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Basic principles of transcranial magnetic stimulation (TMS) and

A R T I C L E I N F O A B S T R A C T

Article history: Transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS) are indirect and non-invasive
Received 13 March 2015 methods used to induce excitability changes in the motor cortex via a wire coil generating a magnetic
Accepted 31 May 2015 eld that passes through the scalp. Today, TMS has become a key method to investigate brain functioning
in humans. Moreover, because rTMS can lead to long-lasting after-effects in the brain, it is thought to be
Keywords: able to induce plasticity. This tool appears to be a potential therapy for neurological and psychiatric
Transcranial magnetic stimulation (TMS) diseases. However, the physiological mechanisms underlying the effects induced by TMS and rTMS have
Human
not yet been clearly identied. The purpose of the present review is to summarize the main knowledge
Cortex
available for TMS and rTMS to allow for understanding their mode of action and to specify the different
parameters that inuence their effects. This review takes an inventory of the most-used rTMS paradigms
in clinical research and exhibits the hypotheses commonly assumed to explain rTMS after-effects.
2015 Elsevier Masson SAS. All rights reserved.

1. Introduction 2. Animal experiments

Over the past decades, neuroscience researchers have beneted During the 20th century, animal studies provided the rst
from technical advancements in non-invasive brain stimulation in evidence of the effect of a single electrical pulse given by a probe
humans. Transcranial magnetic stimulation (TMS) is one method directly applied over the motor cortex [1]. In these experiments,
used to deliver electrical stimuli through the scalp in conscious the skull was removed to expose the brain. This set-up with
humans. In general, single-pulse TMS (including paired-pulse TMS) implanted electrodes allowed for recording the discharges from
is used to explore brain functioning, whereas repetitive TMS subcortical bers and bers of the pyramidal decussation. Later,
(rTMS) is used to induce changes in brain activity that can last Patton and Amassian showed that the response evoked in
beyond the stimulation period. Non-invasive TMS of the motor pyramidal bers by electrical stimulation of the motor cortex
cortex leads to a twitch in the target muscle evoking motor-evoked were spaced from 1 to 2 ms [2]. At a response threshold, anodal
potential (MEP) on electromyography. The MEP is usually used to stimulation evoked a rst volley in the pyramidal tract, which was
assess the corticospinal tract excitability. The physiological bases followed, with increasing stimulation intensity, by later volleys
underlying modulations induced by TMS and rTMS have not been separated by a periodicity of 1.5 ms. Different conditions were
elucidated. The main knowledge is still from animal studies and in tested to determine the origins of these descending volleys
vitro experiments performed on hippocampal slices. The purpose induced by anodal stimulation. The rst volley recruited appeared
of the present review is to discuss the main points of TMS to allow not to be affected by cortex cooling and was maintained after
for a better understanding of its mechanisms. removal of the cortical grey matter, whereas later volleys were
depressed by cortex cooling and disappeared when the grey matter
was removed. The authors hypothesized that the rst volley
resulted from direct stimulation of pyramidal tract axons, called
direct wave (D-wave), whereas later volleys came from synaptic
* Corresponding author. ER6 UPMC University Paris 6, Service MPR,
Hopital Pitie-Salpetriere, 47, boulevard de lHopital, 75651 Paris cedex 13, France.
activation of the same pyramidal tract neurons, called indirect
Tel.: +33 1 42 16 11 00; fax: +33 1 42 16 11 02. waves (I-waves). The recruitment order of descending volleys
E-mail address: alexandra.lackmy@upmc.fr (A. Lackmy-Vallee). evoked in the pyramidal tract by anodal stimulation was

