Contribution of transcranial magnetic stimulation to the understanding of cortical

mechanisms involved in motor control

Janine Reis, Orlando B. Swayne, Yves Vandermeeren, Mickael Camus, Michael A.

Dimyan, Michelle Harris-Love, Monica A. Perez, Patrick Ragert, John C. Rothwell and
Leonardo G. Cohen

J. Physiol. 2008;586;325-351; originally published online Nov 1, 2007;

DOI: 10.1113/jphysiol.2007.144824

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J Physiol 586.2 (2008) pp 325–351 325

TOPICAL REVIEW

Contribution of transcranial magnetic stimulation to the

understanding of cortical mechanisms involved in motor
control
Janine Reis1 , Orlando B. Swayne1,2 , Yves Vandermeeren1 , Mickael Camus1 , Michael A. Dimyan1 ,
Michelle Harris-Love1 , Monica A. Perez1 , Patrick Ragert1 , John C. Rothwell2 and Leonardo G. Cohen1
1
Human Cortical Physiology and Stroke Neurorehabilitation Section, National Institute of Health, National Institute of Neurological Disorders
and Stroke, 10 Center Drive, Bethesda, MD 20892, USA
2
Sobell Department of Motor Neuroscience, Institute of Neurology, 8–11 Queen Square, London WC1N 3BG, UK

Transcranial magnetic stimulation (TMS) was initially used to evaluate the integrity of the
corticospinal tract in humans non-invasively. Since these early studies, the development
of paired-pulse and repetitive TMS protocols allowed investigators to explore inhibitory
and excitatory interactions of various motor and non-motor cortical regions within and
across cerebral hemispheres. These applications have provided insight into the intracortical
physiological processes underlying the functional role of different brain regions in various
cognitive processes, motor control in health and disease and neuroplastic changes during
recovery of function after brain lesions. Used in combination with neuroimaging tools, TMS
provides valuable information on functional connectivity between different brain regions, and
on the relationship between physiological processes and the anatomical configuration of specific
brain areas and connected pathways. More recently, there has been increasing interest in the
extent to which these physiological processes are modulated depending on the behavioural
setting. The purpose of this paper is (a) to present an up-to-date review of the available electro-
physiological data and the impact on our understanding of human motor behaviour and (b)
to discuss some of the gaps in our present knowledge as well as future directions of research
in a format accessible to new students and/or investigators. Finally, areas of uncertainty and
limitations in the interpretation of TMS studies are discussed in some detail.
(Received 11 September 2007; accepted after revision 30 October 2007; first published online 1 November 2007)
Corresponding author L. G. Cohen: Human Cortical Physiology Section, National Institute of Health, National Institute
of Neurological Disorders and Stroke, 10 Center Drive, Bldg 10, Rm 5 N226, Bethesda, MD 20892, USA.
Email: [email protected]

Introduction (TMS) pulse delivered to M1. The MEP amplitude elicited

by stimulation of M1 can be modulated by a preceding
Recent work on electrophysiology of non-invasive brain
conditioning pulse delivered either to the same cortical
stimulation has contributed to identifying physiologically
area or elsewhere, allowing the exploration of intra- and
active interactions between different cortical regions in
inter–regional physiological interactions in real time.
awake, healthy human subjects. The cortical motor output
Detailed study of the corticofugal discharge in response
has been studied in particular detail, as the output of the
to a motor cortical stimulus by Amassian et al. (1989)
primary motor cortex (M1) can be objectively measured
revealed multiple components of the MEP. These can be
in the form of a motor evoked potential (MEP). Using
observed either by epidural recordings or by measuring
surface electromyographic (EMG) recording electrodes,
single motor unit recordings with needle electrodes, and
most commonly positioned on the skin overlying the hand
consist of a short latency direct wave (D-wave) followed
muscles, a compound MEP can be elicited in response to
by several longer latency indirect waves (I-waves). The
a single suprathreshold transcranial magnetic stimulation
D-wave is thought to result from direct depolarisation
of the initial axon segment of the corticospinal neuron
J. Reis and O. B. Swayne contributed equally to this work. and is most effectively activated in human subjects by


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326 J. Reis and others J Physiol 586.2

transcranial electrical stimulation or high intensity TMS. Resting and activity-dependent interactions between
The I-waves following the d-wave occur sequentially with M1 and other regions or afferents are grouped into intra-
a periodicity of approximately 1.5 ms, reflecting the delay hemispheric (within M1), interhemispheric (M1 to M1)
required for synaptic discharge. Thus, the first I-wave (I1 ) and interregional (e.g. premotor cortex or cerebellum to
is thought to be generated through the depolarisation of M1). For the sake of simplicity, these interactions are
an axon synapsing directly onto a corticospinal neuron separated into inhibitory and excitatory, but it should
(i.e. monosynaptically), while following I-waves (I2 and be kept in mind that they are likely to overlap to some
later) may require local polysynaptic circuits. I-waves can extent, such that what is measured represents a net
be elicited using relatively low TMS intensities in humans effect. Separating such influences often requires subtle
and are thus readily amenable to study. manipulations of stimulus parameters. A summary of the
The last few years have seen a flurry of investigations into net interregional influences to be considered is provided in
inter-regional physiological interactions linking M1 with Fig. 1.
other ipsilateral and contralateral motor regions, parietal
cortex, cerebellum and sensory afferents. A new picture of
M1 is gradually emerging in which its role is considerably Intrahemispheric interactions within M1
greater than that of the passive servant of higher order The interactions within M1 that are currently known to
motor regions – rather, M1 may be seen as performing a modulate its output are illustrated in Fig. 2.
complex integration of multiregional influences that result
in purposeful motor behaviour. Some of the mechanisms
involved in this process are now better understood, but Facilitation within M1. Facilitatory interactions
many questions remain unanswered. occurring locally within M1 can be studied by delivering
The first aim of this review is to update the reader on two TMS pulses through the same coil (or two over-
this rapidly changing subject, highlighting in the process lapping coils targeting the same cortical area), referred
the gaps in current knowledge. The second aim is to to generically as paired-pulse TMS. This approach has
assist investigators by illustrating the electrophysiological revealed two categories of local facilitation.
interactions tested with TMS that may influence goal Intracortical facilitation (ICF) of a test MEP can be
specific motor behaviour in humans. elicited at interstimulus intervals (ISIs) of 6–25 ms, using
Because of the very extensive literature on TMS, a subthreshold conditioning stimulus (CS) to influence
we chose to review in this paper electrophysiological the response to a subsequent suprathreshold test stimulus
interactions tested with TMS in particular detail, rather (TS). This effect was first described by Kujirai et al. (1993)
than extensively reviewing work on the use of TMS to in a now classic paper reporting facilitation of the test MEP
induce a ‘virtual lesion’, only partially discussed, or on the at intervals of 10–15 ms. Facilitation becomes stronger
interactions of TMS with other techniques like EEG, MEG with increasing CS intensity (Kujirai et al. 1993), but tends
and MRI. to be weaker with increasing TS intensity (Daskalakis et al.

Figure 1. Summary of inter-regional influences on

the primary motor cortex
The currently described influences of other brain areas
on the output of the primary motor cortex (M1) are
shown. Open arrows denote facilitation, while filled
arrows denote inhibition. In many cases the influence
shown represents a net effect of several specific
interactions, whose details are discussed in the relevant
section of the text and are shown in subsequent figures.
These influences include projections from motor areas in
the ipsi- and contralateral hemispheres and the effects
of afferent sensory input. PMd = dorsal premotor
cortex; PMv = ventral premotor cortex; SMA =
supplementary motor area; PPC = posterior parietal
cortex; CBL = cerebellum; THAL = thalamus; PNS =
peripheral nervous system.


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J Physiol 586.2 TMS and motor control 327

2004). The question arises as to whether ICF may be merely the CS in this context was supported by the findings that
a ‘rebound’ phenomenon from the robust inhibition the CS intensity required to elicit this effect was below the
described by these authors at shorter interstimulus threshold for producing an MEP and that spinal H-reflexes
intervals (see below) or whether it represents a separate were unaffected. This was investigated further by studying
phenomenon. Ziemann et al. (1996c) demonstrated that the effect of the CS on descending volleys recorded in
short interval intracortical inhibition (SICI) occurs at cervical epidural electrodes. This approach demonstrated
lower CS intensities than ICF, becoming stronger with facilitation of the late I-waves at an interstimulus
increasing intensities. Furthermore the two phenomena interval of 25 ms, suggesting a synaptic interaction within
behave differently depending on the current direction M1 (Nakamura et al. 1997). However, a recent study by Di
of conditioning and test pulses: while inhibition can be Lazzaro et al. (2006) examined cervical descending volleys
elicited regardless of the direction of current flow, reliable in more detail: while facilitation of late I-waves was again
ICF requires a conditioning stimulus to be induced in a seen at 25 ms, no changes in the amplitudes or number
postero-anterior (PA) direction. The authors concluded of I-waves were seen at 10 and 15 ms, despite facilitation
that separate neuronal populations were likely to mediate of the compound MEP. This raises the possibility that
intracortical inhibition and facilitation (Ziemann et al. facilitation at these shorter intervals may be mediated by
1996c). A cortical (rather than spinal) site of action of subtle changes in spinal excitability. However, in the same

Figure 2. Interactions within the primary motor cortex

Intracortical interactions believed to modulate the output of the primary motor cortex (M1) are shown. Each
element represents a separate neuronal population within M1. Facilitatory and inhibitory populations are shown as
open and filled elements, respectively. This layout forms the ‘common basis’ onto which interregional influences (in
following figures) are superimposed. I1 and ‘late I-waves’ represent the populations responsible for generating the
earliest and later I-waves (respectively) in response to transcranial magnetic stimulation. These are shown here in
series, reflecting the temporal sequence following stimulation, but this does not necessarily reflect their anatomy.
Short and long interval intracortical inhibition (SICI and LICI) and intracortical facilitation (ICF) at an interstimulus
interval of 25 ms are believed to modulate the later I-waves. Short interval intracortical facilitation (SICF) enhances
both early and later components of the I-wave. ICF at 10–15 ms is shown as a dotted line, as there is uncertainty
regarding relative cortical and spinal contributions.


