Rapid Modulation of Distributed Brain Activity by Transcranial Magnetic Stimulation of Human Motor Cortex
Rapid modulation of distributed brain activity by Transcranial Magnetic Stimulation of human motor cortex
Lucy Lee 2
Hartwig Siebner 0 1
Sven Bestmann 2
0 Department of Neurology, Christian-Albrechts-University , Kiel , Germany
1 NeuroImageNord Kiel-Hamburg-Lu ̈ beck at Hamburg University Hospital , Hamburg , Germany
2 Wellcome Department of Imaging Neuroscience , 12 Queen Square, London, WC1N 3BG , UK
This paper reviews the effects of single and repetitive transcranial magnetic stimuli (rTMS) delivered to one cortical area and measured across distributed brain regions using electrophysiological measures (e.g. motor thresholds, motor evoked potentials, paired-pulse stimulation), functional neuroimaging (including EEG, PET and fMRI) and behavioural measures. Discussion is restricted to changes in excitability in the primary motor cortex and behaviour during motor tasks following transcranial magnetic stimulation delivered to primary motor and premotor areas. Trains of rTMS have lasting effects on the excitability of intrinsic and corticofugal neurones, altering the responsiveness of local and remote sites. These effects lead to distributed changes in synaptic activity at rest, and during a range of motor tasks. It is possible to impair or improve performance following rTMS, but for most simple motor tasks performance is unaltered. Changes in distributed activity observed with functional imaging during motor behaviour may represent compensatory activity, enabling maintenance of performance; stimulation of additional cortical areas appears to impair performance. A detailed understanding of the distributed changes in excitability following rTMS may facilitate future attempts to modulate motor behaviour in the healthy brain and for therapeutic purposes.
The aim of this paper is to provide an overview of
the effects of transcranial magnetic stimuli (TMS) in
areas remote from the site of stimulation. When
using a standard figure-of-eight coil the strength of the
magnetic field produced during a TMS pulse decreases
progressively with distance from the centre of the coil;
effective direct stimulation occurs in a limited area of
cortex close to the centre of the coil [
effects of TMS seen outside this area are thought to be
mediated by cortico-cortical and
cortico-subcorticalcortical connections. This review forms part of a series
of papers discussing the use of transcranial magnetic
stimulation (TMS) to disrupt the brain with the aim of
enhancing human cognitive abilities. The focus of this
paper will be restricted to studies of TMS in the
human motor system. Studies of the motor system offer
a unique opportunity to combine data from different
techniques in order to establish a more complete
characterisation of the interaction between local and remote
effects of TMS on excitability and behaviour.
The effects of TMS on the excitability of the
motor system can be assessed directly by measuring
motor evoked potentials (MEPs) or indirectly by
functional neuroimaging (e.g. positron emission
tomography (PET), functional magnetic resonance imaging
(fMRI), electroencephalography (EEG)) and measures
of motor behaviour (e.g. force generation, movement
velocity, movement accuracy, reaction times, response
accuracy, sequence learning). Each of these methods
has strengths and weaknesses. Electrophysiological
techniques provide a direct, objective measure of
cortical and/or corticospinal excitability. The first
section introduces methods available for assessing the
excitability of the motor system, and reviews studies
using such techniques to demonstrate that TMS delivered
to one area of the motor system alters the
excitability of a remote area. These methods use the size of
the motor evoked response to characterise changes in
corticomotor excitability. However, it is only possible
to obtain direct measures of excitability from primary
motor cortex and to examine changes in the
responsiveness of the primary motor cortex to inputs from
distant motor areas. It is not possible to assess the
excitability of sub-cortical structures, neither is it
possible examine the effects of changes in the excitability
of primary motor cortex on other areas. Functional
neuroimaging enables the characterisation of TMS
effects on synaptic activity throughout the brain, both at
rest and during task performance. However, functional
neuroimaging does not provide a direct measure of
excitability. The role of functional neuroimaging in
evaluating the distributed effects of focal TMS is discussed
in section two. Perhaps most importantly in the
context of improving brain function neither directly
measured changes in cortical excitability nor changes in
synaptic activity measured with functional
neuroimaging necessarily translate into improvements or
impairments of task performance. Behavioural correlates of
motor function, such as changes in reaction times,
performance accuracy, and rate of learning can provide
this information. However, there are several
potential problems with the interpretation of changes or the
lack of changes in such outcome measures. These are
discussed in section three.
The results of studies using a combination of the
methods outlined above are discussed in section four.
