lobes and
Mental State Attribution
R . S H AY N A R O S E N BAU M A N D J E N N I F E R S . R A B I N
It has long been recognized that frontal lobe damage can result in complex social
and emotional consequences (e.g., Damasio et al., 1994; Goldstein, 1944; Kleist,
1934; Macmillan, 2000; Meyer & Beck, 1945; Rylander, 1939; Stuss & Benson,
1986; Welt, 1888). These consequences are difficult to detect with many existing
neuropsychological measures, though they can be devastating to everyday func-
tion. Among the most prominent of these consequences are difficulties inferring
other people’s current thoughts and feelings during theory of mind (ToM) and
making appropriate self-reflective inferences, such as when recollecting past per-
sonal episodes during autobiographical memory. Though these deficits may reflect
a common root or substrate, they are poorly understood in terms of their own
underlying neural mechanisms and relationship with other functional capacities.
Despite the tremendous difficulty in pinpointing such elusive constructs within
what continues to be regarded as the most mysterious part of the brain, Don Stuss
helped bring together a multidisciplinary team of collaborators to carry on and
refine the tradition of examining the functional consequences of focal frontal
lesions in single cases and patient groups. Don’s work with focal lesion patients,
some of which will be reviewed here, was instrumental in uncovering both the
complexity and fragility of the frontal lobes. It continues to influence theoretical,
methodological, and clinical approaches to understanding the basis of functions
that may be at the core of what makes us human.
Much of the early work examining the functional and neural substrates of ToM
was born from the autism literature and led researchers to suggest that a dedi-
cated neural system or module might underlie ToM abilities (Baron-Cohen, 1995;
Leslie, 1992). This idea was based on the observation that children with autism
performed poorly on tests of ToM while other abilities remained intact (Baron-
Cohen, Leslie, & Frith, 1985). Others, however, have argued against the modular-
ity view, making the case that ToM draws on a variety of domain-general resources
123
that serve abilities other than ToM (e.g., Stone & Gerrans, 2006). Neuroimaging
and lesion studies have helped fuel this debate, with a focus on whether frontal
versus non-frontal regions are necessary, sufficient, and/or specific to ToM
function.
Although there is general acceptance of frontal lobe involvement in mental
state reasoning and attribution, there is debate about its specialization relative to
other, more posterior regions, especially regions within the temporoparietal junc-
tion (TPJ), which include the angular gyrus, supramarginal gyrus, and posterior
portion of the superior temporal gyrus (Saxe, Carey, & Kanwisher, 2004).
Disorders of ToM following damage to frontal and parietal regions, including
changes to their connectivity, may reflect a more general deficit in cognitive con-
trol or reasoning ability (e.g., Charlton, Barrick, Markus, & Morris, 2009; Decety
& Lamm, 2007), in inhibiting one’s own perspective in favor of others’ perspec-
tives (Bull, Phillips, & Conway, 2008; Samson et al., 2005; Sampson, Apperly, &
Humphreys, 2007), and/or in visual attention (cf. Corbetta, Patel, & Shulman,
2008; Mitchell, 2008; Young, Dodell-Feder, & Saxe, 2010). They may also reflect a
breakdown of frontal lobe involvement in applying intact knowledge to guide self-
relevant behavior, representing a “thought–action” or “thought–feeling” dissocia-
tion (Luria, 1973; Milner, 1964; Stuss & Benson, 1984). Recent research has
emphasized dissociations of cognitive from affective and empathic forms of ToM
in human lesion studies (e.g., Shamay-Tsoory & Aharon-Peretz., 2007), and self-
referential processing from processing other people’s mental states in neuroimag-
ing studies (e.g., Mitchell et al., 2005, 2006; Olsson & Ochsner, 2008). A separate
line of research has examined common processing requirements of autobiograph-
ical memory, ToM, and future imagining in efforts to understand similar activa-
tion patterns underlying these seemingly disparate abilities (e.g., Buckner &
Carroll, 2007; Hassabis et al., 2007; Rosenbaum et al., 2007; Schacter et al., 2008;
Spreng, Mar, & Kim, 2009; Wheeler, Stuss, & Tulving, 1997). This chapter honors
Don’s accomplishments by characterizing frontal lobe specialization in represent-
ing one’s own and other people’s mental states. It also considers other progress
that has been made in the context of interactions with posterior brain regions and
their processing capacities.
Changes in Socially Relevant Behavior

after Frontal Lobe Damage
Functional specialization of mental state representations within prefrontal cortex
(PFC) has been informed by observations of dissociable loss of function in
patients with focal lesions to distinct areas of PFC. This work can be traced back to
the account of Phineas Gage published over a century and a half ago after an
iron tamping bar passed through his ventromedial PFC/orbitofrontal cortex
The Fr ontal Lobes an d M e n t al S t at e At t ribu t ion 125
(Damasio et al., 1994; Macmillan, 2000). His case clearly illustrates that lesions to
this region of the brain can result in a pattern of disturbed socially relevant behav-
iors, indicated by his impaired social insight and inability to effectively use emo-
tions to guide high-level personal decision-making. Even before Gage’s profile was
formally revisited by Damasio and colleagues (Bechara et al., 1994, 1997; Damasio,
1994), there were efforts to verify it in other patients with lesions to orbitofrontal
cortex or medial PFC (mPFC) who showed difficulties processing certain types of
emotion, respecting social norms, and assigning reward value or personal mean-
ing to decision-making (e.g., Eslinger & Damasio, 1985; see also Blair & Cipolotti,
2000; Rolls, 1996). Some of this work had hinted at an influence of ToM deficits
in a failure to appreciate other people’s mental states as separate from one’s own.
Some of the most striking clinical examples were captured by Stuss and Benson in
their 1983 chapter on the “Emotional Concomitants of Psychosurgery” (prefron-
tal leucotomy) and in their seminal 1986 book on the frontal lobes, themselves
noting Kleist (1934), Rylander (1939), Goldstein (1944), and Meyer and Beck
(1945), among others, as drawing functional distinctions between medial-orbital
and dorsolateral frontal regions. Another clear example was provided by Alexander
and Stuss in their interactions with the patient Bob, whose knowledge and ongo-
ing experiences may be described as no longer “affectively burnt in” and lacking
personal connectedness following ventromedial PFC damage due to stroke (Stuss
& Alexander, 1999).
It is not surprising, therefore, that emotional-behavioral consequences of
frontal lobe damage have been described as specific disorders of self-awareness
and in mentally representing subjective experiences across time (i.e., “autonoetic
consciousness”; Stuss, Rosenbaum, Malcolm, Christiana, & Keenan, 2005; Wheeler
et al. 1997). The original ideas were grounded in observations from patient and
early PET studies of frontal lobe involvement in “remember” (re-experiencing)
judgments associated with studied words and in source memory for the context in
which the word was studied. More recent neuroimaging evidence suggests only
partial overlap in the frontal regions mediating lab-based episodic memory and
real-world autobiographical memory retrieval (Gilboa, 2004; McDermott,
Szpunar, & Christ, 2009). Nonetheless, the original theory continues to have pre-
dictive value. For example, the patient M.L., described soon after the publication
of Wheeler and colleagues, seemed to lack a sense of re-experiencing his personal
past secondary to a lesion deep to ventrolateral prefrontal regions that disrupted
frontotemporal connectivity (Levine et al., 1998, 2009). His inability to recollect
the contextual, perceptual, and emotional qualities necessary to relive auto
biographical events in memory contrasts with a feeling of familiarity that the
event had occurred in the past, similar to the familiarity that a word may have
appeared on a studied list when making a “know” judgment. More medial damage
in some patients results in confabulation when retrieving self-related memories,
suggesting a lack of an “intuitive feeling of rightness” that otherwise would have
led the patients to reject implausible personal happenings (Gilboa et al., 2006;
Moscovitch & Winocur, 2002; Stuss et al., 1978). When forced to take an objective
stance in reviewing their own confabulations, these patients often recognize the
absurdity of the retrieved content but continue to maintain confidence in the
accuracy of their memories (Moscovitch, 1995; see also Alexander, Stuss, &
Benson, 1979, and Stuss & Benson, 1983, for similar findings in Capgras syn-
drome). This discrepancy between intact knowledge on the one hand, and an
inability to act on that knowledge on the other, had been noted in independent
observations of clinical cases in the context of a range of behaviors and lesion
locations within the frontal lobes. In their 1984 paper, Stuss and Benson com-
mented, “Prefrontal damage can separate action (response) from knowledge . . .
prefrontal patients were often unable to use language (knowledge) to correctly
guide even simple motor actions (p. 22)” (for other examples, see Alexander et al.,
1979; Milner, 1964; Owen et al., 1991). This connection between knowledge and
the subjective experience of that knowledge may be reflected in recent attempts
to characterize “cognitive” and “affective” ToM as separate entities, residing in
dissociable regions of PFC, which we review in the next section.
Two major factors resulted in renewed efforts in studying social disturbance
affecting awareness of the self and others after frontal lobe damage: (1) improved
techniques for functional localization within the frontal lobes, and (2) the devel-
opment of assessment tools to detect and isolate more subtle deficits. Indeed,
research in the past decade has focused on examining ToM in larger groups of
neurological patients with more discrete lesions to the frontal and temporal lobes
as defined by detailed anatomical localization methods, using tasks that require
varying degrees of emotional and cognitive analysis. A summary of patient stud-
ies on ToM, with a focus on frontal lobe patients, is presented in Table 7.1.
Affective and Cognitive Contributions to ToM

Success on most tests of ToM depends in part on processes beyond possessing a
concept of another person’s mind (Stone & Gerrans, 2006). Deficits in monitor-
ing, planning, mental flexibility, inhibition of a prepotent response, and strategic
retrieval from long-term memory have been theorized as other potential mecha-
nisms underlying ToM dysfunction (Siegal & Varley, 2002). However, this more
“executive” set of abilities is often associated with lesions restricted to dorsolat-
eral sectors of PFC, not ventral or medial regions (Levine et al., 1997; Moscovitch
& Winocur, 1992; Stuss, 2006; Stuss & Alexander, 2007; Stuss & Levine, 2002;
Stuss et al., 1994). For example, ToM is most frequently assessed with the false
belief test, which involves predicting a character’s mistaken belief about the loca-
tion of an object. Findings that the second-order trials are particularly vulnerable
to dorsolateral PFC lesions in adult patients suggest that it might be the working
memory aspect that is responsible for frontal lobe involvement (Stone, Baron-
Cohen, & Knight, 1998). When stripped of executive demands, it is apparent that
Table 7.1. Patient Studies of Frontal Involvement in ToM Conducted from 1998 to 2009
Authors # Of Patients Per Eitology Comparison Group ToM Tests Results

Group/Lesion Location
Stone et al. 10 frontal: 5 L DL, 5 B DL: middle cerebral artery 5 controls First-order false belief, Orbitofrontal patients
(1998) orbitofrontal; 1 infarcts second-order false belief, performed poorly on the
nonfrontal: 1B TP Orbitofrontal: head trauma faux pas faux pas test.
Shammi & 13 frontal: 1 B orbital, Frontal: 5 tumor, 2 trauma, 10 controls Appreciation of humorous Right and bilateral
Stuss (1999) 4 medial (1 L, 2R, 1B), 3 stroke, 1 lobectomy, verbal statements, joke frontal patients: impaired
2 R DL, 5 medial+DL 1 leucotomy, 1 infarct and story completion, on all three humor tasks;
(3 L, 2 B), 1 L unspecified Nonfrontal: 4 lobectomy, non-verbal cartoon most patients who were
8 nonfrontal: 6 temporal 3 stroke, 1 hemorrhage appreciation test impaired on these tests
(3 L, 3 R), 1 R parietal, 1 had lesions to the right
R temporal+parietal frontal lobe.
Blair & Case J.S.: R frontal, Acquired sociopathy due to Patient C.L.A. with Emotion attribution task, Emotion attribution task:
Cipolotti including B possible head injury dysexecutive advanced impaired ability to
(2000) orbitofrontal syndrome (supra- and ToM task attribute fear, anger, and
infratentorial atrophy, embarrassment to story
R frontal white matter characters; advanced ToM
changes), 10 healthy task: intact performance
male controls,
5 psychopathic male
inmates, 5 non-
psychopathic male
inmates
(Continued)

Channon & 19 frontal: 1 R medial, Frontal and nonfrontal: 60 controls Story comprehension test L frontal group:
Crawford 10 lateral (3 L, 7 R), 8 16 vascular damage, impairment, with failure
(2000) orbital+medial+lateral 7 head injury, to make non-literal
(3 L, 5 R) 5 tumors, 2 abscess, interpretations; R frontal
12 nonfrontal: 4 1 sclerosis and posterior: unimpaired
temporal
(1 L, 3 R), 4 parietal
(1 L, 3 R), 2
temporal+parietal
(1 L, 1 R),
2 temporal+occipital
(1 L, 1 R)
Rowe et al. 31 frontal: 4 orbital 15 resection/lobectomy, 31 controls First-order false belief, R and L frontal: impaired
(2001) (2 L, 2 R), 1 L medial, 7 meningioma, second-order false belief on first- and second-
10 orbital+medial 3 oligodendroglioma, order false belief (28/31
(6 L, 4 R), 3 R DL, 4 hemorrhage, 2 focal head of the patients had
3 R medial+DL, injury damage that included
1 R orbital+DL, medial and/or orbital
9 orbital+medial+DL regions; only 3 of the
(7 L, v R) patients had lesions
restricted to DLC)
Happé et al. Case P.B.: two B lesions Neurosurgery - steretotactic 19 controls; Case D.R. Story task (advanced ToM PB: impaired on all tests
(2001) to anterior limb of subcaudate tractomy to treat with history of bipolar task), single cartoon task,
internal capsule bipolar disorder. Surgery disorder cartoon pairs task
involved.
Stuss et al. 19 frontal: 8 L, Frontal and nonfrontal: 14 controls Visual perspective-taking Right and bilateral
(2001) 4 R, 7 B stroke, hemorrhage, task, deception task frontal patients: impaired
13 non-frontal: lobectomy, tumor, trauma on the second level of the
8 L, 5 R visual perspective-taking
task and
on the deception
task
Shamay- 25 frontal: 6 L, 6 R, Frontal: 19 head injury, 4 19 controls Self-report empathy scale, VM frontal
Tsoory et al. 13 B (12 VM, 6 DL, meningioma, 1 faux pas (particularly R):
(2003) 7 VM+DL) encephalomacia, 1 lower empathy
17 nonfrontal: aneurysm scores, impaired
9 L, 8 R Nonfrontal: not on faux pas test
specified
Apperly et al. 4 frontal: 1 L inferior, Frontal: 3 stroke, 1 anoxia Used chance as Nonverbal belief- Frontal: impaired, but
(2004) middle, and superior Nonfrontal: 6 stroke, criterion and 3 reasoning task with few explained by working
frontal gyri (D.S.); 1 B 2 herpes simplex controls executive demands, memory deficits; TPJ:
superior and medial encephalitis narrative-based first- impaired
frontal (F.K.), 2 R order false belief task
inferior and middle
frontal gyri and
(Continued)

superior temporal
gyrus (W.B.A., P.W.)
8 nonfrontal: 3 MTL,
1 L thalamus, 4 L TPJ
Bird et al. Case G.T.: extensive B Anterior cerebral artery Controls varied Picture sequences, Intact performance on
(2004) medial PFC/ infarction depending on task advanced ToM test, picture sequences,
orbitofrontal violation of social norms, advanced ToM, and
faux pas test, animations Animations. Some
impairment on violation
of social norms and
performed at the lower
end of controls on the
faux pas test.
Samson et al. Case W.B.A.: R inferior Stroke Used chance as Low self-perspective Intact on low-inhibition
(2005) and middle frontal criterion; 3 controls inhibition false-belief task false belief task, but
gyri extending into R (non-verbal), high scored below chance level
superior temporal self-perspective inhibition on high-inhibition task;
gyrus false-belief task, visual additional egocentric
perspective-taking test, errors on visual and
social perspective-taking social perspective-taking
test tasks relative to controls.
Shamay- 25 frontal: 6 L, 6 R, 13 Frontal: 6 hematoma, 11 17 healthy controls Sarcasm, faux pas Frontal patients
Tsoory, B (11 VM, 7 DL, contusion, 4 meningioma, (particularly R VM):
Tomer, & 7 VM+DL) 2 encephalomalacia, impaired on sarcasm and
Aharon- 17 nonfrontal: 1 aneurysm, 1 craniectomy faux pas
Peretz 9 L, 8 R Nonfrontal: 3 hematoma,
(2005) 2 contusion, 4 meningioma,
6 CVA, 1 not specified
Shamay- 26 frontal: 12 VM Frontal: 19 head injury, 13 healthy controls Second-order false belief, VM frontal (particularly
Tsoory, (1 L, 4 R, 7 B), 7 DL 5 meningioma, 1 aneurysm, detection of Irony, faux R) patients: impaired on
Tomer, (3 L,3 R, 1 B), 1 encephalomalacia pas, empathic ability irony and faux pas
Berger, et al. 7 VM+DL (2 L, 5 B) Nonfrontal: not specified (affective ToM); intact on
(2005) 13 nonfrontal second-order false belief
(9 L, 4 R) test (cognitive ToM)
Apperly et al. 4 frontal: 1 L inferior, Frontal: 3 stroke, 1 anoxia Used chance as Video-based false 3/4 frontal patients
(2007) middle and superior Nonfrontal: 4 stroke, 2 criterion photograph task failed the false belief and
frontal gyri (D.S.), 1 herpes simplex encephalitis, false photograph trials;
bilateral superior and 1 anoxia all but 1 medial frontal
medial frontal, left patient (F.K.) performed
medial frontal (F.K.), well on the inhibition
and 2 right inferior control trials. F.K. and
and middle frontal P.W. made errors on the
gyrus memory control trials.
(W.B.A. and P.W.) The other frontal patient
(W.B.A.) was above
(Continued)

8 nonfrontal: 3 MTL chance on the false belief

patients, 4 left and photograph trials,
temporal-parietal but not on one each of
patients (3 TPJ) the inhibition and
memory control trials.
Baird et al. 3 ACC patients: 2 R P1: glioma; P2: 8–15 controls Joke interpretation, P2 impaired on both
(2006) ACC (P1 and P3), 1 oligodendroglioma; P3: advanced ToM test tests; P1 and P3 showed
bilateral ACC lesion hemorrhage intact performance.
and lesions involving
the temporal lobe (P2)
Shamay- 32 frontal: 10 VM (4 L, Frontal: 23 head injury, 18 controls Cognitive and affective VM frontal patients were
Tsoory et al. 4 R, 2 B), 9 DL (3 L, 4 4 meningioma, 2 CVA, tests of: second-order impaired on the irony
(2006) R, 2B, 13 VM+DL (3 L, 1 aneurysm, 1 anaplastic false beliefs, false and detection of lies tests
7 R, 3 B) astrocytoma, 1 glioblastoma attribution, irony, and but intact on cognitive
12 nonfrontal: 5 Nonfrontal: 4 head injury, detection of lies ToM tests.
superior parietal (3 L, 4 CVA, 1 meningioma,
2R), 7 TPJ (5 L, 2 R) 1 oligodendroglioma,
1 pilocytic astrocytoma,
1 melanoma
Channon 23 frontal: 9 L, 11 R, 3 Frontal: 1 lymphoma, 8 26 controls Pragmatic comprehension Frontal: impaired on
et al. (2007) B meningioma, 2 metastasis, 1 task (control physical mentalizing tasks for
22 nonfrontal: 6 L, 16 abscess, 10 glioma, 1 events, human actions, actions and direct/indirect
R (includes 3 L TPJ/ hemangioma Nonfrontal: 4 and direct and indirect sarcasm, with greater
STS, 2 R TPJ/STS, 3 R meningioma, 1 metastasis, sarcastic remarks) involvement of lateral
MTL, 5 R MTL+TP, 1 R 15 glioma, 1 CVA, 1 frontal regions in
TP + STS) neurocytoma generating free responses
and right frontal regions,
particularly VM, in
selecting among
competing alternatives;
Posterior: unimpaired
Samson et al. Case W.B.A.: R inferior Stroke 8 controls Nosy neighbor task W.B.A.: intact on true
(2007) and middle frontal (3-option false belief task) belief conditions but
gyri extending into R poor performance on
superior temporal false belief conditions
gyrus; P.F.: L TPJ (responded based on own
perspective). P.F.: below
chance in both
conditions.
(Continued)

Shamay- 33 frontal (10 L, 17 R, Frontal: 26 head injury, 5 44 controls Cognitive and affective VM frontal patients:
Tsoory & 6 B): 10 VM, 9 DL, 14 tumor, 2 CVA tests of first- and impaired on affective
Aharon- VM+DL Nonfrontal: 8 head injury, 5 second-order mental state ToM tests; extensive
Peretz 17 nonfrontal: 11 L, 6 tumor, 4 CVA attributions (based on prefrontal damage:
(2007) R verbal and eye gaze cues), impaired on cognitive
false belief test, detection ToM tests
of cognitive and affective
irony
Note: Only studies that included patients with selective frontal lesions and that assessed ToM specifically (e.g., not empathy) were included.
Abbreviations: ToM, theory of mind; L, left; B, bilateral; DL, dorsolateral; R, right, VM, ventromedial; MTL, medial temporal lobe; TPJ, temporal-parietal junction;
PFC, prefrontal cortex; CVA, cerebrovascular accident; ACC, anterior cingulate cortex; STS, superior temporal sulcus; TP, temporal pole.
some ToM tasks are of greater affective quality than others in requiring analysis
of emotion cues inherent in the stimuli themselves and/or in generating an emo-
tional reaction in the participant, and this might determine PFC involvement,
especially ventromedial sectors.
This was noted in early work by Stuss and Benson (1983) investigating the
functional sequelae of prefrontal leucotomy compared to similar psychiatric
patients who had not received the surgery. Patients with PFC excisions demon-
strated dissociations between identifying emotions depicted in pictures of every-
day situations and the reason for selecting the emotion. Some patients focused on
unemotional aspects of the situations when providing explanations, even when
the correct emotion was chosen. Others offered inappropriate self-reflective infer-
ences, such as describing a funeral scene as happy because the patient was not the
one in the coffin. A detailed case study examining the nature of “acquired sociopa-
thy” observed in the patient J.S. included a similar measure of the ability to infer
emotionality (Blair & Cipolotti, 2000). J.S. showed significant difficulty in assign-
ing fear, anger, and embarrassment to story characters, whereas he performed
normally on a false belief test of ToM. While these earlier cases were crucial, inter-
pretation of them was limited because the leucotomized patients in Stuss and
Benson’s leucotomy series had a pre-existing psychiatric condition, different fron-
tal regions were not represented, and the anatomical localization techniques
lacked precision.
Examination of anatomical specificity in the frontal lobes based on large
patient groups with clear evidence of focal lesions has helped verify that regions
within PFC may be differentially involved in ToM depending on task demands.
Indeed, other work by Stuss and colleagues supports the view that medial lesions,
particularly on the right and possibly specific to the frontal pole, may be recruited
when cognitive–affective integration is necessary. Such patients fail to appreciate
humor (Shammi & Stuss, 1999) or realize that they are being engaged in a task of
deception in which they must point to the location opposite to one that an exper-
imenter chooses (Stuss et al., 2001). The impairment exhibited by these patients
might suggest difficulties adopting someone else’s psychological perspective when
it is emotionally significant and when personal gain is at stake.
More direct evidence comes from studies involving a modified version of the
classic false belief test of ToM that controls for comprehension difficulties and
reduces memory load while retaining first-order (“Louis thinks that . . .”) and
second-order (“Rachel thinks that Louis thinks that . . .”) levels of questioning.
Researchers have contrasted performance on this version of the false belief test,
which has been considered a “cold” test of cognitive ToM, with the faux pas test,
which has been viewed as a complementary “hot” measure of ToM that includes
an affective component (see Brothers & Ring, 1992, for further discussion of
“cold” vs. “hot” aspects of ToM). In contrast to the false belief test, participants
are asked to identify whether a character unintentionally says something hurtful
to a second character as a result of not knowing certain information that the
second character might find upsetting or insulting (Baron-Cohen et al., 1997).

Therefore, to know that a faux pas has occurred, one must integrate a false belief
representation with a feeling of empathy. A study by Stone and coworkers (1998)
was among the first to demonstrate a general division between cognitive and
more affective components in ToM reasoning in patients with lesions to dorsolat-
eral versus orbitofrontal sectors of PFC, with the former group performing with-
out error on both false belief and faux pas tests and the latter showing a selective
deficit on faux pas. This contrasts with Rowe and colleagues’ finding that patients
with dorsolateral, orbital, and medial PFC lesions are equally impaired on false
belief tests (Rowe et al., 2001), but there is a suggestion that this finding might
reflect nonspecific pathology (Bird et al., 2004). Indeed, Shamay-Tsoory and col-
leagues reached conclusions similar to those of Stone and associates in a series of
studies that contained larger groups of patients with lesions to ventromedial or
dorsolateral PFC, or to both regions. Their work shows that ToM tests with an
added affective component, such as the faux pas test as well as a detection of irony
test (Shamay-Tsoory et al., 2003), a novel test based on verbal and eye gaze cues,
and even an affective version of the false belief test (Shamay-Tsoory & Aharon-
Peretz, 2007), are particularly vulnerable to ventromedial PFC lesions, and that
performance on such tests is correlated with scores on separate empathy scales.
Unlike the results reported by Rowe and colleagues, however, there was no evi-
dence of impaired first- or second-order false belief judgments in either patient
group, suggesting that attributions of emotional and cognitive states may be
separable.
Overall, these findings suggest that attributions of affective mental states are
particularly sensitive and possibly specific to ventromedial PFC function.
Convergent support is garnered from fMRI studies showing preferential engage-
ment of orbitofrontal/ventromedial PFC areas during affective versus cognitive
perspective-taking (Hynes, Baird, & Grafton, 2006) and a recent repetitive tran-
scranial magnetic stimulation (rTMS) study showing accelerated reaction times
on a cognitive, but not affective, test of ToM following stimulation of the right
dorsolateral PFC (Kalbe et al., 2010). By contrast, non-affective tests of mental
state attribution, such as the false belief test, do not appear to be associated with
ventromedial PFC function and, instead, appear to rely on the TPJ. It is on this
basis that the TPJ is considered by some as a ToM module (cf. Young et al., 2010;
Mitchell, 2008).
However, most neuroimaging studies that speak to this question have exam-
ined cognitive versus affective dissociations only indirectly, instead focusing on
affective mental state attributions of the self versus other people (e.g., Mitchell
et al., 2006; Ochsner et al., 2004; reviewed below) or on empathy (e.g, Carr et al.,
2003; Lam, Meltzoff, & Decety, 2010; for reviews, see Amodio & Frith, 2006;
Olsson & Ochsner, 2008; Singer & Lam, 2009). The picture is further complicated
by findings that damage to orbitofrontal/ventromedial PFC regions impairs emo-
tional control (Olsson & Ochsner, 2008) as well as attention or adherence to social
knowledge (Blair & Cipolotti, 2000), as mentioned above. Damage to orbitofron-

tal cortex in particular also impairs reward/risk value judgments (Bechara et al.,
1994, 1997; Damasio, 1994; Eslinger & Damasio, 1985; Rolls, 1996). Balancing
reward and risk requires computation of one’s own needs and feelings now versus
later, which may require mental time travel to simulate one’s own future mental
states, itself a form of ToM (Buckner & Carroll, 2007). As mentioned earlier, it has
been suggested that this subjective awareness of remembering the past, intro-
specting or experiencing the present, and imagining the future (autonoetic con-
sciousness) depends on frontal lobe function (Stuss et al., 2005; Wheeler et al.,
1997). Temporal lobe regions, including the temporal poles (TPs), amygdala, and
hippocampus, may provide the necessary input to make these affective, associa-
tive, and experiential-based computations possible.
Posterior Contributions to ToM

The specific role of the medial PFC in ToM has been questioned (Bird et al., 2004;
Saxe et al., 2004), despite real-world impairment described in some patients with
relatively focal lesions (Stuss & Alexander, 1999). It has been suggested that sev-
eral posterior brain regions may serve as specialized ToM modules. As discussed
below, however, even if these regions are proven to be critical to ToM, their func-
tion is not necessarily specific to it and may be determined by the processing
demands or social-perceptual information that is available in the task in question
(see Adolphs, 2009, and Stone & Gerrans, 2006, for related ideas). Posterior func-
tions implicated in ToM include associative social knowledge associated with the
anterior temporal lobes (Olson, Plotzker, & Ezzyat, 2007), emotion processing
associated with the amygdala (Heberlein & Adolphs, 2004), the ability to perceive
biological motion and eye gaze, associated with the TPJ/posterior-superior tem-
poral sulcus (pSTS; Gobbini et al., 2007; Saxe & Kanwisher, 2003), and past per-
sonal experiences that may be recombined into simulated experiences or that
enable self-projection, drawing on hippocampal function (discussed in the next
section; Buckner & Carroll, 2007; Gallagher & Frith, 2003; Hassabis et al., 2007).
Suggestion that the anterior temporal lobes, amygdala, and TPJ/pSTS play
major roles in ToM is largely based on findings from neuroimaging (Castelli,
Happé, Frith, & Frith, 2000; Frith & Frith, 2003; Gobbini et al., 2007; Ross &
Olson, 2010; Saxe et al., 2004; Simmons, Reddish, Bellgowan, & Martin, 2010),
with some support from case studies (Heberlein & Adolphs, 2004; Samson et al.,
2004; Stone et al., 2003). The anterior temporal lobes, and TPs more specifically,
believed by some to serve as a “semantic hub” in representing conceptual knowl-
edge and scripts (e.g., Rogers et al., 2004), are also consistently activated in stud-
ies of ToM based on a wide range of tasks (Frith & Frith, 2003; Olson et al., 2007).
Recent fMRI studies have supported the idea that this region plays a more special-
ized “social semantic” role. Ross and Olson (2010) found an overlapping anterior
temporal lobe region that responds to both social attribution in the Animations
task and lexical decisions of abstract social versus non-social words, as well as to
narratives, but only those with ToM content. In a separate study, Simmons and
colleagues (2010) found an area of the anterior temporal lobe that was sensitive
to encoding facts about unfamiliar people but not non-social entities and, based
on resting-state functional connectivity analysis, formed a network with other
brain regions previously implicated in social reasoning. These ideas could be tested
further in patients with anterior temporal lobe damage, such as those diagnosed
with semantic dementia, the temporal variant of frontotemporal dementia. The
amygdala has also enjoyed a special status in social cognition due to its widely
accepted role in processing emotion from faces, which can reliably signal another
person’s mental state (Adolphs, 2009). Involvement in social behavior toward
others and reward learning that parallels involvement of orbitofrontal cortex to
which it is strongly interconnected, as well as in disorders such as schizophrenia
and autism, which are known for compromised ToM, suggest further links
between amygdala function and ToM. A few studies have documented deficits in
social attribution in patients with early-onset amygdala lesions (Fine, Lumbsden,
& Blair, 2001) and bilateral amygdala lesions incurred later in life (Heberlein &
Adolphs, 2004; Stone et al., 2003) on ToM tasks, including narrative-based and
animated shapes tests that do not require the processing of facial expression.
Other researchers have suggested that the TPJ is selectively involved in repre-
senting other people’s beliefs (e.g., Gobbini et al., 2007; Samson et al., 2004; Saxe
et al., 2004), a role that had been previously assigned to medial PFC (Rowe et al.,
2001; Siegal & Varley, 2002) and reassigned to more lateral regions (e.g., Stone
et al., 1998). Saxe and colleagues identified a region of right TPJ that responds
preferentially to representing others’ mental states in false belief stories but not
to physical representations in stories associated with a map or photograph. This
region’s activity appears to be dissociable from an adjacent region of right pSTS,
which is activated maximally in response to inferring intentions of animated tri-
angles based on their movement (Gobbini et al., 2007) and has also been impli-
cated in processing gaze direction (e.g., Hoffman & Haxby, 2000), providing
additional information about others’ emotion and intent. Patient studies have
identified the left TPJ as the critical site for false belief attribution and have
accounted for the additional possibility that impaired performance on false belief
tasks is also due to a failure to inhibit one’s own privileged knowledge of the cor-
rect location by controlling for both types of executive demands (see Apperly,
Samson, Chiavarino, & Humphreys, 2004; Samson et al., 2004, 2005), but per-
haps not for spatial attention (cf. Mitchell, 2008; Young et al., 2010). These stud-
ies concur with other patient studies in showing that impaired false belief
reasoning in patients with frontal lesions may be explained by deficits in execu-
tive functions (Apperly et al., 2004) and that performance on Animations tests of
ToM might not depend on frontal lobe function at all (Bird et al., 2004). However,
these findings may speak more to the validity of the false belief and Animations
tests as measures of ToM, as visual spatial attention and biological motion pro-
cessing, respectively, may be more important to performance on these particular
tests of mental state reasoning (Zackheim et al., 2009).
Finally, patient studies show that lesions to the TP and TPJ are associated with
intact performance on ToM tests with an affective component (Channon et al.,
2007; Hynes & Mar, 2008; Shamay-Tsoory et al., 2006). There is also evidence
that deficits on a non-affective, non-verbal false belief task observed in patients
with TPJ lesions are not actually specific to ToM and apply to physical meta-
representations on a false photograph test, which does not require belief reason-
ing (Apperly et al., 2007). Likewise, impairment in patients with acquired amygdala
lesions does not appear to be unique to ToM and may be due to a more basic
impairment in processing facial emotion (Shaw et al., 2007). In sum, these regions
may provide the mPFC with the necessary input for deciphering other people’s
minds based on processing demands and perceptual cues that are idiosyncratic to
the task at hand. However, none of these regions plays a specific role in ToM, nor
is any region sufficient to support mental state inferences on its own, calling into
question a modular view of ToM. Here, we support the view that ToM emerges
through an interplay of multiple regions that form a network. Recruitment of at
least some of these regions is due to idiosyncratic task demands that may be inci-
dental to ToM, whereas other regions play an essential, though nonspecific, role
in mental state attributions in relation to the self and to other people.
Correspondence of “Self” and “Other”

in Mental State Attributions
Examination of dissociations in performance in focal lesion patients has indicated
that the medial PFC is critical to ToM and that its involvement may depend on the
affective quality of an attribution. Theories of how the human brain makes sense
of its social world by constructing a ToM have also pointed to the relationship
between ToM and mental state attributions relating to the self, with much of this
research influenced by debate about simulation as the basis for ToM.
Functional neuroimaging studies have shown that representations of current
mental states relating to the self and to other people share common underlying
mechanisms governed by regions of medial PFC. A common network of anterior
and posterior regions emerges across studies, with medial PFC as a key shared
region. Identification of a neural substrate common to representations of “self”
and “other” encouraged several investigators to directly examine mental state
attributions relating to oneself and to other people using fMRI. In one such study,
participants were scanned as they imagined themselves or other people acting as
characters described in story vignettes (Vogeley et al., 2001). Medial and right
lateral PFC were activated regardless of whether participants took their own per-
spective or someone else’s perspective when judging the story character’s actions
or intentions. In a more recent investigation, a dorsal polar region of medial PFC

was identified as a common area of activation for self- and other-focused infer-
ences relating to emotional scenes (Ochsner et al., 2004). Recruitment of addi-
tional regions of medial PFC in the “self” condition (including anterior cingulate)
and lateral PFC in the “other” condition might reflect processing demands specific
to “mentalizing” about internally versus externally generated information, respec-
tively. Consistent with these finding, Mitchell and colleagues (2006) found fur-
ther dissociations within the medial PFC area in ToM according to the perceived
similarity of participants to the agents whose mental states they were assuming
(see below).
In a parallel line of research, there is a growing body of data to suggest that the
brain regions supporting autobiographical memory share a functional and neural
substrate with other non-mnemonic abilities, including future imagining, ToM,
certain forms of navigation, and the default network (Buckner & Carroll, 2007;
Hassabis et al., 2007; Spreng et al., 2009). These regions include the hippocampus
and related medial temporal lobe structures, medial PFC, anterior cingulate
cortex, posterior cingulate/retrosplenial cortex, precuneus, TP, and TPJ. In addi-
tion to a shared neuroanatomical substrate, theories have been advanced that
argue for an analogical reasoning component to ToM in which one draws on a
personal repertoire of past events in order to infer another person’s current
mental state (Gallagher & Frith, 2003). In addition, awareness of one’s own and
other people’s minds requires the abstraction or imagining of imperceptible
mental states that do not lend themselves to physical inspection.
Autobiographical memory and future episodic imagining have been directly
compared within the same neuroimaging studies (Addis, Wong, & Schacter, 2007;
Okuda et al., 2003; Szpunar et al., 2007) and have been found to be impaired
together in amnesic patients (Hassabis et al., 2007; Klein et al., 2002; Rosenbaum
et al., 2009; Tulving, 1985). Until recently, however, evidence for a shared brain
network underlying autobiographical memory and ToM had been based on com-
parisons of independent neuroimaging studies investigating one ability or the
other. Moreover, these surveys have typically focused on common brain regions,
paying little or no attention to areas of unique activity. To address this issue, we
adapted a paradigm that enabled direct comparisons between autobiographical
memory (AM) and ToM as participants reconstructed their own mental states, or
imagined those of others (i.e., strangers), while viewing family photographs
during fMRI scanning (Rabin et al., 2010). In this way, AM and ToM conditions
were closely matched, such that the only difference between the two was the
perspective from which the event was re-experienced or imagined (i.e., self
for AM and other person for ToM). It was also the case that the events depicted in
the photos were not inherently emotional, as confirmed by the narratives pro-
duced by participants. As predicted by surveys of the separate AM and ToM litera-
tures, results indicated extensive neural overlap of AM and ToM during event
construction (i.e., search phase of an event) and elaboration (i.e., expanding on
event details), though differences in the strength and extent of activations within
areas of convergence did emerge. Specifically, during the elaboration phase, medial
frontal, medial and lateral temporal, and medialparietal lobe regions were engaged
during both AM and ToM. However, midline structures, including the medial PFC,
were activated to a greater extent during AM, whereas lateral frontal and tempo-
ral-parietal regions showed greater activity during ToM (see Spreng & Grady,
2010, for similar findings). Notably, an interesting dissociation emerged within
the medial PFC, with a more ventral pattern of activity associated with AM and a
more dorsal pattern associated with ToM (Fig. 7.1). These findings are consistent
with work by Mitchell and colleagues (Mitchell et al., 2005, 2006), who have found
that more ventral regions predominate during tasks that involve self-referential
processing, whereas more dorsal regions are involved when inferring the contents
of other people’s minds, particularly when the other person is perceived as
dissimilar from the self (see also Olsson & Ochsner, 2008). These researchers
suggest that when inferring the minds of similar others, we are more likely to
employ self-referential strategies and as a result engage more ventral regions of
the medial PFC.
Preliminary data from our lab extend these findings to mentalizing about
known others with whom we are familiar (Rabin & Rosenbaum, 2010). These find-
ings are based on an adapted version of the paradigm used by Rabin and colleagues
(2010) that includes a personal ToM condition involving familiar others (i.e., rela-
tives and close friends). In this study, we directly compared AM with personal
ToM and AM with ToM that involved unfamiliar people (impersonal others), and
found that activity within the medial PFC and posterior midline regions was
greatly diminished during the former comparison relative to the latter compari-
son. This finding indicates that there is greater functional overlap between AM
and inferring the mental states of familiar others relative to unfamiliar others.
These results are consistent with simulation accounts of social cognition and
A AM B ToM
Baseline Baseline
AM vs. Baseline ToM vs. Baseline
Figure 7.1. Sagittal slices of the left hemisphere illustrating the brain regions engaged
during (A) AM detail elaboration versus baseline and (B) ToM detail elaboration versus
baseline. Images are at a threshold of p < 0.005. The functional maps are overlaid on
the average anatomical image from all participants. Activations shown include areas
>120 mm3. (See Color Plate Section for a color version of this figure.)
AM vs. impersonal ToM

A AM
L L R Impersonal
ToM
AM vs. personal ToM
B
AM
L L R Personal
ToM
Personal ToM vs. impersonal ToM
C Personal
ToM
L L R
Impersonal
ToM
Figure 7.2. Axial and sagittal slices illustrating common brain regions engaged during
(A) AM versus impersonal ToM, (B) AM versus personal ToM, and (C) personal ToM
versus impersonal ToM. All images are at a threshold of p < 0.005. The functional maps
are overlaid on the average anatomical image from all participants. Activations shown
include areas >120 mm3. Images follow neurological convention (left side of the brain is
presented on the left). (See Color Plate Section for a color version of this figure.)
suggest that ToM tasks that involve people with whom we can relate may draw on
the same neural and functional resources as AM. Interestingly, when we compared
the two ToM conditions, we observed significant differences, which was remark-
able considering that the conditions differed only with respect to one’s familiarity
with the target person in the photo. The medial PFC was engaged to a greater
extent when inferring another person’s mental state in the personal ToM condi-
tion relative to the impersonal ToM condition, whereas lateral regions including
the left ventrolateral PFCextending into premotor regions and left TPJ showed
the opposite pattern, with greater activity during impersonal ToM (Fig. 7.2).
The results from Rabin and colleagues (2010) and Rabin and Rosenbaum
(2010) may be explained in terms of broader core processes, namely those that are
internally versus externally focused (Lieberman, 2007; Olsson & Ochsner, 2008).
Internally focused processes, typically supported by midline regions, involve
focusing one’s attention on interior psychological worlds, including one’s own or
another’s mental state. Therefore, the greater midline activity observed during
AM and personal ToM relative to impersonal ToM is likely due to greater personal
significance or episodic richness in relation to mentalizing about ourselves and
familiar others relative to unfamiliar people. In contrast, lateral regions are asso-
ciated with more externally focused processes that focus on one’s own or anoth-
er’s visible features and actions. The greater lateral activity observed across the
brain during impersonal ToM relative to personal ToM and AM suggests that
when inferring unfamiliar minds, we focus more on interpreting actions and gen-
erating semantic narratives compared to when we think about ourselves and
people with whom we can easily relate. It also leaves open the possibility that a
mirror neuron system, which is involved in imitation and is believed to include
ventrolateral and premotor frontal regions and inferior parietal cortex adjacent to
TPJ (Gallese et al., 2004; Iacoboni, 2009), may be involved in generic forms of
ToM. However, this system is unlikely to serve as the basis of simulation pro-
cesses that underlie personal ToM and empathy (Saxe, 2005). There is additional
debate about whether the “mirror neuron” regions identified in humans meet the
criteria of a mirror neuron system as defined by Gallese and colleagues (Lingnau
et al., 2009) or whether it is even capable of representing internal mental states.
A Theoretical Framework for ToM