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328 J. Reis and others J Physiol 586.2

study, test MEPs generated by delivering an electrical TS stimulus, CS) (Ziemann et al. 1998c), or alternatively when
directly to cervical epidural electrodes were not facilitated two stimuli near motor threshold are given consecutively
by a magnetic cortical CS, making such a spinal inter- (Tokimura et al. 1996). Using this approach, facilitation
action unlikely. An alternative and more likely possibility can be demonstrated at three distinct ISIs after the first
is that any additional corticospinal discharge produced in stimulus: 1.1–1.5, 2.3–2.9 and 4.1–4.4 ms. If S2 is fixed at
the presence of a CS is temporally dispersed, and thus not 90% of resting motor threshold (RMT) and the intensity
apparent in the mean I-wave traces. Thus, while ICF at of S1 is gradually increased, the first facilitatory peak is
25 ms appears likely to have a cortical origin, the site of observed with an S1 of 70% RMT: further increasing
facilitation at 10–25 ms is less clear. the intensity of S1 produces second and third peaks at
Excitatory glutamatergic interneurons within M1 approximately 90% and 100%, respectively, with latencies
and N -methyl-d-aspartate (NMDA) receptors appear that shorten with increasing S1 intensity. This effect is
to influence ICF (Ziemann, 2003). NMDA antagonists absent if S1 precedes a transcranial electric (instead of
have been shown in two separate studies to abolish magnetic) S2, implying a cortical site of such facilitation,
(dextromethorphan) or even reverse (memantine) ICF and it was proposed that the three facilitatory peaks
measured at 10 or 15 ms (Ziemann et al. 1998a; observed reflect the generation of subsequent I-waves by
Schwenkreis et al. 1999). This issue has been clouded S1 (Tokimura et al. 1996; Ziemann et al. 1998c). This was
somewhat by the demonstration that ICF is unaffected demonstrated conclusively for the earliest such peak by
by the non-competitive NMDA antagonist ketamine, showing similar effects in the descending volleys generated
given at a subanaesthetic dose (Di Lazzaro et al. 2003). by such stimuli in cervical epidural electrodes (DiLazzaro
However, while ketamine is thought to reduce trans- et al. 1999). A study of the precise timings of these
mission at NMDA receptors, it is also believed to increase interactions and their relation to stimulus intensity shed
glutamate release and transmission at AMPA synapses. light on the contrast between this phenomenon and that
Furthermore, the increase in unconditioned test MEP mediating inhibition at similar intervals. If S1 < S2 (with
amplitude after ketamine makes the lack of effect on ICF S1 subthreshold and S2 suprathreshold) inhibition occurs
difficult to interpret. ICF is also thought to be modulated mainly in the I3 -wave. By contrast, if S1 = S2 or S1 > S2
by GABAA activity, since it is reduced by the GABAA agonist (with S1 suprathreshold), facilitation occurs, but this is
lorazepam and abolished by ethanol, which potentiates primarily in the I2 (or even I1 ) wave latency range. Thus
GABA-mediated currents (Ziemann et al. 1995, 1996b; the facilitation appears to take place one I-wave cycle earlier
Ziemann, 2004). This is consistent with the idea that the than the inhibition. Ilic and colleagues have proposed that
inhibition of I3 waves that is responsible for short interval this is because after a suprathreshold S1 the excitatory
inhibition (SICI – see below) may persist as late as 20 ms interneurons mediating the later I-waves are still hyper-
after the CS (Hanajima et al. 1998). Thus the phenomenon excitable at the time of the earlier I-waves resulting from
of ICF is likely to be influenced by glutamatergic facilitation S2 (Ilic et al. 2002). Thus, while SICI and ICF are mediated
tempered by persisting GABAergic inhibition. via a trans-synaptic action on excitatory interneurons,
The interactions between ICF and other physiological SICF may instead involve a direct action on the initial
processes have not been explored extensively. Ziemann axon segment of these excitatory interneurons (Ilic et al.
et al. (1996c) demonstrated in a triple pulse TMS protocol 2002).
that SICI and ICF can be shown to interact in an The effects of SICF are suppressed in the period
approximately linear relation, e.g. strong SICI might following a peripheral sensory stimulus, suggesting
abolish ICF, further supporting a different origin for these an inhibitory interaction between afferent inputs and
two processes. In another triple pulse TMS protocol, ICF the interneuron populations responsible for I-wave
tested in M1 in the setting of cerebello-M1 inhibition generation. There is also a suppression of ICF in this
(described below) appears to be enhanced (Daskalakis context, but this occurs at lower CS intensities than for
et al. 2004). However, a within-group correlation analysis SICF (Zittel et al. 2006), reinforcing the hypothesis of
suggested that this is likely to be due to a reduction in the different mechanisms for these two phenomena.
SICI component rather than an increase in the excitatory
component (tested at 10 ms), making a direct interaction
with the excitatory population unlikely. Inhibition within M1. Two principal types of local
A different kind of facilitatory interaction can be intracortical inhibition can be studied using paired pulse
demonstrated within M1 over shorter interstimulus TMS. Short interval intracortical inhibition (SICI) was
intervals. This short interval intracortical facilitation first described by Kujirai et al. (1993) and can be elicited
(SICF, also known as I-wave facilitation) occurs when by a subthreshold CS followed by supra threshold TS.
a suprathreshold stimulus (S1, in this case considered At interstimulus intervals (ISIs) of 1–6 ms the test motor
as the test stimulus, TS) is followed by a subthreshold response is inhibited by the conditioning shock. Two main
stimulus (S2, in this case considered as the conditioning phases of inhibition have been described, at ISIs of 1 ms


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J Physiol 586.2 TMS and motor control 329

and 2.5 ms (Fisher et al. 2002; Roshan et al. 2003). Based at ISIs of approximately 50–200 ms (Valls-Sole et al. 1992;
on indirect evidence such as the lack of change in spinal Wassermann et al. 1996) – thus two MEPs are elicited,
reflexes, Kujirai et al. (1993) originally suggested that SICI of which the second is smaller in amplitude. Previous
was the result of synaptic interactions occurring within evidence has suggested that LICI at ISIs longer than
M1. A later study used direct recordings of descending 50 ms is mediated within M1 rather than subcortical
spinal cord volleys to confirm that the initial I1 -wave was structures (Nakamura et al. 1997). Although this evidence
suppressed by the CS, indicating that SICI seems to be supports the view that LICI is related to reduced cortico-
mediated at the cortical level (Nakamura et al. 1997). An fugal excitability, it still remains unclear whether the
important limitation of this study was that the intensity of same population of neurons mediates LICI and SICI.
the CS was relatively large, raising the possibility that the Pharmacological studies suggest that LICI is mediated
CS alone could depolarize the axon, causing subsequent by GABAB receptors (Werhahn et al. 1999; McDonnell
refractoriness during TS delivery. Therefore, it was not et al. 2006) while SICI is primarily mediated by GABAA
until 1998 that Di Lazzaro and collaborators provided the receptors (Ziemann, 2003). Nevertheless, the involvement
first direct evidence that SICI originated at the cortical of different receptor subtypes does not in itself exclude
level (DiLazzaro et al. 1998). In their study, a subthreshold the possibility of a shared neuronal population mediating
CS suppressed the size of both the descending spinal these two inhibitory phenomena.
cord volleys and the MEP evoked by the suprathreshold Recent studies have shown that SICI and LICI
TS. Inhibition of the descending spinal volleys was most interact with each other. SICI increases with higher test
pronounced at an ISI of 1 ms and disappeared by 5 ms. MEP amplitudes, while LICI decreases with higher test
This inhibition was evident for all later I-waves but not MEP amplitudes (Chen & Curra, 2004). These findings
the I1 -wave. Pharmacological studies have continued to suggest that motor cortical neurons recruited at low TS
provide more detailed information about the mechanisms intensities are more susceptible to LICI than to SICI, while
of SICI. It has been shown that GABAA agonists enhance those recruited at higher intensities appear to be more
SICI (Ziemann et al. 1996a; Ilic et al. 2002). However, a susceptible to SICI than LICI. On this basis, it is likely that
single dose of the GABAA antagonist flumazenil did not different populations of inhibitory interneurons mediate
alter SICI, suggesting that there might be no tonic activity LICI and SICI. In addition, previous evidence has shown
at the benzodiazepine binding site of the GABAA receptor that SICI is reduced in the presence of LICI at matched
in the normal human M1 (Jung et al. 2004). It has also size of test MEP amplitude and test stimulus intensity,
become apparent that inhibition at the short ISI of 1 ms suggesting an inhibitory effect of LICI on SICI (Chen &
does not depend on GABAA , while ‘true’ SICI at an ISI of Curra, 2004). While most studies of SICI and ICF have
2.5 ms is likely to be mediated by GABAergic inhibition been implemented using distal hand muscles, it has been
at the intracortical level (Fisher et al. 2002; Roshan et al. shown that relatively similar phenomena occur also in
2003), supporting the point of view that they are mediated more proximal arm representations as well (Chen et al.
by different mechanisms. Previously, Fisher et al. (2002) 1998).
proposed that SICI at an ISI of 1 ms may be due to
refractoriness or changes in axonal excitability of excitatory Interhemispheric interactions (M1–M1)
interneurons. In this scenario the subthreshold CS would
convey excitatory interneurons into the refractory state, The interhemispheric interactions between homologous
leading to less impact of the TS reflected as inhibition. M1s currently described, and their relationships to
Thus, with increasing TS intensity less inhibition would intracortical processes, are illustrated in Fig. 3.
be expected, as the TS would activate more non-refractory
interneurons. However, the fact that SICI at 1 ms increases Interhemispheric facilitation between primary motor
with TS intensity at rest and decreases with voluntary cortices. Transcallosal projections between the two M1
muscle contraction (Roshan et al. 2003) argues against hand areas are known to exist in monkeys (Jenny,
simple axonal refractoriness. In addition, a recent study 1979). That such projections can convey information
showed that SICI at an ISI of 1 and 2.5 ms decreased to between the hemispheres is suggested by the detection of
a similar extent during the cortical silent period (CSP) evoked potentials over M1 following electrical or magnetic
(Ni et al. 2007). Since the CSP is unlikely to affect stimulation of the contralateral M1, both in animal models
axonal refractoriness, a synaptic mechanism is very likely and in humans (Hanajima et al. 2001; Chowdhury &
responsible for SICI at 1 ms ISI. Matsunami, 2002). Using a paired pulse TMS technique
While SICI can be considered as a well-characterised with one coil over each M1 hand area, Ferbert et al.
‘standard’ TMS parameter, much less is known about (1992) investigated interactions between the two M1s.
the inhibitory phenomenon occurring at longer inter- While inhibition was their most striking finding (see
stimulus intervals. Long interval intracortical inhibition below), they also described a facilitation occurring in
(LICI) is elicited by a suprathreshold CS and TS applied some subjects, at shorter ISIs, which was ‘capricious’


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330 J. Reis and others J Physiol 586.2

and poorly reproducible. This phenomenon was further using an electrical CS (inducing a contralateral d-wave)
investigated by Hanajima et al. (2001), who found that such and it was originally suggested that corticospinal discharge
interhemispheric facilitation (IHF) is reliably obtainable may be necessary for IHF to occur, whether mediated
under particular conditions. Small test MEPs were by axon collaterals of pyramidal cells or by a separate
used (approximately 0.3 mV) with slight tonic voluntary neural population. However, further investigation of IHF
contraction of the right FDI (ipsilateral to the site of at low CS intensities makes this conclusion unlikely.
the conditioning stimulus) maintained throughout, and Baumer et al. (2006) demonstrated reliable IHF at rest
facilitation occurred only with a TS delivered such that the following a conditioning stimulus to M1 at two very
induced current is in an antero-posterior (AP) direction, subthreshold intensities. At 60% of active motor threshold,
suggesting that it primarily affects the I3 -wave generators. IHF occurred at an interval of 6 ms, with the TS current in
The ISI required for facilitation was 4–5 ms, but allowing a postero-anterior (PA) direction (unlike Hanajima et al.).
for the time taken to generate I3 waves in the target hemi- At 80% of AMT, IHF occurred at 6–8 ms ISI, with the
sphere, this implies a facilitatory interaction approximately TS current in an antero-posterior (AP) direction. The
10 ms after the CS. Facilitation only occurred following a I-wave components of the test pulse affected in these
CS of relatively low intensity (5–10% above active motor two conditions are likely to be predominantly I1 and I3 ,
threshold (AMT)) given with the induced current in a respectively. The authors suggested that the longer ISIs
medial direction. A similar effect could also be produced could be explained by the activation of slower-conducting

Figure 3. Interhemispheric interactions between primary motor cortices

Interhemispheric inhibition and facilitation (IHI and IHF) at the interstimulus intervals shown are illustrated, along
with their interactions with local intracortical circuits where known. Open arrows denote facilitation, while filled
arrows denote inhibition. Thus IHI is shown as mediated by a facilitatory transcallosal population synapsing onto
a local inhibitory population. IHI10 (shown here as the second interhemispheric interaction from the top) can be
conditioned by short or long interval intracortical inhibition (SICI and LICI) in the conditioning hemisphere, and
itself suppresses SICI in the target hemisphere. IHI40 (shown as the top-most interaction) may share a common
inhibitory effector population with LICI. Of the interactions described, only IHF at 6 ms is thought to modulate the
early I-waves, while the others affect later I-waves. Of the facilitatory interhemispheric interactions shown, IHI6
requires a test stimulus with current flow in an anterior direction, while IHI6–8 requires a posterior current.


