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The use of transcranial magnetic stimulation as a treatment for movement

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 REVIEW

The Use of Transcranial Magnetic Stimulation as a Treatment

for Movement Disorders: A Critical Review
Anna Latorre, MD,1,2 Lorenzo Rocchi, MD,1 Alfredo Berardelli, MD,2,3
Kailash P. Bhatia, FRCP, MD,1 and John C. Rothwell, PhD1*

1
Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology University College London, London, UK
2
Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy
3
IRCCS Neuromed Institute, Pozzilli, Isernia, Italy

A B S T R A C T : Background: Transcranial magnetic stim-
ulation is a safe and painless non-invasive brain stimula-
tion technique that has been largely used in the past
30 years to explore cortical function in healthy participants
and, inter alia, the pathophysiology of movement disor-
ders. During the years, its use has evolved from primarily
research purposes to treatment of a large variety of
neurological and psychiatric diseases. In this article, we
illustrate the basic principles on which the therapeutic
use of transcranial magnetic stimulation is based and
review the clinical trials that have been performed in
patients with movement disorders.
Methods: A search of the PubMed database for research
and review articles was performed on therapeutic appli-
cations of transcranial magnetic stimulation in movement
disorders. The search included the following conditions:
Parkinson’s disease, dystonia, Tourette syndrome and
other chronic tic disorders, Huntington’s disease and
choreas, and essential tremor. The results of the studies
and possible mechanistic explanations for the relatively
minor effects of transcranial magnetic stimulation are dis-
cussed. Possible ways to improve the methodology and
achieve greater therapeutic efficacy are discussed.
Conclusion: Despite the promising and robust rationales
for the use of transcranial magnetic stimulations as a treat-
ment tool in movement disorders, the results taken as a
whole are not as successful as were initially expected.
There is encouraging evidence that transcranial magnetic
stimulation may improve motor symptoms and depression
in Parkinson’s disease, but the efficacy in other movement
disorders is unclear. Possible improvements in methodol-
ogy are on the horizon but have yet to be implemented in
large clinical studies. © 2019 International Parkinson and
Movement Disorder Society
Key Words: movement disorders; neurophysiology; plas-
ticity; repetitive transcranial magnetic stimulation; trans-
cranial magnetic stimulation

What Is Transcranial Magnetic been largely used to explore cortical function in healthy
subjects and in patients with neurological and psychiat-
Stimulation? ric disorders, both for experimental and clinical purposes.
Transcranial magnetic stimulation (TMS) is a nonin- Most of this work has been performed on the human
primary motor cortex (M1) and has given important
vasive neurophysiological technique that can stimulate
pathophysiological and clinical insights in the field of
the human brain through the intact skull without pro-
movement disorders (MD).2-4
ducing significant discomfort. TMS was developed in
Magnetic stimulators consists of capacitors able to dis-
1985 by Barker and colleagues,1 and since then it has
charge a large current (with a peak of amplitude of up
-*Correspondence
- - - - - - - - - - - - - - -to:- - Dr.
- - - John
- - - - -C.- -Rothwell,
- - - - - - - 33
- - -Queen
- - - - - -Square,
- - - - - - London
------- to 10000 A) that lasts about 1 millisecond and flows
WC1N 3BG, UK; E-mail: j.rothwell@ucl.ac.uk through an induction coil placed on the scalp.5 This cur-
Relevant conflicts of interests/financial disclosures: Nothing to rent produces a strong magnetic field, perpendicular to
report. the coil, which can reach values of up to 3 Tesla; it easily
Received: 16 December 2018; Revised: 4 April 2019; Accepted: passes through the scalp and skull and induces a second-
7 April 2019 ary electric (“eddy”) current in the brain.2 The intensity
Published online 00 Month 2019 in Wiley Online Library
of the magnetic field declines quickly with distance from
(wileyonlinelibrary.com). DOI: 10.1002/mds.27705 the coil so that it is usually assumed that neural stimulation

