NeuroImage 61 (2012) 464–477

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NeuroImage
journal homepage: www.elsevier.com/locate/ynimg

Review

The motor system and its disorders

James B. Rowe a, b, c,⁎, Hartwig R. Siebner d
a
Department of Clinical Neurosciences, Cambridge University, Cambridge, UK
b
Medical Research Council Cognition and Brain Sciences Unit, Cambridge, UK
c
Behavioural and Clinical Neuroscience Institute, Cambridge, UK
d
Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital, Hvidovre, Denmark

a r t i c l e i n f o a b s t r a c t

Article history: The motor system has been intensively studied using the emerging neuroimaging technologies over the last
Accepted 15 December 2011 twenty years. These include early applications of positron emission tomography of brain perfusion, metabolic
Available online 27 December 2011 rate and receptor function, as well as functional magnetic resonance imaging, tractography from diffusion
weighted imaging, and transcranial magnetic stimulation. Motor system research has the advantage of the
Keywords:
existence of extensive electrophysiological and anatomical information from comparative studies which
Motor system
Transcranial magnetic stimulation
enables cross-validation of new methods. We review the impact of neuroimaging on the understanding of
Magnetic resonance imaging diverse motor functions, including motor learning, decision making, inhibition and the mirror neuron system.
Positron emission tomography In addition, we show how imaging of the motor system has supported a powerful platform for bidirectional
Stroke translational neuroscience. In one direction, it has provided the opportunity to study safely the processes of
Parkinson's disease neuroplasticity, neural networks and neuropharmacology in stroke and movement disorders and offers a
Dystonia sensitive tool to assess novel therapeutics. In the reverse direction, imaging of clinical populations has pro-
moted innovations in cognitive theory, experimental design and analysis. We highlight recent developments
in the analysis of structural and functional connectivity in the motor system; the advantages of integration of
multiple methodologies; and new approaches to experimental design using formal models of cognitive–
motor processes.
© 2011 Published by Elsevier Inc.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
Early characterisation of the motor systems' organisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
The extended motor system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
Motor control and learning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
Movement selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
Motor inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
Action observation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
Mapping motor dysfunction and therapy after stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
Mapping functional brain networks after motor stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
How to analyse with impaired motor performance? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
Functional brain mapping in movement disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
Resting state fMRI studies in Parkinson's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
Functional MRI studies of motor control in Parkinson's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
Functional MRI studies of ‘non-motor’ functions in Parkinson's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
Imaging the genetic influences on Parkinson disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
Transcranial brain stimulation and brain imaging: multimodal imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
New methods and integration of methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472

⁎ Corresponding author at: Department of Clinical Neurosciences, Cambridge University, Cambridge, UK. Fax: + 44 1223 359062.
E-mail address: james.rowe@mrc-cbu.cam.ac.uk (J.B. Rowe).

1053-8119/$ – see front matter © 2011 Published by Elsevier Inc.

doi:10.1016/j.neuroimage.2011.12.042
 J.B. Rowe, H.R. Siebner / NeuroImage 61 (2012) 464–477
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction
From the earliest development of functional brain imaging technolo-
gies, the motor system has been studied in health and disease. Major his-
torical landmarks include the systematic analysis of lesions to map
multiple motor centres (Ferrier, 1876); the identification of an electroen-
cephalographic (EEG) signature of voluntary movement, the bereitschaft-
spotential (Kornhuber and Deecke, 1965); and the use of xenon enhanced
single photon computerised tomography to study movement and motor
stroke (Lassen et al., 1978). However, in the last 20 years, imaging of
the motor system has been dominated by magnetic resonance imaging
(MRI), positron emission tomography (PET) and transcranial magnetic
stimulation (TMS). In this review we focus on these methods, and their
integration with cognitive theory and clinical neurology.
We consider first the early successes of motor neuroimaging in de-
scribing the structural and functional principles of the motor system,
before reviewing applications to motor learning, control and inhibition.
In the third section, we show how the motor system has been the centre
of translational imaging studies. In the final section, we highlight recent
innovations in studying the motor system.
Early characterisation of the motor systems' organisation
The motor system, like the visual system, has close homologues in
non-human primates. This has allowed the motor system to be used
for validation of emerging neuroimaging methods and as a comparative
model between species. Many types of movement elicit ‘activation’ of
the motor cortex, measured in terms of increased perfusion in H2O 15
PET or higher BOLD fMRI signal. Manual actions such as button presses
or joystick control predominate in the literature, but proximal arm
movements such as reaching or pointing, leg or mouth movements,
and motor imagery have all been studied.
The basic principles of motor system organisation were re-established
in early neuroimaging studies, drawing on neuropsychology and compar-
ative neurophysiology. These principles included (1) motor somatotopy,
(2) rate- and force-correlations with activation, (3) close integration
of sensory and motor cortex, and (4) discrete cortico-spinal, cortico-
cerebellar and cortico-striato-thalamo-cortical circuits.
Motor somatotopy has been demonstrated in primary motor cor-
tex and supplementary motor areas (SMA) (Colebatch et al., 1991;
Fink et al., 1997; Fox et al., 1985; Grafton et al., 1991, 1993), consis-
tent with stimulation studies (Godschalk et al., 1995; Wassermann
et al., 1996). However, the somatotopic resolution was coarse, with
distributed and partially overlapping representations of movement
by neighbouring body parts (Beisteiner et al., 2001; Indovina and
Sanes, 2001). Somatotopy was even coarser in premotor cortex and
SMA and was associated with multiple rather than single motor
maps, with greater functional complexity (Gentilucci et al., 1989;
Luppino et al., 1991).
The basic electrophysiological properties of motor neurons were
also sought in the mass action underlying a regional activation. For
example, electrophysiological recording of motor pyramidal cells
demonstrated a monotonic relationship between force and firing
rate. Early PET studies confirmed this relationship in primary motor,
premotor cortex and SMA (Blinkenberg et al., 1996; Cramer et al.,
2002; Dettmers et al., 1995; Riecker et al., 2003; Sadato et al., 1997;
VanMeter et al., 1995), albeit with non-linear associations attributed
to the limits of neurovascular coupling.
A recurrent feature of early studies was the close relationship be-
tween motor and sensory cortical activation. Many authors used the
465
472
472
term ‘sensorimotor cortex’. This partly reflected a lack of anatomical
precision and resolution in early PET and MRI, but also built on the
tradition of integrated sensorimotor function in peri-rolandic cortex
(Meyer, 1978). The frequent co-activation of sensory and motor cor-
tex also indicated a close functional integration between these re-
gions. Moreover, activity in motor cortex was observed with passive
motor tasks, indicating proprioceptive responses in ‘motor’ cortex
(Weiller et al., 1996). Conversely, with transient sensory deafferenta-
tion there is movement related activation in somatosensory cortex,
suggesting sensory predictions of action (Christensen et al., 2007).
