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Transcranial magnetic stimulation

Article  in  Current Biology · April 2007

DOI: 10.1016/j.cub.2007.01.030 · Source: PubMed

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summate. This allows one to TMS also has secondary effects

Primer target focal regions of cortical on connected areas of cortex,
tissue. The coil is placed on the and these are useful in both
scalp, and the resulting magnetic basic and applied studies. If one
Transcranial field passes through the skull stimulates, say, the left motor
magnetic and induces an electrical field in
the underlying cortex. The effect
cortex, there are three likely
effects of stimulation: a change in
stimulation is to stimulate neuronal activity activity in the targeted region; a
and change the excitation and change in activity in immediately
organisation of neuronal firing in surrounding areas of cortex;
Jacinta O’Shea1 and the stimulated region. and a change in the activity of
Vincent Walsh2 Since Anthony Barker and cortical areas directly connected
colleagues first demonstrated with the stimulated region. These
As any schoolboy with a toolkit TMS in 1985 it has been are important considerations in
or a broken toy soon appreciates, used widely to stimulate both preventing naive interpretations
to find out how a machine works peripheral nerves and brain of the effects of TMS, and
you need to take it apart, and tissue in studies encompassing also in allowing for studies of
to put it back together again, motor conduction in human cortico- cortical interactions (see
you need to know how it works. development, motor control, below).
The next lesson is that, no movement disorders, swallowing, There is sometimes a
matter how hard you try, you vision, attention, memory, misconception that TMS is a
always end up with a handful of speech and language, epilepsy, spatially crude technique, but
leftover nuts and bolts. These depression, stroke, pain and the effective resolution may be
remaining components can be plasticity. It has proved to be a in the order of a few millimetres
informative: will your machine still versatile technique and is now and very good inferences can
work without them? The same also being used in combination be made about the physiological
logic applies to one approach with electroencephalography effectiveness of the stimulation
to understanding human brain (EEG), functional magnetic area. TMS over primary motor
function: by investigating the resonance imaging (fMRI) and cortex evokes muscle twitches
effects of lesions in animals single unit recording. from the fingers, hand, arm, face,
and accidental brain damage Pulses of TMS can be trunk and leg in a manner that
in humans we can ask which applied at varying intensities, matches the organisation of the
parts are necessary for specific and in single pulses or in motor ‘homunculus’. Positioning
functions. Over the past twenty repetitive trains (rTMS) of low the coil on the scalp at locations
years, it has become possible or high frequency. The choice spaced between 0.5 and 1 cm
to interfere with human brain of stimulation parameters apart is sufficient selectively to
functions safely and reversibly, determines whether the effects activate these different muscles.
and to control when and where of stimulation are excitatory A similar effective
the interference is induced. The or inhibitory. For example, two spatial resolution has been
technique, known as transcranial single pulses separated by less demonstrated in primary
magnetic stimulation (TMS), has than 5 milliseconds can produce visual cortex. Depending on
become a mainstay of cognitive intracortical inhibition, while the intensity and experimental
neuroscience. two single pulses separated conditions, TMS over occipital
by a gap greater than 10 and (visual) cortex causes people to
What is TMS? less then 30 milliseconds can experience either a spot of light
TMS is based on the principle produce intracortical facilitation. (a phosphene) or a blind spot
of electromagnetic induction. Repetitive TMS at a frequency of (a scotoma) in their visual field.
Michael Faraday showed that 1 Hz has the effect of depressing The location of the phosphene
when an electrical current cortical excitability for a period or scotoma corresponds with
is passed through a wire, of time after the train of pulses the coil position over the visual
it generates a time-varying has finished, whereas repetitive cortex. With coil positions 0.5–1
magnetic field. If a second wire stimulation at 10 Hz or more may cm apart, the region of the visual
is placed nearby, the magnetic increase excitability. Theta burst field in which the phosphene
field induces electrical current stimulation, applying trains of 50 or scotoma is induced can be
flow in that second wire. In TMS, Hz stimulation in bursts every controlled with an accuracy as
the ‘first wire’ is the stimulating 200 milliseconds, has the effect precise as 1° of visual angle
coil and the ‘second wire’ is a of depressing cortical activity for (estimates of the cortical distance
targeted region of the brain. a period following stimulation. representing the central 2° of
The most common coil in use in Theta has been used in few visual angle of between 20 and
TMS is a figure-of-eight shape in studies but its effects are clearly 30 mm).
