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Parkinsonism and Related Disorders

journal homepage: www.elsevier .com/locate/parkreldis

Review

Therapeutic applications of repetitive transcranial magneticstimulation (rTMS) in movement disorders: A review

Nitish Kamble, M. Netravathi, Pramod Kumar Pal*

Department of Neurology, National Institute of Mental Health & Neurosciences (NIMHANS), Hosur Road, Bangalore 560029, Karnataka, India

a r t i c l e i n f o

Article history:Received 14 November 2013Received in revised form10 March 2014Accepted 18 March 2014

Keywords:Repetitive transcranial magneticstimulationCortical excitabilitySilent periodMotor evoked potentialIntracortical facilitationIntracortical inhibition

* Corresponding author. Tel.: þ91 80 26995147; faxE-mail address: [email protected] (P.K. P

http://dx.doi.org/10.1016/j.parkreldis.2014.03.0181353-8020/� 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Kamble N,disorders: A review, Parkinsonism and Rela

a b s t r a c t

Repetitive transcranial magnetic stimulation (rTMS) is emerging as a valuable adjunctive therapeuticmodality in movement disorders. It is a non-invasive technique of repeated stimulation of the cerebralcortex by a train of magnetic pulses. The therapeutic effect of rTMS was first noted in depression. Laterseveral researchers have investigated the role of rTMS in various movement disorders, notably Parkin-son’s disease, dystonia, Tourette’s syndrome etc. The rTMS protocols used in these studies vary widely,lacks uniformity and often the results are not consistent. The optimal rTMS parameters for each disorderare yet to be established. This review discusses the current knowledge on the therapeutic applications ofrTMS in various movement disorders.

� 2014 Elsevier Ltd. All rights reserved.

1. Introduction

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique of repeated stimulation of the cerebral cortex bya train of magnetic pulses. Transcranial magnetic stimulation wasfirst introduced in late 1980’s [1] and rTMS was introduced in 1989.Since then a large number of studies have involved rTMS as aninvestigational tool as well as a potential treatment for a variety ofneurological and psychiatric disorders. Early studies on healthyvolunteers demonstrated that rTMS to the primary motor cortex(M1) can modulate the cortical excitability, thereby producingchanges in several physiological parameters [2]. These changes areseen in motor threshold (MT), motor evoked potential (MEP), silentperiod (SP), intracortical facilitation (ICF), intracortical inhibition(ICI) and cortical plasticity. The definitions of these terminologiesare given in Table 1. These changes have implications in the treat-ment of movement disorders. Stimulating the cerebral cortex atfrequencies �1 Hz is referred to as low-frequency rTMS, whereasstimulation at frequencies >1 Hz is referred to as high-frequencyrTMS [3]. This distinction is based on the different physiologicaleffects and the risks associated with high and low frequencystimulations [3]. High frequency stimulation induces an increase incortical excitability and low frequency stimulation causes a

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et al., Therapeutic applicationted Disorders (2014), http://d

decrease in cortical excitability [4,5]. However this is not true in allthe circumstances as it depends on the site of stimulation. Thetaburst stimulation (TBS) is a type of rTMS introduced by Huang. InTBS high frequency repetitive stimulation is used for modulatingthe cerebral cortical function. The different modalities of TBSinclude intermittent TBS (iTBS) and continuous TBS (cTBS). Thepattern consists of three pulses delivered at 50 Hz every 200 ms,simulating a theta like-rhythm. In iTBS, 10 bursts are grouped andrepeated every 10 s, for a total duration of 191.84 s resulting in 20trains with 600 pulses. In cTBS 40 s train of 50 Hz burst repeated at5 Hz (200 bursts) are delivered without interruption for a totalduration of 40.04 s resulting in 600 pulses [6]. This review discussesthe applications of rTMS in various movement disorders.

1.1. Physiological basis of rTMS

The primary motor cortex (M1) (Brodmann area 4) consists ofpyramidal or Betz cells in layer V that give rise to numerousexcitatory corticospinal projections. These projections control thehand movements by virtue of fast conducting fibers. Most of thesefibers are oriented perpendicularly to the brain surface while somerunparallel to brain surface. Direct electrical stimulation of exposedbrain in animal studies demonstrates direct, D waves which are theearliest descending volley. Synaptic activation of corticospinalprojections gives rise to indirect, I waves. Removal of the graymatter abolishes I waves but not the D waves. TMS stimulates the

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Table 1Terminology [139,140].

Terminology Definition

Motor evokedpotential (MEP)

An EMG potential obtained after stimulating themotor cortex

Motor threshold (MT) Lowest stimulator intensity that elicits an MEPof >50 mV in amplitude in muscles at rest or200 mV in active muscles in at least 5 out of10 consecutive stimulus

Silent period (SP) A period of EMG suppression induced by single pulseTMS during voluntary contraction of the muscle

Intracorticalfacilitation (ICF)

An increase in the test MEP amplitude followingconditioning stimulus at interstimulus intervalsof 8e30 ms using paired stimulus

Intracorticalinhibition (ICI)

A decrease in the test MEP amplitude followingconditioning stimulus at interstimulus intervalsof 1e6 ms using paired stimulus

Table 2Cortical excitability changes in various movement disorders.

Study Changes in cortical excitability

(A) Parkinson’s diseaseDick et al., 1984 [109] No change in MTCantello et al., 1991 [110] Y MT, short SPValls-Solé et al., 1994 [111] Y MT, short SP, [ MEP sizePriori et al., 1994 [112] No change in MT, short SPEllaway et al., 1995 [113] [ MTStrafella et al., 2000;

Pierantozzi et al., 2001;Bares et al., 2003. [114e116]

Y SICI

Sailer A et al., 2003 [117] Y LAI, Y SAI on more affected side inmedicated patients

Spagnolo F et al., 2013 [118] Y MT, short SP(B) Levodopa induced dyskinesia (LID)Morgante F et al., 2006 [119] [ CSPBarbin L et al., 2013 [120] Y SICI(C) Huntington’s diseaseMeyer et al., 1992 [121] [ Motor threshold, CMCT, Y MEP amplitudeTegenthoff et al., 1996 [97] [ CSPAbbruzzese et al., 1997 [122] Decreased ICIModugno et al., 2001 [123] Normal MEP latency, MEP size, [ CSPNardone et al., 2007 [124] Normal MT, CMCT, SP, Y ICFSchippling et al., 2009 [125] [ MT, MEP recruitment e more

gradual; [ SAI threshold(D) Tic disordersZiemann U et al., 1997 [126] Normal MT, Y CSP and SICIMoll GH et al., 2001 [127] Y CSP and SICIOrth M et al., 2008 [128] Normal MT, Y SICIOrth M et al., 2009 [129] [ MT and ICF, Y SAIHeise KF et al., 2010 [130] Short SICI(E) DystoniaRidding et al., 1995 [131] Reduced cortical inhibitionRona et al., 1997 [132] Normal MT, short SPChen et al., 1997 [133] Reduced inhibition and Y SP on

symptomatic sideFilipovi�c SR et al., 1997 [134] Y SP(F) Essential tremorRomeo S et al., 1998 [135] Normal cortical excitability and CSPShukla G et al., 2003 [136] Normal CSPPinto AD et al., 2003 [137] Normal cortical excitability(G) Corticobasal degenerationPal PK et al., 2008 [101] [ MT (both RMT and AMT), Y ISP, absent ppIHI

Abbreviations: CMCT e central motor conduction time, CSP e cortical silent period,ICF e intracortical facilitation, ISP e ipsilateral silent period, iTBS e intermittenttheta burst stimulation, LAI e long latency inhibition, MEP e motor evoked po-tential, MTeMotor threshold, ppIHIe paired pulse interhemispheric inhibition, SAIe sensory afferent inhibition, SICIe short intracortical inhibition, SP e silent period,[ e increased, Y e decreased.