The motor system is not a unitary system but composed of several
motor ‘systems’ (Ferrier, 1876), many of which had been well defined
before human brain imaging. These included (a) corticospinal tracts;
(b) cortico-cerebellar circuits, and (c) cortico-striato-thalamo-cortical
circuits (Alexander et al., 1986). Early PET and fMRI confirmed
coactivation of the components of these circuits, with propagation of
the force- and rate-properties throughout (Colebatch et al., 1991; Fox
et al., 1985; Grafton et al., 1991, 1993). Somatotopy was also shown to
be partially preserved through the subcortical connections, leading to
the conclusion that “…the properties of neurons within the basal gang-
lia or cerebellar components of these circuits resemble the properties of
neurons within the cortical areas subserved by these loops” (Middleton
and Strick, 2000). A decade later, diffusion weighted imaging (DWI)
confirmed the critical cortico-subcortical pathways in humans and
across species (Johansen-Berg et al., 2005; Parker et al., 2002) including
the major somatotopies (Verstynen et al., 2011). However, even in
these highly conserved circuits, there are important inter-individual
differences in the structure and function of motor circuits (Boorman
et al., 2007; Kloppel et al., 2008).
The extended motor system
The early confirmatory imaging studies referred to comparative
neuroanatomical and neurophysiological “gold standards”, but human
brain imaging has subsequently led to a deeper understanding of the
mechanisms of motor learning, action selection, inhibition and action
observation. In addition, many classical “motor” areas have been
shown to be associated with non-motor tasks, including perception,
emotion, language and music.
Motor control and learning
Motor learning requires plasticity in the nervous system. Although
traditionally inferred from changes of performance (Schmidt, 1975),
neuroimaging can show whether learning has occurred together
with its neural substrate. With learning, we establish internal models
that combine knowledge of the motor effector, the environment, the
meaning of cues and the consequences of actions. This knowledge is
embedded in extended motor systems, through macroscopic structural
changes (identifiable by MRI-based morphometry) and microscopic
changes in synaptic weights (inferred from functional imaging or TMS).
Here we highlight two major organisational principles of motor
learning. The first is that motor learning exploits models that make spe-
cific predictions about the consequences of actions. Secondly, motor
learning occurs in phases, with distinct properties, temporal scales
and anatomy.
Motor learning encompasses both associative learning (sometimes
referred to as cognitive aspects of motor learning) and ‘on line’ motor
control (sometimes referred to as kinematic learning). Both can be
framed in terms of predictive or generative models. For example,
466 J.B. Rowe, H.R. Siebner / NeuroImage 61 (2012) 464–477
actions are associated with predictions of their consequences, whether
sensory (Christensen et al., 2007), visual or reward based. The actual
outcome may deviate from this prediction, leading to a prediction
error which enables a principled change in the movement or action de-
cision. This model supports a reciprocal rather than a hierarchical rela-
tionship between action and sensation, in which internal models of
action explain how sensations arise, while perception enables the opti-
misation of movement and action (Friston and Kiebel, 2009; Friston et
al., 2010). While generative models with predictive coding may under-
lie many aspects of motor learning, they do not imply a unitary system
for motor learning.
Neuropsychological theories have emphasised differences between
multiple facets of motor learning, separating for example the strategic
process of goal selection; sequencing of actions or sub-goals; and the
sensorimotor integration required for kinematic control of motor effec-
tors in an uncertain or changing environment (Doyon and Benali, 2005;
Willingham, 1998). Imaging studies confirm that cortical and subcorti-
cal motor circuits make different contributions to these different forms
of motor learning, including motor sequences (Chen et al., 2012; Debas
et al., 2011; Jueptner and Weiller, 1998; Jueptner et al., 1997), visuomo-
tor associations (Boettiger and D'Esposito, 2005; Toni et al., 1998, 2001),
conditioned responses (Ramnani et al., 2000) and kinematic control of
the movement or motor adaptation (Orban et al., 2011).
The conditioning of eye blinks offers a precise model for motor learn-
ing, drawing on extensive characterisation of the critical pathways in
animal models. Discriminatory eye-blink conditioning has been studied
with fMRI (Ramnani et al., 2000), to reveal learning-related activations
in cerebellum, ventral premotor cortex and hippocampus. By using par-
tial reinforcement, the cerebellar response was shown to be due to the
violations of learned sensory predictions.
Motor learning occurs over time, with differences between “fast”
learning over minutes within a session, a period of consolidation
over hours, and “slow” learning over weeks (Karni et al., 1995,
1998). These phases may be followed by a period of automaticity
and long term retention (Doyon and Benali, 2005). fMRI is well suited
to study the fast learning phase for motor sequences and visuomotor
associations. Many studies have reported a functional dissociation be-
tween striatum and cerebellum (Jueptner and Weiller, 1998; Mentis
et al., 2003; Orban et al., 2010; Penhune and Doyon, 2002; Smith
and Shadmehr, 2005). For example, cerebellar-cortical circuits are
implicated in sensorimotor integration (Penhune and Doyon, 2002)
and temporal aspects of sequential movements (Sakai et al., 2002),
whereas basal ganglia-cortical circuits are involved in learning the
order of sequential movements (Sakai et al., 2002). Commonly,
early learning is associated with activation of prefrontal, SMA and
premotor cortex, and striatum, whereas late learning is characterised
by changes in cerebellar regions (Boettiger and D'Esposito, 2005;
Chen et al., 2012; Debas et al., 2011; Jueptner et al., 1997; Tamas
Kincses et al., 2008; Toni et al., 1998, 2001). The hippocampus is
also associated with consolidation of motor sequence learning during
sleep (Albouy et al., 2008) adding to compelling evidence of a hippo-
campal role in motor learning (Schendan et al., 2003).
In addition to such functional changes, structural change is detect-
able with MRI within a few weeks of motor learning e.g. white matter
architecture is altered in humans (Scholz et al., 2009) and macaques
(Quallo et al., 2009). Conversely, the restriction of manual skilled ac-
tion and retraining causes a reduction and restoration of primary
motor cortical grey matter respectively, using voxel based morphom-
etry (Granert et al., 2011).
MRI also illuminates the neurochemical mechanisms of motor skill
learning. For example, in vivo magnetic resonance spectroscopy of
GABA concentration in human primary sensorimotor cortex (Floyer-
Lea et al., 2006) reveals that motor learning reduces GABA concentra-
tion contralateral to the hand used for learning by almost 20%. This
suggests rapid and specific modulation of GABAergic neurotransmis-
sion. Transcranial direct current stimulation (tDCS) decreases GABA
in motor cortex. tDCS induced reductions in GABA correlate with
both the degree of motor learning and the degree of fMRI signal
change in motor cortex, confirming the role of GABAergic cortical sig-
nalling in fast motor learning (Stagg et al., 2011).
Movement selection
The extended motor system is active during action decisions. Ac-
tion decisions include whether to make a movement, which action
to make, or when to make it (Brass and Haggard, 2008; Willingham,
1998). Neuroimaging has provided critical insights into each of
these strategic processes. Early PET studies compared instructed or
specified actions with actions that the volunteer chose themselves
(Deiber et al., 1991; Frith et al., 1991). Differential activation of medi-
al and lateral prefrontal cortex, the SMA, pre-SMA, anterior cingulate
cortex and parietal cortex (intraparietal sulcus, superior and inferior
lobules) was found. These findings have been reproduced with fMRI
(Forstmann et al., 2008c; Hyder et al., 1997; Rowe et al., 2005,
2008a, 2010a; Spence et al., 1997). Similar activation is seen for the
selection of motor task-sets (Forstmann et al., 2007; Rowe et al.,
2008a; Rushworth et al., 2004). Within this network, the selection
of an action increases effective connectivity from prefrontal cortex
to pre-SMA (Rowe et al., 2010b), an area associated with the genera-
tion of action plans (Nachev et al., 2005). These types of action deci-
sion may begin several seconds before the movement is made.