which electrical current flows in more reliable than those of 1 Hz. Outside primary sensory
opposite directions around each Although stimulation effects and motor cortices, spatial
of the windings, converging at the are maximal in the cortical region resolution must be inferred from
centre-point where the currents directly underneath the coil, diminishing effects of TMS on
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cognitive tasks. The induced three-letter (trigram) combination cortex of the unstimulated
current dissipates rapidly with like ‘TGN’ — impaired subjects’ hemisphere, and a changed
distance from the centre of the ability to identify the letters. pattern of interaction between
TMS coil. Thus, spatial resolution When subjects were shown the stimulated cortex and other
can be estimated effectively by two trigrams in succession, motor regions, suggesting that
measuring how a stimulation- for example ‘TGN’ followed the motor system is capable of
induced behavioural effect — an by ‘XDU’, the second trigram functional remapping in response
increase in reaction time or masked the first, and they were to interference from TMS.
the frequency of errors, for unable to identify the TGN In a related study, Heidi
example — dissipates as the coil stimulus accurately. When TMS Johansen-Berg and colleagues
is moved gradually away from was applied approximately 100 demonstrated the potential
a targeted cortical site. Studies milliseconds after the second importance of remapping in
that have combined TMS with trigram, the induced neural noise a group of patients who had
imaging methods have shown weakened the representation of suffered a left hemisphere stroke
good correspondence between XDU and subjects were again and consequent impairment in
the spatial extent of a functional able to identify the TGN stimulus. moving their right hand. First,
region defined in such a way by This experiment illustrates two the authors showed that stroke
TMS and that defined by other of the most valuable aspects of patients, compared to healthy
measurement techniques. TMS as a lesion technique that controls, exhibited increased
make it an advance on traditional activity in motor areas of the
TMS as an interference neuropsychological or animal undamaged hemisphere when
technique studies: a temporal resolution in performing finger movements
The effect of TMS is to induce the millisecond range, and the with the stroke-affected hand.
activity changes, excitatory or ability to interfere selectively with They then demonstrated the
inhibitory, that are effectively competing representations, in this functional significance of this
random with respect to the case that of the two trigrams. In newly emergent activity by
organised signals required the second experiment one might applying TMS while subjects
to perform a task. This be tempted to conclude that TMS performed the finger movement
is an important yet often has improved vision, but it did so task with the stroke-affected
misunderstood point. Stimulating only by selectively interfering with hand: TMS caused significant
the motor cortex will make a a competing visual process. This reaction time delays in
subject’s hand twitch and will logic of disinhibiting one function patients, but not in controls.
make it harder for him or her by suppressing another has been This suggests that it may be
to point accurately at or grasp harnessed effectively in studies possible to incorporate TMS into
an object. It will not cause the of plasticity. rehabilitation programmes — to
subject to produce an organised change the relative excitability of
action. Stimulating the visual TMS in plasticity and and interactions between the two
cortex will cause subjects to rehabilitation cerebral hemispheres.