Studies of the motor system offer a unique
opportunity to examine the effects of TMS because
electrophysiological, metabolic and behavioural measures can
readily be combined. Examining the relationships
between distributed changes in activity caused by TMS
and changes in task-related activity during periods of
abnormal cortical/subcortical excitability reveal
interesting features of the motor system. Specifically, the
motor system appears to be able to adapt quickly to
TMS induced changes in the excitability and effective
connectivity of the areas engaged in a motor task,
maintaining task performance. This may explain why
attempts to impair or improve motor performance with
TMS have had limited success, and to point to future
directions of research that may be more successful.
These issues are addressed in section five.
2. Measuring and modulating the excitability of the motor cortex and corticospinal tract with TMS
TMS can be used in a variety of ways to measure
the excitability of the motor cortex and corticospinal
tract. Several comprehensive reviews describe the
different techniques and their biophysical and
physiological mechanisms [
In brief, the motor threshold (MT) describes the
lowest intensity of TMS that can elicit a motor evoked
potential of approximately 50 µV. This is thought to reflect
neuronal membrane excitability because it is increased
by drugs that alter membrane conductance [
can be measured in resting or activated muscles (RMT
and AMT respectively). The RMT represents the
intensity of stimulation required to activate cortico-spinal
neurones, and therefore it is assumed that stimulation
at or above the RMT will also activate cortico-cortical
]. Given the focus of this review on
distributed effects of TMS, we will use the RMT to
define the threshold of stimulation delivered in the
studies described below. Subthreshold stimulation refers
to stimulation given below RMT, whereas
suprathreshold describes stimuli at intensities at or above RMT
i.e. eliciting muscle twitches.
The amplitude of the motor evoked potential (MEP)
elicited from a peripheral muscle represents a measure
of the excitability of the cortex, sub-cortex and spinal
tract. The silent period (SP) describes a short
cessation of muscle activity when a single pulse of TMS
is delivered during voluntary muscle contraction. The
duration of the late phase of the SP provides a measure
of the excitability of cortical inhibitory interneurons
(presumably GABAb-ergic) [
Further characterisation of cortical excitability can
be obtained with paired-pulse TMS using a
conditioning-test paradigm. The most frequently used
paired-pulse paradigm [
] gives a subthreshold
conditioning stimulus to condition the MEP amplitude
elicited by a subsequent suprathreshold test stimulus.
At inter-stimulus intervals (ISIs) of 1–5 ms the
amplitude of the test MEP is inhibited (intracortical
inhibition: ICI), and at longer ISIs (8–30 ms) the response is
facilitated (intracortical facilitation: ICF). These
phenomena appear to occur in the cortex [
GABA agonists and glutamatergic antagonists increase
ICI and decrease ICF whereas drugs that alter
membrane conductance have no effect [
2.1. Intra-hemispheric effects of TMS
The most rapid modulation of cortical excitability by
TMS occurs within milliseconds of stimulation. Using
a variation of the paired-pulse techniques described
above Civardi et al.  demonstrated that at an ISI
of 6 ms stimulation of the premotor (PM) cortex (3–
5 cm anterior to the motor hand area) with sub- and
suprathreshold conditioning stimuli lead to inhibition
and facilitation of the amplitude of MEPs elicited from
the ipsilateral cortex hand area, respectively.
Modulating the excitability of the premotor cortex
with rTMS can induce more enduring changes in the
excitability of the ipsilateral primary motor cortex (M1).
1 Hz rTMS to M1 and dorsal premotor cortex (PMd)
reduces the amplitude of MEPs elicited from M1 [
]. 5 Hz rTMS to M1 and PMd increases the
amplitude of MEPs elicited from M1 [
]. The direction
of distributed changes in cortical excitability appears to
be frequency-dependent (see Fig. 1) and the direction
of effects on MEP amplitude appears to be similar for
M1 and PMd stimulation. However, other measures
of corticocortical excitability such as paired-pulse
excitability may not follow such a straightforward
relationship. For example, subthreshold 1 Hz rTMS to PMd
increases ICF at 7 ms for up to one hour  whereas
subthreshold 5 Hz rTMS decreases ICF in M1 .