Based on the preceding review, we support a theoretical model that builds on sev-
eral recent frameworks, including those proposed by Amodio and Frith (2006),
Lieberman (2007), Mitchell and colleagues (2006), Olson and colleagues (2007),
Olsson and Ochsner (2008), and Stone and Gerrans (2006), among others. Taken
together, these models place the medial PFC, and possibly the TPs, at the core of
ToM, but do not view ToM as modular. We suggest that additional brain regions
that are peripheral to ToM are recruited depending on the processing demands
and social-perceptual cues that are involved in the ToM task in question (Fig. 7.3).
In other words, poor performance on a given ToM task may not necessarily reflect
a ToM deficit, but rather impairment in a more specific process that is necessary
for task performance (e.g., eye gaze, working memory, spatial attention). This is
not to suggest that the medial PFC and TPs are domain-specific ToM modules, but
rather that they play a crucial role in ToM, among other abilities. Finally, this
model suggests that there are multiple routes to ToM: the particular strategy that
is adopted and the neural network recruited may depend on one’s current goals,
the information/cues or processing resources available, one’s past experiences, etc.
Given the early stages of research in this area, it is possible that future work,
particularly with patients, will lead to modifications of the current model. We pro-
pose several key questions and areas of research that will be particularly informa-
tive. First, we suggest that future efforts focus on developing and testing patients
on more ecologically valid and sensitive measures of ToM that can predict real-life
impairment, such as the family photos test described earlier. This will help to
Cognitive processes
a) Reflective
Spatial/visual attention
TPJ
b) Extemally
generated Action/eye gaze
pSTS
Dorsomedial PFC processes
Online semantic processing
VLPFC
c)
d)
Frontal poles
Associative social knowledge
TPs
Medial
Executive ToM
PFC Working memory
demands
DLPFC
Ventromedial
PFC
Affective processes
Emotion processing
Orbitofrontal Amygdala
b) Internally
cortex
generated
processes Simulation/experiential
Hippocampus
a) Stimulus-driven
Figure 7.3. A diagram illustrating the brain regions and processes involved in ToM
abilities. The brain regions depicted in blue boxes are viewed as domain-general and
necessary for ToM. Regions depicted in green boxes are believed to be recruited based
on task-specific processing demands and social-perceptual cues and are neither
necessary nor sufficient for ToM. (a) Dorsal regions (dorsomedial PFC) support
reflective and cognitive processes and are preferentially engaged when mentalizing
about dissimilar others. In contrast, ventral regions (e.g., orbitofrontal cortex and
ventromedial PFC) predominately support stimulus-driven and affective processes and
are engaged when mentalizing about the self and similar others (Amodio & Frith, 2006;
Mitchell et al., 2006; Olsson & Ochsner, 2008). (b) Lateral regions (TPJ, pSTS) support
externally generated processes associated with non-affective mental state reasoning
about false beliefs. In contrast, posterior midline regions (amygdala, hippocampus)
underlie more internally generated processes and are associated with affective and
experiential-based ToM reasoning (Lieberman, 2007; Olsson & Ochsner, 2008).
(c) The frontal poles are recruited for integration along the various axes and are viewed
as necessary, but not specialized, for ToM (e.g., Burgess et al., 2007). (d) The TPs are
part of a neural network that support ToM by recruiting social semantic knowledge
and scripts necessary for understanding the minds of others. Abbreviations: DLPFC,
Dorsolateral prefrontal cortex; L., left; pSTS, posterior superior temporal sulcus;
PFC, prefrontal cortex; TPJ, temporal-parietal junction; TPs, temporal poles;
VLPFC, ventrolateral prefrontal cortex.
144
determine whether the medial PFC and TPs are indeed necessary for ToM. Second,
it is unknown whether the TPs are necessary for both the development of ToM
and “online” ToM performance. It is possible that lesions to the TPs acquired later
in life do not affect associative social knowledge or ToM; perhaps it is only when
damage occurs congenitally or early in life that these abilities are impaired (see
Shaw et al., 2004, 2007, for similar ideas on the amygdala). Third, laterality effects
need to be examined more closely, particularly within the TPJ and TP regions.
This issue is beyond the scope of the current chapter and thus not included in the
model. Finally, future research might address how the entire network would
respond when a single region is lesioned. Combining patient work with fMRI
using ecologically valid paradigms will allow us to examine how the network might
be disrupted and/or reorganized following damage.
Conclusions
Prominent debate in the field of cognitive neuroscience surrounds content-
versus process-oriented organization of brain function. For example, findings of
hippocampal involvement in functions ranging from autobiographical episodic
memory and future imagining, as reviewed above, to perception and working
memory have indicated that the traditional “hippocampus as a memory module”
view is far too restrictive. Conversely, the functional role of other parts of the
brain, such as posterior parietal cortex, perhaps best known for its contributions
to visual attention and egocentric spatial cognition, is now being redefined based
on complementary fMRI and patient findings of parietal involvement in episodic
recollection (Cabeza et al., 2008; Simons et al., 2010). So, too, brain regions impli-
cated in ToM must be considered more broadly in terms of their processing capac-
ities and not as isolated, domain-specific, structures nor as all-encompassing,
capable of all things relating to mental state inferences (see also Stone & Gerrans,
2006). Identifying a region’s functional properties is a necessary first step, far
from trivial. Of equal importance, however, is determining how that region fits
into the bigger picture as part of a functional network, and how it relates to other
regions within that network. Don’s work in mapping function to discrete regions
of the frontal lobes has helped clear the path to investigating pathways, which
Don himself continues to pursue in this new, exciting chapter in his career as a
frontal lobe scientist and clinician.
Acknowledgments
This work was funded by a Canadian Institutes of Health Research (CIHR) New
Investigator Award and Operating Grant (MOP 93535) to R.S.R. and a CIHR
Banting and Best Doctoral Award to J.S.R.
References
Addis, D. R., Wong , A. L., & Schacter, D. L . (2007). Remembering the past and imagining the
future: common and distinct neural substrates during event construction and elaboration.
Neuropsychologia, 45, 1363–1377.
Adolphs, R . (2009). The social brain: neural basis of social knowledge. Annual Review in Psychology,
60, 693–716.
Alexander, M. P., Stuss, D. T., & Benson, D.F. (1979). Capgras syndrome: a reduplicative phenom-
enon. Neurology, 29, 334–339.
Amodio, D. M., & Frith, C. D. (2006). Meeting of minds: the medial frontal cortex and social cogni-
tion. Nature Reviews Neuroscience, 7, 268–277.
Apperly, I. A., Samson, D., Chiavarino, C., & Humphreys, G. W. (2004). Frontal and temporo-
parietal lobe contributions to theory of mind: neuropsychological evidence from a false-belief
task with reduced language and executive demands. Journal of Cognitive Neuroscience, 16,
1773–1784.
Apperly, I. A., Samson, D., Chiavarino, C., Bickerton, W. L., & Humphreys, G. W. (2007). Testing the
domain-specificity of a theory of mind deficit in brain-injured patients: evidence for consis-
tent performance on non-verbal, “reality-unknown” false belief and false photograph tasks.
Cognition, 103, 300–321.
Baird, A., Dewar, B. K., Critchley, H., Dolan, R., Shallice, T., & Cipolotti, L . (2006). Social and emo-
tional functions in three patients with medial frontal lobe damage including anterior cingu-
late cortex. Cognitive Neuropsychiatry, 11(4), 369–388.
Baron-Cohen, S. (1995). Mindblindness: an essay on autism and theory of mind. Cambridge, MA: MIT
Press.
Baron-Cohen, S., Jolliffe, T., Mortimore, C., & Robertson, M. (1997). Another advanced test of
theory of mind: evidence from very high functioning adults with autism or Asperger syn-
drome. Journal of Child Psychology and Psychiatry, 38, 813–822.
Baron-Cohen, S., Leslie, A., & Frith, U. (1985). Does the autistic child have a theory of mind.
Cognition, 21, 37–46.
Bechara, A., Damasio, A. R., Damasio, H., & Anderson, S.W. (1994). Insensitivity to future conse-
quences following damage to human prefrontal cortex. Cognition, 50, 7–15.
Bechara, A., Damasio, H., Tranel, D., & Damasio, A. R . (1997). Deciding advantageously before
knowing the advantageous strategy. Science, 275, 1293–1295.
Bird, C. M., Castelli, F., Malik, O., Frith, U., & Husain, M. (2004). The impact of extensive medial
frontal lobe damage on “theory of mind” and cognition. Brain, 127, 914–928.
Blair, R. J., & Cipolotti, L . (2000). Impaired social response reversal: a case of “acquired sociopathy.”
Brain, 123, 1122–1141.
Brothers, L., & Ring , B. (1992). A neuroethological framework for the representation of minds.
Buckner, R. L., & Carroll, D. C. (2007). Self-projection and the brain. Trends in Cognitive Neuroscience,
11, 49–57.
Bull, R., Phillips, L.H., & Conway, C.A . (2008). The role of control functions in mentalizing: dual-
task studies of theory of mind and executive function. Cognition, 107, 663–672.
cortex (area 10) function. Trends in Cognitive Sciences, 11, 290–298.
Cabeza, R . (2008). Role of parietal regions in episodic memory retrieval: the dual attentional pro-
cesses hypothesis. Neuropsychologia, 46, 1813–1827.
Carr, L., Iacoboni, M., Dubeau, M.C., Mazziotta, J. C., & Lenzi, G. L . (2003). Neural mechanisms of
empathy in humans: A relay from neural systems for imitation to limbic areas. Proceedings of
the National Academy of Sciences, USA, 100, 5497–5502.
Castelli, F., Happé, F., Frith, U., & Frith, C. (2000). Movement and mind: a functional imaging study
of perception and interpretation of complex intentional movement patterns. NeuroImage, 12,
314–325.
Channon, S., & Crawford, S. (2000). The effects of anterior lesions on performance on a story com-
prehension test: left anterior impairment on a theory of mind-type task. Neuropsychologia,
38, 1006–1017.
Channon, S., Rule, A., Maudgil, D., Martinos, M., Pellijeff, A., Frankl, J., Drury, H., & Shieff, C.
(2007). Interpretation of mentalistic actions and sarcastic remarks: effects of frontal and pos-
terior lesions on mentalising. Neuropsychologia, 45, 1725–1734.
Charlton, R. A., Barrick, T. R., Markus, H. S., & Morris, R. G. (2009). Theory of mind associations
with other cognitive functions and brain imaging in normal aging. Psychology and Aging, 24,
338–348.
Corbetta, M., Patel, G., & Shulman, G. L. (2008). The reorienting system of the human brain: From
environment to theory of mind. Neuron, 58, 306–324.
Damasio, A. (1994). Descartes’ Error: Emotion, Reason and the Human Brain. New York: Grosset.
Damasio, H., Grabowski, T., Frank, R., Galaburda, A. M., Damasio, A. R. (1994). The return of Phineas
Gage: Clues about the brain from the skull of a famous patient. Science, 264, 1102–1105.
Decety, J., & Lamm, C. (2007). The role of the right temporoparietal junction in social inter-
action: how low-level computational processes contribute to meta-cognition. Neuroscientist,
13, 580–593.
Eslinger, P. J., & Damasio, A. R . (1985). Severe disturbance of higher cognition following bilateral
frontal lobe ablation: Patient EVR . Neurology, 35, 1731–1741.
Fine, C., Lumsden, J., & Blair, R. J. R . (2001). Dissociation between “theory of mind” and executive
functions in a patient with early left amygdala damage. Brain, 124, 287–298.
Frith, C. D., & Frith, U. (2003). Development and neurophysiology of mentalizing. Philosophical
Transactions of the Royal Society B: Biological Sciences, 358, 459–473.
Gallagher, H. L., & Frith, C. D. (2003). Functional imaging of “theory of mind.” Trends in Cognitive
Science, 7, 77–83.
Gallese, V., Keysers, C., & Rizzolatti, G. (2004). A unifying view of the basis of social cognition.
Trends in Cognitive Sciences, 8, 396–403.
Gilboa, A . (2004). Autobiographical and episodic memory—one and the same? Evidence from
prefrontal activation in neuroimaging studies. Neuropsychologia, 42, 1336–1349.
Gilboa, A., Alain, C., Stuss, D. T., Melo, B., Miller, S., & Moscovitch M. (2006). Mechanisms of
spontaneous confabulations: a strategic retrieval account. Brain, 129, 1399–1414.
Gobbini, M. I., Koralek, A. C., Bryan, R. E., Montgomery, K. J., & Haxby, J. V. (2007). Two takes on
the social brain: a comparison of theory of mind tasks. Journal of Cognitive Neuroscience, 19,
1803–1814.
Goldstein, K . (1944). The mental changes due to frontal lobe damage. Journal of Psychology,
17, 187.
Happé, F., Malhi, G. S., & Checkley, S. (2001). Acquired mind-blindness following frontal lobe sur-
gery? A single case study of impaired “theory of mind” in a patient treated with stereotactic
anterior capsulotomy. Neuropsychologia, 39, 83–90.
Hassabis, D., Kumaran, D., Vann, S. D., & Maguire, E. A . (2007). Patients with hippocampal amnesia
cannot imagine new experiences. Proceedings of the National Academy of Sciences, USA, 104,
1726–1731.
Heberlein, A. S., & Adolphs, R . (2004). Impaired spontaneous anthropomorphizing despite intact
perception and social knowledge. Proceedings of the National Academy of Sciences, USA, 101,
7487–7491.
Hoffman, E. A., & Haxby, J. V. (2000). Distinct representations of eye gaze and identity in the dis-
tributed human neural system for face perception. Nature Neuroscience, 3, 80–84.
Hynes, C.A., Baird, A. A., & Grafton, S. T. (2006). Differential role of the orbital frontal lobe in
emotional versus cognitive perspective-taking. Neuropsychologia, 44, 374–383.
Hynes, C. A., & Mar, R. A . (2008). A case study of long-term cognitive and social functioning follow-
ing a right temporal lobectomy in infancy. Neurocase, 15, 37–46.
Iacoboni, M. (2009). Understanding others: imitation, language, empathy. In S. Hurley & N. Chater
(Eds.), Perspectives on imitation: from cognitive neuroscience to social science (pp. 77–100).
Kalbe, E., Schlegel, M., Sack, A. T., Nowak, D. A., Dafotakis, M., Bangard, C., Brand, M., Shamay-
Tsoory, S. G., Onur, O. A., & Kessler, J. (2010). Dissociating cognitive from affective theory of
mind: a TMS study. Cortex, 46, 769–780.
Klein, S. B., Loftus, J., & Khilstrom, J. F. (2002). Memory and temporal experience: The effects of
episodic memory loss on an amnesic patient’s ability to remember the past and imagine the
future. Social Cognition, 20, 353–379.
Kleist, K . (1934). Kriegverletzungen des Gehirns in ihrer Bedeutung für Hirnlokalisation und
Hirnpathologie. Leipzig: Barth.
Lamm, C., Meltzoff, A. N., & Decety, J. (2010). How do we empathize with someone who is not like
us? Journal of Cognitive Neuroscience, 2, 362–376.
Leslie, A. M. (1992). Pretense, autism, and the theory-of-mind module. Current Directions in
Psychological Science, 1(1), 18–21.
Levine, B., Black, S. E., Cabeza, R., Sinden, M., McIntosh, A. R., Toth, J. P., Tulving , E., & Stuss,
D. T. (1998). Episodic memory and the self in a case of retrograde amnesia. Brain, 121,
1951–1973.
Levine, B., Stuss, D. T., & Milberg , W. P. (1997). Effects of aging on conditional associative learning:
process analyses and comparison with focal frontal lesions. Neuropsychology, 11, 367–381.
Levine, B., Svoboda, E., Turner, G. R., Mandic, M., & Mackey, A. (2009). Behavioral and functional
neuroanatomical correlates of anterograde autobiographical memory in isolated retrograde
amnesic patient M. L. Neuropsychologia, 47, 2188–2196.
Lieberman, M. D. (2007). Social cognitive neuroscience: a review of core processes. Annual Review
of Psychology, 58, 259–289.
Lingnau, A., Gesierich, B., & Caramazza, A . (2009). Asymmetric fMRI adaptation reveals no evi-
dence for mirror neurons in humans. Proceedings of the National Academy of Sciences, USA,
106, 9925–9930.
Luria, A. R . (1973). The frontal lobes and the regulation of behavior. In K. H. Pribram & A. R. Luria
(Eds.), Psychophysiology of the frontal lobes (pp. 3–26). New York: Academic Press.
Macmillan, M. (2000). Nineteenth-century inhibitory theories of thinking: Bain, Ferrier, Freud
(and Phineas Gage). History of Psychology, 3, 187–217.
McDermott, K. B., Szpunar, K. K., & Christ, S. E. (2009). Laboratory-based and autobio-
graphical retrieval tasks differ substantially in their neural substrates. Neuropsychologia, 47,
2290–2298.
Meyer, A., & Beck, E. (1945). Neuropathological problems arising from prefrontal leucotomy.
Journal of Mental Science, 91, 411–425.
Milner, B. (1964). Some effects of frontal lobectomy in man. In J. M. Warren & K. Akert (Eds.), The
frontal granular cortex and behavior (pp. 313–334). New York: McGraw-Hill.
Mitchell, J. P. (2008). Activity in right temporo-parietal junction is not selective for theory-of-
mind. Cerebral Cortex, 18, 262–271.
Mitchell, J. P., Banaji, M. R., & Macrae, C. N. (2005). The link between social cognition and self-
referential thought in the medial prefrontal cortex. Journal of Cognitive Neuroscience, 17,
1306–1315.
Mitchell, J. P., Macrae, C. N., & Banaji, M. R . (2006). Dissociable medial prefrontal contributions to
judgments of similar and dissimilar others. Neuron, 50, 655–663.
Moscovitch, M. (1995). Recovered consciousness: a hypothesis concerning modularity and episodic
memory. Journal of Clinical and Experimental Neuropsychology, 17, 276–291.
Moscovitch, M., & Winocur, G. (1992). The neuropsychology of memory and aging. In F. I. M. Craik
& T. A. Salthouse (Eds.), The handbook of aging and cognition (pp. 315–372). Hillsdale, NJ:
Erlbaum.
Moscovitch, M., & Winocur, G. (2002). The neuropsychology of memory and aging. In D. T. Stuss
& R. T. Knight (Eds.), Principles of frontal lobe function (pp. 188–209). New York: Oxford
University Press.
Ochsner, K. N., Knierim, K., Ludlow, D. H., Hanelin, J., Ramachandran, T., Glover, C., & Mackey, S.
C. (2004). Reflecting upon feelings: an fMRI study of neural systems supporting the attribu-
tion of emotion to self and other. Journal of Cognitive Neuroscience, 16, 1746–1772.
Okuda, J., Fujii, T., Ohtake, H., Tsukiura, T., Tanji, K., Suzuki, K., Kawashima, R., Fukuda, H., Itoh,
M., & Yamadori, A . (2003). Thinking of the future and past: the roles of the frontal pole and
the medial temporal lobes. NeuroImage, 19, 1369–1380.
Olson, I. R., Plotzker, A., & Ezzyat, Y. (2007). The enigmatic temporal pole: a review of findings on
social and emotional processing. Brain, 130, 1718–1731.
Olsson, A., & Ochsner, K. N. (2008). The relationship between emotion and social cognition. Trends
in Cognitive Science, 12, 65–71.
Owen, A. M., Roberts, A.C., Polkey, C. E., Sahakian, B. J., & Robbins T. W. (1991). Extradimensional
versus intradimensional set shifting performance following frontal lobe excisions, temporal
lobe excisions or amygdalohippocampectomy in man. Neuropsychologia, 29, 993–1006.
Rabin, J. S., Gilboa, A., Stuss, D. T., Mar, R. A., & Rosenbaum, R. S. (2010). Common and unique
neural correlates of autobiographical memory and theory of mind. Journal of Cognitive
Rabin, J. S., & Rosenbaum, R. S. (2010). Degree of familiarity with situations and people influences the
functional overlap between theory of mind and autobiographical memory. Paper presented at the
17th Annual Cognitive Neuroscience Society Meeting , Montreal, QC.
Rogers, T. T., Lambon Ralph, M. A., Garrard, P., Bozeat, S., McClelland, J. L., Hodges, J. R., &
Patterson, K. (2004). The structure and deterioration of semantic memory: A neuropsycho-
logical and computational investigation. Psychological Review, 111, 205–235.
Rolls, E. T. (1996). The orbitofrontal cortex. Philosophical Transactions of the Royal Society of London,
B, Biological Sciences, 351, 1433–1443.
Rosenbaum, R. S., Stuss, D. T., Levine, B., & Tulving , E. (2007). Theory of mind is independent of
episodic memory. Science, 318, 1257.
Rosenbaum, R. S., Gilboa, A., Levine, B., Winocur, G., & Moscovitch, M. (2009). Amnesia as an
impairment of detail generation and binding: evidence from personal, fictional, and semantic
narratives in K.C. Neuropsychologia, 47, 2181–2187.
Ross, L. A., & Olson, I. R . (2010). Social cognition and the anterior temporal lobes. NeuroImage,
49, 3452–3462.
Rowe, A. D., Bullock, P. R., Polkey, C. E., & Morris, R. G. (2001). “Theory of mind” impairments
and their relationship to executive functioning following frontal lobe excisions. Brain, 124,
600–616.
Rylander, G. (1939). Personality changes after operations on the frontal lobes: a clinical study of 32 cases.
London: Humphrey Milford.
Samson, D., Apperly, I. A., Chiavarino, C., & Humphreys, G. W. (2004). The left temporo-
parietal junction is necessary for representing someone else’s belief. Nature Neuroscience, 7,
449–500.
Samson, D., Apperly, I. A., & Humphreys, G. W. (2007). Error analyses reveal contrasting defi-
cits in “theory of mind”: neuropsychological evidence from a 3-option false belief task.
Samson, D., Apperly, I. A., Kathirgamanathan, U., & Humphreys, G. W. (2005). Seeing it my way: a
case of a selective deficit in inhibiting self-perspective. Brain, 128, 1102–1111.
Saxe, R . (2005). Against simulation: the argument from error. Trends in Cognitive Sciences, 9,
174–179.
Saxe, R., Carey, S., & Kanwisher, N. (2004). Understanding other minds: linking developmental
psychology and functional neuroimaging. Annual Review of Psychology, 55, 87–124.
Saxe, R., & Kanwisher, N. (2003). People thinking about thinking people: fMRI investigations of
theory of mind. NeuroImage, 19, 1835–1842.
Schacter, D. L , Addis, D. R., & Buckner, R. L . (2008). Episodic simulation of future events: Concepts,
data, and applications. Annals of the New York Academy of Sciences, 1124, 39–60.
Shamay-Tsoory, S. G., & Aharon-Peretz, J. (2007). Dissociable prefrontal networks for cognitive
and affective theory of mind: a lesion study. Neuropsychologia, 45, 3054–3067.
Shamay-Tsoory, S. G., Tibi-Elhanany, Y., & Aharon-Peretz, J. (2006). The ventromedial prefrontal
cortex is involved in understanding affective but not cognitive theory of mind stories. Social
Shamay-Tsoory, S. G., Tomer, R., & Aharon-Peretz, J. (2005). The neuroanatomical basis of under-
standing sarcasm and its relationship to social cognition. Neuropsychology, 19, 288–300.
Shamay-Tsoory, S. G., Tomer, R., Berger, B. D., & Aharon-Peretz, J. (2003). Characterization of
empathy deficits following prefrontal brain damage: the role of the right ventromedial pre-
frontal cortex. Journal of Cognitive Neuroscience, 15, 324–337.
Shamay-Tsoory, S. G., Tomer, R., Berger, B. D., Goldsher, D., & Aharon-Peretz, J. (2005). Impaired
“affective theory of mind” is associated with right ventromedial prefrontal damage. Cognitive
and Behavioral Neurology, 18, 55–67.
Shammi, P., & Stuss, D. T. (1999). Humour appreciation: a role of the right frontal lobe. Brain, 122,
657–666.
Shaw, P., Lawrence, E., Bramham, J., Brierley, B., Radbourne, C., & David, A. S. (2007). A prospec-
tive study of the effects of anterior temporal lobectomy on emotion recognition and theory of
mind. Neuropsychologia, 45, 2783–2790.
Shaw, P., Lawrence, E. J., Radbourne, C., Bramham, J., Polkey, C. E., David, A. S. (2004). The
impact of early and late damage to the human amygdala on ‘theory of mind’ reasoning. Brain,
1535–1548.
Siegal, M., & Varley, R . (2002). Neural systems involved in “theory of mind.” Nature Reviews
Simmons, W. K., Reddish, M., Bellgowan, P. S., & Martin A . (2010). The selectivity and functional
connectivity of the anterior temporal lobes. Cerebral Cortex, 20, 813–825.
Simons, J. S., Peers, P. V., Mazuz, Y. S., Berryhill, M. E., & Olson, I. R . (2010). Dissociation between
memory accuracy and memory confidence following bilateral parietal lesions. Cerebral Cortex,
20, 479–485.
Singer, T., & Lamm, C. (2009). The social neuroscience of empathy. Annals of the New York Academy
of Sciences, 1156, 81–96.
Spreng, R. N., & Grady, C. L . (2010). Thinking about the past, the future, and other people engage
the default mode network. Journal of Cognitive Neuroscience, 22, 1112–1123.
Spreng , R. N., Mar, R. A., & Kim, A. S. N. (2009). The common neural basis of autobiographical
memory, prospection, navigation, theory of mind and the default mode: a quantitative meta-
analysis. Journal of Cognitive Neuroscience, 21, 489–510.
Stone, V. E., Baron-Cohen, S., Calder, A. C., Keane, J., & Young , A. W. (2003). Acquired theory
of mind impairments in individuals with bilateral amygdala lesions. Neuropsychologia, 41,
209–220.
Stone, V. E., Baron-Cohen, S., & Knight, R. T. (1998). Frontal lobe contributions to theory of mind.
Stone, V. E., & Gerrans, P. (2006). What’s domain-specific about theory of mind? Social Neuroscience,
1, 309–319.
Stuss, D. T. (2006). Frontal lobes and attention: processes and networks, fractionation and integra-
tion. Journal of the International Neuropsychological Society, 12, 261–271.
Stuss, D. T., & Alexander, M. (1999). Affectively burnt in: a proposed role of the right frontal lobe.
In E. Tulving (Ed.), Memory, consciousness, and the brain: the Tallinn Conference (pp. 215–227).
of the Royal Society of London, B, Biological Sciences, 362, 901–915.
Stuss, D. T., Alexander, M. P., Lieberman, A., & Levine, H. (1978). An extraordinary form of con-
fabulation. Neurology, 28, 1166–1172.
Stuss, D. T., Alexander, M. P., Palumbo, C. L., Buckle, L., Sayer, L., & Pogue, J. (1994). Organizational
strategies of patients with unilateral or bilateral frontal lobe injury in word list learning tasks.
Neuropsychology, 8, 355–373.
Stuss, D. T., & Benson, D. F. (1983). Emotional concomitants of psychosurgery. In K. M. Heilman
& P. Satz (Eds.), Advances in neuropsychology and behavioral neurology: vol. 1. Neuropsychology of
human emotion (pp. 111–140). New York: Guilford Press.
Bulletin, 95, 3–28.
mind.” Brain, 124, 279–286.
Stuss, D. T., Rosenbaum, R. S., Malcolm, S., Christiana, W., & Keenan, J. P. (2005). The frontal lobes
and self-awareness. In T. E. Feinberg & J. P. Keenan (Eds.), The lost self: pathologies of the brain
and identity (pp. 50–64). New York: Oxford University Press.
Szpunar, K. K., Watson, J. M., & McDermott, K. B. (2007). Neural substrates of envisioning the
future. Proceedings of the National Academy of Sciences, USA, 104, 642–647.
Tulving , E. (1985). Memory and consciousness. Canadian Psychologist, 25, 1–12.
Vogeley, K., Bussfeld, P., Newen, A., Herrmann, S., Happé, F., Falkai, P., Maier, W., Shah, N. J.,
Fink, G.R., & Zilles, K . (2001). Mind reading: neural mechanisms of theory of mind and self-
perspective. NeuroImage, 14, 170–181.
Welt, L . (1888). Ueber Charakterveränderungen des Menschen infolge von Läsionen des Stirnhirns.
Deutsches Archiv für Klinische Medizin, 42, 339–390.
Wheeler, A. M., Stuss, D. T., & Tulving, E. (1997). Toward a theory of episodic memory: the frontal
Young , L., Dodell-Feder, D., & Saxe, R . (2010). What gets the attention of the temporo-parietal
junction? An fMRI investigation of attention and theory of mind. Neuropsychologia, 48,
2658–2664.
Zackheim, L., Stuss, D. T., Gillingham, S., Rewilak, D., Murphy, K. J., & Rosenbaum, R. S. (2009). The
effects of extensive damage to a “theory of mind” network on “theory of mind” performance.
Poster presented at the 39th Annual Society for Neuroscience Conference, Chicago, IL .
8
Monitoring and Alerting
Two Forests Among the Trees
IAN H. ROBERTSON
In their 2007 review of their research “Is there a dysexecutive syndrome?” Don
Stuss and Mick Alexander (Stuss & Alexander, 2007) set out their view of the
frontal attentional systems of the human brain as follows: “Evidence for three
separate frontal attentional processes is presented . . . and evidence for impair-
ments of each process after lesions in specific frontal regions. These processes
and their coarse frontal localizations are energization—superior medial, task
setting—left lateral and monitoring—right lateral” (p. 901).
This bold characterization of the outcome of approximately 1.58 million scien-
tific papers (the number generated by the search term “executive function” in
Google Scholar) could be made with credibility and confidence by very few
people—of whom Don Stuss is one.
Very few scientists are capable of seeing the big forest, particularly one that
has one and a half million trees in it. But there are so many researchers lost in that
forest that the bold “seeing the forest” statements by people with the stature and
the background to make them are essential for fields to progress. Don Stuss has
been one of the world’s most influential scientists in characterizing executive and
frontal lobe function. He has been able to do so through a combination of wide
reading, influential research, and quite remarkable clinical expertise and experi-
ence with real people with different types of damage to the prefrontal cortex.
Michael Posner did a similar service to an even more confused cohort of
researchers wandering through the giant forest of attention (4.22 million papers
on Google Scholar) during the 1980s. In collaboration with Steve Petersen
(Posner & Petersen, 1990), his similarly bold characterization of the attentional
forest proposed the existence of three supramodal attentional control systems—
alertness, control, and orientation/selection—which he daringly mapped onto
the norepinephrinergic, dopaminergic, and cholinergic neurotransmitter systems
respectively.
152
M on it orin g an d Al e rt in g 153
All theories are wrong, but the question is whether they are useful. Don Stuss
and Michael Posner have both, with their bold characterizations of otherwise dis-
mayingly fragmented fields, allowed researchers, particularly those trying to
translate cognitive science to suffering clinical groups and their families, to benefit
from the sophisticated but sometimes obscure and mutually contradictory find-
ings and paradigm-limited terminology of much basic cognitive neuroscience.
An obvious question arises here: what is the relationship between the “forests”
discerned by these two paragons of modern cognitive and clinical neuroscience?
How does Stuss’s typology link up with Posner’s? Both are tackling the attentional
systems of the brain. Is there some superordinate forest to emerge gestalt-like
from their two forests? Likely there is, but we do not have it yet. Each of these two
researchers is still, to a certain extent, prisoner of his own collection of paradigms
and observational arenas—and how could it be anything else for the most com-
plex region of the most complex entity in the known universe?
What is clear is this: the left lateral prefrontal cortex is strongly linked with the
establishment (and possibly switching) of attentional sets, the right lateral pre-
frontal cortex with the monitoring of adherence to these sets. That hugely impor-
tant forest we owe in considerable measure to the forester Don Stuss and his
clinical and experimental research over the past 30 years. It is equally clear that,
as Michael Posner has found, the anterior cingulate is a key node in a network for
conflict resolution and associated attentional control, and that the parietal cortex
is associated with attentional selection. These are complementary rather than
contradictory concepts, and it should be possible to see them integrated without
losing the viability of the underlying constituent concepts.
Don Stuss’s intriguing notion of “energization” (Stuss & Alexander, 2007), a
putative function of the superior medial regions of the prefrontal cortex, is less
familiar and less easily linked to other typologies and concepts. But so it was for
“monitoring” three decades ago, and I have a suspicion that this concept may, a
couple of decades from now, be found to have validity and importance, if Don
Stuss’s track record is anything to go by.
Stuss’s “monitoring” concept and Posner’s “alerting” construct, both attrib-
uted to a network including the right dorsolateral prefrontal cortex, have the
clearest potential overlap, but their different origins and conceptualization offer
the sort of friction and challenge that useful theories throw up. In this chapter,
I will try to explore the relationship between these two elements of two hugely
important and influential typologies of attention.
Sustaining Attention: A Question of Monitoring

and Alertness
Human beings find it surprisingly difficult to attend to unchanging or unchalleng-
ing repetitive stimuli and responses. We may find it easy to concentrate when
traversing a complex traffic junction or playing a fast and difficult computer game,
yet when all that is required of us is to drive down a long unchanging road, we
struggle to maintain attention to the task and to keep alert. Why do civil engi-
neers build curves into highways across flat land where there is no geographical or
geological need to do so? They do so because our brains cannot reliably focus
attention for even quite modest periods without requiring the small attentional
and psychomotor challenge that the bends induce.
Evolutionary advantage must have accrued to our ancestors who could over-
ride the brain’s overwhelming predictive tendency. This propensity to allocate
attention to the novel stimulus but to revert to a tick-box, low-awareness register-
ing of subsequent exemplars of that stimulus is an essential design feature with-
out which we would be unable to function because of sensory and decision
overload. Without this fast and probably low-level capacity to screen out back-
ground stimuli—the noise of traffic outside our windows for instance, or the word
processing icons cluttering the top of this page as I type—we would not be able to
function.
But all design features have their downsides. The novelty-primed, fast-
habituating brain of earlier evolution may well have helped propagate the genes of
individuals in certain environments: the swiftest to detect the flicker of move-
ment of the camouflaged prey against the forest canopy, for instance. But it may
have disadvantaged others: the deer with a random mutation making it more
capable of overriding the predictive, habituating, novelty-hungry mode may have
survived to pass on these genes because this wary vigilance spared it in certain
environments.
Of the 4.22 million articles on attention, the vast majority are focused on the
first of these classes of attention: selection of stimuli and responses. Only rela-
tively few have focused on the second class of attention. This gap was a major
reason why attention research became so fragmented and allowed distinguished
scientists such as Alan Allport (Allport, 1993) and Giacomo Rizzolatti (Rizzolatti
& Camarda, 1987) to dismiss the need for attention as an explanatory concept: in
their eyes, attention was essentially just an early stage of motor preparation, and
to invoke causal properties to attention was equivalent to the introduction of a
homunculus.
But the fact is that early motor preparation is an unlikely candidate for the
non-musician being able to follow the viola’s line of music from the combined
sounds of the string quartet. Attention will not go away as a concept, but nor will
it survive as a unitary variable: Don Stuss, Michael Posner, and others have taught
us that.
If there are these broad classes of modality-nonspecific attention systems, a
clear implication of this is that there should exist not one reservoir of attentional
capacity in the brain, but two or more. Is there evidence for this?
One aspect of monitoring is the monitoring of errors in one’s performance
during a task. Such error awareness fluctuates, presumably in line with the
operation of some sort of attentional monitoring system of the type proposed by

Stuss. A recent study by my colleague Redmond O’Connell and others in my lab
examined the neural basis for such fluctuating monitoring of errors.
In this study (O’Connell, Dockree, Robertson, et al., 2009) participants moni-
tored a continuous stream of patterned stimuli for the occurrence of an infre-
quent target: an identical stimulus that appeared for approximately half a second
longer than the other stimuli. This setup means first that the matched physical
features of target and standard stimuli tend to bypass the sometimes problematic
issue of target salience, automatically engaging attention and obviating the top-
down processes under investigation, and second, that a continuous demand is
imposed on top-down attention because stimulus classification cannot be com-
pleted until the stimulus length noticeably exceeds that of the non-targets. By
tracking changes in a range of well-known attention-sensitive markers in the EEG
while participants performed the temporal expectancy task, we were able to chart
the elements of compromised brain activity across multiple timescales and hierar-
chical processing levels prior to lapses of attention. Our data revealed specific
maladaptive trends with slow endogenous increases in alpha-band power begin-
ning approximately 20 seconds before a momentary lapse, followed by short-term
(3 to 4 seconds pre-error) disruption of task-related monitoring mechanisms that
was indexed by two event-related components; the P300 and contingent negative
variation. The gradual increase in alpha amplitude appears consistent with the
emergence of cortical idling or a resting state as monitoring processes go off-line
(Mantini, Perrucci, Del Gratta, Romani, & Corbetta, 2007; Pfurtscheller & Lopes
da Silva, 1999).
These studies highlight the fact that although sustained attention is subject to
gradual decrements with time-on-task, equal consideration must be given to sub-
minute fluctuations in attentional engagement. This underlines a major flaw of
the typical continuous performance/vigilance-decrement paradigms that have
been used in the field. Since there are large gaps between the responses made by
the participant during continuous performance tasks, it is not actually possible
to measure moment-to-moment changes in engagement during these tasks.
Extensive work in our lab has demonstrated that sustained attention can be better
isolated by adopting task paradigms that require continuous routine action and
analysis strategies, such as Fourier transform of reaction time data and pre-error
EEG time series, that can elucidate the temporal characteristics of the underlying
neural networks (Dockree, Kelly, Robertson, Reilly, & Foxe, 2005; Johnson et al.,
2007; Manly et al., 2003; O’Connell, Dockree, Robertson, et al., 2009).
The onset of this “idling” that predicted a failure to monitor performance is
likely to be in the right dorsolateral prefrontal cortex. In an analysis of fMRI data,
my colleagues Hester and Garavan showed that awareness of error is associated
with right dorsolateral prefrontal cortex functioning (Hester, Foxe, Molholm,
Shpaner, & Garavan, 2005), using a paradigm that we went on to use in a study
(Shalgi, O’Connell, Deouell, & Robertson, 2007) that is relevant to the issue as to
whether the selection and monitoring components may represent separate capac-
ities in the brain.
The test in question, devised by Rob Hester, was the Error Awareness Test
(EAT). The EAT is a motor Go/No-Go response inhibition task in which partici-
pants are presented with a serial stream of single color words. Participants
were trained to respond to each of the words with a single button press timed
to the offset of the word, and to withhold this response if the same word is
presented on consecutive trials or if the word and font color did not match. This
kind of “response-locking” has been shown to reduce inter-individual variability
and eliminate speed–accuracy tradeoffs (Stuss, Murphy, Binns, & Alexander,
2003). Participants were additionally instructed to press a button signaling they
were aware of having made an error following a false press on No-Go trials.
Delaying response until stimulus offset allowed ruling out the possibility that
certain undetected errors could be attributed to an overemphasis on speed over
accuracy.
Twenty participants performed the task under two conditions. In one condi-
tion (Immediate), participants were asked to respond as quickly and as accurately
as possible to each Go stimulus, and in the other condition (Delayed) they were
asked to time their responses to the offset of the stimulus, thereby decreasing
task difficulty and imposing a more automated response set. As expected, speed-
ing increased the error rate. However, contrary to the expectation (and to partici-
pants’ subjective reports) that speeding would impair awareness of performance,
we found the opposite to be true: errors were less likely to be monitored when the
task was easier (Shalgi et al., 2007).
This gives some support to the existence of separate classes of error—of selec-
tion on the one hand, and of monitoring on the other—which lends support to
the possible existence of two separate attentional capacities. The unmonitored
errors may reflect lapses in a monitoring/alertness/sustained attention system
with a strong node in the right dorsolateral prefrontal cortex, while the errors in
the speeded condition may reflect the capacity limits of a system of response
selection and inhibition.
This argument for the existence of two types of error arising out of two differ-
ent types of attention emerged in another EEG/ERP study from our lab (O’Connell,
Dockree, Bellgrove, et al., 2009). We compared the action errors that occurred in
two tasks that were identical except in one respect. In both tasks, the digits 1 to 9
appeared approximately every 1.4 seconds and the respondent had to press to
every number except the digit 3 (the Sustained Attention Response Task [SART]).
The only difference between the two tasks was that the digits appeared randomly
in one condition (random SART) and in a fixed sequence, 1 to 9. in the other (fixed
SART).
The errors of interest in this task were the errors of commission—pressing
to the 3, which happened in both tasks. These action errors, however, according
to the EEG and ERP evidence, happened for quite different underlying reasons
in the brain. Participants performed the fixed SART (designed to encourage atten-
tional drift) and the random SART (designed to place more emphasis on response
selection and inhibition) in separate blocks. Electrocortical markers associated
with goal maintenance (late positivity, alpha synchronization) distinguished
correct and incorrect performance in the fixed condition, whereas errors in the
random condition were linked to a diminished N2–P3 inhibitory complex. In
addition, there was no error-related negativity in the fixed condition, consistent
with the view that errors in this condition do not arise from a failure to resolve
response competition. Our data provided an electrophysiological dissociation of
sustained attention and response inhibition.
A separate sustained attention system may have evolved to function so rela-
tively imperfectly because there are survival advantages associated with periodic
disengagement from the current focus of attention—in other words, “lapses.”
While under certain circumstances continually directing attention to the burrow
where the prey might emerge is adaptive, such prolonged attention, if overly
focused, may lead to lack of detection of danger and consequently becoming the
prey oneself. Sustained attention and drifting attention may therefore both have
separate costs and benefits. Today, however, we live in a constantly changing
world where the fast pace of technological advances has presented us with chal-
lenges and dangers that the human race has never faced before. It is only in very
recent history that a simple lapse of attention by a single individual could result
in the death or injury of hundreds of people, as in the cases of air and rail travel.
Similarly, our system of education has evolved in such a way that a heavy pre-
mium is now placed on one’s ability to maintain focus over long periods of time.
It is for these reasons that the relative under-exploration of the sustained atten-
tion/monitoring/alertness network is of such practical importance.
Monitoring and Insight

The winner of the year 2000 IgNoble Awards for Psychology was a paper with the
intriguing title “Unskilled and unaware of it: How difficulties in recognizing one’s
own incompetence lead to inflated self-assessments” (Kruger & Dunning, 1999).
This was just one of a considerable literature showing that normal, non–brain-
impaired populations show consider levels of inaccuracy, usually overestimation,
of their levels of attainment and competence across a broad range of domains.
Furthermore, those judged objectively to be least competent in a particular
domain (for instance, sense of humor) are the least accurate in self-evaluating
their level of competence, showing high levels of overestimation.
Kruger and Dunning’s findings of an inverse relationship between competence
and accuracy of self-evaluation is echoed in several other studies. The explanation
proposed is that incompetence robs people of the metacognitive resources to
simultaneously perform the task and monitor their own performance at it.
The present question is whether we can better define the “metacognitive resource”
that may underpin such inaccurate self-assessments. A study from our lab goes
some way to helping address this question.
We gave 79 healthy people between the ages of 18 and 53 a battery of neurop-
sychological tests as well as two self rating scales (the Frontal Systems Behavior
Scale and the Cognitive Failures Questionnaire). Their self-ratings were compared
with the ratings of a close relative or friend, and discrepancy scores were calcu-
lated. We hypothesized, for the reasons outlined above, namely that online moni-
toring of performance requires intact sustained attention to performance, that
people who underestimated their level of error and disorganized behavior in
everyday life would show impairment on tests of sustained attention. This is
indeed what we found: people who underestimated the level of disorganization in
their lives had significantly higher errors on a test of sustained attention com-
pared to accurate estimators or over-estimators (Hoerold et al., 2008).
Sustained attention ability is therefore correlated, as predicted, with accuracy
of self-evaluation (i.e., with monitoring ability). Performance on the SART test
used by Hoerold is also known to be associated with activation of the right dorso-
lateral prefrontal cortex (Manly et al., 2003), leading to the question of whether
this monitoring/alertness/sustained attention system is associated with insight
in clinical conditions where lack of insight is a major clinical problem.
Traumatic brain injury (TBI) is an example of one condition that can result in
a disabling deficit in self-evaluation, which can be a major obstacle to rehabilita-
tion. We have shown that self-rated versus other-rated discrepancies are apparent
in only a proportion of TBI individuals, however (O’Keeffe, Dockree, Moloney,
Carton, & Robertson, 2007), and sustained attention impairment measures cor-
relate only with other-reported ratings of everyday attention problems and not
with self-reported ratings, confirming the inaccuracy of self-evaluation in at least
a proportion of TBI individuals (Robertson, Manly, Andrade, Baddeley, & Yiend,
1997).
The hypothesis arises, therefore, that adequate sustained attention may be a
necessary, if not necessarily sufficient, prerequisite for accurate self-monitoring
and that this is strongly linked to right dorsolateral prefrontal cortex activation.
Is there any evidence that such activation is in turn associated with accurate
self-assessment? An fMRI study of TBI individuals showed that indeed there is.
Accuracy of self-evaluation was significantly correlated with functional activation
of the right dorsolateral prefrontal cortex (Schmitz, Rowley, Kawahara, &
Johnson, 2006). In a quite different disorder, schizophrenia, the level of insight
has been shown to be significantly correlated with right dorsolateral prefrontal
cortex volume (Shad, Muddasani, & Keshavan, 2006).
The right dorsolateral prefrontal cortex is strongly linked to impaired self-
evaluation across a range of disorders, and this can also be observed in the
neurodegenerative conditions the tauopathies, namely frontotemporal dementia,
corticobasal degeneration, and progressive supranuclear palsy. My doctoral student,
Fiadhnait O’Keeffe, found that the condition most strongly affecting the prefron-
tal cortex—frontotemporal dementia (FTD)—was associated with the greatest
level of unawareness, consistent with the view that the unawareness does have a
specific relationship to prefrontal frontal cortex functioning. O’Keeffe found that,
at only around 20% of errors being detected, error awareness among FTD patients
was less than half that of corticobasal degeneration and progressive supranuclear
palsy individuals (O’Keeffe, Murray, et al., 2007).
Monitoring and Arousal

Posner and Petersen’s view of the alerting system is very much linked to the role
of norepinephrine (NE) in cognitive function, and they view this system as func-
tioning in a relatively low-level, bottom-up way, with the NE increasing signal-to-
noise ratio for target stimuli and hence improving performance in most respects.
While they invoke the right dorsolateral prefrontal cortex as having a role in
this system, as well as the locus coeruleus, they do not articulate clearly the puta-
tive role of the frontal systems in this otherwise low-level arousal network.
Don Stuss’s notion of a right dorsolateral prefrontal cortex “monitoring” system
may be a necessary explanatory concept for the phenomenon of alerting and its
consequences.
There are many different neurotransmitters associated with arousal, and the
tonic and phasic levels of locus coeruleus-mediated norepinephrinergic activation
have a particular role. Their action both enhances the signal-to-noise ratio of
neural signals underpinning perceptual and cognitive representations and
increases the error rate, particularly at high levels of NE activation. Arousal varies
with circadian rhythms and shows an inverted-U function such that performance
is impaired when NE levels are both below and above optimal levels (Aston-Jones
& Cohen, 2005).
In 1908, Yerkes and Dodson studied the effects of different degrees of arousal
(by varying the degree of shock) on the ability of mice to learn discriminations
between the luminance of two compartments (Yerkes & Dodson, 1908). They
found that where lightness levels were easily discriminated, the mice performed
better at high levels of arousal, whereas difficult light discriminations were best
learned at low levels of arousal. On the basis of these experiments, they formu-
lated the Yerkes-Dodson law. This law proposed that any task will have an
optimal level of arousal below and beyond which performance will decline; they
hypothesized this optimal level is lower in challenging tasks than in routine
tasks. Similarly, Broadbent (Broadbent, 1971) showed that while stress can
improve performance on routine, non-demanding tasks, the same levels of stress
can impair performance on more complex and demanding tasks. These classic
psychological studies, suggesting an interaction between arousal levels, optimal
performance, and degree of challenge in a task, mesh well with the notion of an
interplay of bottom-up and top-down processes in attention, which have impor-

tant echoes in the concepts of alerting and monitoring.
This view is supported by neuropharmacological studies, for instance with clo-
nidine, which inhibits NE release. One study (Smith & Nutt, 1996) confirmed that
NE suppression in humans led to lapses of performance in the form of unmoni-
tored errors, but they also showed that this effect was much attenuated when the
participants were exposed to loud white noise while performing the task. This
suggests that external stimuli can induce “bottom-up” or exogenous modulation
of the cortical systems responsible for monitoring of performance, which is at the
core of vigilance and sustained attention. Coull and her colleagues confirmed that
this is indeed the case (Coull, Frackowiak, & Frith, 1998), showing that clonidine-
induced norepinephrinergic suppression impaired sustained attention perfor-
mance much more when the task was familiar than when it was unfamiliar—and
thus more challenging. Furthermore, research by Arnsten and Contant (1992)
showed that clonidine affected delayed response performance during a delay
period less when a distractor was interpolated into the delay period than when the
period was free of distractors. This apparently paradoxical effect, where the dele-
terious effect of a drug is reduced by making the task more difficult, is a key finding
in understanding how the sustained attention system might function. More
recently, an fMRI study by Coull and colleagues (Coull, Jones, Egan, Frith, & Maze,
2004) explored the functional anatomical correlates of exogenous modulators of
attention in a group of participants who were sedated by an alpha-2 adrenergic
receptor agonist. The improvement in performance following phasic white noise
stimulation was associated with a selective increase in activation of the left medial
pulvinar nucleus of the thalamus. What these findings suggest is that maintain-
ing performance across different environments demands the interplay of endog-
enous and exogenous systems that are well represented in Stuss’s notion of
monitoring, and Posner’s of alerting.
A study by Paus and colleagues (Paus et al., 1997) provided even stronger sup-
port for this. Volunteers were asked to perform a simple continuous performance
task, a measure of sustained attention, for around 60 minutes. Every 10 minutes,
regional cerebral blood flow (PET) and EEG were measured. Over the 60 minutes,
the researchers saw reductions in blood flow in subcortical structures, including
the thalamus, substantia innominata, and putamen, and in right hemisphere cor-
tical areas, including frontal and parietal cortex. Increases in low theta activity,
associated with reduction in arousal, were also observed on the EEG as the task
progressed. Importantly, however, the changes in the subcortical (arousal) net-
work were not correlated over time with the changes in the right fronto-parietal
(attentional) network. In other words, even though both arousal and sustained
attention declined, they declined independently. Furthermore, despite the reduc-
tion in blood flow in the right hemisphere “attentional” network and the subcorti-
cal “arousal” network, the number of successful target detections did not
significantly decline over the hour of the task. Paus and his colleagues argued that
this was because detection of targets in the vigilance task became more automatic
and hence less dependent on a monitoring/sustained attention system, whose
capacity waned over the course of the task.
Had Paus’s task been less stimulating, on the other hand, the mid-brain net-
work arousal changes may have been smaller. Such a conclusion would be sup-
ported by Coull and associates (Coull, Frackowiak, & Frith, 1998), who also found
decreases in thalamic and right fronto-parietal perfusion over an 18-minute task
period in which participants had to respond to any stimulus appearing intermit-
tently (within a range of 10 to 30 seconds) on the screen. In contrast, when the
task was made relatively more difficult by requiring participants to respond selec-
tively to red B’s interspersed among red and blue B’s and G’s, no significant decline
in the right frontal and parietal cortices was observed. This is in line with the ear-
lier arguments concerning the effects of exogenous demand on sustained atten-
tion, and suggests that this right fronto-parietal system for sustained attention
is, at least in part, a system that is needed to maintain alert and reasonably accu-
rate responding in the absence of strong external demands or stimuli that other-
wise promote alert responding.
Assuming this to be the case, then a major role of the right fronto-parietal
system is to modulate arousal, particularly where that arousal is not externally gen-
erated by task demand or stimulus. Modulating arousal in this way presupposes a
degree of monitoring of internal state, hence demonstrating one further impor-
tant function of Stuss’s monitoring system: monitoring the state of alertness.
In summary, the two forests proposed by Don Stuss and Mike Posner emerge
as Siamese twins of one key aspect of attention—the sustaining of attention, in
particular when exogenous demands on attention are low. During such periods of
low external demand, these twins of alertness/arousal on the one hand, and mon-
itoring of performance and alertness on the other, are essential partners in the
enterprise of effective performance and, in the distant past, of survival.
References
Allport, A . (1993). Attention and control—have we been asking the wrong questions: a criti-
cal review of 25 years. In D. E. Meyer & S. Komblum (Eds.), Attention and Performance XIV:
Synergies in experimental psychology, artificial intelligence and cognitive neuroscience (pp. 183–218).
Arnsten, A. F., & Contant, T. A. (1992). Alpha-2 adrenergic agonists decrease distractibility in aged
monkeys performing the delayed response task. Psychopharmacology (Berl), 108(1–2), 159–169.
Aston-Jones, G., & Cohen, J. D. (2005). An integrative theory of locus coeruleus-norepinephrine
function: adaptive gain and optimal performance. Annual Review Neuroscience, 28, 403–450.
Broadbent, D. E. (1971). Decision and stress. London: Academic Press.
Coull, J. T., Frackowiak, R. S. J., & Frith, C. D. (1998). Monitoring for target objects: activation of right
frontal and parietal cortices with increasing time on task. Neuropsychologia, 36, 1325–1334.
Coull, J. T., Jones, M. E. P., Egan, T. D., Frith, C. D., & Maze, M. (2004). Attentional effects of
noradrenaline vary with arousal level: selective activation of thalamic pulvinar in humans.
NeuroImage, 22(1), 315–322.
Dockree, P. M., Kelly, S. P., Robertson, I. H., Reilly, R. B., & Foxe, J. J. (2005). Neurophysiological
markers of alert responding during goal-directed behavior: a high-density electrical mapping
study. NeuroImage, 27(3), 587–601.
Hester, R., Foxe, J. J., Molholm, S., Shpaner, M., & Garavan, H. (2005). Neural mechanisms involved
in error processing: a comparison of errors made with and without awareness. NeuroImage,
27(3), 602–608.
Hoerold, D., Dockree, P., O’Keeffe, F., Bates, H., Pertl, M., & Robertson, I. (2008). Neuropsychology
of self-awareness in young adults. Experimental Brain Research, 186(3), 509–515.
Johnson, K. A., Kelly, S. P., Bellgrove, M. A., Barry, E., Cox, M., Gill, M., et al. (2007). Response
variability in attention deficit hyperactivity disorder: evidence for neuropsychological hetero-
geneity. Neuropsychologia, 45, 630–638.
Kruger, J., & Dunning , D. (1999). Unskilled and unaware of it: how difficulties in recognizing
one’s own incompetence lead to inflated self-assessments. Journal of Personality and Social
Psychology 77, 1121–1134.
Manly, T., Owen, A. M., Datta, A., Lewis, G., Scott, S., Rorden, C., et al. (2003). “Busy doing noth-
ing?”: Increased right frontal and parietal activation associated with self-sustained attention
to an “unchallenging” task. Neuroimage, 13, S331–S331.
Mantini, D., Perrucci, M. G., Del Gratta, C., Romani, G. L., & Corbetta, M. (2007). Electrophysiological
signatures of resting state networks in the human brain. Proceedings of the National Academy of
Sciences U S A, 104(32), 13170–13175.
O’Connell, R. G., Dockree, P. M., Bellgrove, M. A., Turin, A., Ward, S., Foxe, J. J., et al. (2009).
Two types of action error: electrophysiological evidence for separable inhibitory and sus-
tained attention neural mechanisms producing error on go/no-go tasks. Journal of Cognitive
O’Connell, R. G., Dockree, P. M., Robertson, I. H., Bellgrove, M. A., Foxe, J. J., & Kelly, S. P. (2009).
Uncovering the neural signature of lapsing attention: electrophysiological signals predict
errors up to 20 s before they occur. J. Neurosci., 29(26), 8604–8611.
O’Keeffe, F. M., Dockree, P. M., Moloney, P., Carton, S., & Robertson, I. H. (2007). Characterising
error-awareness of attentional lapses and inhibitory control failures in patients with trau-
matic brain injury. Experimental Brain Research, 180, 59–67.
O’Keeffe, F. M., Murray, B., Coen, R. F., Dockree, P. M., Bellgrove, M. A., Garavan, H., et al. (2007).
Loss of insight in frontotemporal dementia, corticobasal degeneration and progressive supra-
nuclear palsy. Brain, 130, 753–764.
Paus, T., Zatorre, R. J., Hofle, N., Caramanos, Z., Gotman, J., Petrides, M., et al. (1997). Time-
related changes in neural systems underlying attention and arousal during the performance
of an auditory vigilance task. Journal of Cognitive Neuroscience, 9, 392–408.
Pfurtscheller, G., & Lopes da Silva, F. H. (1999). Event-related EEG/MEG synchronization and
desynchronization: basic principles. Clinical Neurophysiology, 110(11), 1842–1857.
Posner, M. I., & Petersen, S. E. (1990). The attention system of the human brain. Annual Review
Rizzolatti, G., & Camarda, R . (1987). Neural circuits for spatial attention and unilateral neglect. In
M. Jeannerod (Ed.), Neurophysiological and neuropsychological aspects of neglect (pp. 289–313).
Amsterdam: North Holland Press.
Robertson, I. H., Manly, T., Andrade, J., Baddeley, B. T., & Yiend, J. (1997). Oops! Performance cor-
relates of everyday attentional failures in traumatic brain injured and normal subjects: the
Sustained Attention to Response Task (SART). Neuropsychologia, 35, 747–758.
Schmitz, T. W., Rowley, H. A., Kawahara, T. N., & Johnson, S. C. (2006). Neural correlates of self-
evaluative accuracy after traumatic brain injury. Neuropsychologia, 44(5), 762–773.
Shad, M. U., Muddasani, S., & Keshavan, M. S. (2006). Prefrontal subregions and dimensions of
insight in first-episode schizophrenia—A pilot study. Psychiatry Research: Neuroimaging,
146(1), 35–42.
Shalgi, S., O’Connell, R., Deouell, L., & Robertson, I. (2007). Absent minded but accurate: delay-
ing responses increases accuracy but decreases error awareness. Experimental Brain Research,
182(1), 119–124.
Smith, A., & Nutt, D. (1996). Noradrenaline and attention lapses. Nature, 380, 291.
of the Royal Society B: Biological Sciences, 362(1481), 901–915.
Stuss, D. T., Murphy, K. J., Binns, M. A., & Alexander, M. P. (2003). Staying on the job: the frontal
lobes control individual performance variability. Brain, 126(Pt 11), 2363–2380.
Yerkes, R. M., & Dodson, J. D. (1908). The relation of strength of stimulus to rapidity of habit-
formation. Journal of Comparative and Neurological Psychology, 18, 459–482.
9
Cognitive Rehabilitation in Old Age
The Rotman Initiative
GORDON WINOCUR
Don Stuss was on the path to priesthood when, in 1970, he answered his true
calling and, happily for the rest of us, redirected his professional life towards
clinical neuroscience. Early on, he staked his claim to the frontal lobes, a brain
region so little understood at the time that investigators referred to it as
“the silent cortex,” as if to imply that it didn’t really have much of a purpose.
Thanks to Don (and others; e.g., Damasio, 1979; Fuster, 1980; Shallice, 1988),
that misconception changed rapidly. One of Don’s major contributions to this
movement was to show that, far from not having a particular function, the frontal
lobes are involved in many functions. His scrupulous examination of the literature
and his observations of countless patients led him to conclude that the frontal
lobes play a critical role in a range of higher-order processes that cannot be sepa-
rated from any aspect of human activity and, indeed, are crucial to an individual’s
identity.
How do the frontal lobes perform this role? Many of the basic processes that
Don linked to the frontal lobes (e.g., sensorimotor, attentional, perceptual,
memory) were known to be localized elsewhere in the brain and, moreover,
damage to the frontal lobes did not usually affect their expression. As is apparent
in his seminal 1986 book, The Frontal Lobes (with Frank Benson), he saw the
frontal lobes as imposing a mental order by integrating all forms of information
and organizing behavior in a goal-directed manner. He used the term “super-
ordinate control”, to characterize the function of the frontal lobes, and much
of his research was dedicated to discovering how they work with other brain
regions in exercising this control. An important part of this exercise was to show
that the homogeneous-looking frontal lobes are anything but homogeneous.
Through sophisticated architectonic analyses of frontal-lobe pathology, he was
able to demonstrate precise links between numerous psychological processes
164
Cog nitiv e R e h abil it at ion in Ol d Ag e 165
and anatomical correlates (e.g., Levine, Stuss, et al., 1998; Stuss, et al., 1994;
Stuss et al., 2000). As evidence mounted for these diverse relationships,
Don became increasingly uncomfortable with the popular notion of the frontal
lobes as a central executive, as well as the idea that damage to the structure
would yield a singular deficit (dysexecutive syndrome). As an alternative, he
saw value in fractionating the executive system and drawing up broad categories
of function with numerous components and exemplars in each category (Stuss
et al., 2002).
In Don’s scheme, one such category is dedicated to the regulation of atten-
tional and affective processes. Another relates to the process of initiating and
sustaining cognitive and behavioral responses. A third category relates to insight-
ful metacognitive processes and involves the integration of a range of attributes
that are fundamental to social perception, personality features, and theory of
mind. Finally, there is executive cognitive function, which embodies the higher
cognitive processes that control and direct lower, more automatic functions. The
last category is further divided into two components: the first is involved in the
planning and initiation of a task, and the second in performing a monitoring
function that entails online checking and behavioral adjustments (see Levine,
Turner, & Stuss, 2008; and Stuss & Alexander, 2007, for more complete accounts
of this conceptualization).
The clinician in Don directed him quite naturally to treatment and rehabilita-
tion, particularly of cognitive functions that are impaired following damage to
the frontal lobes. Historically, the common approach in cognitive rehabilitation
was to target specifically affected functions with focused training techniques,
an approach that, at best, yielded mixed results (see Anderson, Winocur, &
Palmer, 2003). The problem that arises in many cases involving, for example, trau-
matic brain injury, stroke, normal and pathological aging, is that frontal-lobe
impairment can be extensive, resulting in widespread deficits. In that scenario,
adopting a more comprehensive approach that builds on his conceptualization
of functional categories seemed to make more sense. A common theme in
Don’s writings is that generalized cognitive impairment must be related to mul-
tiple biological and non-biological factors and a breakdown in the application of
appropriate cognitive strategies. A central assumption is that, in cognitively
impaired individuals, the capacity for strategic organization and planning is
compromised and under-utilized, but not absent. With the right direction and
support, such individuals are capable of regaining a strategic approach to cogni-
tive challenges, especially those regularly encountered in the real world. That
proved to be the guiding principle for a group of Rotman clinicians and scientists
who, under Don’s guidance, took up the task of launching a new rehabilitation
initiative aimed at cognitive recovery, initially in aged individuals whose perfor-
mance was compromised by normal loss of strategic functions under frontal-lobe
control.
Advances in Improving Cognitive Function

in the Elderly
Traditional approaches to cognitive rehabilitation in older adults have empha-
sized the use of formal training in the use of mnemonics (e.g., method of loci;
visual imagery) or the improvement of basic cognitive processes (e.g., working
memory; information processing at encoding or retrieval). While positive results
have been associated with such techniques (e.g., Campbell & Charness, 1990;
Jennings & Jacoby, 2003; Kliegl, Smith, & Baltes, 1989; Verhaeghen, Marcoen, &
Goosens, 1992), in general, the benefits in terms of overall cognitive performance
have been relatively modest and/or of brief duration. On the other hand, the early
efforts inspired the use of more broadly based, multidimensional programs that
attempted to work on combinations of cognitive skills, and here the results were
more promising. Importantly, the efficacy of several of these programs has been
evaluated in well-conducted, randomized control trials.
One of the first such programs in the field of cognitive aging, developed by
Oswald and his colleagues (Oswald, Rupprecht, Gunzelmann, & Tritt, 1996),
focused on three specific areas: memory, everyday coping, and psychomotor func-
tion. For the trial, normal aged adults received 9 months of training in one of
these areas, or in the psychomotor module combined with either the memory or
coping module. When tested after training, participants showed clear signs of
benefit, although improvements were restricted to the functional areas in which
they had received specific training; there was virtually no transfer of benefits to
the other areas. An important feature of this study was that participants were fol-
lowed for 2 years for symptoms of dementia. Interestingly, the group that had
received combined memory and psychomotor training exhibited fewer symptoms
of dementia than the other groups.
A similar approach was taken by Ball and her colleagues in launching their
Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE)
program (Ball et al., 2002). In the trial to evaluate the program, which was con-
ducted on 2,802 older adults, participants received 10 sessions over a 6-week
period in which they were trained in memory skills, reasoning ability, or speed of
information processing. Also, 60% of the participants in each training group
received booster training 11 months after the initial training. As in the study by
Oswald and colleagues (1966), there were significant benefits, but they were lim-
ited to the module in which participants were trained. A disconcerting feature of
the results was that, while there was clear improvement on standard neuropsy-
chological testing, the benefits did not extend to practical measures of cognitive
performance. On the positive side, participants were followed for 5 years, and
retesting indicated that, for the most part, savings held up over that period,
especially in individuals who had received training in information processing
(Wolinsky et al., 2006).
Finally, Belleville and her colleagues (Belleville, Gilbert, Fontaine, Gagnon,

Menard, & Gauthier, 2006) used a combined skills-training approach and showed
that this type of multidimensional training could be applied usefully to older
adults with varying degrees of cognitive impairment. They were particularly inter-
ested in people diagnosed with amnestic mild cognitive impairment (MCI), so
their 8-week program attached special importance to mnemonics training to
enhance episodic memory. The protocol also provided training in executive con-
trol and cognitive speed. Their program was evaluated in a trial that included a
sample of MCI patients and a group of age-matched older adults who were experi-
encing normal cognitive decline (Belleville et al, 2006). The results showed that,
shortly after training, both groups exhibited significantly improved performance
on various objective and subjective tests of memory. The trial did not assess
improvements in other cognitive domains, or over the long term.
The essential feature that is common to multidimensional rehabilitation pro-
grams is the recognition that cognitive impairment associated with brain impair-
ment or normal aging is multifactorial in terms of its nature and contributing
factors. The treatments that emerged reflect this approach and were broader than
those that emphasized specific cognitive abilities. Notwithstanding their limita-
tions, they represent a promising new direction and provided the context for the
Rotman initiative.
The Rotman Project: A Strategic Approach

The Roman Cognitive Rehabilitation project and the initial trial that was con-
ducted to evaluate it are described in detail in a series of papers published in the
Journal of the International Neuropsychological Society (Craik et al., 2007; Levine
et al., 2007; Stuss et al., 2007; Winocur et al., 2007a, 2007b). The following is an
overview of the history and development of the project, as well as a summary of
the trial’s main results.
B A C K G R O U N D A N D R AT I O N A L E
The seeds for the project were planted in 1995, during a Rotman-sponsored con-
ference that had cognitive rehabilitation as its central theme. It was a successful
conference but at the same time exasperating, as speaker after speaker lamented
the difficulties in developing effective programs and the lack of progress in that
regard. Commonly cited difficulties included the following:
1. Lack of generalization: To be sure, there were frequent reports of improvement

following interventions, particularly when the treatments focused on specific
cognitive abilities, but too often the benefits were restricted to a limited range
of tasks and didn’t necessarily extend to other tasks or other environments.
2. Questionable outcome measures: Effects of interventions were typically evalu-

ated in clinical observations, or subjective reports, with insufficient emphasis
on formal assessment that included measures of real-world performance.
3. Clinical trials: A number of trials had been conducted to evaluate various pro-
grams, but several suffered from design limitations, including issues of subject
selection and potential confounds related to co-existing treatments.
4. Cost effectiveness: Many programs were administered individually over
long periods of time; and demanded substantial commitment of time and
resources.
5. Target population: Most cognitive rehabilitation programs in use at the time
were developed for people with traumatic brain injury whose cognitive status
was stable. As a result, they were less suitable for older adults and individuals
experiencing progressive cognitive decline, such as those diagnosed with MCI
or early dementia.
Following the conference, a group of Rotman scientists and associated clinical

scientists gathered to brainstorm ideas that could form the basis of a new approach
to cognitive rehabilitation, one that would address many of the concerns expressed
at the meeting. For example, from the outset it was determined that, to be most
effective, a program should be as comprehensive as possible—that is, it should
address the range of cognitive processes that can be affected by brain impairment
and also take into account the personal and social difficulties that cognitively
impaired individuals frequently experience. Also, there would be advantages to a
versatile protocol that, with appropriate modification, could be adapted to cogni-
tively impaired individuals with different etiologies. The group felt also that the
protocol should be evidence-based, drawing heavily on relevant scientific research
and current theory in rehabilitation practice. Finally, there was a strong feeling
that, before adopting the protocol as a clinical instrument, it must be submitted
to a rigorous clinical/experimental trial that would assess its effectiveness in a suit-
able population under controlled conditions.
In developing the program, the group was guided by a number of broad prin-
ciples, many of which had been laid out by Don in various papers (e.g., Cicerone,
et al., 2006; Stuss, 2008; Stuss & Binns, 2008). For example, although cognitively
impaired people, regardless of the origin of their impairment, express some
common symptoms (e.g., memory loss, poor problem solving), there are impor-
tant differences in the patterns of lost and spared function. Moreover, in progres-
sive conditions, specific functional processes decline at different rates. Because
the objective was to devise a program that could be applied as widely as possible,
the group rejected the practice of training specific abilities or skills in favor of an
emphasis on strategic processing. For example, rather than trying to enhance
memory capacity per se, it was felt that patients would benefit from being guided
in the use of strategies that are important in acquiring new information,
or retrieving previous experiences. Moreover, there was no plan to teach new
strategies—this would have been a formidable (and probably fruitless) task.