see a blur or a flash of light, TMS of sufficient intensity over Massimiliano Oliveri and
or will make it harder for them the motor cortex induces muscle colleagues applied this strategy
to detect or identify a visual activity, measured as motor to patients suffering from
object. It will not make them evoked potentials (MEPs), in visuospatial neglect, a form
see a country scene or see the the contralateral hand, because of attentional bias where the
words on a page more clearly. in a normal motor system each subjects appear to be unaware
In this sense the application of cerebral hemisphere controls of events in one half of their
TMS introduces noise into the movements of the contralateral visual field. They applied
system being stimulated, and effectors. This simple fact transient repetitive TMS to the
it can therefore be employed has allowed several groups to parietal cortex of the undamaged
as a lesion technique with study short term remapping of hemisphere while patients
many advantages over lesion the motor system, to assess carried out a line bisection
studies in neuropsychological the role of undamaged areas task (a common measure of
patients and non-human animals. of motor cortex in recovery of attentional bias). They found
This concept of noise is also function, and to explore the use that TMS transiently decreased
important in understanding of TMS for neurorehabilitation. the magnitude of neglect. This
reports of perceptual or cognitive John Rothwell and colleagues kind of work demonstrates the
enhancements induced by TMS. applied low frequency repetitive potential of applying TMS to
A classic series of experiments TMS to the motor cortex of one neurorehabilitation.
on occipital cortex by Vahe hemisphere in neurologically It is appropriate to mention
Amassian exemplifies the use intact subjects, and used a methodological relative of
of TMS to induce what have fMRI to observe TMS-induced TMS at this point. Transcranial
come to be called ‘virtual changes in brain activity while direct current stimulation (TDCS)
lesions’. Amassian showed that subjects performed a finger changes cortical excitability by
TMS applied after the onset of movement task. They observed the application of constant, weak
a visual stimulus — such as a increased activity in the premotor electrical current to the scalp.
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Figure 1. An example of Combining TMS and other

Moving ­ sing the temporal resolu-
u techniques
tion of magnetic stimula-
TMS is now routinely combined
tion to examine cortical
Stationary with other techniques, most
­connectivity.
This approach is based
commonly with anatomical MRI
No phosphene on the differential effects scans to coregister the position
100 ms 50 0 50 100 ms of high and low intensity of the TMS coil on the scalp with
stimulation and double coil the underlying cortical target site
V1 TMS before V5 V5 TMS before V1 stimulation. TMS was deliv-
in individual subjects. It is also
ered over MT/V5 to induce becoming increasingly common
Current Biology
the perception of movement
and either preceding or fol-
to use an fMRI precursor study to
lowing this pulse a single pulse of subthreshold TMS was applied over V1. The results determine the sites of stimulation
show that the perception of movement was ­degraded or abolished when V1 stimulation for a TMS study. Tomas Paus and
post-dated V5 stimulation by approximately 15–40 milliseconds. (After Pascual-Leone Peter Fox were among the first
and Walsh, 2001.) to combine TMS with positron
emission tomography, and
It has several advantages: it and a single sub-threshold or their findings were important in
can selectively excite or inhibit supra- threshold TMS pulse showing that TMS applied over
cortex depending on the polarity is applied over each site at one brain region, such as the
of the current; the changes in various inter-pulse intervals. By frontal eye fields or the motor
excitability can last for hours; it is varying the temporal interval and cortex, can have secondary
especially useful in combination stimulation intensity, subjects’ effects in anatomically connected
with pharmacological visual perceptions can be areas. Similar findings emerged
manipulations; and because it modified. When a supra-threshold from the combination of TMS
does not create acoustic noise TMS pulse over V5 is followed by with EEG.
or muscle twitch artefacts and is a sub-threshold pulse over V1, More recently, TMS has been
portable, it can be used with ease subjects either fail to perceive combined with fMRI and EEG
in patients. Walter Paulus’ group phosphenes, or when they do to investigate the functioning of
in Goettingen have developed they are no longer moving, but these resting-state connections
the use of the technique in as stationary (Figure 1). Conversely, when they are recruited in the
many areas as TMS is used, with a sub-threshold TMS pulse over service of a cognitive task.