Intriguingly, multivariate pattern analysis of fMRI indicates that the
rostromedial prefrontal cortex encodes information that is predictive
of the outcome of action decisions as much as 10 s before the decision
is executed (Bode et al., 2011; Soon et al., 2008). This is much earlier
even than behavioural and electroencephalographic estimates of the
awareness of an intention to act (Libet et al., 1983; Matsuhashi and
Hallett, 2008), perhaps due to the difference between the awareness
of an intention to act and the action decision process itself (Lau et al.,
2006).
Action selection may be determined by differences in expected re-
ward. The neural mechanisms of reward processing are beyond the
scope of this article. However, the anterior cingulate cortex plays a
central role, and is associated with action–reward associations in im-
aging, electrophysiological and primate lesion studies (Hadland et al.,
2003; Rudebeck et al., 2008; Rushworth et al., 2005). The anterior cin-
gulate cortex is also activated when action selection does not involve
an experimental manipulation of reward, yet it is possible that there
are implicit rewards for actions in these studies (Deiber et al., 1991;
Forstmann et al., 2008c; Frith et al., 1991; Hyder et al., 1997; Rowe
et al., 2005, 2008a, 2010a; Spence et al., 1997).
There are other potential confounds in action selection paradigms,
including differential attention to action, (Lau et al., 2004b; Rowe et
al., 2002a, 2002b) or attention to the intention to act (Lau et al.,
2004a) both of which modulate pre-SMA, dorsal prefrontal cortex
and intraparietal cortex (each associated with action selection). The
action selection network may also be engaged in remembering previ-
ous moves or in making in a switch-stay decision that is contingent
on memory for prior moves (Deco and Rolls, 2005; Rushworth et al.,
2002; Sakai, 2008). The inhibition of prior actions by SMA or inferior
frontal cortex is considered in greater depth in the next section.
Action decisions can also be made about when (Cunnington et al.,
2002; Wiese et al., 2004, 2005) or whether to act (Karch et al., 2009),
or indeed whether to act at all (Brass and Haggard, 2007; Sumner et
al., 2007). With self-initiated actions there is activity in the SMA,
the premotor and primary motor cortex, anterior cingulate gyrus,
and the inferior parietal lobe, but interestingly not the lateral prefron-
tal cortex (Wiese et al., 2004). However, activity of lateral prefrontal
cortex and inferior parietal lobe does occur during periods of self-
initiated actions, even though activity is not time locked to individual
responses (Wiese et al., 2005) suggesting a temporally dissociated
 J.B. Rowe, H.R. Siebner / NeuroImage 61 (2012) 464–477
process that may include greater attention to action or monitoring of
task performance.
Motor inhibition
The ability to stop an action is essential for motor control. Failure
to inhibit manifests as impulsivity in a wide range of neuropsychiatric
disorders. Multiple mechanisms for inhibition exist, differing in their
cortical and subcortical interactions and psychopharmacology. Motor
inhibition has provided a strong platform for translational neurosci-
ence, spanning animal models, pharmacological imaging and disease
states.
Specific anatomical structures are implicated in response inhibition,
including the inferior frontal gyrus (IFG) (Aron et al., 2004; Levy and
Wagner, 2011; Wager et al., 2005) with converging evidence from
lesions (Aron et al., 2003; Swick et al., 2008), extensive fMRI and PET
studies (Asahi et al., 2004; Chikazoe et al., 2007, 2009a; Del-Ben et al.,
2005; Konishi et al., 1998, 1999; Langenecker et al., 2007; Rubia et al.,
2005; Simmonds et al., 2008; Zheng et al., 2008) and electrophysiology
(Swann et al., 2009). Both right and left IFG are necessary correlates of
motor inhibition (Aron et al., 2003; Rubia et al., 2001b; Swick et al., 2008).
Inhibition of action includes the restraint when the action is prepo-
tent (from context of recent history or current stimuli). This type of
inhibition is typified by the NoGo paradigm, in which a movement
(e.g. button press) is made repeatedly to one or more Go stimuli, but
no movement is made to a pre-specified NoGo stimulus (usually pre-
sented with low frequency). There is an associated activation of lateral
prefrontal, premotor and parietal cortex with successful inhibition in
NoGo trials (Asahi et al., 2004; Chikazoe et al., 2007, 2009a; Del-Ben
et al., 2005; Konishi et al., 1998, 1999; Langenecker et al., 2007; Rubia
et al., 2005; Simmonds et al., 2008; Zheng et al., 2008).
In contrast to restraint of action, one may need to cancel an action
after it has been initiated. This type of inhibition is typified by the
Stop Signal Task (SST) (Logan et al., 1984; Verbruggen and Logan,
2008). The functional anatomy of SST and NoGo have much in common
(Rubia et al., 2001b; Swick et al., 2008) including the inferior frontal cor-
tex, but also medial frontal cortex including pre-SMA, anterior cingulate
cortex, and parietal cortices, with convergent evidence from lesion
studies (Aron et al., 2003; Swick et al., 2008), morphometric correlates
of SST performance (Menzies et al., 2007) and fMRI activations (Boehler
et al., 2011; Chamberlain et al., 2009; Chikazoe et al., 2009b; Rubia et al.,
2001a, 2001b; Swick et al., 2008).
Significant individual differences exist in the behavioural response to
the stop signal. For example in healthy adults, better inhibition with
shorter stop-signal reaction times is associated with greater activation
of premotor and superior medial frontal cortex (Li et al., 2006) and in-
creased grey matter in right inferior frontal regions (Menzies et al.,
2007). A genetic influence is revealed by proband-relative comparisons
(Menzies et al., 2007) and one potential factor is the polymorphism of
the norepinephrine receptor gene (ADRA2B) which is associated with
activation of the right IFG in a large fMRI study of the SST (n = 645)
(Whelan et al., 2011).
Despite the homologous functional anatomy, the NoGo and SST
tasks have importance differences. For example, a clear dissociation
between serotonergic and noradrenergic systems for NoGo and SST
tasks is seen in human pharmacologically modulated fMRI studies
(Chamberlain et al., 2009; Del-Ben et al., 2005; Lamar et al., 2009;
Rubia et al., 2005), supported by animal studies (Eagle et al., 2008).
Further pharmacological imaging studies of serotonergic and noradren-
ergic systems are required to understand their specific roles in impulse
control.
The caudate and subthalamic nucleus (STN) both regulate motor
inhibition, in animal studies (Eagle and Robbins, 2003; Eagle et al.,
2008), clinical populations (Obeso et al., 2011), after deep brain stim-
ulation (DBS) (Mirabella et al., 2011; Ray et al., 2009) and in healthy
human imaging studies. They contribute to distinct striatal and
467
subthalamic (hyperdirect) pathways for inhibition. Event-related
fMRI of the SST showed that stopping an action activated right inferi-
or frontal cortex and STN: the higher the STN activation, the better
the SST performance (Aron and Poldrack, 2006) consistent with STN
suppression of thalamocortical output to motor regions. The proposed
“hyperdirect” pathway from IFC and pre-SMA to STN, contrasted with
the well established direct and indirect cortico-striato-thalamo-cortical
pathways. DWI based tractography has supported the existence of this
hyperdirect pathway (Aron et al., 2007). Indeed, deep brain stimulation
of the STN in Parkinson's disease increased the activity of the STN, but
reduced activity in the thalamus and its cortical connections in frontal
cortex (Ballanger et al., 2009; Campbell et al., 2008; Geday et al., 2009).