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J Physiol 586.2 TMS and motor control 331

fibres at these lower CS intensities, and that at higher neurons (Gerloff et al. 1998; Daskalakis et al. 2002); (2)
intensities such facilitation may have been overwhelmed both require a suprathreshold CS (Kujirai et al. 1993;
by concomitant inhibition. In cats the cortical area of the Daskalakis et al. 2002; Chen et al. 2003); and (3) both
distal forelimb has an excitatory transcallosal connection inhibit SICI in the receiving hemisphere (Sanger et al.
to the homologous motor cortex, but this is surrounded by 2001; Chen, 2004). However, a third phenomenon, long
a larger area of inhibition (Sanuma & Okuda, 1962). It may afferent inhibition (LAI – discussed below), helps to shed
be that the relatively poor spatial resolution of TMS means more light on the relationship between IHI and LICI. It is
that this robust surround inhibition predominates in most known that LAI directly inhibits LICI (Sailer et al. 2002;
circumstances. The role of this form of interhemispheric Chen, 2004). Kukaswadia et al. (2005) found that LAI also
facilitation in motor control of bilateral arm movements directly inhibits IHI40 . They therefore concluded that LICI
remains to be determined (Swinnen et al. 1993; Whitall is probably more closely related to IHI40 than to IHI10 .
et al. 2000; Schambra et al. 2003; Luft et al. 2004; Duque This idea is consistent with the finding that IHI8 decreases
et al. 2005). with voluntary muscle activation (Chen et al. 2003), while
IHI40 (Chen et al. 2003) and LICI (Valls-Sole et al. 1992;
Wassermann et al. 1996) both show little change. Thus
Interhemispheric inhibition between primary motor
far, the differential effects of LICI on IHI40 versus IHI10 in
cortices. In contrast to interhemispheric facilitation,
the target hemisphere have not yet to our knowledge been
interhemispheric inhibition (IHI) is more robust and
tested directly. The relationships between SICI and IHI40
occurs over a wide range of ISIs (6–50 ms) (Ferbert
versus IHI10 have likewise not been directly compared (in
et al. 1992; Daskalakis et al. 2002). This form of
fact, little is known regarding the relationship between SICI
inhibition is lacking in patients with ischaemic lesions
and IHI40 ). However, it is known that IHI10 inhibits SICI
affecting transcallosal populations, supporting the idea
in the target hemisphere and is decreased in the presence
that this phenomenon is mediated via the corpus callosum
of LAI (Kukaswadia et al. 2005). This occurs only under
(Boroojerdi et al. 1996). Emerging evidence suggests
certain conditions and, more importantly, the amount of
that IHI elicited at relatively short ISIs (e.g. 8–10 ms)
decrease in IHI10 is not related to the strength of LAI or
is mediated by different mechanisms than that elicited
IHI10 . Thus, LAI probably does not inhibit IHI10 directly,
at longer intervals (e.g. 40 ms). Therefore short (IHI10 )
but both may act on a similar neuronal population (Gilio
and long (IHI40 ) interval IHI will be discussed separately.
et al. 2003). In contrast, LAI strongly inhibits IHI40 , in
Other than the ISI, the stimulation parameters required
most cases changing inhibition to facilitation, and the
to elicit IHI10 and IHI40 are similar. Both require a
decrease in IHI40 is directly related to the strength of LAI
suprathreshold CS and TS intensity adequate to elicit
(Kukaswadia et al. 2005). Therefore, LAI and IHI40 seem
an MEP of 0.5–1.5 mV in amplitude (Kukaswadia et al.
to show a direct inhibitory interaction, with LAI inhibiting
2005). Both are also believed to be dependent on
IHI40 .
GABAB -mediated neurotransmission in the target hemi-
sphere (IHI10 : Daskalakis et al. 2002; Kukaswadia et al.
2005; IHI40 : Kukaswadia et al. 2005). This was confirmed
for long latency IHI by a recent study of pharmacological Interactions within the conditioning hemisphere. The
modulation by GABA agonists: IHI at ISIs of up to 200 ms above studies describe intracortical interactions with IHI
was strengthened after application of the GABAB agonist within the target hemisphere. A recent study has examined
baclofen, suggesting that long interval IHI is most likely the effects of such intracortical interactions within the
mediated by postsynaptic GABAB receptors (Irlbacher et al. conditioning hemisphere on IHI targeting the contra-
2007). lateral hemisphere (Lee et al. 2007). IHI10 and IHI40
were elicited with the CS in the presence or absence
of SICI, LICI or ICF (with stimulus intensities adjusted
to maintain MEP amplitudes). Both forms of IHI were
Interactions within the target hemisphere
suppressed in the presence of SICI or LICI but were
Evidence for differing mechanisms of IHI at these two unaffected by ICF. This last result could be interpreted
ISIs comes primarily from studies of their interactions as suggesting that the corticospinal output and the
with other inhibitory phenomena. A number of studies transcallosal projections mediating IHI arise from
have examined the interactions of such phenomena with different neuronal populations. However, this conclusion
IHI within the ‘target’ hemisphere (i.e. that receiving should be guarded in view of the recent data casting doubt
the inhibition), and it has been suggested that LICI and on the cortical site of ICF’s action (Di Lazzaro et al. 2006).
IHI40 may be mediated by an overlapping population of Moreover, in a separate study the effect of SICF within
inhibitory neurons. As nicely reviewed by Kukaswadia the conditioning hemisphere on IHI40 (but not IHI10 )
et al. (2005) the evidence for this is three-fold: (1) both was examined (Avanzino et al. 2007). IHI was enhanced
parameters preferentially affect lower threshold M1 inter- by SICF at identical latencies to the facilitation of the


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332 J. Reis and others J Physiol 586.2

contralateral MEP (1.5 ms and 3.0 ms, coinciding with Two main approaches have been taken to investigating
the I1 and I2 waves, respectively), suggesting that circuits PMd’s influence on its ipsilateral M1. The first involves
modulating transcallosal and corticospinal projections applying repetitive TMS (rTMS) to PMd, using a protocol
have at least similar properties. The fact that IHI10 and known to up- or down-regulate cortical excitability,
IHI40 are affected similarly by SICI, LICI and ICF (Lee and afterwards assessing motor cortical excitability
et al. 2007) raises the possibility that a shared population in M1 with single pulse TMS. An rTMS protocol
may convey each form of inhibition across the corpus used to produce a transient reduction in excitability,
callosum, with different target populations influenced applying subthreshold stimuli at 1 Hz, was applied to
at different latencies. However, the impact of SICI on PMd and resulted in a reduction of MEP amplitudes
IHI might depend on the intensity of the CS for SICI elicited from M1 (Gerschlager et al. 2001) but increased
(Kujirai et al. 1993), which was kept constant in the paired pulse excitability at a 7 ms ISI and shortened the
study. cortical silent period (Munchau et al. 2002). Conversely,
applying an rTMS protocol that increases cortical activity
Summary of interhemispheric M1–M1 interactions. As (5 Hz at 90% AMT) to PMd had the opposite effects: MEP
described above, the approach of paired pulse TMS amplitudes were increased and paired pulse excitability
between the two M1 hand areas has revealed at least at 7 ms ISI was reduced (Rizzo et al. 2004). Together,
three facilitatory and two inhibitory distinct interactions, these rTMS studies show that manipulations of PMd
depending on the parameters used (ISI, coil orientation excitability modulate M1 corticospinal excitability in a
and intensities of CS and TS). Facilitation or inhibition similar direction, suggesting at first glance a facilitatory
can even be produced at overlapping ISIs, depending influence of PMd on M1.
on the nature of the CS and TS, suggesting that such The second approach has employed two coils in a
interactions are likely to occur in parallel. With regard paired pulse protocol. Civardi et al. (2001) showed that a
to the cell populations involved, it is likely that even in subthreshold CS (defined by the M1 MEP threshold) over
the case of IHI the transcallosal projections are excitatory, PMd reduces the excitability of the ipsilateral M1, with
synapsing onto local inhibitory circuits within the target a maximum effect at an ISI of 6 ms – this ipsilateral
hemisphere. From such manipulation of physiological PMd–M1 inhibition requires a CS given at 90% of AMT
parameters as described above it is not possible to infer with antero-posterior current flow. The authors argued
whether the various phenomena are mediated by distinct that this interaction did indeed involve conditioning PMd
transcallosal populations or whether common projections rather than acting via current spread to M1, on the basis
are used with, for example, different coding characteristics. of spatial separation (conditioning at an intermediate
Consistent with these findings, it was reported that point produces no inhibition), temporal separation (a time
down-regulation of excitability of one motor cortex course that is distinct from SICI) and the effect of coil
modulates cortical excitability in the opposite M1 and orientation (Civardi et al. 2001). However, in addition
motor function in the ipsilateral hand in health (Schambra to this inhibitory interaction, facilitation could also be
et al. 2003; Kobayashi et al. 2004; Johansen-Berg et al. 2007) elicited if a higher conditioning intensity was used (120%
and disease (Ward & Cohen, 2004; Talelli et al. 2006; Fregni AMT).
& Pascual-Leone, 2006). Mochizuki et al. (2004a) applied a similar paired pulse
approach to investigate the interhemispheric interaction
between PMd and the contralateral M1. At ISIs between
Inter-regional interactions 4 and 20 ms (with a CS to the right PMd and a TS
to the left M1), they found significant inhibition of the
The inter-regional cortico–cortical interactions currently test MEP using a CS intensity of either 90% RMT (with
described that are known to modulate the output of M1 an ISI of 8 ms) or 110% RMT (ISI of 8–10 ms). This
(excluding M1-to-M1) are illustrated in Fig. 4. interhemispheric PMd–M1 inhibition is spatially specific
for PMd (as not detected when stimulating 2 cm anterior,
Interactions between non-primary and primary motor lateral or medial to the target area) but not for the
areas. M1–PMd interactions. Non-primary motor hemisphere (Baumer et al. 2006). Stimulation of the left
areas are also capable of influencing motor cortical PMd and right M1 revealed the same results (Baumer
output including the ventral and dorsal premotor et al. 2006; Koch et al. 2006). This interaction can be
cortex, supplementary motor area and cingulate cortex distinguished from M1-to-M1 IHI at the 90% CS intensity
(Chouinard & Paus, 2006). The dorsal premotor cortex (on the basis of a lower threshold and differing effects
(PMd) has attracted particular attention in this regard of voluntary contraction) but this distinction is less
because of its recognised role in movement selection clear at the suprathreshold intensity. Interhemispheric
(Cisek & Kalaska, 2005) and its dense anatomical PMd–M1 inhibition has also been described at the longer
connection to M1 in monkeys (Ghosh & Porter, 1988). interstimulus interval of 150 ms, using a latero-medial CS