N. Kamble et al. / Parkinsonism and Related Disorders xxx (2014) 1e132

corticospinal fibers indirectly producing the I waves [7]. These Iwaves occurs as continuing cycles appearing at regular intervalssuggesting a synchronizing mechanism. rTMS by stimulating themotor cortex induces a change in cortical plasticity. Cortical plas-ticity refers to the functional reorganization of the inter neuronconnections, representation patterns and neuronal properties.rTMS can either cause excitation or inhibition of the cerebral cortexand thereby modulate cortical plasticity. Modulation of corticalplasticity may have beneficial or detrimental effects and dependsupon the site of stimulation and the rTMS protocol used. The exactmechanisms by which rTMS modulates the cortical excitabilitybeyond the duration of rTMS are not clear. Inhibition of theGABAergic pathways produces cortical excitation [8]. The changesin synaptic plasticity brought by rTMS are explained by long termpotentiation (LTP) and long term depression (LTD) [9]. LTP isinduced by high frequency stimulation and LTD by low frequencystimulation. The cellular basis of LTP is mediated by the post-syn-aptic N-methyl-D-aspartate (NMDA) receptor which has an intrinsiccalcium channel. Activation of this NMDA receptor leads to calciumflux into the post-synaptic neuron with induction of LTP [10]. Cal-cium then activates downstream enzymatic pathways and changesin pre- and post-synaptic neurons. This increases the synapticstrength. It also induces the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on the post-synaptic neuron which increases the cells sensitivity to glutamate[11].

The persistent or long lasting effect of rTMS (late-LTP or L-LTP) isthought to be exerted by gene induction and protein synthesis. Theeffects may last hours, days or even weeks [11]. Gene expressionhas resulted in increased synthesis of c-fos mRNA in the para-ventricular nucleus of the thalamus [12], parietal cortex [13], BDNFmRNA in the hippocampus and parietal cortex [14].

LTD on the other hand is characterized by depression of thesynaptic transmission. It is induced by low frequency stimulationover long periods. It is dependent on the activation of NMDA re-ceptors but the resultant calcium influx is slowand small. This leadsto internalization of AMPA receptors with consequent reducedsensitivity of the post-synaptic neuron to glutamate [11].

rTMS has also been found to modulate the brain monoaminesand neurotransmitters. rTMS reduces dopamine in frontal cortexand increased levels in the striatum [15]. Serotonin was increasedin hippocampus [15] and there was reduced release of argininevasopressin from the hypothalamus [16]. rTMS also exerts its effectby modulation of the brain receptors. The antidepressant effect isdue to the upregulation of beta adrenergic receptors [17] and re-ductions of 5HT2 receptors in the frontal cortex in animal behav-ioral models of depression. Increased 5HT1A receptors in frontal and

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cingulate cortex and NMDA receptors expression in the hypothal-amus has also been found in animal models [18].

1.2. rTMS protocols

There are several rTMS protocols depending on the variousstimulation parameters as described earlier. It can be classified intosimple rTMS and patterned rTMS protocols [19]. Simple rTMSprotocols have an identical interstimulus interval (ISI) between thedifferent pulses. It can be low frequency or high frequency protocol.Patterned protocols have different ISIs. This include theta burststimulation (continuous or intermittent TBS), paired pulse stimu-lation (PPS) and quadripulse stimulation (QPS). The effects of TBSon the primary motor cortex have been found to be similar withconventional rTMS [20]. There are several advantages of TBS overrTMS. The duration of TBS is shorter, uses low intensity, less heatingof the coil and more tolerable to children.

The use of several protocols for treating the same disorder sug-gests that an ideal rTMS protocol is yet to emerge. The various rTMSprotocols used in different rTMS studies arepresented inTables 3e9.

s of repetitive transcranial magnetic stimulation (rTMS) in movementx.doi.org/10.1016/j.parkreldis.2014.03.018

Table 3Therapeutic uses of rTMS in motor symptoms of PD.

Author No. of patients Aims Type of study Methodology Result Safety

High frequency stimulationPascual

et al., 1994 [29]6 PD and 10 controls Effect on choice reaction

time movement time anderror rate

Prospective case controlstudy

5 Hz rTMS over MC in a single session Improves motor performance No adverseevents noted

Siebner et al., 1999 [41] 12 unmedicated PD Effect on bradykinesia Sham controlled study Real-rTMS applied to M1 contralaterally to themore severely affected limb and frontal sham-rTMSwas applied 3 cm anteriorly to Fz in a random orderon 2 separate days. Stimulus intensity 10% below MT

Significant decrease in totalmovement time

No adverseevents noted

Khedr et al., 2003 [39] 55 PD Effect on motorperformance

Prospective case controlstudy

6 consecutive daily sessions (3000 stimuli each) of25 Hz rTMS of M1 and occipital stimulation

Improved UPDRS score, walkingand self assessment scale


Lomarev et al., 2006 [37] 18 PD To assess safety andefficacy of rTMS

Double blind placebocontrolled study

8 rTMS sessions of 25 Hz rTMS of M1 over 4 weeks,300 pulses each over right and left MC, DLPFC

Cumulative benefit ofimproving gait and upperlimb bradykinesia


Hamada M et al., 2009 [34] 98 PD To assess the effect ofrTMS on motor symptoms

Double blind multicentresham controlled parallelstudy

5 Hz rTMS,110% MT, train of 50 pulses over SMA onesession per week for 8 weeks

Improves bradykinesiain PD patients


Benninger et al., 2012 [36] 26 PD To study safety andefficacy of 50-Hz rTMSin PD

Randomized, doubleblind, sham-controlledstudy

2 groups e 13 received 50 Hz real rTMS and 13received sham stimulation over MC for 2 weeks in8 sessions

Short lived improvementin on state ADL (UPDRS-II)with no improvement inmotor symptoms


Randhawa BK et al., 2013 [43] 10 PD To assess the effect ofrTMS on SMA onhandwriting

Randomized blind realand sham crossover study

1200 pulses of rTMS at 110% of MT at 5 Hz over SMA Increased vertical size ofhandwriting and diminishedaxial pressure