Movement Disorders, 2019 1

L A T O R R E E T A L
is limited to the cortex and superficial subcortical white
matter.6 Stimulation over M1 can produce descending
activity in the corticospinal pathway that activates muscles
on the opposite side of the body and produces a visible
twitch that is easily measured using surface electromyogra-
phy.7 This is known as a motor evoked potential (MEP).
In addition to a single pulse, TMS pairs of pulses can be
delivered through the same coil to study intracortical
inhibitory and excitatory circuits.8-12 TMS can also assess
inputs to M1 from other areas by observing how the
MEP is modulated by a preceding stimulus, the latter
being either a magnetic pulse applied over a different
cortical area13 or a stimulus activating afferents from var-
ious sensory modalities.14-16 It is also possible to apply
repetitive TMS (rTMS) in the form of short17,18 or long
trains, either regular or patterned,19-24 or associated with
diverse cortical or sensory stimulation.14,18,25 These pro-
tocols can induce long-term changes in cortical excitabil-
ity that are the result of changes in synaptic plasticity.
The most common patterns of stimulation of rTMS are
described in Table 1 and Figure 1.26,27
Why rTMS Might Be Used
as a Therapeutic Tool
The rational use of non-invasive brain stimulation as
a therapeutic tool is to provide additional benefit to
conventional treatment, especially for refractory symp-
toms or in patients in whom surgical approaches are
contraindicated. With this purpose and in view of its
safety and lower side effects when compared with elec-
troconvulsive therapy, rTMS was used for the first time
in 1993 to treat drug-resistant major depression disor-
der.28 In light of the successful results, rTMS was then
applied in other psychiatric and neurological condi-
tions, including MD, as a possible therapy.
TABLE 1. Commonly used rTMS techniques
rTMS: consecutive TMS stimuli at a specific frequency, with variable
interstimulus intervals.
• Short train of regular 5 Hz rTMS: MEP facilitation
• Long train of regular ≤1 Hz rTMS: MEP inhibition
• Long train of regular ≥5 Hz rTMS: MEP facilitation
• Short high-frequency trains (bursts) at a predefined repetition rate-
TBS: intermittent TBS induces MEP facilitation (LTP-like plasticity),
continuous TBS-induced MEP inhibition (LTD-like plasticity)
• Paired associative stimulation (PAS): 100-200 pairs of electrical
stimuli at the median nerve at the wrist and TMS stimuli to the
contralateral M1 (interval of about 25 milliseconds) are given every
4-10 seconds (LTP-like plasticity)
rTMS, repetitive transcranial magnetic stimulation; LTD, long-term depres-
sion; LTP, long-term potentiation; MEP, motor evoked potential; TBS, theta
burst stimulation.
2 Movement Disorders, 2019
In all of these cases, it is assumed that therapeutic
effects depend on changes in synaptic plasticity pro-
duced by periods of rTMS.
TMS and Synaptic Plasticity
The data supporting rTMS effects on synaptic plastic-
ity in the brain mostly come from TMS studies of M1.
Depending on the intensity and direction of the current,
TMS can activate the large corticospinal neurones that
constitute the corticospinal (or pyramidal) tract either
directly or trans-synaptically. In the second case, the
TMS pulse first discharges an unknown set of neurons
that secondarily activate the corticospinal neurones via
excitatory synapses.2,29 Therefore, when a TMS pulse
is given, activity at these synapses causes discharge of
the corticospinal neurones and consequent conduction
of the impulses to the spinal cord and muscle. It is well
known from animal experiments that repetitive stimula-
tion at the synaptic level can enhance or reduce synap-
tic transmission, a phenomenon known as long-term
potentiation (LTP) or long-term depression (LTD). LTP
is often induced by a short period of high-frequency
repetitive stimulations, whereas LTD usually occurs after
low-frequency stimulation.30 Because TMS indirectly acti-
vates synapses, repeated pulses of TMS (ie, rTMS) can in
theory activate the same set of synaptic connections multi-
ple times and therefore replicate the situation seen in ani-
mal experiments. Thus, rTMS over M1 can lead to
medium-term changes in the amplitude of MEPs that per-
sists after the end of stimulation. By analogy with the ani-
mal experiments, high-frequency rTMS increases MEPs,
whereas low frequency reduces MEPs, reflecting an
increase or decrease of cortical excitability. It is thought
that these changes are caused respectively by synaptic
LTP/LTD because they are no longer present in individ-
uals pretreated with drugs that interfere with N-methyl-
D-aspartate receptor (NMDA), receptors (known to be
involved in LTP/LTD processes).27,31
Because the after-effects persist only 30 minutes after
repetitive stimulation, they probably represent the early
phase of plasticity (early LTP/LTD) in animal experi-
ments. This is a stage where the change in efficiency is
probably the result of a combination of increased trans-
mitter release from the presynaptic neurone and an
increase in response to transmitter by the postsynaptic
neurone (eg, by inserting more receptors in the mem-
brane). Protein synthesis is required to produce more
permanent changes, such as increases in synaptic effi-
cacy or the formation of new synapses.30 These conclu-
sions have been reinforced by experiments in which
rTMS has been applied to the brains of rodents. These
have revealed changes at a molecular level that would
be consistent with the idea that rTMS in humans may
be able to interact with synaptic plasticity. The data
reveal structural effects on synaptic morphology32 as
 R T M S F O R
FIG. 1. The most common patterns of stimulation of rTMS. cTBS, continuous theta burst stimulation; ES, electrical stimulation; HF, high frequency;
iTBS, intermittent theta burst stimulation; LF, low frequency; MS, magnetic stimulation; PAS, paired associative stimulation; rTMS, repetitive transcranial
magnetic stimulation.
well as changes in Calcium ion (Ca2+) dynamics, which
then modulate the expression of glutamate receptors33
and immediate early genes that regulate the expression of
specific genes.34
In addition to rTMS, the effects on synaptic plasticity
can be produced by a second method known as spike-
timing dependent plasticity. This involves repeated
pairing of synaptic inputs to a neurone with a subse-
quent discharge (spike) of the neurone itself. This can
be replicated in humans by pairing an input to cortex
produced by electrically stimulating a peripheral nerve
(eg, median nerve) with a TMS pulse to the cortex. In
humans this is called paired associative stimulation
(PAS).35 PAS can increase or decrease MEPs for 30
minutes similarly to rTMS. Novel PAS protocols, using
a cortical–cortical approach or different sensory stimuli,
have also been applied in humans.14,18,25
There are other mechanisms that might mediate the
effect of rTMS and are probably independent of synap-
tic plasticity. For instance, rTMS has been shown to act
on the neuroendocrine system by decreasing corticoste-
roid levels in rats36 and humans.37 Other effects include
the prevention of neuronal death, as demonstrated by
applying low-intensity magnetic stimulation in cultures
of cortical neurons,38 and increased expression of the
glial fibrillary acidic protein in astrocytes.39 Overall,
data on the effects of rTMS beyond synaptic plasticity
are still scarce, but increasing information in this regard
might help to improve the therapeutic role of rTMS.