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J Physiol 586.2 TMS and motor control 333

at 110% of AMT (Mochizuki et al. 2004b), but at such with the intracortical circuits described above are not well
a long interval the effect cannot be assumed to be trans- known. The only study to directly address this question
mitted transcallosally. The effect of PMd stimulation on has been Mochizuki et al. (2004a), who showed that
the contralateral M1 seems to depend on the stimulation interhemispheric PMd–M1 inhibition was associated with
intensities used, as demonstrated recently by Baumer et al. a reduction in intracortical inhibition in the target
(2006). Conditioning the left PMd with low stimulus hemisphere (SICI at ISI of 2 ms).
intensity (80% of AMT) and targeting the right M1 (with M1–SMA interactions. The supplementary motor area
small test MEPs), interhemispheric PMd–M1 facilitation (SMA) is by contrast a more difficult area to target
was described at an ISI of 8 ms (Baumer et al. 2006). This than the lateral premotor cortex (PMd and PMv), as
facilitation was dependent on a postero-anterior current it is located in the interhemispheric fissure, relatively
flow for the TS, providing indirect evidence that this form unexposed on the surface of the hemisphere. TMS can
of facilitation preferentially affects I1 waves in the target reliably elicit MEPs from leg muscles by stimulating the
hemisphere. leg area of M1 adjacent to SMA (Gerloff et al. 1997; Perez
A mechanism proposed for these interregional effects et al. 2004). Stimulation of the SMA is therefore possible
is the activation of long distance projections from if cortical elements targeted by TMS have a threshold
the PMd to ipsi- or contralateral M1, consistent with comparable in the lower limb area of M1 and in the
anatomical studies showing dense connections between SMA. However, there are few electrophysiological studies
those areas, which are known to be both inhibitory and of SMA stimulation in healthy subjects. Civardi et al.
facilitatory (Ghosh & Porter, 1988; Tokuno & Nambu, (2001) found that a conditioning stimulus applied over
2000). Details of how these long-range projections interact the SMA, defined as a cortical area 3 cm anterior to the M1

Figure 4. Model of Inter-regional interactions of nonprimary cortical areas with M1

Interactions with M1 are shown of both ispi- and contralateral dorsal premotor cortices (PMd) and posterior parietal
cortices (PPC), and of ipsilateral supplementary motor area (SMA). Open arrows denote facilitation, while filled
arrows denote inhibition. Interactions with local intracortical circuits are shown where known, but for most only
a facilitatory or inhibitory influence has been demonstrated. Inter-regional projections are shown as facilitatory,
synapsing onto facilitatory or inhibitory local circuits, but this arrangement is not certain. The influence of the PMd
on either side is facilitatory or inhibitory depending crucially on the conditioning stimulus intensity used.


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334 J. Reis and others J Physiol 586.2

leg area (1–4 cm anterior to Cz), reduced the excitability and (2) repetitive peripheral nerve stimulation as a tool
of the ipsilateral M1 at an ISI of 6 ms, indicating that to elicit changes in cortical excitability (with or without
SMA stimulation is likely to lead to changes in activity implementing the paired-pulse technique).
in anatomically connected regions in a way similar to Activity in afferent pathways can condition
that seen after stimulation of PMd (Civardi et al. 2001). motor cortical excitability in a paired-pulse protocol
Matsunaga et al. (2005) used 5 Hz suprathreshold rTMS (summarised in Fig. 5). For example, a conditionings
(110% AMT) over the SMA to investigate the effects on electrical stimulus applied to a mixed nerve (most often
ipsilateral M1 excitability. Stimulation increased the MEP the median or digital nerve at the wrist) has an inhibitory
amplitudes (as for PMd), but in this case SICI/SICF was effect on motor cortex excitability. These effects, more
unchanged as were cortical silent period and H-reflexes. evident at ISIs of 20 ms and 200 ms, are described as
Thus an inhibitory interaction is suggested by the paired short- (SAI) and long-latency afferent inhibition (LAI),
pulse approach (Civardi et al. 2001), whereas excitatory respectively (Tokimura et al. 2000).
rTMS appears to cause facilitation (Matsunaga et al. Many experiments have confirmed that the M1 hand
2005). area receives short latency input from peripheral receptors
(Friedman & Jones, 1981; Darian-Smith & Darian-Smith,
1993). The most direct evidence that somatosensory
Posterior parietal cortex (PPC). The two coil paired-pulse
input modulates the motor output at a cortical level in
approach has recently also revealed a facilitatory humans comes from recordings of corticospinal volleys
interaction between the posterior parietal cortex (PPC, in patients with implanted electrodes in the cervical
defined as the P4 position on the 10–20 EEG system) epidural space (Tokimura et al. 2000). These showed that
and both the ipsilateral and contralateral M1 (Koch et al. I2 and I3 waves were reduced at an interval appropriate
2007). Significant facilitation of an MEP elicited from the for SAI, whereas the I1 wave remained unchanged at
ipsilateral M1 was observed at ISIs of 4 ms and 15 ms when any ISI. Similar findings were observed for mixed nerve
a CS of 90% RMT was used (postero-anterior current stimulation and digit nerve stimulation of separate fingers.
direction). This PPC–M1 facilitation was not seen at higher Based on these findings, it seems likely that reduced
or lower CS intensities, or with the opposite conditioning corticofugal output is the cause of the reduced MEPs.
coil orientation. Single motor unit recordings suggested However, whether the afferent input travels directly to M1
that PPC stimulation enhances the I3 -wave component of or proceeds via the primary somatosensory cortex (S1)
the test MEP, a finding that may explain the surprisingly is still under investigation. Pharmacological investigations
short ISI of 4 ms (as late I-waves may take as long as have revealed roles for both the cholinergic and GABAergic
7 ms to leave the motor cortex – Day et al. 1989). In systems in SAI. The anticholinergic drug scopolamine
addition to the ipsilateral effect, facilitation of MEPs reduces SAI (Di Lazzaro et al. 2000), which is also impaired
elicited from the contralateral M1 was also observed. in Alzheimer’s disease (Di Lazzaro et al. 2004). SAI shows
This was seen at a CS intensity of 90% RMT and ISIs dissociated responses to positive allosteric modulators of
of 6 ms and 12 ms. The precise anatomical pathways the GABA receptor, lorazepam and diazepam, becoming
mediating these effects are not known, and it may be that weaker with the former and stronger with the latter (Di
such facilitation involves parieto-premotor projections Lazzaro et al. 2005). Given that SAI may be seen as a
(which are known to be more numerous than direct marker of cholinergic function, it is interesting to consider
parieto-motor projections). An interesting feature of this that these two benzodiazepines are also dissociated with
effect is that, unlike premotor-M1 or M1–M1 interactions respect to their effects on memory function (profoundly
inhibition was not observed at any of the CS intensities impaired by lorazepam but not diazepam). Thus it may
tested. be that lorazepam reduces SAI via an effect on cholinergic
function.
Afferent input and somatosensory cortex. Although Indirect evidence for a cortical site of action of LAI
peripheral nerve stimulation provides a strong and originates from the finding that F-wave amplitudes remain
temporally precise afferent input, it stimulates a mixed unchanged at an ISI of 200 ms (Chen et al. 1999). As
population of nerve fibres, including muscle afferents, for SAI, it remains to be determined if this effect is
cutaneous afferents, joint afferents and motor efferents. mediated through direct somatosensory projections to M1
Hence, it is not surprising that studies of the effects or indirectly through the primary somatosensory cortex.
of peripheral nerve stimulation on cortical excitability As mentioned above, in the presence of LAI, both LICI
provide a set of heterogeneous results whose underlying and IHI40 are reduced (Sailer et al. 2002; Kukaswadia et al.
mechanisms and origin of the interactions are difficult to 2005).
interpret. Two different approaches are most frequently Similar results have been shown for cutaneous
used: (1) a paired-pulse protocol combining a peripheral stimulation of digital nerves. MEPs were inhibited when
and a cortical stimulus to study sensorimotor interactions, a TMS pulse was delivered 25–50 ms after homotopic


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J Physiol 586.2 TMS and motor control 335

stimulation of a digital nerve (Classen et al. 2000; consists of a peripheral stimulus (most often electrical
Tamburin et al. 2005). However, when the TMS pulse stimulation of the median nerve at the wrist) that is
preceded the cutaneous stimulus (ISI 16–22 ms) or if followed by a suprathreshold TMS stimulus to the
the ISI was longer than 50 ms (up to 200 ms) MEPs contralateral M1 targeting a muscle innervated by the
were facilitated. In a muscle heterotopic to the site of stimulated nerve.
the cutaneous stimulus a reversed pattern of MEP size The ISI is determined by the time lag in evoking an
was found. In the presence of a cutaneous stimulus MEP from M1 via activation of the primary somatosensory
applied ∼35 ms before a conditioning TMS pulse, a cortex (S1). The shorter the ISI for facilitatory PAS (shorter
reduction in SICI was described (Ridding & Rothwell, than 25 ms), the more likely later inputs to corticospinal
1999), suggesting that the afferent input provoked by the neurons are targeted by PAS, as the afferent input would
digital stimulus had a direct effect on circuits involved arrive after firing of the initial input (I1 input) produced
in intracortical inhibition, most likely as an interference by the TMS pulse. Thus, if the peripheral stimulus is
with later I-waves weakening the efficacy of the cortical given approximately at the N20 latency of a somatosensory
conditioning stimulus. evoked potential (SEP) plus ∼1–4 ms for the S1 to M1
Introduced by Stefan et al. (2000) another approach transit time (ISI of approximately 20–25 ms) an increase in
combines peripheral and low frequency cortical the conditioned MEP can be found, if the PAS procedure
stimulation in a repetitive, timing-specific pattern. is repeated for a period of ∼30 min (Stefan et al. 2000).
Resembling mechanisms of associative plasticity in Conversely, at even shorter ISIs, most often 10 ms, a
animal slice preparations by pairing pre- and postsynaptic decrease of cortical excitability as measured by a reduced
action potentials (Wigstrom et al. 1986; Markram et al. MEP size is found after repeated stimulation (Wolters et al.
1997), this paired associative stimulation (PAS) protocol 2003).

Figure 5. Influence of somatosensory afferent input on M1 excitability

The effects of long and short afferent inhibition (LAI and SAI) and of muscle vibration (VIBR) on M1 excitability
and on intracortical circuits are shown. Open arrows denote facilitation, while filled arrows denote inhibition. LAI
and SAI suppress late I-waves in the contralateral M1. Vibration increases M1 excitability but the effect on the
I-wave profile is not known. The effect of IHI from the opposite M1 is reduced in the presence of LAI. Muscle
vibration reduces SICI but increases LICI in the contralateral M1, while increasing IHI targeting the ipsilateral M1
(with increased SICI and reduced M1 excitability in that hemisphere).