http://dx.doi.org/10.1016/j.rehab.2015.05.005
1877-0657/ 2015 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Klomjai W, et al. Basic principles of transcranial magnetic stimulation (TMS) and repetitive TMS
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accurately dened by Kernell and Chien-Ping, who conrmed that underneath the coil. If the circular coil is placed at on the scalp,
the D-wave was the rst volley recruited and showed that it was currents ow in a plane parallel to both the coil and the scalp. The
followed 3 and 4.5 ms later by an I2-wave and I3-wave, respectively force of magnetic eld induced by TMS can be reduced by
[3]. However, an I1-wave occurring 1.5 ms later than the D-wave extracerebral tissues (scalp, bone, meninges), but it is still able to
was evoked only with high stimulation intensities. The authors induce an electrical eld sufcient to depolarize supercial axons
also found that the amplitude of descending volleys induced in the and to activate networks in the cortex [7]. However, because the
pyramidal neurons increased in parallel with stimulation intensity impedance of gray matter is greater than that of white matter,
of the motor cortex. electrical currents in subcortical structures are weaker than in
supercial layers, so subcortical structures such as the basal
3. First experiments of transcranial stimulation in humans ganglia and thalamus are not activated by TMS.

In 1980, Merton and Morton succeeded in electrically 4. Spinal motoneuron recruitment in response to TMS
stimulating the motor cortex through the scalp in conscious
humans by using transcranial electrical stimulation (TES) [4]. The On the basis of the Tofts model [6], TMS preferentially activates
electrical impulse was given by 2 electrodes placed over the scalp, neurons oriented horizontally in a plane that is parallel to both the
one applied over the arm motor area and the other 4 cm above the coil and the brain surface. As with TES, TMS applied over the motor
rst one. Electrodes were connected to a high-capacity condenser cortex induces descending volleys in the pyramidal tract projecting
(0.1 mF) charged up to 2000 V. TES led to a twitch in contralateral on spinal motoneurons, also termed corticospinal tracts. Motor-
arm muscles, which evoked MEP on electromyography (EMG). neuron activation in response to corticospinal volleys induced by
However, TES appeared to be uncomfortable and painful. Only TMS evokes MEP on EMG recorded by using surface electrodes
some fraction of the current was thought to pass through the scalp applied over the muscle belly. In practice, the peak-to-peak
and reach the cortex, whereas the main fraction of the current amplitude of the MEP and the motor threshold (MT), dened by the
spreading between the 2 electrodes was considered to evoke minimum TMS intensity required to evoke MEP of at least 50 mV in
contraction of the scalp muscles and induce local pain. In 1985, about 50% of 5 to 10 consecutive trials [8], are both parameters
Baker and colleagues proposed replacing TES with TMS [5]. TMS used to estimate the excitability of corticospinal pathways (Fig. 1).
directs a magnetic eld of several Teslas via a wire coil. In 1990, In 1987, a study showed that the rst motor unit recruited during
Tofts proposed a model of the distribution of TMS-induced minimal voluntary contraction was also that recruited by TMS of
currents in the central nervous system [6]. He suggested that as the motor cortex; the order of recruitment was the same with TMS
the magnetic eld changes rapidly, circular electrical currents are and with voluntary contraction [9]. Motor units are recruited in an
induced. The currents ow in a plane perpendicular to the orderly sequence from the smallest to the largest according to the
magnetic eld. So, current ows induced by TMS are in an annulus size principle [10].

Fig. 1. Transcranial magnetic stimulation (TMS) applied over the motor cortex preferentially activates interneurons oriented in a plane parallel to the brain surface. This
placement leads to a transynaptic activation of pyramidal cells evoking descending volleys in the pyramidal axons projecting on spinal motoneurons, also termed the
corticospinal tract. Motoneuron activation in response to corticospinal volleys induced by TMS leads to a contraction in the target muscle evoking a motor-evoked potential
(MEP) on electromyography (EMG) recorded by using surface electrodes applied over the muscle belly. Its peak-to-peak amplitude is used to estimate excitability of the
corticospinal tract.