T H E T R E A T M E N T O F M O V E M E N T D I S O R D E R S
Approaches to Using rTMS as a Therapy
The effects of rTMS in humans are transitory and last
about 30 to 60 minutes, depending on parameters such
as the number of pulses applied, the rate of application,
and the intensity of each stimulus.31 Practically this
would seem to have a limited therapeutic effect because
the intent is to induce lasting changes in patients’ symp-
toms. Nevertheless, in animal experiments, it is possible
to produce more permanent changes in synapses if stim-
ulation is repeated after a pause of a few minutes or
hours.40 Repeated induction of plasticity is thought to
reinforce the change from transitory early to more per-
manent late LTP/LTD. The approach in humans is simi-
lar, and there is evidence that repeated rTMS
administration might produce cumulative effects, which
depend on the number of sessions.41-44 In most cases,
rTMS is given daily for 5, 10, or more days.45 For
instance, in depression the remission rates are higher
with longer rTMS treatment (up to 6 weeks),46,47 and
more recent studies indicate that at least 20 to 30 ses-
sions are required to have optimal effects48; in fact,
even longer courses might be needed in some cases.49 It
is thought that rTMS can gradually induce changes in
functional and structural connectivity that normalize
the depression-associated network dysfunctions.50
Because of the bulk of the stimulating coil and its
electrical supply, TMS is usually given when patients
are seated and relaxed. For example, in the treatment
of depression, patients are given rTMS daily when seated
Movement Disorders, 2019 3
L A T O R R E E T A L
in a comfortable chair. A different approach is to give
rTMS prior to a training intervention (eg, prior to stan-
dard physiotherapy if treating stroke patients51-53). The
rationale is that therapy involves learning, which itself
changes the effectiveness of synaptic connections that are
required to improve performance in the task. Giving
rTMS prior to this training might increase the effective-
ness of this process and result in a more highly targeted
set of synaptic changes.
Evidence That rTMS Might Be a Useful Therapy
The best evidence that rTMS might be practically use-
ful as a therapy comes from its use in patients with
drug-resistant major depression disorder. The rationale
for using rTMS originates from imaging studies where
patients with depression showed reduced activity (eg,
Blood oxygenation level dependent (BOLD) or glucose
metabolism) of the left dorsolateral prefrontal cortex
(DLPFC).54 High-frequency rTMS was therefore sup-
posed to increase excitability by strengthening synaptic
connections, as suggested by the appropriate changes in
activation seen after a course of rTMS in imaging stud-
ies.55,56 However, more recently this hypothesis has
been reviewed. Major depression disorder is now con-
sidered a disorder of dysregulated neural networks.57
Several functional networks have been studied in major
depression disorder, but two are of particular interest:
the anterior cinguloinsular network or salience network
and the ventromedial network or reward network.58
Although the salience network is crucial for cognitive
control and response inhibition and involves the
DLFPC, the reward network corresponds to the classic
reward circuit and involves the ventromedial prefrontal
cortex. These two networks play opposite roles in
behavioral regulation, and it is conceivable that one is
active when the other is not and vice versa. Major
depression disorder has been associated to a pattern of
salience network hypoactivity and reward network
hyperactivity,59-61 and it has been supposed that excit-
atory rTMS intervention targeting the salience network
by stimulating DLPFC should exert a therapeutic effect
by enhancing cortico-striatal-thalamic connectivity,
whereas an intervention to target the reward network
through the ventromedial prefrontal cortex should
exert therapeutic effect by reducing cortico-striatal-
thalamic connectivity.58 Some imaging studies have
confirmed the hypothesis for the salience network.62
rTMS treatment also has other effects and can lead to
significant changes in neural activity in fronto-limbic
brain regions,55,63,64 in neurotransmission (not only
close to the stimulation site),65-67 in hypothalamic-pitui-
tary-adrenal axis function,68 and in concentrations of
neurotrophic factor.69,70
There have been four large, multicenter, randomized
controlled trials on the antidepressant effect of high-
4 Movement Disorders, 2019
frequency prefrontal rTMS (for a total of 782 subjects
studied).47,71-73 Of these (291 participants), two revealed
negative results with no difference in the responder rates
of the real and the sham treatment groups71,73 (differ-
ently from the others, one of these studies involved
adjunctive TMS and medications starting simultaneously
rather than TMS as the primary treatment or mon-
otherapy71). The other two trials showed positive results,
that is, 3 to 6 weeks of daily (weekdays only) high-
frequency rTMS over the left DLPFC improved clinical
outcomes significantly more than placebo.47,72 In 2008,
the Food and Drug Administration approved the first
TMS device for therapeutic clinical use in drug-resistant
depression, and since then several other studies further
confirmed its effectiveness in clinical practice.74-77 More-
over, several meta-analyses have reported that the sham-
controlled evidence base for the use of TMS in depres-
sion is clinically and statistically significant.78-82 These
trials led to a positive endorsement by specialty societies
and technology assessment entities48,83-85 and a wide
acceptance of TMS as a treatment in routine clinical
practice for patients who have not benefited from treat-
ment with antidepressant medications.
Rationale for rTMS in Basal Ganglia Disease
The core anatomical and functional impairment in
MD resides in the basal ganglia, which lie too deep to
be readily stimulated with conventional TMS coils.
However, it is well known that the basal ganglia are
part of a group of parallel closed circuits (the basal
ganglia-thalamo-cortico-basal ganglia loop) that origi-
nate in the cerebral cortex, traverse the thalamus, and
return to their individual sites of origin in the frontal
lobe.86 Thus by analogy to depression, it could be that
even if direct effects of TMS are limited to the cortex,
stimulation over an appropriate cortical region that is
part of the basal ganglia circuitry can influence activity
within these loops and potentially produce clinical ben-
efit. In confirmation of this idea, functional MRI
(fMRI) studies in humans show that TMS of the left
dorsal premotor cortex (PMC) and presupplementary
motor area (SMA) can increase the BOLD signal in the
striatum and thalamus,87,88 and PET imaging reveals
that TMS can produce a transient release of dopamine
in the striatum.89,90 Similarly, cortical TMS can sup-
press beta activity in the subthalamic nucleus (STN),91
and this might be therapeutically relevant in
Parkinson’s Disease (PD) because enhanced beta syn-
chronization is related to parkinsonian symptoms.92
Data in animal experiments are consistent with this
notion that interacting with one node of a complex circuit
can change activity at some distance from the node. In
rodent models of PD, optogenetic studies suggest that
stimulation of STN afferent projections from the cortex
ameliorates bradykinesia and hypokinesia and causes
 R T M S F O R T H E T R E A T M E N T O F M O V E M E N T D I S O R D E R S