The STN also contributes to NoGo inhibition, at least in the context of
Parkinson's disease (Hershey et al., 2010).
The role of the STN has been formalised in a computational model of
decision making (Frank, 2006; Frank et al., 2007) in which the STN
inhibits thalamocortical interactions (within cortico-striato-thalamo-
cortical circuits for motor and premotor cortex, supplementary motor
area, and the pre-SMA). This prevents response execution, especially
under high conflict conditions, allowing time to optimise response deci-
sions. Functional connectivity measures based on fMRI indicate that
both STN and striatal pathways contribute to inhibition, but in different
ways (Jahfari et al., 2011).
Movement and inhibition are subject to a speed-accuracy trade-off
that needs to be adjusted according to circumstances. Dynamic speed-
accuracy tradeoffs have been studied in combination with ultra-high
resolution structural imaging and tractography of the STN and striatum
(Forstmann et al., 2010a). Although inconclusive on cortico-STN con-
nectivity, this combination of methods demonstrated that connectivity
from pre-SMA to striatum correlated with subjects' ability to adjust
decision thresholds. It is likely that speed-accuracy tradeoffs for Stop
vs Go decisions depend on similar networks. Given the small size and
complex anatomy around the STN, such studies benefit from the resolu-
tion of high field imaging and dedicated imaging sequences (Schafer et
al., 2011).
Despite the apparent convergence of imaging, lesion data, compara-
tive structural and pharmacological studies of motor inhibition, the in-
terpretation of the NoGo and SST tasks and their neural correlates
remains controversial. For example, it is not universally accepted that
the activations represent either the source or target of inhibition. They
might reflect other task-relevant processes, such as monitoring of per-
formance, reflexive orienting to task relevant information/stimuli,
reprogramming of responses or strategic adjustments of performance
(Aron, 2010; Hampshire et al., 2010; Levy and Wagner, 2011). However,
fMRI, DWI and TMS imaging modalities have been combined to demon-
strate that in some contexts at least, the premotor to motor cortical
interactions are both directional and inhibitory. This includes the reduc-
tion of corticospinal excitability (O'Shea et al., 2007b) and inhibition
among inferior frontal cortex, pre-SMA, and primary motor cortex
(Neubert et al., 2011).
Action observation
A prominent example of functional homology across species is the
mirror neuron system. Functional brain mapping has not only confirmed
this homology, but enabled the investigation of mirror neuron systems in
multiple brain regions and across multiple disorders. In non-human pri-
mates, mirror neurons are a particular class of visuomotor neurons, orig-
inally discovered in the ventral premotor cortex of monkeys (area F5)
and the rostral inferior parietal lobule (Rizzolatti et al., 1996, 2001). Mir-
ror neurons discharge when the monkey performs a particular hand or
mouth action and when the monkey observes another individual per-
forming a similar action (di Pellegrino et al., 1992; Gallese et al., 1996;
Rizzolatti et al., 1996a). They do not respond to pantomime of an action
if the object is absent or to observation of an action-related object
(Gallese et al., 1996; Rizzolatti et al., 1996a). Further, mirror neurons
468 J.B. Rowe, H.R. Siebner / NeuroImage 61 (2012) 464–477
display a differential response to actions observed in peripersonal or
extrapersonal space suggesting that mirror neurons process action fea-
tures that are relevant to generating behaviours (Caggiano et al., 2009).
The invasive recordings in monkeys motivated functional neuro-
imaging studies in humans to identify cortical areas that express a
functional signature analogous to mirror neurons. Distinct clusters
in the human posterior inferior frontal gyrus and supramarginal
gyrus were consistently activated, when human volunteers observed
or imitated actions performed by others (Decety et al., 1997; Grafton
et al., 1996; Hari et al., 1998; Iacoboni et al., 1999; Koski et al., 2002;
Grezes et al., 2003). Mirror neurons also demonstrate macroscopic
somatotopy (Buccino et al., 2001).
Based on these findings, it was proposed that the posterior inferior
frontal gyrus and supramarginal gyrus form a specialized frontoparietal
circuit which matches observed actions to the corresponding internal
motor representation. This circuit is critical to the understanding of
actions made by others by “providing a first-person grasp of the
motor goals and intentions of other individuals” (Rizzolatti and
Sinigaglia, 2010). The activation of this frontoparietal mirror circuit is
not automatically triggered by the observation of actions, but depends
on the experimental context (Jonas et al., 2007; Molenberghs et al.,
2012), such as attempting to understand the actions, identify their
physical features or passively observe them. Although several mecha-
nisms may facilitate the understanding of other people's behaviour,
the inferior frontoparietal mirror circuit unifies action perception and
action execution. The mirror mechanism supports the simulation of ac-
tions and their goals which is critical to observational and imitation
learning, inferring motor intentions of others, and has been implicated
in the development of language (Buccino et al., 2004; Iacoboni et al.,
2005; Rizzolatti and Craighero, 2004). The exact contribution of the
human mirror system to these important brain functions continues to
be a subject of intense research.
Neuroimaging of the human frontoparietal mirror system for actions
has a much broader impact beyond human motor control. For instance,
the concept of “mirror mechanisms” that match external representations
(observation) and internal representations (execution) has been ex-
panded to studies of the observation and experience of touch (Keysers
et al., 2004), emotional processing (Wicker et al., 2003), and social cogni-
tion (Gallese et al., 2004). The existence of analogous mirror mechanisms
which respond to the mental or emotional state of others from the obser-
vation of facial and body expressions has been postulated (Iacoboni et al.,
2005; Keysers and Fadiga, 2008; Wicker et al., 2003). Another important
avenue of neuroimaging research has started to address the potential
clinical relevance of the human mirror system (Rizzolatti et al., 2009)
to autism (Bastiaansen et al., 2011; Cattaneo et al., 2007) or rehabilitation
after stroke (Buccino et al., 2006; Ertelt et al., 2007).
Several studies have shown that shared activation during action
observation and execution comprises a larger set of cortical areas
than the core mirror system in the inferior frontoparietal cortex
(Biermann-Ruben et al., 2008; Gazzola and Keysers, 2009). A topic
for future research will be to integrate the frontoparietal mirror sys-
tem into a larger framework of neural systems involved in the gener-
ation of internal models, sensory and motor simulation and predictive
motor control.
Mapping motor dysfunction and therapy after stroke
Functional brain mapping of the motor system was from the begin-
ning strongly influenced by neurologists interested in the mechanisms
of recovery after stroke (Di Piero et al., 1992; Weiller et al., 1992) and
the pathophysiology of movement disorders (Jenkins et al., 1992). How-
ever, studying patient populations has promoted a two-directional
dialogue between clinical specialties and non-clinical neurosciences: ap-
plying clinical and cognitive neurosciences to understand and shape the
treatment of disease while studying patients as lesion paradigms.