Mak MK et al., 2013 [32] 22 PD To study corticomotorexcitability andimprovement inwalking

Randomized blindedcontrolled trial

Of 22 patients, 11 each were randomly allocated tocontrol and experimental group. Experimental groupreceived 5 Hz rTMS over leg area of MC for 6 min for12 sessions over 4 weeks for experimental group andcontrol group received sham stimulation

Improvement in fast walkingspeed in experimental group


Benninger DH et al., 2009 [35] 10 PD To determine safetyof 50 Hz rTMS

Randomized prospectivestudy

50 Hz rTMS on primary motor cortex (M1) using 60%RMT and 0.5 s train duration and then increased to 90%intensity and train duration increased in steps to 2 s

No improvement in UPDRS,Grooved Pegboard Test,

No adverseeffects

Rothkegel et al., 2009 [51] 22 PD To determine the suitablerTMS protocol in PDpatients

Pseudo-randomized twoprotocol rTMS and shamstudy

5 different rTMS protocols on 5 consecutive days in apseudo-randomized and counterbalanced order. Theprotocols tested were 2 conventional rTMS protocols(0.5 and 10 Hz) with cTBS and iTBS and a shamcondition. The site of stimulation being M1

Neither of the protocolsdiffered from placebo

No adverseeffects

Low frequency stimulationArias et al., 2010 [28] 18 PD To study the efficacy

of low frequency rTMSon motor symptomsin PD

Randomized double-blindplacebo-controlled trialdesign

1 Hz rTMS 90% MT, over 10 days on vertex with eachsession consisting of 2 trains of 50 stimuli each. 9patients received real and 9 received sham rTMS

Total UPDRS and motorpart improved


Kimura H et al., 2011 [45] 12 PD To study safety andefficacy rTMS on motorsymptoms of PD

Crossover placebocontrolled study

0.2 Hz rTMS of 4-week sham rTMS followed by4-week real rTMS. Real rTMS using 0.2 Hz overmotor and SMA. Sham rTMS was applied with thecoil placed vertically at 5% anterior from Fz accordingto the 10e20 system.

Improvement in UPDRSscores after real rTMS


Okabe S et al., 2003 [138] 85 PD To study efficacy of lowfrequency rTMS in PD

Sham controlled study 3 groups of PD: Group 1 and 2 received 100 stimulusof 0.2 Hz at 1.1 times of MT once a week for 8 weeksover motor cortex and occipital respectively andgroup 3 sham electrical stimulation

No significant difference inUPDRS and HDRS


Filipovi�c SR et al., 2010 [50] 10 PD Effect of 1 Hz rTMS onmotor functions in PD

Placebo controlled study 1800 stimuli at 1 Hz rate delivered over the motorcortex for four consecutive days on two separateoccasions. On one of these real rTMS was used andon the other sham rTMS (placebo) was used

No improvement in UPDRS IIIand also in Motor Scalesubscores for axial symptoms,rigidity, bradykinesia

No adverseeffects

(continued on next page)

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bleN,etal.,Therapeutic

applicationsofrepetitive

transcranialmagnetic

stimulation

(rTMS)in

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(2014),http://dx.doi.org/10.1016/j.parkreldis.2014.03.018

Table

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Abbreviations:

ADLe

activities

ofdaily

living,

DLP

FCe

dorsolateralp

refron

talco

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motor

cortex

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motor

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se,P

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scranialm

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UPD

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Unified

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1.3. Rationale of using rTMS in movement disorders

rTMS has been shown to modulate the motor cortical excit-ability and depending on the stimulation parameters it can eitherexcite or inhibit the brain. These parameters include the intensity,frequency, number, duration of stimulation and the number ofsessions delivered. Studies involving TMS in movement disordershave shown changes in the cortical excitability. The cortex may beeither hyperexcitable or hypoexcitable. In hyperexcitable states MT,silent period (SP), short intracortical inhibition (SICI) are reducedand intracortical facilitation (ICF) is increased, whereas in hypo-excitable states MT, SP, SICI are increased and ICF is reduced.Various studies have shown that high frequency stimulation in-creases cortical excitation [21,22] and low frequency stimulationinhibits cortical excitability [3,23]. The effect on corticospinalexcitability following rTMS persists for seconds to minutes andsometimes hours. The corticospinal excitability is measured interms of the size or amplitude of the motor evoked potential (MEP)and the motor threshold. This evidence forms the basis of usinglow-frequency rTMS to treat disorders with cortical hyperexcit-ability and high frequency rTMS in conditions with low corticalexcitability (Table 2). Primary motor cortex (M1) is linked withother ipsilateral and contralateral motor regions, parietal cortex,cerebellum and sensory afferents. rTMS over primary motor cortex(M1) influences PMC, SMA, thalamus and cerebellum with itsconnections. These influences include projections from M1 in theipsilateral and contralateral hemispheres. The interactions of M1with other structures may be classified as excitatory or inhibitory,however there is overlap to some extent. The output represents anet effect of several specific interactions [24]. In view of this com-plex interaction, various studies have used PMC, SMA and cere-bellum as the site of stimulation with different effects. Cerebellarstimulation induces long lasting changes in the cerebello-thalamo-cortical circuit and also the limbic areas as shown in many studies.Cerebellar rTMS modulates motor control, cognitive functions,emotion and mood.

2. Therapeutic applications in movement disorders

2.1. Parkinson disease (PD)

PD is a chronic degenerative disorder of the brain characterizedby degeneration of the dopaminergic neurons in substantia nigrapars compacta (SNPc) leading to a hypokinetic rigid state. Thedisease is characterized by tremor, rigidity, bradykinesia andpostural instability [25].

2.2. Motor symptoms of PD

PD is the most studied movement disorder with regard to TMSespecially in treating the motor symptoms [26]. Initially, drugs likelevodopa or dopaminergic agonists are able to control thesesymptoms, but with the progression of the disease these drugsbecome less effective. Abnormalities in cortico-basal ganglia-tha-lamo-cortical circuit are responsible for the symptoms of PD. As PDis due to abnormal neuronal activity within the basal ganglia andcortical regions, including the primary motor cortex (MC), pre-motor cortex (PMC)/supplementary motor cortex (SMA), severalstudies have used rTMS to improve brain function in PD.

Depending on the target, cortical stimulation has been shown toimprove motor performance or other symptoms associated withPD, such as depression [27]. rTMS has shown promising results inimproving gait and other motor symptoms providing a therapeuticalternative. Significant clinical effects have been obtained in PDpatients by stimulating different cortical regions with rTMS at


Table 4Therapeutic uses of rTMS in non-motor symptoms of PD.