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336 J. Reis and others J Physiol 586.2

In a relaxed muscle, the intensity of the peripheral 1–2 h immediately preceding the motor training period
stimulus and the TMS stimulus used for PAS need to be (Kaelin-Lang et al. 2005; Sawaki et al. 2006). Interestingly,
suprathreshold to induce long-lasting changes in cortical proprioceptive input originating in the training motions
excitability (Stefan et al. 2000; Wolters et al. 2003). The does not appear to be sufficient to elicit substantial changes
reason for this is still unclear, but it is thought that in cortical plasticity (Kaelin-Lang et al. 2005; Lotze et al.
associative plasticity requires either a certain amount 2003).
of synaptic activity or the neuronal population that is Another form of somatosensory input is provided
targeted by PAS might have high thresholds for activation. by low amplitude muscle vibration, which stimulates
Interestingly, weak voluntary muscle contraction further predominantly large Ia fibres and can mimic joint proprio-
enhances the after-effect of PAS compared to a resting ception (Burke et al. 1976), clearly influencing excitability
condition (Kujirai et al. 2006). Also, the direction of in somatosensory pathways (Cohen & Starr, 1985). If M1
the current flow in the brain following a subthreshold corticospinal excitability is tested using a TMS pulse after
TMS pulse significantly alters the effectiveness of this 1 s of hand muscle vibration, MEP amplitudes are found
procedure: tested during voluntary contraction, PAS using to increase in the vibrated muscle while decreasing in
subthreshold TMS with AP current flow and 25 ms ISI adjacent non-vibrated muscles (Rosenkranz & Rothwell,
is superior to PAS using subthreshold TMS with PA 2003). Although muscle vibration certainly alters spinal
current flow (Kujirai et al. 2006) in eliciting excitability excitability (Claus et al. 1988), there are associated changes
changes, presumably reflecting the later arrival of inputs in paired pulse TMS parameters which strongly suggest an
preferentially activated by AP pulses (I3 input; Di Lazzaro effect at the level of M1: SICI targeting the vibrated muscle
et al. 2001). is reduced, while LICI is enhanced (the converse changes
The after-effects of PAS are relatively long lasting are seen in surrounding muscles, Rosenkranz & Rothwell,
(duration up to 90 min) and have topographical specificity 2003). This muscle-specific surround inhibition suggests
(Stefan et al. 2000). Furthermore they can be abolished that the effects of proprioceptive input on M1 are more
by the application of the N -methyl-d-aspartate (NMDA) spatially specific at rest than those of cutaneous inputs,
receptor antagonist dextromethorphan (Stefan et al. 2002; which give rise to less exquisitely somatotopic changes
Wolters et al. 2003). Recently it was described that motor (Classen et al. 2000; Tamburin et al. 2001). Such a cortical
learning prior to PAS can also prevent induction of the change in response to muscle vibration is consistent with
LTP-like plasticity in M1 for several hours (Stefan et al. the observation in baboons that proprioceptive afferent
2006) suggesting the occlusion of further plastic changes input, unlike cutaneous input, projects directly to the
after maximized LTP following training. Conversely, motor cortex (Hore et al. 1976). Using a two-coil paired
Ziemann et al. (2004) found even greater reduction in pulse approach, it has been shown that vibration of a
cortical excitability following a PAS protocol that usually hand muscle is also associated with stronger IHI targeting
elicits LTD-like plasticity when it was preceded by motor the motor cortical representation of the contralateral
learning, supporting the idea that PAS exerts its action via homologous muscle, with increased SICI and reduced
LTP/LTD-like mechanisms. MEP amplitudes in that muscle (Swayne et al. 2006).
A modulation of cortical excitability can also be elicited Cutaneous anaesthesia of one hand increases MEP
by repetitive mixed peripheral nerve stimulation (PNS). amplitudes in muscles immediately proximal to the
Trains of five slightly suprathreshold pulses of 1 ms deafferented hand (Ziemann et al. 1998b; Brazil-Neto
duration delivered at 10 Hz for at least 1.5 h resulted in a et al. 1993) and in hand muscles in the unanaesthesized
somatotopically specific increase of MEPs only in muscles hand (Werhahn et al. 2002b) in the absence of excitability
innervated by the stimulated nerve (Ridding et al. 2000a; changes in other body part representations. This effect
Ridding & Taylor, 2001; Kaelin-Lang et al. 2002), outlasting was blocked by a positive modulator of the GABAA
the end of the stimulation by ∼20 min (Kaelin-Lang receptor, lorazepam. MEPs resulting from brainstem
et al. 2002). The somatotopy and the fact that MEPs and electrical stimulation remained unchanged suggesting that
maximal peripheral M-waves were not altered in response the effect is probably of cortical origin. Additionally, IHI
to electrical brainstem stimulation suggest a cortical site targeting the unanaesthesized hand muscles decreased
of action (Kaelin-Lang et al. 2002), consistent with the during the anaesthetic procedure (Werhahn et al. 2002b).
lack of alteration of F-waves (Ridding et al. 2000a). No These results were interpreted as indicative that acute
changes in motor thresholds (RMT and AMT), SICI and hand deafferentation can elicit a focal increase in cortical
ICF have been found after repetitive mixed PNS, but excitability in the hand motor representation contralateral
pharmacological blockage of the effect of PNS was seen to the deafferented cortex that is influenced by trans-
after administration of lorazepam, a positive allosteric callosal interactions and GABAergic neurotransmission.
modulator of the GABAA receptor (Kaelin-Lang et al. Interestingly, these effects appeared to rebalance in the
2002). PNS has also been shown to increase the beneficial setting of chronic deafferentation following amputations.
effects of motor training when applied for a period of In the somatosensory domain, cutaneous anaesthesia


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J Physiol 586.2 TMS and motor control 337

of one hand results in focal rapid improvements in modulate the motor cortical output is the cerebellum
tactile spatial acuity in the opposite hand that are (summarised in Fig. 6). Cerebello-cortical (CbC) inter-
accompanied by increased cortical SEP amplitudes elicited actions in humans were originally described by Ugawa
by stimulation of the unanaesthesised hand (Werhahn et al. (1995). They investigated how a CS over the
et al. 2002b). These results are consistent with the idea cerebellum influences the amplitude of an MEP elicited
that deafferentation of a cortical representation influences by a subsequent TS over the contralateral M1. Either an
the homotopic representation in the opposite hemi- electrical (Ugawa et al. 1991) or a magnetic cerebellar
sphere; perhaps supporting the unanaesthesised hand’s CS (Ugawa et al. 1995) resulted in a net suppression of
need to tackle enhanced environmental requirements, and corticomotor excitability at ISIs of 5–7 ms, as reflected in
is consistent with interhemispheric competition models of the decreased amplitude of MEPs elicited by a magnetic TS
sensory processing. It is of relevance that these principles over M1 (Ugawa et al. 1995). In contrast, CbC inhibition
appear to operate also after cortical lesions like stroke, was not observed when an electrical TS was applied
in which cutaneous anaesthesia of a healthy hand exerts over M1, suggesting an interaction upstream of the
beneficial effects on motor function of a paretic hand after corticospinal neurons. Inhibition of TMS-induced MEP
stroke in both motor and somatosensory domains (Floel in M1 by a magnetic cerebellar CS has been consistently
et al. 2004; Voller et al. 2005). replicated (Pinto & Chen, 2001; Daskalakis et al. 2004).
CbC inhibition can be best obtained with a double-cone
Cerebello-thalamo-cortical interactions. The most coil positioned 3–5 cm lateral to the inion, with the
distant brain area over which TMS has been shown to induced current flowing upward in the cerebellar cortex

Figure 6. Cerebello-thalamo-cortical interactions modulating M1 excitability

A magnetic stimulus over the cerebellar cortex (CX) suppresses excitability of the contralateral M1 in response
to a second stimulus. This interaction is shown here: open arrows denote facilitation, while filled arrows denote
inhibition. Stimulation is thought to activate inhibitory projections from the purkinje cells of the cortex (PURK)
to the dentate nucleus (DN), suppressing an excitatory projection to the ventrolateral thalamus (VL), and in
turn suppressing thalamocortical projections. Although M1 excitability is suppressed, short interval intracortical
inhibition (SICI) is decreased in this context. While intracortical facilitation (ICF) also appears to be increased, this
is thought to result from the reduced SICI rather than a change in facilitatory circuits.


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338 J. Reis and others J Physiol 586.2

(Meyer et al. 1994; Werhahn et al. 1996). The intensity of stimulation of the cerebellum. One should remark that the
the cerebellar CS is usually set at 5–10% below AMT for use of a flat figure-of-eight coil in these studies would
direct recruitment of the corticospinal tract at the level promote simultaneous activation of afferent peripheral
of the foramen magnum when the double-cone coil is nerve fibres in the brachial plexus (Ugawa et al. 1995;
placed over the inion (Werhahn et al. 1996). Werhahn et al. 1996) and therefore might lead to this
A truly cerebellar origin of the suppression of M1 evoked result. Thus, a specific inhibitory effect of rTMS on the
by a magnetic CS applied over the base of the skull has dentate-thalamo-cortical pathway has yet to be proven.
been challenged. Indeed, with a flat figure-of-eight coil, CbC inhibition is more pronounced for small test MEPs
a significant amount of such inhibition elicited at ISIs of (0.5 mV) elicited by slightly suprathreshold TS than for
7–9 ms results from the simultaneous activation of afferent large test MEPs (2 mV) (Ugawa et al. 1995; Pinto & Chen,
peripheral nerve fibres in the brachial plexus (Ugawa et al. 2001). This may reflect either a preferential inhibition
1995; Werhahn et al. 1996). This is supported by the of the neuronal elements generating the I1 wave (which
fact that 1 Hz rTMS over the right cerebellum results in have a lower threshold than the D-wave and later I-waves)
a reduction of MEPs elicited from the contralateral M1 or the fact that the dentato-thalamo-cortical pathway
that is comparable to the MEP reduction after 1 Hz rTMS projects predominantly to the core of cortical muscle
over the posterior neck area (Gerschlager et al. 2002). representations, where the motor threshold may be lower
However, when a double-cone coil is positioned over the (Pinto & Chen, 2001). The cell populations within M1
base of the skull for the CS, the suppression of MEP targeted by these projections are likely to include both
amplitudes in a paired-pulse protocol (CbC-M1) starts pyramidal cells and inhibitory interneurons (Shinoda et al.
at latencies similar to that of an electrical cerebellar CS, i.e. 1993; Daskalakis et al. 2004).
5 ms (Liepert et al. 2004; Battaglia et al. 2006). Moreover, CbC interactions with the intracortical populations
this MEP suppression is absent in patients with lesion of mediating SICI, ICF and LICI have been tested by
the cerebellar cortex or efferent cerebello-thalamo-cortical Daskalakis et al. (2004), who used a triple-pulse TMS
pathway, or when an electrical TS is applied over M1 protocol with small adjustments of the test MEP
(Ugawa et al. 1995). Therefore, the net suppression of M1 amplitudes. A magnetic cerebellar CS reduces SICI in
elicited at ISI 5 ms by a double-cone coil over the base of the opposite M1, most likely through reduced facilitatory
the skull has been attributed to genuine CbC inhibition. dentato-thalamo-cortical drive to intracortical inhibitory
As recently suggested by studies in patients with a variety interneurones. This reduction in SICI may shift the intra-
of strokes, the key cerebellar structures involved in CbC cortical balance of excitability toward excitation, leading
interactions elicited by a magnetic cerebellar CS are the to the observed increase in ICF. Finally, in the presence
superior cerebellum and the dentate nucleus (Liepert et al. of LICI, CbC inhibition is decreased. The mechanism of
2004; Battaglia et al. 2006). The dentate nucleus exerts a this interaction is unclear and could result either from a
background tonic facilitatory drive onto the contralateral saturation effect if LICI and CbC inhibition converge onto
M1 through synaptic relay in the ventral lateral thalamus. the same population of cortical inhibitory interneurons,
This dentato-thalamo-cortical pathway is one of the many or alternatively from changes in subcortical excitability.
cerebello-cortical loops that specifically link cerebellar and Further evidence for the presence of a tonic facilitatory
cortical areas through dedicated channels (Middleton & drive from the dentate-thalamo-cortical pathway onto M1
Strick, 2000; Dum et al. 2002; Ramnani, 2006). The activity in healthy humans is provided by studies in patients with
of the dentate nucleus is under the inhibitory control of cerebellar stroke or degeneration. These have consistently
the Purkinje cells, whose axons are the exclusive output of demonstrated an increased RMT in the contralateral M1
the cerebellar cortex. It has been proposed that a magnetic (as well as increased SICI and decreased ICF) (Liepert et al.
cerebellar CS activates the Purkinje cells; this results in 2004; Battaglia et al. 2006).
an inhibition of the dentate nucleus that leads in turn to a
disfacilitation of the contralateral M1, due to a reduction in
dentato-thalamo-cortical facilitatory drive (Pinto & Chen,
Interrupting tonic contraction: silent periods
2001; Daskalakis et al. 2004). However, this is still under
debate as the short ISIs of ∼5 ms to elicit inhibition of Contralateral silent period. In a voluntarily contracted
the dentate nuclei would necessitate an extremely fast muscle, the MEP elicited by a single suprathreshold TMS
inhibitory system. Moreover, data from rTMS studies over pulse is followed by a period of EMG inhibition called
the cerebellum inconclusively showed a reduction (Fierro the contralateral silent period (CSP) (Fuhr et al. 1991).
et al. 2007) or an increase (Oliveri et al. 2005) of ICF in While there is evidence that the early part of the CSP is
M1, but no changes in SICI. However, as reviewed above, mediated by spinal mechanisms, the later part is thought to
the origin of ICF at shorter interstimulus intervals may be result from suppression of neural output by interneurons
mediated by subtle changes in spinal excitability, further at the cortical level (Fuhr et al. 1991; Tergau et al. 1999).
supporting the possibility of peripheral effects of magnetic Cracco et al. (1989) have shown that cortical stimulation