Instead, the emphasis was on strategies that were already part of most people’s
cognitive repertoire but were no longer being implemented on a regular basis. It
was assumed that, like many cognitive skills and non-declarative information, to
varying degrees, these strategies were available, but it was necessary to tap into
them and encourage their use. The rationale was that, as participants became
increasingly comfortable in identifying and drawing on task-appropriate strate-
gies, there would be a greater tendency to apply them to related tasks, both in the
clinical environment and the real world.
There was recognition that a number of quality-of-life issues can be associated
with loss of cognitive function. Cognitively impaired individuals often have con-
siderable insights into their condition and, as a result, can experience frustration,
loss of self-esteem, or depression, which can exacerbate their cognitive problems.
For some time, advocates of holistic rehabilitation programs (e.g., Ben-Yishay,
1996; Prigatano, 1999) have appreciated that the cognitive status of brain-
damaged individuals often is directly related to the personal and emotional diffi-
culties associated with their condition. Consequently, it was decided to include
in the protocol a psychosocial component that focused on issues related to psy-
chological well-being.
THE PROGRAM
The protocol that emerged took the form of a 12-week program comprising three
distinct modules, each 4 weeks long. Given the longer duration of most rehabilita-
tion programs, the 12-week period was a genuine concern. However, it was over-
ridden by the consideration that a short program would be well received by
brain-damaged and older individuals, who are known to lose motivation during
long programs. The protocol was designed for groups of five or six people who
would meet once a week with a group leader. The group format was also thought
to be somewhat of a risk, given the individualized nature of people’s cognitive
problems, but in the end this turned out to be a positive feature. The dynamic
interactions among participants and with the group leader promoted group chem-
istry and increased motivation, which undoubtedly were major factors in ensur-
ing full participation, completing homework assignments, and so forth. As a
complement to the group-oriented approach and to introduce a personal element,
several one-on-one meetings were scheduled with the leader to establish goals
and monitor progress.
The modules consist of three distinct but integrated training programs: (1)
memory skills training, where participants are aided in the use of various mne-
monic strategies for purposes of learning, retaining, and recalling information; (2)
practical task training, where the emphasis is on managing goal-directed behavior
in real-life situations; and (3) psychosocial training, which was designed to enhance
participants’ self-esteem and build confidence in their cognitive abilities.
Memory Skills Training

This module is based on research that shows that brain-damaged and older
adults do not spontaneously use the mental strategies that normal, young
adults automatically apply when trying to register and remember specific events.
The assumption is that participants would be familiar with commonly used mne-
monic strategies, but that more conscious effort is needed for their successful
implementation.
This module begins with an introduction to the various types of memory and
the important point that certain types are more vulnerable than others.
Participants are then introduced to the idea that consciously adopting a strategic
approach to remembering can help in overcoming memory problems. Two types
of strategies are emphasized. First, external strategies that depend on the use of
external reminders such as Post-it notes, diaries, and even electronic managers
are discussed. The second and more important focus is on the use of internal
strategies that individuals themselves invoke to help encode and retrieve infor-
mation. The strategies make use of well-known mnemonic techniques (e.g., visual
imagery, story making, meaningful processing), and participants are presented
with scientific evidence of their value. Care is taken not to direct participants to
particular strategies; rather, they are encouraged to experiment with all of them
and to use those that they feel work best for them.
Practical Task Training

In this module, the objective is to show that a strategic approach to remembering
information and performing various cognitive tasks can be applied to one’s day-
to-day routine. To accomplish this, we used a modified version of Goal Management
Training (GMT; Levine et al., 2000; Robertson, 1996), a metacognitive interven-
tion that is derived from theories of goal neglect and sustained attention (Duncan
et al., 1996). Emphasis is placed on the importance of setting up strategic aims
that include simplifying complex tasks into manageable units, maintaining
focused attention on the task at hand, resisting distraction, and, importantly,
monitoring progress in relation to the goal. To help incorporate this practice into
participants’ approach to cognitive challenges, they are encouraged to articulate
specific commands to direct each stage of the process. Thus, when confronted
with a task, they would STOP what they are doing, STATE the main goal, SPLIT
the task into a series of sub-tasks, and always CHECK to be sure they are on-task.
Practical assignments during the sessions (e.g., puzzle solving) and at home
(e.g., organizing a car pool) are important components of this module.
Psychosocial Training
This module was inspired by a growing literature showing that effective manage-
ment of quality-of-life issues can contribute to overall functional status, including
cognition in elderly (e.g., Arbuckle, Gold, & Andres, 1986; Dawson & Winocur,
2008) and brain-damaged (Dawson, Schwartz, Winocur, & Stuss, 2007; Moore &
Stambrook, 1992) individuals. In a series of studies, Winocur and Moscovitch

(Dawson, Winocur, & Moscovitch, 1999; Winocur, Moscovitch, & Freedman,
1987) showed that scores on tests that measured a range of lifestyle-related
personal attributes (e.g., activity, personal control, optimism) consistently pre-
dicted performance on cognitive tasks in older adults living in the community, or
in various institutional settings. Such work led to the conclusion that personal
and social difficulties that followed from a loss of brain function exacerbated
cognitive problems, and it was decided to include a psychosocial component in
the protocol.
In this module, the various attributes that contribute to psychological well-
being are reviewed and the scientific evidence demonstrating their relationship to
cognitive function is presented. The reciprocity of the relationship is emphasized—
that is, successfully performing cognitive tasks can lead to enhanced self-esteem
and greater confidence, which, in turn, can lead to better performance on new
tasks. Participants are encouraged to explore their feelings following successful
performance and build on the derived confidence in confronting new challenges.
In a major home assignment, participants are asked to identify a longstanding
project and apply the skills and strategies they learned during training to its
completion.
THE TRIAL
As a preliminary step, an early version of the protocol was administered to several
groups of individuals with cognitive dysfunction resulting from different causes
(e.g., head injury, stroke, old age). During these pilot trials, the protocol under-
went further modification and fine-tuning. When the protocol was deemed ready,
it was decided to conduct a formal trial on a sample of older adults who were
experiencing normal age-related cognitive decline; the decision to work initially
with this population was made on the basis of the availability of older adults, and
other practical reasons. The design of the trial is summarized here, but interested
readers are referred to Stuss and colleagues (Stuss et al., 2007) for a detailed
description.
Forty-nine community-dwelling, English-speaking older adults (27 women,
22 men; 71 to 87 years old) participated in the trial. All lived independently
and functioned successfully but complained of loss of memory and related cogni-
tive functions. The screening process also included a battery of neuropsychologi-
cal tests to screen for cognitive impairments (e.g., Mini-Mental State Exam,
National Adult Reading Test-Revised, Wisconsin Card Sorting Test) and psychoso-
cial problems (e.g., Beck Anxiety Index, Geriatric Depression Scale [GDS]).
The design of the trial is presented in Table 9.1. Following admission to the
trial, participants were assigned quasi-randomly to an early training group (ETG)
or a late training group (LTG) and were administered the first round of neuropsy-
chological testing to establish baseline performance (Assessment A). The battery
Table 9.1. Design and Timeline of the Trial
Assessment A 0–3 mo. Assessment B 4–6 mo. Assessment C Assessment D
Early Baseline Rehab Post-rehab Control Testing Follow-up

Training testing testing testing
Group
(ETG)
Late Baseline Control Testing Rehab Post-rehab Follow-up
Training testing testing testing
Group
(LTG)
Assessments B and C were conducted in both groups immediately after rehabilitation training or
the control procedure (depending on the condition). Assessment D was conducted 6 months following
the completion of rehabilitation training in each group.
included memory tests (e.g., Hopkins Verbal Learning Test-Revised [HVLT-R]),

Logical Memory Test, Alpha-Span Test of Working Memory), simulated real-life
tasks (SRLTs) (e.g., organizing a car pool), and tests of psychosocial status (e.g.,
Dysexecutive Questionnaire [DEX], Self-Efficacy Scale, Locus of Control Scale).
Following the design, the ETG entered the rehabilitation phase immediately
after baseline testing, while the LTG entered the limited-contact control condi-
tion during which participants underwent regular testing according to the sched-
ule and were in frequent telephone contact with the group leader. Three months
later, all participants received an alternate version of the complete battery
(Assessment B). The main predictions for this assessment were that, as a result of
rehabilitation training: (1) the ETG generally would outperform the LTG; (2) the
ETG would perform better than at Assessment A; and (3) the LTG would perform
at the same level as at Assessment A.
After Assessment B, there was a crossover in which the ETG switched to the
control condition and the LTG underwent the 3-month training program. At the
end of this period, when it was expected that the LTG would have caught up to the
ETG, a third version of the test battery was administered (Assessment C). The
main predictions for Assessment C were that: (1) the LTG and the ETG would not
differ in overall performance; (2) the LTG would perform better than at
Assessments A and B; and (3) the ETG would maintain its level of performance.
Finally, 6 months after the end of rehabilitation training (3 months later for
the ETG and 6 months later for the LTG), a fourth assessment was conducted
(Assessment D) with yet another version of the test battery. The predictions for
the long-term follow-up were that: (1) the benefits of training would hold up
equally well in both groups and (2) there would be no between-group differences
in performance.1
R E S U LT S
The results of the memory, SRLT, and psychosocial testing are presented in con-
siderable detail in the papers by Craik and coworkers (2007), Levine and cowork-
ers (2007), and Winocur and coworkers (2007a). Here, a sample of the results in
each domain is provided to illustrate the type of effects that were obtained.
For consistency and ease of presentation, rather than presenting group results
at each assessment, the results for selected tests were converted to percentage
scores that reflect percentage change in performance, relative to baseline, at
immediate (Assessment B for the ETG and Assessment C for the LTG) and long-
term follow-up (Assessment D) assessments.
Psychosocial
The psychosocial test results are presented first because they highlight an unex-
pected, but potentially very important, consequence of our experimental design.
To obtain an overall measure of psychological well-being, a composite index was
devised, made up of several psychosocial attributes (e.g., personal control, opti-
mism, happiness) that, while quite different, nevertheless correlated significantly
with each other (Fig. 9.1; in this case only, actual scores were provided). As can be
seen in Figure 9.1, there were differences favoring the ETG. This effect, which will
be discussed below, was seen in other psychosocial tests (e.g., Ways of Coping),
but not universally, and when it was observed, it did not necessarily negate train-
ing-induced benefits to the LTG. For example, as can be seen in Figure 9.2, follow-
ing rehabilitation training both groups improved on the GDS and the DEX. On the
GDS, the LTG exhibited more improvement than the ETG, whereas there was no
Psychological well-being
composite index
2.5
ETG
2
LTG
1.5
1
Index
0.5
–0.5
–1
–1.5 Baseline Post-training Long-term

assessment
Figure 9.1. Composite index scores for early and late training groups at baseline,
immediately following training, and at the 6-months follow-up. (Error bars ± S.E.M.)
Geriatric Depression Scale Dysexecutive Questionnaire
40 ETG 40
LTG
Percent improvement
Percent improvement
30 30
20 20
10 10
0 0
Post-training Long-term Post-training Long-term
Figure 9.2. Percent change in the post-training and 6-month follow-up scores, relative
to baseline, for early and late training groups on the Geriatric Depression Scale and
Dysexecutive Questionnaire. (Error bars ± S.E.M.)
group difference on the DEX. The DEX is a particularly interesting instrument

because it assesses strategic approaches to coping with social problems, and pro-
vides a useful measure of generalization of our methods to other types of cogni-
tive challenges.
Finally, in addition to formal assessment of psychosocial status, a self-assess-
ment questionnaire (SAQ) was administered at the end of the program. The SAQ
measures participants’ personal evaluations of the training program. The results
indicated that both groups felt that, as a result of the program, they were leading
more meaningful lives, their memories were better, and they were better at set-
ting and realizing practical goals. These results must be treated cautiously, but it
is noteworthy that the pattern of the SAQ responses is consistent with the results
of formal testing.
Memory
Not surprisingly, rehabilitation training had little effect on short-term memory
(as measured by the Brown-Peterson test) and recognition memory (as measured
by the HVLT-R test); these types of memory are scarcely affected by normal aging.
At the same time, working memory, which is identified with frontal lobe function,
and is considered vulnerable to the effects of aging, also did not respond to our
training program. Although traditionally thought to have a strategic component,
it is possible that the mental operations required to perform successfully on our
alpha-span test of working memory were so familiar to our relatively high-func-
tioning older adults that performance was more “automatic” than “strategic.”
On the other hand, significant benefits of training were observed in long-term
recall (HVLT-R; Logical Memory Test), which is thought to be mediated by medial
Hopkins verbal learning test-revised

(secondary memory)
30
ETG
LTG
Percent improvement
20
10
0
Post-training Long-term
to baseline, for early and late training groups on the secondary memory measure on
the Hopkins Verbal Learning Test-Revised. (Error bars ± S.E.M.)
temporal lobe structures, and which declines precipitously with age. As can
be seen in Figures 9.3 and 9.4, substantial improvements in this measure were
apparent on the HVLT-R and Logical Memory tests immediately after training.
Moreover, they held up over the long term, especially in the ETG.
The HVLT-R results also showed that enhanced long-term memory perfor-
mance could be related to increased application of appropriate strategies.
Logical memory
(delayed recall)
50 ETG
LTG
40
Percent improvement
30
20
10
–10
to baseline, for early and late training groups on the delayed recall measure on the
Logical Memory test. (Error bars ± S.E.M.)
Hopkins verbal learning test-revised

(secondary memory)
Strategic processing
80
ETG
LTG
Percent improvement
60
40
20
0
to baseline, for early and late training groups on measures of strategic processing in the
secondary memory test of free recall on the Hopkins Verbal Learning Test-Revised.
(Error bars ± S.E.M.)
There are a number of strategies that could be used to learn and remember
the lists of words that make up this test, but the most efficient ones are those
that entail subjective or categorical organization of the words. As can be seen in
Figure 9.5, after training, there was a dramatic increase in the use of these types
of strategies and, again, particularly in the ETG. A similar effect was noted in the
Logical Memory Test test, where scoring is in terms of general aspects of the
stories or specific details. Both groups, and especially the ETG, exhibited a
dramatic increase in the recall of highly specific information, a process that is
presumed to require strategic retrieval.
Practical Task Planning

Performance on the SRLTs was of particular interest because these tasks provided
our best measures of how well skills and strategies, acquired and/or reinforced
during training, transferred to real-world cognitive problems. Here, the results
were extremely encouraging. The SRLTs entailed organizing various activities
(e.g., car pools, swimming lessons) and depended on the effective use of various
processes, including working memory, attention, and strategic planning, for a
successful outcome. Several measures (e.g., preparation, task-setting) contributed
to overall performance, which is reflected in Figure 9.6. As can be seen, both the
ETG and LTG improved following training and the benefits held up, particularly in
the ETG. When the strategic aspects of the task were examined separately (e.g.,
types of strategy employed; monitoring performance) both groups increased their
use of practical strategies in solving the problems, as is evident from Figure 9.7.
Simulated real-life tasks

(total performance)
40
ETG
LTG
30
Percent improvement
20
10
0
to baseline, for early and late training Groups on total performance measures of the
Simulated Real-Life Tasks. (Error bars ± S.E.M.)
Simulated real-life tasks

(total performance)
Task strategy Checking/error correction
ETG
LTG
80 80
Percent improvement
Percent improvement
60 60
40 40
20 20
0 0
Post-training Long-term Post-training Long-term
to baseline, for early and late training groups on measures of strategic processing in the
Simulated Real-Life Tasks. (Error bars ± S.E.M.)
C O N C L U S I O N S A N D C O N S I D E R AT I O N S
The most important result of the trial is that there were significant benefits of treat-
ment in all functional domains, immediately following rehabilitation training and
on long-term follow-up. There was also important support for the underlying
hypothesis that improvements in each domain would be related to improvements in
strategic processing under executive control. Moreover, as seen, for example, in the
HVLT-R results, as participants became more strategic in dealing with cognitive
tasks, their reliance on less strategic approaches declined. The observed improve-
ment in all domains was in itself considered important in that it showed that the
benefits were not limited to specific areas. Notably, the improvements in the SRLTs
and in various aspects of psychosocial function speak to the broad range of benefits.
A particularly encouraging result was that, for the most part, treatment-related
benefits were maintained over the 6-month follow-up period. In some cases (e.g.,
HVLT-R, Logical Memory Test, there was even continued improvement in the
ETG during that time. While the possible influence of practice effects cannot be
ruled out entirely, the results suggest that the benefits were holding and that, to
some extent, participants were continuing to improve as a result of training.
An unexpected finding was that, while both groups benefited from rehabilita-
tion training, improvements were generally greater and more long-lasting in
the ETG. The differences could not be attributed to demographic, health, or func-
tional differences between the groups. While the reason for this outcome is not
clear, a possible explanation may lie in the design of the trial, which may have
contributed to differences in the groups’ preparedness for the training program.
Although all participants were fully briefed as to the schedule of events, the LTG
may not have been sufficiently well prepared for the 3-month delay in beginning
rehabilitation training. Inadvertently, this may have induced a “wait-list” effect
and contributed to a negative reaction that adversely affected their attitude and
performance. This explanation was reinforced by informal comments and frustra-
tion expressed by some of the participants in the LTG.
Notwithstanding the promising results, it is important to acknowledge some
caveats and limitations. There are several issues to be addressed:
1. Despite our considerable efforts to be comprehensive in assessing outcome

and including measures related to practical performance (e.g., SRLTs), there
was no direct measurement of performance in the real world. This was not
feasible at the time, but as we continue to refine the program, the plan is to
include such tests in future trials.
2. The limited-contact control condition was a concern because it exposed the
potential confound that the benefits following training were nonspecific
effects of group interaction and activity. Nonspecific effects cannot be ruled
out unequivocally, but the consistency of the results across testing domains
and the finding that long-term benefits in all domains were related to improve-
ments in executive function and strategic processing point to benefits of reha-
bilitation training. Nevertheless, for subsequent studies, we have devised a
control condition in which the group leader engages participants in mind-
stimulating activities that are unrelated to the training program.
3. In a prospective study such as this, one always has to be on guard for possible
practice effects. Care was taken to minimize such effects by using different
versions of the same tests wherever possible. In general, we were able to deter-
mine that rehabilitation effects were over and above those that could be attrib-
uted to repeated assessments.
4. There were differences in the participants’ response to training, and it was not
always possible to identify the specific strategies adopted by individuals in the
various tasks. This was due in part to individual differences in the type and
number of strategies used. A better understanding of the process of strategy
selection and those that are not particularly helpful in various situations
would be helpful in guiding participants in fruitful directions.
5. Finally, while the decision was made early on to experiment with a broadly
based, comprehensive protocol, it was impossible to determine if observed
benefits were the result of the training program as a whole, or of one or more of
the modules. A study is under way to determine whether the same (or greater)
benefit can be achieved from some combination of the individual modules.
Summary
The results of an experimental evaluation of a new approach to cognitive rehabili-
tation are presented. In designing the protocol, scientists at the Rotman Research
Institute were guided by a general model of strategic processing. The program is
based on the premise that older adults and younger adults with brain damage
need assistance in selecting and implementing strategies that are appropriate to
specific tasks. As participants become increasingly familiar with the application of
various strategies in responding to cognitive demands, it was predicted that this
essential operation would be accomplished with reduced effort and incorporated
into their daily lives.
The program consists of a 12-week training protocol divided into three compo-
nents: (1) memory skills training, where the emphasis is on using internal and
external strategies to acquire, retain, and recover information; (2) practical task
training, in which mnemonic and problem-solving strategies are applied to “real-
life” situations; and (3) psychosocial training, in which the aim is to enhance psy-
chological well-being and establish the link between overall functional status and
cognitive function.
The protocol was tested on a sample of normal old people who complained of
memory loss and related cognitive problems. The study is unique in several ways:
it is one of a small number of trials to use a multiple baseline design; it is compre-
hensive in assessing the relative importance of various factors that affect reha-
bilitation of cognitive performance; it spans a 12-month period and includes a
follow-up assessment of long-term benefits; and it provides a wide range of behav-
ioral, neuropsychological, and psychosocial outcome measures.
The results indicated significant benefits of rehabilitation on a broad range
of cognitive and psychosocial measures. The experimental design supported the
conclusion that observed improvements in performance were the direct result of

rehabilitation, and not secondary to general participation or repeated assess-
ments. The success of the program is attributed to a variety of factors, including
the emphasis on strategic processes in lab-based and practical training, psychoso-
cial factors that relate to cognitive function, the dynamics of the supportive group
session, commitment to home assignments, as well the identification and realiza-
tion of individual goals.
There is clearly much to be done in terms of refining the program and assessing
its suitability for other populations. Nevertheless, the promising results of the
present trial indicate a clear direction for this and related programs. They also
provide a strong endorsement of Don Stuss’s long-advocated approach to cogni-
tive rehabilitation. As Don pointed out several years ago, we’re not likely to
advance the field by narrowly focusing on improving specific cognitive operations,
an approach that was in vogue for many years. Rather, he argued, the benefits are
to be found by emphasizing higher-order processes that are deficient in most cog-
nitively impaired individuals. Whether or not the frontal lobes are primarily
affected, this region and the control processes it subserves are likely to be impaired
when brain function is disrupted. By striving to upgrade organizational skills,
strategic approaches to learning and remembering, and practical problem solving,
as we do in our program, the prospects are favorable for achieving long-lasting
benefits across a range of functional domains. Thanks, Don, for leading the way
and getting us on the right track.
Acknowledgments
The research reported in this chapter was supported by a grant from the
J. S. McDonnell Foundation. Preparation of the chapter was supported by a grant
from the Canadian Institutes for Health Research. The technical support of Nick
Hoang is gratefully acknowledged.
Notes
1. Module-specific tests were administered after each module during the 3-month training period.
The results generally paralleled those of the complete battery and are not considered here.
References
Anderson, N. D., Winocur, G., & Palmer, H. (2003). Principles of cognitive rehabilitation. In P. W.
Halligan, U. Kischka, & J. C. Marshall (Eds.), Handbook of clinical neuropsychology (pp. 48–69).
Oxford: Oxford University Press.
Arbuckle, T. Y., Gold, D., & Andres, D. (1986). Cognitive functioning of older people in relation to
social and personality variables. Psychology of Aging, 1, 55–62.
Ball, K., Berch, D. B., Helmers, K. F., Jobe, J. B., Leveck, M. D., Marsiske, M., Morris, J. N., Rebok,
G. W., Smith, D. M., Tennstedt, S. L., Unverzagt, F. W., & Willis, S. L . (2002). Effects of
cognitive training interventions with older adults: a randomized controlled trial. JAMA,
288, 2271–2281.
Belleville, S., Gilbert, B., Fontaine, F., Gagnon, L., Menard, E., & Gauthier, S. (2006). Improvement
of episodic memory in persons with mild cognitive impairment and healthy older adults:
evidence from a cognitive intervention program. Dementia & Geriatric Cognitive Disorders,
22, 486–499.
Ben-Yishay, Y. (1996). Reactions on the evolution of the therapeutic milieu concept.
Neuropsychological Rehabilitation, 6, 327–343.
Campbell, J. I. D., & Charness, N. (1990). Age-related declines in working-memory skills: evidence
from a complex calculation task. Developmental Psychology, 26, 879–888.
Cicerone, K., Levin, H., Malec, J., Stuss, D., & Whyte, J. (2006). Cognitive rehabilitation interven-
tions for executive function: moving from bench to bedside in patients with traumatic brain
injury. Journal of Cognitive Neuroscience, 18, 1212–1222.
Craik, F. I. M., Winocur, G., Palmer, H., Binns, M. A., Edwards, M., Bridges, K., Glazer, P., Chavannes,
R., & Stuss, D. T. (2007). Cognitive rehabilitation in the elderly: effects on memory. Journal of
the International Neuropsychology Society, 13, 132–142.
Damasio, A. R . (1979). The frontal lobes. In K. M. Heilman & E. Valenstein (Eds.), Clinical neuropsy-
chology (pp. 360–412). New York: Oxford University Press.
Dawson, D., Winocur, G., & Moscovitch, M. (1999). The psychosocial environment and cognitive
rehabilitation in the elderly. In D. T. Stuss, G. Winocur, & I. H. Robertson (Eds.), Cognitive
neurorehabilitation (pp. 94–108). Cambridge, UK: Cambridge University Press.
Dawson, D. R., Schwartz, M. L., Winocur, G., & Stuss, D. T. (2007). Return to productivity follow-
ing traumatic brain injury: cognitive, psychological, physical, spiritual, and environmental
correlates. Disability & Rehabilitation, 29, 301–313.
Dawson, D. R., & Winocur, G. (2008). Psychosocial considerations in cognitive rehabilitation.
In D. T. Stuss, G. Winocur, & I. H. Robertson (Ed.), Cognitive neurorehabilitation: evidence and
application (2nd ed., pp. 232–249). Cambridge, UK: Cambridge University Press.
Duncan, J., Emslie, H., Williams, P., Johnson, R., & Freer, C. (1996). Intelligence and the frontal
lobe: the organization of goal-directed behavior. Cognitive Psychology, 30, 257–303.
Fuster, J. M. (1980). The prefrontal cortex. Anatomy, physiology, and neuropsychology of the frontal
lobe. New York: Raven Press.
Jennings, J. M., & Jacoby, L.L . (2003). Improving memory in older adults: training recollection.
Neuropsychological Rehabilitation, 13, 417–440.
Kleigl, R., Smith, J., & Baltes, P. (1989). Testing-the-limits and the study of adult age differences in
cognitive plasticity of a mnemonic skill. Developmental Psychology, 25, 247–256.
Levine, B., Stuss, D. T., Milberg , W. P., Alexander, M. P., Schwartz, M., & MacDonald, R . (1998). The
effects of focal and diffuse brain damage on strategy application: evidence from focal lesions,
traumatic brain injury and normal aging. Journal of the International Neuropsychology Society,
4, 247–264.
Levine, B., Robertson, I. H., Clare, L., Carter, G., Hong , J., Wilson, B. A., et al. (2000). Rehabilitation
of executive functioning: an experimental-clinical validation of goal management training.
Journal of the International Neuropsychology Society, 6, 299–312.
Levine, B., Stuss, D. T., Winocur, G., Binns, M. A., Fahy, L., Mandic, M., Bridges, K., & Robertson, I. H.
(2007). Cognitive rehabilitation in the elderly: effects on strategic behavior in relation to goal
management. Journal of the International Neuropsychology Society, 13, 143–152.
Levine, B., Turner, G.R., & Stuss, D.T. (2008). Rehabilitation of frontal lobe functions. In D. Stuss,
T., Winocur, G., & Robertson, I. H. (Ed.), Cognitive neurorehabilitation: evidence and application
(2nd ed., pp. 464–486). Cambridge, UK: Cambridge University Press.
Moore, A. D., & Stambrook, M. (1992). Coping strategies and locus of control following traumatic
brain injury: relationship to long-term outcome. Brain Injury, 6, 89–94.
Oswald, W. D., Rupprecht, R., Gunzelmann, T., & Tritt, K . (1996). The SIMA-project: effects of
1 year cognitive and psychomotor training on cognitive abilities of the elderly. Behavioral
Brain Research, 78, 67–72.
Prigatano, G. P. (1999). Motivation and awareness in cognitive rehabilitation. In D. T. Stuss, G.
Winocur, & I. H. Robertson (Eds.), Cognitive neurorehabilitation (pp. 29–50). Cambridge, UK:
Cambridge University Press.
Robertson, I. H. (1996). Goal management training: a clinical approach. Cambridge, UK: PsyConsult.
Shallice, T. (1988). From neuropsychology to mental structure. Cambridge, UK: Cambridge University
Press.
Stuss, D. T. (2008). Rehabilitation of frontal lobe dysfunction: a working framework. In M. Oddy
& A. Worthington (Eds.), Rehabilitation of executive disorders (pp. 3–18). New York: Oxford
University Press.
of the Royal Society of London Part B, Biological Sciences, 362, 901–915.
Stuss, D. T., Alexander, M. P., Hamer, L., Palumbo, C., Dempster, R., Binns, M., Levine, B., &
Izukawa, D. (1998). The effects of focal anterior and posterior brain lesions on verbal fluency.
Journal of the International Neuropsychology Society, 4, 265–278.
Stuss, D. T., Alexander, M. P., Floden, D., Binns, M. A., Levine, B., McIntosh, A. R., Rajah, N., &
Hevenor, S. J. (2002). Fractionation and localization of distinct frontal lobe processes:
evidence from focal lesions in humans. In D. T. Stuss & R. T. Knight (Eds.), Principles of frontal
lobe function (pp. 392–407). New York: Oxford University Press.
Stuss, D. T., Alexander, M. P., Palumbo, C. L., Buckle, L., Sayer, L., & Pogue, J. (1994). Organizational
strategies of patients with with unilateral or bilateral frontal lobe injury in word list learning
tasks. Neuropsychology, 8, 355–373.
Stuss, D. T., & Binns, M.A . (2008). The patient as a moving target: the importance to rehabilitation
of understanding variability. In D. T. Stuss, G. Winocur, & I. H. Robertson (Eds.), Cognitive
neurorehabiltation: evidence and application (2nd ed., pp. 39–61). Cambridge, UK: Cambridge
University Press.
Stuss, D. T., Levine, B., Alexander, M. P., Hong , J., Palumbo, C., Hamer, L., Murphy, K. J., & Izukawa,
D. (2000). Wisconsin Card Sorting Test performance in patients with focal frontal and
posterior brain damage: effects of lesion location and test structure on separable cognitive
processes. Neuropsychologia, 38, 388–402.
Stuss, D. T., Robertson, I. H., Craik, F. I. M., Levine, B., Alexander, M. P., Black, S., Dawson, D.,
Binns, M. A., Palmer, H., Downey-Lamb, M., & Winocur, G. (2007). Cognitive rehabilita-
tion in the elderly: a randomized trial to evaluate a new protocol. Journal of the International
Neuropsychology Society, 13, 120–131.
Verhaegen, P., Marcoen, A., & Goosens, L . (1992). Improving memory performance in the aged
through mnemonic training: A meta-analytic study. Psychology & Aging, 7, 242–251.
Winocur, G., Craik, F. I. M., Levine, B., Robertson, I. H., Binns, M. A., Alexander, M., Black, S.,
Dawson, D., Palmer, H., McHugh, T., & Stuss, D. T. (2007a). Cognitive rehabilitation in the
elderly: overview and future directions. Journal of the International Neuropsychology Society,
13, 166–171.
Winocur, G., Moscovitch, M., & Freedman, J. (1987). An investigation of cognitive function in rela-
tion to psychosocial variables in institutionalized old people. Canadian Journal of Psychology,
41, 257–269.
Winocur, G., Palmer, H., Dawson, D., Binns, M. A., Bridges, K., & Stuss, D. T. (2007b). Cognitive
rehabilitation in the elderly: an evaluation of psychosocial factors. Journal of the International
Neuropsychology Society, 13, 153–165.
Wolinsky, F. D., Unverzagt, F. W., Smith, D. M., Jones, R., Stoddard, A., & Tennstedt, S. L . (2006).
The ACTIVE cognitive training trial and health-related quality of life: protection that lasts for
5 years. Journal of Gerontology Part A, Biological Science & Medical Science, 61, 1324–1329.
10
Effects of Aging on
Memory and Attention
A Frontal Lobe Problem?
FERGUS I. M. CRAIK
Many of us, like Woody Allen, have our favorite body parts, but it is clear that
Don Stuss is a frontal lobe man! It thus seemed appropriate, when contemplating
what to present in this volume celebrating Don’s huge contributions to science
and society, to examine the extent to which my own work might overlap with this
interest of his. Many of the experiments conducted in my lab over the years have
dealt with changes in memory and attention as a function of the normal aging
process, so the focus would presumably be on the extent to which age-related
cognitive changes reflect deterioration of processes located in (or governed by)
the frontal lobes.
The observation that there are similarities between the cognitive consequences
of aging and of frontal lobe damage is not new. The notion was suggested explic-
itly by Albert and Kaplan (1980) and by Veroff (1980), both of whom found that
older community-living adults tended to give responses on a variety of “frontal”
tests that resembled responses given by patients with frontal lobe pathology.
The suggestion, therefore, is that at least some elderly adults show signs of mild
frontal dysfunction, and that these signs may be associated with mild structural
and functional impairment of the frontal lobes themselves. Further confirmatory
evidence on this point was presented by Heaton (1981), who found that a group
of older adults (over 60 years) made many more perseverative errors than a
younger group (under 40 years) on the Wisconsin Card Sorting Test—a pattern
associated with frontal lobe dysfunction. Similarly, Whelihan and Lesher (1985)
reported that responses to a battery of neuropsychological tests given to adults
aged between 60 and 92 years indicated that frontal lobe functions decline
with age. Importantly, they also suggest that frontal functions may show greater
impairment with age than do numerous non-frontal higher cortical functions
183
(Whelihan & Lesher, 1985, p. 375); that is, frontally mediated functions are
particularly sensitive to the effects of aging on the brain.
Why might this be? Whelihan and Lesher suggest as one possibility that since
the frontal lobes are the last to develop ontogenetically, they may also be the first
to show functional decline. This possibility is supported by more recent studies
of differential age-associated losses in cortical volume (e.g., Raz, 2000). Another
possibility mentioned by Whelihan and Lesher is that in the course of declin-
ing vascular efficiency, blood supply may be preferentially allocated to such “fun-
damental” mechanisms as sensory and motor function at the expense of areas
concerned principally with higher cognitive abilities. These and other arguments
were summarized and discussed in a “frontal theory” of cognitive aging by West
(1996).
With regard to the relations among memory, aging, and frontal lobe function-
ing, Schacter, Harbluk, and McLachlan (1984) had reported that frontal lobe
patients exhibited a marked deficit in remembering where and when they
had encountered specific facts—a deficit they termed “source amnesia.” We
thought it would be interesting to test this ability in older adults, and indeed
found that they too showed a milder form of source amnesia, again suggesting a
commonality with frontal patients (McIntyre & Craik, 1987). This commonality
was explored further in a study by Craik, Morris, Morris, and Loewen (1990)
in which we asked whether there is a relation between the degree of source amne-
sia exhibited by normal older adults and scores on neuropsychological tests of
frontal function.
We used the paradigm developed by Schacter and colleagues (1984) in which
participants aged 60 to 84 years were given statements about public personalities
to study. The statements were mostly made-up but plausible “facts” such as “Jane
Fonda always eats oatmeal for breakfast,” and the personalities were well known,
somewhat known, or fictional; in addition, 24 true facts about well-known people
were presented. One week later participants were given a test list of questions
pertaining to the facts they had learned, plus further questions related to new
facts about famous and non-famous people. If they knew the fact, they were also
asked to state where they had first learned it: on TV, radio, book, newspaper, from
a friend—or in the experiment. Source amnesia was measured as the number of
correctly recalled made-up “facts” from the week before that were incorrectly
attributed to some other source. In this case 30% of recalled facts were source
errors, a much higher value than the 7% of such errors made by the young par-
ticipants in the McIntyre and Craik study. In the 1990 study, we also gave the
older participants the Wisconsin Card Sorting Task, the Verbal Fluency Test (FAS),
and the WAIS-R to give a measure of general intellectual functioning. In essence,
the results showed that source amnesia correlated reliably (negatively) with verbal
fluency and the number of categories achieved on the WCST; also, source amnesia
correlated positively with the number of perseverative errors. This last correlation
remained significant after partialing out performance IQ from the WAIS, so the
E ffects of Ag ing on M e m ory an d At t e n t ion 185
relation does not appear to be secondary to a general cognitive impairment.

Finally, we also found that the measure of source amnesia did not correlate
reliably with memory for the facts themselves, again suggesting that source for-
getting does not simply reflect a general memory impairment. In summary, this
experiment enabled us to demonstrate substantial source amnesia in a group of
normal elderly people and to show that the incidence of source amnesia is associ-
ated with measures of frontal lobe inefficiency within this group.
The results of Craik and colleagues (1990) showed that whereas measures of
fact recall and source amnesia did not correlate, nevertheless both measures fell
off reliably with age within the group of older adults. This finding suggests the
eminently reasonable possibility that other areas of the brain besides the frontal
lobes are negatively affected by aging, and that fact recall and source recall are
mediated by different brain areas. In an impressive paper, Glisky, Polster, and
Routhieaux (1995) illustrated this point by classifying a group of older adults,
aged 65 to 87, as High or Low Frontals and also as High or Low Medial-Temporal
responders on the basis of a battery of tests assessing both frontal and medial-
temporal functions. The researchers presented sentences to remember, where the
sentences were spoken by different voices; participants were later tested for
memory of both the sentences themselves and the voice of presentation. The
results showed that the high/low frontal split had no effect on sentence memory,
but that people high on frontal tests performed better on voice memory; in a
complementary fashion, people high on the medial-temporal classification showed
no advantage on voice memory, but outscored the low medial-temporal group on
sentence memory. Glisky and colleagues therefore concluded that, for these mate-
rials at least, context memory was mediated by frontal functions, whereas item
memory was mediated by medial-temporal functions.
Recent work in cognitive neuroscience has confirmed that other areas of the
brain are indeed affected by aging—the work includes both structural analyses
(e.g., Raz, 2000) and functional analyses (e.g., Grady & Craik, 2000). One specific
suggestion is that degeneration of the caudate region underlies age-related cogni-
tive problems (Rubin, 1999), although it is also a fact that this region is tied inti-
mately to the frontal lobes (Pandya & Barnes, 1987). Generally, it seems likely
that the areas principally affected by aging will be those responsible for complex
higher-order integrative functions rather than those areas responsible for “house-
keeping,” routine, and automated activities (Hasher & Zacks, 1979).
Frontal Lobe Mechanisms

What aspects of frontal lobe functioning might be involved in these age-related
memory losses? The frontal lobes occupy a large proportion of total brain volume
after all, so it is reasonable to suppose that more than one frontal function may
be implicated. Don Stuss’s recent research work is focused on just this point—the
idea that different frontal regions subserve different functions (Stuss & Alexander,
2000; Wheeler & Stuss, 2003; Wheeler, Stuss & Tulving, 1997). My own previous
publications also suggest at least two possible frontal candidates responsible for
such age-related losses. The first is the suggestion (Craik, 1983, 1986) that older
adults are deficient in their ability to “self-initiate” cognitive activities. The idea
stems from observations that age-related deficits tend to be less in situations
where the external environment supports or induces appropriate mental opera-
tions, as opposed to situations in which the person has to “bootstrap” these oper-
ations from within. One example is recognition memory compared to recall; in
the former case, items to be recollected are re-presented and the participant
chooses ones experienced previously, whereas in cases where the person is
attempting to recollect in a different context and without many cues, he or she
must self-initiate the necessary mental processes. It is also known that frontal
patients have greater deficits in free recall than in recognition (Wheeler, Stuss, &
Tulving, 1995). According to Stuss (e.g., Wheeler & Stuss, 2003; Wheeler et al.,
1995) the ability to initiate cognitive operations is associated with superior medial
areas of the prefrontal cortex.
A second candidate is the left ventral prefrontal cortex, which appears to be
associated with deep semantic encoding operations, and therefore with good
values of subsequent memory (Kapur, Craik, Tulving, et al., 1994). It is known
that both aging (Grady et al., 1995) and division of attention (Shallice et al., 1994)
are associated with reduced levels of activity in this region. My suggestion has
therefore been that (to some extent at least) aging resembles division of attention
effects in young adults; both are examples of reduced processing resources, and
both result in less rich, elaborate conceptual encoding, and thus in reduced levels
of subsequent memory performance (Craik, 1982). This notion that many effects
of aging can be attributed to a reduction in processing resources and thus can
resemble the effects of divided attention has been questioned, however. Naveh-
Benjamin (2000, 2001) has argued that older adults show a deficit in the ability to
form new associative connections, and that this deficit is not shared by younger
adults working under divided attention conditions. At first my lab contested this
conclusion; for example, Castel and Craik (2003) found that young participants
working under divided attention conditions did show an associative deficit,
although admittedly not as large a deficit as that shown by older adults working
under full attention conditions. But later work by Craik, Luo, and Sakuta (2010)
addressed the point directly and found that the function relating item and asso-
ciative recognition was different for older adults, although essentially the same
for young adults working under either full or divided attention. This experiment
and its implications are described in greater detail later in the chapter. For the
moment, I will maintain the point that activation of the left ventral prefrontal
cortex is associated with degrees of semantic analysis (“levels of processing”), that
aging (like divided attention) appears to reduce such levels of activation, and that
this in turn is associated with lower levels of subsequent memory.
Some Empirical Demonstrations

Much of my empirical work on age-related differences in memory over the past
20 years has addressed the point that such differences are quite variable: older
adults show marked decrements in some situations while showing only slight
losses in others. My suggestion is that age-related losses are substantial when the
memory task requires a great amount of self-initiated processing and when nei-
ther the external environment nor internal learned schemas provide compensa-
tory support (Craik, 1983, 1986). Free recall of word lists is a lab task that fits this
description; a real-life example would be trying to remember who had attended a
party or a business meeting at a later time, without hints or clues, and in a very
different context. On the other hand, age-related memory losses are often slight
or negligible in situations where the task or external context provides good envi-
ronmental support—recognition memory, for example, or being back in the room
where the previous business meeting took place. It is also important to recognize
that “schematic support” from acquired knowledge can act like external environ-
mental support to compensate for at least some age-related losses.
As an additional point, I see no reason why all age-related problems of memory
and attention should necessarily reflect the same underlying neural inefficiency;
it is quite possible that several systems, processes, and mechanisms decline in
efficiency in older adulthood. Thus, whereas an increasing age-related difficulty in
organizing and carrying out self-initiated processes may be one problem, there
may be others such as difficulties in forming new associations, difficulty in manip-
ulating information held in working memory, and difficulty in accessing factual
information that has not been retrieved recently or is of a highly specific nature.
The following experimental demonstrations illustrate some of these problems.
After describing the studies and their implications, I will attempt a summary of
our current understanding of why some aspects of memory and attention decline
as we get older.
Environmental and Schematic Support

If older adults are less able to initiate mental operations owing to inefficient fron-
tal lobe function, this will make them particularly dependent on “support” from
the outside environment. The basic idea is that mental operations appropriate to
a given situation are typically induced partly by the external context and partly by
internal thoughts, intentions, and decisions. To the extent that support from one
of these sources is lacking, the person will need to recruit further support from
the other source in order to function effectively. In this sense, the current task
and surroundings may provide “environmental support,” but in addition the indi-
vidual’s stock of relevant knowledge and learned habits will provide “schematic
support” for the required function.
An experiment carried out to illustrate these principles was performed by

Troyer, Häfliger, Cadieux, and Craik (2006). In this study, we tackled the problem
of learning and remembering names, which is a difficulty experienced by many
older adults. In this case, environmental support was manipulated by testing
memory for the newly learned names either by free recall (low support) or recog-
nition memory (high support); schematic support was varied by means of a levels-
of-processing manipulation, as described below. The materials were 32 surnames
of moderate frequency taken from the local telephone directory; each name was
randomly assigned the title Mr. or Mrs., and printed on a separate piece of paper.
The participants were 20 university students (mean age = 21 years) and 20 older
community-dwelling adults (mean age = 72 years). They were told that they would
be shown a number of names, some of which they should attempt to learn for a
later memory test, and others that they need not learn but would have to answer
specific questions about the name. These questions followed the model of the
levels-of-processing paradigm (Craik & Tulving, 1975), and induced the partici-
pant to process a given name either in terms of its orthographic properties (“state
the name’s first letter”), its phonemic properties (“generate a word that rhymes
with the name”), or its semantic properties (“generate a definition or an associa-
tion to the name”). So, for the name “Mr. Dean,” the participant might respond
“D” in the first condition, “queen” in the second, and “a university administrator”
in the third.
The 32 names were allocated to 4 different processing conditions for each par-
ticipant (intentional learning, first letter, rhyme, and semantic), with 8 names in
each condition, randomly mixed throughout the list of 32. After all 32 names had
been presented and processed, participants were given a distracter task for
20 seconds, and then asked to recall as many of all 32 names as they could.
Following this free recall phase, participants were given a sheet with the 32 names
plus a further 64 similar distracter names mixed together; they were asked to
circle the names they recognized from the first phase. For scoring purposes, the
recalled and recognized names were re-allocated to their original encoding condi-
tion, and expressed as a proportion correct out of 8.
The results are shown in Figure 10.1. The left-hand panel shows the recall
results, with the younger participants’ scores illustrating the typical “levels” pat-
tern of low performance for physical (“first letter”) processing, better for phone-
mic and semantic processing, and best for intentional learning. The older group’s
scores follow the same pattern at a lower level, but with equivalent scores for
semantic and learn conditions. The same pattern holds again for the recognition
results shown in the right-hand panel, but the dramatic finding here is that the
older adults now actually have the highest level of performance—in the semantic
processing condition. Thus, interestingly, older adults’ memory for names was
higher after incidental generation of rhymes and associations than after inten-
tional learning. Also, the typical age-related memory decrement for names was
Name recall Name recognition

1.00
Physical
0.80
Phonemic
Proportion correct
Semantic
0.60
Learn
0.40
0.20
0.00
Young Old Young Old
Figure 10.1. Proportions recalled and recognized as a function of age and type of
processing (Troyer, Häfliger, Cadieux & Craik, 2006).
eliminated by a combination of semantic processing at encoding (schematic

support) and a recognition test at retrieval (environmental support).
The virtual equivalence of performance between the age groups under seman-
tic processing and recognition conditions should not be construed as meaning
that older adults do not “really” have a memory problem, however. Rather, the
point is that as a consequence of less efficient frontal (and probably medial-
temporal) functioning, they do have a problem, but one that can be reduced or
even eliminated by “repairing” both encoding and retrieval.
Another example illustrates the power of contextual reinstatement to provide
environmental support in conjunction with the ability of compatible materials to
tap into schematic support. We assume that the combination of both factors
should provide cognitive compensation that is particularly beneficial to older
adults. In a study conducted with Astrid Schloerscheidt (Craik & Schloerscheidt,
2011) we presented items to learn that were concrete nouns in one half of the
experiment and pictures of the objects in the other half—for example either the
words ANGEL, GUITAR, etc., or small pictures of an angel, a guitar, and so on.
These items were shown at encoding superimposed on one of 10 different scenes
(a beach scene, a street scene, etc.) with instructions to both learn the item and
attempt to associate it with its accompanying scene. In all, 12 words were paired
with each of 10 scenes for a total of 120 items learned; different groups of younger
and older adults were presented with 120 comparable pictures of the objects,
again superimposed on 10 different scenes.
The memory test was recognition memory for the words or pictured objects,
and the degree of contextual reinstatement was manipulated by re-presenting the
item either with its original scene, with another scene (switched context), with no
scene at all (item alone), or with a new scene that the participant had not encoun-
tered before. In terms of theory, the idea here was that pictures of objects would
evoke a richer encoding of the item, and so might benefit the older adults differ-
entially (a benefit of schematic support, in a sense). Second, at retrieval, greater
environmental support was provided as the background context was made closer
to the encoding context; that is, context reinstatement increased from new to no,
to switched, to original context. Our prediction was that the age-related differ-
ence in performance would thus be greatest with words and no or new contexts,
and least with pictured items under original context conditions.
The results are shown in Figure 10.2. The left-hand panel shows recognition
memory scores (hits minus false alarms) when target items were words. Younger
adults performed better overall, and this main effect of aging interacted with
condition such that the advantage to younger participants was greatest when
words were presented with new scenes, and least when words were re-presented
with their original context. Another notable feature of the word data is that the
younger adults performed best with the original context, but performed at a
slightly lower but equivalent level in the other three conditions. On the other
hand, the older adults’ performance fell off progressively from original to new
contexts. The older adults thus appear to be particularly dependent on contextual
reinstatement to perform at a decent level.
The data for the picture stimuli are shown on the right-hand panel. The most
obvious point is that recognition levels are considerably higher with pictured
objects (mean = 0.72) than with their verbal equivalents (mean = 0.48)—the stan-
dard picture superiority effect (Nelson, Reed, & Walling, 1976). Two further
Words Pictures
1.00 Young 1.00 Young

Old 0.90 Old
0.90
0.80 0.80
0.70
Probability correct
0.70
0.60 0.60
0.50 0.50
0.40 0.40
0.30 0.30
0.20 0.20
0.10 0.10
0.00 0.00
Original Switched None New Original Switched None New
Context Context
Figure 10.2. Proportions of items recognized as a function of age, type of material,

and context condition (Craik & Schloerscheidt, 2011).
points are first that context has a much smaller modulating effect with pictures
than with words, and second—most dramatically—the older adults now outper-
form their younger counterparts under all conditions. The first point (seen to
some degree with younger adults even with words) suggests that strongly encoded
or distinctive stimuli can be well recognized despite changes in context; you rec-
ognize a friend even if you encounter her unexpectedly in an unusual location.
The second point again illustrates the finding that the memory performance of
older adults can approach or even exceed that of much younger adults if the mate-
rials are congenial and distinctive (pictures) and the test provides good environ-
mental support.
Aging and Attentional Resources

One theme that has been central to my thinking about age-related problems of
cognitive performance is the notion that the older mind/brain suffers from a
lack of processing resources (e.g., Craik, 1982, 1983; Craik & Byrd, 1982). By
“processing resources” I mean the attentional energy required to fuel encoding
and retrieval operations, as well as such other cognitive activities as concentrating
and thinking. Most cognitive psychologists do not like the energy metaphor, and
Larry Jacoby has been telling me for years that I am really talking about control
processes or executive functions. One reason for sticking with the concept of
attentional resources has been my observation over the years that younger adults
performing a task (e.g., memory encoding) under dual-task conditions end up
behaving very much like older adults working under full attention. The implica-
tion is that by withdrawing processing resources from young adults, we have made
them functionally (if temporarily) into older adults.
One rather compelling illustration of this idea comes from an experiment by
Nicole Anderson (Anderson, Craik, & Naveh-Benjamin, 1998). In different parts
of the study, the memory task was either free recall of 15 common nouns, or a
cued recall task in which 12 pairs of unrelated nouns were presented, and the
participant was later given the first word of each pair as a cue for the second word.
In this latter task, participants were encouraged to form some kind of bond
between the members of each word pair. Older and younger adult participants
encoded the words either under full attention or while also performing a continu-
ous reaction time task.
Table 10.1 shows some values of average recall scores for the two age groups,
when words were encoded either under full attention or divided attention condi-
tions. The table also shows mean reaction time scores for the secondary task—
again either when the reaction time task was performed by itself or in dual-task
mode while the participant was learning the list. The point of the demonstration
is simply the excellent correspondence between scores of the older adults working
under full attention conditions, and the younger adults working under heavy
Table 10.1. Recall Probabilities and Reaction Times as a Function of Age

and Experimental Condition
Experimental Condition Memory Reaction Time
Young Old Young Old
Free Recall
Full attention .82 .53 408 570
Divided attention .51 .28 530 815
Cued Recall
Full attention .85 .50 404 510
Divided attention .49 .25 502 745
Data from Anderson, Craik, & Naveh-Benjamin, 1998.
divided attention conditions; the corresponding values are shown in bold face
type in Table 10.1.
Note that the similarity applies both to memory scores and to reaction time
scores. These results (and other similar results reported by Craik, 1982, and Craik
& Byrd, 1982) thus give good support to the conclusion that young adults work-
ing under divided attention conditions perform quite similarly to adults who are
50 years older than they are, and who are working under full attention conditions.
In turn, the data also support the claim that at least some aspects of cognitive
aging may be characterized in terms of withdrawal of attentional resources.
This conclusion has been challenged by my colleague Moshe Naveh-Benjamin,
however. In a series of papers (e.g., Naveh-Benjamin 2000, 2001) he has taken the
position that the effects of aging are not equivalent to those associated with divi-
sion of attention in young adults—in particular, that older adults have a specific
deficit in the ability to form associative links between items, between events, and
between events and their contexts of occurrence. In response, I have agreed that
older adults find associative learning difficult, and even demonstrated that point
in some of my own studies. For example, McIntyre and Craik (1987) showed that
memory for the source of new information was relatively impaired in older adults
when compared with memory for the new items themselves. Similarly, Castel and
Craik (2003) compared the effects of aging with those of divided attention in
younger adults in a recognition memory study, and found some similarities but
also some differences. Compared to young adults working under full attention
conditions, both older adults and a young group working under divided attention
showed deficits in the recognition of item information. The older adults and the
young divided attention group also showed deficits in recognition of associative
information (ability to recognize word pairs), but performance of the older group
was differentially poorer than that of the young divided attention group in the
associative test, largely owing to the older participants’ propensity to make many
false alarms. Since the distractor stimuli were recombined word pairs (that is,
words that had been studied, but in different pairs), the finding of a high false
alarm rate in older adults suggests a greater reliance on familiarity processes in
recognition memory.
Despite the similarity between the effects of aging and divided attention,
Castel and Craik (2003) considered it possible that older adults might be differen-
tially impaired when dealing with associative information. Lynn Luo, Yuiko
Sakuta and I thus designed a study to examine this possibility directly (Craik,
Luo, & Sakuta, 2010). Three groups of subjects were tested: a group of young
adults who studied the materials to be remembered under full attention (Young-FA
group), a second group of young adults who studied under conditions of divided
attention (Young-DA group), and a group of older adults (Old group; mean age =
73 years) who studied under full attention conditions. Participants studied a long
series of word–scene pairs; in all, 120 different scenes were presented on the com-
puter screen, with an unrelated word superimposed on each picture. Each partici-
pant’s task was to prepare for a later memory test by remembering the items
themselves (words and scenes) as well as the individual word–scene pairings. To
obtain a range of values for both item recognition and associative (word–scene)
recognition, the word–picture pairs were presented at one of four presentation
rates (2, 4, 6, 8 seconds for the Young-FA group; 4, 6, 8, 10 seconds for the
Young-DA and Old groups).
After the study phase, participants were given three recognition tests—one for
the words, one for the scenes, and one for the word–scene associations. In this
last test, all test items had been seen before, but were either in their original pairs
or were recombined words and scenes. The divided attention task was a long series
of auditory digits, and the participant’s task was to detect targets, defined as runs
of two successive odd digits (e.g., 7–9, 5–1, 3–3).
Figure 10.3A shows one informative way to present the results. Associative
recognition is plotted directly against item recognition—defined here as the aver-
age of word and scene recognition. Our assumption was that faster presentation
rates would be associated with lower levels of both item and associative informa-
tion, and the distribution of data points on Figure 10.3 confirms that this occurred.
In fact, for all three groups performance levels decreased linearly as study time
decreased. If the effects of divided attention and aging were qualitatively similar
to the effects of shorter study time, then the data points for the Young-DA and
Old groups should simply fall on the same function as the one derived from the
Young-FA participants, but at lower levels. Figure 10.3A shows that the data points
for the Young-DA participants fit that description, but the points for the older
adults clearly do not. For a given value of item recognition the function fitting
the older adults indicates a lower value of associative recognition—that is, older
adults appear to show an associative deficit over and above the reductions in
A Associative vs. item B Associative vs. word