Mapping functional brain networks after motor stroke
Functional brain mapping after subcortical motor stroke has char-
acterised how cortical motor networks undergo functional reorgani-
sation; clarified which reorganisation patterns are associated with
motor recovery (Sharma et al., 2009a); and assessed how therapeutic
interventions influence motor reorganisation and promote recovery of
motor function (Grefkes et al., 2010; Wang et al., 2011). Early cross-
sectional studies were soon complemented by prospective longitudinal
studies mapping the temporal evolution of stroke-related activation
abnormalities (Calautti et al., 2001; Small et al., 2002; Ward et al.,
2004). A common finding was a bilateral activation of motor, premotor,
and parietal cortical areas during movements of the paretic hand
(Calautti et al., 2001). A persisting bilateral activation pattern was associ-
ated with a poor outcome and was originally interpreted as maladaptive
or dysfunctional. However, contralateral regions can also effectively con-
tribute to motor recovery (Rehme et al., 2011; Riecker et al., 2010).
Better prediction of recovery of motor function in the early phase
after stroke is required (Stinear, 2010) and for this requirement,
objective functional neuroimaging complements other methods
such as TMS and structural neuroimaging (Lindenberg et al., 2010,
2011; Zhu et al., 2010). While fMRI studies have pinpointed acute ab-
normalities of cortical activation and connectivity that correlate with
outcome, the predictive value of fMRI remains the subject of intensive
research (Buma et al., 2010; Calautti et al., 2001; Marshall et al., 2009;
Zarahn et al., 2011). Since motor functions are supported through
functional integration across the extended motor system network,
the assessment of connectivity patterns after stroke could give clearer
insights into stroke recovery than mapping regional brain activity
alone. Altered connectivity within the ipsilesional hemisphere as
well as between hemispheres relates to motor impairment after
stroke, more than alterations in regional activation (Sharma et al.,
2009a). For example, dynamic causal modelling (DCM) of fMRI data
(Friston et al., 2003, 2011) identifies changes in effective connectivity
in a bilateral network of motor and premotor cortex in patients with
subcortical ischemic stroke (Grefkes et al., 2008; Rehme et al., 2011).
During fMRI of paced hand movements the network modelling indi-
cated a reduced influence of ipsilesional SMA and lateral premotor
cortex on ipsilesional motor cortex after stroke (Grefkes et al., 2008;
Rehme et al., 2011). This acute reduction in coupling improved over
time and was associated with better recovery of motor function. In
the chronic stage, a persisting suppressive influence of the contrale-
sional motor cortex on ipsilesional motor cortex correlated with
motor function (Rehme et al., 2011). The norepinephrine transporter
inhibitor reboxetine partially normalised the abnormal connectivity
pattern in frontal motor areas after stroke (Wang et al., 2011).
Usually fMRI data is acquired during an experimental session and
analysed off-line. However, a recent study has analysed the fMRI data
on-line, using it for biofeedback in stroke patients who were trained
to regulate their neural activity in ventral premotor cortex (Sitaram
et al., 2011). While this proof-of-principle study shows that brain–
computer interface applications of real-time fMRI are feasible in
stroke patients, it remains to be shown how fMRI-based biofeedback
compare to EEG-based approaches in a clinical setting.
How to analyse with impaired motor performance?
Motor studies are difficult to interpret in patients who are not able
to perform the task or who exert more effort. This poses a special
challenge for neuroimaging of stroke recovery: how can one dissoci-
ate between brain activity (or connectivity) changes mediating
motor recovery from changes that reflect differential performance
(Price and Friston, 1999)? One solution is motor imagery as described
above. However, it is possible that the ability to imagine a movement
also changes, especially after cortical stroke.
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A second approach is motor imagery, as it does not involve overt
movements (Calautti et al., 2007; Page et al., 2009; Sharma et al.,
2009a, 2009b). However, it is still possible that the ability to imagine a
movement also changes, especially after cortical stroke. In a recent
study, stroke patients with preserved motor imagery (Sharma et al.,
2009b) underwent fMRI while they imagined or performed a finger–
thumb opposition sequence. Motor imagery and execution of the affect-
ed hand resulted in a similar activation of the anterior part of motor cor-
tex and dorsal premotor cortex. Further, the hemispheric balance of
activation in the posterior part of motor cortex (BA4p) correlated posi-
tively with motor performance. The cortical motor networks upstream
from motor execution may therefore be a suitable target for rehabilita-
tion in more severely impaired patients. Another strategy is to match
the motor task in terms of effort rather than matching the executive as-
pects of movements (Ward et al., 2004). This procedure ensured that
the repeated fMRI measurements were matched in terms of relative
task difficulty.
One can also minimise performance confounds by studying pa-
tients at rest. Resting-state fMRI measures the low frequency sponta-
neous changes in the blood-oxygen-level dependent (BOLD) signal
(b0.1 Hz) (Biswal et al., 1995). The regional BOLD signal fluctuations
are temporally correlated within functional brain networks (Fox and
Raichle, 2007). Several groups have used resting-state fMRI to the
study alterations in functional connectivity in patients with motor
stroke. A cross-sectional study found reduced interhemispheric func-
tional connectivity within the motor network (at rest) was associated
with motor impairment after stroke (Carter et al., 2010). A longitudi-
nal study of subcortical motor stroke revealed higher functional con-
nectivity with the ipsilesional fronto-parietal networks, bilateral
thalamus, and cerebellum (Park et al., 2011). Interestingly, the func-
tional connectivity of the ipsilesional motor cortex with thalamus,
SMA and middle frontal gyrus shortly after stroke showed a positive
correlation with motor recovery 6 months later. This suggests that
initial functional resting-state connectivity might be used as predictor
for motor recovery.
Functional brain mapping in movement disorders
Over the past 20 years, functional neuroimaging has greatly ad-
vanced the pathophysiological understanding of movement disorders
such as Parkinson's disease (PD) (Eckert et al., 2007; Eidelberg, 2009;
Playford et al., 1992; Rowe et al., 2008b), dystonia (Ceballos-Baumann
et al., 1995a; Ceballos-Baumann et al., 1995b; Peller et al., 2006; Siebner
et al., 2003), and Huntington's disease (Bartenstein et al., 1997; Calautti
et al., 2007; Kloppel et al., 2009; Weeks et al., 1997; Wolf et al., 2008).
These studies have provided new insights into the role of dopamine
and basal ganglia in motor control, cognition and reward processing
(Stoessl et al., 2011).
Radiotracer based imaging has mainly been used to assess disease re-
lated changes in the nigrostriatal dopaminergic system, but also to assess
the function of other neurotransmitters in PD (Brooks and Piccini, 2006;
Ravina et al., 2005; Stoessl, 2011). In addition, (18)F-fluorodeoxyglucose
(FDG) PET has been used to identify spatial patterns of altered regional
brain metabolism. Spatial covariance analysis has identified characteris-
tic metabolic covariance patterns in PD (Tang and Eidelberg, 2010). The
expression of one metabolic covariance pattern correlates with the se-
verity of motor symptoms in PD, while another covariance pattern corre-
lates with cognitive dysfunction (Huang et al., 2008; Mattis et al., 2011).
The motor-related covariance pattern precedes the appearance of motor
signs by approximately 2 years (Tang et al., 2010a) and may enable early
and accurate diagnostic classification of patients with parkinsonism
(Tang et al., 2010b).