widespread increased glutamatergic activity in the thalamus TABLE 2. Number of participants in rTMS studies to treat
and other brain regions.93 In primates, implanted electrical motor symptoms in PD
stimulation of motor cortex can alleviate MPTP-induced
Number of patients
symptoms of parkinsonism,94 although attempts to repli- Study included in the study
cate this in humans have not been successful.94,95
In summary, rTMS may affect the strength of synap- 1 Pascual-Leone et al, 1994188 6
tic connections in the human cortex. The evidence for 2 Siebner et al, 1999189 12
3 Siebner et al, 200096 10
this comes mainly from experiments in motor cortex, 4 Shimamoto et al, 200197 9
but it is usually assumed that similar effects will be 5 Boylan et al, 2001115 8
observed in all areas of neocortex. In basal ganglia dis- 6 Khedr et al, 200398 36
ease, it is argued that changing the function of cortical 7 Ikeguchi et al, 200399 12
regions directly with rTMS may have secondary effects 8 Okabe et al, 2003100 85
9 Lefaucheur et al, 2004101 12
on connected structures in the basal ganglia–cortex 10 Bornke et al, 2004102 12
loops. This is the basis for attempting to use it thera- 11 Koch et al, 2005123 8
peutically in basal ganglia disease. Finally, previous evi- 12 Brusa et al, 2006190 10
dence from depression suggests that rTMS can be a 13 Khedr et al, 2006118 55
useful therapeutic option. 14 Lomarev et al, 2006191 18
15 del Olmo et al, 2007192 13
16 Khedr et al, 2007114 20
The Use of rTMS for the 17 Wagle-Shukla et al, 2007121 6
18 Filipovic et al, 2009122 10
Treatment of MD 19 Hamada et al, 2008103 98
20 Koch et al, 2009124 10
Methods: Literature Review 21 Benninger et al, 2009193 10
To select studies for inclusion in this review, the 22 Rothkegel et al, 2009116 22
23 Sedlackova et al, 2009104 10
Medline database (via PubMed, a service of the 24 Arias et al, 2010105 18
National Library of Medicine’s National Center for 25 Filipovic et al, 2010113 10
Biotechnology Information; https://www.ncbi.nlm.nih. 26 Kang et al, 2010194 11
gov) was searched for peer-reviewed papers published 27 Kimura et al, 2011106 12
from 1993 to present day using the following terms: 28 Gonzalez-Garcia et al, 2011195 17
29 Benninger et al, 2011133 26
Parkinson’s disease OR dystonia OR Tourette syn- 30 Benninger et al, 2012107 26
drome OR tics OR Huntington’s disease OR chorea 31 Mak et al, 2013196 22
OR essential tremor AND repetitive transcranial mag- 32 Shirota et al, 2013108 106
netic stimulation OR rTMS OR repetitive TMS OR 33 Maruo et al, 2013109 21
treatment TMS. All types of original articles were 34 Sayin et al, 2014125 17
35 Bologna et al, 2015130 13
included if rTMS protocols were performed for thera- 36 Cerasa et al, 2015126 11
peutic purposes, whereas pure pathophysiological stud- 37 Kim et al, 2015127 17
ies were excluded. Only articles written in English were 38 Tard et al, 2016129 15
included, whereas studies using other forms of non- 39 Brys et al, 2016110 50
invasive brain stimulation techniques were excluded. 40 Mally et al, 2017111 66
41 Kim et al, 2018128 12
Review articles (including meta-analysis) were checked 42 Yokoe et al, 2018112 19
to include relevant articles and information not inde- Total 961
xed in the electronic database.
rTMS, repetitive transcranial magnetic stimulation.