1.0 1.0
0.9 0.9
Associative recognition
0.8 0.8
0.7 0.7 y = 0.96x – 0.10
2
0.6 y = 1.11x – 0.006 0.6 R = 0.85
R2 = 0.92
0.5 0.5
0.4 FA 0.4 FA
0.3 y = 1.10x – 0.09 DA 0.3 DA
2
0.2 R = 1.00 O 0.2 O
0.1 0.1
0.0 0.0
0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0
Item recognition Word recognition
C Associative vs. scene

1.0
0.9
0.8
y = 1.23x – 0.11
0.7 R2 = 0.97
0.6
0.5
0.4
FA
0.3
DA
0.2 y = 1.08x – 0.21
2
R = 0.91 O
0.1
0.0
0.0 0.2 0.4 0.6 0.8 1.0
Scene recognition
Figure 10.3. Item and associative recognition scores as a function of experimental

condition (data from Craik, Luo & Sakuta, 2010). Panel A graphs associative recognition
against the mean of word recognition (panel B) and scene recognition (panel C).
performance associated with the withdrawal of processing resources. It seems

that Naveh-Benjamin (2000, 2001) was right after all!
Conclusions
At the beginning of this chapter I asked the questions: How similar are the effects
of normal aging to the effects of frontal lobe damage? To what extent is cognitive
aging a frontal lobe problem? My present answer is that there are substantial
similarities between the two conditions, although of course the degree of similar-
ity must presumably depend on the precise location of frontal degeneration or
damage in the two cases. What seems clear is that both older adults (Craik, 1983,
1986) and frontal patients (Lhermitte, 1986; Stuss & Alexander, 2000) have prob-
lems of self-initiation, and therefore profit differentially from environmental and
schematic support. According to Don Stuss, this difficulty is related to inefficient
functioning of superior medial regions of the frontal lobes (Wheeler & Stuss,
2003).
What about the similarity (or partial similarity, as it turns out!) between the
effects of aging and division of attention in young adults? Both are associated
with reductions in activation of left inferior prefrontal regions (e.g., Brodmann

areas 45, 46, 47, and 10; Kapur et al., 1994; Shallice et al., 1994), so this appears
to be a further point of contact. A third point of convergence may well lie with
executive functions and working memory, usually associated with dorsolateral
areas of the frontal lobes. Evidence for poorer executive control and working
memory performance in older adults is well established (see Braver & West, 2008,
for a review).
The results of Naveh-Benjamin (2000) and the more recent study by Craik and
colleagues (2010) make it clear that frontal inefficiency is not the whole story,
however, nor can cognitive aging be characterized simply as a consequence of
reduced processing resources (Craik & Byrd, 1982). Whereas withdrawal of
resources, either by providing less time or by dividing attention, reduces item and
context information proportionately, aging is associated with a disproportionate
loss of contextual information, so that the function relating item and context
information is displaced to the right of the corresponding function for young adults
(see Fig. 10.3). This additional component of age-related inefficiency may be attrib-
utable to declining function in medial-temporal regions (Glisky et al., 1995).
As a final speculative flourish, I will suggest that the “frontal” aspects of age-
related losses in memory and possibly other cognitive processes are mimicked by
withdrawal of processing resources (e.g., by division of attention) in young adults.
On the other hand, the further age-related associative deficit is not mimicked by
division of attention, and may be attributable to medial-temporal problems. We
know that some effects of aging and frontal damage can be compensated for by
the provision of greater degrees of environmental support; it remains to be seen
whether medial-temporal problems are also receptive to compensatory methods.
Finally, I should emphasize that frontal and medial-temporal problems are unlikely
to constitute the whole story of cognitive aging; other factors, such as cognitive
slowing (Salthouse, 1996), loss of inhibitory efficiency (Hasher, Zacks, & May,
1999), and loss of access to highly specific information (Craik, 2006), clearly play
a role. In cognitive aging we tend to focus on our one favorite theory and neglect
the others, but a multifactor account is likely to be nearer the truth.
However the final story is told, Don Stuss’s work on the frontal lobes is certain
to be a key component. I thank him warmly for his inspiration and friendship over
the years.
References
Albert, M. S., & Kaplan, E. (1980). Organic implications of neuropsychological deficits in the elderly.
In L. W. Poon, J. L. Fozard, L. S. Cermak, D. Arenberg , & L. W. Thompson (Eds.), New directions
in memory and aging (pp. 403–432). Hillsdale, NJ: Lawrence Erlbaum Associates.
Anderson, N. D., Craik, F. I. M., & Naveh-Benjamin, M. (1998). The attentional demands of encoding
and retrieval in younger and older adults: I. Evidence from divided attention costs. Psychology
and Aging, 13, 405–423.
Braver, T. S., & West, R . (2008). Working memory, executive control and aging. In F. I. M. Craik &
T. A. Salthouse (Eds.), The handbook of aging and cognition (3rd ed., pp. 311–372). New York:
Psychology Press.
Castel, A. D., & Craik, F. I. M. (2003). The effects of aging and divided attention on memory for item
and associative information. Psychology and Aging, 18, 873–885.
Craik, F. I. M. (1982). Selective changes in encoding as a function of reduced processing capacity. In
F. Klix, J. Hoffman, & E. Van der Meer (Eds.), Cognitive research in psychology. Berlin: DVW.
Craik, F. I. M. (1983) On the transfer of information from temporary to permanent memory.
Philosophical Transactions of the Royal Society, Series B, 302, 341–359.
Craik, F. I. M. (1986). A functional account of age differences in memory. In F. Klix, et al. (Eds.),
Human memory and cognitive capabilities. Amsterdam: North-Holland.
Craik, F. I. M. (2006). Remembering items and their contexts: Effects of aging and divided atten-
tion. In H. Zimmer, A. Mecklinger & U. Lindenberger (Eds.), Binding in human memory: A neu-
rocognitive perspective (pp. 571–594). New York: Oxford University Press.
Craik, F.I.M., & Byrd, M. (1982). Aging and cognitive deficits: the role of attentional resources. In
F. I. M. Craik & S. E. Trehub (Eds.), Aging and cognitive processes. New York: Plenum.
Craik, F. I. M., Luo, L., & Sakuta, Y. (2010). Effects of aging and divided attention on memory for
items and their contexts. Psychology and Aging, 25, 968–979.
Craik, F. I. M., Morris, L. W., Morris, R. G., & Loewen, E. R . (1990). Relations between source
amnesia and frontal lobe functioning in a normal elderly sample. Psychology and Aging, 5,
148–151.
Craik, F. I. M., & Schloerscheidt, A. M. (2011). Age-related differences in recognition memory:
Effects of materials and context change. Psychology and Aging, in press.
Craik, F. I. M., & Tulving , E. (1975). Depth of processing and the retention of words in episodic
memory. Journal of Experimental Psychology: General, 104, 268–294.
Glisky, E. L., Polster, M. R., & Routhieaux, B. C. (1995). Double dissociation between item and
source memory. Neuropsychology, 9, 229–235.
Grady, C. L. & Craik, F. I. M. (2000). Changes in memory processing with age. Current Opinion in
Neurobiology, 10, 224–231.
Grady, C. L., McIntosh, A. R., Horwitz, B., Maisog , J. M., Ungerleider, L. G., Mentis, M. J., Pietrini,
P., Schapiro, M. B., & Haxby, J. V (1995). Age-related reductions in human recognition memory
due to impaired encoding. Science, 269, 218–221.
Hasher, L., & Zacks, R. T. (1979). Automatic and effortful processes in memory. Journal of
Experimental Psychology: General, 108, 356–388.
Hasher, L., Zacks, R. T., & May, C. P. (1999). Inhibitory control, circadian arousal, and age. In
D. Gopher & A. Koriat (Eds.), Attention and performance XVII. Cognitive regulation of perfor-
mance: Interaction of theory and application (pp. 653–675). Cambridge, MA: MIT Press.
Heaton, R. K (1981). Wisconsin Card Sorting Test Manual. Odessa, FL: Psychological Assessment
Resources, Inc.
Kapur, S., Craik, F. I. M., Tulving , E., Wilson, A. A., Houle, S., & Brown, G. M. (1994). Neuroanatomical
correlates of encoding in episodic memory: levels of processing effect. Proceedings of the
National Academy of Sciences U S A, 91, 2008–2011.
Lhermitte, F. (1986). Human autonomy and the frontal lobes: Part II. Patient behavior in complex
and social situations: “the environmental dependency syndrome.” Annals of Neurology, 19,
335–343.
McIntyre, J. S., & Craik, F. I. M. (1987). Age differences in memory for item and source information.
Canadian Journal of Psychology, 41, 175–192.
Naveh-Benjamin, M. (2000). Adult age differences in memory performance: tests of an associa-
tive deficit hypothesis. Journal of Experimental Psychology: Learning, Memory and Cognition,
26, 1170–1187.
Naveh-Benjamin, M. (2001). The effects of divided attention on encoding processes: underlying
mechanisms. In M. Naveh-Benjamin, M. Moscovitch, & H. L. Roediger (Eds.), Perspectives on
human memory and cognitive aging: essays in honour of Fergus Craik (pp. 193–208). New York:
Psychology Press.
Pandya, D. N., & Barnes C. L. (1987). Architecture and connections of the frontal lobe. In: Perecman, E.
(Ed.), The frontal lobes revisited (pp. 41–72) New York: IRBN.
Nelson, D. L., Reed, V. S., Walling, J. R . (1976). Pictorial superiority effect. Journal of Experimental
Psychology: Human Learning & Memory, 2, 523–528.
Raz, N. (2000). Aging of the brain and its impact on cognitive performance: integration of struc-
tural and functional findings. In F. I. M. Craik & T. A. Salthouse (Eds.) Handbook of aging and
cognition–II, (pp. 1–90). Mahwah, NJ: Erlbaum.
Rubin, D.C. (1999). Frontal-striatal circuits in cognitive aging: evidence for caudate involvement.
Aging, Neuropsychology, and Cognition, 6, 241–259.
Salthouse, T. A . (1996). The processing-speed theory of adult age differences in cognition.
Psychological Review, 103, 403–428.
Schacter, D. L., Harbluk, J. L., & McLachlan, D. (1984). Retrieval without recollection: an experimen-
tal analysis of source amnesia. Journal of Verbal Learning and Verbal Behavior, 23, 593–611.
Shallice, T., Fletcher, P., Frith, C. D., Grasby, P., Frackowiak, R. S. J., & Dolan, R. J. (1994). Brain
regions associated with acquisition and retrieval of verbal episodic memory. Nature, 368,
633–635.
Stuss, D. T., & Alexander, M. P. (2000). Executive functions and the frontal lobes: a conceptual view.
Psychological Research, 63, 289–298.
Troyer, A. K., Häfliger, A., Cadieux, M. J., & Craik, F. I. M. (2006). Name and face learning in older
adults: the effects of level of processing, self-generation, and intention to learn. Journal of
Gerontology: Psychological Sciences, 61B, 67–74.
Veroff, A.E. (1980). The neuropsychology of aging: qualitative analysis of visual reproductions.
Psychological Research, 41, 259–268.
West, R. L . (1996). An application of prefrontal cortex function theory to cognitive aging.
Psychological Bulletin, 120, 272–292.
Wheeler, M. A., & Stuss, D. T. (2003). Remembering and knowing in patients with frontal lobe
injuries. Cortex, 39, 827–846.
Wheeler, M. A., Stuss, D. T., & Tulving , E. (1995). Frontal lobe damage produces episodic memory
impairment. Journal of the International Neuropsychological Society, 1, 525–536.
Whelihan, W. M., & Lesher, E. L. (1985). Neuropsychological changes in frontal functions with
aging. Developmental Neuropsychology, 1, 371–380.
11
The Aging Brain
An Alternative Perspective on Age-Related Changes
E L I Z A B E T H C . L E R I T Z , R E G I N A E . M C G L I N C H E Y,
D AV I D H . S A L AT, A N D W I L L I A M P. M I L B E R G
The aging brain undergoes a complex spectrum of changes that likely begins in
middle age and continues throughout adulthood. Early neuropsychological stud-
ies of cognitive aging suggest that the process of growing older affects some
regions of the brain and associated functions in a selective manner (Moscovitch &
Winocur, 1995). In particular, initial work implicated the frontal lobes and pre-
frontal cortex as being highly vulnerable to the aging process, documented
through studies demonstrating that cognitive abilities attributed to frontal lobe
function show a greater decline; this decline is evident at an earlier age than are
functions supported by other brain regions (West, 1996). Support for this idea,
which has become know as the “frontal aging theory” or the “frontal lobe hypoth-
esis of cognitive aging,” has come from both neuroimaging and behavioral stud-
ies. This work has revealed substantial compromise to both gray and white matter
within the frontal lobe (Kalpouzos et al., 2009; Salat et al., 2004, 2005), reduced
patterns of activation as seen through functional MRI (Grady, Springer,
Hongwanishkul, McIntosh, & Winocur, 2006; Prakash, et al., 2009), and concom-
itant deficits on neuropsychological tests of executive function (Balota, 2000;
Head, Kennedy, Rodrigue, & Raz, 2009; Isella et al., 2008). Additional support for
these hypotheses comes from neuropathological and postmortem studies of brain
tissue that similarly show compromise to histopathological processes in frontal
lobe regions (Kemper, 1984), as reviewed by Raz and Rodrigue (2006), as well as
from imaging data suggesting greater frontal changes than other areas (Raz et al.,
1997). However, despite the abundant support, it has also become clear that other
brain regions and cognitive functions are also affected, suggesting that the impact
of age on neural tissue is a more heterogeneous process. Thus, focusing on one
target region, or even on just age itself, may in fact be too simplistic.
198
T h e Ag in g Brain 199
Historically, studies investigating the impact of age on brain structure and

function have used chronological age as the primary index of biological aging.
While certainly this seems to be the most logical, more recent research suggests
that this might not be the best approach. There is now accumulating evidence that
age is best viewed as a reflection of where an individual lies along a continuum of
variability in physiological systems and metabolic states. It is these complex and
interactive systems that provide the broad biological framework in which the cen-
tral nervous system is embedded, and it is becoming increasingly clear that intra-
individual variability within this context determines how successfully an individual
ages overall. For example, variations in pathological and pre-pathological states
affecting cardiovascular function and metabolic regulation over the lifespan may
actually be the underlying cause of many of the specific changes in the central
nervous system, and these conditions happen to become less regulated with
increasing age. In this chapter, we first review the past and current literature on
the associations between aging, the brain, and cognition, then discuss the impact
that biological factors have on these complex interactive systems, and finally,
provide suggestions for future research.
Aging and the Brain: Neuroimaging Findings

Structural changes in the aging brain are well documented. Supporting the theory
that aging preferentially results in alterations to the anterior brain, both cross-
sectional and longitudinal studies have provided robust evidence of age-associ-
ated volume reductions in prefrontal regions (Bergfield et al., 2010; Miyahira, Yu,
Hiramatsu, Shimazaki, & Takeda, 2004; Raz & Rodrigue, 2006; Raz, Rodrigue,
Kennedy, & Acker, 2007; Zimmerman et al., 2006), more pronounced thinning of
the cortical ribbon and increases in sulcal width (Salat et al., 2004), and increases
in ventricular volume (Chow et al., 2008). Compared with younger counterparts,
older individuals also demonstrate smaller volumes and reduced density of sub-
cortical structures such as the neostriatum, which have extensive connections to
the frontal lobe (Bergfield et al., 2010; Cherubini, Peran, Caltagirone, Sabatini, &
Spalletta, 2009; Raz & Rodrigue, 2006). The integrity of white matter microstruc-
ture, myelin-rich fiber bundles connecting various brain regions, also shows age-
related compromise, in part because of the vulnerability to vascular insult of small
fibers that are often involved (Schmahmann, Smith, Eichler, & Filley, 2008).
Increases in the number of white matter signal abnormalities, seen as hyperinten-
sities on T1-weighted MRI scans, are widely reported, and the majority of studies
suggest that these are found predominantly in periventricular, frontal and pre-
frontal brain regions (Holland et al., 2008; Kuchel et al., 2009; Lee et al., 2009;
Oosterman et al., 2008; Vannorsdall, Waldstein, Kraut, Pearlson, & Schretlen,
2009). Diffusion tensor imaging (DTI) has made it possible to assess specific prop-
erties of white matter such as fractional anisotropy (FA), a metric that provides
information about integrity. Several studies of normal healthy aging have reported
increased diffusivity and reduced FA, both of which indicate reduced integrity of
myelinated pathways in frontal white matter relative to more posterior brain
regions (Kennedy & Raz, 2009; Salat, Tuch, Greve, et al., 2005; Yoon, Shim, Lee,
Shon, & Yang, 2008), as well as in the genu of the corpus callosum (Leritz et al.,
2010). These findings suggest that as the brain ages, there may be alterations to
tissue affecting the ability of nerve fibers to transmit information from one brain
region to another, and this process may be more prominent in frontal and pre-
frontal cortex. There is even indication that the actual volume of prefrontal white
matter decreases with age, attesting to this idea (Salat et al., 1999, 2009).
Postmortem neuropathological and histopathological studies have also supported
the frontal aging hypothesis (Morrison & Hof, 1997). There are numerous reports
of processes such as cell body shrinkage (Uemura & Hartmann, 1978), reduction
in synaptic density (Dickstein et al., 2007), and deafferentiation (Kalaria et al.,
1989), all of which result in observed volume loss and damage to white matter
connectivity, and it appears that the frontal and prefrontal cortex are more
vulnerable to these processes than other brain regions (Kemper, 1984). These
studies are consistent with neuroimaging findings of reduced integrity of
frontal lobe brain regions, and have provided support for the frontal aging
theory.
Neuropsychological Correlates of Aging

Neuropsychological impairments on tests of executive function are also well
described in the cognitive aging literature, providing a strong basis of support for
the frontal aging theory (Alvarez & Emory, 2006; Bherer, Belleville, & Hudon,
2004). Dating back to the early 1990s, studies have reported deficits on tasks
purported to measure functions subsumed by the frontal and prefrontal cortex,
spawning many years of work suggesting that the “normal” aging process is dom-
inated by a decline in executive abilities (Daigneault & Braun, 1993; Nyberg,
Winocur, & Moscovitch, 1997; Winocur & Moscovitch, 1990). These impairments
have included such domains as planning and organization (Janowsky & Thomas-
Thrapp, 1993), sequencing (Hanninen et al., 1997), and attention (Commodari &
Guarnera, 2008; West & Bell, 1997). One of the most prevalent “executive” find-
ings has been that older adults have difficulty inhibiting distracting information,
a result that has been demonstrated in a variety of different experimental and
standardized clinical measures (Fisk & Sharp, 2004; Vallesi, McIntosh, & Stuss,
2009). For example, Levine and coworkers (1997) reported that older adults were
impaired on a conditional associative learning paradigm, a task that requires
adequate inhibitory abilities that have been tied to the dorsolateral prefrontal
cortex (Levine, Stuss, & Milberg, 1997). Similarly, a more recent paper found that
older adults were more impaired in a Go/No-go task that requires the inhibiting
of irrelevant stimuli (Vallesi, Stuss, McIntosh, & Picton, 2009). The idea that aging
is associated with impairments in successful inhibition has also been useful
in explaining memory deficits that are thought to stem in part from attentional
difficulty and thus an inability to effectively process to-be-remembered infor-
mation (Anderson & Craik, 2000; Balota, 2000). In fact, knowledge of what is
encompassed under the “executive” rubric has become quite vast over the years,
and as such, it has become clear that some tasks professed to measure other cog-
nitive domains also contain executive components. For example, memory pro-
cesses that require organizational or monitoring abilities are more sensitive to
age-related decline (Simensky & Abeles, 2002). Several aging studies have docu-
mented more prominent deficits and decline in aspects of memory that involve
monitoring, organization, and retrieval, aspects that carry more executive com-
ponents (Glisky, Poslter, & Routhieaux, 1995; Wegesin, Jacobs, Zubin, Ventura, &
Stern, 2000). Examples include source memory, prospective memory, and free
recall (Glisky, Rubin, & Davidson, 2001; Logie & Maylor, 2009).
Following the advent of magnetic resonance technology, the ability to more
definitively relate cognitive performance to brain regions became possible, result-
ing in a burgeoning area of research examining structure–function relationships
in healthy aging. Many studies reporting executive function deficits have reported
concomitant frontal lobe changes, such as volume loss or reductions in white
matter integrity (Salat et al., 2004, 2009; Zimmerman et al., 2006), and have pro-
vided evidence that age itself may be a moderating factor in these relationships.
For example, Brickman and colleagues (2006) reported that age differences in
neuropsychological performance on tasks of executive function and memory were
mediated by the volume of frontal lobe white matter (Brickman et al., 2006). A
recent study found significantly lower FA in the genu of the corpus callosum in
older adults compared with younger adults; correlations were also found between
FA and lower performance on cognitive tasks of perceptual-motor processing,
supporting a structure–function connection in anterior brain regions (Davis et al.,
2009).
Functional magnetic resonance imaging studies, which allow for examination
of region-specific neural activity in response to cognitive tasks, have also been a
large corpus of support for the frontal aging hypothesis. Common findings across
the normal aging literature have been reduced activation in frontal lobe brain
regions while engaging in tasks of executive function (Rajah, Languay, &
Valiquette, 2010), as well as certain memory tasks that are believed to contain
more of an executive component (Rosen et al., 2002). Such results lend support by
implying that lower activity is indicative of poor function, which is also likely
related to evidence of structural pathology (Cook, Bookheimer, Mickes, Leuchter,
& Kumar, 2007). Interestingly, aging has also been associated with greater recruit-
ment of frontal brain regions, or less laterality than is typically found in younger
adults (Cabeza, Anderson, Locantore, & McIntosh, 2002; Reuter-Lorenz & Cappell,
2008). For example, several studies have reported bilateral frontal lobe activation
while engaging in a cognitive task, relative to younger individuals who appear to

recruit fewer brain regions for successful performance (Cabeza et al., 2002).
Findings such as these have led to the belief that due to decreased neural resources,
older adults engage more compensatory strategies when involved in cognitive
processing (Dennis et al., 2008). Many of these increased activation patterns have
been in frontal cortex, thus providing further support for the frontal aging
hypothesis.
Frontal Lobes and Aging: Not the Whole Picture?

Despite the mounting evidence that age-related changes tend to predominate in
frontal and prefrontal brain regions, a review of the literature suggests that in fact
age-associated alterations are perhaps more widespread than regionally specific.
For example, age-associated shrinkage of the hippocampus has emerged as a
common finding, in the absence of, or in addition to, documented frontal lobe
pathology (Golomb et al., 1993; Raz et al., 2004; Zimmerman et al., 2008). A more
recent large-scale study found consistent volume reductions in the overall cortex,
pallidum, putamen, and nucleus accumbens, while regions such as the cerebral
white matter, caudate, and hippocampus were more variable across the sample
and did not show consistent patterns of age-related decline (Walhovd et al., 2009).
Salat and colleagues (2004) reported thinning in primary visual, motor, and audi-
tory cortices in addition to the prefrontal cortex, and such findings have been
replicated across multiple independent samples of older adults (Fjell et al., 2009).
Along these lines, while some studies report impairments predominantly in exec-
utive function, others report deficits in other cognitive domains as more promi-
nent (Ylikoski et al., 1999), and some do not even find evidence of executive
dysfunction (Small, Stern, Tang, & Mayeux, 1999). In neuroimaging studies, even
deficits in executive abilities have been related to brain regions outside of the
frontal cortex. (Elderkin-Thompson, Ballmaier, Hellemann, Pham, & Kumar, 2008;
Kennedy & Raz, 2009; Oosterman et al., 2008). Moreover, some findings have
been difficult to replicate, and often studies emphasize different hypotheses,
which affects interpretation of results or patterns of impairments. Thus, it is likely
that the phenotypic expression of age-related neuropathological and neuropsy-
chological changes may be more complex than can be explained by a theory such
as the frontal aging hypothesis, or even by age itself. This raises the question as to
whether there may be additional factors moderating the relationship between
aging, the brain, and cognition. Explanations for the heterogeneous findings in
normal cognitive aging research include differences in study methodology, as well
as differing theories of age-related changes. (Greenwood, 2000). However, we
assert that these differences can be reconciled by a host of variables, including
genetic, physiological, and environmental. This approach does not aim to contra-
dict or refute the frontal hypothesis of aging; instead, in what follows, our goal is
to provide evidence that differences across studies and among theories may be
explained by the biological context of the particular sample studies, and to high-
light some of the factors that may have more of a role in “normal aging” than was
once believed.
Moderators of the Impact that Aging Has on the

Brain and Cognition and of the Relationship
Between the Brain and Behavior
In the past decade, a great deal of research in older adults has focused on differen-
tiating “normal aging” from “pathological” age-related diseases involving cogni-
tive decline such as Alzheimer’s disease and vascular dementia. This has led to the
discovery that even preclinical or prodromal syndromes can be characterized at
both the neural and behavioral level, and we are now identifying the subtle mark-
ers that may differentiate a normal versus disease-related trajectory of aging.
Moreover, it is becoming clearer that risk factors for dementia syndromes such as
Alzheimer’s disease and vascular dementia are themselves associated with subtle
neural changes, even in the absence of overt clinical symptoms (Kennedy & Raz,
2009; Leritz et al., 2011, 2010). Such variables are not routinely considered in
studies of normal aging, representing important but uncontrolled sources of dis-
crepancy or variability across studies. It is likely not a simple coincidence that
even while the normal cognitive aging literature converges on a consensus that
changes in executive functions and the integrity of the frontal cortices are the
core features of age-related neuroanatomical and neuropsychological alterations,
so does the literature on many factors that place an individual at risk for cognitive
decline. In fact, vascular risk factors, such as high blood pressure, high choles-
terol, atherosclerosis, and diabetes, all of which have been linked to the develop-
ment of dementia syndromes, almost double for each decade of life (American
Heart Association, 2010), and a review of the cognitive aging literature suggests
that these conditions are vastly underrepresented.
As mentioned above, it is becoming more widely known that risk factors for
dementia can have a significant impact on neural integrity and function. For
example, while there is evidence of a seemingly widespread impact on brain struc-
ture, the predominant finding has been that high blood pressure has at least an
initial direct and selective impact on anterior brain regions, particularly in the
absence of overt dementia or severe cognitive impairment. These morphological
changes include a greater percentage of white matter lesions (Murray et al., 2005;
Verdelho et al., 2007) and damage to white matter fiber tracts (Leritz et al., 2010),
as well as reduced volume of cortical gray matter in the frontal cortex (Gianaros,
Greer, Ryan, & Jennings, 2006; Leritz et al., 2011). Not surprisingly, hypertension
has also been associated with decrements in executive function, demonstrated in
various studies reporting poor performance on neuropsychological measures of

attention, concentration, and higher-order thinking (Brady, Spiro, & Gaziano,
2005); these findings have also been tied to structural brain alterations such as
those described above (Raz et al., 2007). Other risk factors, such as high choles-
terol or conditions with persistently elevated glucose levels, also have been related
to brain structure and function (Brady et al., 2005; Taki et al., 2009; Leritz et al.,
2011). Though not examined exclusively to the degree that blood pressure has,
conditions associated with cholesterol such as atherosclerosis have been associ-
ated with alterations to both gray and white matter, and there is some indication
of a propensity to target frontal cortical regions (Kin et al., 2007). Diabetes has
been tied to memory abilities, and it is believed that abnormal glucose levels have
a specific negative impact on neural function in regions such as the hippocampus
and medial temporal lobe (Korf et al., 2007). In fact, several recent studies have
documented reduced hippocampal volumes, in conjunction with poor memory, in
patients with diabetes (Musen et al., 2006).
Despite evidence of regionally and domain-specific findings, however, it is not
uncommon for these factors to occur comorbidly, and as such, many investigators
employ a composite “vascular risk” score that typically encompasses variables
such as blood pressure, cholesterol, and diabetes, as well as other risk factors such
as body mass index and smoking history (Llewellyn et al., 2008). Such investiga-
tions of vascular risk have found alterations to neural tissue across the whole
brain, but have also revealed that prefrontal brain regions and executive function
may be more vulnerable in individuals who possess higher degrees of risk
(Llewellyn et al., 2008; Seshadri et al., 2004). Not only do these studies provide
evidence of a negative impact of these variables on brain structure, but they also
highlight their prevalence. The lack of control for these factors may help to explain,
at least in part, the variation in findings in studies of normal aging. For example,
the evidence presented above suggests that both anterior (i.e., frontal lobes) and
posterior (i.e., hippocampus) brain regions, as well as executive and memory pro-
cesses, may be vulnerable to such factors, and these are the neural regions and
neuropsychological domains that are implicated most often in the normal aging
literature (Curiati et al., 2009; Miyahira et al., 2004; Raji, Lopez, Kuller, Carmichael,
& Becker, 2009; Salat, Tuch, Hevelone, et al., 2005).
It is becoming more apparent that even subclinical levels of these risk factors,
which are below the threshold for a clinical diagnosis such as hypertension, may
influence brain structure and cognition, albeit on a much subtler level. In our
work, we have evidence that even subclinically elevated levels of variables known
to affect brain function, such as blood pressure and cholesterol, have an impact
on brain structure (Leritz et al., 2011). We reported that higher levels of blood
pressure, including levels below those considered to represent clinically signifi-
cant hypertension, are associated with reduced FA in the genu of the corpus cal-
losum, a major white matter pathway in the anterior brain that has extensive
connections with frontal cortex. This association held even when controlling
for age, providing further support for the selective impact of blood pressure on
the anterior brain. Importantly, the genu and other anterior white matter have
been implicated in normal aging (Madden et al., 2009; Salat et al., 2009; Yoon
et al., 2008), suggesting that variables such as blood pressure may have been play-
ing a role in past studies even when excluding for diagnosed hypertension or overt
cerebrovascular disease and related cognitive decline. Decrements in neuropsy-
chological functioning have also been found in patients with subclinical risk. In a
large sample of middle-older aged adults, we found that individuals with higher
levels of subclinical vascular risk performed more poorly on traditional tasks of
executive function (Barber et al., 2006). In this same sample, we found that
memory processes underlying performance on the California Verbal Learning
Test (CVLT-II) that are more tied to executive functioning were more impaired in
association with elevated risk (Barber et al., 2006). More specifically, we found
that the ability to generate a strategy that supported successful remembering,
such as semantic clustering, was used more in the low-risk group. This study
importantly demonstrates that executive functioning and memory, the very
domains that are implicated in association with normal aging, are also implicated
when examining the impact of cardiovascular risk factor levels, even when those
levels fall below what would be considered for clinical diagnosis. Ultimately, this
heightens the importance of taking into account these variables in studies of
normal aging.
To this point, we have discussed some of the most epidemiologically common
physiological and metabolic risk factors in older adults, although it is important
to mention that there are likely many other variables that influence the inter-
action between aging and the brain and cognition. These include other metabolic
indicators of vascular health such as homocysteine levels (Jakubowski, 2008;
Raz & Rodrigue, 2006; Selhub, 2008), obesity (Raji, Ho, et al., 2010) environmen-
tal factors such as low socioeconomic status (Clark, DesMeules, Luo, Duncan, &
Wielgosz, 2009; Kroger et al., 2009) and genetic variants such as the apolipopro-
tein 4 allele (apoE4), which is associated with an approximately 40% risk for the
development of Alzheimer’s disease (Corder et al., 1993; Raber, Huang, & Wesson
Ashford, 2004; Saunders et al., 1993). Homocysteine, an amino acid associated
with risk for cardiovascular disease, is often included in studies of vascular-related
cognitive decline, many of which have demonstrated that elevated levels are
related to poor neuropsychological function (Chee et al., 2009) and brain struc-
tural integrity (Seshadri et al., 2008). High body mass index has been associated
with poor executive function (Gunstad et al., 2007). Studies of the relationship
between apoE4, brain structure, and cognition are plentiful and have revealed
subtle cognitive changes in memory, as well as alterations to brain structures such
as the hippocampus in individuals who have the allele but who are otherwise
healthy (Caselli, 2009; Caselli et al., 2009; Honea, Vidoni, Harsha, & Burns, 2009).
Longitudinal studies have revealed that not all of these individuals progress to
Alzheimer’s disease, suggesting that the mere possession of the gene may interact
with the aging process to influence brain structure and cognition (Bu, 2009;
Kim, Basak, & Holtzman, 2009; Riley et al., 2000). Recent advances in genetic
technology have also described other genes that may be associated with the devel-
opment of late-life diseases such as Alzheimer’s disease or vascular dementia
(Dresner-Pollak et al., 2009; Emanuele et al., 2009; Minoretti et al., 2006), and
these variants may harbor subtle phenotypic expression even before a diagnos-
able pathological process is present (Cacabelos, 1996, 2004). Genetic makeup is
also believed to play a role not only in neuropathology, but also in the phenotypic
expression of structural alterations. The concept of cognitive reserve suggests
that more hereditary factors such as IQ, as well as “environmental” factors such as
education and occupation, can minimize or delay cognitive decline in the face of
underlying brain changes, suggesting that these are additional factors to consider
when interpreting results (Stern, 2003). While we are not able to describe to
exhaustion all risk factors that exist to varying degrees in the “normal” aging pop-
ulation, there certainly are other variables that may influence brain structure and
behavior and that may have roles in neural and cognitive change. It would be
impossible to examine every contributing biological factor in any given study, and
simply including them as exclusion criteria from one’s experimental cohort does
not solve the problem of understanding normal cognitive aging, as the resulting
sample would be biased away from characteristics that may in fact define the
“norm.” Studies that examine neuropsychological and neuroanatomical aspects of
aging while accounting for variation in even just one of these factors will help us
to continue clarifying these issues and understanding how normal aging affects
the brain. This is not to assert that the process of aging does not have an impact
on brain structure; in fact, age may often be the most significant correlate of
change and is the overarching biological context driving normal aging research.
The question is this: To what extent is cognitive aging a reflection of a programmed
biological process versus a reflection of alterations in brain function that occur in
the context of the development of age-related disease states, or the risk factors
for those disease states?
Suggestions for Future Research and Conclusions

In light of what has been presented here, we advocate that future research exam-
ine aging in the context of physiological and metabolic variables that are known
to have a greater impact on older adults. We also advocate for both cross-sectional
and longitudinal investigations of older individuals, as it is possible that the
length of time exposed to biological stresses produced by risk factors may also be
responsible for variation in findings. Finally, we advocate for the continued inte-
gration of both structural and functional neuroimaging techniques in studies of
aging, as these enable correlations to be drawn between neural integrity and
behavior. Imaging of resting-state brain networks has become more popular
recently because of its ability to provide an assessment of baseline communication

between brain areas (Buckner, Andrews-Hanna, & Schacter, 2008). Several stud-
ies have described a “default network,” which comprises correlations between
occipital and frontal regions (Vincent, Kahn, Snyder, Raichle, & Buckner, 2008).
Reductions in these functional correlations have been found in aging, and it has
been suggested that such studies may provide important clues in differentiating
variations in the aging process (Andrews-Hanna et al., 2007). In addition, resting-
state studies, particularly when combined with behavioral data, will help to clarify
the potential pattern of age-related brain changes that occur.
In summary, our goal has been to present the current literature on normal
cognitive aging, highlighting its convergence on the frontal lobes as a primary
target of the aging process, while also taking into account other prevalent findings
such as decreases in hippocampal size and associated cognitive functions. We
have also aimed to present data indicating that the normal aging process may not
be as uniform as can be captured by one single theory or explanation, stressing
the importance of considering other potential mediators of age-related change.
We do not aim to challenge or negate the frontal aging theory, but instead suggest
that normal variation in factors that may ultimately contribute to cognitive
decline may be at least partly responsible for findings that support it. In other
words, we suggest that individual differences in a complex set of biological and
physiological parameters contribute to brain aging, and it is these interactions
that ultimately influence what is commonly observed as “age-related” changes in
cognition.
Acknowledgments
This work was supported by grants from the National Institute of Neurologic
Disorders and Stroke (F32NS051942 and K23NS062148), by a grant from the
National Institute of Nursing Research (R01NR010827), and by Medical Research
Service VA Merit Review Awards to William Milberg and Regina McGlinchey. The
authors would also like to thank Roxana Moayer and Colleen Barber for their
assistance in the final preparations of this chapter.
References
Alvarez, J. A., & Emory, E. (2006). Executive function and the frontal lobes: a meta-analytic review.
Neuropsychology Review, 16(1), 17–42.
American Heart Association. (2010). From www.americanheart.org
Anderson, N. D., & Craik, F. I. M. (2000). Memory in the aging brain. In E. Tulving & F. I. M. Craik
(Eds.), The Oxford handbook of memory (pp. 411–425). Oxford: Oxford University Press.
Andrews-Hanna, J. R., Snyder, A. Z., Vincent, J. L., Lustig, C., Head, D., Raichle, M. E., & Buckner, R.
L . (2007). Disruption of large-scale brain systems in advanced aging. Neuron, 56(5), 924–935.
Balota, D. A., Dolan, P. O., & Duchek, J. M. (2000). Memory changes in healthy older adults. In
E. Tulving & F. I. M. Craik (Eds.), The Oxford handbook of memory (pp. 395–409). Oxford:
Oxford University Press.
Barber, C., Grande, L., Ahlquist, M., Rudolph, J., Schnyer, D., McGilnchey, R., & Millberg , W. (2006).
The relationship of CVLT clustering scores to memory and executive functions in elderly
African-Americans at cardiovascular risk. [Poster presented at the 34th annual meeting of
the International Neuropsychological Society]. Journal of the International Neuropsychological
Society, 12(S1), 178.
Bergfield, K. L., Hanson, K. D., Chen, K., Teipel, S. J., Hampel, H., Rapoport, S. I., Moeller, J. R.,
& Alexander, G. E. (2010). Age-related networks of regional covariance in MRI gray matter:
reproducible multivariate patterns in healthy aging. Neuroimage, 49(2), 1750–1759.
Bherer, L., Belleville, S., & Hudon, C. (2004). [Executive function deficits in normal aging,
Alzheimer’s disease, and frontotemporal dementia]. Psychologie & Neuropsychiatrie du
Vieillissement, 2(3), 181–189.
Brady, C. B., Spiro, A., & Gaziano, J. M. (2005). Effects of age and hypertension on cognition: the
Veterans Affairs Normative Aging Study. Neuropsychology, 19(6), 770–777.
Brickman, A. M., Zimmerman, M. E., Paul, R. H., Grieve, S. M., Tate, D. F., Cohen, R. A., Williams,
L. M., Clark, C. R., & Gordon, E. (2006). Regional white matter and neuropsychological func-
tioning across the adult lifespan. Biological Psychiatry, 60(5), 444–453.
Bu, G. (2009). Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis
and therapy. Nature Reviews Neuroscience, 10(5), 333–344.
Buckner, R. L., Andrews-Hanna, J. R., & Schacter, D. L . (2008). The brain’s default network: anatomy,
function, and relevance to disease. Annals of the New York Academy of Sciences, 1124, 1–38.
Cabeza, R., Anderson, N. D., Locantore, J. K., & McIntosh, A. R . (2002). Aging gracefully: compen-
satory brain activity in high-performing older adults. Neuroimage, 17(3), 1394–1402.
Cacabelos, R . (1996). Diagnosis of Alzheimer’s disease: defining genetic profiles (genotype vs phe-
notype). Acta Neurologica Scandinavica. Supplementum, 165, 72–84.
Cacabelos, R . (2004). Genomic characterization of Alzheimer’s disease and genotype-related phe-
notypic analysis of biological markers in dementia. Pharmacogenomics, 5(8), 1049–1105.
Caselli, R. J. (2009). Age-related memory decline and apolipoprotein E e4. Discovery Medicine,
8(41), 47–50.
Caselli, R. J., Dueck, A. C., Osborne, D., Sabbagh, M. N., Connor, D. J., Ahern, G. L., Baxter, L. C.,
Rapcsak, S. Z., Shi, J., Woodruff, B. K., Locke, D. E., Snyder, C. H., Alexander, G. E., Rademakers,
R., & Reiman, E. M. (2009). Longitudinal modeling of age-related memory decline and the
APOE epsilon4 effect. New England Journal of Medicine, 361(3), 255–263.
Chee, M. W., Chen, K. H., Zheng , H., Chan, K. P., Isaac, V., Sim, S. K., Chuah, L. Y., Schuchinsky, M.,
Fischl, B., & Ng , T. P. (2009). Cognitive function and brain structure correlations in healthy
elderly East Asians. Neuroimage, 46(1), 257–269.
Cherubini, A., Peran, P., Caltagirone, C., Sabatini, U., & Spalletta, G. (2009). Aging of subcorti-
cal nuclei: microstructural, mineralization and atrophy modifications measured in vivo using
MRI. Neuroimage, 48(1), 29–36.
Chow, T. W., Binns, M. A., Freedman, M., Stuss, D. T., Ramirez, J., Scott, C. J., & Black, S. (2008).
Overlap in frontotemporal atrophy between normal aging and patients with frontotemporal
dementias. Alzheimer Disease and Associated Disorders, 22(4), 327–335.
Clark, A. M., DesMeules, M., Luo, W., Duncan, A. S., & Wielgosz, A. (2009). Socioeconomic status and
cardiovascular disease: risks and implications for care. Nature Reviews Cardiology, 6(11), 712–722.
Commodari, E., & Guarnera, M. (2008). Attention and aging. Aging Clinical and Experimental
Research, 20(6), 578–584.
Cook, I., Bookheimer, S., Mickes, L., Leuchter, A., & Kumar, A . (2007). Aging and brain activation
with working memory tasks: an fMRI study of connectivity. International Journal of Geriatric
Psychiatry, 22(4), 11.
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D., Gaskell, P. J., & Small, G. W.
(1993). Gene does of apolipoprotein E E4 allele and sex-specific risk of Alzheimer’s disease.
Science, 261, 921–923.
Curiati, P. K., Tamashiro, J. H., Squarzoni, P., Duran, F. L., Santos, L. C., Wajngarten, M., Leite, C. C.,
Vallada, H., Menezes, P. R., Scazufca, M., Busatto, G. F., & Alves, T. C. (2009). Brain structural
variability due to aging and gender in cognitively healthy elders: results from the Sao Paulo
Ageing and Health Study. AJNR American Journal of Neuroradiology, 30(10), 1850–1856.
Daigneault, S., & Braun, C. M. (1993). Working memory and the Self-Ordered Pointing Task: fur-
ther evidence of early prefrontal decline in normal aging. Journal of Clinical and Experimental
Davis, S. W., Dennis, N. A., Buchler, N. G., White, L. E., Madden, D. J., & Cabeza, R . (2009). Assessing
the effects of age on long white matter tracts using diffusion tensor tractography. Neuroimage,
46(2), 530–541.
Dennis, N. A., Hayes, S. M., Prince, S. E., Madden, D. J., Huettel, S. A., & Cabeza, R . (2008). Effects
of aging on the neural correlates of successful item and source memory encoding. Journal of
Experimental Psychology. Learning, Memory, and Cognition, 34(4), 791–808.
Dickstein, D. L., Kabaso, D., Rocher, A. B., Luebke, J. I., Wearne, S. L., & Hof, P. R . (2007). Changes
in the structural complexity of the aged brain. Aging Cell, 6(3), 275–284.
Dresner-Pollak, R., Kinnar, T., Friedlander, Y., Sharon, N., Rosenmann, H., & Pollak, A . (2009).
Estrogen receptor beta gene variant is associated with vascular dementia in elderly women.
Genetic Testing and Molecular Biomarkers, 13(3), 339–342.
Elderkin-Thompson, V., Ballmaier, M., Hellemann, G., Pham, D., & Kumar, A. (2008). Executive func-
tion and MRI prefrontal volumes among healthy older adults. Neuropsychology, 22(5), 626–637.
Emanuele, E., Lista, S., Ghidoni, R., Binetti, G., Cereda, C., Benussi, L., Maletta, R., Bruni, A. C.,
& Politi, P. (2009). Chromosome 9p21.3 genotype is associated with vascular dementia and
Alzheimer’s disease. Neurobiology of Aging, Aug. 5 [E-pub].
Fisk, J. E., & Sharp, C. A . (2004). Age-related impairment in executive functioning: updating,
inhibition, shifting, and access. Journal of Clinical and Experimental Neuropsychology, 26(7),
874–890.
Fjell, A. M., Westlye, L. T., Amlien, I., Espeseth, T., Reinvang , I., Raz, N., Agartz, I., Salat, D. H.,
Greve, D. N., Fischl, B., Dale, A. M., & Walhovd, K. B. (2009). High consistency of regional
cortical thinning in aging across multiple samples. Cerebral Cortex, 19(9), 2001–2012.
Gianaros, P. J., Greer, P. J., Ryan, C. M., & Jennings, J. R . (2006). Higher blood pressure predicts
lower regional grey matter volume: consequences on short-term information processing.
Neuroimage, 31(2), 754–765.
Glisky, E. L., Poslter, M. R., & Routhieaux, B. C. (1995). Double dissociation between item and
source memory. Neuropsychology, 9(2), 229–235.
Glisky, E. L., Rubin, S. R., & Davidson, P. S. (2001). Source memory in older adults: an encoding or
retrieval problem? Journal of Experimental Psychology. Learning, Memory, and Cognition, 27(5),
1131–1146.
Golomb, J., de Leon, M. J., Kluger, A., George, A. E., Tarshish, C., & Ferris, S. H. (1993). Hippocampal
atrophy in normal aging. An association with recent memory impairment. Archives of
Neurology, 50(9), 967–973.
Grady, C. L., Springer, M. V., Hongwanishkul, D., McIntosh, A. R., & Winocur, G. (2006). Age-
related changes in brain activity across the adult lifespan. Journal of Cognitive Neuroscience,
18(2), 227–241.
Greenwood, P. M. (2000). The frontal aging hypothesis evaluated. Journal of the International
Neuropsychological Society, 6, 705–726.
Gunstad, J., Paul, R. H., Cohen, R. A., Tate, D. F., Spitznagel, M. B., & Gordon, E. (2007). Elevated
body mass index is associated with executive dysfunction in otherwise healthy adults.
Comprehensive Psychiatry, 48(1), 57–61.
Hanninen, T., Hallikainen, M., Koivisto, K., Partanen, K., Laakso, M. P., Riekkinen, P. J., Sr., &
Soininen, H. (1997). Decline of frontal lobe functions in subjects with age-associated memory
impairment. Neurology, 48(1), 148–153.
Head, D., Kennedy, K. M., Rodrigue, K. M., & Raz, N. (2009). Age differences in perseveration: cog-
nitive and neuroanatomical mediators of performance on the Wisconsin Card Sorting Test.
Neuropsychologia, 47(4), 1200–1203.
Holland, C. M., Smith, E. E., Csapo, I., Gurol, M. E., Brylka, D. A., Killiany, R. J., Blacker, D., Albert,
M. S., Guttmann, C. R., & Greenberg , S. M. (2008). Spatial distribution of white-matter
hyperintensities in Alzheimer disease, cerebral amyloid angiopathy, and healthy aging. Stroke,
39(4), 1127–1133.
Honea, R. A., Vidoni, E., Harsha, A., & Burns, J. M. (2009). Impact of APOE on the healthy aging
brain: a voxel-based MRI and DTI study. Journal of Alzheimer’s Disease, 18(3), 553–564.
Isella, V., Mapelli, C., Morielli, N., Pelati, O., Franceschi, M., & Appollonio, I. M. (2008). Age-
related quantitative and qualitative changes in decision making ability. Behavioural Neurology,
19(1–2), 59–63.
Jakubowski, H. (2008). The pathophysiological hypothesis of homocysteine thiolactone-mediated
vascular disease. Journal of Physiology and Pharmacology, 59 Suppl 9, 155–167.
Janowsky, J. S., & Thomas-Thrapp, L. J. (1993). Complex figure recall in the elderly: a deficit in
memory or constructional strategy? Journal of Clinical and Experimental Neuropsychology,
15(2), 159–169.
Kalaria, R. N., Andorn, A. C., Tabaton, M., Whitehouse, P. J., Harik, S. I., & Unnerstall, J. R . (1989).
Adrenergic receptors in aging and Alzheimer’s disease: increased beta 2-receptors in prefron-
tal cortex and hippocampus. Journal of Neurochemistry, 53(6), 1772–1781.
Kalpouzos, G., Chetelat, G., Baron, J. C., Landeau, B., Mevel, K., Godeau, C., Barre, L., Constans,
J. M., Viader, F., Eustache, F., & Desgranges, B. (2009). Voxel-based mapping of brain gray
matter volume and glucose metabolism profiles in normal aging. Neurobiology of Aging, 30(1),
112–124.
Kemper, T. L . (1984). Neuroanatomical and neuropathological changes in normal aging. In M. L.
Albert (Ed.), The clinical neurology of aging. Oxford: Oxford University Press.
Kennedy, K. M., & Raz, N. (2009). Aging white matter and cognition: differential effects of
regional variations in diffusion properties on memory, executive functions, and speed.
Neuropsychologia, 47(3), 916–927.
Kim, J., Basak, J. M., & Holtzman, D. M. (2009). The role of apolipoprotein E in Alzheimer’s disease.
Neuron, 63(3), 287–303.
Kin, T., Yamano, S., Sakurai, R., Kajitani, M., Okahashi, Y., Nishiura, N., Saito, Y., & Ueno, S. (2007).
Carotid atherosclerosis is associated with brain atrophy in Japanese elders. Gerontology, 53(1),
1–6.
Korf, E. S., van Straaten, E. C., de Leeuw, F. E., van der Flier, W. M., Barkhof, F., Pantoni, L., Basile,
A. M., Inzitari, D., Erkinjuntti, T., Wahlund, L. O., Rostrup, E., Schmidt, R., Fazekas, F., &
Scheltens, P. (2007). Diabetes mellitus, hypertension and medial temporal lobe atrophy: the
LADIS study. Diabetic Medicine, 24(2), 166–171.
Kroger, K., Dragano, N., Stang , A., Moebus, S., Mohlenkamp, S., Mann, K., Siegrist, J., Jockel, K.
H., & Erbel, R . (2009). An unequal social distribution of peripheral arterial disease and the
possible explanations: results from a population-based study. Vascular Medicine, 14(4),
289–296.
Kuchel, G. A., Moscufo, N., Guttmann, C. R., Zeevi, N., Wakefield, D., Schmidt, J., Dubeau, C. E., &
Wolfson, L . (2009). Localization of brain white matter hyperintensities and urinary inconti-
nence in community-dwelling older adults. Journals of Gerontology. Series A, Biological Sciences
and Medical Sciences, 64(8), 902–909.
Lee, D. Y., Fletcher, E., Martinez, O., Ortega, M., Zozulya, N., Kim, J., Tran, J., Buonocore, M.,
Carmichael, O., & Decarli, C. (2009). Regional pattern of white matter microstructural changes
in normal aging, MCI, and AD. Neurology, 73(21), 1722–1728.
Leritz, E. C., Salat, D. H., Milberg, W. P., Williams, V. J., Chapman, C. E., Grande, L. J., Rudolph, J. L.,
Barber, C. E., Lipsitz, L., Fischl, B., & McGlinchey, R. E. (2010). Variation in blood pressure
is associated with white matter microstructure but not cognition in African Americans.
Leritz, E. C., Salat, D. H., Williams, V. J., Schnyer, D. M., Rudolph, J. L., Lipsitz, L. A., Fischl, B.,
McGlinchey, R. E., Milberg , W. P. (2011). Thickness of the human cerebral cortex is associated
with metrics of cerebrovascular health in a normative sample of community-dwelling older
adults. Neuroimage, 2011; 54, 2659–2671.
Levine, B., Stuss, D. T., & Milberg , W. P. (1997). Effects of aging on conditional associative learning:
process analyses and comparison with focal frontal lesions. Neuropsychology, 11(3), 367–381.
Llewellyn, D. J., Lang, I. A., Xie, J., Huppert, F. A., Melzer, D., & Langa, K. M. (2008). Framingham
Stroke Risk Profile and poor cognitive function: a population-based study. BMC Neurology, 8, 12.
Logie, R. H., & Maylor, E. A . (2009). An Internet study of prospective memory across adulthood.
Psychology and Aging, 24(3), 767–774.
Madden, D. J., Spaniol, J., Costello, M. C., Bucur, B., White, L. E., Cabeza, R., Davis, S. W., Dennis, N. A.,
Provenzale, J. M., & Huettel, S. A . (2009). Cerebral white matter integrity mediates adult age
differences in cognitive performance. Journal of Cognitive Neuroscience, 21(2), 289–302.
Minoretti, P., Gazzaruso, C., Vito, C. D., Emanuele, E., Bianchi, M., Coen, E., Reino, M., & Geroldi, D.
(2006). Effect of the functional toll-like receptor 4 Asp299Gly polymorphism on susceptibil-
ity to late-onset Alzheimer’s disease. Neuroscience Letters, 391(3), 147–149.
Miyahira, Y., Yu, J., Hiramatsu, K., Shimazaki, Y., & Takeda, Y. (2004). [Brain volumetric MRI study
in healthy elderly persons using statistical parametric mapping]. Seishin Shinkeigaku Zasshi,
106(2), 138–151.
Morrison, J. H., & Hof, P. R . (1997). Life and death of neurons in the aging brain. Science, 278(5337),
412–419.
Moscovitch, M., & Winocur, G. (1995). Frontal lobes, memory, and aging. Annals of the New York
Academy of Sciences, 769, 119–150.
Murray, A. D., Staff, R. T., Shenkin, S. D., Deary, I. J., Starr, J. M., & Whalley, L. J. (2005). Brain
white matter hyperintensities: relative importance of vascular risk factors in nondemented
elderly people. Radiology, 237(1), 251–257.
Musen, G., Lyoo, I. K., Sparks, C. R., Weinger, K., Hwang , J., Ryan, C. M., Jimerson, D. C., Hennen,
J., Renshaw, P. F., & Jacobson, A. M. (2006). Effects of type 1 diabetes on gray matter density
as measured by voxel-based morphometry. Diabetes, 55(2), 326–333.
Nyberg , L., Winocur, G., & Moscovitch, M. (1997). Correlation between frontal lobe functions and
explicit and implicit stem completion in healthy elderly. Neuropsychology, 11(1), 70–76.
Oosterman, J. M., Vogels, R. L., van Harten, B., Gouw, A. A., Scheltens, P., Poggesi, A., Weinstein,
H. C., & Scherder, E. J. (2008). The role of white matter hyperintensities and medial temporal
lobe atrophy in age-related executive dysfunctioning. Brain and Cognition, 68(2), 128–133.
Prakash, R. S., Erickson, K. I., Colcombe, S. J., Kim, J. S., Voss, M. W., & Kramer, A. F. (2009). Age-
related differences in the involvement of the prefrontal cortex in attentional control. Brain
and Cognition, 71(3), 328–335.
Raber, J., Huang , Y., & Wesson Ashford, J. (2004). ApoE genotype accounts for the vast majority of
AD risk and AD pathology. Neurobiology of Aging, 25, 641–650.
Rajah, M. N., Languay, R., & Valiquette, L . (2010). Age-related changes in prefrontal cortex activ-
ity are associated with behavioural deficits in both temporal and spatial context memory
retrieval in older adults. Cortex, 46(4), 535–549.
Raji, C. A., Ho, A. J., Parikshak, N. N., Becker, J. T., Lopez, O. L., Kuller, L. H., Hua, X., Leow, A. D.,
Toga, A. W., & Thompson, P. M. (2010). Brain structure and obesity. Human Brain Mapping,
31(3), 353–364.
Raji, C. A., Lopez, O. L., Kuller, L. H., Carmichael, O. T., & Becker, J. T. (2009). Age, Alzheimer dis-
ease, and brain structure. Neurology, 73(22), 1899–1905.
Raz, N., Gunning , F. M., Head, D., Dupuis, J. H., McQuain, J., Briggs, S. D., Loken, W. J., Thornton,
A. E., & Acker, J. D. (1997). Selective aging of the human cerebral cortex observed in vivo: dif-
ferential vulnerability of the prefrontal gray matter. Cerebral Cortex, 7(3), 268–282.
Raz, N., Gunning-Dixon, F., Head, D., Rodrigue, K., Williamsom, A., & Acker, J. (2004). Aging, sexual
dimporphism, and hemispheric asymmetry of the cerebral cortex: replicability of regional dif-
ferences in volume. Neurobiology of Aging, 25(3), 20.
Raz, N., & Rodrigue, K. M. (2006). Differential aging of the brain: patterns, cognitive correlates and
modifiers. Neuroscience and Biobehavioral Reviews, 30(6), 730–748.
Raz, N., Rodrigue, K. M., Kennedy, K. M., & Acker, J. D. (2007). Vascular health and longitudi-
nal changes in brain and cognition in middle-aged and older adults. Neuropsychology, 21(2),
149–157.
Reuter-Lorenz, P., & Cappell, K . (2008). Neurocognitive aging and the compensation hypothesis.
Current Direction in Psychological Science, 17(3), 6.
Riley, K. P., Snowdon, D. A., Saunders, A. M., Roses, A. D., Mortimer, J. A., & Nanayakkara, N. (2000).
Cognitive function and apolipoprotein E in very old adults: findings from the Nun Study.
Journals of Gerontology. Series B, Psychological Sciences and Social Sciences, 55(2), S69–75.
Rosen, A. C., Prull, M. W., O’Hara, R., Race, E. A., Desmond, J. E., Glover, G. H., Yesavage, J. A.,
& Gabrieli, J. D. (2002). Variable effects of aging on frontal lobe contributions to memory.
Neuroreport, 13(18), 2425–2428.
Salat, D. H., Buckner, R. L., Snyder, A. Z., Greve, D. N., Desikan, R. S., Busa, E., Morris, J. C., Dale,
A. M., & Fischl, B. (2004). Thinning of the cerebral cortex in aging. Cerebral Cortex, 14(7),
721–730.
Salat, D. H., Greve, D. N., Pacheco, J. L., Quinn, B. T., Helmer, K. G., Buckner, R. L., & Fischl, B.
(2009). Regional white matter volume differences in nondemented aging and Alzheimer’s
disease. Neuroimage, 44(4), 1247–1258.
Salat, D. H., Stangl, P. A., Kaye, J. A., & Janowsky, J. S. (1999). Sex differences in prefrontal volume
with aging and Alzheimer’s disease. Neurobiology of Aging, 20(6), 591–596.
Salat, D. H., Tuch, D. S., Greve, D. N., van der Kouwe, A., Hevelone, N. D., Zaleta, A. K., Rosen, B. R.,
Fischl, B., Corkin, S., Rosas, H. D., & Dale, A. M. (2005). Age-related alterations in white matter
microstructure measured by diffusion tensor imaging. Neurobiology of Aging, 26, 1215–1227.
Salat, D. H., Tuch, D. S., Greve, D. N., van der Kouwe, A. J., Hevelone, N. D., Zaleta, A. K., Rosen, B. R.,
Fischl, B., Corkin, S., Rosas, H. D., & Dale, A. M. (2005). Age-related alterations in white
matter microstructure measured by diffusion tensor imaging. Neurobiology of Aging, 26(8),
1215–1227.
Salat, D. H., Tuch, D. S., Hevelone, N. D., Fischl, B., Corkin, S., Rosas, H. D., & Dale, A. M. (2005).
Age-related changes in prefrontal white matter measured by diffusion tensor imaging. Annals
of the New York Academy of Sciences, 1064, 37–49.
Saunders, A. M., Strittmatter, W. J., Schmechel, D., George-Hyslop, P. H., Pericak-Vance, M. A., &
Joo, S. H. (1993). Association of apolipoprotein E allele epsilon 4 with late-onset familial and
sporadic Alzheimer’s disease. Neurology, 43, 1467–1472.
Schmahmann, J. D., Smith, E. E., Eichler, F. S., & Filley, C. M. (2008). Cerebral white matter: neuro-
anatomy, clinical neurology, and neurobehavioral correlates. Annals of the New York Academy
of Sciences, 1142, 266–309.
Selhub, J. (2008). Public health significance of elevated homocysteine. Food and Nutrition Bulletin,
29(2 Suppl), S116–125.
Seshadri, S., Wolf, P. A., Beiser, A., Elias, M. F., Au, R., Kase, C. S., D’Agostino, R. B., & DeCarli, C.
(2004). Stroke risk profile, brain volume, and cognitive function: the Framingham Offspring
Study. Neurology, 63(9), 1591–1599.
Seshadri, S., Wolf, P. A., Beiser, A. S., Selhub, J., Au, R., Jacques, P. F., Yoshita, M., Rosenberg, I. H.,
D’Agostino, R. B., & DeCarli, C. (2008). Association of plasma total homocysteine levels with
subclinical brain injury: cerebral volumes, white matter hyperintensity, and silent brain
infarcts at volumetric magnetic resonance imaging in the Framingham Offspring Study.
Archives of Neurology, 65(5), 642–649.
Simensky, J. D., & Abeles, N. (2002). Decline in verbal memory performance with advancing age:
the role of frontal lobe functioning. Aging & Mental Health, 6(3), 293–303.
Small, S. A., Stern, Y., Tang , M., & Mayeux, R . (1999). Selective decline in memory function among
healthy elderly. Neurology, 52(7), 1392–1396.
Stern, Y. (2003). The concept of cognitive reserve: a catalyst for research. Journal of Clinical and
Experimental Neuropsychology, 25(5), 589–593.
Taki, Y., Kinomura, S., Sato, K., Goto, R., Kawashima, R., & Fukuda, H. (2009). A longitudinal study
of gray matter volume decline with age and modifying factors. Neurobiology of Aging, June 2
[E-pub].
Uemura, E., & Hartmann, H. A . (1978). RNA content and volume of nerve cell bodies in human
brain. I. Prefrontal cortex in aging normal and demented patients. Journal of Neuropathology
and Experimental Neurology, 37(5), 487–496.
Vallesi, A., McIntosh, A. R., & Stuss, D. T. (2009). Temporal preparation in aging: a functional MRI
study. Neuropsychologia, 47(13), 2876–2881.
Vallesi, A., Stuss, D. T., McIntosh, A. R., & Picton, T. W. (2009). Age-related differences in process-
ing irrelevant information: evidence from event-related potentials. Neuropsychologia, 47(2),
577–586.
Vannorsdall, T. D., Waldstein, S. R., Kraut, M., Pearlson, G. D., & Schretlen, D. J. (2009). White matter
abnormalities and cognition in a community sample. Archives of Clinical Neuropsychology,
24(3), 209–217.
Verdelho, A., Madureira, S., Ferro, J. M., Basile, A. M., Chabriat, H., Erkinjuntti, T., Fazekas, F.,
Hennerici, M., O’Brien, J., Pantoni, L., Salvadori, E., Scheltens, P., Visser, M. C., Wahlund,
L. O., Waldemar, G., Wallin, A., & Inzitari, D. (2007). Differential impact of cerebral white
matter changes, diabetes, hypertension and stroke on cognitive performance among non-
disabled elderly. The LADIS study. Journal of Neurology, Neurosurgery, and Psychiatry, 78(12),
1325–1330.
Vincent, J. L., Kahn, I., Snyder, A. Z., Raichle, M. E., & Buckner, R. L . (2008). Evidence for a frontopa-
rietal control system revealed by intrinsic functional connectivity. Journal of Neurophysiology,
100(6), 3328–3342.
Walhovd, K. B., Westlye, L. T., Amlien, I., Espeseth, T., Reinvang , I., Raz, N., Agartz, I., Salat, D. H.,
Greve, D. N., Fischl, B., Dale, A. M., & Fjell, A. M. (2009). Consistent neuroanatomical age-
related volume differences across multiple samples. Neurobiology of Aging, June 29 [E-pub].
Wegesin, D. J., Jacobs, D. M., Zubin, N. R., Ventura, P. R., & Stern, Y. (2000). Source memory and
encoding strategy in normal aging. Journal of Clinical and Experimental Neuropsychology, 22(4),
455–464.
West, R., & Bell, M. A . (1997). Stroop color-word interference and electroencephalogram activa-
tion: evidence for age-related decline of the anterior attention system. Neuropsychology, 11(3),
421–427.
West, R. L . (1996). An application of prefrontal cortex function theory to cognitive aging.
Psychological Bulletin, 120(2), 272–292.
Winocur, G., & Moscovitch, M. (1990). Hippocampal and prefrontal cortex contributions to learn-
ing and memory: analysis of lesion and aging effects on maze learning in rats. Behavioral
Neuroscience, 104(4), 544–551.
Ylikoski, R., Ylikoski, A., Keskivaara, P., Tilvis, R., Sulkava, R., & Erkinjuntti, T. (1999). Heterogeneity
of cognitive profiles in aging: successful aging, normal aging, and individuals at risk for cogni-
tive decline. European Journal of Neurology, 6(6), 645–652.
Yoon, B., Shim, Y. S., Lee, K. S., Shon, Y. M., & Yang , D. W. (2008). Region-specific changes of cere-
bral white matter during normal aging: a diffusion-tensor analysis. Archives of Gerontology and
Geriatrics, 47(1), 129–138.
Zimmerman, M. E., Brickman, A. M., Paul, R. H., Grieve, S. M., Tate, D. F., Gunstad, J., Cohen, R. A.,
Aloia, M. S., Williams, L. M., Clark, C. R., Whitford, T. J., & Gordon, E. (2006). The relationship
between frontal gray matter volume and cognition varies across the healthy adult lifespan.
American Journal of Geriatric Psychiatry, 14(10), 823–833.
Zimmerman, M. E., Pan, J. W., Hetherington, H. P., Katz, M. J., Verghese, J., Buschke, H., Derby,
C. A., & Lipton, R. B. (2008). Hippocampal neurochemistry, neuromorphometry, and verbal
memory in nondemented older adults. Neurology, 70(18), 1594–1600.
12
Structural Brain Imaging and
Cognitive Aging
JOEL RAMIREZ AND SANDRA E. BLACK
Across our lifespan, the human brain undergoes profound structural changes that
affect how we think and behave. From childhood to adolescence and into adult-
hood, age-related changes can be studied in vivo using advanced neuroimaging
techniques. Innovative computational manipulations performed using magnetic
resonance imaging (MRI) allow us to evaluate various properties of the brain at
different points in the aging process. Researchers and clinicians are now armed
with MRI-derived measures ranging from tissue volumetrics to microstructural
integrity, to better understand so-called normal aging in contrast to pathological
aging of the human brain.
Such noninvasive brain neuroimaging techniques, along with advances in com-
putational analysis of brain images and neuroinformatics, are transforming our
ability to measure structural brain changes through the human lifespan, as well as
the disabling pathologies that can alter the “bookends of human development”:
its first and last few decades.
Since the start of the 20th century, life expectancy has almost doubled in devel-
oped countries and is quickly increasing in the developing world. Hence, new
norms for cognitive aging have to be derived, informed by concurrent structural
brain imaging, to understand correlations with brain aging changes, which include
not only hippocampal atrophy and gray matter (GM) and white matter (WM)
alterations, but also aging of the intracranial vessels, particularly small vessel
occlusive disease, which can affect both arterioles and venules. Small vessel dis-
ease may represent a widespread vascular senescence affecting other body organs,
especially if hypertension or other vascular risk factors have been at play
(Thompson & Hakim, 2009). Unlike the case with large vessel occlusion, which is
often signaled by sudden onset of symptoms, such as limb weakness or speech
loss, reflecting infarction and necrosis of the area deprived of blood, the damage
caused by small vessel disease is often covert and insidious, located in WM or in
deep gray nuclei. The injury from small vessel disease can accumulate gradually,
214
S tr uctur al Br ain Im ag in g an d C og n it iv e Ag in g 215
initially allowing compensatory adaptation, until the damage reaches a threshold