While early activation studies of task related brain activation in-
volved PET measurements of regional cerebral blood flow (Jahanshahi
et al., 1995; Jenkins et al., 1992; Playford et al., 1992; Samuel et al.,
1997), BOLD sensitive fMRI has largely replaced PET of cerebral blood
469
flow as the imaging method of choice. fMRI does not involve exposure
to radiation and offers superior spatial and temporal resolution, the lat-
ter allowing for analysis of event-related activity. This partly explains
why fMRI has been widely adopted to study regional brain activity
and connectivity, at rest as well as during motor- and non-motor
tasks. One notable exception is functional neuroimaging of PD patients
who are treated with deep brain stimulation (Haslinger et al., 2005;
Schroeder et al., 2002) (see also motor inhibition section above).
Resting state fMRI studies in Parkinson's disease
Resting state fMRI of spontaneous low-frequency fluctuations of
the BOLD signal is well suited for network connectivity studies in
PD (Skidmore et al., 2011b; Wu et al., 2009), since the connectivity
differences are relatively unconfounded by motor deficits. Using the
amplitude of low frequency BOLD signal fluctuations at rest as an
index of brain activity (Skidmore et al., 2011b), PD has been shown
to decrease activity in SMA and prefrontal cortex and alter cerebellum
activity. Based on the expression of this activity pattern it was possi-
ble to distinguish between PD patients and healthy controls with 92%
sensitivity and 87% specificity (Skidmore et al., 2011b). Other resting
state activity patterns are associated with the presence of apathy or
depression (Skidmore et al., 2011a). For example, apathy was pre-
dicted by the amplitude of the low frequency fluctuations at rest in
the left SMA, lateral- and orbital-frontal cortex whereas depression
was associated with the amplitude in the subgenual cingulate.
Disease severity was reflected by the amplitude of resting-state low
frequency fluctuations in the putamen (Skidmore et al., 2011a).
Resting state fMRI has also been used to identify disease related
changes in the connectivity profile of a specific region of interest
such as the subthalamic nucleus (STN) or putamen. Early-stage PD
patients displayed increased resting state connectivity between STN
and cortical motor and premotor cortical areas relative to healthy
controls (Baudrexel et al., 2011), and abnormal connectivity between
parietal cortex putamen (Helmich et al., 2010).
Functional MRI studies of motor control in Parkinson's disease
Frontal motor areas are abnormally activated when patients with
PD perform manual motor tasks (Buhmann et al., 2003; Haslinger et
al., 2001; Rowe et al., 2008b, 2010b; Sabatini et al., 2000a; Wu and
Hallett, 2005; Wu et al., 2010b), including primary motor cortex,
pre-SMA, lateral premotor and prefrontal cortex. However, the sign
(i.e., increase or decrease in activation) as well as the spatial pattern
varies considerably among the different studies suggesting that the
abnormal activation depends strongly on the specific task. One factor
is the amount of attention that is assigned to the motor task, or a
distracter task (Rowe et al., 2002b). With a simple paced and over-
learned sequence task, PD patients off medication had increased acti-
vation in SMA during the motor task, but failed to augment SMA
activity when asked to attend to their actions. PD is associated with
decreased activity in SMA and striatum, but there is often increased
activity in premotor cortex (Sabatini et al., 2000b; Samuel et al.,
1997; Wu et al., 2010b). The regional activation differences in PD
are partially normalised by clinically effective therapies, including
dopaminergic drugs and deep brain stimulation (Buhmann et al.,
2003; Haslinger et al., 2001) although the normalisation of activation
is age-dependent (Hughes et al., 2010).
Functional neuroimaging of PD has concentrated interest in net-
work connectivity over many years (Grafton et al., 1994; Rowe et
al., 2010b; Tang and Eidelberg, 2010; Wu et al., 2010a, 2011), using
structural equation modelling (Grafton et al., 1994; Rowe et al.,
2002b), psychophysiological interactions (Wu et al., 2010a; Wu et
al., 2011), dynamic causal modelling of activations (Rowe et al.,
2010b), and multivariate analysis of regional metabolism (Tang and
Eidelberg, 2010). These studies have indicated that PD patients fail
470 J.B. Rowe, H.R. Siebner / NeuroImage 61 (2012) 464–477
to modulate effective connectivity between PFC, premotor cortex and
SMA, especially off medication. This functional disconnection of the
SMA and pre-SMA might account for the under-activation of the
SMA during motor tasks (Buhmann et al., 2003; Haslinger et al.,
2001; Rowe et al., 2008b, 2010b; Sabatini et al., 2000a; Wu and
Hallett, 2005; Wu et al., 2010b). Alongside the reduction in frontal
cortical and cortico-striatal connectivity there is increased prefrontal
coupling with motor and premotor areas and cortico-cerebellar con-
nectivity. Again, clinically effective therapies partially normalise the
network abnormalities, with much in common between pharmaco-
logical and DBS treatments (Asanuma et al., 2006).
Functional MRI studies of ‘non-motor’ functions in Parkinson's disease
Even in early stages of PD, patients present with deficits in cogni-
tive and limbic brain functions. The nature of non-motor deficits in PD
patients is complex, as they depend on disease severity, medication
and genotype (Rowe et al., 2008b; Williams-Gray et al., 2008), but
they are related to abnormal function of regions traditionally viewed
as motor structures such as the striatum. In PD patients, the optimal
dose of levodopa-replacement is usually based on motor improve-
ment. The optimal dopamine-level can be described by an inverted
U-relationship with function in motor, cognitive and limbic domains.
Dopaminergic medication is generally adjusted to optimise dorsal
striatum-mediated motor symptoms. However, this may be at the
expense of functions subserved by ventral parts of the striatum, by
delivering too high levels of dopamine (Cools and D'Esposito, 2011;
MacDonald et al., 2011).
This balance between motor and non-motor systems has a direct
impact on altered reward processing in PD (Rowe et al., 2008b) and
its clinical manifestation in terms of impulse control disorders
(ICD). These include pathological gambling or compulsive shopping,
are frequently observed in PD patients treated with dopamine ago-
nists (Voon and Dalley, 2011; Weintraub et al., 2010). The link be-
tween dopaminergic therapy and impulse in PD has been addressed
in pharmacological fMRI studies involving patients with and without
ICDs (Voon et al., 2010, 2011). In the first study, patients performed a
probabilistic learning task in which participants had to learn if a sym-
bol was associated with reward or loss (Voon et al., 2010). Patients
with ICDs showed an increased striatal prediction error signal in the
gain condition after intake of dopamine agonists. It was inferred
that this enhanced response in ventral striatum signals a better than
expected outcome for chosen actions, and this might bias behavioural
decisions in PD patients. The second fMRI study employed a risk tak-
ing task to show that PD patients with ICDs made more risky choices
in the gain condition along with decreased activity in OFC and ACC
(Voon et al., 2011). The opposite pattern was found in PD controls
without ICDs. In patients with ICDs, dopamine agonists decreased ac-
tivity in the ventral striatum and biased decisions towards greater
risk. Even without ICDs, reward processing may be abnormal: activa-
tion of the anterior cingulate cortex during reward expectation de-
creased with motor disease severity, while activation here after an
actual reward increased. This failure to predict rewarding outcomes,
while retaining responses to actual reward, may bias goal-oriented
behaviours in PD (Rowe et al., 2008b).