Parkinson’s Disease
Motor Symptoms. Several rTMS studies have been con-
ducted with the objective of improving motor symptoms in
PD (Table 2); overall they provided mixed results (for a
review, see ref. 45). These studies differed with regard to
rTMS protocols (high/low frequency), cortical areas stimu-
lated (M1, prefrontal cortex), sample size, disease duration,
and therapeutic aims (bradykinesia, handwriting, tremor,
gait, etc.). The degree and type of motor signs that improve
varies among studies. The main outcome used is the motor
part of the Unified Parkinson’s Disease Rating Scale
(UPDRS),96-114 assessing the overall improvement of the
motor symptoms, including bradykinesia, tremor, rigidity,
postural instability, and gait. Alongside the UPDRS,
some of the studies also evaluated motor planning and
walking tests.98,99,101,104,105,107,109,111,115-117
The results from three large randomized controlled
trials have shown reasonable evidence that 1 Hz and
5 Hz rTMS over SMA significantly improves UPDRS
motor scores (the former stimulation being more effec-
tive on posture and gait, whereas the latter had greatest
effect on bradykinesia) and that rTMS is a promising
add-on therapy for motor symptoms of PD. In contrast,
a slower stimulation frequency (0.2 Hz) seems to have
beneficial effects similar to sham stimulation.100,103,108