Low frequency stimulationPotrebi�c et al., 2001 [64] 8 PD patients

fulfilling DSMIV criteria fordepression (5) anddysthymia (3)

Effect of rTMS in PDwith depression asmeasured by HDRS

Prospective real rTMS study 0.5 Hz rTMS with 80% MT and B/L 4 site stimulation(prefrontal, frontal, parietal and occipital areas) for10 consecutive days

Significant fall in HamiltonDepression Rating Scale (HDRS)

Safe to use

Furukawa et al., 2009 [25] 6 PD Effect on cognitivedysfunction

Prospective rTMS study in PDpatients

0.2 Hz rTMS of frontal region (Fz) at 1.2 times MT 100stimuli per session and its effect on Trail Making Testpart B (TMT-B), WCST, Wechsler Adult IntelligenceScale Revised (WAIS-R), self-rating depression scale(SDS), Functional Independence Measure (FIM) wasevaluated

Improvement in TMT-B,Wisconsin card sorting test(WCST), SDS score and 20 mwalk time

No adverseeffects

Brusa et al., 2009 [63] 8 PD Effect of 1 Hz rTMSin PD patients withbladder disturbances

Prospective real rTMS study in PDpatients with lower urinary tract(LUT) dysfunction

1 Hz rTMS 65% of MT and 900 stimuli daily for 5consecutive days over 2 weeks delivered at about1 cm ahead of Cz. Urodynamic parameters (volume,pressure and flow variables) were evaluated

Increased bladder capacityand the first sensation of fillingphase. Reduction of InternationalProstate Symptom Score (IPSS)

No adverseeffects

High frequency stimulationBoggio et al., 2005 [60] 25 PD To study the effect

of rTMS on cognitivefunction in PD withconcurrent depression

Randomized prospectivecomparison study of rTMS versusfluoxetine. Neuropsychologicalbattery was assessed at baselineand after 2 and 8 weeks afterrTMS

25 PD patients randomly divided into 2groups e group I received active rTMS (15 Hz110% MT and 10 daily sessions of left DLPFC plusplacebo) and group II received sham rTMS andfluoxetine 20 mg/d

Improvement of Stroop,Hooper and Wisconsin testperformances in both groups

No adverseeffects

Dias et al., 2006 [55] 30 PD Effect of rTMS onvocal function in PD

Real and sham rTMS using tworTMS parameters

15 Hz rTMS (110% of MT 3000 pulses per session) ofDLPFC and 5 Hz (90% of MT and 2250 pulses) of M1(mouth area)

DLPFC stimulation lead tomood amelioration and subjectiveimprovement of the V-RQOL and M1stimulation lead to improvement ofthe fundamental frequency andvoice intensity

No adverseeffects

Srovnalova et al., 2011 [57] 10 PD Effect of rTMS oncognitive processing

Randomized pilot crossover studyusing real and sham rTMS

1 active and 1 sham session of 25 Hz on day 1 and 3sequentially over B/L IFG

Improvement in allStroop test subtests (word,color, color-word)

No adverseeffects

Benninger et al., 2011 [33] 26 PD Safety and efficacyof rTMS

Randomized, double-blind,sham-controlled study

13 received iTBS e 50 Hz burst of 3 pulses 8 sessionover 2 weeks on MC and DLPFC and 13 received shamstimulation

Beneficial effects on moodbut no effect on gait, UPDRSscore and bradykinesia

No adverseeffects noted

Murdoch et al., 2012 [53] 10 PD Effect of rTMS onarticulatory dysfunctionin PD

Real rTMS versus sham placeborTMS

5 Hz rTMS applied to 10 active stimulation and10 sham stimulation for 10 min/day (3000 pulses),for 10 days

Improved speechintelligibility, communicationefficiency ratio, maximumvelocity of tongue movementsand distance of tonguemovements at 2 and 12 monthspost-stimulation

No adverseeffects noted

Eliasova I et al., 2013 [56] 12 PD and 21healthycontrols

Effects of high-frequencyrTMS on motor aspectsof speech

Randomized case control study Two sessions of 10 Hz rTMS applied over the primaryorofacial sensorimotor area (SM1) and the left DLPFC

Stimulation of SM1 resulted inimprovement in voice qualityand intensity and an increasein speech rate and tonguemovements

No adverseeffects

Abbreviations: B/Le bilateral, DLPFCe dorsolateral prefrontal cortex, FIMe Functional IndependenceMeasure, HDRSeHamilton Depression Rating Scale, IFGe inferior frontal gyrus, MCemotor cortex, MTemotor threshold,PD e Parkinson’s disease, PMC e premotor cortex, rTMS e repetitive transcranial magnetic stimulation, SDS e self-rating depression scale, SRTT e Serial Reaction Time Task, SMA e supplementary motor area, TMT-B e TrailMaking Test part B, UPDRS e Unified Parkinson’s Disease Rating Scale, WAIS-R e Wechsler Adult Intelligence Scale Revised, WCST e Wisconsin card sorting test.

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Table 6Therapeutic use of rTMS in tic disorders.


Chae JH et al., 2004 [82] 8 TS To assess improvement intic score

Single session, single blinded,placebo controlled, crossover

rTMS at 110% of MT over left MC (twice)or left PFC (twice) using either 1 Hz or15 Hz over 5 days

No significant improvement in YGTSS,YBOCS and CGI score

No adverse effect

Mantovani et al., 2006 [74] 10 patients(5 with OCD,3 with TS, 2with OCD and TS)

Effect of low frequencyrTMS on OCD in TS

Prospective cohort study 1 Hz rTMS 100% of MT delivered overSMA with 1200 stimuli per day for 10daily sessions

Improves tics and reductions were seenin the YBOCS, YGTSS, CGI, HARS, HDRS,SAD, BDI, SCL-90, and SASS.

No adverse effects

Mantovani et al., 2007 [80] 2 TS To assess improvementin tic score

Prospective unblinded study 1 Hz with 100% MT and 1200 pulses,5 times a week for 2 weeks

Improvement noted in YGTSS No adverse effectsnoted

Kwon et al., 2011 [78] 10 TS Efficacy of rTMS in childrenwith TS

Open label cohort study 1 Hz rTMS 100% of MT delivered overSMA with 1200 stimuli per day for10 daily sessions

Significant reductions were seen inthe Yale Global Tourette’s SyndromeSeverity Scale (YGTSS) and ClinicalGlobal Impression (CGI) and reductionof tics

No adverse effectsand worsening ofsymptoms

Le et al., 2013 [75] 25 TouretteSyndrome (TS)

Effect on various ticseverity scales

Prospective real rTMS study inchildren with TS

1 Hz rTMS of 110% MT delivered overB/L SMA for 20 daily sessions

Significant reductions on the YaleGlobal Tic Severity Scale, Clinical GlobalImpression Scale, Swanson, Nolan andPelham Rating Scale, version IV forattention-deficit hyperactivity disorder,Children’s Depression Inventory, SpenceChildren’s Anxiety Scale and a novelAttention Test

No adverse effects

Abbreviations: CGI e Clinical Global Impression, FIM e Functional Independence Measure, HDRS e Hamilton Depression Rating Scale, MC e motor cortex, MT e motor threshold, OCD e obsessive compulsive disorder, PMC e

premotor cortex, rTMS e repetitive transcranial magnetic stimulation, SAD, SASS, SDS e self-rating depression scale, SMA e supplementary motor area, TS e Tourette’s syndrome, YBOCS e Yale Brown obsessive compulsivedisorder scale, YGTSS e the Yale Global Tourette’s Syndrome Severity Scale.