impressive results. Following the V5 followed by a supra-threshold Many of the technical problems
findings of Johansen-Berg and pulse over V1 causes subjects of combining TMS with fMRI
colleagues, Leonardo Cohen’s to perceive moving phosphenes have been addressed, and the
group applied TDCS to patients of a size and shape that have combination of techniques has
who had suffered a stroke a mixture of the properties of demonstrated the importance of
and hemiparesis. All patients V1 and V5 phosphenes. These reafferent feedback from evoked
showed an improvement on effects are only obtained when movements to the motor cortex
measures of hand function and the second TMS pulse over V1 and remote effects of frontal eye
this improvement was correlated is delivered between 10 and 50 fields on visual cortex. The main
with increased motor cortex milliseconds after the first pulse strength of TMS in behavioural
excitability in the damaged over V5. studies is to parse behaviour in
hemisphere. These are small These results have also time, but a limitation of combined
beginnings for transcranial been extended to real moving TMS and fMRI lies in the poor
stimulation in plasticity and stimuli, and critical periods temporal resolution of fMRI.
rehabilitation, but the potential for both feedback and The combination of TMS with
is clear. feedforward processing have EEG, however, can enhance our
been identified. In combination, temporal partition of behaviour
Studies of connectivity this set of studies argues that and has already successfully
A series of studies have exploited the perception of visual motion revealed interactions between
TMS-evoked phosphenes and requires fast back- projections the frontal eye fields and visual
the temporal resolution of TMS from V5 to V1, and that it is cortex and between parietal
to explore back-projections from the level of activity in V1 that cortex and visual cortex. Paul
visual area V5 (MT) to V1 that may determines whether motion Taylor and colleagues applied
mediate awareness of motion. signals in V5 reach awareness. magnetic stimulation over the
While phosphenes elicited by V1 In the context of TMS as a frontal eye fields while subjects
TMS are stationary, those evoked technique they are a good prepared to make a spatial
from V5 are often moving. A TMS example of how temporal response in a visual detection
coil can be positioned over each resolution, knowledge of task. TMS modulated the
area until the phosphenes evoked anatomical connections, and electrophysiological signals
from either site overlap in space. the use of TMS to both initiate measured from visual cortex
The intensity of stimulation and disrupt processing can be both during the task preparation
(threshold) required to produce used to explore human cortical period, and in response to
a phosphene is then measured processes. the presentation of a visual
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stimulus. Rich opportunities area of cognitive neuroscience.

exist for further exploration Areas in which we can expect Correspondence
of correspondences between the next major advances in the
behaviour, TMS and other use of TMS (and TDCS) include:
physiological measures. the combination of TMS with Asymmetric
Little is known at the
single-neuron level about
other techniques to investigate
causal interactions between tail-wagging
the mechanisms mediating
TMS effects. One recent
cortical areas; the development
of new paradigms to change
responses by
study by Klaus Funke and selectively the baseline state dogs to different
colleagues reported that a of cortical excitation prior to
single high- intensity TMS further magnetic stimulation; and emotive stimuli
pulse applied to V1 neurons the incorporation of TMS into
produced a temporal sequence neuro- rehabilitation programmes. A. Quaranta1, M. Siniscalchi1
of initial suppression of neuronal and G. Vallortigara2
excitability, lasting about Further reading
Huang Y.Z., Edwards, M.J., Rounis, E., Bhatia,
100– 200 milliseconds, followed K.P., and Rothwell, J.C. (2005). Theta Research on behavioural
by a period of rebound excitation. burst stimulation of the human motor asymmetries associated with
Understanding how such long cortex. Neuron 45, 201–206. specialisation of the left and right
Hummel, F., Celnik, P., Giraux, P., Floel, A.,
suppression effects may cause Wan-Hsun, W., Gerloff, C., and Cohen,
side of the brain has focused on
interactions between TMS pulses L.G. (2005). Effects of non-invasive asymmetric use of paired organs,
delivered in trains will be an cortical stimulation on skilled motor such as forelimbs [1]. However,
function in chronic stroke. Brain 128,
important step in clarifying the 490–499.