of clinical detectability and begins to undermine cognitive function, balance, and
gait (Mungas et al., 2005). This small vessel parenchymal damage is readily evi-
dent on proton density (PD) and T2-weighted MRI as focal, patchy, or confluent
signal changes that are hyperintense to GM. It is so common with human aging
that it has been called “age-related white matter changes” (Wahlund et al., 2001),
though high signal changes can also be seen in the thalamus and corpus striatum,
where they can disrupt frontal-subcortical circuits (Cummings, 1993).
To detect and manage this chronic vascular brain disorder, we need to better
understand underlying mechanisms and evolution over time in the aging brain.
Treatment and prevention could include pharmacotherapies that target mecha-
nisms such as oxidative stress, apoptosis, and inflammation; vasculoprotective
lifestyle choices; and cognitive rehabilitation techniques that may target specific
cognitive deficits.
In the current era of increasing human longevity, it is important to establish
and map out the normal limits of different cognitive processes in the elderly,
including octogenarians and nonagenarians, especially in attention, inhibitory
control and other executive functions, episodic memory, and speed of informa-
tion processing, which seem to be more vulnerable to aging. Sensitivity to lifespan
changes in cognitive circadian rhythms must also be taken into account (Hasher
et al., 2002). Understanding age-related cognitive changes will better equip us to
help older people compensate more effectively, capitalizing on advances in infor-
mation and computer technologies, as well as targeted cognitive-behavioral meth-
ods, such as goal-management training (Levine et al., 2007; Stuss et al., 2007;
Winocur et al., 2007). Essential to that understanding will be in vivo quantifica-
tion of the brain changes that may underpin cognitive trajectories of aging. The
brain changes through the human lifespan reported in recent studies with struc-
tural MRI are highlighted in the following sections.
Whole Brain Changes

It is quite apparent that whole brain parenchymal volumes generally decrease
with age. The Framingham Heart Study, a community-based cross-sectional study
with 2,200 normal participants, reported a steady decline of brain volumes after
the age of 60 years. Total brain volume declined approximately 0.2% of total cra-
nial volume (TCV) per year, a decline that was more pronounced in men than
women (DeCarli et al., 2005). Whole brain volume changes, using co-registration
techniques (e.g., boundary shift integral), estimate shrinkage rates of 0.2% per
year in normal elderly compared to 2% per year in Alzheimer’s disease (Fox et al.,
1999). See Figures 12.1 and 12.2 for examples.
A recent neurostereological study reported that glial cell counts remain
relatively stable when comparing young adult versus old brains (old: 36 billion,
Figure 12.1. An axial slice from T1-weighted MRIs obtained from a 28-year-old man
(left) and a 76-year-old man (right). Note the enlarged ventricles, increased subdural
CSF, and decreased brain parenchyma of the old versus young brain. (Images provided
courtesy of LC Campbell Cognitive Neurology Research Unit.)
Figure 12.2. Axial slice from T1-weighted MRIs obtained from (left to right) a
28-year-old man (red), a 26-year-old man (yellow), a 28-year-old woman (blue), and
a 22-year-old woman (green). Images were aligned along the axis showing the
anterior and posterior commissure for comparison. Note the variability of head sizes,
emphasizing the importance of correction using some form of total intracranial
capacity-volume measure that includes tissue below the dura mater. (Images provided
courtesy of LC Campbell Cognitive Neurology Research Unit.) (See Color Plate Section
for a color version of this figure.)
young: 39 billion; p > 0.05, NS) (Pakkenberg et al., 2003). With an age range of 20
to 90 years, the same study reported a 9.5% decrease in neocortical nerve cells,
noting a loss of approximately 85,000 neurons daily (approximately 1 neuron per
second!). In contrast to previous reports, however, no changes were observed in
GM volumes or neocortical thickness.
Age-Related Changes in Brain Tissues and Regions

Using MRI-derived tissue segmentation techniques, regional GM and WM volume
changes have been shown to change differentially. In normal development from
childhood (6 to 7 years) into adolescence (up to 20 years), recent studies have
demonstrated general decreases in cortical GM combined with linear increases in
WM (Giedd et al., 1999; Giorgio et al., 2010a, 2010b; Paus et al., 2001; Sowell
et al., 2003; Toga et al., 2006). The general decline in whole brain GM continues
along with an eventual decline of WM.
Although several studies have shown similar patterns in whole brain tissue
changes, some studies have revealed different results when regional parcellations
are implemented. In one cross-sectional study of 70 healthy men ranging from
19 to 76 years, frontal and temporal GM showed a linear decline with age, while
WM volume in these regions increased until the age of 50 years, prior to eventual
decline (Bartzokis et al., 2001). Using a different methodology to estimate GM,
a contrasting study on 176 individuals (7 to 87 years) found a nonlinear decline in
GM density over dorsal frontal and parietal association areas, with a differential
increase in posterior temporal GM up until age 30 (followed by eventual decline)
(Sowell et al., 2003). In another cross-sectional study, whole brain GM volume
decreased linearly while WM exhibited a similar quadratic equation function
(increasing until 30 to 50 years and then declining) (Ge et al., 2002). A cross-
sectional study, similar in size and age range, revealed a similar age-related pat-
tern but reported greater decline in WM volumes, showing a 26% decrease starting
at age 30 (Jernigan et al., 2001). These studies suggest that a quadratic function
best describes WM changes (Salat et al., 2009), while total GM tissue volumes
appear to generally decline in a more linear fashion with age (Paus et al., 2001).
Despite this general finding, some studies have reported conflicting results,
with WM showing few or no age effects (Good et al., 2001; Sullivan et al., 2004;
Tisserand et al., 2004). One longitudinal study reported no significant differences
in rates of change across age groups, with minimal brain volume loss after age 65
(Mueller et al., 1998). More advanced WM imaging techniques such as diffusion
tensor imaging (DTI) may be required to resolve these contradictory results.
It is unclear what these results suggest in terms of development and the
aging process. From childhood to adolescent development, the decrease in GM
has been explained by two prevailing theories regarding normal development:
increased myelination of intracortical neurons or synaptic pruning, which is
thought to lead to greater efficiency, shaped by environmental experience. The
eventual decline in adulthood of both GM and WM, combined with a linear
increase in cerebrospinal fluid (CSF), has been attributed to an inevitable human
aging process (Sowell et al., 2004). This leads to an important question: What
brain changes can really be attributed to normal aging? A recent commentary
projecting the slope of decline in neocortical synapses predicted that the eventual
loss in synaptic functioning would reach the dementia range at about age 130
(Terry & Katzman, 2001).
Declines in frontal and temporal volume, increases in ventricle size, and sex
differences (both at baseline and rate of decline) are well documented in the lit-
erature (Coffey et al., 1992; Gunning-Dixon et al., 1998; Jernigan et al., 2001;
Murphy et al., 1996; Paul et al., 2009; Scahill et al., 2003; Sullivan et al., 1995).
A recent study of 251 adults (18 to 79 years) found age-related reduction in
prefrontal volume that was significantly related to poorer cognitive function (Paul
et al., 2009). Ventricles show an inverse relationship with age, increasing in
volume by 0.04% per year, with one longitudinal study reporting a mean volume
change of 650 mm3 per year (Scahill et al., 2003). In addition to sex differences, in
the Framingham study there were regional differences, with greater volume
decreases in the frontal (0.15% per year) and temporal (0.2% year) lobes but little
change in the parietal and occipital lobes over the course of 34 to 97 years, with
men showing smaller relative frontal lobar volumes throughout the lifespan
(DeCarli et al., 2005).
A recent 5-year longitudinal study of 72 participants revealed a similar pattern
of results, showing quadratic and linear decline in volumes of the hippocampus,
inferior temporal, and prefrontal WM (Raz et al., 2005). In contrast, the Baltimore
Longitudinal Study of Aging, a 5-year longitudinal study of 92 healthy adults,
showed similar declines in aging but implicated different brain regions and tissue
types (Resnick et al., 2003). Specifically, frontal and parietal regions exhibited greater
decline than temporal and occipital lobes, with greatest losses in inferior frontal,
cingulate, insula, and inferior parietal GM. Whole brain volume decreased 5.4 cm3
per year and ventricles enlarged 1.4 cm3 per year. Hemispheric differences were also
observed, with greater WM loss in the left than the right temporal regions.
Hippocampus and Medial Temporal Lobe Atrophy

The hippocampus and medial temporal lobe are regions of particular interest in
aging due to their intimate relationship with memory and the limbic system.
Hippocampal and medial temporal lobe atrophy has been reported in many of the
aforementioned studies, showing decreases in volume with age. In one serial MRI
study of 39 participants, head size-corrected hippocampal atrophy rates of 0.82%
were reported (Scahill et al., 2003). Another longitudinal study found a yearly
decline of 1.18% in hippocampal volume after the age of 50, more than double the
rate of shrinkage compared to the entorhinal cortex (Raz et al., 2004). This find-
ing was elucidated in a follow-up study revealing that hypertension was a factor in
hippocampal shrinkage; years of hypertension appeared to have a cumulative and
progressive interaction with age-related hippocampal atrophy. One cross-sectional
study of individuals 30 to 99 years old reported a 35% volume loss in the
hippocampus beginning at 30 years, compared to 14% in cerebral GM and 26% in
WM, none of which was related to the presence of genetic risk factors (Apo-E
allele) (Jernigan et al., 2001). More importantly, however, this study revealed that
hippocampal shrinkage was associated with GM decreases in other brain areas.
Medial temporal lobe atrophy was also found to be a strong predictor of the Trail
Making Test part B, a highly sensitive measure of age-related changes in cognitive
function (Oosterman et al., 2010).
Not surprisingly, longitudinal decrease in medial temporal lobe volume is often
more pronounced in Alzheimer’s patients compared to controls (Jack et al., 1997)
and may be used to predict conversion of mild cognitive impairment (MCI) to
Alzheimer’s disease (Busatto et al., 2003; Mungas et al., 2005; Wang et al., 2009).
This risk may be modified by genotype; for example, in women with MCI, apolipo-
protein E e4 genotype was associated with greater hippocampal atrophy and worse
memory performance (Fleisher et al., 2005). Using T1-weighted MRIs realigned
to the long axis of the hippocampus, the Sunnybrook Dementia Study developed
a “low-tech,” simple linear measure of the thinnest medial temporal lobe width
that was able to discriminate mild Alzheimer’s from controls with a sensitivity of
86%, a specificity of 95%, and an accuracy of 92% (Gao et al., 2003, 2004).
In one study using visual rating on MRIs of 192 participants enrolled in the
Florida Alzheimer’s Disease Research Center, medial temporal lobe atrophy was
used to classify probable Alzheimer’s from no cognitive impairment, with an over-
all correct rate of 82%. Interestingly, the overall correct rate was improved to 87%
when combined with measures for WM hyperintensities (Appel et al., 2009).
Medial temporal atrophy in this Florida study was also used to compare non-am-
nestic MCI patients with amnestic MCI patients, with the amnestic MCI patients
showing greater medial temporal atrophy than the non-amnestic patients and
controls (Appel et al., 2009). In a similar study conducted on 329 participants
selected from the European Alzheimer’s Disease DESCRIPA study, isolated medial
temporal atrophy was also mainly associated with the amnestic MCI subtype,
especially in older subjects (van de Pol et al., 2009). These results suggest the
amnestic MCI subtype may have underlying Alzheimer’s pathology and medial
temporal lobe atrophy may be used to predict MCI conversion to Alzheimer’s.
Automatic methods of hippocampal segmentation are in rapid development, and
with current international efforts to harmonize different landmarks and segmen-
tation techniques, this approach may reach clinical application in the near future
(Derakhshan et al., 2010).
A recent investigation from the Honolulu-Asia Aging Study (HAAS), using a
novel 3D parametric shape analysis comparing hippocampi of 104 normal con-
trols with 24 Alzheimer’s patients and 14 vascular dementia (VaD) patients, found
hippocampal asymmetry in the non-demented group compared to patients, show-
ing the right to be significantly larger than the left in normals (Xu et al., 2008).
Interestingly, age effects of hippocampal volume were also found, but only in the
non-demented group. Future investigations using this novel 3D shape analysis
were suggested in a larger sample of the diseased groups.
In addition to volumetric studies, cortical thickness has also been used to

index atrophy in the aging brain, with various studies demonstrating age-related
cortical thinning (Dale et al., 1999). In one study of 106 participants (18 to
93 years), the cortical rim was shown to decrease by 0.01 mm per decade. Men
had thicker cortex, although this disappeared with head size correction (see
Fig. 12.2 for head size examples) (Salat et al., 2004). In this study, cortical
thinning was greatest in the inferior prefrontal, precentral, and supramarginal
regions. Interestingly, cortical thickness within the temporal lobe was relatively
preserved. A recent study reported that cortical thickness distinguished
Alzheimer’s from normal elderly controls with an overall accuracy of 75%, sensi-
tivity of 79%, and specificity of 71%; however, cortical thickness in the parahip-
pocampal gyrus provided the highest accuracy (94%) (Lerch et al., 2008). Increased
availability of automated cortical thickness estimation software will allow
future studies to combine this measure with other techniques for structural
analysis of the aging brain. A precaution, however, is that these techniques may
not work well in patients with significant amounts of WM disease.
Age-Related White Matter Changes

As previously mentioned, it is generally accepted that the brain’s WM begins to
deteriorate sometime after 30 years, although correlates with cognition and infor-
mation processing remain somewhat controversial. Age-related white matter
changes (ARWMC) can be observed as hyperintense signal abnormalities on T2,
PD, and fluid-attenuated inversion recovery (FLAIR) MRI (Jack et al., 2001;
Kertesz et al., 1988). Various terms are used to describe this phenomenon (e.g.,
subcortical hyperintensities, leukoariosis, ischemic events, silent strokes), but in
this chapter they will be referred to as “white matter hyperintensities” (WMHs).
See Figures 12.3 and 12.4 for examples.
Parenchymal injury from cerebrovascular disease (CVD) is sensitively detected
as WMH on standard structural MRI as mentioned above. It is apparent that
WMHs increase with age, especially with common vascular risk factors (e.g.,
hypertension, diabetes, hypercholesterolemia) (De Leeuw et al., 2001; Liao et al.,
1996; Sachdev et al., 2008). The Cardiovascular Health Study reported that only
4.4% of its 3,300 participants were free from WMHs, and recent reports indicate
they increase risk for dementia, stroke, and other disabilities (Kuller et al., 2007;
Longstreth et al., 1996, 2005). Another study reported that only 6.5% of partici-
pants aged 63 to 84 were free from WMH burden as assessed on MRI (Williams
et al., 2010). The distribution of WMHs is varied, although one study reported
more rapid age-related increases of WMHs in frontal regions compared to tempo-
ral and parietal lobes (Jernigan et al., 2001). These WM changes appear to be
highly inheritable (Atwood et al., 2004).
Figure 12.3. Axial slice from PD MRIs obtained from a 22-year-old woman (left) and
an 88-year-old cognitively normal woman (right). Note the age-related white matter
changes (ARWMC) on the scan of the elderly brain identified as white matter
hyperintensities (WMHs). (Images provided courtesy of LC Campbell Cognitive
Neurology Research Unit.)
Whether the location of WMHs is also important remains unclear. Some stud-
ies claim localization effects (Artero et al., 2004; Burton et al., 2004), including
one study in a dementia population showing that hyperintensities in the antero-
medial thalamus correlated with episodic and working memory, and that WMHs
involving cholinergic tracts compromised executive functions (Swartz, 2002;
Swartz et al., 2003). Others report frontal dysfunction irrespective of location
(Reed et al., 2004; Tullberg et al., 2004). In Alzheimer’s disease, periventricular
WM changes have been reported in 48% to 100% of cases (Brun & Englund, 1986;
Erkinjuntti & Hachinski, 1993; Erkinjuntti et al., 1987), with moderate to severe
degree reported in 33% to 50% of Alzheimer’s subjects, particularly associated
Figure 12.4. Left to right: Coregistered T1-weighted, T2-weighted, and PD MRIs with
lesion segmentation overlaid on the right. Lesions are segmented by WMH subtypes,
with periventricular WMH (red), subcortical WMH (blue), and partial lacunar infarction
within a WMH (yellow). Images were segmented using Lesion Explorer imaging pipeline
(Ramirez et al., 2011), images provided courtesy of LC Campbell Cognitive Neurology
Research Unit. (See Color Plate Section for a color version of this figure.)
with older age (Erkinjuntti & Hachinski, 1993; Fazekas et al., 1987). WMHs may
contribute to cognitive decline, especially executive dysfunction in Alzheimer’s
patients, though this may be stage-dependent (DeCarli et al., 1996; Hsu et al.,
2002; Smith et al., 2000; Wen et al., 2008).
Thus, the clinical significance of WM vasculopathy remains somewhat contro-
versial (DeCarli et al., 1995, 1996; Erkinjuntti et al., 1994). Even the question of
whether WMHs contribute independently to cognitive deficits over and above
global atrophy remains unclear due to conflicting results (Esiri et al., 1997; Looi
et al., 2002; Mungas et al., 2001). Recently, this issue has begun to be addressed
by quantifying both atrophy and CVD burden simultaneously (Fein et al., 2000;
Laakso, 2002; Mungas et al., 2001; Swartz et al., 2008; Wiseman et al., 2004).
In normal individuals, the presence of WMHs and their relationship with cog-
nition appears to vary with age as well. In a recent report from the John Hopkins
ABC study on aging, WMH burden showed little to no effect on cognition in those
aged 20 to 59 years, but participants over the age of 60 exhibited steep cognitive
declines with increased WMH burden (Vannorsdall et al., 2009). The presence of
WMHs may begin as early as 30 years, with one large epidemiological study of 428
normal individuals in their forties (44 to 48 years) reporting a WMH prevalence
of 51% (Wen et al., 2008).
There are multiple pathological correlates of WMH, including ischemic tissue
damage via arteriosclerosis and lipohyalinosis (Babikian & Ropper, 1987; van
Swieten et al., 1991); multiple lacunar infarcts (Longstreth et al., 1996); état criblé
or dilated perivascular spaces in the absence of gliosis and infarction (Awad et al.,
1986); demyelination and subependymal gliosis; amyloid angiopathy (Pantoni &
Garcia, 1997); clasmatodendrosis from cytoplasmic swelling and vacuolation of
astroglia with beading of dendrites (Sahlas et al., 2002); and rarefaction, espe-
cially of myelin, and periventricular venous collagenosis (Black et al., 2009; Gao
et al., 2008; Moody et al., 1995).
In general, WMHs and lacunes are believed to indicate the presence of some
form of small vessel disease and are particularly relevant in the study of the aging
population (Hachinski et al., 2006; van der Flier et al., 2005). Traditionally, this
has been attributed to arteriolar disease. The pial arteries give rise to arterioles
that penetrate into the WM a short distance with no collaterals, such that if a
penetrating arteriole occludes, the cylinder of tissue it supplies will die. The
periventricular WM is relatively oligemic, as shown in a recent cerebral blood flow
study (Brickman et al., 2009), and not surprisingly, the periventricular region is
topographically where the most confluent and highest volumes of WMH are dis-
tributed. A common underlying vasculopathy in this location was elucidated in
the mid-1990s with a series of papers by Moody and coworkers (Moody et al.,
1995), using postmortem MRI to allow precise MRI–pathological correlations. As
discussed recently (Andersson, 2010; Black et al., 2009), arteriolar small vessel
disease may not be the only culprit, though clearly arteriolar occlusive disease of
the long penetrating arteries would be expected to cause ischemic damage to the
WM around the ventricles that depend on this supply. In addition, however,

Moody, Brown, and colleagues have described venous collagenosis in the deep
medullary veins that drain in toward the ventricles (Moody et al., 1995). This
appears to be an aging response, worsened by vascular risks such as hypertension
or hypotension, which may arise in response to relative hypoperfusion of these
deep regions, leading to gradual venous occlusion with resulting venous leakage
and perivenous edema that may explain the confluent hyperintense signal seen
around the ventricle in aging adults (Gao et al., 2008).
Studies of the clinical significance of WMHs in Alzheimer’s disease and normal
aging have shown varied results, although in general WMHs appear to be associ-
ated with cognitive performance, executive function, memory, and gait distur-
bances, as well as GM reduction and medial temporal lobe atrophy (Appel et al.,
2009; Heo et al., 2009; Schmidt et al., 2010; van de Pol et al., 2009; Venkatraman
et al., 2010; Wakefield et al., 2010). A recent study using an MRI-based semi-au-
tomated segmentation on 99 geriatric participants demonstrated that total
WMHs can predict functional measures of urinary incontinence, mobility, execu-
tive function, and processing speed (Wakefield et al., 2010). Activation patterns
from executive control functioning tasks, as measured with fMRI, may also be
related to WMHs, particularly in the posterior parietal lobe (Venkatraman et al.,
2010). In Alzheimer’s patients, WMHs have been correlated with Mini-Mental
State Examination (MMSE) scores and Clinical Dementia Ratings (CDR) scores,
even after adjusting for potentially compounding variables such as age, sex, and
cardiovascular risk factors (Heo et al., 2009). WMHs have also been implicated in
risk of cognitive decline, stroke, and mortality (Debette et al., 2010) in the
Framingham study, and one recent series reported that periventricular WMHs are
predictive of poorer functional stroke outcome (Liou et al., 2010).
Although there is no consensus on classifying WMH subtypes, many neuroim-
aging studies use this method to distinguish between periventricular (pvWH) and
deep white (dWH) lesions, and some have demonstrated differential associations
with GM atrophy, ventricular dilatation, cognition, and motor performance (Iseki
et al., 2010; Sachdev et al., 2005; Sachdev & Wen, 2005; Silbert et al., 2008). Some
studies suggest that pvWH lesions may be more related to gait disorders and
reductions in attention and cognitive speed (Iseki et al., 2010; Sachdev et al.,
2008), although other studies report gait disturbances to be independent of WMH
volume (Guo et al., 2001; Rosano et al., 2007). In a recent SPECT-MRI study exam-
ining gait disturbances, decreases in perfusion were found in the supplementary
motor area, visual cortex, and thalamus in subjects with age-related WM changes
(Iseki et al., 2010).
Increased prevalence of WMHs combined with a reduction in hippocampal
volume may also be related to late-onset depression after the age of 60 (Janssen
et al., 2007). The presence of WMHs appears to have an association with both cog-
nition and depression, such that WMHs predicted cognitive deficits in people with
late-life depression compared to those without depression (Kohler et al., 2010).
Late-life depression has been associated with a number of volumetric measures, in

particular reductions in left temporal lobe GM and left frontal WM (Dotson et al.,
2009), with one SPECT study reporting decreased perfusion in left superior
frontal and anterior cingulate in Alzheimer’s patients with depressive symptoms
(Levy-Cooperman et al., 2008a). A recent study performed on Alzheimer’s patients
found greater frontal WMH in Alzheimer’s patients with apathy, and greater right
parietal WMH in Alzheimer’s patients with depression, suggesting a link between
late-life depression and apathy (Starkstein et al., 2009).
Lacunes are another lesion subtype that require particular attention (Gouw
et al., 2008; Reed et al., 2004; Vermeer et al., 2007). These lesions are believed to
be focal cystic covert infarcts and appear hyperintense (bright) on T2-weighted
MRIs but hypointense (CSF intensity, dark) on T1 images. Due to this relative
intensity difference, a T1-weighted MRI is required in addition to the standard
T2-PD or FLAIR images typically used for WMH identification. The Leukoariosis
and Disability Study (LADIS) reported that 47% of 633 elderly people over the
age of 65 had at least one lacune, with thalamic lacunes associated with poorer
memory, speed and motor control, and executive function, independent of the
WMH volume (Benisty et al., 2009). Participants in the PATH Through Life com-
munity-based longitudinal study (n = 477) showed a significant increase in lacu-
nar infarct volume over the course of 4 years (Chen et al., 2009). Although lacunar
infarction has been associated with a number of risk factors, hypertension appears
to be a common finding (Chen et al., 2009; Das et al., 2008; Prabhakaran et al.,
2008; Vermeer et al., 2003). Some studies suggest that WMHs may be more
related to diffuse cognitive decline, while multiple silent lacunar infarcts may be
more associated with frontal lobe dysfunction (Koga et al., 2009).
Because of the potential impact of WMHs and lacunes, segmentation tech-
niques to quantify them should be employed in studies involving elderly popula-
tions. Consensus-derived harmonization standards recommend the minimal
imaging protocols needed for the quantification of WMHs (Hachinski et al., 2006).
One study demonstrated that failure to segment WMHs separately could inflate
GM tissue volume estimates by as much as 5% in those with significant confluent
pvWH (Levy-Cooperman et al., 2008b), which occurs in 20% of elders (Longstreth
et al., 1996). Documenting the location, quantity, and subtype of WM abnormali-
ties is needed to better understand correlations of WM disease with neuropsycho-
logical deficits. Dissociations among specific age-sensitive cognitive skills and
their neuroanatomical substrates suggest that age-related cognitive declines are
unlikely to stem from a single cause.
Diffusion Tensor Imaging

Diffusion tensor imaging (DTI) provides an estimate of the 3-D shape of water
diffusion in the brain, with the assumption that highly ordered healthy WM
bundles pose a unidirectional barrier to the free diffusion of water (Mori & Zhang,
2006). In contrast, conditions where there is a disruption in the WM’s structural
integrity would allow for the free diffusion of water in all directions. Fractional
anisotropy (FA) is a commonly used metric in DTI, with FA values ranging from
0 to 1, where lower values indicate free diffusion (worse structural integrity) and
higher values indicate unidirectional diffusion (better structural integrity). See
Figure 12.5 for an example.
Although still in its infancy, DTI studies on normal aging have added to our
understanding of the aging brain’s WM. In a large study conducted on 315 healthy
individuals ranging from 5 to 59 years, FA values obtained from regions of inter-
est derived from tractography-based corpus callosal projections were shown to
increase from childhood to adolescence, peaking from 21 to 29 years in the orbital
frontal and temporal regions, and then declining after age 30, with the anterior
frontal areas declining more rapidly than other regions (Lebel et al., 2010).
Studies using DTI suggest that WM integrity may be related to WMHs, WM
atrophy, GM thickness, and cortical activation. Recent work by a group from the
Netherlands reported a decrease in FA values of 832 normal elderly people, which
were explained by WM atrophy and the presence of WMHs (Vernooij et al., 2008).
A similar report was published earlier, indicating that whole brain FA measures
were negatively correlated with WMH volumes. A contrasting study conducted on
a smaller sample size showed similar correlations with DTI and WMH, FA and
hypertension, but no relationship with DTI and regional WM volumes (Burgmans
et al., 2010).
When examining the relationships between DTI measures and GM, one study
demonstrated that FA was positively correlated with GM thickness, particularly
in the left hemisphere (Kochunov et al., 2007). A recent study on Alzheimer’s
patients combining measures from positron emission tomography (PET) with
Figure 12.5. Left to right: Image mask of normal-appearing white matter (NAWM)
with colors representing regional parcellations, a FA map derived from DTI, and the
NAWM overlaid onto the FA map for regions-of-interest analysis of FA. (Images
provided courtesy of LC Campbell Cognitive Neurology Research Unit.). (See Color
Plate Section for a color version of this figure.)
DTI showed that GM metabolism in the left temporal and parietal regions was
associated with left prefrontal FA, and left prefrontal metabolism was correlated
with left posterior temporal FA (Kuczynski et al., 2010). These results suggest
that WM degeneration is associated with GM hypometabolism, particularly in
Alzheimer’s patients.
Age-related degradation of the anterior corpus callosum, frontal WM, WMH,
and correlations with cognitive decline and processing speed have been well docu-
mented in the DTI literature (Charlton et al., 2006; Kochunov et al., 2007, 2010;
Salat et al., 2005; Schulte et al., 2005; Sullivan et al., 2006). Regional analysis of
specific WM tracts in the elderly has shown age-related effects on the WM integ-
rity of the anterior tracts (genu, fornix, uncinate), with lower FA values in these
regions. This decrease in FA was correlated with measures of problem solving,
working memory, and motor factors (Zahr et al., 2009), with one recent study
demonstrating lower FA values in the genu of the corpus callosum associated with
abnormal gait in a sample of 173 normal elderly persons (Bhadelia et al., 2009).
Another recent study revealed age-related changes in 118 adults’ (50 to 90 years)
WM integrity, which was shown to directly affect working memory performance
(Charlton et al., 2008). Similar results were demonstrated in a follow-up study
from the same group, reporting DTI correlations with episodic long-term memory,
WMH, and whole brain volume, suggesting that poorer episodic long-term
memory performance in aging is related to reduced WM integrity (Charlton et al.,
2010).
WM integrity in the prefrontal areas (pericallosal and genu) has also been asso-
ciated with reaction time measures for episodic memory, revealing that the
decrease in FA mediated perceptual speed and episodic retrieval reaction time
(Bucur et al., 2008). In another response time study, FA in the splenium of younger
adults was the best predicator of response time in a visual task; in contrast, FA in
the internal capsule was the best predictor for the older adults. One Canadian
study using CSF-suppressed versus standard DTI reported a 10% to 19% decrease
in FA in the subcortical WM of elderly subjects compared to young ones (Bhagat
& Beaulieu, 2004).
In summary, DTI has opened the microstructural doors for our understanding
of WM integrity in the context of aging. While still in its infancy, novel reports of
microstructural compromise in anterior portions of the corpus callosum, prefron-
tal WM, and other anterior tracts may be associated with memory and speed of
processing as well as aging.
Conclusion
The study of brain aging is also the study of cerebrovascular aging, and we need to
recognize in future work that it will no longer be sufficient to do cognitive testing
on normal elderly people as controls for studies of patient populations without
appropriate brain imaging that can be quantified to evaluate the degree of