Conversely, subthreshold 1 Hz rTMS to M1 decreases
] whereas 5 Hz rTMS to M1 decreases ICI but
does not affect ICF [
2.2. Inter-hemispheric effects of TMS
Stimulation of the primary motor cortex has
immediate effects on the excitability on distributed brain
areas, the most readily measured of which being the
contralateral homologous motor cortex. Cracco et al. 
first demonstrated TMS-evoked transcallosal responses
and Ferbert et al.  subsequently showed that
conditioning stimuli delivered to one motor cortex
inhibited MEPs elicited from the contralateral motor
cortex 5–6 ms later. Lower intensity conditioning
stimuli to motor and ventral premotor cortices also inhibit
contralateral test MEPs and somatosensory evoked
potentials (SEPs)s . Other studies report inhibitory
interactions between homologous primary motor hand
areas whereby silent periods are induced in tonically
active muscles ipsilateral to the site of stimulation [48,
49]. Subtle facilitatory interactions have been reported
between the primary motor hand areas at ISIs (4–5 ms)
with inhibition occurring at longer ISIs [
]. For a
more complete review of this area see Chen et al. .
rTMS to the primary motor cortex can alter the
excitability of the contralateral motor cortex, and the
magnitude of interhemispheric effects, for longer periods
of time. Recent studies have shown opposing effects
of 1 Hz rTMS on the excitability of the stimulated and
contralateral hemispheres. Suprathreshold 1 Hz rTMS
decreased MEP amplitude in the stimulated hemisphere
while decreasing intracortical inhibition [
increasing the slope of MEP recruitment curves [
the contralateral hemisphere. Gilio et al. [
increased MEP amplitudes in the contralateral
hemisphere and a reduction of the early phase of
pairedpulse inhibition from the stimulated (conditioned) to
the non-stimulated (test) hemisphere. Using a series
of control experiments, these authors concluded that
these effects were predominantly mediated by
corticocortical circuits rather than spinal mechanisms or
afferent feedback. A comparison of 0.5 Hz and 5 Hz
subthreshold rTMS on the excitability of the contralateral
hemisphere revealed increased MEP amplitude with
5 Hz rTMS, but no change with 0.5 Hz [
The exact mechanisms of interhemispheric effects
of TMS are incompletely understood. Direct
transcallosal projections between the motor representations of
the hand are sparse [
] but rTMS to the primary
motor cortex undoubtedly results in a range of lasting
changes in the excitability of distributed brain areas that
is mediated via direct corticocortical  or
corticosubcortical-cortico pathways [
3. Measuring the effects of TMS on synaptic activity
The techniques outlined in Section 1 only
monitor excitability changes in the primary motor cortex
or changes in the responsiveness of the primary
motor cortex to inputs from distant motor areas.
Functional neuroimaging enables the visualisation of TMS
effects on synaptic activity throughout the brain, both
at rest and during task performance. However, it does
not provide a direct measure of excitability.
Electroencephalography (EEG) measures mean postsynaptic
potentials in the neocortex. EEG data can be analysed
to provide information about local changes in
postsynaptic potentials during a specific event (event related
potentials: ERPs), amplitude changes in defined
frequency bands (power spectra analysis) and changes in
the phase consistency between pairs of signals in each
frequency band (coherence analysis). Local changes
in frequency band amplitude can occur during
cognitive tasks, providing information about local cortical
activity; changes in coherence between distributed
cortical areas provide a measure of interactions within a
network of areas .
Imaging techniques such as positron emission
tomography (PET) and the blood oxygen level
dependent (BOLD) signal acquired in functional magnetic
resonance imaging (fMRI) provide indirect measures
of neuronal activity. These techniques rely on the
coupling between increased synaptic activity and
increased oxygen and glucose consumption (rCMR-glc,
measured with [18F] FDG-PET); and subsequent
increases in cerebral blood flow (CBF) (measured with
H125O PET and BOLD fMRI). Although a relationship
between neuronal activity, metabolic rate and blood
flow undoubtedly exists, the specific details are far from
clear. For reviews on the subject see Raichle,
Bonvento et al. and Logothetis and Wandell [
Neuroimaging measures appear to be convincingly coupled
with synaptic activity and therefore enable the
investigation of remote cortical and subcortical influences
of TMS. Changes in local field potential are correlated
with increased CBF, implying that local processing of
inputs is the driving force for changes in cortical
haemodynamics and hence the BOLD signal [
]. By contrast, increases in neuronal firing rate may
not be the best predictor for increases in either rCBF or
Areas where activity is altered by TMS can be
identified in a number of ways. Using PET or SPECT a
simple contrast of pre and post rTMS sessions can be
used to identify areas where synaptic activity has
increased or decreased as a result of rTMS with the
subject at rest. Alternatively, linear contrasts can be used
to identify areas where activity was increased (or
decreased) by rTMS and is returning to a baseline level
of activity over the time course of the scanning session.
It is also possible to use a factorial design to explore
interactions between the effects of rTMS on resting
synaptic activity and task-related activity by
comparing changes in task-related activity (movement minus
baseline) between pre and post rTMS sessions. When
using fMRI to explore the enduring effects of rTMS it
is only possible to use this third category of experiment
design because of the confounding effects of different
sessions on mean activity. The three design categories
yield complementary information about the effects of
rTMS on synaptic activity.