Imaging the genetic influences on Parkinson disease
There is growing evidence that genetic factors play an important
role in the aetiology of PD. Several single gene mutations have been
associated with autosomal dominant (SNCA and LRRK2 gene) or re-
cessive (Parkin, PINK1, DJ-1, and ATP13A2 gene) forms of PD. Neuro-
imaging of individuals carrying a mutation in one of the PD genes has
opened up new possibilities for research into the pathogenesis of PD
(Bruggemann et al., 2010; van der Vegt et al., 2009). Functional neu-
roimaging of mutation carriers with overt disease can establish links
between the pathogenesis at the molecular and system level via in-
termediate neuroimaging phenotypes (Bruggemann et al., 2010; van
Eimeren et al., 2010). Furthermore, functional neuroimaging of non-
manifesting mutation carriers can disclose mechanisms of adaptive
motor reorganisation that may prevent or delay clinical manifestation
(Buhmann et al., 2005; van Nuenen et al., 2009a). For instance, non-
manifesting heterozygous carriers of recessively inherited Parkin
and PINK1 mutations show latent nigrostriatal dopaminergic degen-
eration (Eggers et al., 2010; Hilker et al., 2001).
This provides the unique opportunity to identify how the motor
system copes with a subclinical dopaminergic dysfunction (van
Nuenen et al., 2009a). When performing sequential finger-to-thumb
opposition movements, non-manifesting carriers of a Parkin mutation
showed a stronger activation of rostral cingulate motor area and dor-
sal premotor cortex during internally cued compared to externally
cued movements. Furthermore, there was increased effective connec-
tivity between rostral cingulate and the dopamine-deficient posterior
putamen (Buhmann et al., 2005). fMRI of non-manifesting carriers of
mutations in the PINK1 or Parkin gene (van Nuenen et al., 2009b)
showed that carriers have increased activation of pre-SMA and the
dorsal premotor cortex relative to healthy controls. Together, the results
indicate show that a subclinical nigrostriatal dysfunction triggers a
compensatory increase in activity of motor cortical areas within task-
specific networks.
Such compensatory mechanisms could explain why patients with
sporadic PD first become symptomatic several years after the neuro-
degeneration of dopaminergic striatonigral neurons has started. In
addition, it might be possible to predict PD using fMRI even before
motor symptoms become manifest. An alternative strategy is to per-
form fMRI studies in populations with clinical signs such as anosmia
or REM sleep disorder that commonly precede the motor manifesta-
tion of PD (Savica et al., 2010).
Transcranial brain stimulation and brain imaging: multimodal
imaging
Over the last 20 years, stimulation techniques have been intro-
duced to study awake humans. The most prominent techniques are
TMS and tDCS. TMS induces brief electric current pulses in the cortex
via a rapidly changing magnetic field (Barker et al., 1985), which can
depolarize cortical neurons and induce action potentials from the
stimulated cortex. A single TMS pulse given to the primary motor cor-
tex can elicit a peripheral motor response which can be measured as
the motor evoked potential (MEP) (Barker et al., 1985). TMS of the
primary motor cortex was rapidly adopted as a clinical tool to assess
the function of cortical motor projections in patients with paresis, and
as a research tool to study motor control in healthy subjects and pa-
tients with movement disorders (Hallett and Rothwell, 2011; Reis et
al., 2008b). The mechanism of brain stimulation is fundamentally dif-
ferent for TDCS. The induced tissue current is sub-threshold for induc-
ing action potentials in cortical neurons (Stagg and Nitsche, 2011) but
there is a shift in the membrane potential which alters the level of in-
trinsic post-synaptic activity.
In contrast to PET and fMRI, both TMS and tDCS are interventional
methods. They transiently and reversibly interfere with neuronal activ-
ity in targeted brain networks, adding a causal dimension to human
brain mapping. This has motivated researchers to combine transcranial
stimulation with functional brain mapping techniques.
For both TMS and tDCS, much of the physiologic mechanisms have
been learned from studies of the primary motor hand area (M1-
HAND). Here, the efficacy of TMS can be easily assessed by recording
the hand muscles' motor evoked potentials. Therefore, the pioneering
work combining TMS or tDCS with functional brain mapping tech-
niques primarily focussed on the motor system. In 1997, the simulta-
neous use of TMS and functional brain imaging was introduced and
several groups managed to map the acute effects of focal TMS on
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brain function with EEG (Ilmoniemi et al., 1997), PET (Fox et al.,
1997), or fMRI (Bohning et al., 1997). TMS during neuroimaging has
been subsequently exploited by many groups to compare neural acti-
vation associated with internally generated (i.e., voluntary) move-
ment, externally specified movement (Siebner et al., 2001a) and
functional connectivity of the motor system (Bestmann et al., 2003,
2004; Paus et al., 1998; Siebner et al., 2001b).
Combined TMS–neuroimaging has the potential to trace task-state
dependent effects of TMS on causal interactions in the human motor
system. In an interleaved TMS–fMRI study, TMS applied to the left
dorsal premotor cortex (PMd) increased regional activity in contra-
lateral dorsal premotor cortex and M1-HAND at high stimulation in-
tensity (Bestmann et al., 2008). This effect was reversed during a
visually guided grip force task. These results show that TMS can causally
affect activity in contralateral motor regions, and that these influences
critically depend on the motor state. This experimental approach has
also been used to study the contribution of the contralesional premotor
cortex to motor function after stroke (Bestmann et al., 2010). In that
study, residual motor impairment was associated with a stronger facil-
itatory influence of TMS over contralateral PMd on regional activity in
posterior parts of ipsilesional sensorimotor cortex during hand grip
which may reflect a physiological mechanism by which the contrale-
sional premotor cortex supports hand function after stroke.
Repetitive TMS (rTMS) and tDCS can be used to increase or de-
crease the excitability in focal areas of the brain (Ziemann et al.,
2008). These conditioning effects of TMS have been used to facilitate
motor performance and motor learning in healthy volunteers and pa-
tients with motor deficits (Reis et al., 2008a). Here functional neuro-
imaging techniques can map the functional impact of a conditioning
rTMS or tDCS session on motor activity and connectivity across the
whole brain (Siebner et al., 2009). Typically, functional neuroimaging
has been performed after a conditioning session of rTMS or tDCS to
map the lasting effects of brain stimulation on functional activity
and connectivity. This conditioning-and-mapping approach has
yielded new insights into the function of motor networks. Both,
rTMS and tDCS of cortical motor areas, can induce robust changes in
the distributed activity within motor networks at rest (Siebner et al.,
2000) and during various motor tasks (Lee et al., 2003; O'Shea et al.,
2007a; Siebner et al., 2000; Ward et al., 2010). Offline neuroimaging
after focal inhibitory 1 Hz rTMS to the M1-HAND (Lee et al., 2003) or
left PMd (O'Shea et al., 2007a) identified distinct patterns of rTMS-
induced short-term reorganisation in the motor system. This reorganisa-
tion involved changes in task-related activity and cortico-cortical con-
nectivity and was interpreted in terms of functional compensation to
maintain normal motor behaviour despite of the rTMS-induced interfer-
ence. Offline fMRI has also been used to identify neuronal correlates of
behavioural improvement following rTMS (Ward et al., 2010). Inhibitory
1 Hz rTMS of left rPMd improved the ability to dynamically adjust visuo-
spatial response mapping. This behavioural improvement was associated
with stronger left-hemispheric connectivity between the stimulated
PMd and the ipsilateral supramarginal gyrus.