tissue compartment atrophy and vascular damage, as well as microstructural
integrity. Such brain imaging should also be included in longitudinal population
studies. Brain perfusion, resting state, and amyloid labeling scans may also in the
future be available to investigate relations between amyloid burden, vascular
pathology, and effects on resting state networks. By using these complementary
advanced imaging methodologies, we can really begin to understand the extent to
which cognitive aging is really a reflection of an individual’s burden of chronic
vascular damage or amyloidopathy, alone or in combination. Other neurodegen-
erative pathologies such as synucleinopathy may also become detectable with
molecular imaging techniques. From the few who escape these common, gradu-
ally cumulative cerebral insults, not to mention the typical vision and hearing
losses that accompany human longevity, we may learn the true limits of healthy
cognitive aging, as well as the role of cognitive/biological reserve and lifestyle
factors. Such knowledge and advances in therapeutics may allow us to assist the
majority of elders to combat these common pathologies and better preserve
independent function and a good quality of life in the second half of a lifespan
that appears to be increasingly available to the human population in the decades
to come.
References
Andersson, T. (2010). What do white matter hyperintensities really represent? Stroke, 41, 574.
Appel, J., Potter, E., Bhatia, N., Shen, Q., Zhao, W., Greig , M. T., et al. (2009). Association of white
matter hyperintensity measurements on brain MR imaging with cognitive status, medial tem-
poral atrophy, and cardiovascular risk factors. AJNR American Journal of Neuroradiology, 30,
1870–1876.
Artero, S., Tiemeier, H., Prins, N. D., Sabatier, R., Breteler, M. M., & Ritchie, K . (2004).
Neuroanatomical localisation and clinical correlates of white matter lesions in the elderly.
Journal of Neurology, Neurosurgery and Psychiatry, 75, 1304–1308.
Atwood, L. D., Wolf, P. A., Heard-Costa, N. L., Massaro, J. M., Beiser, A., D’Agostino, R. B., et al.
(2004). Genetic variation in white matter hyperintensity volume in the Framingham Study.
Stroke, 35, 1609–1613.
Awad, I. A., Johnson, P. C., Spetzler, R. F., & Hodak, J. A . (1986). Incidental subcortical lesions
identified on magnetic resonance imaging in the elderly. II. Postmortem pathological correla-
tions. Stroke, 17, 1090–1097.
Babikian, V. & Ropper, A. H. (1987). Binswanger’s disease: a review 1. Stroke, 18, 2–12.
Bartzokis, G., Beckson, M., Lu, P. H., Nuechterlein, K. H., Edwards, N., & Mintz, J. (2001). Age-
related changes in frontal and temporal lobe volumes in men: a magnetic resonance imaging
study. Archives of General Psychiatry, 58, 461–465.
Benisty, S., Gouw, A. A., Porcher, R., Madureira, S., Hernandez, K., Poggesi, A. et al. (2009).
Location of lacunar infarcts correlates with cognition in a sample of non-disabled subjects
with age-related white-matter changes: the LADIS study. Journal of Neurology, Neurosurgery,
and Psychiatry, 80, 478–483.
Bhadelia, R. A., Price, L. L., Tedesco, K. L., Scott, T., Qiu, W. Q., Patz, S., et al. (2009). Diffusion
tensor imaging, white matter lesions, the corpus callosum, and gait in the elderly. Stroke, 40,
3816–3820.
Bhagat, Y. A. & Beaulieu, C. (2004). Diffusion anisotropy in subcortical white matter and corti-
cal gray matter: changes with aging and the role of CSF-suppression. Journal of Magnetic
Resonance Imaging, 20, 216–227.
Black, S. E., Gao, F. Q., & Bilbao, J. (2009). Understanding white matter disease: Imaging-
pathological correlations in vascular cognitive impairment. Stroke, 40, S48–S52.
Brickman, A. M., Zahra, A., Muraskin, J., Steffener, J., Holland, C. M., Habeck, C., et al. (2009).
Reduction in cerebral blood flow in areas appearing as white matter hyperintensities on mag-
netic resonance imaging. Psychiatry Research, 172, 117–120.
Brun, A., & Englund, E. (1986). A white matter disorder in dementia of the Alzheimer type:
a pathoanatomical study. Annals of Neurology, 19, 253–262.
Bucur, B., Madden, D. J., Spaniol, J., Provenzale, J. M., Cabeza, R., White, L. E., et al. (2008). Age-
related slowing of memory retrieval: contributions of perceptual speed and cerebral white
matter integrity. Neurobiology of Aging, 29, 1070–1079.
Burgmans, S., van Boxtel, M. P., Gronenschild, E. H., Vuurman, E. F., Hofman, P., Uylings, H. B.,
et al. (2010). Multiple indicators of age-related differences in cerebral white matter and the
modifying effects of hypertension. Neuroimage, 49, 2083–2093.
Burton, E. J., Kenny, R. A., O’Brien, J., Stephens, S., Bradbury, M., Rowan, E., et al. (2004). White
matter hyperintensities are associated with impairment of memory, attention, and global
cognitive performance in older stroke patients. Stroke, 35, 1270–1275.
Busatto, G. F., Garrido, G. E., Almeida, O. P., Castro, C. C., Camargo, C. H., Cid, C. G., et al. (2003).
A voxel-based morphometry study of temporal lobe gray matter reductions in Alzheimer’s
disease. Neurobiology of Aging, 24, 221–231.
Charlton, R. A., Barrick, T. R., Markus, H. S., & Morris, R. G. (2010). The relationship between
episodic long-term memory and white matter integrity in normal aging. Neuropsychologia,
48, 114–122.
Charlton, R. A., Barrick, T. R., McIntyre, D. J., Shen, Y., O’Sullivan, M., Howe, F. A., et al. (2006).
White matter damage on diffusion tensor imaging correlates with age-related cognitive
decline. Neurology, 66, 217–222.
Charlton, R. A., Landau, S., Schiavone, F., Barrick, T. R., Clark, C. A., Markus, H. S., et al. (2008).
A structural equation modeling investigation of age-related variance in executive function
and DTI measured white matter damage. Neurobiology of Aging, 29, 1547–1555.
Chen, X., Wen, W., Anstey, K. J., & Sachdev, P. S. (2009). Prevalence, incidence, and risk factors of
lacunar infarcts in a community sample. Neurology, 73, 266–272.
Coffey, C. E., Wilkinson, W. E., Parashos, I. A., Soady, S. A., Sullivan, R. J., Patterson, L. J., et al.
(1992). Quantitative cerebral anatomy of the aging human brain: a cross-sectional study
using magnetic resonance imaging. Neurology, 42, 527–536.
Cummings, J. L . (1993). Frontal-subcortical circuits and human behavior. Archives of Neurology,
50, 873–880.
Dale, A. M., Fischl, B., & Sereno, M. I. (1999). Cortical surface-based analysis. I. Segmentation and
surface reconstruction. Neuroimage., 9, 179–194.
Das, R. R., Seshadri, S., Beiser, A. S., Kelly-Hayes, M., Au, R., Himali, J. J., et al. (2008). Prevalence
and correlates of silent cerebral infarcts in the Framingham Offspring Study. Stroke, 39,
2929–2935.
De Leeuw, F. E., De Groot, J. C., Achten, E., Oudkerk, M., Ramos, L. M., Heijboer, R., et al. (2001).
Prevalence of cerebral white matter lesions in elderly people: a population based magnetic
resonance imaging study. The Rotterdam Scan Study. Journal of Neurology, Neurosurgery, and
Debette, S., Beiser, A., DeCarli, C., Au, R., Himali, J. J., Kelly-Hayes, M., et al. (2010). Association
of MRI markers of vascular brain injury with incident stroke, mild cognitive impairment,
dementia, and mortality: the Framingham Offspring Study. Stroke, 41, 600–606.
DeCarli, C., Grady, C. L., Clark, C. M., Katz, D. A., Brady, D. R., Murphy, D. G. M., et al. (1996).
Comparison of positron emission tomography, cognition, and brain volume in Alzheimer’s
disease with and without severe abnormalities of white matter. Journal of Neurology,
Neurosurgery and Psychiatry, 60, 158–167.
DeCarli, C., Massaro, J., Harvey, D., Hald, J., Tullberg , M., Au, R. et al. (2005). Measures of brain
morphology and infarction in the Framingham Heart Study: establishing what is normal.
Neurobiology of Aging, 26, 491–510.
DeCarli, C., Murphy, D. G. M., Tranh, M., Grady, C. L., Haxby, J. V., Gillette, J. A., et al. (1995). The
effect of white matter hyperintensity volume on brain structure, cognitive performance, and
cerebral metabolism of glucose in 51 healthy adults. Neurology, 45, 2077–2084.
Derakhshan, M., Caramanos, Z., Giacomini, P. S., Narayanan, S., Maranzano, J., Francis, S. J., et al.
(2010). Evaluation of automated techniques for the quantification of grey matter atrophy in
patients with multiple sclerosis. Neuroimage, 52(4), 1261–1267.
Dotson, V. M., Davatzikos, C., Kraut, M. A., & Resnick, S. M. (2009). Depressive symptoms and
brain volumes in older adults: a longitudinal magnetic resonance imaging study. Journal of
Psychiatry & Neuroscience, 34, 367–375.
Erkinjuntti, T., Gao, F., Lee, D. H., Eliasziw, M., Merskey, H., & Hachinski, V. C. (1994). Lack of
difference in brain hyperintensities between patients with early Alzheimer’s disease and con-
trol subjects. Archives of Neurology, 51, 260–268.
Erkinjuntti, T., & Hachinski, V. (1993). Rethinking vascular dementia. Cerebrovascular Diseases,
3, 3–23.
Erkinjuntti, T., Ketonen, L., Sulkava, R., Vuorialho, M., & Palo, J. (1987). CT in the differential
diagnosis between Alzheimer’s disease and vascular dementia. Acta Neurologica Scandinavica,
75, 262–270.
Esiri, M. M., Wilcock, G. K., & Morris, J. H. (1997). Neuropathological assessment of the lesions
of significance in vascular dementia. Journal of Neurology, Neurosurgery, and Psychiatry, 63,
749–753.
Fazekas, F., Chawluk, J. B., Alavi, A., Hurtig , H. I., & Zimmerman, R. A . (1987). MR signal abnor-
malities at 1.5 T in Alzheimer’s dementia and normal aging. American Journal of Roentgenology,
149, 351–356.
Fein, G., DiSclafani, V., Tanabe, J. L., Cardenas, V., Weiner, M. W., Jagust, W. J., et al. (2000).
Hippocampal and cortical atrophy predict dementia in subcortical ischemic vascular disease.
Neurology, 55, 1626–1635.
Fleisher, A., Grundman, M., Jack, C. R., Jr., Petersen, R. C., Taylor, C., Kim, H. T., et al. (2005). Sex,
apolipoprotein E epsilon 4 status, and hippocampal volume in mild cognitive impairment.
Fox, N. C., Scahill, R. I., Crum, W. R., & Rossor, M. N. (1999). Correlation between rates of brain
atrophy and cognitive decline in AD. Neurology, 52, 1687–1689.
Gao, F. Q., Black, S. E., Leibovitch, F. S., Callen, D. J., Lobaugh, N. J., & Szalai, J. P. (2003).
A reliable MR measurement of medial temporal lobe width from the Sunnybrook Dementia
Study. Neurobiology of Aging, 24, 49–56.
Gao, F. Q., Black, S. E., Leibovitch, F. S., Callen, D. J., Rockel, C. P., & Szalai, J. P. (2004). Linear
width of the medial temporal lobe can discriminate Alzheimer’s disease from normal aging:
the Sunnybrook Dementia Study. Neurobiology of Aging, 25, 441–448.
Gao, F. Q., van Gaal, S., Levy-Cooperman, N., Ramirez, J., Scott, C. J., Bilbao, J., et al. (2008). Does
variable progression of incidental white matter hyperintensities in Alzheimer’s disease relate
to venous insufficiency? Alzheimer’s and Dementia, 4(4), T368–T369.
Ge, Y., Grossman, R. I., Babb, J. S., Rabin, M. L., Mannon, L. J., & Kolson, D. L . (2002). Age-related
total gray matter and white matter changes in normal adult brain. Part I: volumetric MR imag-
ing analysis. AJNR American Journal of Neuroradiology, 23, 1327–1333.
Giedd, J. N., Blumenthal, J., Jeffries, N. O., Castellanos, F. X., Liu, H., Zijdenbos, A., et al. (1999).
Brain development during childhood and adolescence: a longitudinal MRI study. Nature
Giorgio, A., Santelli, L., Tomassini, V., Bosnell, R., Smith, S., De, S. N., et al. (2010a). Age-related
changes in grey and white matter structure throughout adulthood. Neuroimage., 51,
943–951.
Giorgio, A., Watkins, K. E., Chadwick, M., James, S., Winmill, L., Douaud, G. et al. (2010b).
Longitudinal changes in grey and white matter during adolescence. Neuroimage, 49, 94–103.
Good, C. D., Johnsrude, I. S., Ashburner, J., Henson, R. N., Friston, K. J., & Frackowiak, R. S. (2001).
A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage.,
14, 21–36.
Gouw, A. A., van der Flier, W. M., Pantoni, L., Inzitari, D., Erkinjuntti, T., Wahlund, L. O., et al.
(2008). On the etiology of incident brain lacunes: longitudinal observations from the LADIS
study. Stroke, 39, 3083–3085.
Gunning-Dixon, F. M., Head, D., McQuain, J., Acker, J. D., & Raz, N. (1998). Differential aging of the
human striatum: a prospective MR imaging study. AJNR American Journal of Neuroradiology,
19, 1501–1507.
Guo, X., Steen, B., Matousek, M., Andreasson, L. A., Larsson, L., Palsson, S., et al. (2001). A pop-
ulation-based study on brain atrophy and motor performance in elderly women. Journals of
Gerontology Series A: Biological Sciences and Medical Sciences, 56, M633–M637.
Hachinski, V., Iadecola, C., Petersen, R. C., Breteler, M. M., Nyenhuis, D. L., Black, S. E., et al. (2006).
National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular
cognitive impairment harmonization standards. Stroke, 37, 2220–2241.
Hasher, L., Chung , C., May, C. P., & Foong , N. (2002). Age, time of testing, and proactive interfer-
ence. Canadian Journal of Experimental Psychology, 56, 200–207.
Heo, J. H., Lee, S. T., Kon, C., Park, H. J., Shim, J. Y., & Kim, M. (2009). White matter hyperin-
tensities and cognitive dysfunction in Alzheimer disease. Journal of Geriatric Psychiatry and
Neurology, 22, 207–212.
Hsu, Y. Y., Schuff, N., Amend, D. L., Du, A. T., Norman, D., Chui, H. C., et al. (2002). Quantitative
magnetic resonance imaging differences between Alzheimer disease with and without subcor-
tical lacunes. Alzheimer Disease and Associated Disorders, 16, 58–64.
Iseki, K., Hanakawa, T., Hashikawa, K., Tomimoto, H., Nankaku, M., Yamauchi, H., et al. (2010).
Gait disturbance associated with white matter changes: a gait analysis and blood flow study.
Neuroimage, 49, 1659–1666.
Jack, C. R., Jr., O’Brien, P. C., Rettman, D. W., Shiung , M. M., Xu, Y., Muthupillai, R., et al. (2001).
FLAIR histogram segmentation for measurement of leukoaraiosis volume. Journal of Magnetic
Resonance Imaging, 14, 668–676.
Jack, C. R., Jr., Petersen, R. C., Xu, Y. C., Waring , S. C., O’Brien, P. C., Tangalos, E. G., et al. (1997).
Medial temporal atrophy on MRI in normal aging and very mild Alzheimer’s disease. Neurology,
49, 786–794.
Janssen, J., Hulshoff Pol, H. E., De Leeuw, F. E., Schnack, H. G., Lampe, I. K., Kok, R. M., et al.
(2007). Hippocampal volume and subcortical white matter lesions in late life depression: com-
parison of early and late onset depression. Journal of Neurology, Neurosurgery and Psychiatry,
78, 638–640.
Jernigan, T. L., Archibald, S. L., Fennema-Notestine, C., Gamst, A. C., Stout, J. C., Bonner, J., et al.
(2001). Effects of age on tissues and regions of the cerebrum and cerebellum. Neurobiology of
Aging, 22, 581–594.
Kertesz, A., Black, S. E., Tokar, G., Benke, T., Carr, T., & Nicholson, L . (1988). Periventricular and
subcortical hyperintensities on magnetic resonance imaging. “Rims, caps, and unidentified
bright objects.” Archives of Neurology, 45, 404–408.
Kochunov, P., Coyle, T., Lancaster, J., Robin, D. A., Hardies, J., Kochunov, V., et al. (2010). Processing
speed is correlated with cerebral health markers in the frontal lobes as quantified by neuroim-
aging. Neuroimage, 49, 1190–1199.
Kochunov, P., Thompson, P. M., Lancaster, J. L., Bartzokis, G., Smith, S., Coyle, T., et al. (2007).
Relationship between white matter fractional anisotropy and other indices of cerebral health
in normal aging: tract-based spatial statistics study of aging. Neuroimage, 35, 478–487.
Koga, H., Takashima, Y., Murakawa, R., Uchino, A., Yuzuriha, T., & Yao, H. (2009). Cognitive conse-
quences of multiple lacunes and leukoaraiosis as vascular cognitive impairment in communi-
ty-dwelling elderly individuals. Journal of Stroke and Cerebrovascular Diseases, 18, 32–37.
Kohler, S., Thomas, A. J., Lloyd, A., Barber, R., Almeida, O. P., & O’Brien, J. T. (2010). White matter
hyperintensities, cortisol levels, brain atrophy and continuing cognitive deficits in late-life
depression. British Journal of Psychiatry, 196, 143–149.
Kuczynski, B., Targan, E., Madison, C., Weiner, M., Zhang , Y., Reed, B., et al. (2010). White matter
integrity and cortical metabolic associations in aging and dementia. Alzheimer’s & Dementia,
6, 54–62.
Kuller, L. H., Arnold, A. M., Longstreth, W. T., Jr., Manolio, T. A., O’Leary, D. H., Burke, G. L., et al.
(2007). White matter grade and ventricular volume on brain MRI as markers of longevity in
the cardiovascular health study. Neurobiology of Aging, 28, 1307–1315.
Laakso, M. P. (2002). Structural imaging in cognitive impairment and the dementias: an update.
Current Opinion in Neurology, 15, 415–421.
Lebel, C., Caverhill-Godkewitsch, S., & Beaulieu, C. (2010). Age-related regional variations of the
corpus callosum identified by diffusion tensor tractography. Neuroimage, 52(1), 20–31.
Lerch, J. P., Pruessner, J., Zijdenbos, A. P., Collins, D. L., Teipel, S. J., Hampel, H., et al. (2008).
Automated cortical thickness measurements from MRI can accurately separate Alzheimer’s
patients from normal elderly controls. Neurobiology of Aging, 29, 23–30.
Levine, B., Stuss, D. T., Winocur, G., Binns, M. A., Fahy, L., Mandic, M., et al. (2007). Cognitive reha-
bilitation in the elderly: effects on strategic behavior in relation to goal management. Journal
of the International Neuropsychological Society, 13, 143–152.
Levy-Cooperman, N., Burhan, A. M., Rafi-Tari, S., Kusano, M., Ramirez, J., Caldwell, C., et al.
(2008a). Frontal lobe hypoperfusion and depressive symptoms in Alzheimer disease. Journal
of Psychiatry & Neuroscience, 33, 218–226.
Levy-Cooperman, N., Ramirez, J., Lobaugh, N. J., & Black, S. E. (2008b). Misclassified tissue vol-
umes in Alzheimer disease patients with white matter hyperintensities: importance of lesion
segmentation procedures for volumetric analysis. Stroke, 39, 1134–1141.
Liao, D., Cooper, L., Cai, J., Toole, J. F., Bryan, N. R., Hutchinson, R. G., et al. (1996). Presence and
severity of cerebral white matter lesions and hypertension, its treatment, and its control. The
ARIC Study. Atherosclerosis Risk in Communities Study. Stroke, 27, 2262–2270.
Liou, L. M., Chen, C. F., Guo, Y. C., Cheng , H. L., Lee, H. L., Hsu, J. S., et al. (2010). Cerebral white
matter hyperintensities predict functional stroke outcome. Cerebrovascular Diseases, 29,
22–27.
Longstreth, W. T., Jr., Arnold, A. M., Beauchamp, N. J., Jr., Manolio, T. A., Lefkowitz, D., Jungreis,
C., et al. (2005). Incidence, manifestations, and predictors of worsening white matter on
serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study.
Stroke, 36, 56–61.
Longstreth, W. T., Jr., Manolio, T. A., Arnold, A., Burke, G. L., Bryan, N., Jungreis, C. A., et al.
(1996). Clinical correlates of white matter findings on cranial magnetic resonance imaging of
3301 elderly people. The Cardiovascular Health Study. Stroke, 27, 1274–1282.
Looi, J., Sachdev, P., Brodaty, H., Valenzuela, M., Lorentz, L., & Sims, J. (2002). Correlation of
neuroimaging and neuropsychological function in the Sydney longitudinal study of stroke.
Neurobiology of Aging, 23(Suppl 1), S54.
Moody, D. M., Brown, W. R., Challa, V. R., & Anderson, R. L . (1995). Periventricular venous collag-
enosis: association with leukoaraiosis. Radiology, 194, 469–476.
Mori, S., & Zhang , J. (2006). Principles of diffusion tensor imaging and its applications to basic
neuroscience research. Neuron, 51, 527–539.
Mueller, E. A., Moore, M. M., Kerr, D. C., Sexton, G., Camicioli, R. M., Howieson, D. B., et al. (1998).
Brain volume preserved in healthy elderly through the eleventh decade. Neurology, 51,
1555–1562.
Mungas, D., Harvey, D., Reed, B. R., Jagust, W. J., DeCarli, C., Beckett, L., et al. (2005). Longitudinal
volumetric MRI change and rate of cognitive decline. Neurology, 65, 565–571.
Mungas, D., Jagust, W. J., Reed, B. R., Kramer, J. H., Weiner, M. W., Schuff, N., et al. (2001). MRI
predictors of cognition in subcortical ischemic vascular disease and Alzheimer’s disease.
Neurology, 57, 2229–2235.
Murphy, D. G., DeCarli, C., McIntosh, A. R., Daly, E., Mentis, M. J., Pietrini, P., et al. (1996). Sex
differences in human brain morphometry and metabolism: an in vivo quantitative magnetic
resonance imaging and positron emission tomography study on the effect of aging. Archives of
General Psychiatry, 53, 585–594.
Oosterman, J. M., Vogels, R. L., van, H. B., Gouw, A. A., Poggesi, A., Scheltens, P., et al. (2010).
Assessing mental flexibility: neuroanatomical and neuropsychological correlates of the Trail
Making Test in elderly people. Clinical Neuropsychology, 24, 203–219.
Pakkenberg , B., Pelvig , D., Marner, L., Bundgaard, M. J., Gundersen, H. J., Nyengaard, J. R., et al.
(2003). Aging and the human neocortex. Experimental Gerontology, 38, 95–99.
Pantoni, L., & Garcia, J. H. (1997). Pathogenesis of leukoaraiosis: a review. Stroke, 28, 652–659.
Paul, R., Grieve, S. M., Chaudary, B., Gordon, N., Lawrence, J., Cooper, N., et al. (2009). Relative
contributions of the cerebellar vermis and prefrontal lobe volumes on cognitive function
across the adult lifespan. Neurobiology of Aging, 30, 457–465.
Paus, T., Collins, D. L., Evans, A. C., Leonard, G., Pike, B., & Zijdenbos, A . (2001). Maturation of
white matter in the human brain: a review of magnetic resonance studies. Brain Research
Bulletin, 54, 255–266.
Prabhakaran, S., Wright, C. B., Yoshita, M., Delapaz, R., Brown, T., DeCarli, C., et al. (2008).
Prevalence and determinants of subclinical brain infarction: the Northern Manhattan Study.
Neurology, 70, 425–430.
Ramirez, J., Gibson, E., Quddus, A., Lobaugh, N. J., Feinstein, A., Levine, B., Scott, C. J. M., Levy-
Cooperman, N., Gao, F. Q., and Black, S. E. (2011). Lesion Explorer: a comprehensive segmen-
tation and parcellation package to obtain regional volumetrics for subcortical hyperintensities
and intracranial tissue. NeuroImage, 54(2), 963–973.
Raz, N., Lindenberger, U., Rodrigue, K. M., Kennedy, K. M., Head, D., Williamson, A., et al. (2005).
Regional brain changes in aging healthy adults: general trends, individual differences and
modifiers. Cerebral Cortex, 15, 1676–1689.
Raz, N., Rodrigue, K. M., Head, D., Kennedy, K. M., & Acker, J. D. (2004). Differential aging of the
medial temporal lobe: a study of a five-year change. Neurology, 62, 433–438.
Reed, B. R., Eberling , J. L., Mungas, D., Weiner, M., Kramer, J. H., & Jagust, W. J. (2004). Effects of
white matter lesions and lacunes on cortical function. Archives of Neurology, 61, 1545–1550.
Resnick, S. M., Pham, D. L., Kraut, M. A., Zonderman, A. B., & Davatzikos, C. (2003). Longitudinal
magnetic resonance imaging studies of older adults: a shrinking brain. Journal of Neuroscience,
23, 3295–3301.
Rosano, C., Aizenstein, H. J., Studenski, S., & Newman, A. B. (2007). A regions-of-interest volumet-
ric analysis of mobility limitations in community-dwelling older adults. Journal of Gerontology
Series A: Biological Sciences and Medical Sciences, 62, 1048–1055.
Sachdev, P., Chen, X., & Wen, W. (2008). White matter hyperintensities in mid-adult life. Current
Opinion in Psychiatry, 21, 268–274.
Sachdev, P., & Wen, W. (2005). Should we distinguish between periventricular and deep white
matter hyperintensities? Stroke, 36, 2342–2343.
Sachdev, P. S., Wen, W., Christensen, H., & Jorm, A. F. (2005). White matter hyperintensities are
related to physical disability and poor motor function. Journal of Neurology, Neurosurgery and
Sahlas, D. J., Bilbao, J. M., Swartz, R. H., & Black, S. E. (2002). Clasmatodendrosis correlating with
periventricular hyperintensity in mixed dementia. Annals of Neurology, 52, 378–381.
Salat, D. H., Buckner, R. L., Snyder, A. Z., Greve, D. N., Desikan, R. S., Busa, E., et al. (2004). Thinning
of the cerebral cortex in aging. Cerebral Cortex, 14, 721–730.
Salat, D. H., Greve, D. N., Pacheco, J. L., Quinn, B. T., Helmer, K. G., Buckner, R. L., et al. (2009).
Regional white matter volume differences in nondemented aging and Alzheimer’s disease.
Neuroimage, 44, 1247–1258.
Salat, D. H., Tuch, D. S., Greve, D. N., van der Kouwe, A. J., Hevelone, N. D., Zaleta, A. K., et al.
(2005). Age-related alterations in white matter microstructure measured by diffusion tensor
imaging. Neurobiology of Aging, 26, 1215–1227.
Scahill, R. I., Frost, C., Jenkins, R., Whitwell, J. L., Rossor, M. N., & Fox, N. C. (2003). A longitudinal
study of brain volume changes in normal aging using serial registered magnetic resonance
imaging. Archives of Neurology, 60, 989–994.
Schmidt, R., Ropele, S., Ferro, J., Madureira, S., Verdelho, A., Petrovic, K., et al. (2010). Diffusion-
weighted imaging and cognition in the Leukoariosis and Disability in the Elderly Study.
Stroke, 41, e402–e408.
Schulte, T., Sullivan, E. V., Muller-Oehring , E. M., Adalsteinsson, E., & Pfefferbaum, A . (2005).
Corpus callosal microstructural integrity influences interhemispheric processing: a diffusion
tensor imaging study. Cerebral Cortex, 15, 1384–1392.
Silbert, L. C., Nelson, C., Howieson, D. B., Moore, M. M., & Kaye, J. A . (2008). Impact of white
matter hyperintensity volume progression on rate of cognitive and motor decline. Neurology,
71, 108–113.
Smith, C. D., Snowdon, D. A., Wang , H., & Markesbery, W. R . (2000). White matter volumes
and periventricular white matter hyperintensities in aging and dementia. Neurology, 54,
838–842.
Sowell, E. R., Peterson, B. S., Thompson, P. M., Welcome, S. E., Henkenius, A. L., & Toga, A. W. (2003).
Mapping cortical change across the human life span. Nature Neuroscience, 6, 309–315.
Sowell, E. R., Thompson, P. M., & Toga, A. W. (2004). Mapping changes in the human cortex
throughout the span of life. Neuroscientist, 10, 372–392.
Starkstein, S. E., Mizrahi, R., Capizzano, A. A., Acion, L., Brockman, S., & Power, B. D. (2009).
Neuroimaging correlates of apathy and depression in Alzheimer’s disease. Journal of
Neuropsychiatry and Clinical Neurosciences, 21, 259–265.
Stuss, D. T., Robertson, I. H., Craik, F. I., Levine, B., Alexander, M. P., Black, S., et al. (2007).
Cognitive rehabilitation in the elderly: a randomized trial to evaluate a new protocol. Journal
of the International Neuropsychological Society, 13, 120–131.
Sullivan, E. V., Adalsteinsson, E., & Pfefferbaum, A . (2006). Selective age-related degradation
of anterior callosal fiber bundles quantified in vivo with fiber tracking. Cerebral Cortex, 16,
1030–1039.
Sullivan, E. V., Marsh, L., Mathalon, D. H., Lim, K. O., & Pfefferbaum, A . (1995). Age-related decline
in MRI volumes of temporal lobe gray matter but not hippocampus. Neurobiology of Aging,
16, 591–606.
Sullivan, E. V., Rosenbloom, M., Serventi, K. L., & Pfefferbaum, A . (2004). Effects of age and sex on
volumes of the thalamus, pons, and cortex. Neurobiology of Aging, 25, 185–192.
Swartz, R. H. (2002). Evaluating the impact of cerebrovascular disease on cognition using quantitative
MRI. University of Toronto, Toronto.
Swartz, R. H., Sahlas, D. J., & Black, S. E. (2003). Strategic involvement of cholinergic pathways cor-
relates with visuospatial and executive dysfunction: does the location of white matter signal
hyperintensities matter? Journal of Stroke and Cerebrovascular Diseases, 12, 29–36.
Swartz, R. H., Stuss, D. T., Gao, F., & Black, S. E. (2008). Independent cognitive effects of atrophy
and diffuse subcortical and thalamico-cortical cerebrovascular disease in dementia. Stroke,
39, 822–830.
Terry, R. D., & Katzman, R . (2001). Life span and synapses: will there be a primary senile dementia?
Neurobiology of Aging, 22, 347–348.
Thompson, C. S., & Hakim, A. M. (2009). Living beyond our physiological means: small vessel
disease of the brain is an expression of a systemic failure in arteriolar function: a unifying
hypothesis. Stroke, 40, e322–e330.
Tisserand, D. J., van Boxtel, M. P., Pruessner, J. C., Hofman, P., Evans, A. C., & Jolles, J. (2004). A
voxel-based morphometric study to determine individual differences in gray matter density
associated with age and cognitive change over time. Cerebral Cortex, 14, 966–973.
Toga, A. W., Thompson, P. M., & Sowell, E. R . (2006). Mapping brain maturation. Trends in
Neurosciences, 29, 148–159.
Tullberg, M., Fletcher, E., DeCarli, C., Mungas, D., Reed, B. R., Harvey, D. J., et al. (2004). White
matter lesions impair frontal lobe function regardless of their location. Neurology, 63,
246–253.
van de Pol, L. A., Verhey, F., Frisoni, G. B., Tsolaki, M., Papapostolou, P., Nobili, F., et al. (2009).
White matter hyperintensities and medial temporal lobe atrophy in clinical subtypes of mild
cognitive impairment: the DESCRIPA study. Journal of Neurology, Neurosurgery and Psychiatry,
80, 1069–1074.
van der Flier, W. M., Van Straaten, E. C., Barkhof, F., Verdelho, A., Madureira, S., Pantoni, L., et al.
(2005). Small vessel disease and general cognitive function in nondisabled elderly: the LADIS
study. Stroke, 36, 2116–2120.
van Swieten, J. C., Geyskes, G. G., Derix, M. M., Peeck, B. M., Ramos, L. M., van Latum, J. C.,
et al. (1991). Hypertension in the elderly is associated with white matter lesions and cognitive
decline. Annals of Neurology, 30, 825–830.
Vannorsdall, T. D., Waldstein, S. R., Kraut, M., Pearlson, G. D., & Schretlen, D. J. (2009). White matter
abnormalities and cognition in a community sample. Archives of Clinical Neuropsychology, 24,
209–217.
Venkatraman, V. K., Aizenstein, H., Guralnik, J., Newman, A. B., Glynn, N. W., Taylor, C., et al.
(2010). Executive control function, brain activation and white matter hyperintensities in
older adults. Neuroimage, 49, 3436–3442.
Vermeer, S. E., Den, H. T., Koudstaal, P. J., Oudkerk, M., Hofman, A., & Breteler, M. M. (2003).
Incidence and risk factors of silent brain infarcts in the population-based Rotterdam Scan
Study. Stroke, 34, 392–396.
Vermeer, S. E., Longstreth, W. T., Jr., & Koudstaal, P. J. (2007). Silent brain infarcts: a systematic
review. Lancet Neurology, 6, 611–619.
Vernooij, M. W., de, G. M., van der, L. A., Ikram, M. A., Krestin, G. P., Hofman, A., et al. (2008).
White matter atrophy and lesion formation explain the loss of structural integrity of white
matter in aging. Neuroimage, 43, 470–477.
Wahlund, L. O., Barkhof, F., Fazekas, F., Bronge, L., Augustin, M., Sjogren, M., et al. (2001). A
new rating scale for age-related white matter changes applicable to MRI and CT. Stroke, 32,
1318–1322.
Wakefield, D. B., Moscufo, N., Guttmann, C. R., Kuchel, G. A., Kaplan, R. F., Pearlson, G., et al.
(2010). White matter hyperintensities predict functional decline in voiding, mobility, and
cognition in older adults. Journal of the American Geriatrics Society, 58, 275–281.
Wang , H., Golob, E., Bert, A., Nie, K., Chu, Y., Dick, M. B., et al. (2009). Alterations in regional brain
volume and individual MRI-guided perfusion in normal control, stable mild cognitive impair-
ment, and MCI-AD converter. Journal of Geriatric Psychiatry and Neurology, 22, 35–45.
Wen, W., Sachdev, P. S., Li, J. J., Chen, X., & Anstey, K. J. (2008). White matter hyperintensities in
the forties: their prevalence and topography in an epidemiological sample aged 44–48. Human
Brain Mapping, 30(4), 1155–1167.
Williams, L. R., Hutchinson, C. E., Jackson, A., Horan, M. A., Jones, M., McInnes, L., et al. (2010).
Clinical correlates of cerebral white matter hyperintensities in cognitively normal older adults.
Archives of Gerontology and Geriatrics, 50, 127–131.
Winocur, G., Craik, F. I., Levine, B., Robertson, I. H., Binns, M. A., Alexander, M., et al. (2007).
Cognitive rehabilitation in the elderly: overview and future directions. Journal of the
International Neuropsychological Society, 13, 166–171.
Wiseman, R. M., Saxby, B. K., Burton, E. J., Barber, R., Ford, G. A., & O’Brien, J. T. (2004).
Hippocampal atrophy, whole brain volume, and white matter lesions in older hypertensive
subjects. Neurology, 63, 1892–1897.
Xu, Y., Valentino, D. J., Scher, A. I., Dinov, I., White, L. R., Thompson, P. M., et al. (2008). Age effects
on hippocampal structural changes in old men: the HAAS. Neuroimage, 40, 1003–1015.
Zahr, N. M., Rohlfing , T., Pfefferbaum, A., & Sullivan, E. V. (2009). Problem solving, working
memory, and motor correlates of association and commissural fiber bundles in normal aging:
a quantitative fiber tracking study. Neuroimage, 44, 1050–1062.
13
The Effects of Focal and Diffuse
Brain Injury on Behavior
Assessing “A Slice of Life” with Neuropsychology and
Multimodal Neuroimaging
BRIAN LEVINE
Don Stuss’s 1995 presidential address to the International Neuropsychological

Society was entitled “The challenge of neuropsychology: A slice of life and how to
measure it.” How to measure the real-life deficits of patients with frontal damage
is a classic conundrum within neuropsychology: the patients’ deficits are difficult
to characterize with standard laboratory testing even though the patients and
their family members complain of serious difficulties in completing real-life tasks
following recovery from their brain injury.
Perhaps Don’s major legacy, as reflected in many of the chapters in this volume
(those by Shallice, Burgess, D’Esposito, and Rosenbaum), will relate to the analy-
sis of discrete elements of behavior in relation to areas of brain damage in patients
with focal frontal lesions. This approach is necessary to deconstruct tasks into
their constituent parts towards building a model of frontal lobe function. An
alternative, ecologically based approach is to assess the slice of life holistically.
In the first part of this chapter, I will describe our work in this area using novel
measures designed to simulate real-life behavior in the laboratory. Much of this
work included patients with traumatic brain injury (TBI), an area where Don also
made significant contributions.
It is well known that behavior in TBI patients mimics that of patients with
frontal lesions (Goldberg & Bilder, 1987; Stuss & Gow, 1992; Vilkki, 1992). This is
in part because the patients have focal lesions, usually localized to the ventral
frontal and anterior temporal regions (Courville, 1937). Diffuse axonal injury
(DAI), however, is more ubiquitous than focal lesions in TBI (Povlishock & Katz,
2005) and perhaps of even greater functional significance than focal lesions,
particularly in relation to the complex real-life tasks that are so disabled in
235
these patients. In the second part of this chapter, I will describe our attempts at
characterizing the diffuse lesion of TBI and its relation to behavior.
Generally speaking, diffuse injury is much more common than focal lesions as
classically studied in the literature on frontal lobe function. For example, the inci-
dence of TBI is 101/100,000 (Hirtz et al., 2007). By contrast, incidence estimates
for meningioma, a common cause of focal lesions in neuropsychological studies,
is 2.9/100,000 for men and 13/100,000 for women (Larjavaara, Haapasalo,
Sankila, Helen, & Auvinen, 2008). The most common neurological disorder,
stroke, occurs in 183/100,000 (Hirtz et al., 2007). Stroke patients with large
vessel disease are also commonly used for focal lesion studies, yet 80% of strokes
are subcortical, with ischemic damage due to occlusion in penetrating arteries
(Tullberg et al., 2004). This ischemic white matter disease may be undiagnosed
even though it causes significant cognitive changes (Hakim, 2007; see Leritz et al.,
this volume [Chapter 11]). Moreover, aging and dementia, epilepsy, and psychiat-
ric conditions are all associated with diffuse lesions affecting integrated network
functioning. Indeed, such damage is also present in the patients with focal lesions
due to distal lesion effects, edema, and so on. Thus, it is necessary to understand
diffuse damage in addition to focal damage to better characterize the brain–behav-
ior relationships in both patients and healthy adults and children. Moreover,
if one accepts a network (as opposed to modular) model of brain function (see
Voytek and Knight, this volume [Chapter 6]), a diffuse lesion model is as crucial to
understanding brain function as is a focal lesion model.
Assessing Strategic Behavior in Patients with

Focal and Diffuse Damage
Our perspective in assessing real-life behavior was informed by how various sec-
tors of the prefrontal cortex and frontal lobes are involved in behavior. A funda-
mental distinction governing this approach was that between ventral and dorsal
sectors of the prefrontal cortex, with ventral sectors mediating reward- and emo-
tion-related processes and the dorsal sectors mediating cognitive functions (Stuss
& Levine, 2002). We reasoned that patients with ventral frontal damage, includ-
ing those with TBI, perform normally on neuropsychological tests because those
tests do not properly assess their reward-related deficits (Levine, Katz, Black, &
Dade, 2002). Standard neuropsychological tests, on the other hand, were devel-
oped and validated in patients with dorsolateral prefrontal cortex damage. For
example, in Milner’s (1963) classic study of the Wisconsin Card Sorting Test,
patients with ventral frontal damage performed normally, likely because of their
intact ability to perform a “cognitive” extra-dimensional shift (Dias, Robbins, &
Roberts, 1996; Stuss et al., 2000). Thus, new measures were required to assess
these deficits.
The E ffects of Focal and Diffuse Brain I n ju ry on Be h av ior 237
The syndrome of intact test performance with impaired real-life function was
most elegantly described in the classic paper by Shallice and Burgess (1991) in
which patients with large frontal lesions failed miserably when given unstruc-
tured, relatively novel tasks in which there were no clear right answers, and the
patients had to formulate their own strategies. By contrast, these same patients
performed normally (or were in some instances superior) on tests of intelligence
and neuropsychological functions. Shallice and Burgess labeled this syndrome
“strategy application disorder.”
In fact, such cases had been described for decades, going back to the classic case
study of Phineas Gage (Harlow, 1868). Shallice and Burgess, however, were the
first to attempt to quantify these deficits with a test. (See Burgess’s chapter in this
volume [Chapter 4] for additional details on these studies.) In addition to the
open-ended Multiple Errands Test, in which patients have to solve mildly novel
problems in an actual shopping district, Shallice and Burgess created a desktop
test (the Six Element Test) designed to mimic such open-ended, real-life scenarios
in the laboratory. In this test, patients were asked to perform various paper-and-
pencil or other tasks (i.e., “elements”) that could be done at the desk, but they
were given a limited time and were required to sample from all of the elements. To
maximize productivity, patients had to switch strategically from one element of
the test to another. As in the Multiple Errands Test, the patients with prefrontal
damage were impaired, for example spending all of their time on one element to
the exclusion of others.
It is well known that strategy application disorder is not limited to select
patients, as described classically in the literature or in more contemporary studies
such as the one by Shallice and Burgess. As stated above, these cases were remark-
able for the dissociation between intact cognitive functions on the one hand and
impaired real-life behavior on the other hand. It is self-evident, however, that
patients with impaired cognitive functions can also have strategy application dis-
order, although it may be more difficult to rule out effects of cognitive deficits in
their behavioral syndrome. Similarly, some individuals (patients or healthy adults)
may have a more subtle version of strategy application disorder that spares them
the gross errors as described in the case study literature but is nonetheless dis-
abling in that they act without cognitive control in unstructured, novel situations
where routines are not sufficient to guide behavior. Clinically, such patients are
similar to those with memory or language deficits without the pathognomonic
amnesia and aphasia syndromes that define the extremes of these conditions. For
patients with amnesia or aphasia, a clinical examination is sufficient to make the
diagnosis. For patients with more subtle deficits in these capacities, psychometric
tasks are required to quantify the deficit. This was a major contribution of Shallice
and Burgess.
One limitation of the original Six Element Test was that it was designed for
patients with super-normal cognitive functions; for example, the arithmetic ele-
ment contained calculus problems. There was a need for a test with more basic
elements for patients falling within the normal spectrum of abilities or for those
with other cognitive deficits that would interfere with their ability to perform the
basic elements of the test. (One such version of the Six Element Test is included
as part of the Behavioral Assessment of the Dysexecutive Syndrome test battery
[Wilson, Evans, Alderman, Burgess, & Emslie, 1997], but this tool assesses only
rule breaks and therefore does not fully capture strategic behavior involved in
task switching under conditions of diminishing returns, a crucial feature of the
original Six Element Test.)
Our initial attempt at formulating a more widely applicable measure (Levine
et al., 1998) was to design a Strategy Application Test with simple items that could
be completed by anyone with intact basic perceptual and motor functions: naming
simple pictures, completing simple math problems, and copying simple drawings.
Like the original Six Element Test, there were too many items than could be com-
pleted within the time allotted for the task. Critically, half of the items were
framed with a dotted line. Patients were instructed that they would receive 15
points for completing these items and 1 point for completing the unframed items.
The most strategic approach required skipping over the items to maximize points.
Thus, a simple dependent variable to characterize strategy application on this test
was the proportion of items completed that were framed. Our reasoning was that
frontal patients, particularly those with ventral frontal damage, would not be gov-
erned by the reward value of the items but would rather complete the items in a
typical manner governed by spatial contiguity.
As predicted, frontal patients were impaired on the task—they did not modu-
late their behavior according to the items’ reward value. This was especially the
case for patients with ventral frontal damage. Had we limited our sample to fron-
tal patients, that would have made a tidy story. However, we also tested patients
with posterior cortical lesions. Half of them were impaired, particularly those
with right-lateralized damage (see also Burgess, Veitch, de Lacy Costello, &
Shallice, 2000, for evidence of the role of posterior damage on a related task). We
also tested a sample of patients with TBI, about half of whom were impaired (with
no effect of TBI severity), but the presence of a focal lesion was not necessarily
associated with impairment in patients with TBI. Moreover, we also tested healthy
older adults, who showed subtle but significant deficits relative to younger adults.
Therefore, multiple types of lesions (i.e., ventral frontal damage, right-lateralized
damage, DAI due to TBI, and age-related changes) could be associated with
impaired strategy application as measured by our test.
Although the Six Element Test and our Strategy Application Test appeared to
be sensitive to strategic deficits in patients with focal and diffuse damage, what
was lacking in these studies was a correlation to actual real-life behavior (for
exception, see Burgess, Alderman, Evans, Emslie, & Wilson, 1998). Because our
Strategy Application Test tended to have a bimodal distribution (patients either
selected only framed items or did items in spatial sequence without respect to
item value), we revised the test to increase its sensitivity. In the revised version,
we adopted the original Six Element Test procedure of having items become pro-
gressively more complex, and therefore with progressively diminishing returns.
To avoid issues of task difficulty we maintained the simplicity of the items while
manipulating the time to completion. For example, subjects had to count items in
an array by placing numbers inside each item, with the number in each array vary-
ing from 6 to 60 (Fig. 13.1). Instead of copying drawings, subjects had to trace
either very simple geometric drawings or more intricate drawings. The third activ-
ity involved copying sentences that were linguistically simple, but increasing in
length. With all items being of equal value, the strategic approach was to do simple
items to the exclusion of complex items. Conceptually, the main dependent vari-
able on this test was the same as in the previous test: the proportion of brief items
relative to total items reflected the most strategic approach.
We administered this Revised Strategy Application Test to a separate sample of
TBI patients (Levine, Dawson, Boutet, Schwartz, & Stuss, 2000). Unlike the ear-
lier Strategy Application Tests, this test was sensitive to TBI severity as deter-
mined by depth of coma at the time of injury. As in our prior study, TBI patients
with right-lateralized lesions were particularly impaired. Most importantly, the
proportional score was significantly correlated with psychosocial outcome on a
self-report measure of adjustment problems (the Sickness Impact Profile; Bergner,
Bobbitt, Pollard, Martin, & Gilson, 1976) that is widely used in the TBI literature.
This relationship held even after accounting for variance due to inattention and
slowing as measured by the Trail Making Test (Part B) (Army Individual Test
Battery, 1944), the Digit Symbol subtest of the WAIS-R (Wechsler, 1985), and the
Pat swung hard at the pitch.

Vacations are more
He felt a solid crack as the
Dress for success. than just getting out
bat met the ball. He hit a
of town.
home run.
Figure 13.1. Sample items from the Revised Strategy Application Test (R-SAT; Levine
et al., 2000). The tasks were to trace the figures (a), copy the sentences (b), and number
the objects by writing numbers inside the objects (c). As the participant moved through
the pages in the task, items increased in duration to completion but not in difficulty of
completion. (From Levine et al., 1999, with permission from Oxford University Press.)
Stroop interference condition (Comalli, Wapner, & Werner, 1962), all of which are
classically sensitive to TBI.
Some patients in both of our Strategy Application Test studies failed to apply
the correct strategy in spite of intact knowledge of the strategy as demonstrated
by post-test interviews (or even by spontaneous acknowledgment, as in the par-
ticipant who said, “This is crazy! There are no points here. What am I doing?”).
This dissociation of knowledge from action is classically described in case studies
of patients with frontal damage (Luria, 1966). However, we found that this dis-
sociation was not specific to patients with frontal lesions, and could occur in
patients with DAI and no evidence of frontal lesions. This underlined the impor-
tance of DAI in strategic behavior.
Quantifying the Diffuse Lesion of TBI with

Structural Neuroimaging
It is much easier to identify, trace, quantify, and localize focal lesions than is
the case for diffuse lesions; indeed, significant diffuse injury is often undiagnosed
on radiological examinations. Quantified evaluation of brain images is necessary
to derive estimates of diffuse volume loss. In collaboration with Sandra Black,
who is interested in quantifying volume loss in dementia and cerebrovascular
disease (see Chapter 12), we developed a pipeline for robustly segmenting high-
resolution T1-weighted structural MRI images into gray, white, and cerebrospinal
fluid (CSF) compartments (Kovacevic et al., 2002) by applying a mask to the seg-
mented image, allowing us to interrogate the volumes of 38 brain regions as
defined by a semi-automated region of interest protocol (SABRE; Dade et al.,
2004). In a series of 70 patients drawn from consecutive admissions to Sunny-
brook Hospital, Canada’s largest trauma center, using multivariate partial least
squares (PLS; McIntosh, Bookstein, Haxby, & Grady, 1996) analysis, we found
that regional volume loss was related to injury severity as defined by depth of
coma at the time of injury (at least 1 year prior to scanning) in a dose–response
fashion, such that patients with moderate and severe injury had greater volume
loss than patients with mild injury, who in turn had greater volume loss than
non-injured comparison subjects (Fig. 13.2; Levine et al., 2008). (This finding
with mild TBI patients requires further investigation as the comparison subjects
were not matched for socioeconomic status. However, our conclusions are
not dependent on the difference between mild TBI patients and non-injured
comparison subjects. The moderate to severe TBI patients were matched to
the mild TBI patients for these characteristics and showed relatively greater
volume loss.)
Although volume loss was noted in the frontal and temporal regions classically
associated with TBI damage, it also distributed across the cortical mantle.
CSF
1
0.5
Correlation
–0.5
–1
Non-Inj. Mild Mod. Severe
Lower Higher
volume volume
Figure 13.2. Latent variable from partial least squares analysis indicating the
association of TBI severity in patients with “pure” diffuse injury with increased
cerebrospinal fluid (i.e., reduced parenchyma). Left: Group pattern associated with
the latent variable, expressed as correlations of group membership (coded as 1 or 0)
with the pattern of volume changes. Error bars represent 99% confidence intervals.
Group differences are indicated by non-overlapping error bars. Right: Regional plots
of bootstrap ratios indicating pattern of cerebrospinal fluid changes. The color bar
indicates the coding scheme according to the level of the bootstrap ratio, interpreted
similar to a Z-score. Images were thresholded at a bootstrap ratio of 3.0, corresponding
approximately to p < 0.001. Axial images are displayed in radiologic convention
(right hemisphere displayed on left side of image). (From Levine et al., 2008, with
permission from Lippincott Williams & Wilkins.) (See Color Plate Section for a color
version of this figure.)
This provides a structural basis (i.e., a diffuse lesion) for network dysfunction that
would correspond to behavior, as demonstrated in our follow-up studies described
below. This widespread volume loss was identified in patients with “pure” DAI—
that is, the findings held when those with significant (more than 3 mm on two or
more contiguous slices) focal lesions were excluded. Thus, parenchymal volume
loss in TBI is significant in patients both with and without focal lesions. Patients’
scans were also interpreted by a clinical neuroradiologist. In many cases of sig-
nificant volume loss, the scan was interpreted as normal, indicating that quanti-
fied image analysis is necessary to reveal DAI effects in TBI.
Our findings are not merely a reflection of the general sensitivity of our image-
processing pipeline. In a separate study (Fujiwara, Schwartz, Gao, Black, & Levine,
2008), the specificity of this pipeline was supported by an association of smell
identification with volume loss in the ventromedial frontal sector, which contains
olfactory association cortex. Interestingly, the left posterior temporal cortex also
emerged in the pattern related to smell identification. Although this region is not
directly involved with olfactory function, it is involved in naming, which is
required by the smell identification test used in this study. These findings demon-
strate the capacity of multivariate structural brain–behavior analysis to reveal the
distributed functional anatomy of various tasks.
These patients were also administered a neuropsychological test battery. We
found robust relationships between volume loss and specific measures of speeded
information processing (Levine et al., submitted). Standard tests of frontal lobe
function, such as the Wisconsin Card Sorting Test, were not strongly related to
patterns of volume loss, perhaps because such tests were designed to measure the
effects of cognitive deficits following dorsolateral damage, or because these tests
are untimed and therefore not sensitive to the processing-speed deficits charac-
teristic of TBI.
Effects of the Diffuse Lesion of TBI on

Functional Neuroimaging
These structural imaging data suggest a diffuse lesion model for understanding
distributed network function and dysfunction. Functional neuroimaging can aug-
ment these data by describing the consequences of the diffuse lesion on brain
function. A main concern in functional neuroimaging of TBI is the presence of
both focal and diffuse damage in the same subjects. In patients with the large
frontal and temporal contusions that are common in TBI, it is difficult to interpret
signal changes associated with experimental manipulations, which could be
attributable to either focal damage, diffuse damage, or both. A main advantage of
the Toronto TBI study was the availability of a high-quality, quantified structural
scan that could be used to rule out the presence of focal lesions, providing a rela-
tively “pure” DAI sample.
Working memory, particularly the executive component involving manipula-
tion of information held online, is classically impaired following TBI. As an emer-
gent property of distributed frontal–parietal interaction (Postle, 2006), it is also a
useful construct for testing models related to integrated brain function. We
assessed functional neuroanatomy of working memory in TBI using a modifica-
tion of an established paradigm, Alpha Span, which was developed by Craik (1986)
and later studied in detail in functional imaging studies by Postle, D’Esposito, and
colleagues (D’Esposito, Postle, Ballard, & Lease, 1999; Postle, Berger, & D’Esposito,
1999). An advantage of this paradigm is a separation of working memory mainte-
nance from manipulation processes. In the maintenance condition, subjects
merely rehearse the sequence of letters, whereas in the manipulation condition
they must reorder the letters in alphabetical sequence. Additionally, there were
two levels of working memory load: low (three letters) and high (five letters). We
found that patients with moderate to severe TBI and pure DAI had numerous
regions of increased activation during the executive (manipulation) element of
the task, including increased bilateral frontal and parietal activation (Fig. 13.3;
Turner & Levine, 2008). This finding could not be attributed to performance dif-
ferences, as the TBI and comparison subjects were well matched for performance.
Nor could the findings be attributed to slowing or to load-related factors.
This augmented functional recruitment suggested compensatory changes in
frontal lobe function, as commonly reported in the healthy aging literature
(Cabeza, 2002). From these data alone, we could not determine if this compensa-
tion reflected altered engagement of already existing functional networks or
engagement of novel networks (i.e., functional reorganization). In addition to
the theoretical importance of this distinction to understanding the recovery pat-
terns following TBI and other conditions with diffuse injury, this distinction is
pertinent to approaches to rehabilitation. If TBI patients are performing the task
using novel networks not normally associated with task performance, these net-
works could be trained to optimize performance for TBI patients with impaired
Controls
TBI
Interaction
Figure 13.3. TBI patients and control subjects’ activation on a working memory task.
Activations reflect signal change in the executive demand contrast, in which the letters
held in working memory must be reordered alphabetically as contrasted to simply
rehearsing the letters in the same order as presented. Patients with TBI show augmented
activation relative to controls in the left middle frontal gyrus and the right inferior
frontal gyrus, as depicted in the circled regions in the Group × Executive Demand
interaction (bottom row). (From Turner & Levine, 2008, with permission from Lippincott
Williams & Wilkins.) (See Color Plate Section for a color version of this figure.)
working memory. Alternatively, if the TBI patients are using the same functional
networks that healthy adults engage when challenged with increased task
demands, training novel networks might interfere with performance.
In a separate PLS analysis of these data simultaneously examining functional
connectivity and brain–behavior correlations (Turner, McIntosh, & Levine, 2011),
we found evidence in support of the altered engagement hypothesis. Among all
subjects, bilateral functional connectivity within the prefrontal cortex was evident
whenever load was increased or when executive demands were present. However,
the threshold at which this expanded right prefrontal network was correlated
with working memory performance was reduced in the TBI patients. In other
Baseline Load (M5) or Load and

(M3) Alphabetize (A3) Alphabetize (A5)
MFG ii. iv.
IFG i. iii.
Controls
L R
ii. iv.
i. iii.
TBI
Figure 13.4. Conceptual representation of combined behavioral and seed partial

least squares analysis for working memory task in patients with TBI and control
subjects (Turner et al., 2011). Dashed lines connecting seed regions represent
functional connectivity between these regions. Solid lines signify both functional
connectivity and correlations between activity in the network and task accuracy.
Roman numerals signify seed regions: (i) left inferior frontal gyrus; (ii) left middle
frontal gyrus; (iii) right posterior middle frontal gyrus; (iv) right anterior middle
frontal gyrus. Whereas both controls and TBI patients show behaviorally relevant
functional connectivity involving the right anterior middle frontal gyrus at the highest
level of task difficulty (third column; highest load, alphabetize [executive] condition),
only patients with TBI show such connectivity in response to moderate levels of task
difficulty (second column, either highest load or alphabetize condition). (Figure used
with permission of authors.)
words, the same compensatory frontal activity was observed in TBI patients and
healthy controls, but it was engaged at a lower level of task difficulty in the TBI
patients (Fig. 13.4).
This engagement of more widespread networks at an earlier stage of task dif-
ficulty in TBI likely reflects the effects of DAI on integrated brain function.
Engagement of prefrontally mediated control processes, normally required only
at the highest level of task difficulty, is also required at early stages of task diffi-
culty in patients with TBI in order to overcome these effects. This may explain why
patients with TBI complain of mental fatigue on effortful tasks, even when their
performance appears normal.
Relating Behavioral and Imaging Findings to

“A Slice of Life” in Patients with TBI
Our findings provide an anatomical basis in support of Stuss’s earlier observation
of subtle deficits in patients with TBI on tests of complex attention, but not stan-
dardized tests (Stuss et al., 1985). Patients’ attentional and slowing deficits are
attributable to a widespread disconnection syndrome (i.e., a diffuse lesion). These
deficits are in turn reflected on complex tasks such as our Strategy Application
Test, and real-life complaints as measured by self-report and reports from signifi-
cant others (i.e., a slice of life). The pathophysiology underlying these deficits is
now clarified by structural and functional neuroimaging studies.
These studies reflect a tradition established by Don Stuss in which advanced
cognitive paradigms are combined with a neuroanatomical approach to reveal
deficits in patients that have serious practical implications even when they evade
detection by standard measures. Most of this volume, and indeed most of Don’s
research, is focused on revealing these effects in patients with lesions to specific
sectors of the frontal lobe. This work focuses on another aspect of Don’s contribu-
tion: analysis of subtle deficits in patients with TBI. This work is also a product of
Don’s administrative legacy in building the Rotman Research Institute. There are
very few centers where this research could have been conducted, combining cut-
ting-edge behavioral and imaging technologies. I am truly grateful to Don for cre-
ating an atmosphere where this research could flourish and for giving me the
opportunity to participate.
Acknowledgments
Thanks are due to the many patients and families who participated in our research.
I also thank Gary Turner, Randy McIntosh, Natasa Kovacevic, Sandra Black,
Fuqiang Gao, Charlene O’Connor, Nadine Richard, Esther Fujiwara, Lauren Dade,
Michael Schwartz, Simon Graham, Marina Mandic, Irina Nica, Adriana Restango,
Catherine Hynes, Karen Spreng, Ann Campbell, Sabitha Kanagasabai, Colleen

O’Toole, and Jovanka Skocic for their contributions to this research. This research
was supported by grants from the Canadian Institutes of Health Research (CIHR;
MGP-62963) and the National Institute of Child Health and Human Development
(NICHD;HD42385).
References
Army Individual Test Battery. (1944). Manual of Directions and Scoring. Washington, D.C.:
War Department, Adjutant General’s Office.
Bergner, M., Bobbitt, R. A., Pollard, W. E., Martin, D. P., & Gilson, B. S. (1976). The Sickness Impact
Profile: validation of a health status measure. Medical Care, 14, 57–67.
Burgess, P. W., Alderman, N., Evans, J., Emslie, H., & Wilson, B. A . (1998). The ecological valid-
ity of tests of executive function. Journal of the International Neuropsychological Society, 4(6),
547–558.
Burgess, P. W., Veitch, E., de Lacy Costello, A., & Shallice, T. (2000). The cognitive and neuroana-
tomical correlates of multitasking. Neuropsychologia, 38(6), 848–863.
Cabeza, R . (2002). Hemispheric asymmetry reduction in older adults: the HAROLD model.
Psychology and Aging, 17(1), 85–100.
Comalli, P. E. J., Wapner, S., & Werner, H. (1962). Interference effects of Stroop Color-Word Test in
childhood, adulthood, and aging. Journal of Genetic Psychology, 100, 47–53.
Courville, C. B. (1937). Pathology of the central nervous system, part 4. Mountain View, CA: Pacific
Press Publishing.
Craik, F. I. M. (1986). A functional account of age differences in memory. In F. Klix & H. Hagendorf
(Eds.), Human memory and cognitive capabilities, mechanisms and performances (pp. 409–422).
New York: Elsevier Science.
D’Esposito, M., Postle, B. R., Ballard, D., & Lease, J. (1999). Maintenance versus manipulation of
information held in working memory: an event-related fMRI study. Brain and Cognition, 41(1),
66–86.
Dade, L. A., Gao, F. Q., Kovacevic, N., Roy, P., Rockel, C., O’Toole, C. M., et al. (2004). Semiautomatic
brain region extraction: a method of parcellating brain regions from structural magnetic
resonance images. NeuroImage, 22(4), 1492–1502.
Dias, R., Robbins, T. W., & Roberts, A. C. (1996). Dissociation in prefrontal cortex of affective and
attentional shifts. Nature, 380(6569), 69–72.
Fujiwara, E., Schwartz, M. L., Gao, F., Black, S. E., & Levine, B. (2008). Ventral frontal cortex
functions and quantified MRI in traumatic brain injury. Neuropsychologia, 46(2), 461–474.
Goldberg , E., & Bilder, R. M. J. (1987). The frontal lobes and hierarchical organization of cognitive
control. In E. Perecman (Ed.), The frontal lobes revisited (pp. 159–187). New York: IRBN Press.
Hakim, A. M. (2007). Vascular disease: the tsunami of health care. Stroke, 38(12), 3296–3301.
Harlow, J. M. (1868). Recovery after severe injury to the head. Publication of the Massachusetts
Medical Society, 2, 327–346.
Hirtz, D., Thurman, D. J., Gwinn-Hardy, K., Mohamed, M., Chaudhuri, A. R., & Zalutsky, R . (2007).
How common are the “common” neurologic disorders? Neurology, 68(5), 326–337.
Kovacevic, N., Lobaugh, N. J., Bronskill, M. J., Levine, B., Feinstein, A., & Black, S. E. (2002).
A robust method for extraction and automatic segmentation of brain images. NeuroImage,
17(3), 1087–1100.
Larjavaara, S., Haapasalo, H., Sankila, R., Helen, P., & Auvinen, A . (2008). Is the incidence of menin-
giomas underestimated? A regional survey. British Journal of Cancer, 99(1), 182–184.
Levine, B., Dawson, D., Boutet, I., Schwartz, M. L., & Stuss, D. T. (2000). Assessment of strategic
self-regulation in traumatic brain injury: its relationship to injury severity and psychosocial
outcome. Neuropsychology, 14(4), 491–500.
Levine, B., Freedman, M., Dawson, D., Black, S. E., & Stuss, D. T. (1999). Ventral frontal
contribution to self-regulation: Convergence of episodic memory and inhibition. Neurocase,
5, 263–275.
Levine, B., Katz, D., Black, S. E., & Dade, L . (2002). New approaches to brain-behavior assessment
in traumatic brain injury. In D. T. Stuss & R. Knight (Eds.), Principles of frontal lobe function
(pp. 448–465). New York: Oxford University Press.
Levine, B., Kovacevic, N., Nica, E. I., Cheung, G., Gao, F., Schwartz, M. L., et al. (2008). The Toronto
traumatic brain injury study: injury severity and quantified MRI. Neurology, 70(10), 771–778.
Levine, B., Kovacevic, N., Nica, I., Cheung , G., Schwartz, M. L., & Black, S. E. (submitted).
The Toronto Traumatic Brain Injury Study II: Quantified MRI and cognition.
Levine, B., Stuss, D. T., Milberg , W. P., Alexander, M. P., Schwartz, M., & Macdonald, R . (1998).
The effects of focal and diffuse brain damage on strategy application: Evidence from focal
lesions, traumatic brain injury, and normal aging. Journal of the International Neuropsychological
Society, 4, 247–264.
Luria, A. R . (1966). Higher cortical functions in man. New York: Basic Books.
McIntosh, A. R., Bookstein, F. L., Haxby, J. V., & Grady, C. L . (1996). Spatial pattern analysis of
functional brain images using partial least squares. NeuroImage, 3, 143–157.
Milner, B. (1963). Effects of different brain lesions on card sorting: the role of the frontal lobes.
Postle, B. R . (2006). Working memory as an emergent property of the mind and brain. Neuroscience,
139(1), 23–38.
Postle, B. R., Berger, J. S., & D’Esposito, M. (1999). Functional neuroanatomical double dissociation
of mnemonic and executive control processes contributing to working memory performance.
Proceedings of the National Academy of Sciences U S A, 96(22), 12959–12964.
Povlishock, J. T., & Katz, D. I. (2005). Update of neuropathology and neurological recovery after
traumatic brain injury. Journal of Head Trauma Rehabilitation, 20(1), 76–94.
Shallice, T., & Burgess, P. W. (1991).Deficits in strategy application following frontal lobe damage
in man. Brain, 114, 727–741.
Stuss, D. T., Ely, P., Hugenholtz, H., Richard, M. T., LaRochelle, S., Poirier, C. A., et al. (1985).
Subtle neuropsychological deficits in patients with good recovery after closed head injury.
Neurosurgery, 17, 41–47.
Stuss, D. T., & Gow, C. A . (1992). “Frontal dysfunction” after traumatic brain injury. Neuropsychiatry,
Neuropsychology, and Behavioral Neurology, 5(4), 272–282.
38(4), 388–402.
Tullberg , M., Fletcher, E., DeCarli, C., Mungas, D., Reed, B. R., Harvey, D. J., et al. (2004).
White matter lesions impair frontal lobe function regardless of their location. Neurology,
63(2), 246–253.
Turner, G. R., & Levine, B. (2008). Augmented neural activity during executive control processing
following diffuse axonal injury. Neurology, 71(11), 812–818.
Turner, G. R., McIntosh, A. R., & Levine, B. (2011). Prefrontal compensatory engagement in TBI is
due to altered functional engagement of existing networks and not functional reorganization
Frontiers in Systems Neuroscience. 5:9. doi: 10.3389/fnsys.2011.00009.
Vilkki, J. (1992). Cognitive flexibility and mental programming after closed head injuries and ante-
rior or posterior cerebral excisions. Neuropsychologia, 30(9), 807–814.
Wechsler, D. (1985). The Wechsler Adult Intelligence Scale-Revised. New York: Psychological
Corporation.
Wilson, B. A., Evans, J. J., Alderman, N., Burgess, P. W., & Emslie, H. (1997). Behavioural assess-
ment of the dysexecutive syndrome. In P. Rabbitt (Ed.), Methodology of frontal and executive
function (pp. 239–250). East Sussex, UK: Psychological Press.
14
Does The Future Exist?
ENDEL TULVING AND KARL K. SZPUNAR
Introduction
This essay is dedicated to Don Stuss, a good friend, a fabulous colleague, and a
unique role model. Don’s lifelong seminal contributions to the exploration and
understanding of the role of the frontal lobes of the human brain in higher cogni-
tive functions have made him a giant in his field. This pursuit has brought
him face to face with many topics that for a long time were regarded as suspicious
by many scientists, and still are by some, topics such as consciousness, self-
awareness, subjective time, and mental time travel. Future belongs to this group.
“Future” is one of the most important words in the human lexicon, and the
entity to which it refers is a principal determinant of much of what human beings
do. Its influence on human behavior is overwhelming, ubiquitous, and undeni-
able. Yet, future does not exist in physical reality. No textbook in physics is likely
to mention future. The same holds for the “past,” future’s twin on the other side
of the “present.” The concept of “time,” of course, does play a major role in physics,
but that time is different from the kind that is used to define past and future.
The idea that neither past nor future exists in physical reality has been dis-
cussed by a number of philosophers. One of the best-known proponents of the
idea is McTaggart (1908), an English philosopher, who distinguished between two
kinds of time “series”: A series, in which terms like “past,” “present,” and “future”
make sense, and B series, in which they do not. We can think of the A series as self-
centered on an observer, and the B series as independent of any observer. The
status of time points in the A series can change—what was once in the future can
become the present and then the past. The status of time points in the B series
never changes—one time point precedes, is simultaneous with, or follows
another, and the relation between them will always remain the same, regardless
of whether they are in the future, present, or past. According to McTaggart,
the mental experiences that people have with the changes of an event’s status
in time (i.e., future, present, and past) leads to the belief that the passage of time
248
Doe s T h e F u t u re E x is t ? 249
is a real phenomenon that exists in physical reality, although in fact “future” and
“past” do not exist outside of the mind.
If future does not exist in physical reality, but nevertheless plays an
extremely important role in governing and regulating human affairs, we have
an apparent paradox on our hands, and if not a paradox then at least a puzzle:
How can something that does not exist exert any influence on something that
clearly does exist? There have been similar puzzles in science. For instance, the
puzzle created by Isaac Newton’s discovery that physical bodies attract each other
even at long distances (“action at a distance”) still has no solution that would be
comprehensible to an average intelligent person. But in that case we have two
bodies whose masses and distances can be measured, and whose very existence
holds the promise of a solution. But what can we do with a situation in which we
are dealing with a relation between something that does not exist and something
that does?
In this essay we discuss the “paradox of the nonexistent future,” and proffer a
solution for it. The story we tell has few original parts in it, although some combi-
nations of the parts may appear novel. The story is rather personal, as befits a
contribution to a book of this sort. We make no attempt to present a balanced
view of the matters we discuss, whatever a “balanced view” of an impossibly com-
plicated topic might mean.
The essay has four sections: (1) memory and the past, (2) memory and the
future, (3) mental time travel, and (4) two realities of our world. The first three
sections tell the story of how “future” emerged as a topic of scientific inquiry.
Briefly, like any novel topic of study, the idea to ask questions about the “future”
did not simply appear from out of the blue. Rather, it was in the context of the
field of memory research in which memorists (students of memory) began asking
questions about the relevance of the concept of “past” to their labors. These ques-
tions, somewhat unexpectedly but not unnaturally, led to related questions about
future. Out of these developments emerged the concept of “mental time travel”
that initially involved “travel” only into the past but then also came to include the
future. In the final section of the paper we discuss some broader implications of
this “memory-based” research and theorizing for the question we pose in the title
of the paper.
We hope Don Stuss finds something of interest in our story.
Memory and the Past