Table 5Therapeutic use of rTMS in levodopa induced dyskinesias.


Low frequency stimulationBrusa et al., 2006 [67] 10 advanced

PD with LIDEffect on peak dose dyskinesia Combined sequential real and

sham rTMS90% MT and 900 pulses of 1 Hz rTMS for15 min over B/L SMA

Transient reduction of dyskinesias No adverseeffects

Filipovi�c et al., 2009 [70] 10 PD withprominentdyskinesias

Effect on peak dose dyskinesia Placebo-controlled, single-blinded,crossover study

1 Hz rTMS 1800 pulses delivered over MCfor 4 consecutive days twice e once by realrTMS and next by sham rTMS

Reduction of clinically assesseddyskinesia scores and also subjectiveimprovement was seen

No adverseeffects

Kodama et al., 2011 [68] 1 patient Effect of rTMS in painful offperiod dystonia e LID

Case report 0.9 Hz rTMS over contralateral MC and SMA Stimulation of MC reduced the painfuldystonia and walking disturbances

No adverseeffects

High frequency stimulationKoch G et al., 2009 [69] 10 PD with

peak dosedyskinesia

To investigate whether modulationof cerebellothalamocortical circuitsmay result in modification of LID

Placebo controlled singleblind study

Single session cTBS e 3 pulse bursts of50 Hz with 80% MT over lateral cerebellumfollowed 1 week later by sham stimulation

Y SICI and [ LICI with reduction ofLID. 2 week course of B/L cerebellarcTBS reduced LID for 4 weeks

No adverseeffects

Abbreviations: B/L e bilateral, cTBS e continuous theta burst stimulation, DLPFC e dorsolateral prefrontal cortex, LICI e long interval intracortical inhibition, LID e levodopa induced dyskinesia, MCemotor cortex, MTemotorthreshold, PD e Parkinson’s disease, PMC e premotor cortex, rTMS e repetitive transcranial magnetic stimulation, SICI e short intracortical inhibition, SMA e supplementary motor area, SP e silent period, [ e increased, Y e

decreased.

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Table 7Therapeutic use of rTMS in dystonia.


Siebner et al.,1999 [88]

16 focal handdystonia

To evaluate the effectivenessof low frequency rTMS inwriters cramp

Single session, singleblinded, placebocontrolled, crossover

1 Hz rTMS with 90% MTand 1200 pulses over M1 area

Reduction in penpressure and numberof stroke inversionsand self reportedimprovement

No adverseeffects

Lefaucher et al.,2004 [85]

3 generalizeddystonia patients

Effect on painful axial spasms Pilot study in 3 patients 1 Hz rTMS of premotorcortex (PMC)

Reduced the painfulspasms

No adverseeffects

Murase et al.,2005 [87]

9 writer’s crampand 7 controls

Effect on writer’s cramp Prospective cohort study 0.2 Hz rTMS over PMC,SMA and MC. Silent periodand handwriting assessmentwas done before and afterrTMS to each of 3 areas

Improves handwritingin writers cramp onstimulation of PMC only

No adverseeffects

Allam et al.,2007 [86]

1 patient of primarycervical dystonia

Effect of rTMS in primarysegmental dystonia

Case report 1 Hz rTMS with 90% MTand 1200 stimuli per dayfor 5 daily sessions over PMC

A reduction of 50% inthe neck subset of theBurke, Fahn and Marsdentorsion dystonia scale(BFM) was observed

No adverseeffects

Abbreviations: CHBF e cerebellar hemisphere blood flow, MC emotor cortex, MT emotor threshold, PET e positron emission tomography, PMC e premotor cortex, rTMS e

repetitive transcranial magnetic stimulation, SMA e supplementary motor area.

Table 8Therapeutic use of rTMS in essential tremor.


Gironell et al.,2002 [90]

10 ET Effect of rTMS ofcerebellum in ET

Double-blind, crossover,placebo-sham controlleddesign

1 Hz active rTMS with 100% ofMT spread over 1 week sessioneach of 30 trains of 10 s durationover cerebellum followed bysham stimulation

Tremor improvementas evidenced by a significantreduction in scores on theclinical rating scale andaccelerometric values 5 minpost-active rTMS

No adverseeffects

Avanzino et al.,2009 [93]

15 ET and11 controls

Effect of low frequencyrTMS in changing thetiming properties andmotor behavior inpatients of ET

Prospective cohort study 1 Hz rTMS of ipsilateral lateralcerebellum

Patients of ET had longertouch duration (TD) and alower inter tapping interval(ITI) which was normalized.Coefficient of variation of ITIwas also restored to normalvalues

No adverseeffects

Hellriegel et al.,2012 [92]


Effect on ET Prospective placebocontrolled study

cTBS of left MC (hand area) at80% (real cTBS) and 30% (controlcTBS) of active MT in two separatesessions one week apart

A subclinical reduction intremor was observed asmeasured with accelerometry

No adverseeffects

Popa et al.,2013 [91]


Efficacy of 1 week ofrTMS on tremors andcerebello-thalamo-corticalcircuit dysfunction

Open label trial 1 Hz rTMS applied to B/Lposterior cerebellum

Significantly improved totaland specific (tremor, drawing,functional disability) scores,and reduced tremor amplitude.The effects persisted for 3weeks post-rTMS

No adverseeffects

Abbreviations: B/L e bilateral, cTBS e continuous theta burst stimulation, ET e essential tremor, MT emotor threshold, rTMS e repetitive transcranial magnetic stimulation.

Table 9Therapeutic use of rTMS in other neurodegenerative disorders.


Shimizu et al., 1999 [107] 4 SCA Therapeutic efficacyof rTMS in SCA

Case series rTMS of 100% MT daily for21 days over B/L cerebellarhemispheres

Number of feasible steps intandem gait test increased,blood flow of the cerebellarhemisphere, putamen andpons were significantlyincreased

No adverseeffects

Brusa et al., 2005 [98] 4 HD patients Effect of rTMS onchorea in HD

Pilot study 5 Hz rTMS delivered at110% MT and 18 trains of50 stimuli over SMA ofboth hemispheres

Improvement of choreicsymptoms in HD patients

No adverseeffects

Ihara et al., 2005 [106] SCA Effect on diseaseseverity and changesin CSF of SCA patients

Prospectivecohort study

rTMS of SCA patients Reduction of AFR in CSF,decline in ataxia severityand increased CHBF

No adverseeffects

Santens et al., 2009 [95] Small group ofPSP patients

Effect of rTMS in PSP Pilot study 5 Hz high frequencyrTMS of MC

Improved axial symptomsin PSP patients

No adverseeffects

Abbreviations: AFR e ascorbate free radical, B/L e bilateral, CHBF e cerebellar hemisphere blood flow, CSF e cerebrospinal fluid, HD e Huntington’s disease, MC e motorcortex, MT e motor threshold, PMC e premotor cortex, PSP e progressive supranuclear palsy, rTMS e repetitive transcranial magnetic stimulation, SCA e spinocerebellarataxia, SMA e supplementary motor area, [ e increased, Y e decreased.