It is important to establish a ‘proof of principle’,
demonstrating that it is possible to detect local effects of
TMS at subthreshold intensities. Subthreshold TMS
alters the responsiveness of the cortex to subsequent
stimuli; therefore it should be possible to detect changes in
synaptic activity using imaging techniques. The use of
suprathreshold TMS in the motor system is more
problematic because, by definition, suprathreshold stimuli
will cause movement and therefore re-afferent feedback
will contribute to any changes seen at the site of
stimulation. Recording EEG activity over the whole cortex
Ilmoniemi et al. [
] showed that single subthreshold
TMS pulses elicited an immediate increase in local
activity, spreading to adjacent ipsilateral motor and
premotor areas within 3–10 ms, and to the homologous
contralateral M1 within 20 ms. Using H125O PET
Siebner et al. [
] found frequency dependent changes in
regional cerebral blood flow (rCBF) restricted the site
of stimulation (M1) during short trains of subthreshold
stimulation (1–5 Hz rTMS). Takano et al. (2004) report
increases in rCBF at the site of stimulation (M1)
following short trains of subthreshold 5 Hz rTMS. The
magnitude of the rCBF changes correlated with changes in
paired-pulse excitability, suggesting that rCBF is
sensitive to changes in excitability measured using direct
techniques. Given that it is possible to measure local
effects of TMS with functional imaging techniques, we
can now examine distributed effects. These are
discussed in two categories: immediate effects of single
pulse and repetitive TMS measured during stimulation
and enduring effects of rTMS measured after
ing short trains of sub- and suprathreshold rTMS at a
range of frequencies (3, 4, and 10 Hz) using three
different field strengths (1.5 T, 2 T and 3 T). No changes
in BOLD signal were observed at the site of
stimulation with subthreshold 4 Hz rTMS at 1.5 T [
] or 3 Hz
rTMS at 3 T [
]. In both studies local BOLD
signal changes occurred only with suprathreshold stimuli.
Distributed increases in BOLD signal were seen during
both sub- and suprathreshold rTMS trains in the
supplementary motor area (SMA) and premotor cortices, and
decreases in BOLD signal were seen in the contralateral
M1. Localised subcortical activations were observed
in the putative motor thalamic nuclei and basal
ganglia. Simultaneous recordings of electromyographic
activity confirmed that these were not caused by covert
peripheral muscle movements [
] see Fig. 2. At 2 T
no BOLD signal changes were seen in M1 or
premotor cortex with subthreshold stimulation to M1 (10 Hz
rTMS) or suprathreshold stimulation to premotor
cortex, whereas BOLD signal changes were detected in
M1 during suprathreshold stimulation and voluntary
finger movement. BOLD signal changes were seen
in the SMA and premotor cortex with suprathreshold
]. These functional neuroimaging studies
demonstrate that short subthreshold stimulus trains are
able to evoke distributed changes within cortical and
subcortical motor structures.
A further examination of the effects of intensity
(subto suprathreshold) with 1 Hz rTMS [
increases in rCBF (measured with H215O PET) at site of
stimulation (M1), contralateral cerebellum and in
bilateral sub-cortical structures. The data presented in this
paper suggest a non-linear relationship between
intensity and rCBF at the site of stimulation: subthreshold
stimulation appears not to evoke a significant increase
in rCBF; whereas suprathreshold stimulation does.
3.1. Immediate effects of TMS measured with
3.2. Enduring effects of rTMS measured with functional imaging
Using ERP and spectral analysis techniques Paus et
] demonstrated that single suprathreshold pulses
of TMS led to distinctive local ERP waveforms (P30
and N45) and brief periods of increased activity in the
beta range (15–30 Hz) at the site of stimulation. A
series of technically challenging experiments [
report increases in BOLD signal in the stimulated M1
measured in the MRI scanner during 1 Hz rTMS at
suprathreshold intensities, and in the stimulated and
contralateral M1 in response to single TMS pulses.
Several studies have investigated BOLD responses
durDifferent frequencies of rTMS delivered to primary
and premotor cortices can alter the excitability of
distributed brain areas. Suprathreshold 1 Hz rTMS to
left M1 lead to increased rCBF during stimulation that
slowly decreased in magnitude after cessation of
stimulation. Positive correlations with the rCBF changes
at the site of stimulation were seen in the ipsilateral
sensory and premotor areas and contralateral SMA
while negative correlations were seen in contralateral
M1 . Subthreshold 5 Hz rTMS to M1 induced
lasting increases in synaptic activity (measured using
[18F] FDG-PET) at the site of stimulation and the SMA,
with increased rCMR-glc also observed in contralateral
Comparing the effects of subthreshold rTMS 1 Hz
to M1 and premotor cortex Chouinard et al. 
correlated changes in MEP amplitude with changes in rCBF.