In the popular mind there exists an intimate connection between memory and
the past. People in almost every culture learn the connection early in their life and
do not think much about the relation. “Memory and past” constitutes only one
pair in the large category of inevitable togethernesses: situations where you
cannot have one without the other.
Aristotle knew it all long before us. He lectured on “Memory and Reminiscence”
more than two thousand years ago in what in many ways is a remarkably “modern”
conceptual treatment. In his lecture, Aristotle admonished his disciples to always
remember that one cannot remember the future. The future has to do with antici-
pation, he said, and the present has to do with perception. Memory and remem-
bering, however, have to do with the past.1 To make sure that his disciples got the
point he was careful to repeat it; in the introduction to his opus he said, “memory
relates to the past,” and then, a few lines later, “the object of memory is the past”
(Aristotle, 350 b.c.).
Aristotle’s plain statement has never been rejected. A long row of wise sages
and distinguished scholars have accepted and reasserted it unquestioningly.
Among the more recent ones was William James (1890, Chapter 16), who was
precise and adamant that a mental experience cannot be called memory unless
the experiencer has a feeling of “pastness” about the experience. James was
equally precise and adamant about the inclusion of the rememberer’s “self” among
the defining features of memory. According to James, the remembered experience
had to be felt as having its origin in the individual’s own past (see also Bertrand
Russell, 1921).
Given these firmly held convictions about remembering having to do with the
individual’s own past, it must be regarded as curious that the experimental study
of memory that was launched around the same time that William James published
his highly influential magnum opus almost completely ignored the personal past.
Probably the ground was prepared for such a curious development by Hermann
Ebbinghaus, the “father” of the experimental study of memory, who published his
seminal 1885 monograph under the general title of “Memory” but in fact studied
learning and forgetting of nonsense syllables. His original methods and general
orientation were adopted by several generations of psychologists whose research
became known as “verbal learning.” The basic orientation of “verbal learners,” as
the practitioners were called, was behavioral and functional. There was no room in
it for the mind. Verbal learners did not use the term “memory,” and they would
have found the term “future” just as unacceptable (see Cofer, 1961).
The personal past crept back into memory with the development of episodic
memory (Tulving, 1983) as a part of the cognitive revolution (see Miller, 2003).
Episodic memory is a descendant of what William James called just “memory.”
Today, the concept of “episodic memory” shares with James’s concept of “memory”
the defining features of past and self (see Piolino, Desgranges, & Eustache, 2009,
and Reinhold & Markowitsch, 2009), but it also incorporates some subtle but cru-
cial differences whose discussion here would take us too far afield.2 But, anticipat-
ing what is to come in this essay, we note that one feature that distinguishes
“episodic memory” from William James’s “memory” is the tie between episodic
memory and the concept of “future.” At the time of William James, such a tie
probably would have been regarded as science fiction (and it is easy to imagine
that Aristotle would not have approved of these developments).
Memory and the Future

Aristotle would have been even more upset if he had seen the title of a paper
written by David Ingvar, “Memory of the future: An essay on the temporal
organization of conscious awareness” (Ingvar, 1985). With this provocative title,
Ingvar had in mind the capacity for humans to bring to mind well-rehearsed action
plans that help to organize their behavior on the temporal dimension, leading
from the present moment into the future. For instance, whenever people think
about executing a movement, count numbers, or hum a musical tune, they call to
mind a previously executed sequence of actions that will help to currently guide
their behavior beyond the present moment. Although Aristotle was quite right in
arguing that the future, in the strictest sense, has yet to take place, Ingvar sug-
gested that people might rely on their memories of having previously executed
various action sequences to help guide their behavior.
Moreover, Ingvar made the astute observation that these “memories of the
future” appear to be subserved by the prefrontal cortex of the human brain,
regardless of the specific behavior. This observation suggested to Ingvar an impor-
tant connection between two apparently disparate literatures: (1) the behavioral
consequences associated with frontal lobe damage and (2) brain activity associ-
ated with the healthy human brain at rest.
Briefly, people who incur some form of damage to their frontal lobe(s) consis-
tently manifest an inability, or lack of desire, to introspect about their lives and in
what direction their lives are headed (for a comprehensive overview of frontal
lobe pathology see Stuss & Benson, 1986; see also Stuss & Levine, 2002). According
to Ingvar, these behavioral consequences of frontal lobe damage may reflect an
inability to draw upon stored action sequences to guide behavior or, in his own
words, “a defective ‘memory of the future’” (p. 132). Secondly, Ingvar alluded to
early brain imaging studies that showed that the prefrontal cortex was particu-
larly active, relative to other regions of the brain, when healthy human adults
were asked to lie still and relax. According to Ingvar, this “hyperfrontal” pattern
suggested that in a state of rest the human brain “rehearses stored information
from the past, relates it to the present Now-situation, and makes up a behavioral
repertoire for the future” (p. 132).
The connection of these literatures, however tenuous at the time, was impor-
tant because it represented the first instance, to our knowledge, in which converg-
ing lines of evidence were related to the hypothesis that the frontal lobes play an
important role in the capacity to think about one’s future. More important, for
the purpose of our story, is the fact that Ingvar invoked the concept of memory in
describing his proposed connection between the frontal lobes and future think-
ing. Nonetheless, it would be some time before the rest of the neuropsychological
community would notice Ingvar’s contribution.
Indeed, it was another decade before the possibly important relation between
memory, future, and the frontal lobes was explicitly articulated. It was a paper
titled “Toward a theory of episodic memory: The frontal lobes and autonoetic con-
sciousness” and Don Stuss, happily, was one of the protagonists in that venture
(Wheeler, Stuss, & Tulving, 1997). But we are getting ahead of the story.
As it happened, at about the same time David Ingvar was organizing his
thoughts regarding the relation of memory and the future, one of us (E.T.) and my
colleagues at the Unit for Memory Disorders at the University of Toronto were
intensively studying a very interesting case of amnesia involving a young man
who suffered heavy brain trauma in a motorcycle accident in 1981. The most
striking feature about him was that in addition to his deep anterograde amnesia
it turned out that he did not remember a single personally experienced event
from his life, although his general knowledge of the world, acquired before the
accident that caused his amnesia, was surprisingly intact. The young man, initially
named N.N. (no name), eventually became well known in the neuropsychological
literature on memory and amnesia under his true initials (K.C.).
In the early 1980s, I (Tulving) was a newcomer to the land of neuropsychology.
I did not quite know its customs and mores. I also was totally unaware of Aristotle’s
admonitions regarding memory and future. Therefore, in addition to talking to
K.C. about what he remembered and knew about his past, as had been done with
amnesic individuals for a hundred years, I also asked K.C. about his future plans
and intentions. On the very first of these occasions I asked K.C. questions like,
“What will you do after we are finished and you leave here?” “What are you going
to do tomorrow?” and “What are your plans for the summer?” I had discussed my
intention to do so beforehand with Daniel Schacter, my younger colleague who
was the “chief” of the Unit for Memory Disorders at the time and who also knew
K.C. well. We agreed that K.C., being intelligent and rational, most likely would
respond by generating “scripts” of what a typical young man who lives in his par-
ents’ house in a Toronto suburb would do on a Saturday (the interview took place
on a Friday, and K.C., after consulting his watch, knew it), or how he would spend
at least part of his summer, given that the family owned a summer “cottage” that
K.C. knew well, and where he had spent a lot of time in earlier summers.
This clever prediction was totally off the mark. K.C. greeted the questions with
silence. He usually answered any question put to him the best he could, even if it
was simply, “I do not know.” We also already knew at that time that he does not
confabulate and does not guess at a possible and plausible answer, although when
he is asked to guess, he readily complies with the request.3 His silence, therefore,
implied that he had nothing to say. Indeed, when he was asked what his mind was
like when he was thinking about these questions about his future activities he
said that it was “blank.”
Of course, I did know that one cannot generalize from a single case, and there-
fore I was appropriately cautious in interpreting the meaning of K.C.’s ability
(or lack thereof) to answer questions about his future any more readily than he
could do so about his past. But I did suggest that K.C., apparently as a result of his
brain damage, had lost the kind of consciousness that is necessary for thinking
about one’s self in the context of subjective time (i.e., one’s own remembered past
and imagined future). I dubbed this capacity “autonoetic consciousness” (Tulving,
1985) and also casually referred to “mental time travel” as something enabled by
autonoetic consciousness:
“A normal healthy person who possesses autonoetic consciousness is

capable of becoming aware of her own future: she is capable of mental
time travel, roaming at will over what has happened as readily as over
what might happen, independently of the physical laws that govern the
universe. N.N. seems to be completely incapable of doing so. It is this fact
that provides the basis for the conclusion that he is severely or com-
pletely lacking in autonoetic consciousness” (Tulving, 1985, p. 5).
K.C.’s brain damage was extensive and diffuse. It did involve the medial tempo-
ral lobes, one of the main players in the neural networks that support remember-
ing and knowing. It also included the left prefrontal cortex. But in light of all the
regions that showed up as dysfunctional on brain scans, it was not possible to
relate the absence of his ability to “think future” to any single region. Nevertheless,
there was no evidence against the hypothesis that autonoetic consciousness
depended, at least partly, on the integrity of the frontal lobes.
Mental Time Travel

So, here we have the past and the future side by side, clinically but nevertheless
empirically speaking. Some time after I (Tulving, 1985) had formally presented
my initial musings on the matter, Wheeler and coworkers (1997) took a more
systematic approach and, in the spirit of David Ingvar’s seminal observations,
drew upon converging lines of evidence in relating the concept of “autonoetic con-
sciousness” to the frontal lobes of the human brain. As was the case with Ingvar,
however, the authors’ strongest case for relating the past and future to one
another was the apparent inability for people with frontal lobe damage to engage
in “mental time travel.”
At the same time that Wheeler and coworkers (1997) were speculating about
the relation of the past and the future to the frontal lobes, Thomas Suddendorf
and Michael Corballis presented to the world the first serious and systematic trea-
tise on “mental time travel” (Suddendorf & Corballis, 1997). Their focus was on
the concept’s evolutionary significance and the question of whether or not non-
human animals could match humans in this respect (see also Clayton, Bussey, &
Dickinson, 2003; Clayton, Bussey, Emery, & Dickinson, 2003; Hasselmo, 2009;
Hoerl, 2008; Roberts & Feeney, 2009; Suddendorf & Busby, 2003a, 2003b). At the
time, they too had to rely greatly on speculation. But the future course of mental
time travel was set. Only 10 years later, the concept was firmly ensconced in the
literature (Suddendorf & Corballis, 2007).
“Mental time travel,” of course, is a metaphor. But like many others that prop
up the uncertain understanding of new territories, it is useful. Two particular
advantages may be worth mention.
First, it draws a simple but clear boundary between remembering and know-
ing, as well as between episodic and semantic memory, which are easily conflated.
In daily life one comes constantly across components of a person’s intellectual
repertory that are or are not based on mental time travel. For example, it is not
uncommon to hear someone claim to remember the names, in the correct order,
of all the kings, presidents, or prime ministers, or one’s social insurance number,
or the whole of a long poem learned in school, or the meaning of “carpe diem,” or
thousands of other bits of knowledge that they have learned at some point in
their lives. When they say that they remember all these things we know that in no
sense are they revisiting the past, their own or anyone else’s. The expression of
many things that people know needs no mental time travel.
Second, the metaphor has drawn people’s attention to the theme of “subjective
future” or “personal future” as an object of scientific interest in a way that the
earlier ways of talking about memory did not. David Ingvar’s daring invocation of
“memory of the future” turned out to be a bit of prescient vision, but it escaped
closer scrutiny. Only when the idea of mental time travel was enmeshed in ongo-
ing neuropsychological research and, later, cognitive (e.g., McDonough & Gallo,
2010) and developmental psychology (e.g., Atance & Meltzoff, 2005; Russell,
Alexis, & Clayton, 2010) did the idea of “personal future” begin to attract atten-
tion. And when mental time travel was taken under careful scrutiny in neuroim-
aging, the “personal future” moved to the center stage of a small but rapidly
growing research specialty.
And there are indeed interesting things happening on the “future scene.”
Because future plays such an important role in human affairs it is not surprising
that psychologists have taken keen interest in it in the past. In social and person-
ality psychology, topics such as planning for the future (e.g., Hayes-Roth & Hayes-
Roth, 1979), daydreaming about the future (Singer, 1966), the “future perspective”
that people take (Zimbardo & Boyd, 1999), individual differences in being influ-
enced by thoughts about future (e.g., Taylor & Schneider, 1989), and kindred
other issues have spawned a rich literature (see Schacter, Addis, & Buckner, 2008,
and Taylor, Pham, Rivkin, & Armor, 1998, for reviews).
In the broad field of cognitive neuroscience, the “future” inherent to mental
time travel is approached from a somewhat different vantage point. In the previ-
ous work, the emphasis was on the manner in which people might use thoughts
about their future to guide their behavior. The role of the future was similar
to that of any one of a large number of intended goal objects of one’s existence.
There was little concern with the “future as such;” that is, the capacity to envision
one’s future was taken for granted. In cognitive neuroscience, future as such has
become a focus of interest for increasingly larger groups of researchers. Some of
the major questions that students of mental time travel ask are: (1) what exactly
is this future that plays such a dominant role in determining people’s behavior,
(2) how is it related to other “times” in which mental time travel takes place—past
and present, (3) what are the “scenarios” that the time traveler meets in the future
and where do they come from, and (4) what can we find out about its “neural
correlates”—the anatomical, physiological, and neurochemical components of
brain activity that make mental travel possible. Our own query here, does the
future exist, fits into this broad framework.
Within this context, questions raised about the future cover a broad front. The
rich terminology alone that has been spawned to describe the nature of meta-
phorical “travel” into the future, or what one “does with” the future, gives the
impression of the panoply of approaches. For instance, writers have written about
“thinking about the future” (Okuda et al., 2003), “episodic future thinking”
(Atance & O’Neill, 2001; Szpunar, 2010), “imagining the future” (Klein, Loftus, &
Kihlstrom, 2002; Schacter, Addis, & Buckner, 2007), “episodic simulation”
(Schacter & Addis, 2007; Schacter, Addis, & Buckner, 2008), “self-projection” into
the future (Arzy, Collette, Ionta, Fornari, & Blanke, 2009; Buckner & Carroll,
2007), “envisioning” the future (Buckner, 2010; Szpunar, Watson, & McDermott,
2007), “pre-experiencing” the future (D’Argembeau & Van der Linden, 2004), the
“personal future” (Abraham, Schubotz, & von Cramon, 2008), and “prospecting”
(Gilbert & Wilson, 2007). Although each term or phrase that has been introduced
into the literature carries with it the researcher’s own idiosyncratic views of the
topic, each converges on attempting to describe what might be happening when
we mentally travel into the future.
Some questions raised about the future are similar to the kinds of questions
that previous generations had posed about remembering one’s past; others are
novel. For instance, the popular query of, “where do the scenarios come from that
people imagine as occurring in their own future,” is novel. This question was never
asked about the past—the source of the remembered “scenarios” was perfectly
clear even for the interesting cases where people remember events that never
happened (e.g., Loftus, 1979; Roediger & McDermott, 1995; Schacter, 2001).
Perhaps most relevant to our earlier discussion, students of mental time travel
have primarily focused their efforts on delineating the relation of the personal
future to the personal past. Especially telling material has come from neuropsy-
chology and functional brain imaging. Research groups led by Stanley Klein and
Eleanor Maguire have presented further cases of amnesic patients who are inca-
pable of mentally traveling back in time to their own past or forward into their
own future (Hassabis, Kumaran, Vann, & Maguire, 2007; Klein, et al., 2002).
Various other patient populations that have long been known to exhibit difficul-
ties with calling to mind their personal past (e.g., patients with schizophrenia,
Alzheimer’s disease) have likewise been shown to exhibit a parallel deficit of
mental time travel into their future (Addis, Sacchetti, Ally, Budson, & Schacter,
2009; D’Argembeau, Raffard, & Van der Linden, 2008).
Studies of functional brain imaging have revealed that various frontal and pos-
terior regions of the brain become similarly engaged as healthy human adults
mentally travel back into their personal past and forward into their personal
future (Addis, Wong, & Schacter, 2007; Botzung, Denkova, & Manning, 2008;
Okuda et al., 2003; Szpunar et al., 2007). Among the more posterior regions of the
brain that show this pattern are the medial temporal lobes, which have tradition-
ally been associated with retrieval of one’s past experiences (Cabeza & St. Jacques,
2007; Maguire, 2001; Svoboda, McKinnon, & Levine, 2006). That thinking about
one’s personal future engages this region of the brain in a similar manner has
been taken as particularly striking evidence that similar processes underlie both
facets of mental time travel. Importantly, this pattern of similarity is restricted to
thoughts about one’s self in time: thinking about the past and future in an imper-
sonal manner does not appear to engage an identical network of brain activity
(see Abraham et al., 2008; see also Buckner, 2010, Schacter, Addis, & Buckner,
2007, 2008, and Szpunar, 2010, for reviews).
If all of these studies really have identified all these neural correlates of think-
ing about non-present times, past and future, then we seem to be forced to con-
clude that future may not exist in the physical reality but it does exist in the
neurocognitive reality. For any human being who is heading for a grocery store or
planning a vacation on the beach, working for a monthly paycheck or a university
degree, planting flowers in the garden or buying shares of a company, getting a
vaccination against flu or training for a half-marathon, or engaging in any one of
a thousand activities that promise a payoff at a time that has not yet arrived, for
any such person future is real.
If things exist in the physical reality and things exist in a person’s mental real-
ity, are these two realities the same, or are they different? In the next and last
section of the paper we argue that they are different but related, and that it is not
only possible but also natural for things to exist in one reality but not in the
other.
Two Realities of Our World

So, does the future exist? Yes and no. It does not exist in the physical reality but it
certainly exists in the mental reality. Is there a paradox or a puzzle in the fact that
the physically nonexistent future affects the physically existent members of the
human race? Yes and no. There is a paradox if one assumes that the two realities
are identical but not if one assumes that the two are different.
To try to make sense of what we have just said, we have to clarify what we mean
by “reality” or “realities,” and try to justify our assumption of two realities.
By “reality” here we simply mean the sum total of everything that exists, or
everything that “has a being,” as philosophers sometimes say. And by existence we
simply mean “having properties or qualities, or relations.” Thus, if we assert that
something exists, we say that this something has properties or qualities that an
observer can describe, or that it stands in a certain relation to other things that
exist. Conversely, anything that has properties or qualities or relations exists, by
definition.
The way thinkers have thought about issues having to do with existences and
realities has changed with historical times and geographic places. In our current
“Western” culture the traditional views about reality hold that there is only one,
the physical reality.
We here have adopted the idea that, in addition to the physical reality, there
also exists another reality, neurocognitive (or mental) reality. Despite doubts that
some thinkers, through the ages, have suffered privately or expressed publicly,
mental reality is as “real” as physical reality. The two realities are similar in that
both consist of real (actually existing) lower-order constituents, but they also
differ in fundamental ways.
Physical reality is singular, absolute, everlasting, boundless, and completely
independent of anything else. It functions according to its own laws and princi-
ples. Its constituents include “things” to which we humans have given names,
such as galaxies, stars, planets, dark matter, atoms, energy, radiation, oceans,
waves, clouds, pebbles on the beach, sand in the desert, plants in the field, ani-
mals, roots, leaves, limbs, hearts, brains, blood, neurons, spikes, synapses, mole-
cules, atoms, quarks, neutrinos, along with innumerable things that humans do
not know about and that, therefore, have no names. Behind every name in the
very long list is something that “is out there” regardless of whether we are or are
not “here.”
Mental reality, on the other hand, unlike physical reality, is very much depen-
dent on something outside it, namely physical reality. Most directly it owes its
existence to those parts of the physical reality that constitute the nervous system.
Another fundamental difference from physical reality is that mental reality
assumes a myriad of different shapes and forms. Every single living thing is
embraced by and lives in its own neurocognitive reality, which is uniquely differ-
ent from that of everyone else’s. Like Heraclitus’s river, neurocognitive reality
changes moment by moment; it is never the same. Also, unlike physical reality,
which is boundless in space and time, neurocognitive reality is bound within the
skin of the organism and firmly centered on the “self.” Finally, like many other
things in living nature, mental reality comes to an end when the individual’s life
comes to an end.
Constituents of mental reality include things such as (1) sights and sounds—
of an infinite variety of things and their properties and relations, (2) thoughts
and images—of an infinite variety, (3) memories—of an infinite variety of objects,
facts, events, and situations, and their properties and relations, and (4) experi-
ences, dreams, feelings, hopes, fears, longings, faith, beliefs, doubts, jealousies,
regrets, love, loyalties, ambitions, and a myriad other such—an infinite variety of
different kinds. The central constituent of the human mental reality, the true linch-
pin, is the individual’s awareness of its “self” as an entity existing in subjective
space and subjective time and separate from everything else that exists in the phys-
ical reality. One’s self and personal identity is defined by his or her mental reality.
Although mental reality is utterly dependent on physical reality, in the sense
that it could not exist in the absence of physical reality, it is also independent of
physical reality in the sense that what exists in mental reality does not exist in
physical reality. Because this assertion may sound startling, it is worth repeating:
There is not a single thing that exists in mental reality that also exists in physical
reality. There are no thoughts and images, no memories, no experiences, dreams,
feelings, hopes, fears, longings, faith, beliefs, doubts, jealousies, regrets, love, loy-
alties, or ambitions in physical reality. There is no duty, sadness, injustice, exalta-
tion; no learning, no forgetting, no memory; neither light nor sound, neither pain
nor happiness, neither beauty nor ugliness, neither wisdom nor stupidity; neither
faith nor disbelief. There is neither personal past nor personal future. There is no
mental time travel. There is no “self.” There is no “will,” free or otherwise.
The converse is also true: There is not a single thing that exists in physical real-
ity that also exists in mental reality. There are no mountains or rivers, trees or
flowers, no brain, no blood, no neurons or synapses, no molecules or atoms in
mental reality.
What we have said about the two realities, and the total lack of overlap in their
constituents, may sound like old-fashioned dualistic thinking about body and
soul, or mind and matter. In fact nothing could be further from the truth. Like all
other cognitive neuroscientists we accept as axiomatic that mental reality, fully
dependent on the brain, is continuous with the brain and the rest of the physical
reality. The brain and the mind are made of the “same stuff.” We do not yet know
what that “stuff ” is, but we have reason to believe it will eventually be discovered.
We know that the brain and the mind are not identical, as some people are wont
to declare. The brain and the mind are different entities constituted of the same
basic “stuff.”
The most powerful argument for the sameness of the “stuff ” we are talking
about comes from the knowledge we have of the process of reproduction. All
higher organisms, including human beings, start their life as fertilized eggs.
A fertilized egg, another marvel of nature, consists of an extremely complex but
highly organized bundle of molecules, each of which is a highly complex but highly
organized bunch of atoms, each of which is most definitely a “physical” thing that
embodies the as-yet-unknown “stuff ” that we are postulating here. As the organ-
ism develops and matures from this highly “physical” beginning it does not acquire
any qualities or powers that are not inherent in the same stuff that was there at
the very beginning of the reproductive process. Whether we call it physical or

material or something else does not matter much.
The idea of two realities does suggest a simple resolution of the “paradox of the
non-existent future.” The paradox, you may recall, was expressed as follows: How
can something, like future, that does not exist in physical reality exert any influ-
ence on something that does, like human action? The solution is this: It is not the
non-existent physical future that does the influencing but rather the fully existent
mental future of the individual. Individuals with free will are perfectly capable of
adjusting their behavior in light of their mental-reality knowledge and initiate
action now that will change what will happen in their future. Thus, there is no
paradox. The “paradox” comes about only because of the assumption of a single
reality. It vanishes when we take into account both of the two realities. With the
thought of two realities in our minds—in our mental reality—everything is per-
fectly humdrum, perfectly natural.
There is nothing terribly original in the general idea of two realities, of course.
Its roots can be traced to what earlier modern philosophers called “the ancients,”
and discussions and debates about issues of reality versus appearance, material
versus immaterial, body versus soul, or brain versus mind have kept countless
philosophers, theologians, and other sages gainfully occupied over long stretches
of time. Here we have taken a simple commonsense stance on the same kind of
issue, of the kind that befits practicing scientists. We are happy to leave the
nuances, details, and refinements to people wiser than we are. In many ways our
own rendering of two realities mimics Karl Popper and John Eccles’ three-world
theory of mind–brain relations (Popper & Eccles, 1977). Briefly, Popper and
Eccles put forth a conceptualization of the universe that consists of three “worlds”:
(1) the physical universe; (2) the mental universe; and (3) the products of the
mental universe (i.e., products of the human mind, both concrete and abstract).
We differ from Popper and Eccles in at least two ways. First, we do not distin-
guish between their worlds 1 and 3 (i.e., the physical universe and the products of
the human mind) because we do not need the distinction for our purposes. World
1 entities, according to Popper and Eccles, include things like stars, galaxies, peb-
bles on the beach, sand in the desert, plants in the field, roots, leaves, oak trees,
meadows, and so on. These are entities of the sort we mentioned earlier in rela-
tion to our conceptualization of physical reality. Popper and Eccles, however, dis-
tinguish “natural” physical entities from manmade physical entities such as books,
artworks, musical scores, musical instruments, buildings, bridges, planes, trains,
automobiles and so on. Although the distinction between “natural” and manmade
entities is a clear one, for our purposes the origin of physical objects—divine,
natural, or human—is unimportant.
Second, and perhaps more relevant, is our conception of the relation between
the two realities: (1) mental reality completely depends on physical reality, and (2)
mental reality transcends physical reality in that its constituents do not belong to
physical reality. This view of the relation between the two realities, expressed in
the conjunction of the two points just made, the dependence and transcendence
of mental reality, has interesting ramifications and implications that may not
have appeared as readily in other sorts of formulations of the relation.
We conclude by returning to what we said at the beginning of our essay about
memory. The musings that we have put down here naturally evolved out of
research on memory, aided and abetted by thoughts about the frontal lobes as the
main agents of shaping human uniqueness. In that sense the idea of two equally
important realities can be viewed as the grand payoff for the research on memory.5
But once we have arrived at the idea about the dependence and transcendence of
mental reality, and reflecting about its basic nature, it is easy to see that memory
is relevant to mental reality yet in another way: Memory is one of the main deter-
minants of what the mental reality of any given individual is like and what its
“constituents” are, perhaps even the most important single determinant. Aristotle
would have been amazed.
Notes
1. “Remembering” for Aristotle meant what we would now refer to as retention, or perhaps as
“memory trace.”
2. They can be found in an article titled “Episodic Memory” in Scholarpedia (Tulving & Szpunar,
2009).
3. K.C.’s deep “episodic amnesia” has lasted to this day, almost 30 years later. And the way he
answers questions and the absence of confabulation are also largely unchanged (Rosenbaum
et al., 2005).
4. “Neurocognitive” would provide a more apt characterization of the “other” reality (“mental”),
but because of its five syllables it sounds a bit officious. Its use would be more appropriate in
scientific journals and in situations where we study the relation between the two realities.
In more casual conversations, and in publications such as Festschrifts, “mental” is to be
preferred because it rolls more readily off the tongue.
5. When we take off our scientific hats and don the caps of amateur practical moralists we are
willing to argue that of the two realities the mental reality is very much more important than
the physical reality. Indeed, physical reality as such does not matter at all in daily life; only
mental reality does. It is an individual’s mental reality that guides and controls his or her
conduct.
References
Abraham, A., Schubotz, R. I., & von Cramon, D. Y. (2008). Thinking about the future versus the past
in personal and non-personal contexts. Brain Research, 1233, 106–119.
Addis, D. R., Wong , A. T., & Schacter, D. L . (2007). Remembering the past and imagining the
future: common and distinct neural substrates during event construction and elaboration.
Addis, D. R., Sacchetti, D. C., Ally, B. A., Budson, A. E., & Schacter, D. L . (2009). Episodic simulation
of future events is impaired in mild Alzheimer’s disease. Neuropsychologia, 47, 2660–2671.
Arzy, S., Collette, S., Ionta, S., Fornari, E., & Blanke, O. (2009). Subjective mental time: the func-
tional architecture of projecting the self to past and future. European Journal of Neuroscience,
30, 2009–2017.
Atance, C. M., & Meltzoff, A. N. (2005). My future self: young children’s ability to anticipate and
explain future states. Cognitive Development, 20, 341–361.
Atance, C. M., & O’Neill, D. K . (2001). Episodic future thinking. Trends in Cognitive Sciences, 5,
533–539.
Aristotle. (350 b.c.). On memory and reminiscence. (J.I. Beare, Trans.). Retrieved Feb. 18, 2010,
from http://classics.mit.edu/Aristotle/memory.html.
Botzung , A., Denkova, E., & Manning, L . (2008). Experiencing past and future events: Functional
neuroimaging evidence on the neural bases of mental time travel. Brain and Cognition, 66,
202–212.
Buckner, R. L . (2010). The role of hippocampus in prediction and imagination. Annual Review of
Psychology, 61, 27–48.
Buckner, R. L., & Carroll, D. C. (2007). Self-projection and the brain. Trends in Cognitive Sciences,
11, 49–57.
Cabeza, R., & St. Jacques, P. (2007). Functional neuroimaging of autobiographical memory. Trends
in Cognitive Sciences, 11, 219–227.
Clayton, N. S., Bussey, T. J., & Dickinson, A . (2003). Can animals recall the past and plan for the
future? Nature Reviews Neuroscience, 4, 685–691.
Clayton, N. S., Bussey, T. J., Emery, N. J., & Dickinson, A . (2003). Prometheus to Proust: the case
for behavioural criteria for “mental time travel.” Trends in Cognitive Sciences, 7, 436–437.
Cofer, C. N. (1961). Verbal learning and verbal behavior. New York: John Wiley.
D’Argembeau, A., Raffard, S., & Van der Linden, M. (2008). Remembering the past and imagining
the future in schizophrenia. Journal of Abnormal Psychology, 117, 247–251.
D’Argembeau, A., & Van der Linden, M. (2004). Phenomenal characteristics associated with
projecting oneself back into the past and forward into the future: influence of valence and
temporal distance. Consciousness and Cognition, 13, 844–858.
Ebbinghaus, H. (1885/1964). Memory: a contribution to experimental psychology. (H. A. Ruger & C. E.
Bussenius, Trans.). New York: Dover.
Gilbert, D. T., & Wilson, T. D. (2007). Prospection: experiencing the future. Science, 317,
1351–1354.
Hassabis, D., Kumaran, D., Vann, D. S., & Maguire, E. A . (2007). Patients with hippocampal amnesia
cannot imagine new experiences. Proceedings of the National Academy of Sciences U S A, 104,
1726–1731.
Hasselmo, M. E. (2009). A model of episodic memory: mental time travel along encoded trajecto-
ries using grid cells. Neurobiology of Learning and Memory, 92, 559–573.
Hayes-Roth, B., & Hayes-Roth, F. (1979). A cognitive model of planning. Cognitive Science, 3,
275–310.
Hoerl, C. (2008). On being stuck in time. Phenomenology and the Cognitive Sciences, 7, 485–500.
Ingvar, D. H. (1985). “Memory of the future:” An essay on the temporal organization of conscious
awareness. Human Neurobiology, 4, 127–136.
James, W. (1890/1983). Principles of psychology. Cambridge, MA: Harvard University Press.
Klein, S. B., Loftus, J., & Kihlstrom, J. F. (2002). Memory and temporal experience: the effects of
episodic memory loss on an amnesic patient’s ability to remember the past and imagine the
future. Social Cognition, 20, 353–379.
Loftus, E. (1979). Eyewitness memory. Cambridge, MA: Harvard University Press.
Maguire, E. A . (2001). Neuroimaging studies of autobiographical memory. Philosophical Transactions
of the Royal Society of London: B, 356, 1441–1451.
McDonough, I. M., & Gallo, D. A . (2010). Separating past and future autobiographical events in
memory: evidence for a reality monitoring asymmetry. Memory & Cognition, 38, 3–12.
McTaggart, J. E. (1908). The unreality of time. Mind, 17, 457–474.
Miller, G. A. (2003). The cognitive revolution: a historical perspective. Trends in Cognitive
Neurosciences, 7, 141–144.
Okuda, J., Fujii, T., Ohtake, H., Tsukiura, T., Tanji, K., Suzuki, K., Kawashima, R., Fukuda, H., Itoh,
M., & Yamadori, A . (2003). Thinking of the future and past: the roles of the frontal pole and
the medial temporal lobes. NeuroImage, 19, 1369–1380.
Piolino, P., Desgrages, B., & Eustache, F. (2009). Episodic autobiographical memories over the
course of time: cognitive, neuropsychological and neuroimaging findings. Neuropsychologia,
47, 2314–2329.
Popper, K., & Eccles, J. C. (1977). The self and its brain. New York: Routledge.
Reinhold, N., & Markowitsch, H.J. (2009). Retrograde episodic memory and emotion: a perspective
from patients with dissociative amnesia. Neuropsychologia, 47, 2197–2206.
Roberts, W. A., & Feeney, M. C. (2009). The comparative study of mental time travel. Trends in
Cognitive Sciences, 13, 271–277.
Roediger, H. L., & McDermott, K. B. (1995). Creating false memories: remembering words not
presented in lists. Journal of Experimental Psychology: Learning, Memory, and Cognition, 21,
803–814.
Rosenbaum, S. R., Kohler, S., Schacter, D. L., Moscovitch, M., Westmacott, R., Black, S. E., Gao, F., &
Tulving , E. (2005). The case of K.C.: contributions of a memory-impaired person to memory
theory. Neuropsychologia, 43, 989–1021.
Russell, B. (1921). The analysis of mind. London: George Allen & Unwin.
Russell, J., Alexis, D., & Clayton, N. (2010). Episodic future thinking in 3- to 5-year-old children:
the ability to think of what will be needed from a different point of view. Cognition, 114,
56–71.
Schacter, D. L . (2001). The seven sins of memory: how the mind forgets and remembers. Boston:
Houghton Mifflin.
Schacter, D. L., & Addis, D. R . (2007). The cognitive neuroscience of constructive memory: remem-
bering the past and imagining the future. Philosophical Transactions of the Royal Society of
London: B, 362, 773–786.
Schacter, D. L., Addis, D. R., & Buckner, R. L . (2007). The prospective brain: remembering the past
to imaging the future. Nature Reviews Neuroscience, 8, 657–661.
Schacter, D. L., Addis, D. R., & Buckner, R. L . (2008). Episodic simulation of future events: concepts,
data, and applications. Annals of the New York Academy of Sciences, 1124, 39–60.
Singer, J. L . (1966). Daydreaming. New York: Random House.
Suddendorf, T., & Busby, J. (2003a). Mental time travel in animals? Trends in Cognitive Sciences, 7,
391–396.
Suddendorf, T., & Busby, J. (2003b). Like it or not? The mental time travel debate: reply to Clayton
et al. Trends in Cognitive Sciences, 7, 437–438.
Suddendorf, T., & Corballis, M. C. (1997). Mental time travel and the evolution of the human mind.
Genetic, Social, and General Psychology Monographs, 123, 133–167.
Suddendorf, T., & Corballis, M. C. (2007). The evolution of foresight: what is mental time travel,
and is it unique to humans? Behavioral and Brain Sciences, 30, 299–313.
Svoboda, E., McKinnon, M. C., & Levine, B. (2006). The functional neuroanatomy of autobiographi-
cal memory: a meta-analysis. Neuropsychologia, 44, 2189–2208.
Szpunar, K. K . (2010). Episodic future thought: an emerging concept. Perspectives on Psychological
Science, 5, 142–162.
Szpunar, K. K., Watson, J. M., & McDermott, K. B. (2007). Neural substrates of envisioning the
future. Proceedings of the National Academy of Sciences U S A, 104, 642–647.
Taylor, S. E., Pham, L. B., Rivkin, I. D., & Armor, D. A . (1998). Harnessing the imagination: mental
simulation, self-regulation, and coping. American Psychologist, 53, 429–439.
Taylor, S. E., & Schneider, S. K . (1989). Coping and the simulation of events. Social Cognition, 7,
174–194.
Tulving , E. (1983). Elements of episodic memory. New York: Oxford University Press.
Tulving , E. (1985). Memory and consciousness. Canadian Psychology, 26, 1–12.
Tulving , E., & Szpunar, K.K . (2009). Episodic memory. Scholarpedia, 4(8), 3332.
Zimbardo, P., & Boyd, J. N. (1999). Putting time in perspective: a valid, reliable individual-differences
metric. Journal of Personality and Social Psychology, 77, 1271–1288.
15
The Necessary Narrative
T E R E N C E W. P I C TO N
Life can only be understood backwards; but it must be lived forwards.

Søren Kierkegaard, Journals, 1843
This chapter allows me to present some ideas that I have developed over the
years, largely as a result of discussions with Don Stuss and the colleagues he
assembled at the Rotman Research Institute. Though triggered by specific data,
particularly those that we gathered from patients with lesions to the frontal
lobes, the ideas have faded a little into the general. This inevitable consequence
of scientific aging can be helpful since details can get lost without general ideas.
I shall consider three basic concepts: models, stories, and levels. The epigraph
comes from someone who, like Don Stuss, left his initial studies of divinity
for more important things. It gives the main thrust of the talk: that human life
is a creative interaction between the brain and the world, between living and
understanding.
Models
The human brain perceives the world creatively. We are never an empty slate.
The infant is attuned to see and hear what its genes expect. The maturing brain
perceives everything in relation to what it has already experienced. I am a part of
all that I have known. Early views of active perception in terms of analysis-by-
synthesis were perhaps too concrete. We do not hear words by mumbling them to
ourselves. However, we do build an internal model of the external world, and
much of our life is involved in its updating (Neisser, 1976).
An interesting problem for a creative perception is the real world. Is there no
real world; are you, the reader, just a figment of my solipsistic imagination? This
issue is typically addressed by some concept of resonance. Gibson (1979) pro-
posed that perceived patterns resonate with physical invariances. A more recent
264
T h e N e ce s s ary N arrat iv e 265
version of this idea (Friston, 2005) uses empirical Bayes modeling: patterns are
generated and fit to input by statistical estimates realized in hierarchical neuronal
networks.
One aspect of this ongoing process of testing our perceptions against reality is
that there are no discrete events: “stimulation does not consist of stimuli. The
flow is continuous” (Gibson, 1979, p. 58). This continuity of perception is some-
thing that physiologists have not easily been able to evaluate, accustomed as we
are to recording discrete responses to discrete stimuli. However, recent work has
shown that we can monitor the brain in real time as it makes plans, confirms
expectancies, or notices discrepancies between the real and the predicted (Spiers
& Maguire, 2007).
One of the most impressive demonstrations of the creativity of perception is
the perception of biological motion (Ahlstrom, Blake & Ahlstrom, 1997; Saygin,
2007; Vanrie & Verfaillie, 2004). A few moving lights can bring to mind a moving
person, even one we can personally recognize. The fact that the movement of the
lights must be continuous and not stroboscopic further supports the idea of per-
ception as a continous process.
Though much of perception occurs automatically, at higher levels the brain is
conscious. We have predictions about what will happen in the world and goals
that we use to explore our environment and organize our actions. When sensory
information is processed, however, consciousness does not intrude until the final
stages. We are aware of visual objects but not the bits and pieces that our sensory
system uses to construct them.
Resonance is still a prominent idea in perceptual theory, but nowadays reso-
nant processes are often considered in terms of rhythmic interactions between
different areas of the brain (e.g., Melloni et al., 2007). What becomes widespread
in its connectivity reaches consciousness, whereas what is only locally rhythmic
goes unperceived. The physiology is not obvious. What is so helpful about oscilla-
tions? Do they indicate the operation of feedback circuits? Why is the extent of
the interaction crucial? Is it really the extent of interaction or simply that it
reaches to the prefrontal cortex (e.g., Crick & Koch, 1998)?
Resonance occurs in the motor system as well as the sensory systems. The exe-
cution of a motor act fits muscle-movements to a “forward model” of the desired
action. As in the sensory system, oscillations between areas may subserve this
fitting process (e.g. Cheyne, Bells, Ferrari, Gaetz, & Bostan, 2008). As in the sen-
sory system, most of the details are unconscious. We do not design how our hand
should move to pick up a cup; we are aware of what we want and the ways to go
about it, but unaware of which muscle fibers are being used.
The conceptual lineage of the model-making brain goes back to cybernetics and
the Test-Operate-Test-Exit idea of Miller, Galanter, and Pribram (1960). Don
Stuss and I have considered how this type of process might be manifest in the
terms of neurons or neuronal networks (Picton & Stuss, 2000; Stuss, Picton &
Alexander, 2001). Figure 15.1 presents another version of our idea: one of many
Generate
Sensory Model Motor
Figure 15.1. Model making. The figure shows how the brain can generate models
that it then fits to incoming sensory information, and creates motor behavior that
fits to a model of desired action. The boxology is loosely derived from Picton and
Stuss (2000). The disconnected arrows at the top indicate how the model making may
proceed at many hierarchical levels. The model works only if there is a real world—here
represented by a part of Huang Gongwang’s scroll painting of Dwelling in the Fu-ch’un
Mountains (1347–1350).
ways to connect boxes into circles and ground them in the world. As in the more
recent and more mathematical work of Friston (2005), the feedback loops can be
connected hierarchically. The most important missing information is how the
system generates the models that can be fit to input or output. What are the neu-
ronal mechanisms for generating patterns of activity and changing them to fit
reality?
A model can change gradually as we better tune our perceptions to reality, or it
can change dramatically when we notice the operation of a cause. The main char-
acteristics of causation are repeated examples of temporal and spatial contiguity.
Much of our current knowledge derives from Hume (1777/1966): “when one par-
ticular species of event has always, in all instances, been conjoined with another,
we make no longer any scruple of foretelling one upon the appearance of the
other… We then call the one object Cause; the other, Effect.”
What happens in the brain when we notice the operation of a cause? Fugelsang,
Roser, Corballis, Gazzaniga, and Dunbar (2005) recorded blood flow changes when
causes were perceived in the colliding of billiard balls. Controls involved motions
that could not be caused, since temporal or spatial contiguity was missing.
Perceiving the causal relationship between moving objects activated right parietal
and frontal areas. Inferring causality in more complex situations involved the left
hemisphere as well (Roser, Fugelsang, Corballis, Gazzaniga, & Dunbar, 2005).
Perceiving the operation of cause and effect is but a pale version of what hap-
pens when we originally figure out how something works. Then, our world model
can be completely recast and myriad disparate details subsumed under a simple
principle.
Stories
Cause and effect is the basis of narrative. After inferring how one event has caused
another, we can tell a story. This crucial ability is evident in our myths, songs,
plays, and novels. We tell stories to explain things as well as to entertain our-
selves. The sequence of cause and effect is the mainstay of any story—or any
scientific paper. Anyone who has ever written such a paper knows that once the
hypotheses have been ventured, the data collected, and the results evaluated, the
next step is to tell a story.
A major contribution to the idea of narrative in the brain derives from the
studies of split-brain patients by Gazzaniga and his colleagues. In a classic experi-
ment (Gazzaniga & LeDoux, 1978), a patient was presented with two brief images,
one in each hemifield, and was asked to point to which of the pictures available on
a set of cards went with the images. When presented with an image of a chicken
claw on the right and an image of a snow scene on the left, the patient subse-
quently picked the pictures of a chicken and a shovel: “The chicken claw goes with
the chicken, and you need a shovel to clean out the chicken shed.” Now the shovel
actually went with the snow scene and was chosen by the right brain, the only
recipient of the image in the left hemifield. The left brain, observing the left hand’s
response (from the right brain), interpreted the response in a context consistent
with its (hemi)sphere of knowledge—one that did not include any information
about the left-side snow scene.
These and other experiments led to the idea that the human brain has an inter-
preter system—one that tells a story about why things happen. This system is
normally localized in the left hemisphere and is intimately part of the language
systems.
These findings suggested that the self can be considered as a center of narrative
gravity (Dennett, 1992): “we are all virtuoso novelists, who find ourselves engaged
in all sorts of behavior, more or less unified, but sometimes disunified, and we
always put the best ‘faces’ on it we can. We try to make all of our material cohere
into a single good story. And that story is our autobiography.”
So now I shall mention some introspective data. These have long been consid-
ered unscientific, but data are data. Often when I am talking, I am aware when
what I am saying is not going over. Everything may be grammatically correct and
meaningful, but my audience is leaving me. I must have another interpreter dif-
ferent from the language interpreter. This other system can interpret the effect of
my language rather than its content and can determine whether my presentation
is either unfolding properly or unraveling completely. My intuition is that there
are many levels of interpretation and that this particular interpretational level
involves a widespread brain system that deals with self-awareness and revolves
around prefrontal regions. Craik and his colleagues (1999) indeed showed activa-
tion of the frontal regions when subjects interpreted simple stimuli in relation to
themselves.
In recent years, neuroscientists have been studying what happens in the brain
when a narrative is being followed. Mar (2004; also Spreng, Mar, & Kim, 2009)
reviewed this work and found that widespread regions of the brain are involved.
Many of these are similar to the regions that Buckner and Carroll (2007) have
suggested as part of the “self projection system”—the networks of the brain
involved in prospection, remembering, and theory of mind. Recent findings have
suggested that the dorsomedial frontal regions may be particularly important in
following a narrative (Yarkoni, Speer, & Zacks, 2008). C. P. Snow (1959) would be
pleased to see this reconciliation between the two cultures of science and art.
Perhaps we can now record the changes in cerebral blood flow that occur when we
read one of his novels!
Any narrative has three main components: place, person, and plot. The initial
section of this chapter has dealt with some aspects of place—the world we live in
and how we construct it. We have already considered the person in terms of the
narrator of my life. However, a person not only looks back on the past but also
plans for the future. How this will turn out is the plot of our narrative. As Endel
Tulving has considered, this can involve the contemplation of what might happen
as well as the interpretation of the past (Wheeler, Stuss, & Tulving, 1997; Tulving,
Chapter 14 in this volume).
One of the basic characteristics of the self is its continuity: it must somehow be
the same from day to day. Organizing our memories around a self would not be
helpful if the self were to vanish when we fall asleep and be different when we
awake. A possible side effect of this need for personal continuity is a sense of
immortality. We have such a long experience resurrecting our wakeful self that we
might consider death like any other sleep.
Crucial to the narrative’s plot is the idea of causation. I have commented on
causation in terms of the perception of physical causes and effects. When persons
become involved, causation becomes agency. This is an area of our knowledge
fraught with dragons. A sense of agency develops as we develop a sense of self. The
self not only interprets what we perceive, but also controls what we do. As we
learn this (or set up this construct), we realize that the world contains other
agents that perceive what we cannot perceive and control what we cannot control.
Thus do we come to a theory of mind—that there are others like us. The frontal
lobes are necessary for the exercise of theory of mind (Stuss, Gallup, & Alexander,
2001). However, episodic memory seems independent: a patient may lose his
sense of self in remembering but can still postulate a self in others (Rosenbaum,
Stuss, Levine, & Tulving, 2007; Rosenbaum, Chapter 7 in this volume).
The attribution of agency can easily be overdone. Gods may derive “from
our overactive disposition to look for agents” (Dennett, 2006). Attributing agency
to actions facilitates social interaction. However, it may also lead to the idea of
agents moving suns and controlling storms—and ultimately to a universe
controlled by God. We are right about other human beings but may be wrong
about the divine.
Agency is basically what has been considered as free will. Michael Gazzaniga
(2005) has presented a nuanced review of the implications of brain science for
ethics and the law. Free will and responsibility are crucial to moral and legal rea-
soning. Extensive recent research and discussion about free will and the brain
derive from an experiment recording event-related potentials—the readiness
potential or Bereitschaftspotential (Libet, 1985; Libet, Gleason, Wright, & Pearl,
1983). This experiment may have been over-interpreted.
The usual procedure for recording the Bereitschaftspotential is for the subject to
make occasional spontaneous movements at irregular intervals of several sec-
onds. The EEG prior to the movement is recorded and averaged opisthochronically
(bent backward in time) using either the EMG or the movement as a timing trig-
ger. The averaged EEG shows a slowly developing negative wave that begins sev-
eral hundred milliseconds before the movement and culminates in a motor
potential just before the movement. In the experiments by Libet and colleagues,
the subject made spontaneous finger flexions while simultaneously watching a
dot that circled around a clock face. The subject “was instructed to ‘let the urge to
act appear on its own at any time without any preplanning or concentration on
when to act,’ that is, to try to be ‘spontaneous’ in deciding when to perform each
act; this instruction was designed to elicit voluntary acts that were freely capri-
cious in origin” (Libet et al., 1983). The subject noted and reported “the time of
appearance of his conscious awareness of ‘wanting’ to perform a given self-initi-
ated movement.” The experience was also described as an “urge,” “intention,” or
“decision.” The major finding of the experiment was that the Bereitschaftspotential
began before the subject became aware of the intention to act. The interpretation
of the experiment has been that our feeling of will occurs after the fact: the brain
initiates the act and we then become aware of it. Our consciousness does not con-
trol our actions, though it may sometimes be able to stop an initiated action (e.g.,
Obhi & Haggard, 2004). Recently, these results have led prominent scientists to
claim that “free will” is an illusion (Blackmore, 2009; Blakemore, 2009).
Allusions rather than illusions come to mind. One is the theological paradox of
free will and predestination: how can we have free will if God always knows every-
thing that we are going to do? Proposing that there is no God provides a simple
resolution to this problem. A second allusion is the behaviorist claim that all
behavior follows willy-nilly from the presented stimuli without any cognitive
intervention. Fifty years ago, mind and meaning returned to psychology in the
cognitive revolution; perhaps neuroscience will also change. Considering some-
thing like awareness and free will as epiphenomenal may be as foolhardy for neu-
roscience as it was for psychology.
The subject’s experience during Bereitschaftspotential experiments is far more
complex than presumed by their design. For many years, Don Stuss, Tim Shallice,
Mick Alexander, and I have been evaluating the effects of focal lesions of the
frontal lobe (e.g., Stuss et al., 2005). We have found that even simple behaviors,
like pressing a button in response to a stimulus, are controlled by many different
cerebral processes, and that these processes may be differentially affected by focal
frontal lesions. Figure 15.2 (derived from Shallice, Stuss, Picton, Alexander, &
Gillingham, 2008) shows a diagram of several of these processes: setting, energi-
zation, monitoring, and attentiveness. Each process is an amalgam of many other
component processes. Crucial to any task performance is the setting up of sche-
mata or rules of behavior. These can operate automatically, but they must be ener-
gized and monitored to make sure that they are fulfilling their goals. And
everything must be evaluated in the light of more general goals (“attentiveness”)—
we must care about our acts (see Shallice, Chapter 3 in this volume).
Perhaps the simple Bereitschaftspotential experiments can be viewed in the
light of our experiments with frontal lobe patients. Doing what the experimenter
asks is not easy. To flex one’s fingers at a rate that is regular but not too regular
requires a complex program of action involving many different cerebral processes.
A timing mechanism must be initiated and monitored to determine when a given
interval of several seconds has passed. A motor executive system must be trig-
gered by the timing system to initiate the movement. The monitoring system
must determine how well the whole program is working—whether the timing is
about right, whether the movements are sufficiently abrupt. Finally, an attentive-
ness system must determine that the behavior fulfils our present goal—to act as
Task-setting (left lateral)
+ –
Stimulus Response
Task rules
processing selection
(superior medial)
(inferior medial)
Attentiveness
Energization
Internal Finger
Initiate
timing flexion
Clock Report
Register
time time
Monitoring (right lateral)
Figure 15.2. Performance of complicated tasks. This model derives from Shallice et al.
(2008), where a similar model was used to explain the processes active during task
switching. The inner white boxes and arrows represent online processes that (following
learning of the task) would be connected together by sensorimotor schemata or
response rules (medium gray). The outer dark boxes and arrows represent supervisory
control processes that are mainly active through connections in the prefrontal cortices.
Different supervisory processes can be specifically affected by lesions to different
regions of the frontal lobe—left lateral, right lateral, superior medial, and inferior
medial.
the experimenter has asked. Watching the clock and assessing the timing of
response initiation would involve an additional program that could most easily
monitor the activity of the internal timing mechanism that triggers the motor
executive.
Where is the will in these interactions? If anywhere, it is in the original setting
up of the programs. Once set up, these programs can proceed without much con-
scious intervention. The human brain is a complex interactive system that does
not work in a discrete way. The search for a specific intention (an “impulse” to act)
is perhaps as futile as the search for a specific stimulus. There is no stimulus: there
is a complex world. There is no intention: there is an individual’s continuous cre-
ative interaction with that world.
Soon, Brass, Heinze, and Haynes (2008) recorded fMRI activation patterns in
regions of frontopolar cortex and the medial parietal lobes occurring about 10
seconds prior to a motor act. These patterns were specific to the choice between
responding with right or left index fingers. They preceded the activations in sup-
plementary motor areas and motor cortex. This fits with the interpretation I am
offering that behavior is planned and set into action long before it actually occurs.
The authors of the paper, however, found that the subjects’ timing of when their
decisions “were consciously formed” was within the 1,000 milliseconds preceding
the act. They proposed therefore that “a network of high-level control areas can
begin to shape an upcoming decision long before it enters awareness.” It does not
make sense to me that the subjects were unconscious of what they were doing
during the 10-second preparatory period; they must have been consciously decid-
ing what to do. The authors only asked when the decision was completed—not
when it was being made.
Most of the problems of interpretation in these experiments come down to
the dualism presupposed in their design (Nelson, 1985; Wood, 1985). The premise
of the experiments is that the brain makes a decision and then informs the
mind. The mind then reports back (through the brain and its connections to the
body) when it received the information. The problems disappear if we admit no
dualism—the brain just makes a decision. The brain is free.
Levels
Our minds are particularly adept at considering ideas at different levels. The interac-
tive networks that mediate our consciousness move easily from one level to another.
Even within general levels we can alternate one explanation with another. At sen-
sory levels we can undergo binocular rivalry or jump from one apex of a Necker
cube to another. At higher levels we can consider a photon as wave or particle.
A hierarchy of levels in the brain was proposed by Hughlings Jackson in the
early days of cerebral neuroscience (Jackson, 1898). His ideas were related to those
of evolution, with higher nervous functions developing to control lower processes.
One of his ideas concerned how cerebral disease, either transiently in epilepsy or
progressively in degenerative disorders, could reverse evolution, removing the
higher functions before the lower in a process of dissolution.
The idea of levels of processing in memory was introduced to psychology by
Craik and Lockhart (1972). The deeper something is processed, the better it is
remembered. What is the metric for depth of processing? Clearly the semantic
interpretation of a word is deeper than recognizing its letters or its sounds.
However, it is difficult to derive some index of processing that determines what is
later remembered (Craik, 2002).The amount of time required for the processing,
the success or failure of the processing (for example, rhyming words are better
remembered than non-rhyming words), and the amount of attention paid to the
processing all contribute to its depth. Does any neurophysiological measure relate
to the depth of processing? The extent of synaptic activation is important—but
this fails to consider the specific interactions between frontal lobes and hippocam-
pus that are necessary to render an event accessible to later recall (Moscovitch,
1995).
Studies with the event-related potentials confirm that multiple processes in
multiple regions of the brain occur during the encoding of our memories (e.g.,
Kim, Vallesi, Picton, & Tulving, 2009; Mangels, Craik, & Picton, 2001). The story
of information on its way to memory involves interactions between sensory asso-
ciation cortices, anterior temporal regions, and the prefrontal cortex.
Levels are intrinsically related to memory. In this context we may wish to con-
sider episodic and semantic memory. Episodic memory has a relation to the self:
a memory of the world and its interaction with the rememberer. The memory for
facts has no such personal flavor. What are their relative levels—is episodic
memory a means to create semantic memory, or is semantic memory a tool for
constructing a biography? Tulving’s (2005) proposal that episodic memory has
evolved only in human beings suggests that it is higher in the hierarchy of memo-
ries than semantic memory.
We could perhaps consider memory in relation to politics. The left views that
the value of a society is determined by how well it improves the general good. This
improvement in the good of all will ultimately lead to the greater freedom of each
individual in the society. The right considers individual freedom paramount, with
the general good deriving from the free endeavors of its individual members. Does
semantic knowledge ultimately become our culture, leaving individual biography
as a transient step on the way, or does our culture derive from the biographies of
its greatest individuals? Hierarchies of values run both ways.
Perhaps human memory is best considered in the metaphor of a tree
(Fig. 15.3). The tree of knowledge goes back to Genesis. Rather than putting epi-
sodic details in the roots and semantic knowledge in the branches (and thus
betraying my leftist tendencies), I have made the tree grow from past to future.
The future is imagined by the person we have developed and implicated by the
principles we have abstracted. I have given semantic memory a parallel time
Implication Imagination
Principle Person
Data Experience
Figure 15.3. Tree of knowledge. The tree is organized to grow from past roots to
future branches. Both semantic memory (left) and episodic memory (right) conceive
the future by abstracting information from sensory data or subjective experience.
course to episodic memory. My suggestion is that semantic memory (in its human
form with all its language and science) is as far evolved as episodic memory.
The tree of knowledge is complex. Both episodic memory and semantic memory
become highly organized with many levels, each supporting each. This organiza-
tion allows meaning to be conveyed. As pointed out by Cohen (2000), social com-
munication largely depends on the telling of stories, and the effectiveness of the
communication will depend on the hierarchical organization of the stories. An
accumulation of detail without purpose is as boring as abstract ideas without
examples.
Sometimes scientists seem bound to one level of explanation. The physicist
may find as little meaning in biology as the biologist in psychology. This problem
has been termed “level chauvinism” (Nunez & Srinivasan, 2006). Perhaps the
most glaring problems come between the levels of science and art. Recently,
Dawkins (1998) has taken Keats to task for saying that science (philosophy in the
older terminology) removes the beautiful mystery of experience:
There was an awful rainbow once in heaven:

We know her woof, her texture; she is given
In the dull catalogue of common things.
Philosophy will clip an Angel’s wings,
Conquer all mysteries by rule and line,
Empty the haunted air, and gnomèd mine –
Unweave a rainbow
Dawkins proposes rather that:
Mysteries do not lose their poetry when solved. Quite the contrary; the
solution often turns out more beautiful than the puzzle and, in any case,
when you have solved one mystery you uncover others, perhaps to inspire
greater poetry.
However, he fails to understand the levels of artistic expression. Keats’ lines

are spoken by a character in the narrative poem “Lamia.” Lamia is one of the
femmes fatales from the ancient legends. Though serpentine in nature, Lamia can
take on the form of a beautiful woman. In Keats’ poem, Lamia falls in love with
the young man Lycius, who becomes entranced by her beauty and decides to marry
her. At the wedding, Lycius’ old teacher Apollonius sees that Lamia is not as she
appears, calls out her name, and thus dissolves her disguise. The comments on the
rainbow (describing the learning of Apollonius) are but prelude to tragedy. Lamia
dies, Lycius dies, Truth prevails. The poem deals with truth and deception, with
desire and despair, mystery and reality. Poetry has many levels. Its advantage is
that these many levels may be contradictory: Keats may both believe and not
believe the words he uses to describe Apollonius. This tension between opposing
meanings is less easily available to science (though possible in quantum mechan-
ics and string theory).
One of the most fascinating exercises in levels involves irony. Irony originally
meant dissembling. Socrates would evaluate an idea by feigning complete igno-
rance and asking for the idea and its consequences to be explained. The resultant
discussion would show up the idea’s failings: if it cannot be explained to a simple
man, it is likely not worth much. Irony also has a major role in theater when the
audience knows what the protagonist does not. Nowadays irony mainly means
saying one thing while meaning another. It is complicated. In terms of communi-
cation there has to be a tacit link between the ironist and the audience—who
must be aware of the contradictory meaning below the surface. It is hard to be
ironical when talking to someone we do not know. Stephen Colbert, perhaps the
most accomplished ironist of our day, is often misinterpreted as being what he
pretends to be (LaMarre, Landreville, & Beam, 2009).
Metaphor is another intriguing way in which the human mind plays with mean-
ing at different levels (Lakoff & Johnson, 1980). Metaphor brings the abstract
down to comprehensible concrete levels. Metaphors can cut both ways, both
explaining and distorting. What we do not always realize is how pervasive meta-
phors are in our language: they permeate prose as well as poetry. When describing
science, we can select from a broad array of metaphors: industry (experiments run-
ning out of steam), containers (conclusions not holding water), journeys (logic
wandering round in circles), agriculture (hypotheses dying on the vine), fashion
(ideas going out of style), or warfare (premises undermined by the data). Two great
descriptions come from Lakoff and Johnson (1980): from architecture—“complex
theories usually have troubles with the plumbing” (p. 53)—and from cooking—
“raw facts, half-baked ideas and warmed-over theories” (p. 46). We have all expe-
rienced such metaphorical disrespect; it is the table-talk of grant committees.
When we consider the levels of meaning implied by metaphor and irony, we
realize the tremendous complexity of our understanding. Recent studies have
shown that complexity has rules of its own that cannot be explained by simpler
principles. Our brains have evolved to understand a world that is increasing in
complexity through a propagating organization (Kauffman, 2008). The universe is
not so much running down as gearing up.
When we consider possible levels of meaning, it is impossible not to come upon
religion. Some brief comments might be in order, since many years ago Don Stuss
followed the path of the spirit before the way of the scientist. Religious explana-
tion occurs at a level of meaning almost completely divorced from that of science.
The touchstone for religious truth is faith rather than experiment. A scientist has
difficulty following the logic of faith and the experience of the numinous—the
“wholly other.” Sometimes manifestly absurd, the numinous beggars analysis—it
is beyond the understanding of those who have not experienced it (Otto,
1917/1958). Recently it has become common for scientists to consider religion
delusional (Dawkins, 2006; Dennett, 2006). At times the discourse has become
uncivil.
Religion involves a set of narratives that explain the why rather than the how
of things. Gods were initially invented to provide a reason for what could not be
predicted, to give rules for proper behavior, and to provide consolation for what
was lost. Human beings have a deep need for such narratives, and this is not ful-
filled elsewhere. I have no argument with whatever makes it all make sense. The
only provision is that we recognize the rights of others to their own narratives.
Not to consider the religious aspect of the human mind is to sleep before eve-
ning. Religion is such an important and pervasive part of human thinking that it
is foolish to ignore it or to discount it as delusional. The mind must make its gods
and hold them sacred—this is part and parcel of the same human creativity that
proposes scientific theories or imagines art (Kauffman, 2008). We must seek to
understand this human need for belief.
Concluding Comments
I have suggested some ways of looking at how the brain perceives and acts in the
world. I suggest the brain manufactures meaning. Central to this process is its
necessary narrative. The human brain is designed to tell stories. These stories
must be grounded in a model of the real world or they are irrelevant. These stories
must be organized at different levels or they cannot be understood. Our models of
the world, the stories we make to understand the world, and the levels at which
those stories operate are all ultimately part of our necessary narrative.
A chapter that begins with an epigraph should end with a postscript. This
comes from the Nachlass of Nietzsche, the uncompleted writings that were left
when Nietzsche became psychotic in 1889. Since his psychosis was likely the
beginning of frontotemporal dementia (Orth & Trimble, 2006), the quotation is
appropriate in a book on the frontal lobes. There are various translations: “We
have art so that we shall not die of the truth” (Coetzee, 1987/1992), “so that we
shall not be destroyed by the truth” (Ondaatje, 2007), or “so that we do not perish
before reality.”
Wir haben die Kunst, damit an der Wahrheit nicht zugrunde gehen.
References
Ahlstrom, V., Blake, R., & Ahlstrom, U. (1997). Perception of biological motion. Perception, 26,
1539–1548.
Blackmore, S. (March 3, 2009). Let’s drop the charade: it’s right to come to terms with the fact that
free will, just like the sense of a higher power, is an illusion. The Guardian.
Blakemore, S. (Feb. 22, 2009). Science is just one gene away from defeating religion. The Observer.
Buckner, R. L., & Carroll, D. C. (2007). Self-projection and the brain. Trends in Cognitive Sciences,
11, 49–57.
Cheyne, D., Bells, S., Ferrari, P., Gaetz, W., & Bostan, A. C. (2008). Self-paced movements induce
high-frequency gamma oscillations in primary motor cortex. Neuroimage, 42, 332–342.
Coetzee, J. M. (1987/1992). Jerusalem Prize acceptance speech. In J. M. Coetzee & D. Attwell (Eds.),
Doubling the point. Essays and interviews (pp. 96–99). Cambridge, MA: Harvard University
Press.
Cohen, G. (2000). Hierarchical models in cognition: do they have psychological reality? European
Journal of Cognitive Psychology, 12, 1–36.
Craik, F. I. M. (2002). Levels of processing: past, present… and future? Memory, 10, 305–318.
Craik, F. I. M., & Lockhart, R. S. (1972). Levels of processing: a framework for memory research.
Journal of Verbal Learning and Verbal Behavior, 11, 671–684.
Craik, F. I. M., Moroz, T. M., Moscovitch, M. Stuss, D. T., Winocur, G., Tulving , E., & Kapur, S.
(1999). In search of the self: a positron emission tomography study. Psychological Science, 10,
26–34.
Crick, F., & Koch, C. (1998). Consciousness and neuroscience. Cerebral Cortex, 8, 97–107.
Dawkins, R . (1998). Unweaving the rainbow: science, delusion and the appetite for wonder. New York:
Houghton Mifflin.
Dawkins, R . (2006). The GOD delusion. New York: Houghton Mifflin.
Dennett, D. C. (1992). The self as a center of narrative gravity. In F. Kessel, P. Cole, & D. Johnson
(Eds.), Self and consciousness: multiple perspectives (pp. 102–115) Hillsdale, NJ: Erlbaum.
Dennett, D. C. (2006). Breaking the spell: religion as a natural phenomenon. New York: Viking (Penguin
Group).
Friston, K . (2005). A theory of cortical responses. Philosophical Transactions of the Royal Society
(London) B Biological Sciences, 360, 815–836.
Fugelsang , J. A., Roser, M. E, Corballis, P. M., Gazzaniga, M. S., & Dunbar, K. N. (2005). Brain
mechanisms underlying perceptual causality. Cognitive Brain Research, 24, 41–47.
Gazzaniga, M. S. (2005). The ethical brain. New York: Dana Press.
Gazzaniga, M. S., & LeDoux, J. (1978). The integrated mind. New York: Plenum.
Gibson, J. J. (1979). The ecological approach to visual perception. Boston: Houghton Mifflin.
Hume, D. (1777/1966). An enquiry concerning human understanding (2nd ed.). LaSalle, IL: Open
Court Publishing Company.
Jackson, J. H. (1898). Relations of different divisions of the central nervous system to one another
and to parts of the body Lancet, i, 79–87.
Kauffman, S. A . (2008). Reinventing the sacred: a new view of science, reason and religion. Philadelphia:
Basic Books.
Kim, A. S., Vallesi, A., Picton, T. W., & Tulving, E. (2009). Cognitive association formation in episodic
memory: evidence from event-related potentials. Neuropsychologia, 47(14), 3162–3173.
Lakoff, G., & Johnson, M. (1980). Metaphors we live by. Chicago: University of Chicago Press.
LaMarre, H. L., Landreville, K. D., & Beam, M. A . (2009). The irony of satire: political ideology and
the motivation to see what you want to see in “The Colbert Report.” International Journal of
Press/Politics, 14, 212–231.
Libet, B. (1985). Unconscious cerebral initiative and the role of conscious will in voluntary action.
Behavioral and Brain Sciences, 8, 529–539 (with commentary pp. 539–558 and author’s
response pp. 558–566).
Libet, B., Gleason, C. A., Wright, E. W., & Pearl, D. K . (1983). Time of conscious intention to act
in relation to onset of cerebral activity (readiness-potential). The unconscious initiation of a
freely voluntary act. Brain, 106, 623–642.
Mangels, J. A., Picton, T. W., & Craik, F. I. M. (2001). Attention and successful episodic encoding: an
event-related potential study. Cognitive Brain Research, 11, 77–95.
Mar, R. A . (2004). The neuropsychology of narrative: story comprehension, story production and
their interrelation. Neuropsychologia, 42, 1414–1434.
Melloni, L., Molina, C., Pena, M., Torres, D., Singer, W., & Rodriguez, E. (2007). Synchronization
of neural activity across cortical areas correlates with conscious perception. Journal of
Miller, G. A., Galanter, E., & Pribram, K . (1960). Plans and the structure of behavior. New York: Holt
Rinehart & Winston.
Moscovitch, M. (1995). Recovered consiciousness. A hypothesis concerning modularity and epi-
sodic memory. Journal of Clinical and Experimental Neuropsychology, 17, 276–290.
Neisser, U. (1976). Cognition and reality: principles and implications of cognitive psychology. San
Francisco: W. H. Freeman.
Nelson, R. J. (1985). Libet’s dualism. Behavioral and Brain Sciences, 8, 550.
Nunez, P. L., & Srinivasan, R . (2006). Electric fields of the brain: the neurophysics of EEG (2nd ed.).
New York: Oxford University Press.
Obhi, S. S., & Haggard, P. (2004). Free will and free won’t. American Scientist, 92, 358–365.
Orth, M., & Trimble, M. R . (2006). Friedrich Nietzsche’s mental illness—general paralysis of the
insane vs. frontotemporal dementia. Acta Psychiatrica Scandanavica, 114, 439–444.
Ondaatje, M. (2007). Divisadero. Toronto: McClelland & Stewart.
Otto, R . (1917/1958). The idea of the holy: an enquiry into the non-rational factor in the idea of the divine
and its relation to the rational. (translation of Das Heilige). London: Oxford University Press.
Picton, T. W., & Stuss, D. T. (2000). Consciousness. In E. E. Bittar & N. Bittar (Eds.), Biological psy-
chiatry (Principles of medical biology, Volume 14, pp. 1–25). Stamford, CT: JAI Press.
Rosenbaum, R. S., Stuss, D. T., Levine, B., & Tulving , E. (2007). Theory of mind is independent of
episodic memory. Science, 318, 1257.
Roser, M. E., Fugelsang , J. A., Dunbar, K. N., Corballis, P. M., & Gazzaniga, M. S. (2005). Dissociating
processes supporting causal perception and causal inference in the brain. Neuropsychology, 19,
591–602.
Saygin, A. P. (2007). Superior temporal and premotor brain areas necessary for biological motion
perception. Brain, 130, 2452–2461.
Shallice, T., Stuss, D. T., Picton, T. W., Alexander, M. P., & Gillingham, S. (2008). Mapping task
switching in frontal cortex through neuropsychological group studies. Frontiers in Neuroscience,
2, 79–85,
Snow, C. P. (1959/1964). The two cultures and a second look. Cambridge: Cambridge University
Press.
Soon, C. S., Brass, M., Heinze, H. J., & Haynes, J. D. (2008). Unconscious determinants of free
decisions in the human brain. Nature Neuroscience, 11, 543–545.
Spiers, H. J., & Maguire, E. A . (2007). Decoding human brain activity during real-world experi-
ences. Trends in Cognitive Science, 11, 356–365.
Spreng , R. N., Mar, R. A., & Kim, A. S. (2009). The common neural basis of autobiographical
memory, prospection, navigation, theory of mind, and the default mode: a quantitative meta-
analysis. Journal of Cognitive Neuroscience, 21, 489–510.
Stuss, D. T., Picton, T. W., & Alexander, M. P. (2001). Consciousness, self-awareness and the frontal
lobes. In S. Salloway, P. Malloy, and J. Duffy (Eds.), The frontal lobes and neuropsychiatric illness
(pp. 101–109). American Psychiatric Press.
Stuss, D. T., Alexander, M. P., Shallice, T., Picton, T. W., MacDonald, R., Borowiec, A., Binns, M., &
Katz, D. (2005). Multiple frontal systems controlling response speed. Neuropsychologia, 43,
396–417.
Stuss, D. T., Gallup, G. G. Jr., & Alexander, M. P. (2001). The frontal lobes are necessary for “theory
of mind.” Brain, 124, 279–286.
Tulving , E. 2005. Episodic memory and autonoesis: uniquely human? In H. S. Terrace & J. Metcalfe
(Eds.), The missing link in cognition (pp. 4–56). New York: Oxford University Press.
Vanrie, J., & Verfaillie, K . (2004). Perception of biological motion: a stimulus set of human point-
light actions. Behavior Research Methods, Instruments & Computers, 36, 625–629.
Wheeler, M. A., Stuss, D. T., & Tulving , E. (1997). Toward a theory of episodic memory: the frontal
Yarkoni, T., Speer, N. K., & Zacks, J. M. (2008). Neural substrates of narrative comprehension and
memory. Neuroimage, 41, 1408–1425.
Wood, C. C. (1985). Pardon, your dualism in showing. Behavioral and Brain Sciences, 8, 557–558.
Index
Page numbers followed by “ f ” or “ t ” refer figures or tables, respectively.
accuracy WM and, , 

self-evaluation relationship with, – WMHs and, 
speed compared to,  aging brain, –, –
ACommA. See anterior communicating artery behavior and, –
aneurysm cortical thinning and, 
action representations, frontal cortex and,  frontal lobes and, –
ACTIVE. See Advanced Cognitive Training for future research on, –
Independent and Vital Elderly neuroimaging findings of, –, 
active monitoring neuropsychological correlates and,
paradigm involving ,  –
ROBBIA proposing deficit of,  volume loss of, –
separability of,  alertness, –
Advanced Cognitive Training for Independent monitoring of, 
and Vital Elderly (ACTIVE),  Posner’s construct of, 
agency,  stimulation and, 
attribution of,  Alexander, Mick, , , , 
age-related attention,  on frontal attentional systems, 
reaction times, –, f lesion evidence and, –
age-related memory rostral PFC and, –, –
environmental support for, – Allport, Alan, 
intentional learning and, –, f Alpha-Span Test of Working Memory, 
phonemic process for, –, f Alzheimer’s disease, , –
processing resources and,  brain volume changes and, 
schematic support for, – hippocampus and, 
semantic processing for, –, f medial temporal lobe volume loss and, 
age-related white matter changes (ARWMC), WM and, –
, , f WMHs and, –
aging. See also cognitive aging; elderly AM. See autobiographical memory
anterior brain alterations and,  amnesia, , –, 
attentional resources and, – incorrect memories and, –
brain volume loss and WM changes in, , source, –
, – spontaneous confabulation differed from,
frontal, , , ,  –
hippocampus and, – Anderson, Nicole, 
PFC volume reduction and, ,  Animations task, 
recognition memory in, , , , f anterior cingulate, 
self-initiation of cognitive activities in,  lesion of the anterior cingulate, 
279
280 I ndex
anterior communicating artery aneurysm autobiographical memory (AM)

(ACommA),  brain regions engaged in, –, f,
confabulation and,  f
general executive impairments and,  ToM overlap with, 
ventromedial lesions after,  autonoetic consciousness, 
anterior cortex,  axonal sprouting , 
anterior PFC. See rostral prefrontal cortex
anterior temporal lobe, 
architectonic template, for lesion Badre, D., , , 
mapping ,  Barbas, H., 
Arnsten, A. F.,  Bayes modeling, 
arousal Beck, E., 
decline of,  Beck Anxiety Index, 
different degrees of, – behavior
mid-brain network changes and,  aging brain and, –
monitoring and, – brain region relation to, 
NE activation and,  frontal lesions and, f
NE suppression and,  strategy application disorder and, 
stress and,  after TBI, 
Yerkes-Dodson law on,  behavioral changes
ARWMC. See age-related white matter changes age-matched control subjects and, 
association cortex, f,  from frontal damage, f, , 
association deficits,  prefrontal leucotomy and, –
associative information,  behavioral organization deficits
associative recognition, –, f from IQ impairment, –
associative retrieval process,  rostral PFC and, 
assumptions regarding baseline activity,  Belleville, S., 
attention,  Benson, Frank, , , , 
continuous patterned stimulus stream Bereitschaftspotential, 
and,  Berlyne, N., , 
control of,  bimodal distribution, 
decline of,  Black, S. E., 
divided, , , –,  Blasi, V., 
early motor preparation and,  Block Design, 
electrophysiological dissociation of,  Bonferroni correction problem, 
as executive cognitive function,  Bonhoeffer, 
idling of, – brain
impairment of,  anterior, , 
lapse of, ,  background stimuli screening out by, 
needed for self-evaluation,  complicated task performance and,
recognition tests and,  , f
sedation influencing,  creative perception of, –
sustaining of, – default network of, 
task performance influenced by, – function organization of, 
theories of,  hierarchy levels of, –
visual, – model making of, –, f
attentional process, of frontal lobe, ,  narrative in, –
attentional resources, aging and, – operation of cause and, 
attention systems predictive tendency of, 
blood flow influencing, – volume of, , –
functioning of,  brain damage
modality-nonspecific types of,  behavioral deficits from, , 
autism, –,  compensatory activity after, f
I n dex 281
frontal compensation following ,  Christoff, K., 

recovery and compensation in, – Cicerone, K., 
subsystem functionality and,  Cipolotti, L., –
understanding of,  Clinical Dementia Ratings (CDRs), 
brain regions clonidine, 
age-related changes in, – clouded consciousness, from confabulation,
AM activation of, –, f, f , 
behavior related to,  coarse-grain approach
fMRI and PET for specificity of,  coping factors of, 
as functional network,  reliability of, –
impairment at different stages in,  of ROBBIA series, –
involved in ToM, f cognitive aging, 
perilesion and intact homologous, ,  attentional resource withdrawal and, 
variable comparisons involved with, caudate region and, 
–t compensatory strategies for, 
brain structure cortical volume loss and, 
Alzheimer’s disease and,  divided attention conditions and, , ,
changes of, –, f –, 
hippocampus,  frontal lobe hypothesis of, 
vascular risk and, – frontal lobe mechanisms and, –
Brambati, S. M.,  frontal lobe pathology vs., 
Brickman, A. M.,  frontal theory of, 
Brixton task,  hypertension and, –
Broadbent, D. E.,  Oswald on, 
Broca’s aphasia,  processing resource reduction and,
Broca’s area,  , 
Brodmann area , , , ,  skills training approach and, 
activation of,  structural brain imaging and, –
cognitive defects and,  cognitive function. See also executive
episodic memory and,  cognitive function
Brown-Peterson test,  of elderly, –, 
Buckner, R. L., ,  irony level of, 
Burgess, Paul, , , ,  localization of, –
multitask performance and, – meaning level of, 
recall and,  metaphor level of, 
strategy application disorder and, ,  regional localization of, 
religion and, 
self-initiation of, 
California Verbal Learning Test (CVLT), cognitive rehabilitation, 
,  of elderly, –
Campanella, F.,  Rotman Project, –
Capgras syndrome, ,  cognitive reserve, 
Cardiovascular Health Study,  cognitive subtraction method, 
cardiovascular risk factors,  Colbert, Stephen, 
Carroll, D. C.,  computational modeling, 
Castel, A. D., , ,  confabulation
causation,  ACommA and, 
CDR. See Clinical Dementia Rating background on, –
cerebral cortex, f Capgras syndrome and, 
cerebrospinal fluid (CSF),  case description on, –, f
cerebrovascular disease (CVD),  from clouded consciousness, , 
Cermak, Laird,  conclusion of, –, 
cholinergic system,  corrective mechanisms and, 
282 I ndex
confabulation (Contd.) dementia, 

diagnosis of,  memory and psychomotor training
early observations of, – for, 
focal lesion responsible for,  Derkzen, D., 
gap-filling test for,  D’Esposito, M., , 
hypotheses resolution and, – DEX. See Dysexecutive Questionnaire
incorrect memories compared to, , – diffuse axonal injury (DAI), 
lesion patterns and, – pure, , f
mechanism views of, – volume loss and, 
momentary compared to fantastic,  diffuse lesions
monitoring levels for, – focal lesion and, , 
oddities of, ,  strategic behavior assessment and,
orbital lesions and, – –
persistent,  diffusion tensor imaging (DTI), , 
personal history influencing, –,  Digit Symbol subtest, 
recall of,  dimension task, , –
retrieval hypothesis for,  dissociation
severe,  daily life activity impairment and, 
specific impairment and,  double, , 
spontaneous, , – electrophysiological, 
as stimulus and environmentally thought-action, 
bound,  thought-feeling , 
Stuss and, , , ,  distributed cortical representations, 
Contant, T. A.,  divided attention conditions, , ,
context task, impairment of, – –, 
contextual reinstatement, –, f Dodson, J. D., 
Corballis, Michael, ,  Donders, F., 
cortical stimulation mapping ,  dopaminergic system, 
corticobasal degeneration,  dorsolateral prefrontal cortex, 
Coull, J. T., ,  DTI. See diffusion tensor imaging
Craik, F. I. M., , , ,  Dunbar, K. N., 
amnesia and, – Duncan, J., , 
on association deficit,  dynamic aphasia, 
memory and, , ,  Dysexecutive Questionnaire (DEX),
CSF. See cerebrospinal fluid –, f
CVD. See cerebrovascular disease dysexecutive syndrome, , 
CVLT. See California Verbal Learning Test
early motor preparation, 

DAI. See diffuse axonal injury EAT. See Error Awareness Test
daily life activity impairment,  Eccles, John, 
complexity of,  elderly
dissociation and,  cognitive functioning improvement of,
impaired prospective memory and,  –
memory function and, ,  cognitive rehabilitation of, –
Multiple Errands Test for, – working memory of, 
from rostral PFC lesions, , – emotional changes, 
Six Element Test for, – due to frontal lobe injury, 
Dalla Barba, G.,  from frontal damage, f, , 
Damasio, Antonio, , ,  impairment control for, 
Davis, S. W.,  environmental factors, 
Dawkins, R., – for vascular health, 
DeLuca, J.,  environmental support
I n dex 283
for age-related memory and attention, focal lesion, , 

– diffuse lesions and, , 
contextual reinstatement and, –, f meningioma as cause for, 
episodic memory, , ,  patient’s EEG and, 
activations of,  responsible for confabulation, 
Brodmann area  and,  strategic behavior assessment and, –
rostral PFC and,  FOK. See feeling of knowing
error FOR. See feeling of rightness
of commission,  foreperiod temporal preparation paradigm,
SART and,  , 
speed increasing rate of,  fractional anisotropy (FA), , , ,
types of,  f
Error Awareness Test (EAT),  measurements of, 
Eslinger, P. J., ,  as neuroimaging findings, –
Evans, J., ,  Framingham Heart Study, , 
evidence-based protocol,  free recall, , , 
executive cognitive function, , ,  frontal aging
attention and sequencing,  hypothesis of, 
cardiovascular risk factors for,  theory of, , , 
deficits,  frontal attentional systems, 
high body mass and,  frontal cortex
hypertension and, – action representations and, 
neuropsychological tests of,  activation of, 
planning and organization,  anatomical tracer studies on, –
hierarchical organization of, 
organization of, –
FA. See fractional anisotropy regional differences within, 
fact recall,  regions of interest in, 
false belief attribution,  representational hierarchy of, , f
false belief test, , – task-setting and, 
false endorsement rate,  frontal damage, 
fantastic confabulation,  emotional-behavioral consequences of,
FAS. See Verbal Fluency Test f, , 
faux pas,  intervention development for, 
Faux Pas test,  know and remember judgment influenced
feeling of knowing (FOK), ,  by, 
feeling of rightness (FOR), , , – social and emotional consequences of, 
fine-grain approach socially relevant behavioral changes after,
methodological problems of,  –
of ROBBIA series, – Stuss on, , 
Fischer, R. S.,  WCST and, 
FLAIR. See fluid-attenuated inversion frontal lesion
recovery acquired sociopathy and, 
Florida Alzheimer’s Disease Research architectonic template for mapping of, 
Center,  behavioral performance and, f, , 
fluid-attenuated inversion recovery case studies on, –, –
(FLAIR),  deficit probability and, 
fluid intelligence higher-order constructs and, –
functional imaging and performance, impairments from, , 
, – neuropsychological test performance and,
IQ distinguished from,  –
fMRI. See functional magnetic resonance overlapping of, , f, , 
imaging patient testing on, –t
284 I ndex
frontal lesion (Contd.) about frontal lobe function, –

posterior cortex top-down failure lesion study motivation from, –
from,  observer-independent method and,
regional effects of, , ,  –
retrieval orientation influenced by,  PFC understanding from, –, 
frontal lobes physiological and lesion
aging brain and, – methods of, 
anatomical connectivity patterns and, qualities of, –
,  response experiment and, , f
cognitive aging hypothesis of, , spatial resolution afforded by, 
,  Stuss as motivation for, 
control processing within,  task levels performed in, –
historical overview of,  Fuster, J. M., 
individual identity and,  future
injury to, –,  aging brain research in, –
Jacobsen’s paradigm on,  concept of, –
mechanisms of, – existence of, –
mental state attribution and, – memory and, –
metacognitive processes of,  as paradox, 
research increase on,  perspective of, 
as silent cortex,  questions raised regarding, 
Stuss as leading authority on, – reality of, –
superordinate control of,  role of, –
frontal lobe function, ,  subjective or personal, 
fMRI studies about, – terminology regarding , 
lesion studies about, –
ToM studies and, –t
WCST for, –, , ,  Gabrieli, J. D., 
frontal lobe pathology, –,  Gage, Phineas, , , 
aging ,  Galanter, E., 
cognitive aging vs.,  Gallese, V., 
dysexecutive syndrome, ,  gap-filling test, 
source amnesia, – Gazzaniga, M., 
TBI as,  GDS. See Geriatric Depression Scale
The Frontal Lobes (Stuss & Benson), generalized cognitive impairment, 
, ,  Geriatric Depression Scale (GDS),
frontal lobe syndrome, ,  –, f
frontopolar cortex. See rostral prefrontal Gerrans, P., 
cortex Geschwind, N., 
lesion of the frontopolar region,  Gläscher, J., , –
frontotemporal dementia (FTD),  GM. See gray matter
Fugelsang, J. A.,  Goal Management Training (GMT), 
functional imaging studies,  Goldman-Rakic, Patricia, , 
advantages of, – Goldstein, L. H., , 
rostral PFC function theory and, ,  Go/No-go task, , 
tumor neurosurgery and,  Goodglass, Harold, 
functional magnetic resonance imaging Grady, C. L., 
(fMRI), –,  Graff-Radford, N. 
conclusion on, –, – Grafman, Jordan, 
consistency of,  gray matter (GM)
dimension and context experiment and, DTI measurements and, –
, f volume of, f, –
feature experiment and, , f Grey Matter and, –
I n dex 285
Greenwich Test,  intentional learning, age-related memory

group focal lesion method,  and, –, f
“g” view, of intelligence,  International Neuropsychological
Society, 
IQ impairment, –
HAAS. See Honolulu-Asia Aging Study ischemic tissue damage, , 
Hayling Sentence Completion Task, 
Heaton, R. K., 
Heilman, Kenneth,  Jackson, Hughlings, 
hippocampus,  Jacobsen, C. F., 
aging and, – Jacoby, Larry, 
Alzheimer’s disease and,  Journal of the International Neuropsychological
medial temporal lobe atrophy and, Society, 
–
Hoerold, R., 
holistic rehabilitation programs,  Kahn, R. L., , 
homocysteine, for vascular health,  Kaplan, E., 
Honolulu-Asia Aging Study (HAAS),  Kassell, 
Hopkins Verbal Learning Test-Revised Klein, Stanley, 
(HVLT-R), , , f, f,  know judgment, 
Hotel Task,  knowledge of rightness (KOR), –
human consciousness,  Koechlin, E., , 
human neuropsychology KOR. See knowledge of rightness
neuroimaging and, –
theorizing constraints and, –
human self-awareness,  lacuna, –
Hume, D.,  implications of, 
HVLT-R. See Hopkins Verbal Learning WMHs and, 
Test-Revised large vessel occlusion, –
hypertension, – LBM. See lesion behavior mapping
Lesher, E. L., –
lesion behavior mapping (LBM), 
IFS. See inferior frontal sulcus lesion evidence
Ig Noble Award for Psychology,  complicating presentations and, 
individual identity, frontal lobe and,  meta-analysis of, –
inferior frontal sulcus (IFS),  normal-level contrast and, 
damage to,  rostral PFC and, –
lesion of, ,  Stuss and Alexander and, –
information processing,  task selection and, 
Ingvar, David, ,  theorizing for, –
insight utilities of, 
monitoring and, – visual illustration of, f
schizophrenia and,  lesion method, –
intelligence level chauvinism, 
as a construct,  Levine, B., , 
explanation of, – Libet, B., 
fluid, , – Lieberman, M. D., 
“g” view of,  life expectancy, 
impairment of,  localization, of cognitive functions, –
rostral PFC and, –,  assumptions regarding baseline activity
intelligence test,  for, 
case studies on,  cognitive subtraction method for, 
rostral PFC lesions and, –, – variability in, 
286 I ndex
Lockhart, R. S.,  reality monitoring and, 

Locus of Control Scale,  rostral PFC and, –, 
Loewen, E. R.,  source and, 
Logical Memory Test, , , f,  memory skills training, , , , 
Luo, L., ,  mental reality
Luria, A. R.,  constituents of, –
dependence on, 
memory and, 
MacLeod, A. K.,  physical reality and, –
magnetic resonance imaging (MRI), , . mental state attribution
See also functional magnetic resonance awareness of, 
imaging frontal lobes and, –
Maguire, Eleanor,  functional specialization of, 
mass-action model, – neuroimaging research and, , 
MCI. See mild cognitive impairment “self” and “other” correspondence in,
McIntosh, A. R.,  –
McIntyre, J. S., ,  of self versus other people, –
McNeil, J.,  sensitivity of, 
medial prefrontal cortex (mPFC),  mental time travel, –
engagement of,  Mercer, B., 
ToM and,  metacognitive process, of frontal lobe, 
medial temporal lobe atrophy, – metacognitive resource, 
Melo, B.,  Methylphenidate, 
memory, ,  Meyer, A., 
age-related, – Miezin, F. M., 
age-related losses of, f Mikkelsen, T., 
AM, –, f. f mild cognitive impairment (MCI), 
cardiovascular risk factors and,  Miller, G. A., 
Craik, F. I. M., and, , ,  Milner, B., , 
daily life activity impairment and, ,  Mini-Mental State Exam (MMSE), , 
encoding of,  Mishkin, M., 
episodic, , , , ,  Mitchell, J. P., , 
fact recall,  MMSE. See Mini-Mental State Exam
free recall, , ,  mnemonics training, , 
future and, – momentary confabulation, 
James, W., on,  monitoring, , –
mental reality and,  arousal and, –
past and, – of confabulation levels, –
process of, ,  insight and, –
prospective,  Stuss’s concept of, 
recognition, , , , f Moniz, E., 
semantic clustering and,  Moody, D. M., 
source amnesia and, – Morris, L. W., 
tree metaphor of, –, f Morris, R. G., 
working, , , , –, , –, Moscovitch, M., , , 
f, f mPFC. See medial prefrontal cortex
memory, incorrect,  MRI. See magnetic resonance imaging
amnesia and, – multi-attribute decision-making , 
confabulation compared to, , – multidimensional confabulation
memory function battery, 
context and,  Multiple Errands Test, –, 
daily life activity impairment and, ,  multitasking performance
lesions influencing,  impairment of, 
I n dex 287
Shallice and Burgess and,  orbitofrontal cortex (OFC), , 

testing for,  orbitomedial injuries, 
orientation/selection, 
oscillatory dynamics, 
narrative gravity Oswald, W. D., 
brain and, –
self as center of, 
National Adult Reading Test-Revised,  Pandya, D. N., , 
Naveh-Benjamin, Moshe, ,  Paus, T., 
NE. See norepinephrinergic system PD. See proton density
neocortex, f Penfield, W., , 
neurogenesis,  perceptual theory, 
neuroimaging persistent confabulation, 
adaptive coding-type characteristics PET. See positron emission tomography
of,  Petersen, S. E., , , 
advent of, – Petrides, Michael, , 
aging brain findings from, –,  Petrie, A., 
episodic memory function activations PFC. See prefrontal cortex
and,  phonemic process, for age-related memory,
specificity of findings,  –, f
functional, – physical reality
human neuropsychology and, – mental reality and, –
lesion data integrated with,  types of, , 
mental state attribution research Pick, , 
and, ,  Picton, T. W., , , 
possibility of,  Picture Arrangement, 
rostral PFC and, –, – Poldrack, R. A., 
structural, –, – Popper, Karl, 
theorizing constraints and, – positron emission tomography (PET), 
ToM findings from,  Posner, Michael, , , , 
neurophysiological group study posterior cortex
control compared to normal group hierarchy of, 
in,  top-down failure of, 
data theorizing and,  practical task training, , , 
methods of,  prefrontal cortex (PFC). See also rostral
vicissitudes and, – prefrontal cortex
neuropsychological test performance, – abstraction thought and, –
norepinephrinergic (NE) system, , activation of, , –
,  attention sets and, 
nucleus accumbens,  cognitive compensation and, 
as critical brain region, 
fMRI studies on, –, 
Ochsner, K. N.,  functional organization of, –
OFC. See orbitofrontal cortex laminar differentiation and, 
O’Keeffe, Fiadhnait,  left ventral area of, 
olfactory function, – lesions, , f, 
oligodendroglioma, right frontal organization of, , , –
removal of,  superior medial area of, , 
Olson, I. R., –,  task-setting and, –, –
Olsson, A.,  tasks involving , 
operation of cause,  top-down signals and, 
optic ataxia, ,  volume reduction in, aging and, , 
orbital lesions, – working memory deficits and, 
288 I ndex
prefrontal leucotomy,  inference evidence converging from, –

behavioral changes and, – inferences drawn from, 
effects of,  methods of, 
premotor cortex, –,  outcome of, 
Pribram, K.,  patient group allocation in, –
primary motor cortex,  processing components localization of, 
processing resource, , ,  right lateral system in, 
progressive supranuclear palsy,  Shallice and, , 
prospective memory,  Stuss and, , , 
proton density (PD),  subgroups in, 
Proverbs,  theoretical perspective of, 
psychomotor function,  Robertson, Ian, 
psychosocial training , , –, ,  Roca, M., , –
Rodrigue, K. M., 
Rotman Cognitive Rehabilitation project. See
quality-of-life, cognitive function loss Rotman Project
and,  Rosenbaum, R. S., , 
Rosenblum, M. L., 
Roser, M. E., 
Rabin, J. S., , ,  Ross, L. A., –
Raichle, M. E.,  rostral prefrontal cortex, , –
Ramirez, J.,  activation patterns and, 
Raz, N.,  behavioral organization deficits and, 
reality monitoring , , – cognitive functions supported by, 
recognition memory, , , , f episodic memory and, 
recollection structure,  function of, , 
recovery and compensation, in brain damage, hemodynamic changes in, 
– intelligence and, –, 
axonal sprouting ,  language and, 
diaschisis reversal,  lesion evidence on, –
distributed cortical representations,  memory function and, –, 
neurogenesis,  neuroimaging and, –, –
neuronal activity,  processing supported by, , , –, ,
perilesion and intact homologous brain –
regions,  removal of, 
PFC for,  role of, , , 
trans-callosal information transfer,  study of, –, 
unmasking,  Stuss and Alexander and, –, –
remember judgment,  task performance and, , –, –
repetitive transcranial magnetic stimulation theories regarding, –
(rTMS) study,  rostral prefrontal cortex lesions
response task, , – daily life activity impairment from, ,
Reverberi, C., , ,  –
Rizzolatti, Giacomo,  humor judgment impairment and, –
ROBBIA series, – impairment caused from, –
active monitoring deficit proposed by,  intelligence test impairment from, –,
advantages of, – –
coarse-grain approach of, – operation for, 
fine-grain approach of, – premorbid functioning and, 
frontal cortex regions of interest in,  WAIS IQ decrements and, –
goals of,  Rotman Cognitive Rehabilitation Project
group study approach of,  background and rationale of, –
impairments in,  clinical trials, 
I n dex 289
comprehensiveness of,  recall and, 

considerations for, – ROBBIA series and, , 
cost effectiveness,  strategy application disorder and, , 
design and timeline of, t Shaw, P., 
DEX in, –, f Simmons, W. K., 
GDS in, –, f simulated real-life tasks (SRLTs), , ,
HVLT-R in, , , f, f,  , f, 
lack of generalization in,  Six Elements Test, –
Logical Memory Test in, , , Greenwich Test compared to, 
f,  limitation of, –
memory results in, – multitasking situations presented by, 
memory skills training in, , ,  as strategic behavior assessment, –
practical task planning results in, – voluntary time-based task switching
practical task training in, , ,  and, 
program, – small vessel disease, –, 
psychosocial results in, – Snow, C. P., 
psychosocial training in, , –,  social attribution, deficits in, 
questionable outcome measures,  source amnesia, –
results, – Spearman, Charles, 
Simulated Real Life Tasks in, , , , spontaneous confabulation, 
f,  amnesia differed from, –
strategic processing emphasis of,  CVLT for, 
target population of,  false endorsement rate and, 
Rotman Research Institute, , ,  recovery from, 
rTMS. See repetitive transcranial magnetic temporality theory and, 
stimulation SRLTs. See simulated real-life tasks
Rylander, G.,  Stone, V. E., 
strategic behavior assessment
in focal and diffuse damage patients,
Sakuta, Y., ,  –
Salat, D. H.,  Six Element Test as, –
SAQ. See self-assessment questionnaire Strategy Application Test as, –
SART. See Sustained Attention strategic processing, , 
Response Task strategic retrieval process, 
Saxe, R.,  strategy application disorder, –
schizophrenia, ,  behavior and, 
Schloerscheidt, Astrid,  Shallice and Burgess and, , 
Schnider, A., ,  TBI and, 
self-assessment questionnaire (SAQ),  Strategy Application Test
Self-Efficacy Scale,  as strategic behavior assessment, –
self-evaluation TBI and, 
attention needed for,  Strategy Application Test, Revised, 
competence and accuracy inverse sample items from, f
relationship with, – stroke, 
impairment of, – Stroop interference tasks, 
TBI causing deficit of,  Stuss, Don, , , , , , 
semantic hub,  confabulation and, , , , 
semantic processing, for age-related memory, energization notion of, 
–, f fMRI experiments motivated by, 
sensorimotor process, of frontal lobe,  on frontal attentional systems, 
Shallice, T., –, , , ,  on frontal damage consequences, , 
multitasking performance and, – on frontal lobe mechanism, –
optic ataxia and,  frontal lobe syndrome and, 
290 I ndex
Stuss, Don (Contd.) deficits of, 

lesion approach of, – facial emotion processing and, 
lesion evidence and, – faux pas and, 
monitoring concept of,  frontal involvement studies and,
on neuropsychology,  –t
on regional effects of lesions,  internally versus externally focused, 
research by, –, – mPFC and, 
ROBBIA series and, , ,  neuroimaging findings on, 
rostral PFC and, –, – posterior contributions to, –
on task-setting ,  processes involved in, f
on TBI deficits,  real life impairment predicted by, 
temporal preparation paradigm of, – task performance and, 
variable-foreperiod effect made by,  theoretical framework for, –
Suddendorf, Thomas,  Thomson, G. H., 
Sunnybrook Dementia Study,  thought-action dissociation, 
Sunnybrook Hospital,  thought-feeling dissociation, 
superior medial area, of PFC, ,  ToM. See theory of mind
supramodal attentional control systems,  total cranial volume (TCV), 
Sustained Attention Response Task (SART), TPJ. See temporoparietal junction
, ,  Trail Making Test, , 
traumatic brain injury (TBI), 
behavior after, 
task appropriate strategies,  deficits from, 
task performance. See also multitasking functional neuroimaging and, –
performance self-evaluation deficit from, 
age-matched control studies and,  strategy application disorder and, 
attention influencing, – Strategy Application Test and, 
complicated, , f structural neuroimaging and, –,
rostral PFC and, , –, – –
simplicity of,  task performance and, 
TBI patients and,  working memory and, –, f, f
ToM and,  tumor neurosurgery, 
task-setting Turner, M. S., –, 
abstraction and, –
frontal cortex and, 
impairment of,  VA. See Veteran’s Administration
implementation and organization of,  VaD. See vascular dementia
PFC and, –, – Vallesi, A., , 
separability of,  vascular brain disorder, 
TBI. See traumatic brain injury vascular dementia (VaD), 
Temporal Context Confusion and,  vascular health
TCV. See total cranial volume environmental factors for, 
temporal context confusion (TCC), , , genetic variants for, 
– homocysteine for, 
temporoparietal junction (TPJ), ,  vascular risk score, 
Test-Operate-Test-Exit,  ventromedial lesions, 
theory of mind (ToM), , , ,  Verbal Fluency Test (FAS), , 
affective and cognitive contributions to, Veteran’s Administration (VA), 
, – visual attention, –
AM overlap with,  Visual Object and Spatial Perception (VOSP)
assessment of,  battery, 
autism and, – VLSM. See voxel-based lesion-symptom
brain regions involved in, f mapping
I n dex 291
VOSP. See Visual Object and Spatial Alzheimer’s disease and, –
Perception battery distribution of, 
voxel-based lesion-symptom mapping implications of, 
(VLSM), , , , f increased prevalence of, 
voxel-based morphometry,  lacuna and, 
Voytek, B., – pathological correlations with, 
small vessel disease and, 
Winocur, G., , 
Wagner, A. D.,  Wisconsin Card Sorting Test (WCST),
WAIS. See Wechsler Adult Intelligence Scale , , 
Walsh, V.,  frontal damage and, 
WCST. See Wisconsin Card Sorting Test as frontal lobe function test, –, ,
Wechsler Adult Intelligence Scale (WAIS), , , 
–,  WM. See white matter
Weinstein, E., ,  WMHs. See white matter hyperintensities
Wheeler, A. M., ,  working memory, , , –
Whelihan, W. M., – deficits of, 
white matter (WM),  in elderly, 
aging and, ,  load of, –
Alzheimer’s disease and, – TBI patients and, –, f, f
integrity of,  Wundt, Wilhelm, 
vasculopathy, 
volume loss, , , –
white matter hyperintensities (WMHs), Yerkes, R. M., 
, f Yerkes-Dodson law, 
aging and,  Yousry, T., –

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Mind and

the Frontal Lobes

Oxford New York

Copyright © 2012 by Oxford University Press, Inc.

Published by Oxford University Press, Inc.

Oxford is a registered trademark of Oxford University Press

All rights reserved. No part of this publication may be reproduced,

Library of Congress Cataloging-in-Publication Data

Thanks to Baycrest Centre, Joseph L. Rotman, the Canadian Institutes of Health

1. Unifying Clinical, Experimental, and Neuroimaging Studies

4. Rostral Prefrontal Cortex: What Neuroimaging

5. Combining the Insights Derived from Lesion

6. Dynamic Communication and Connectivity in

7. The Frontal Lobes and Mental State Attribution 123

8. Monitoring and Alerting: Two Forests Among the Trees 152

9. Cognitive Rehabilitation in Old Age: The Rotman Initiative 164

10. Effects of Aging on Memory and Attention: A Frontal

11. The Aging Brain: An Alternate Perspective

12. Structural Brain Imaging and Cognitive Aging 214

13. The Effects of Focal and Diffuse Brain Injury on Behavior:

14. Does the Future Exist? 248

15. The Necessary Narrative 264

Michael P. Alexander Gil Gonen-Yaacovi

David Badre Robert T. Knight

Regina E. McGlinchey David H. Salat

Terence W. Picton Karl K. Spunzar

R. Shayna Rosenbaum Gordon Winocur

clinicians gathered in Toronto to hear 15 leading researchers in the area of frontal

THE FIRST ERA

THE SECOND ERA

THE THIRD ERA

It wasn’t until Don administered more advanced experimental tests involving

Overview of this Volume

including neuropsychological (focal lesion) studies, traumatic brain injury, aging,

Confabulation is an oddity among cognitive neuropsychological disorders. It is a

1. Signiﬁcant confabulation is seen only in patients who are or recently were

Case Description: A Patient who Exempliﬁes

Extensive bilateral orbital

Complete damage to the

Severe medial polar injury

The lesion ﬁndings can be summarized as follows: (1) comprehensive posterior

Current Views of Mechanisms of Confabulation

determine if they have seen a target previously during a long presentation of

present reality, and that spontaneous confabulation is a failure of “the archaic

produced only if monitoring of the search product is impaired. (Unrelated directly

rightness (KOR), involving monitoring of content. This is equivalent to the veriﬁ-

Resolution of Current Hypotheses

beliefs should not depend on their being preconsciously marked as irrelevant

1. Impaired prospective memory: Many confabulations have implications for

The ROBBIA Set of Studies

The Anatomically Based Neuropsychological

Thus, drawing functional conclusions from an fMRI experiment requires an

Converging Evidence on Inferences

populations with other etiologies, such as stroke (Battaglia-Mayer & Caminiti,

Botvinick, M. M. (2008). Hierarchical models of behavior and prefrontal function. Trends in

The Advent of Neuroimaging: From Famine to Feast?

The proliferation of these theories was perhaps an improvement upon the

Rostral PFC and “Intelligence”

Rostral PFC Lesions Need Not Cause Substantial

The Challenge that Rostral PFC Presents

theorizing based on neuroimaging data by requiring the accounts to be in agree-

Other Ways in which Lesion Evidence

Details about the precise population contributing to these analyses are of