Please cite this article in press as: Klomjai W, et al. Basic principles of transcranial magnetic stimulation (TMS) and repetitive TMS
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5. Physiological bases of TMS measures used to estimate effectiveness of stimulation appears to vary according to the
corticospinal excitability direction of currents induced in the motor cortex [20].
Various kinds of coils with different geometries and sizes have
From pharmacolocial studies with healthy volunteers, TMS been developed and include the circular coil, gure-of-eight coil,
measures used to estimate motor cortical and corticospinal double-cone coil, air-cooled coil and, more recently, the Hesed coil
excitability such as MT and MEP are assumed to rely on different [21], c-Core coil and circular crown coil [7]. Currents induced by
physiological mechanisms. Thus, the MT, which depends on circular coils widely spread under the windings and activate
excitability of cortico-cortical axons and their excitatory contacts supercial cortical layers. Circular coils are recommended for
to corticospinal neurons, is inuenced by agents blocking voltage- stimulating large and supercial motor areas such as upper-limb
gated sodium channels that are crucial in regulating axon motor areas. However, the gure-of-eight coil provides a focused
excitability [11] and by agents acting on ionotropic non-N- stimulation; the electric eld is at its maximum under its center
methyl-D-aspartate (non-NMDA) glutamate receptors such as (hot spot), where the 2 rings meet, for a more accurately dened
ketamine that are responsible for fast excitatory synaptic area. The electric eld of double-cone coils can reach deep cortical
transmission in the cortex [12]. In contrast, other neurotransmit- layers. This coil is mainly recommended for stimulating the motor
ters and neuromodulator systems such as GABA, dopamine, areas of lower limbs that are located deep inside the inter-
norepinephrine, serotonin or acetylcholine have no effect on MT. hemispheric ssure [22]. Nevertheless, the double-cone coil is not
As for MT, the MEP can be depressed by agents that inactivate focal. A single TMS via a double-cone coil over M1 evokes bilateral
sodium channels such as volatile anesthetics [13]. MEP reduction is responses in upper and lower limbs and also a contraction in facial
hypothesized to result from reduced excitability of I-waves due to muscles. The direction of current lines derives from the orientation
sodium-channel inactivation, which leads to decreased action and position of the coil over brain gyri and sulci. In most studies,
potential ring and in turn reduces calcium entry at the presynaptic TMS is used to stimulate M1. If the gure-of-eight coil over M1 is
terminal and nally synaptic transmission [14]. Moreover, MEP oriented parallel to the inter-hemispheric ssure, current ows in
amplitude was found to vary after the application of modulators of the posterioranterior direction and activates the pyramidal tract
inhibitory and excitatory transmission in neuronal networks. For indirectly via the recruitment of excitatory interneurons. Thus,
instance, MEP is depressed by modulators of GABAA receptors or posteriorly directed currents in the brain preferentially elicit late
increased by dopamine agonists and various norepinephrine volleys in the corticospinal tract. However, if the gure-of-eight
agonists. Of note, changes in MEP amplitude can occur without coil is oriented perpendicular to the inter-hemispheric ssure, an
signicant changes in MT, which supports the notion of a early I-wave and even a D-wave can be recorded [23].
fundamental difference in physiology between the 2 measures [15]. Recently, navigated brain stimulation (NBS) has been devel-
oped to facilitate the use of TMS. NBS devices consist of an infrared
camera detecting trackers placed on a headband worn by the
6. Descending volleys induced in the corticospinal tract
subject and on the coil. From MRI brain data, NBS is able to rebuild
the subjects head in 3-D and to record the coil position. Some
In 1990, direct epidural recordings were performed in
devices can measure the strength and direction of the electric eld
anesthetized subjects to compare descending volleys evoked by
induced in the brain by TMS. More than just being an improvement
TES and TMS in the corticospinal tract [16]. The pattern of
of TMS measurement, NBS offers the possibility of reliably
recruitment of corticospinal volleys evoked by TES seemed to
stimulating other brain areas such as the premotor cortex,
closely resemble that evoked in animals by anodal electrical
cerebellum, sensory areas and cognitive areas.
stimulation of the motor cortex: D-wave, late I-waves, then early I-
wave. This nding suggests that TES preferentially activates
cortical neurons in a plane vertical to the surface brain. The D- 8. Paired-pulse TMS methods
wave induced by TES is thought to result from excitation of
pyramidal tract axons at the initial segment [17,18]. Consistent Paired-pulse TMS methods have been developed since the late
with the Tofts model [6], the recruitment pattern of corticospinal 20th century. Paired-pulse TMS consists of 2 successive pulses
volleys induced by TMS differed from that evoked by TES, as through the same coil, delivered with a short inter-stimulus
attested by epidural recordings. With increasing TMS intensity, the interval (ISI) of a few milliseconds or a long ISI (from tens to
I3-wave was rst recruited, followed by the I2-wave, then I1-wave. hundreds of milliseconds). In practice, both pulses are applied over
In a few subjects, the D-wave could be evoked with high TMS the same point of the dominant hemisphere over the motor cortex.
intensities. These results conrmed that TMS preferentially This method is used to explore inhibitory or excitatory intracortical
activates cortical interneurons relaying excitatory inputs to networks depending on the intensity and ISI used [2426]. Never-
pyramidal neurons. theless, paired-pulse TMS can reveal inhibitory cortical networks
more easily than excitatory networks, which are less investigated.
Two TMS pulses can also be delivered over each hemisphere at the
7. Variability of TMS-induced responses
same point of the motor cortex so as to explore inter-hemispheric
inhibition (or transcallosal inhibition) [27].
The path and strength of an electrical eld generated in the
brain by TMS depends on many physical and biological parameters
such as magnetic pulse waveform; shape and orientation of the 9. rTMS methods
coil; intensity, frequency and pattern of stimulation; orientation of
the current lines induced in the brain; and excitable neural Contrary to single-pulse TMS, rTMS is able to change and
elements. TMS can deliver a monophasic pulse or biphasic pulses. modulate cortical activity beyond the stimulation period, as a
Monophasic magnetic pulses are commonly used for single-pulse potential method for the treatment of neurological and psychiatric
experiments, whereas biphasic stimulus waveforms are usually disorders. The physiological bases of rTMS after-effects have not
required in rTMS experiments because of the lower energy yet been clearly identied. Many arguments support the idea that
requirements [19]. The effect of mono- and biphasic pulses can the mechanisms underlying rTMS after-effects resemble long-term
be compared if the second and decisive phase of the biphasic pulse potentiation (LTP) and long-term depression (LTD) described in
is taken as the equivalent of the initial monophasic pulse [7]. The animals.