Movement Disorders, 2019 5

L A T O R R E E T A L

Other cortical targets have also proved successful. One
large, double-blind, sham-controlled, randomized, parallel-
group, fixed-dose study provides class I evidence that in
patients with PD on antiparkinsonian treatment, high-
frequency rTMS (10 Hz) over M1 leads to improvement
in overall motor UPDRS and in particular in rigidity
and bradykinesia, but not in tremor, gait, or axial symp-
toms.110 The effectiveness of high-frequency (5 Hz,
10 Hz and 25 Hz) rTMS over M1 has also been demon-
strated in other studies on patients not receiving anti-
parkinsonian medications.98,114,118 Overall, these data
support the efficacy of rTMS in treating motor symptoms
in PD, as confirmed by meta-analyses119,120; however, it
remains unclear whether SMA or M1 is the best target,
and the results suggest that different rTMS targets might
respond to different frequencies. The remaining studies
(Table 2) showed variable results, possibly because of
the small number of patients included and other con-
founding factors such as the use of non-realistic sham or
the different pharmacological state of the patients, which
might have affected the UPDRS motor scores.119,120
rTMS has also been evaluated as a possible therapeu-
tic tool for levodopa-induced dyskinesia, showing some
positive results when applied on M1 and SMA at low
frequency and on the cerebellum and inferior frontal
cortex using continuous theta burst stimulation (cTBS)
protocol.121-126 Another variable assessed has been
freezing of gait using high-frequency rTMS over M1
and on SMA and intermittent theta burst stimulation
(iTBS) over the premotor cortex,127-129 with contrasting
results. In one study, 1 session of cerebellar cTBS did
not improve rest tremor in PD.130
Importantly, all of the studies showed no major
adverse effects. In addition, they suggest that different
protocols have preferential effects on certain symp-
toms.101 Overall, in the majority of the studies, a greater
rTMS effect was positively associated with a higher
number of pulses across sessions and with the total num-
ber of pulses across sessions adjusted by intensity (ie,
total number of pulses across sessions times intensity).119
Non-motor Symptoms. Among the many non-motor
symptoms seen in PD, speech difficulty, cognitive dys-
function, and depression are the most frequently stud-
ied in rTMS trials. rTMS is an approved therapy in
several countries for refractory major depression disor-
der, and high-frequency rTMS of the DLPFC may offer
a therapeutic option for depression in PD45; in this con-
text, rTMS has been shown to have similar efficacy
to antidepressants.131,132 In one study, iTBS applied
over M1 and DLPFC improved mood, but not motor
symptoms in PD.133 It is important to mention that
among the randomized controlled trials that have
assessed the efficacy of rTMS in treating depression in
PD,134-138 one showed no benefit of left DLPFC rTMS
for mood symptoms.110
Highlights. According to the current evidence-based
guidelines on the therapeutic use of rTMS, the publi-
shed data suggest a possible therapeutic potential for
motor symptoms in PD; however, evidence is not strong
enough to use rTMS as a routine treatment.45 Indeed,
the effectiveness of rTMS in PD should be increased by
finding optimal stimulation parameters. In contrast,
high-frequency rTMS of the left DLPFC has a level B
recommendation (“probable efficacy”) in the treatment
of depression associated with PD.45
Dystonia
The following three principal mechanisms are
thought to play a role in the pathophysiology of dysto-
nia: loss of inhibition at different levels of the central
nervous system, abnormal sensorimotor integration,
and excessive plasticity.139 Based on this concept, the
rationale for the use of rTMS as a therapeutic tool for
dystonia is to reverse the aforementioned abnormalities,
in particular to act on the inhibitory circuits and possi-
bly reducing the excessive cortical plasticity.
The following two rTMS protocols have been
explored as possible treatments for dystonia with the
aim of increasing intracortical inhibition: low-frequency
rTMS and cTBS. They have been applied on M1 and the
PMC, SMA, primary somatosensory cortex, and cerebel-
lum with different protocols in patients with writer’s
cramp and craniocervical dystonia. Some of the studies
showed short-lasting objective or subjective improve-
ment of dystonia, whereas others did not (for a review,
see ref. 140). On the other hand, iTBS, an excitatory
protocol, has been demonstrated in one small study to
be successful in improving cervical dystonic symptoms
when applied on the cerebellum.141
Highlights. At present, there is insufficient evidence to
recommend rTMS as a therapeutic tool for dystonia,
even though some promising results have been publi-
shed.140 Physiological data suggested that inhibition of
the premotor–motor interactions through a cTBS proto-
col might be the promising strategy for dystonia treat-
ment.142 The dorsal PMC seems to be the ideal target
area for this.45,140
Tourette Syndrome and Other Chronic Tic
Disorders
The SMA is involved in the preparation and organiza-
tion of self-initiated movements and has been hypothe-
sized to have an important role in the pathophysiology of
tics.143,144 Neuroimaging studies have identified the SMA
as one of the structures that are hyperactive in Tourette
syndrome,145,146 and this has led to the hypothesis that
normalizing its excitability might be a potential treatment
for tics. Low-frequency rTMS of SMA, but not of M1 or
the PMC, has been shown to reduce tic severity as well as