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J Physiol 586.2 TMS and motor control 339

excites inhibitory interneurons (probably Golgi-II cells MEP (Ferbert et al. 1992; Meyer et al. 1995). Several lines of
with long axons) connected to the pyramidal cells, thus evidence suggest that the iSP is mediated by fibres passing
decreasing corticospinal neuron firing (Cracco et al. 1989). through the corpus callosum: iSPs were absent or delayed
The CSP duration is greater following an antero-posterior in patients with agenesis or surgical lesions of the corpus
and biphasic stimulus than a postero-anterior stimulus, callosum (Meyer et al. 1995), but were preserved in patients
and correlates strongly with the amplitude of the evoked with subcortical cerebrovascular lesions that interrupted
MEP, raising the possibility that it may depend on activity the corticospinal tract but spared the corpus callosum
in recurrent collaterals from discharging pyramidal tract (Boroojerdi et al. 1996). In addition, in young children the
neurons (Orth & Rothwell, 2004). The CSP has been iSP is significantly shorter than in adults; the protracted
reported to be prolonged following administration of development and myelination of the corpus callosum are
either oral tiagabine (a GABA re-uptake inhibitor) or paralleled by the appearance and strengthening of the iSP
intrathecal baclofen (a GABAB agonist), suggesting that (Heinen et al. 1998).
the CSP, like LICI, may be mediated by GABAB populations Several studies have investigated the iSP’s relationship
(Siebner et al. 1998; Werhahn et al. 1999). However, this to IHI (Ferbert et al. 1992; Chen et al. 2003). Chen
effect of baclofen was not replicated in studies using oral et al. (2003) have examined the effects of different
(McDonnell et al. 2006) or intravenous administration stimulus intensities and current directions on the two
(Inghilleri et al. 1996). forms of interhemispheric inhibition. They showed that
The study by Werhahn et al. (1999) also provided paired-pulse IHI measured with a 40 ms ISI, both at rest
evidence of a reciprocal relationship between CSP and and during muscle activation, significantly correlated with
SICI, in that tiagabine increased CSP duration while iSP duration for some of the stimulus intensities and
weakening SICI. Daskalakis et al. (2006) used rTMS in current directions tested, while IHI at an ISI of 8 ms
order to evaluate the effects of several different stimulation and iSP did not correlate under any of the experimental
frequencies (1, 10 and 20Hz) on SICI and CSP (Daskalakis conditions. These results suggest that while common
et al. 2006). They showed that the rTMS-induced change neuronal populations may mediate IHI40 and iSP, the
in SP was associated with a change in SICI and this same is not true of IHI8 . Thus iSP and IHI8 are separate
inverse relationship was greatest in the highest stimulation phenomena, mediated perhaps through different sets of
condition (i.e. 20 Hz). Recently, this interaction was transcallosal fibres or, alternatively, different sets of effector
explored in a human study by Ni et al. (2007). The neurons in the contralateral ‘target’ M1. The duration
authors used a triple-pulse protocol, investigating SICI of the iSP can be modulated by a CS delivered to the
and ICF during different time points of the CSP. While stimulated hemisphere in a paired pulse protocol: the iSP
SICI was decreased (80–140 ms following the stimulus can be suppressed by a subthreshold CS delivered 3 ms
that induced the CSP) ICF was increased, followed by before the suprathreshold TS (Trompetto et al. 2004) or
normalization of both parameters after termination of enhanced by a CS at motor threshold intensity delivered
the CSP. Since the lack of SICI was already present 1.5 or 3 ms after the TS (Avanzino et al. 2007). These are the
at low CS intensities (∼60% aMT) and the threshold same protocols used to elicit SICI and SICF, respectively,
of inhibitory interneurons is known to be lower than implying that the iSP is conditioned in a similar manner to
that of facilitatory interneurons (Chen et al. 1998), the the contralateral corticospinal output – the cell population
decrease of SICI during the CSP is likely to be due to giving rise to the transcallosal projection mediating the iSP
a decreased inhibition rather than increased facilitation. seems therefore to be subject to similar modulation to the
This relationship may be seen as analogous with the pyramidal output, although they do not necessarily have
suppression of SICI in the presence of LICI, another to be the same population.
GABAB -mediated phenomenon (Sanger et al. 2001), and
is consistent with previous lines of evidence from both
animal and human studies demonstrating that activation
State-dependent intra- and interhemispheric
of presynaptic GABAB receptors inhibits further release of
GABA (Deisz, 1999). Interestingly, the inhibition of SICI interactions
by LICI was also observed during the CSP (Ni et al. 2007), We have so far described different physiological inter-
further supporting this hypothesis. actions which modulate the output of M1 while the system
is at rest, defined as muscle relaxation (except for the silent
periods). It may be expected that the behaviour of these
Ipsilateral silent period. Application of a single supra- interactions should change depending on the behavioural
threshold TMS pulse to the M1 ipsilateral to a tonic state. If these parameters play a functional role in motor
voluntary contraction can cause an interruption of the control then one may expect changes when subjects engage
ongoing voluntary EMG activity known as the ipsilateral in preparation or performance of a motor task. Such
silent period (iSP), even in the absence of an ipsilateral movement-related changes have indeed been described for


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340 J. Reis and others J Physiol 586.2

a number of these interactions, but there are still plenty of (Stinear & Byblow, 2003a). SICI also increases after a
unknowns. no-go signal in a go/no-go reaction task protocol (Sohn
et al. 2002). These results are consistent with a role
Changes affecting M1 during movement preparation. of SICI in actively suppressing execution of prepared
Corticospinal and intracortical parameters can be assessed movements. A comparison of synchronized versus
in the context of reaction time protocols, providing a syncopated externally paced finger movements has also
picture of changing physiological interactions leading up suggested that movement-related SICI changes may be task
to movement execution. Using single pulse TMS applied dependent (Byblow & Stinear, 2006).
at a number of time points after a ‘Go’ cue (in a simple The precise timing of SICI changes has been recently
reaction time protocol), three studies have described investigated in a simple reaction time protocol, revealing
a gradual increase in corticospinal excitability starting that inhibition is in fact stronger more than 70 ms before
80–120 ms prior to movement onset (Rossini et al. 1988; movement onset, but is then progressively abolished
Leocani et al. 2000; Nikolova et al. 2006). In the study relative to rest (Nikolova et al. 2006). A trend was also
of Leocani et al., this finding was accompanied by a observed for ICF to become weaker from 150 ms before
suppression of MEPs in the contralateral resting hand (if movement. This reduction in inhibition is likely in fact
the dominant right hand was being moved). The role of to occur closer to the onset of movement than described
excitability changes in the α-motorneuron pool, which here, as this study did not test for early subtle increases in
was not studied in detail in these early investigations, was spinal excitability. With this in mind, it may be the case
evaluated more recently. It appears that the true ‘lead time’ that the reduction in SICI occurs alongside (or later than)
between premovement excitability increases in the motor the increase in MEP amplitudes. If so, this would suggest
cortex and the spinal cord may be of the order of 10–15 ms: that SICI modulation is unlikely to drive the corticospinal
shorter than previously thought (MacKinnon & Rothwell, excitability increase, but may serve to focus it appropriately
2004; Schneider et al. 2004). This faster build-up of motor to the task. There is a further inherent difficulty in this kind
cortex excitability is perhaps not surprising when one of experiment in that premovement MEP facilitation may
considers that healthy volunteers may have a total reaction distort the degree to which apparent SICI in fact reflects
time of around 100 ms. Recent work suggests that motor activity in the inhibitory population. While the phasic
cortical excitability is also modulated by the expectancy movement experiments of Stinear & Byblow (2003b) make
of the need to make a movement. In an elegant version efforts to correct for this, it would be technically very
of the simple reaction time task (SRTT), van Elswijk and challenging to do so across a range of time points – it is
colleagues manipulated the interval between a preparatory possible that such a consideration may affect the changes
stimulus and a response stimulus in order to create four reported by Nikolova and colleagues. In the case of phasic
time intervals at which subjects had various expectancies movements the question arises as to whether afferent
of the likelihood of a cue to move. Not only were feedback, known to focally reduce SICI (Rosenkranz &
reaction times shorter with high cue expectancy (relative to Rothwell, 2003), may be responsible for the observed
intervals with a low expectancy), but MEP amplitudes to changes. However, reduced SICI has been observed during
a single TMS pulse were also increased (van Elswijk et al. imagined thumb abduction movements, suggesting that
2007). Thus it would seem that premovement modulation afferent feedback is not necessary to produce these changes
of M1 excitability is exquisitely sensitive to the precise (Stinear & Byblow, 2003b). Thus it seems likely that both
nature of the upcoming task, and is modulated in advance motor drive and afferent feedback may contribute to
of expected movements. movement-related modulation of SICI.
Paired pulse TMS can be used in a similar manner to Using a two coil approach it is also possible to test the
investigate intracortical excitability changes in relation to activity of inter-regional interactions during movement
movement. Reynolds & Ashby (1999) demonstrated that preparation. If tested in a simple reaction time protocol,
SICI begins to decrease approximately 95 ms prior to the IHI targeting the moving hand is reversed to become IHF
onset of a phasic movement, and that this change is seen in the period immediately before movement onset (Murase
in the agonist but not antagonist muscle groups. As a local et al. 2004). This effect is more prominent when tested for
intracortical phenomenon, SICI would be well placed to IHI targeting the dominant hand (Duque et al. 2007). It
modulate the relationship between adjacent intracortical was suggested that this reversal of tonic inhibition may
representations via changes in horizontal connections. allow for accuracy of movement when the hands need to
It was thus speculated that the reduction in SICI could be used separately. In view of the importance of bimanual
contribute to the focal increase in corticospinal excitability control in primate evolution it could be speculated that
affecting the target muscle (Reynolds & Ashby, 1999). the role of interhemispheric interactions between the hand
Conversely, SICI targeting a neighbouring uninvolved areas may differ between unimanual and bimanual tasks,
hand muscle may become stronger in some subjects but this has not been directly tested yet. Indirect evidence
when tested in relation to phasic finger movements that this may be the case is provided by studying changes in


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J Physiol 586.2 TMS and motor control 341