N. Kamble et al. / Parkinsonism and Related Disorders xxx (2014) 1e13 7

Please cite this article in press as: Kamble N, et al., Therapeutic applications of repetitive transcranial magnetic stimulation (rTMS) inmovementdisorders: A review, Parkinsonism and Related Disorders (2014), http://dx.doi.org/10.1016/j.parkreldis.2014.03.018


inhibitory (low) or excitatory (high) frequency. High-frequency(5 Hz) rTMS is capable of modulating cortical activity and hasbeen reported to have significant benefit to general motor functionin PD [28]. Patients with PD on medications have shownimprovement in psychomotor speed performance using low fre-quency rTMS. The improvement is seen mostly in the off medica-tion state [29]. Studies in patients with PD have disclosed that asingle session of rTMS can improve some or all of the motorsymptoms for 30e60 min and repeated sessions can lead to effectsthat can last for at least 1 month [30]. rTMS applied at 5-Hz fre-quency over the leg area of the motor cortex showed improvementin walking [31,32].

The optimal rTMS parameter to obtain a beneficial effect is stillnot known. Higher frequency may be more effective. High fre-quency rTMS (50 Hz) was found to be safe with marginalimprovement in UPDRS II. A prolongation of the cortical SP wasobserved in these patients following rTMS [33]. The relation be-tween prolongation of silent period and improvement in UPDRS isdifficult to explain.

High frequency rTMS over SMA significantly improves brady-kinesia in PD patients supporting the hypothesis that neuronalactivity of SMA is profoundly associated with hypokinetic symp-toms in PD [34]. Studies have also used 50 Hz rTMS and were foundto be safe andwell tolerated but caution is advised for patients withparoxysmal EEG activity [35]. In a randomized, double blind, sham-controlled study, use of 50-Hz rTMS of the motor cortices in 8sessions over 2 weeks produced a short-lived “on”-state improve-ment in activities of daily living (UPDRS II) without any adverseevents [36]. SMA is a potential stimulation site for PD treatment;application of 5 Hz rTMS leads to improvement in motor symptoms[34]. Compared to 10 Hz occipital stimulation, 25 Hz rTMS overmotor areas had more improvement in UPDRS score. The effect wasobserved to be cumulative and long lasting that was maintained for1 month [30]. In a double-blind placebo-controlled study the ef-fects of 25 Hz rTMS on bilateral MC and dorsolateral prefrontalcortex (DLPFC) on gait and bradykinesia in patients PD wasassessed. rTMS sessions had a cumulative benefit in improving gait,as well as reducing upper limb bradykinesia in PD patients thatcorrelates with increased MEP amplitude evoked by left MC rTMS[37]. High-frequency rTMS over MC has been shown to decreaserigidity and bradykinesia in the upper limb contralateral to thestimulation, while low-frequency rTMS reduces upper limb rigiditybilaterally and improves walking. Thus 10 Hz rTMS increasesintracortical facilitation, while 0.5 Hz rTMS restores intracorticalinhibition. These results support MC as the possible target for rTMSin PD [38]. Similar improvement in motor symptoms as assessed byUPDRS score was seen in other studies also [39,40]. The therapeuticeffect of rTMS onmotor symptoms in PD patients may be due to theinhibition of dopaminergic systems. Improvement in bradykinesiaand UPDRS score has been demonstrated in other studies also bystimulating MC with 5 Hz rTMS [41,42]. In another study, stimu-lation of SMA using 5 Hz rTMS increased vertical size of hand-writing and diminished axial pressure suggesting improvement infine motor tasks [43]. 25 Hz rTMS over bilateral motor hand area(M1) improves bradykinesia which was substantiated by the fMRIfindings of increased caudate activity during complex taping test[44].

Studies involving low frequency stimulation have also shownimprovement in UPDRS score [45,46]. This therapeutic response islikely to be due to the changes in brain monoamine levels inducedby rTMS [47]. SMA is important in motor planning and preparatoryprocesses, since SMA stimulation has no effect on movements intheir later stages when planning is already complete, but maydisrupt movements in their early stages, when preparation for laterstages is still in progress [48].


A meta-analysis of several randomized controlled trials usinghigh frequency rTMS to treat motor symptoms of PD was found tobe beneficial and low frequency had no effect [49]. However thesestudies differ from each other in cortical targets of stimulation,stimulation protocols used, sample size, UPDRS score prior to rTMS,duration of the disease, various pharmacological agents. All thesefactors make it extremely difficult to formulate an ideal stimulationprotocol. In general M1 is themost frequently used cortical target inPD, clinical efficacy is also observed on stimulation of SMA. How-ever there are other studies also that have not shown any benefitafter rTMS [50]. Filipovi�c et al. using low frequency stimulation didnot show any improvement either in the total motor score orsubscores for axial symptoms, rigidity, bradykinesia and tremor.Intermittent TBS (iTBS) of M1 and PFC has not shown anyimprovement in gait, bradykinesia and other motor symptoms ofPD [33]. However iTBS is safe and without any adverse effects. Theeffect of low frequency rTMS on motor symptoms is not clear.Studies have not shown any significant improvement in bradyki-nesia, rigidity and gait abnormality [28,50]. Other studies usinghigh frequency rTMS did not improve UPDRS score [35] and motorperformance (pointingmovement, pronationesupination, walking)[51]. In summary, the efficacy of rTMS in PD patients is still not clearand a consensus on the most effective rTMS protocol is yet toemerge. This calls for multicenter trials to address the issue. Thedetails of the above studies are summarized in Table 3.

2.3. Non-motor symptoms of PD

Non-motor symptoms are frequently seen in patients of PD.These include delusions, depression, visual disturbances, diplopia,bowel and bladder disturbances, daytime sleepiness, vivid dreams,parasomnias, loss of smell and taste, orthostatic dizziness etc. Non-motor symptoms cause significant morbidity [52].

Studies have shown beneficial effect of rTMS on vocal functionin PD. High-frequency rTMS (5 Hz) was evaluated as a therapeutictool for the treatment of articulatory dysfunction in PD. Speechintelligibility, communication efficiency ratio, maximumvelocity oftongue movements and distance of tongue movements improvedafter repeated rTMS [53]. However another study did not find anyimprovement in articulatory abnormality after rTMS probablybecause the patients had no orminimal dysarthria [54]. Stimulationof the left dorsolateral prefrontal cortex (DLPFC) with 15 Hz rTMShas shown mood amelioration and subjective improvement of thevoice-related quality of life (V-RQOL) and stimulation of M1 areausing 5 Hz resulted in significant improvement of the fundamentalfrequency and voice intensity [55]. Eliasova et al. studied the effectsof high-frequency (10 Hz) rTMS applied over the primary orofacialsensorimotor area (SM1) and the left DLPFC on motor aspects ofvoiced speech in PD resulted in measurable improvement in voicequality and intensity and an increase in speech rate and tonguemovements [56].