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10. Potential cellular mechanisms inducing LTP and LTD and duration of the stimulation period [34]. Low-frequency
stimulation (< 1 Hz) has inhibitory effects, whereas high-
LTP and LTD are broad terms that traduce long-term changes in frequency stimulation (> 5 Hz) leads to excitatory effects in the
synaptic strength that can occur in experimental conditions after brain. The duration of the after-effects seems to vary in parallel
brief high-frequency stimulation. LTP is dened as an increase in with the length of the stimulation. A longer stimulation induces a
synaptic strength, whereas LTD reects a decrease in synaptic longer duration of after-effects.
strength. These concepts were introduced in 1973 by Bliss and Simple rTMS protocols have individual stimuli that are spaced
Gardner-Medwin, who showed in rabbits that trains of high- by identical ISI (Fig. 2). In most low-frequency rTMS studies, the
frequency stimulation delivered to pyramidal cell axons in the stimulation frequency is usually set at 1 Hz, with stimulation
hippocampus led to a long-lasting increase in the amplitude of intensity and pulse number varying among studies. Low-
excitatory postsynaptic potentials [28]. Thus, if weak and strong frequency rTMS (1 Hz) is considered to have an inhibitory effect
inputs were activated together, the temporal order of the pre- and but at low intensities (less than MT), 1-Hz rTMS often fails to
post-synaptic spiking determined whether LTP or LTD was induced. have measurable effects on motor excitability. Some ndings
On stimulating rst the presynaptic neuron, then the postsynaptic indicate that variability of response to 1-Hz rTMS might be
neuron (prepost) within an interval of tens of milliseconds, LTP is related to the level of motor cortex excitability of the targeted
induced, whereas with stimulation in the reverse order (postpre), muscle. 1-Hz rTMS suppresses MEP only when the target muscle
LTD is induced. No changes in the synaptic strength were observed if is at rest. The depression of MEP could be increased if 1-Hz rTMS
the ISI was longer than 100 ms [29]. The extensive literature on this is preceded by a high-frequency subthreshold stimulation as
issue stresses that plasticity changes depend on the synapses and the compared to no preconditioning stimulus. This increase in
circuits in which they operate. Several arguments suggest that LTP cortical depression lasts for at least 60 min [35]. In contrast,
can be induced by activation of NMDA receptors. This post-synaptic high-frequency rTMS (5-25 Hz) is thought to increase cortical
receptor has an intrinsic cation-channel blocked by Mg ions when excitability. Berardelli et al. reported that 5-Hz rTMS set at 120%
the cell is at its normal resting potential. When the synaptic neuron of the MT facilitated MEP for 1 s [36]. However, the duration of
is sufciently depolarized, Mg2+ ions are ejected to open the NMDA- effects induced by high-frequency rTMS varies according to
receptor cation-channel. The calcium entrance in post-synaptic cells stimulation intensity, pulse number and stimulation frequency.
activates a calcium-sensitive signalling pathway, which has many High-frequency rTMS after-effects can persist up to 90 min after
downstream targets that induce changes in pre- and post-synaptic stimulation in some cases. However, after-effects induced by
neurons leading to increased synaptic strength. One of these effects high-frequency rTMS could be reversed because of stimulation
is increased post-synaptic neuron sensitivity to glutamate according intensity. Low intensity (less than MT) tends to decrease cortical
to a mechanism involving alpha-amino-3-hydroxyl-5-methyl-4- excitability, whereas high intensity (greater than MT) increases
isoxazolepropionic acid (AMPA) receptors [30]. Moreover, experi- cortical excitability [37]. As for low-frequency rTMS, modula-