MEP amplitudes (in response to a single TMS pulse) in a described by Civardi et al. (2001) would be interesting in
hand muscle before a bimanual movement. MEPs increase this regard, but has not been investigated.
or decrease during this period depending on both the A time-dependent facilitation has also been described
agonist–antagonist and kinematic relationships between between the right posterior parietal cortex (PPC) and the
the two moving fingers (Duque et al. 2005). This suggests ipsilateral M1 in a choice reaction time task (Koch et al.
that information describing such relationships is coded at 2007). Significant facilitation, equivalent to that seen at
the level of M1, but does not directly support a role for rest, was seen 50 ms after the ‘Go’ cue but not at other
IHI/IHF in this process. premovement time intervals. This occurred if the subject
A similar approach has been employed to investigate was preparing to move towards the left hemispace but not
activity in the inhibitory and facilitatory interhemispheric if movement was towards the right, suggesting that the
PMd–M1 interactions described above during a choice PPC may play a role in directional planning early on in
reaction time task (Koch et al. 2006). During movement movement.
preparation these investigators found a crucial timing There is indirect evidence that the cerebellum exerts
dependence: the facilitatory effect on MEP amplitude an influence on M1 during movement preparation: the
was evident 75 ms after the cue if the target hand was premovement facilitation normally observed in response
being moved (but not the contralateral hand), while the to M1 stimulation is reduced in patients with
inhibitory effect was evident 100 ms after the cue if the spinocerebellar degeneration (Nomura et al. 2001).
contralateral hand was being moved (but not the target Furthermore, abnormally diffuse movement-related
hand). Interestingly, both the inhibitory and facilitatory cortical potentials can be demonstrated prior to
influences of PMd on M1 were absent at all other time movement in patients with stroke affecting the contra-
intervals before movement. The authors speculated that lateral cerebellum, a finding that resolves with clinical
the reaction cue may initially cause both left and right hand improvement (Gerloff et al. 1996). It has been suggested
movements to be specified, with the incorrect movement that cerebello-thalamo-cortical projections to M1 intra-
being eliminated at a later stage. The expectation of cortical inhibitory interneurons may dynamically focus
the need to move may thus cause the interhemispheric the motor output through regulation of surround
interactions to be suppressed, only for the relevant cortical inhibition (Pinto & Chen, 2001). However, CbC
interaction to become active during the appropriate interactions have not been studied during movement
premovement time window. Thus, the left PMd exerts preparation, so further evidence is necessary before such
a brief facilitatory or inhibitory influence on the right conclusions can be drawn.
M1 depending on which hand is to be selected to From the work described above, a picture begins to
move, supporting a role for the left PMd in movement emerge of the changes in interactions targeting M1 that
selection. This dependence of the interhemispheric lead up to the execution of a movement – this is illustrated
PMd–M1 interaction on the motor state is in keeping in Fig. 7. The timings shown are likely to be approximate,
with recent work which used the effect of a TMS as subtle changes in spinal excitability were not tested in
input on haemodynamics in remote areas (during fMRI several of the studies cited. It should also be emphasised
imaging) to assess functional connectivity. This approach that the interactions involving PPC and PMd are based
also demonstrated that the PMd–M1 interaction is on choice reaction time experiments, whereas the other
inhibitory at rest but facilitatory during movement changes shown were in the context of a simple reaction
preparation (Bestmann et al. 2007). A recent paper time task. While the PPC and PMd should make more
by Davare et al. (2006) supports this point of view, decisive contributions in the choice reaction time protocol,
demonstrating that 1 Hz rTMS over the left PMd impairs the sequence of events is likely to be similar: a directional
movement preparation as tested in a pinch-lift task. selection (PPC), then a hand selection (PMd), leading to
The brief periods of activity in the PMd–M1 interactions increasing excitability in the relevant M1, which is then
(Koch et al. 2006) occur considerably earlier than the refined by focused task-specific changes in SICI (and IHI),
excitability changes within M1 described above (although followed finally by movement onset. Changes in these
simple and choice reaction time protocols are being interactions may be seen as preparatory tuning of the
compared). This is consistent with the relative timings motor output before release: this is likely to occur at a
of the two regions as revealed by attempting to prolong variety of intervals depending on the advance information
reaction times with a short train of repetitive TMS. This available about the movement being planned. This model
delayed responses if given early in the reaction time to PMd describes movement preparation only in terms of the
or if given later to M1 (Schluter et al. 1998). However, it interactions for which such experiments have been
should be noted that this result refers to the PMd ipsilateral performed. Changes may occur in many or all of the
to the active M1, whereas the PMd–M1 interaction tested other M1 interactions described, and this is a major gap in
by Koch et al. (2006) conditioned the contralateral PMd. current knowledge. Perhaps more importantly, it should
The time course of the ipsilateral PMd–M1 interaction be kept in mind that the validity of this model is likely


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342 J. Reis and others J Physiol 586.2

to vary widely depending on the particular behavioural During slight tonic contraction, IHI targeting the active
setting. hand (tested using a suprathreshold CS to the contralateral
M1) is unchanged, whereas that targeting the contra-
Changes during muscle contraction. Corticospinal lateral resting hand becomes slightly stronger (Ferbert et al.
excitability to single pulse TMS is increased in the agonist 1992). The effect of preactivation of the target muscle has
muscle during established tonic contraction (Hess et al. also been investigated using stimulation parameters that
1986). This is felt to result from a combination of produce IHF at rest (CS of 80% AMT, small target MEP
increases at the cortical and spinal levels. Furthermore, amplitudes). Under these conditions, facilitation is still
changes in the response of the contralateral homologous seen at an ISI of 8 ms but is absent at 6 ms (Baumer et al.
muscle have been documented, with the direction of 2006).
the effect (increase or decrease) depending on the level The intrahemispheric PMd–M1 inhibition observed by
of voluntary contraction as well as the type of muscle Civardi et al. (2001) was significantly weaker if tested with
contractions. While low force levels produced by one hand slight tonic preactivation of the target muscle. Likewise,
lead to a decrease in MEP amplitude in the homologous under conditions that produce interhemispheric PMd–M1
muscle (Liepert et al. 2001), high force levels (25–50% facilitation at rest, this effect is abolished or masked by
MVC) lead to increased responses (Hess et al. 1986; preactivation of the target muscle (Baumer et al. 2006).
Muellbacher et al. 2000). Increased responses are seen However, in both of these studies lower TS intensities were
even in patients with agenesis of the corpus callosum used in the active state (in order not to produce larger
(Meyer et al. 1995) suggesting increased excitability at the baseline MEPs), making it difficult to rule out altered
spinal level. However, the simple reaction time study of I-wave profiles in the test MEP as a possible cause of the
Leocani et al. (2000) reported suppression of responses in observed reduced effect of the CS. Under conditions that at
the contralateral hand soon after the onset of movement. rest produce inhibition in the interhemispheric PMd–M1
This was observed only in the non-dominant hand during interaction, Mochizuki et al. (2004a) investigated instead
movements of the dominant hand. IHI is likewise stronger the effect of preactivating the homonymous muscle contra-
from the dominant to the non-dominant hemisphere than lateral to the target muscle (i.e. contralateral to the CS) –
the other way around (Netz et al. 1995), so it may be that unlike IHI between the motor cortices, this manoeuvre
there is initial transcallosal suppression of contralateral did not affect the PMd–M1 interaction. So for these
excitability followed by a later phase of spinal facilitation, interhemispheric interactions, facilitation has been tested
at least for the tasks in which these parameters have been targeting the active hand, whereas inhibition has been
evaluated. Both SICI and ICF are significantly weaker tested targeting the resting hand – the effects of pre-
during tonic contraction of a hand muscle than at rest – activating the conditioning and target hemispheres remain
this effect is relatively focal in that while it is also observed to be determined.
in neighbouring hand muscles it does not apply to more When considering the changes observed in M1 output
proximal arm muscles (Ridding et al. 1995). during muscle contraction it must be considered whether

Figure 7. Changes affecting M1 excitability during

movement preparation
The increase in excitability of M1 in response to a
magnetic stimulation before movement onset is shown
by the blue line, increasing from approximately 100 ms
prior to the onset of muscle activity. Above, an
approximate sequence of facilitatory inputs from the
posterior parietal cortex (PPC) and dorsal premotor
cortex (PMd) are shown, followed by a reduction of
short interval intracortical inhibition (SICI) and abolition
of interhemispheric inhibition (IHI) from the
contralateral M1. It should be noted that while the
experiments represented all involved physiological
measurements during a reaction time, the timings
shown relate to a variety of types of cue and task and
therefore may not be accurate in relation to each other
(see text). The inputs from the PPC and PMd may select
the hemispace to be moved into and the hand to move,
respectively. It may also be speculated that the relatively
late reduction in SICI, which is muscle group specific,
allows the increasing excitability to be focused
appropriately before the onset of activity.


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J Physiol 586.2 TMS and motor control 343

sensory afferent input may make a contribution. In the Physiological changes resulting from training. Repetitive
context of a muscle contraction it is difficult to separate the training in a simple motor task results in changes in M1
effects of motor drive from those of the resulting proprio- excitability that are well documented. Focally increased
ceptive feedback. The physiological changes described MEP amplitudes (specific to the trained muscle) can
above that can be induced by muscle vibration may, be induced in as little as 30 min of training (Classen
however, provide information about the proprioceptive et al. 1998; Butefisch et al. 2000; Muellbacher et al.
component originating from muscle spindles. In fact, the 2001). The direction of a thumb movement in response
effect of vibration on the contralateral M1 is strikingly to a single TMS pulse can also be altered by training
similar to that of tonic contraction – a focal increase over a similar period, suggesting that motor practice
in corticospinal excitability and decrease in SICI, with can influence directional coding at the level of M1
surround inhibition (Rosenkranz & Rothwell, 2003). Like (Classen et al. 1998). Because changes identified with TMS
tonic contraction, vibration also increases IHI targeting were not present with transcranial electrical stimulation
the contralateral homologous muscle (Swayne et al. 2006). indicating an intracortical substrate (Classen et al. 1998)
While this may contribute to the IHI change seen with and because GABAergic agents dampened this form of
contraction, motor drive is likely to be important as plasticity (Butefisch et al. 2000), modulation of excitability
well, as corticospinal excitability in the contralateral in horizontal connections such as those reported following
M1 is reduced with vibration (whereas it is increased motor training in rats (Rioult-Pedotti et al. 1998) may
in tonic contraction). LAI and SAI resulting from a represent a contributory mechanism. Conversely, low
peripheral nerve stimulus can be tested in the context frequency 1 Hz TMS applied to M1 immediately after
of a movement, such that the test TMS stimulus is practice resulted in disruption of improvement in motor
given soon after the onset of a voluntary movement. At performance in a pinch-grip task. The disruptive effect was
rest LAI obtained from cutaneous stimulation acts not specific for M1 and was not found when stimulating the
only on muscles affecting the stimulated finger (homo- visual cortex indicating that M1 is involved in the early
topic LAI) but also on neighbouring muscles (heterotopic phase of motor consolidation (Muellbacher et al. 2002).
LAI): during movement both forms of LAI affecting ICF is increased following training of a task involving
the resting digit are enhanced, while those affecting simple repetitive wrist movements (Lotze et al. 2003) but
the moving digit are abolished (Voller et al. 2005). In no change in ICF is detected after a complex sensori-
a similar protocol, homotopic SAI is enhanced during motor task (McDonnell & Ridding, 2006). Clear changes
movement in the resting digit and absent in the moving in SICI can also be induced by motor training. Liepert
digit, while heterotopic SAI is absent altogether during et al. (1998) observed that performance of repetitive
movement (Voller et al. 2006). Thus the changes in afferent thumb movements induced a global reduction in SICI
inhibition in the context of movement also appear to targeting hand muscles (Liepert et al. 1998). If subjects
demonstrate properties of surround inhibition, focusing were also instructed to keep the fourth dorsal interosseus
the inhibitory effect onto neighbouring resting muscles muscle relaxed throughout, then SICI targeting this muscle
while disinhibiting the moving muscle. This could be increased, while still decreasing in the thumb (APB). Thus,
explained in theory either by afferent inhibition causing changes in SICI can be muscle and task specific. A similar
surround inhibition or alternatively being shaped by it. It is SICI reduction has been observed in leg muscles following
clear from the case of muscle vibration that sensory afferent skilled (but not un-skilled) training in an ankle movement
input on its own can drive surround inhibition, so it seems task (Perez et al. 2004). It is tempting to conclude from
reasonable that the same might apply to SAI/LAI. This these studies that during acquisition of a new motor skill a
has not been investigated in detail for SAI/LAI induced by reduction in GABAergic inhibition may somehow facilitate
mixed nerve stimulation during movement. an increase in the strength of horizontal cortico-cortical
Cerebello-cortical inhibition, demonstrated in the FDI connections, as has been observed in rat motor cortex
at rest, is absent during voluntary isometric contraction of (Rioult-Pedotti et al. 1998), but a role for SICI in this
the target muscle. This effect may result from a reduction process is yet to be directly demonstrated.
in cerebello-thalamo-cortical pathway excitability or Long-term changes of intracortical excitability after
alternatively from a decreased susceptibility of M1 to CbC repeated training (months to years) have also been
inhibition during contraction of the target muscle (Pinto reported: both ICF and SICI are less strong at baseline
& Chen, 2001). Whereas CbC targeting the right FDI is in musicians, who have undergone extensive training
unaffected by proximal voluntary contraction of the left in complex finger movements than in non-musicians
arm, it is abolished by isometric contraction of the right (Nordstrom & Butler, 2002), and ICF can be increased
arm. This effect can be attributed either to a decreased in pianists following training in an unfamiliar piece of
excitability of the Purkinje cells or to reduced activity music (D’Ausilio et al. 2006). Reduced baseline ICF in
of the dentato-thalamo-cortical pathway during proximal this context may arguably be seen as allowing greater
muscle contraction. scope for increase in response to training, while weak