control of medial organs
effects of repetitive-pulse TMS. Moliadze, V., Zhao, Y., Eysell, U., and Funke, such as the tail would also be
A final area of technical K. (2006). Effects of transcranial magnetic expected to involve hemispheric
stimulation on single unit activity in the
combination is that of using cat primary visual cortex. J. Physiol. 553,
collaboration and, sometimes,
TMS in pharmacological studies. 665–679. competition. Here we report
Following a demonstration that O’Shea, J., Muggleton, N.G., Cowey, A., some unexpected and striking
and Walsh, V. (2006). On the roles of the
rTMS of motor cortex induces human frontal eye fields and parietal
asymmetries in the control
the release of dopamine in cortex in visual search. Visual Cogn. 14, of tail movements by dogs:
the putamen, Strafella and 934–957. differential amplitudes of tail
Pascual-Leone, A., and Walsh, V. (2001). Fast
colleagues delivered rTMS to back-projections from the motion to the
wagging to the left or to the right
the motor cortex of subjects in primary visual area necessary for visual side associated with the type of
the early stages of Parkinson’s awareness. Science 292, 510–512. visual stimulus the animals were
Paulus, W. (2003). Transcranial direct current
Disease (PD) and measured stimulation. Clin. Neurophysiol. 56 (suppl)
looking at.
subsequent changes in dopamine 249–254. Thirty dogs, 15 intact males,
concentration. In the patients’ Rossi, S., and Rossini, P.M. (2004). TMS in 15 intact non-oestrus females, of
cognitive plasticity and the potential
symptomatic hemisphere, for rehabilitation. Trends Cogn. Sci. 8,
mixed breed, with an age range
the TMS-induced dopamine 273–279. of 1–6 years were tested. All
release was less than in the Ruff, C.C., Blankenburg, F., Bjoertomt, O., were family pets whose owners
Bestmann, S., Freeman, E., Haynes, J.D.,
asymptomatic hemisphere Rees, G., Josephs, O., Deichmann, R.,
had consented to participate in
but the area over which it and Driver, J. (2006). Concurrent TMS- the experiment during periodic
was released was greater, fMRI and psychophysics reveal frontal obedience and agility training
influences on human retinotopic visual
suggesting a loss of specificity in cortex. Curr. Biol. 16, 1479–1488.
in a behavioural dog school
corticostriatal communication in Silvanto, J., Lavie, N., and Walsh, V. (2005). associated with the Faculty
early PD. Double dissociation of V1 and V5/MT of Veterinary Medicine of Bari
activity in visual awareness. Cereb.
Cortex. 15, 1736–1741.
University, Italy.
Conclusions Strafella, A., Ko J.H., Grant, J., Fraraccio, The dogs were tested in a
In this Primer we have been M., Monchy, O. (2005). Corticostriatal large rectangular wooden box
functional interactions in Parkinson’s
able to give only a snapshot (250 cm x 400 cm x 200 cm)
disease: a rTMS/[11C]raclopride PET
of the basic features and the study. Eur. J. Neurosci. 22, 2946–2952. uniformly covered inside with
applications of TMS. Some Taylor, P., Nobre, A., Rushworth, M.F. (2007). black plastic that prevented
FEF TMS affects visual cortical activity.
fundamentals of the use of dogs from seeing outside.
Cerebr. Cortex 17, 391–399.
TMS are falling into place as Walsh, V., and Pascual-Leone, A. (2003). Illumination in the box was
we learn more about the effects Transcranial Magnetic Stimulation: provided by four light bulbs
A Neurochronometrics of Mind.
of different combinations of (60 W) symmetrically located
(Cambridge: MIT Press.)
stimulus intensity, frequency, around the walls. The testing
task and behavioural state. We box had a rectangular opening
1Department of Experimental
have not had space to cover (120 cm x 60 cm; 10 cm above
some important areas, such as Psychology, University of Oxford, South the floor level) on the centre of
Parks Road, Oxford OX1 3UD, UK.
studies of depression, language, 2Institute of Cognitive Neuroscience and one of its shorter side to permit
eye movements and basic motor Department of Psychology, University the presentation of the stimuli.
physiology, but the technique College London, London WC1N 3AR, An opaque plastic panel, same
is now used in almost every UK. E-mail: [email protected] size as the rectangular opening,

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