With progression of the disease, PD patients develop cognitivedecline. In PD patients, Sequential application of high frequencyrTMS over both the left and right inferior frontal gyri (IFG)increased the speed of cognitive processing in both the congruentand incongruent conditions of the Stroop test [57]. Improvement inneuropsychological functions (trail making test, Wisconsin cardsorting test) and self-rating depression scale (SDS) has beenobserved with 0.2 Hz rTMS [25]. Alleviation of mood and cognitivedisorders was observed when rTMS is applied to the DLPFC [58]. Inanother study a single session of high-frequency rTMS applied overthe left dorsal PMC and left DLPFC was well tolerated and safe butdid not show any effect on cognitive scale and motor symptoms[59]. This shows that rTMS can affect the functional recovery of thefronto-striatal circuit. Comparison of fluoxetine versus 15 Hz rTMS



of the left DLPFC revealed significant improvement of Stroop(colored words and interference card) and Hooper and Wisconsin(perseverative errors) test performances after both treatments [60].The results show that rTMS can improve some aspects of cognitionin PD patients similar to that of fluoxetine. The mechanisms for thiscognitive improvement are not clear. Abnormalities in the dorso-lateral prefrontal circuit and the associated caudate nucleus arethought to underlie the executive dysfunction [61]. rTMS improvesthe executive functioning as demonstrated by the neuropsycho-logical tests.

PD patients also have impaired time processing in the off state.Application of high frequency (5 Hz) over the right DLPFC leads tosignificant improvement in time processing as evidenced byimprovement in the time reproduction task [62].

5 Hz rTMS over the parietal cortex improved sleep fragmenta-tion (P ¼ 0.0002) and sleep efficiency (P ¼ 0.0002) and reduced theaverage duration of nocturnal awakenings.

Patients with PD may present with lower involuntary detrusoroveractivity. A 2-week course of low frequency 1 Hz rTMS tempo-rarily improved the urinary symptoms by increasing bladder ca-pacity and the first sensation of filling phase. The effect lasted for upto 2 weeks after the end of the stimulation [63].

PD is also associated with depression in a significant number ofpatients [64]. Several open studies have shown that both highfrequency and low frequency may have antidepressant action [15].Low frequency 0.5 Hz rTMS was shown to improve the HamiltonDepression Rating Scale with the effect persisting for 2 weeks [64].Dorsolateral prefrontal cortex (DLPFC) is the target for rTMS indepression [4] and rTMS is a relatively safe and painless methodassociated with antidepressant action in PD patients [60]. The an-tidepressant action of rTMS and its maintenance for two weeksoffers a choice to use this method in subacute depression until thefull effect of medication is reached. 5 Hz rTMS over the left DLPFCimproved depression in PD that lasted for 30 days in a double blindplacebo controlled study [65]. However these handful studies lackuniformity in patient selection and site of stimulation. Sample sizein most of these studies is small to come to any conclusion. DLPFCappears to be the appropriate site for most of the non-motorsymptoms.

2.4. Levodopa induced dyskinesias (LID)

Long-term therapy with levodopa and dopamine agonists in PDpatients often leads to the development of fluctuations in motorresponse known as LID. It is more often seen in advanced PD pa-tients. Presently LIDs are managed by strategies that involve eitherdelaying the introduction of levodopa therapy, use of amantadine,deep brain stimulation (DBS) or continuous dopaminergic stimu-lation using injectable drugs. Glutamate overactivity causesdevelopment of dyskinesias [66]. The role of striato-thalamo-cortical motor circuits has been implicated in its pathogenesiswith overactivation of cortical motor and premotor areas in LID[67]. rTMS has been recently evaluated as a possible therapeutictool in LID. Studies have shown that low-frequency rTMS over theMC and SMA can reduce LID in PD. 1 Hz rTMS over these areas wasable to induce a transient reduction in the severity of LID, con-firming that an over-activity of these areas plays an important rolein the pathophysiology of LID [67]. In a case report of a patient withpainful off-period dystonia involving unilateral lower limb, 0.9 HzrTMS over primary motor area significantly reduced the painfuldystonia and walking disturbances [68]. The prolongation of thecortical SP is the likely explanation for the improvement in UnifiedParkinson’s Disease Rating Scale (UPDRS)-motor score.

Procedures such as deep brain stimulation in LID have shownmetabolic changes in the cerebellum and a 2 week course of


bilateral cerebellar rTMS induced persistent reduction of peak-doseLID for up to four weeks [69]. They observed that cerebellar cTBSreduced SICI and increased LICI, implying cortical reorganizationthat is associated with reduction of LID. This study emphasizes therole of cerebello-thalamo-cortical pathways in LID and the anti-dyskinetic effect of cerebellar cTBS. Peak dose dyskinesias respondmuch better to rTMS. Repetitive 1 Hz stimulation of motor cortexshowed small but significant reduction in dyskinesia severitylasting for 3 days. No adverse effects on motor function and PDsymptoms were noted [70]. Single session of 1 Hz rTMS decreasesthe excitability of SMA with transient reduction of dyskinesias inLID [67]. However, repeated sessions of stimulation failed toenhance and/or prolong the beneficial effects [71]. There was nosignificant improvement when the frequency was increased to5 Hz. These studies show that MC, SMA and cerebellum are thepotential therapeutic sites for treatment of LID and can help inreducing the dose of levodopa.

2.5. Tic disorder

Tourette’s syndrome (TS) is a chronic neuropsychiatric disorderof childhood onset that is characterized by multiple motor andphonic tics [72]. Many children improve by they reach adolescence.However, some adults with TS continue to experience severesymptoms and significant disability. The exact cause is not known,however abnormalities in the basal ganglia-thalamo-cortical circuithave been hypothesized to have an important role in the patho-physiology of involuntary tics. There may be a deficient inhibitorycontrol through this circuit. Brain imaging has shown alteredcorpus callosum (CC) morphology in these patients [73]. Theycombined TMS with diffusion tensor imaging (DTI) to study theinterhemispheric connections between the left and right motorhand areas. The left to right interhemispheric inhibition (IHI) wasweaker than right to left IHI in TS patients. The combined TMSeDTIstudy showed an abnormal functional interhemispheric connec-tivity and altered structureefunction relationship in the motor CCin TS. Evidence suggests that MC, PMC and SMA are hyperexcitablein these patients. Hence rTMS targeting the SMA can reduce ticseverity [74]. Majority of the studies have stimulated the SMAwithpositive results. The other areas stimulated in TS are the MC andPMC. It has been found that 1 Hz rTMS to the SMA can improveclinical symptoms in childrenwith TS for at least six months [75]. Astatistically significant reductions in various tic severity scales wasobserved. Theta burst stimulation (TBS) has been used in childrenwith TS by stimulating the left M1 area [76,77]. TBS was found to besafe and well tolerated in children. rTMS over the SMA has positiveeffects on ameliorating tics. rTMS over the SMA to children with TSresults in a significant clinical improvement possibly by normali-zation of both the hemisphere hyperexcitability [78]. In patientswith TS the above-threshold short intracortical inhibition (SICI)recruitment and sensory afferent inhibition (SAI), a paradigm toexamine sensory motor integration is reduced. This leads toreduced excitability of cortical inhibition that contributes to thedifficulty that patients have in suppressing tics. Reduced SAI in-dicates intracortical inhibition is not only limited to the motorcortex but also involves circuits linking sensory input and motoroutput [72]. The extent of involvement of these neuronal circuitsdetermines the phenotype of Tourette spectrum disorders. rTMS isnow considered as one of the emerging therapies for TS [79]. Lowfrequency rTMS applied to the SMA leads to significant increase inMT which is stable for next 3 months. There is normalization of theoveractive motor cortical regions and restoration of hemisphericsymmetry in motor threshold [80]. Stimulation of left PMC alone orleft PMC followed by right PMC did not show any significantimprovement in tics [81]. This suggests that an appropriate rTMS