Following 1 Hz rTMS to M1 positive correlations with
decreased MEP amplitude were seen in the contralateral
M1, ipsilateral cerebellum, cingulate motor area and
sub-cortical structures. Following subthreshold 1 Hz
rTMS to left premotor cortex widespread positive
correlations with decreased MEP amplitude were seen
bilaterally in the ventral premotor areas, cingulate motor
areas, subcortical structures and a range of prefrontal
and parietal regions. The authors inferred that areas
showing parallel changes in rCBF with MEP amplitude
are likely to be anatomically connected to site of
stimulation (based on the macaque literature). It is also of
note that 1 Hz rTMS to primary and premotor cortex
had similar effects on MEP amplitudes, but that there
was minimal spatial overlap between observed changes
Lee et al. [
] and Siebner et al. [
] examined the
effects of subthreshold 1 Hz rTMS to M1 and PMd
respectively, using the same experimental paradigm.
In both experiments, changes in rCBF were detected
that lasted for at least one hour after the end of
stimulation. The different stimulation sites lead to
profound differences in the direction and location of rCBF
changes: M1 stimulation lead to bilateral increases in
rCBF in primary and premotor areas and the
cerebellum, whereas PMd stimulation lead to widespread
bilateral decreases in rCBF in premotor, prefrontal,
primary motor and subcortical areas.
In the first published work using fMRI to examine the
enduring effects of rTMS Tegenthoff et al. [
correlated the effects of 5 Hz rTMS (delivered to left primary
sensory cortex prior to scanning) on tactile
discrimination thresholds of the right index finger (measured in a
separate experimental session), and cortical activity
induced by electrical stimulation of the right index finger,
suggesting that 5 Hz rTMS results in an expansion of
the index-finger representation in the primary sensory
cortex that may be related to the improvement in tactile
Functional neuroimaging does not consistently
detect changes in synaptic activity at the site of
stimulation following subthreshold stimulation; even at
intensities which are known, from electrophysiological data,
to affect excitability. This may reflect the incomplete
characterisation of the relationship between changes
in neuronal activity, cortical excitability and metabolic
measures of synaptic activity, and is worthy of further
investigation. The majority of studies report changes in
regions that are known to be connected with the site of
stimulation (based on the animal literature) and which
are known from other functional imaging studies to be
involved in motor tasks. Even in the absence of
motor behaviour, changes are seen throughout the motor
The results outlined in Sections 1 and 2 confirm that
the two approaches to measuring changes in activity
and excitability provide complementary information.
Changes in excitability or synaptic efficacy determined
using direct measures, i.e., changes in MEP amplitude
do not have a straightforward relationship with
measures of synaptic activity, measured with functional
imaging. Moreover, neither method provides any
information about the functional relevance of these
alterations in synaptic activity and efficacy. For this it is
necessary to use measures of motor performance.
4. Changes in motor behaviour
TMS can be used to disrupt or enhance motor
performance in two modes: an acute disruptive mode
(singlepulse or short trains of high-frequency rTMS) or a
conditioning mode (prolonged trains of rTMS).
Acute disruptive effects of premotor TMS have been
studied in a series of experiments using simple and
choice reaction tasks [
]. An asymmetry in
premotor contribution to task performance was demonstrated:
TMS to left premotor cortex at short, but not long,
cuestimulus intervals increased reaction times for right and
left handed responses in a choice reaction time task;
whereas TMS to right premotor cortex only increased
reaction times for left handed responses. During
simple reaction time tasks, TMS did not affect reaction
times. The effects of TMS on motor performance
depend on the timing and location of TMS and the type
of task being performed. The disruptive effect of TMS
may also occur by affecting task related activity in a
connected area. Meyer and Voss  showed that
appropriately timed suprathreshold stimuli to the primary
motor hand area can delay ballistic hand movements
performed with the ipsilateral hand.
TMS delivered during motor behaviour may fail to
show any effect of task performance. The area
stimulated may not be uniquely involved in a particular
aspect of the task being tested or other areas can
compensate for the TMS induced disruption. Alternatively,
the stimulated area may be crucial for task performance
but stimulation parameters are inadequate to produce a
substantial perturbation (e.g., intensity too weak,
suboptimal coil orientation) or the timing of the stimulus is
incorrect, i.e., the area is stimulated at a time when it is
not participating in the task. These factors complicate
the interpretation of null results.