6 Movement Disorders, 2019

 R T M S F O R T H E
comorbid obsessive-compulsive disorder.147-149 Neverthe-
less, the results were obtained from open-label studies,
and two more recent double-blind studies did not show a
clear significant tic improvement beyond a placebo
effect.150,151 In one of these double-blind studies, no dif-
ference was found between real and sham rTMS after
3 weeks of treatment; however, after 3 more weeks of
open-label active stimulation, participants that were previ-
ously assigned to the real arm showed a significant reduc-
tion in tic severity when compared with baseline.150
Highlights. Low-frequency rTMS over SMA has shown
favorable results in reducing tic severity and psychiatric
comorbidity (obsessive-compulsive disorder) in open-
label studies. However, the lack of significant effects in
double-blind trials questions the possible efficacy of
the intervention. Larger and appropriately designed
studies to assess rTMS efficacy in treating tic disorders
are needed.
Huntington’s Disease and Other Choreas
To date, only two studies have investigated the effective-
ness of rTMS in Huntington’s disease (HD), giving oppo-
site results. Brusa and colleagues152 found a significant
decrease of the involuntary movements after 1 Hz rTMS
over the SMA, but not after 5 Hz or sham stimulation, in
4 patients. This result has not been confirmed in 2 other
patients with HD.153 In HD, SMA is thought to play a cen-
tral role in maintaining the executive aspects of motor
control that increases with approaching disease onset.154
The effect of rTMS in HD has also been evaluated on
non-motor symptoms, such as depression, showing
sustained improvement in mood after 1 Hz rTMS on M1,
but no effect in the 10 Hz or sham rTMS condition.155
Considering other forms of chorea, cTBS has been tested
for therapeutic purpose in 1 patient with hemichorea
because of hemorrhage of the STN or the substantia nigra
or both of these structures. As a result, one session of real
cTBS produced a dramatic improvement in dyskinesias
during functional tasks, whereas a sham session did
not.156
Highlights. The SMA might be a promising target for
rTMS treatment157; however, the preliminary and con-
troversial results need to be confirmed in a large cohort
of patients with HD. rTMS needs to be tested in other
forms of chorea to prove its efficacy.
Essential Tremor
The pathophysiology of essential tremor (ET) is still
controversial. The findings are heterogeneous, and they
possibly reflect the clinical heterogeneity of ET.158
However, the evidence of a cerebellar involvement in
ET is quite robust, and it is very likely that the tremor
T R E A T M E N T O F M O V E M E N T D I S O R D E R S
is generated by a dysfunction in the cerebello-thalamo-
cortical network.159
To suppress tremor in ET, rTMS of the cerebellum has
been studied with variable results. Some improvement in
tremor rating scales was transiently observed after a sin-
gle session of 1 Hz cerebellar rTMS and for 3 weeks
after 5 days of consecutive sessions of 1 Hz rTMS.160,161
In the first study, the target was 2 centimeters below
the inion, and in the second it was approximately over
the cerebellar lobule VIII. A single session of cerebellar
cTBS did not show modification of tremor frequency,
smoothness of reaching movements, or clinical rating of
tremor.162 Other targets have been stimulated in further
studies, such as M1, through a single session of cTBS,163
and pre-SMA, with 15 daily sessions of 1 Hz rTMS.164
The results on clinical outcomes were null, but cTBS on
M1 could improve tremor measured with an accelerome-
ter.163 Interestingly, recent studies have shown that deliv-
ering DBS pulses at particular phases of the tremor cycle
causes clinically significant tremor relief,165,166 but this
approach has not been tried yet with noninvasive brain
stimulation.
Highlights. Although the cerebellum seems a plausible
target in ET, it remains unclear which rTMS protocol
might be optimal for tremor suppression. The results are
inconclusive so far, and more studies are needed.
Why Didn’t rTMS Induce Clear
Therapeutic Benefits in MD So Far?
Challenges and Future Directions
Despite the promising and robust rationales for the use
of rTMS as a treatment tool in MD, the results are not as
successful as were expected. However, this does not
extend to all MD and symptoms. The evidence of the
efficacy of rTMS in treating motor symptoms as an
add-on therapy to pharmacological treatment in PD is
reasonable,103,108 but despite this it has not had the same
impact as, for example, in major depression disorder.
There might be several explanations for this. The first is
the lack of a clear rationale to stimulate one cortical area
compared with another. For instance, SMA and M1
stimulation have both been reported to be effective,103,108
but it remains unclear whether one target is preferable
than the other or which is the best frequency of rTMS to
use at each site. The matter is different for major depres-
sion disorder because most studies have focused on a sin-
gle recommended site and protocol, producing consistent
results. Moreover, in contrast to major depression disor-
der, other more feasible treatment options are available
in PD. This might have discouraged the promotion of
large rTMS trials and the use of rTMS in a hospital set-
ting. Therefore, it seems that if a preferred target site
and protocol can be agreed on, and if there is a clear
Movement Disorders, 2019 7
L A T O R R E E T A L
demonstration that the benefits of rTMS are additional
to those of standard therapy in PD, then rTMS might
become an acceptable treatment. Unfortunately, at the
present time, this is not true for all PD symptoms (ie,
freezing of gait and dyskinesia) and most importantly
for the other MD. This might be because of the heteroge-
neity of the protocols employed and of the findings as
well as the lack of any large-scale trials.
The lack of success of rTMS in MD can be explained
also by technical reasons, the most obvious being the
large parameter space for rTMS. Studies in the literature
have used very different TMS settings in terms of stimu-
lation frequency and intensity, duration of trains, inter-
train interval, number of sessions, and time between