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344 J. Reis and others J Physiol 586.2

SICI may facilitate such changes. It is interesting in this improvements in not only the trained hand but also the
regard that musicians’ dystonia, a condition regarded untrained hand. Training was associated with reductions
as a form of maladaptive plasticity, is associated with in SICI in either hemisphere, but intriguingly decreased
weak SICI (Rosenkranz et al. 2005). A more recent study IHI targeting the untrained hemisphere correlated with
with musicians examined SICI across a range of CS performance improvements in the untrained hand, that is,
intensities and found that musicians had stronger SICI with the magnitude of the intermanual transfer function
than non-musicians at higher intensities (Rosenkranz (Perez et al. 2007).
et al. 2007). The apparent discrepancy between this result
and that of Nordstrom & Butler (2002) may be due to Discussion
the fact that the earlier study tested SICI at only one
conditioning stimulus (CS) intensity, which was fixed It may be appreciated from the previous sections that the
relative to the active motor threshold. Comparison of the amount of information available and our understanding
two studies reveals that they recorded markedly different of the interactions shaping the characteristics of motor
motor thresholds in the musician groups: with only one CS cortical output have advanced considerably in recent years.
it is impossible to know whether the study of Nordstrom Despite these advances, much more work is required
& Butler was testing SICI in a different part of the CS curve to fully understand the cortical mechanisms underlying
from the later study. The study of Rosenkranz et al. (2007) human motor control. While the review component of
also found steeper MEP recruitment curves and greater this paper focuses to a larger extent on what is known in
changes in excitability following a paired associative the field of TMS, the discussion will focus on what is not
stimulation protocol. The authors argue that the long-term known, possible pitfalls in interpretations of TMS data,
effects of intensive motor practice may be to increase and interesting research directions that emerge from the
the capacity for training-related synaptic modification. described work.
However, it should be kept in mind that these results
may represent epiphenomena of differences in anatomical Caveats in the interpretation of these studies. First, it
structures between musicians and non-musicians (Gaser & is important to point out that direct evidence proving
Schlaug, 2003). Furthermore, differences in baseline skills the anatomical substrates of the interactions modulating
at the time of the testing, genetic predispositions or simply the output of M1, as shown for example in Fig. 1, is
endophenotypic traits may also contribute to inter- largely missing. Wiring diagrams of the sort presented
individual differences. here, and seen frequently in published material, are
In view of these intracortical training effects, it may useful in that they describe the relationships between the
be expected that interhemispheric interactions between several phenomena that TMS is able to probe, and they
the motor cortices would be modulated by training that further provide experimental models against which new
relies on accurate interhemispheric coordination. Indirect hypotheses can be more easily formulated and tested.
evidence that this might be the case is provided by the Also, these models provide new investigators with a
experiments of Shim et al. (2005), in which subjects were comprehensive description of other interactions to be
asked to practise an unfamiliar bimanual task (Shim et al. controlled for in future experiments. While some of
2005). Prior to practice, slight tonic contraction (max the connections depicted in the figures are based on
15% MVC) of the training hand produced inhibition of evidence sound enough to make educated guesses as to
MEP amplitudes (to a single pulse) in the non-training the neural structures involved, others are speculative
hand, whereas after practice this inhibition was selectively and require specific testing. The reader is warned then
reduced in fingers involved in the task. A further hint to interpret these diagrams as works in progress, useful
that IHI as tested with the paired pulse technique may in summarising data already available and posing future
be involved in bimanual training is provided by the questions. The overlapping phenomena of SICI and SICF,
observation that it is significantly weaker in musicians than for example, are ascribed to the differential actions of
in non-musicians (Ridding et al. 2000b). However, a direct low threshold inhibitory or high threshold excitatory
demonstration of a change in IHI with bimanual training interneuron populations, depending on the conditioning
is so far lacking. stimulus intensity used. However, although anatomical
One fundamental skill that human and non-human candidates for these populations are present in the motor
primates have is the ability to execute with one hand a cortex, there is insufficient evidence to confidently assign
task that was learned with the opposite hand, referred these phenomena to particular neuron types. Interneurons
to as intermanual transfer (Halsband & Lange, 2006). may be dedicated to individual kinds of interaction, as the
Recent evidence points to a role for IHI in the intermanual wiring diagrams suggest, or alternatively may be able to
transfer of procedural motor learning (Perez et al. 2007). exert more than one kind of influence on the pyramidal
In this study, subjects were trained in a unimanual cell depending on the input received. Likewise, the
serial reaction time task, resulting in performance interhemispheric interactions discussed above are


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J Physiol 586.2 TMS and motor control 345

described as consisting of excitatory transcallosal the outcome. This is true of intracortical interactions: if
projections onto inhibitory or excitatory local circuits two TMS pulses are applied to M1 separated by 2.5 ms, for
within the target M1. This fits with currently available example, their relative intensities will determine whether
neuroanatomical data (largely based on animal work) and SICF or SICI is elicited (Fisher et al. 2002; Roshan et al.
would explain observed findings, but direct evidence is 2003). This consideration is also crucial in inter-regional
still lacking. It should also be remembered in this regard interactions, where careful changes in CS and TS intensities
that apparent changes in excitability as measured by TMS can change IHI into IHF (Baumer et al. 2006). This
do not necessarily reflect actual changes in neural activity serves to underline the important fact that paired pulse
within the target populations (Similar limitations apply TMS studies by no means provide a clean measure of
for BOLD fMRI or blood flow studies). A neuron which is an isolated neural population – rather they describe the
partially depolarised but has not reached firing threshold outcome of an interaction representing the net effect of
may appear to have increased in activity in response to several overlapping influences. It is also worth bearing
a TMS stimulus while not actually being physiologically in mind that the relative ease with which physiological
active. Thus while excitability to the artificial input of interactions may be elicited in a TMS experiment does not
TMS is likely to be highly correlated with neuronal necessarily reflect the relative importance of their roles
activity, the two are not necessarily equivalent. A recent in vivo: while IHI can be more readily elicited than IHF,
study by Allen et al. (2007) addresses this issue in more for example, this may reflect the way these parameters
detail. are tested rather than aspects of their function. This
Secondly, evidence from recent studies clearly points consideration of overlapping interactions has important
to fundamental differences in the way these intracortical implications for investigators planning to measure the
interactions operate in the setting of different behavioural changes in a particular interaction with regard to a physio-
or cognitive tasks or motor states. In other words, the logical or behavioural manipulation. In order to extract the
review of the literature is consistent with the view that each true behaviour of the neural population of interest it may
behavioural state may condition fundamentally different not be enough to use one set of CS and TS intensities. The
cortical interactions (Allen et al. 2007). Therefore, care safest approach to this potentially confounding problem
should be taken to avoid generalising conclusions on the is to study a range of intensities, providing a recruitment
role of specific inhibitory or excitatory processes to tasks curve for the activity of that interaction. Examples of
or behaviours beyond those specifically studied. Clearly, studies that included this approach are a study of SICI
more work is needed to understand the extent to which after stroke (Butefisch et al. 2003) and another study of
task-specificity influences the direction and magnitude of intermanual transfer of procedural knowledge in healthy
changes in the various TMS measures described above. subjects (Perez et al. 2007).
Finally, the specific relationship between physiological From a behavioural point of view, when considering
changes and motor behaviour remains elusive. Most the activity of a given physiological measure, it is essential
studies have focused on describing the association between to take the particular motor or behavioural state into
specific neurophysiological changes and behavioural consideration. Recent work suggests that monitoring for
modifications. When changes in physiology and behaviour muscle activity at the time of measurement, while useful,
correlate such findings are often interpreted as suggestive may not be enough. For example, motor activity is absent
of a beyond association link. However, it should be kept in when the subject is fully at rest, but also in the milliseconds
mind that these findings do not prove a cause-and-effect preceding a voluntary movement. Despite the comparable
connection between the physiological change and the absence of EMG activity, the cortical excitability in the two
motor behaviour. This is a gap that has not yet been crossed conditions is fundamentally different. The magnitude and
in most studies, except when using TMS as a tool to elicit sign of the physiological interactions described changes
‘virtual lesions’ (O’Shea et al. 2007; Cohen et al. 1997). Still well in advance of movement onset and may vary with
more work is needed to prove that the associations between respect to the task being performed (Duque et al. 2005),
specific functional interactions and behaviour represent the hemispace involved (Koch et al. 2007) and even the
more than mere epiphenomena of the specific behaviour. emotional context (Oliveri et al. 2003). An investigator
The design of these types of experiments represents one of studying changes in physiological interactions with regard
the crucial challenges ahead of us. to movement must thus ensure that such aspects of the
motor state have been taken into account and adequately
Necessary controls. The studies reviewed have over time controlled for.
shown an increasing degree of sophistication, attention to
detail and effort to control for confounding variables. This
Concluding remarks
is quite important to keep in mind. For example, from a
technical point of view, for all the interactions that may be The last few years have seen an increasing sophistication
illustrated by paired pulse TMS protocols the intensities and detail in the characterisation of the role of different
used for the conditioning and test stimuli are crucial to intracortical interactions in motor control. This review,

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346 J. Reis and others J Physiol 586.2

performed by fellows in two active laboratories in the field, Butefisch CM, Netz J, Wessling M, Seitz RJ & Homberg V
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students and investigators (even ourselves) of potential Byblow WD & Stinear CM (2006). Modulation of short-latency
pitfalls in the interpretation of these data and some exciting intracortical inhibition in human primary motor cortex
during synchronised versus syncopated finger movements.
trends for future investigations. In other words, as in other
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Contribution of transcranial magnetic stimulation to the understanding of cortical
mechanisms involved in motor control
Janine Reis, Orlando B. Swayne, Yves Vandermeeren, Mickael Camus, Michael A.
Dimyan, Michelle Harris-Love, Monica A. Perez, Patrick Ragert, John C. Rothwell and
Leonardo G. Cohen

J. Physiol. 2008;586;325-351; originally published online Nov 1, 2007;

DOI: 10.1113/jphysiol.2007.144824
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