Prolonged trains of rTMS can be used to alter motor
behaviour by inducing lasting changes in the
responsiveness of the stimulated cortex and connected areas.
Lasting modulation of motor performance by rTMS
conditioning also requires stimulation of an area
involved in task performance. However, modulating the
excitability of the primary motor cortex, known from
imaging and primate experiments to be active across a
huge range of motor tasks, has met with limited success
in altering task performance. Despite the well
documented effects of 1 Hz rTMS on the excitability of
corticomotor projections [
impairment of manual motor control by 1 Hz rTMS has been
convincingly demonstrated during simple motor tasks,
e.g., paced fist clench [
], finger tapping [
generation of freely selected movement sequences ,
maintenance of tonic contraction [
] peak force and
acceleration during finger pinch . 1 Hz rTMS to
the premotor cortex has also failed to impair finger
tapping and generation of freely selected movement
Recent work has revealed effects of rTMS on more
demanding motor behaviour. Subthreshold 1 Hz rTMS
to M1 decreased finger tapping rates when subjects
were asked to tap as fast as possible with their right
(dominant) hand and in tapping rates for both hands
when tapping at subjects’ fastest comfortable pace [
Subthreshold 1 Hz to left motor and premotor cortices
increased reaction times in a ‘masked prime’ task [
In both studies, the authors infer that the tasks used
were harder than those reported in previous work;
leading to deficits in motor performance. This suggests that
the motor system may be able to compensate, to some
extent, for changes in cortical excitability during simple
tasks, but not during more demanding behaviour. This
concept of compensatory changes in response to
alterations in motor excitability is discussed in Sections 4
Suprathreshold 1 Hz rTMS impairs early
consolidation of motor learning using a simple ballistic
movement task [
]. An additional motor learning
experiment showed that the same rTMS protocol did not
disrupt learning of a dynamic force field [
two studies serve to emphasise that the effects of rTMS
conditioning on motor behaviour can be extremely task
1 Hz rTMS appears to have opposite effects on the
excitability of the stimulated and non-stimulated
primary motor cortex which leads to differences in the
effect on motor performance, specifically, an
improvement in performance of a sequential key-pressing task
with the hand ipsilateral to the stimulated hemisphere,
and no change in performance with the hand
contralateral to the site of stimulation [
]. The authors
postulate that this may be due to a ‘release’ from the
transcallosal inhibition imposed by the stimulated
hemisphere. Differential effects of ipsilateral and
contralateral TMS pulses can also be seen during motor
]. Subjects were required to make repetitive
thumb movements in the opposite direction to
movements induced by TMS. Single pulses of subthreshold
TMS were delivered to the primary motor cortex
contralateral or ipsilateral to the moving hand during
training. TMS pulses delivered contralateral to the
moving hand, synchronously with the movements
significantly enhanced the motor memory developed by the
training period whereas TMS pulses delivered to the
primary motor cortex ipsilateral to the moving hand
lead to a failure to encode the motor memory seen with
training alone (see Fig. 3). The authors postulate that
synchronous TMS pulses delivered to contralateral M1
may enhance training by enhancing Hebbian plasticity;
whereas TMS delivered to the ipsilateral M1 may
enhance interhemispheric inhibition, thus decreasing the
potential for training induced plasticity.
5. Combining functional measures of performance with measures of excitability and synaptic activity
In the motor system, it is possible to investigate
changes in synaptic activity during task performance to
assess how known changes in excitability affect
movement related activity and connectivity. Chen et al. 
used simple paced finger tapping and tonic contraction
to examine the effects of subthreshold 0.9 Hz rTMS to
premotor cortex on task-related EEG-power and EMG
coherence. Decreases in power in the alpha and beta
bands during the tasks were seen prior to rTMS; these
were reduced for prolonged periods after stimulation.
Increased task-related coherence was seen among
cortical motor areas in upper alpha band frequencies; and
decreased cortico-muscular coherence. Following rTMS,
changes in spectral power at rest were restricted to the
lower alpha-band. The authors infer that rTMS to the
premotor cortex suppressed activation of motor areas
during voluntary movement and suggest that transient
reorganisation of movement-related activity in motor
areas may occur.
Following subthreshold 1 Hz rTMS to primary
motor cortex changes in EEG spectral power and
coherence are seen: increases in EEG coherence between the
motor and premotor areas ipsilateral to the site of
stimulation, and increased coherence between the
stimulated and contralateral primary motor areas in the alpha
band during tonic contraction but not during rest [
Using the same protocol, short trains of subthreshold
5 Hz rTMS to M1 causes decreased intrahemispheric
EEG coherence in the alpha band between motor and
premotor cortices ipsilateral to the site of stimulation.