The conditioning-and-mapping approach has also been used to
study clinical populations. In patients with focal hand dystonia, 1 Hz
rTMS of left premotor cortex induced a greater decrease in regional
activity in lateral and medial premotor areas, putamen, and thalamus,
uncovering increased responsiveness of the motor system to the con-
ditioning effects of rTMS (Siebner et al., 2003). In patients with pure
subcortical stroke without cortical involvement, facilitatory 10 Hz
rTMS over ipsilesional M1 improved movement kinematics along
with a reduction in neural activity in contralesional M1 (Ameli et
al., 2009). The same group used fMRI to map the neural correlates
of improved motor performance after inhibitory 1 Hz rTMS of con-
tralesional M1 in patients with subcortical stroke. Dynamic causal
modelling of motor networks revealed that motor improvement
was associated with short-term motor reorganisation (Grefkes et al.,
2010): when patients moved the paretic hand, contralesional 1 Hz
471
rTMS attenuated the negative transcallosal influence of contralesional
M1 on ipsilateral M1 along with a reinforcement of ipsilesional effec-
tive connectivity between SMA and M1. These examples underscore
the potential of the conditioning-and-mapping approach to unravel
spatiotemporal brain dynamics that reflect the causal interplay
among interconnected motor brain regions and to clarify how these
causal dynamics contribute to motor dysfunction or mediate im-
provement in response to therapeutic interventions.
New methods and integration of methods
In the previous sections on motor learning, motor inhibition, stroke
and movement disorders, many of the recent and exciting developments
came from the integration of multiple methods — combining genetic
data, pharmacological challenges or magnetic stimulation with function-
al imaging by PET and fMRI. We have also seen the parallel applications
of functional imaging with structural imaging, including local differences
in brain shape, volume and tractography.
During the next phase of imaging studies of the motor system,
these combinations will be used increasingly to answer critical ques-
tions about development, organisation, degeneration and plasticity of
the motor system. Already functional MRI studies are combining
structural imaging, establishing links between regional microstruc-
tural measures and functional correlates of motor learning or perfor-
mance. For example, cerebellar grey matter volume (as revealed by
voxel based morphometry of T1-weighted MRI) and fractional anisot-
ropy (as revealed by diffusion tensor imaging) were co-localized with
fMRI correlates of learning a visuomotor tracing task (Tomassini et al.,
2011). Structural information can also be used to inform the analysis
of effective connectivity network models. Until recently, this required
comparative anatomy and assumptions of homology across species.
However, human DWI tractography can now be used directly to in-
form network models (Stephan et al., 2009), and applications of this
integrative method are likely to be of particular value in understand-
ing the motor system, exploiting the motor systems somatotopy and
temporal precision.
A second trend is the increasing sophistication of the cognitive
models that lie behind the analysis of brain imaging data. Instead of
direct correlation of activations with experimental task conditions, la-
tent variables are derived from behavioural data and experimental
conditions, expressing the critical cognitive processes which can in
turn be correlated with neural activity. This paradigm shift is partly
driven by developments in cognitive theory, but it also follows devel-
opments in analysis methods and software. For example, early
methods of PET and block-design fMRI identified common activations
across many trials or extended periods of time. Subsequently, event-
related fMRI enabled low frequency events (e.g. stop trials) to be
studied in isolation from high frequency events (e.g. go trials), and
enabled transient responses related to movements or TMS pulses to
be distinguished from sustained activations for context or condition-
ing. However, these methods still examined the commonalities across
multiple trials, while trial to trial variance contributed to error vari-
ance. However, the trial to trial variance in performance can be
exploited, using model based imaging methods. This approach has
been highly successful outside the motor system (e.g. associative
learning models) but is perhaps even more useful in the analysis of
the motor system because of the ability to time critical events such
as the onset of movement.
One technique has been to adopt formal decision models (e.g. ac-
cumulator models) for motor or oculomotor processes. These models
can then guide the analysis or interpretation of fMRI and M/EEG data
for motor systems (Forstmann et al., 2008a; Forstmann et al., 2010b;
Rowe et al., 2010a) comparable to the analysis of perceptual decision
(Ho et al., 2009; Ratcliff et al., 2009). It has been shown that motor
decisions under time pressure are associated with greater activation
of striatum and pre-SMA, promoting faster execution of motor
472 J.B. Rowe, H.R. Siebner / NeuroImage 61 (2012) 464–477
programmes at the expense of a reduced decision threshold
(Forstmann et al., 2008b). Moreover, the connectivity between these
structures (using DWI) correlated with the subjects' ability to make
trial by trial adjustments in the speed-accuracy tradeoff (Forstmann et
al., 2010a).
den Ouden and colleagues took a different approach to capture the
relevance of trial-by-trial variance, in the context of motor learning
(den Ouden et al., 2010). To interrogate a visuomotor task, they com-
bined a hierarchical Bayesian learning model with dynamic causal
modelling of fMRI. Subjects discriminated visual stimuli that were
predicted by auditory cues, but unknown to subjects, the predictive
value of cues changed over time, and both speed and accuracy of
motor responses varied with stimulus predictability. Striatal predic-
tion errors were found to modulate premotor cortical network cou-
pling such that trial-by-trial striatal prediction error determined the
influence of visual stimuli (ventral stream activation) on premotor
activity.
A third example of the value of model based approaches which ex-
ploit trial to trial variance comes from motor learning. Research into
how we learn to optimise goal directed behaviours has often focussed
on the mechanism of stimulus–reward associations, or action–reward
associations for serial single actions (Boorman et al., 2009; Rushworth
et al., 2010; Samejima and Doya, 2007). However, many real behaviours
are complex high dimensional processes, with many sub-actions and
multiple effectors. A compound action could be considered to be the
sum of its sub-actions, and the learned compound reward to be the
sum of sub-actions' reward associations. However, we can also learn
single compound action values. Using dynamic and multiple action
values in combination with fMRI and reinforcement learning models
(using trial by trial prediction error), Gershman and colleagues
showed that humans learn separate action values for components of a
complex behaviour (Gershman et al., 2009). Both ventral striatum and
parietal cortex activation patterns reflected the separable values of the
component actions.
Conclusions
Over the last 20 years, functional imaging has enabled rapid ad-
vances in our understanding of the structure and function of the
motor system, in health and neurological disease. The study of the
motor system has been equally important for the validation of func-
tional imaging methods, and for testing the similarities and differ-
ences across species. Some principles of organisation have been
reinforced, such as the existence of cortico-striato-thalamo-cortical
loops for selection, inhibition and motor learning. However, new im-
aging methods (DWI), new interventional challenges (TMS, DBS and
emerging neurological therapies) and new analytic approaches
(model based imaging retaining trial to trial information) have en-
sured that the study of the motor system remains as interesting and
important for anatomists, cognitive neuroscientists and clinicians as
it ever was.
Acknowledgment
HRS is supported by a Grant of Excellence “ContAct” from
Lundbeckfonden (R59 A5399). JBR is supported by the Wellcome
Trust (088324), the Medical Research Council (MC_US_A060_0001)
and the NIHR Cambridge Biomedical Research Centre.
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