them. This has very likely contributed to the observed
heterogeneity of results and has complicated the issue of
devising effective rTMS protocols. Some biological fac-
tors should also be considered. For instance, it may be
necessary to target particular brain areas to treat specific
symptoms rather than applying a one-design-fits-all
approach (the most effective therapeutic rTMS para-
digms are summarized in Table 3). Additional points
pertain to the low number of participants included in
many studies to possible interactions between drugs
and the effects of TMS and to an inappropriate dosage
of TMS stimulation (ie, low number of pulses and/or
session and low intensity).167
Another issue with rTMS protocols as a therapy is
that their effects are remarkably variable across subjects
as well as within individuals.168-172 Part of this problem
might be addressed by increasing the specificity of TMS
by changing the stimulation parameters. Novel TMS
devices, such as controllable TMS (cTMS),173 allow
changes in the duration and shape of magnetic stimuli.
By varying them, it is possible to activate different sub-
sets of inputs to M1.174,175 This notion can be applied
to rTMS as well; indeed, it has been demonstrated that
the effects of 1 Hz rTMS are greater when monophasic
stimuli delivered via a cTMS device are used when com-
pared with standard biphasic pulses.176 There is also
preliminary evidence that the effects of TBS on M1 are
determined more by the pulse characteristics, and thus
potentially by the specific neural population recruited,
rather than the TBS pattern (intermittent or continu-
ous).169 A second way to achieve greater specificity of
TMS is to use the high time resolution of EEG to deliver
TABLE 3. Summary of the most effective therapeutic rTMS paradigms in each movement disorders condition
PD (motor symptoms) PD (depression)
rTMS protocol High-frequency on M1 High-frequency
or low-frequency rTMS on left
rTMS applied over DLPFC
other frontal regions
DLPFC, dorsolateral prefrontal cortex; ET, essential tremor; HD, Huntington’s disease; PD, Parkinson’s disease; PMC, premotor cortex; rTMS, repetitive trans-
cranial magnetic stimulation; SMA, supplementary motor area; TS, Tourette syndrome.
8 Movement Disorders, 2019
TMS pulses according to different states of cortical excit-
ability. For example, it is known that excitability of M1
is dependent on the phase, power, and dominant fre-
quency of ongoing oscillatory activity.177-180 This means
that if TMS pulses are delivered randomly they are likely
to activate populations of neurones in different func-
tional states. Consequently, attempts have been made
to tune TMS pulses to different brain events detectable
with the EEG, namely, closed-loop stimulation. Kraus
and colleagues181 suggested that it is possible to modify
cortical excitability by delivering TMS pulses during
event-related desynchronization in the beta band during
a motor imagery task, whereas Zrenner and col-
leagues182 demonstrated that plasticity in M1 is more
easily induced if TMS pulses are delivered at negative
peaks of the μ sensorimotor rhythm, which represents a
state of increased excitability of corticospinal neurones.
Although not yet investigated, the possibility to fine tune
the induction of plasticity by increasing spatial or tempo-
ral specificity may open new and exciting scenarios in
the treatment of MD.
Apart from technical issues, the lack of rTMS success
as a therapeutic tool might lie in a more relevant prob-
lem: our limited understanding of the mechanism of
rTMS effects in humans. The first rTMS studies were
based on a simple model in which low-frequency rTMS
would weaken synapses and high-frequency rTMS
would strengthen synapses, thereby increasing or decreas-
ing the excitability of the target area. It was based on
data from experiments carried out in tissue slices of
the hippocampal formation from dead rodents, but
whether these mechanisms are also relevant in the neo-
cortex of awake, behaving humans is not known. It is
likely, in fact, that the sensitivity of different structures
to synaptic plasticity varies across the brain.183 Indeed,
in awake, freely moving rats it is much more difficult to
sustain changes in neocortical synaptic plasticity using
conventional repetitive stimulation protocols than in
slice preparations.184 The limited evidence we have in
humans is that activation of NMDA receptors is impor-
tant in explaining some of the effects of rTMS in the
motor cortex.185,186 Thus, some changes at the synaptic
level seem to be involved in the after-effects of rTMS,
but how these exactly map onto the various types and
stages of the LTP/LTD described in animals is still
unclear. Another complicating factor is that TMS
Dystonia TS HD ET
Low-frequency Low-frequency Controversial Low-frequency
rTMS on dorsal rTMS on SMA data rTMS on
PMC cerebellum
 R T M S F O R T H E
activates a large number of presynaptic and postsynaptic
cellular structures simultaneously, causing a massive syn-
aptic bombardment of excitatory and inhibitory cells.183
Thus, it is impossible to predict how individual neural
types will respond to any protocol. More important, we
do not understand how the effects of rTMS at the site of
stimulation translate into effects at a circuit level, which
might be the critical issue in MD.187 All of these consid-
erations seem to suggest that the term LTP/LTD-like
plasticity, commonly used to describe the rTMS-induced
effects, might not accurately reflect the underlying mech-
anisms that occur in the human brain. Unfortunately,
there are no physiological markers in humans specific
for synaptic plasticity, so further work is certainly
required if rTMS is to be helpful in treating plasticity-
related abnormalities in the human brain.
In conclusion, rTMS has a neuromodulatory poten-
tial that might be successfully used in clinical practice.
However, a better understanding of the underlying
mechanisms, together with an optimization of stimula-
tion protocols, are needed for a more effective applica-
tion of rTMS as a therapy in MD.
Acknowledgment: We confirm that we have read the journal’s position
on issues involved in ethical publication and affirm that this work is con-
sistent with those guidelines.
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