ments with hippocampal slices revealed that nitric oxide (NO), a tions induced by high-frequency rTMS depend on the level of
membrane-soluble neuronal messenger, could contribute to synap- excitability of motor neurons of the target muscle. If subjects
tic plasticity in the brain. Inhibitors of NO synthase (NOS) could perform a brief isometric contraction of the target muscle, the
suppress the induction of LTP in the hippocampus and block LTD in MEP facilitation induced by 5-Hz rTMS is longer than that
the cerebellum [31]. The NO contribution to synaptic plasticity observed in subjects at rest [38].
depends on the strength (i.e., intensity, frequency or duration) of Besides simple rTMS protocols, new rTMS protocols have
tetanic stimulation. Thus, LTP induced by weak tetanic stimulation been developed. The most used is theta burst stimulation (TBS),
would be blocked by NOS inhibitors, whereas stronger tetanic which has been used in animal studies to induce synaptic
stimulation would lead to NO-independent potentiation [32]. More- plasticity. The pattern of TBS is based on the brains natural
over, NO paired with low-frequency stimulation (0.25 Hz) produces theta rhythm occurring in the hippocampus. TBS consists of
long-lasting depression rather than potentiation [33]. Whether NO bursts of high-frequency stimulation (Fig. 2). The intensity is
affects plasticity by facilitating potentiation mechanisms or subthreshold, usually set at 80% of the MT. Different patterns of
contributes to LTP induction by inhibiting LTD is unclear. TBS produce different effects on motor cortex excitability. An
Concerning LTD, its induction reverses the LTP effects or LTD is intermittent TBS (iTBS) protocol, with TBS applied for 2 s and
induced de novo. Several hypotheses suggest that LTD induction then repeated every 10 s, increases motor cortex excitability
also results from activation of NMDA receptors, thereby leading to [34,39,40]. A continuous TBS (cTBS) protocol, with TBS repeated
increased Ca2+ concentration. Contrary to LTP induction, which for 40 s without any pause, induces a consistent depression of
would be due to a large and fast increase in Ca2+ concentration, LTD the MEP. The duration of the TBS after-effects depends on
induction would arise from a small and slow increase in Ca2+ stimulation. iTBS applied for a total of 190 s increases MEP for at
content. In vitro, LTD is induced by low-frequency stimulations least 15 min, whereas 40 s of cTBS depresses MEP for
delivered for long periods (60000 pulses), whereas LTP occurs approximately 60 min. TBS is assumed to produce a mixture
after short train stimulations delivered at high frequencies. of facilitatory and inhibitory effects, facilitation building up
Changes in synaptic strength resulting from LTP or LTD are faster than inhibition [39]. Of note, results of TBS protocols seem
commonly divided into 2 phases: more consistent than those of simple rTMS protocols, likely
because in TBS studies, stimulation intensity and number of
 a short phase (early LTP or LTD) when changes last for only 30 to pulses applied are approximately equal, which is not the case in
60 min; simple rTMS studies [30].
 a long phase (late LTP or LTD) when modications of protein The last TMS protocol detailed in this review is termed paired
synthesis occur [30]. associative stimulation (PAS), introduced by Stefan, in 2000. PAS
protocols combine a repetitive stimulation of somatosensory
afferents with TMS over the contralateral motor cortex [34]
11. rTMS protocols (Fig. 2). PAS is based on models of associative LTP or the Hebbian
concept described in animals. This model supports that converg-
Numerous rTMS protocols have reported different after-effects. ing inputs from various sources, including local intracortical
An after-effect induced by rTMS depends on stimulation frequency bers and corticocortical or thalamocortical afferents, could