These changes were seen during tonic contraction, but
not at rest . These opposite effects of excitatory
(5 Hz) and inhibitory (1 Hz) rTMS on alpha-band
coherence agree with electrophysiological data
demonstrating differing effects of 1 Hz and 5 Hz rTMS on
local and distributed cortical excitability [
because increases in alpha-band coherence are indicative
of increased inhibitory activity, and decreases in
alphaband coherence are an indicator of reduced inhibitory
activity (i.e. increased excitability).
Lee et al. [
] examined the effects of subthreshold
1 Hz rTMS delivered to Left M1 using PET. Following
rTMS, task-dependent increases in rCBF (during
movement of the right hand) were seen in the left primary
motor cortex deep in the central sulcus (ipsilateral to the
site of stimulation) and the dorsal premotor cortex in
the contralateral hemisphere, with no change in motor
performance. Additional analyses of effective
connectivity suggest that after rTMS there is a re-modelling
of the motor system, with increased movement-related
connectivity from the SMA and premotor cortex to the
sites in primary sensorimotor cortex that are unlikely
to have been affected by rTMS (see Fig. 4).
Operational remapping of motor representations [
], recruitment of additional motor areas (Fig. 4) [
and task related changes in cortico-cortical [
] and cortico-muscular  coherence may
reflect compensatory changes in the motor system
enabling maintenance of task performance during
rTMSinduced changes in excitability. Mapping these
patterns of reorganisation in the motor system may provide
a useful method to study acute compensatory plasticity
of the human brain and may help to understand how
the brain reacts in response to more permanent lesions.
However, in order to confirm that the changes in motor
activity during movement after rTMS are functionally
relevant (i.e. to distinguish compensatory changes from
rTMS perturbations with no behavioural consequences)
it is necessary to combine studies such as those
described in this section with the approaches described in
Section 3. This approach has already had some
success with studies of stroke patients, where functional
imaging has been used to identify cortical areas with
increased activity during movement and TMS has then
been used to stimulate these areas during movement to
test the functional relevance of the increased activity.
In this way it has been shown that disrupting
activity in the contralesional premotor  and ipsilesional
] and premotor [
] cortices impairs motor
performance in stroke patients. Strens et al. [
a finger tapping task requiring precise force
generation to show that stimulating either the primary
motor cortex contralateral or ipsilateral to the hand
performing the task with short trains of subthreshold 5 Hz
rTMS had very limited effects on task performance;
whereas stimulating both primary motor cortices
simultaneously had a marked, prolonged, detrimental effect
on finger tapping performance (see Fig. 5). The authors
Fig. 5. Cumulative effects of simultaneous ipsilateral and
contralateral rTMS on finger tapping. Average cumulative sum (n = 7) of
the percentage difference in peak force compared to baseline (effects
of occipital stimulation subtracted). The tapping force became
inappropriately elevated after rTMS was delivered to LM1 from 8 s (95%
confidence limits 1–21 s) to 51 s (43–63 s) after rTMS. RM1
stimulation did not elicit any significant change, and the algebraic sum
of the effects of rTMS over the contralateral and ipsilateral motor
cortices (LM1 + RM1) had the same onset and duration as the effect
of contralateral stimulation alone. The effect of simultaneous
bilateral stimulation of both motor cortices began during stimulation and
continued until 86 s (69–102 s) after rTMS. Used with permission
from Strens et al. 2004 [
suggest that when one primary motor cortex is acutely
disrupted during motor performance, the other motor
cortex provides functionally significant compensation
i.e. that there is inherent redundancy in motor control
systems. This suggests that the changes in
movementrelated activity following longer trains of rTMS
reported in other studies may also represent
functionally significant compensatory activity, although this
remains to be formally tested.
6. Improving and impairing motor function with TMS
The work reviewed in Sections 3 and 4 shows that
the effects of TMS on excitability and synaptic activity
reviewed in Sections 1 and 2 are more likely not to
change motor behaviour than to impair or improve task
performance. The findings of combined studies of
motor behaviour and functional neuroimaging reviewed in
Section 4 reveal potential mechanisms by which the
motor system may be able to compensate for
excitability changes and maintain performance during simple
tasks. The work of Strens et al. [
] suggests that
simultaneous stimulation of multiple areas engaged in
task performance, drawn from neuroimaging studies of
movement-related changes, may provide a more
effective method of impairing motor function with rTMS.