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LF rTMS

1s
HF rTMS

1s

cTBS

1s

0.2s
iTBS

1s
3 pulse train 8s
0.2s

PAS
TMS TMS TMS

Peripheral
nerve smulaon
pre 90 paired-smulaons post
ISI > aerent delay
ISI < aerent delay
Fig. 2. Simple repetitive TMS (rTMS) protocols consist of identical stimuli spaced by an identical inter-stimulus interval (ISI). Effects depend on stimulation frequency: at low
frequency (LF rTMS < 1 Hz), rTMS depresses excitability in the motor cortex, whereas at high frequency (HF rTMS > 5 Hz), cortical excitability is increased. Theta burst
stimulation (TBS) involves bursts of high-frequency stimulation (3 pulses at 50 Hz) repeated with an ISI of 200 ms (5 Hz). In an intermittent TBS (iTBS) protocol, bursts are
delivered for 2 s, then repeated every 10 s (2 s of TBS followed by a pause of 8 s). However, in a continuous TBS protocol (cTBS), bursts are repeated for 40 s without any pause.
Paired associative stimulation (PAS) protocols combine a repetitive stimulation of peripheral nerve afferents of the target muscle with TMS over its motor area. Intervention
consists of 90 to 100 PAS.

interact to reshape local representational cortical patterns receptors. Furthermore, dopamine could also play a role in
[41]. In this concept, the temporal order of the presynaptic and inducing PAS after-effects [30].
postsynaptic spiking determines whether LTP and LTD is induced
when a weak and strong input are activated together [29]. In
humans, the nature of effects induced by PAS depends on the ISI 12. Conclusion
between the electrical peripheral nerve stimulation and cortical
stimulation. If the ISI is shorter than the afferent delay (time The aim of the present review was to summarize the main
required for the peripheral afferent input to reach the brain), PAS knowledge about the physiological bases of TMS and rTMS. Given
depresses the excitability in the motor cortex. In contrast, if ISI is the numerous physical and biological parameters that inuence
longer than the afferent delay, PAS increases cortical excitability TMS responses, effects induced by TMS and rTMS differ among
[42]. Pharmacological studies support that PAS after-effects studies, so calibrated paradigms need to be dened to increase
would rely on mechanisms depending on NMDA and GABAB reproducibility. The great variability in results questions the use of

Please cite this article in press as: Klomjai W, et al. Basic principles of transcranial magnetic stimulation (TMS) and repetitive TMS
(rTMS). Ann Phys Rehabil Med (2015), http://dx.doi.org/10.1016/j.rehab.2015.05.005
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Please cite this article in press as: Klomjai W, et al. Basic principles of transcranial magnetic stimulation (TMS) and repetitive TMS
(rTMS). Ann Phys Rehabil Med (2015), http://dx.doi.org/10.1016/j.rehab.2015.05.005