An important factor to consider when looking for
improvements in motor performance after modulation
of cortical excitability is ‘ceiling’ effects. If some
studies of motor behaviour following rTMS fail to detect
impaired performance because the tasks are too
simple; it may be equally difficult to detect improvements
in performance if subjects are performing ‘perfectly’
prior to an intervention. It is necessary to use tasks, or
subjects, with scope for improvement.
The effects of TMS on motor behaviour may be
more readily observed in groups of subjects with
compromised cortical function. For example, patients
with focal dystonia have abnormal cortical
] and show abnormal rCBF changes following
]. In these subjects rTMS has been shown to
normalise cortical excitability and improve motor
]. As outlined in Section 4, stroke patients
appear to have increased susceptibility to the acute
disruptive effects of TMS during motor tasks [
Changes in motor behaviour can themselves alter the
excitability of the motor cortex . In addition, it has
also been shown in humans [
] and animals [
intensive motor training alters the efficacy with which
subsequent conditioning paradigms modulate cortical
excitability in the circuits engaged in motor learning.
The work of Butefisch et al. [
] suggests that the
reverse may also apply, i.e., modulation of a specific
cortical circuit affects the rate and degree of change of
Kobayashi et al. [
] highlight another potential
method of improving motor function in healthy and
abnormal brains. These researchers stimulated a motor
area not directly involved in the task, reducing the
impact of the stimulated area on the core areas involved in
task performance. This suggests that more subtle,
indirect approaches that aim to alter the balance of
interactions among brain areas may be effective at
improving function, and underlines the fact that researchers
should be careful when selecting ‘control regions’ for
TMS experiments in order to avoid selecting areas that
may have an influence on the site of primary interest.
Within the motor system the availability of direct
measures of cortical excitability, such as interhemispheric
inhibition, can guide such interventions.
One final method of increasing the impact of rTMS
on motor behaviour would be to increase the impact of
stimulation on cortical excitability. Pre-conditioning
or priming the motor cortex with transcranial direct
current stimulation enhances the duration and efficacy
of 1 Hz rTMS on cortical excitability [
the motor cortex with subthreshold 6 Hz rTMS
significantly increases the duration and amount of cortical
depression induced by suprathreshold 1 Hz rTMS. When
two sessions of 1 Hz rTMS are delivered to the
premotor cortex on consecutive days the effects on motor
excitability have a longer duration [
]. This suggests
that the distributed effects of premotor stimulation are
not restricted to an immediate modulation of motor
excitability, but creates a “motor memory” which primes
the responsiveness of the cortex to a second session of
rTMS. While none of these studies examined the
effects of the various interventions on motor behaviour,
it is possible that paradigms with profound and
consistent electrophysiological effects may produce more
consistent and readily detectable behavioural effects.
Single transcranial magnetic stimuli delivered to a
discrete cortical area can alter the responsiveness of a
remote site for a period of several hundred
milliseconds. The direction of the change in responsiveness
(facilitation or inhibition) depends on the timing and
intensity of the conditioning and test stimuli. Changes
in excitability on such short timescales are a valuable
method of discerning the relationship between
activity in distinct cortical areas (such as homologous
primary motor cortices) in the healthy brain, in disorders
of abnormal cortical excitability (e.g. dystonia) and
after brain injury, such as stroke. They are unlikely to
represent a clinically relevant method of modulating
brain activity to improve function. Trains of repetitive
transcranial magnetic stimuli have more enduring
effects on the responsiveness of local and remote sites.
The direction of change in responsiveness in distributed
brain regions may differ from the changes seen at the
site of stimulation; thus altering the relationship among
neuronal activities in the affected areas.
The enduring changes in responsiveness induced by
rTMS lead to changes in the pattern of distributed
synaptic activity at rest, and during a range of motor
tasks. For some types of motor behaviour it has been
possible to impair or improve performance following
rTMS, but for most simple tasks performance is
unaltered. It is therefore possible that changes in
distributed activity observed with functional
neuroimaging during motor behaviour may represent
compensatory activity, enabling maintenance of performance.
Stimulation of additional cortical areas in order to
disrupt compensatory activity appears to impair
performance. Future attempts to modulate motor behaviour
with rTMS should consider the widespread changes in
synaptic activity, the possibility that this may represent
functionally significant plasticity within the motor
system and the potential benefits of indirect stimulation of
areas involved in task performance or the use of
stimulation protocols that enhance the efficacy of subsequent
This work was supported by the Wellcome Trust (LL,
SB) and the Volkswagenstiftung (HRS).
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Computatio nal and Mathematical Methods
Medicine Cellular Longevity and
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