protocols need to be used in order to explore its potential for thetreatment of tics. rTMSwith frequencies of 1 Hz and 15 Hz has beenused in adults with TS [82]. There was no worsening of tics or otherinvoluntary movements and it was safe. Some studies did not findany significant improvement in symptoms with rTMS [83]. Inconclusion use of low frequency rTMS over SMA may reduce motorand vocal tics in TS patients.

2.6. Dystonia

There is increased cortical excitability of the motor cortex andthe brain stem in patients with dystonia [84]. SPECT studies of thebrain have shown abnormalities in glucose metabolism andperfusion. This increased cortical excitation and facilitation can besuppressed by rTMS, thereby reducing the motor symptoms. Thereare only few studies of rTMS in dystonia being limited only to somecase reports and small series. The motor cortex excitability can bereduced by low-frequency (1 Hz) rTMS of PMC and MC. The painfulspasms (proximal and axial musculature) in severe generalizeddystonia can be reduced for few days post-rTMS [85]. Low-frequency rTMS improved primary cervical dystonia in a patientby stimulating the PMC [86]. Patients with focal dystonias likewriter’s cramp also benefit by low frequency rTMS of the PMC. Inwriter’s cramp rTMS prolongs the SP and improves handwriting.This improvement is noted on stimulation of the PMC but not theMC [87,88]. These studies show that PMC is the area wherein lowfrequency rTMS can be applied to improve dystonia, both gener-alized and focal.

2.7. Essential tremor (ET)

Studies have shown overactivity of the deep nuclei and cere-bellar cortex in the generation of ET. Dysfunction of the cerebello-thalamo-cortical (CTC) pathways is involved in the pathogenesis[89]. Animal studies, regional blood flow and imaging studies haveprovided the evidence that ET is due to the abnormal overactivity ofthe cerebellum and its connections. Low-frequency (1 Hz) repeti-tive transcranial magnetic stimulation (rTMS) of the cerebellumeffectively modulates the cerebellar output and induces a transientreduction of tremors [90]. It is postulated that rTMS interferes withthe oscillatory function of the cerebellar neurons and to local in-crease in gamma amino butyric acid (GABA). Repeated rTMS overthe cerebellum significantly improves tremor scores with reductionof tremor amplitude. It also corrects the defective informationprocessing in the CTC network. The effects can persist for 3 weeksafter the last session [91]. Repeated sessions might have a cumu-lative and potentially long-term therapeutic effect on ET. Apartfrom cerebellar stimulation, M1 stimulation can also suppress ET.cTBS of the M1 area has a beneficial effect on ET as it suppresses theexcitability [92]. The benefit was subclinical with no significantchanges in clinical tremor rating. Patients with ET have a longertouch duration (TD) and a lower inter tapping interval (ITI)compared to normal subjects. After 1 Hz-rTMS over ipsilaterallateral cerebellum there was a reduction of TD values andnormalization of ITI [93].

2.8. Progressive supranuclear palsy (PSP)

PSP is a progressive neurodegenerative disorder without anyspecific treatment till date. Low frequency rTMS of the cerebellumhas suppressive effects known as cerebellar inhibition (CBI) [94].This shows that Purkinje cells or the dentate-thalamo-corticalpathways are involved in PSP. This is further confirmed by thepathological findings showing severe degeneration of dentate nu-cleus in PSP patients. Low frequency stimulation of cerebellum


might restore the balance within the circuit and can improve someof the symptoms of PSP. Also application of high frequency rTMSover the motor cortex of clinically diagnosed PSP patients results intransient improvement in the axial symptoms without any sideeffects [95].

2.9. Huntington’s disease (HD)

HD is a genetic neurodegenerative process that is due to CAGtriplet repeat mutation in the short arm of chromosome 4 thatencodes the Huntingtin protein [96]. It is the elongation of tripleCAG that codes for glutamine that causes intracellular aggregates ofthe abnormal protein leading to mitochondrial dysfunction, ATPdepletion and cell death. Studies have shown altered corticalexcitability with dysfunction of motor cortexebasal ganglia circuit[97]. As HD is a hyperkinetic disorder, low frequency rTMS has beenused to study the effect on cortical excitability. Improvement inchoreic movements has been reported by using low frequency(1 Hz) rTMS of MC [98]. rTMS has also been used to study thecortical excitability in patients with HD. rTMS of MC increased thesilent period (SP) duration during voluntary contraction [99].

2.10. Other atypical parkinsonian syndromes

Patients with MSA and CBD also have abnormal motor corticalexcitability. Patients with MSA have significantly large MEP am-plitudes at rest, reduced intracortical inhibition (ICI) and prolongedipsi and contralateral silent periods, whereas CBD patients havesignificantly increased MT, smaller response amplitudes at rest,shortened contralateral silent period, reduced transcallosal inhibi-tion and a reduced ICI [100]. In another study patients with CBDhad increased MT (both AMT and RMT), short ipsilateral silentperiod and absent paired pulse interhemispheric inhibition [101].The motor cortex disinhibition is predominant in patients withMSA and CBD with more severe neuronal cell loss in the motorcortex leading to hypoexcitability of corticospinal and transcallosalpathways. There is impairment of callosal integrity in patients withCBD and PSP as evidenced by the abnormal iSP [102]. Using rTMS itwas found that there is an abnormal inhibition within the motorcortex in MSA-P patients despite dopaminergic treatment [103].

2.11. Spinocerebellar degenerations (SCD)

These are group of both genetic and acquired neurodegenerativediseases that are clinically and pathologically heterogeneous andcharacterized by slowly progressive cerebellar ataxia. The cere-bellum modulates the primary motor cortex through cerebello-thalamo-cortical connections and plays an important role inmovement execution and motor control. This formed the basis forcerebellar stimulation in various studies for SCD, ET [104]. Patientswith SCA have reduced cortical excitability and prolonged centralmotor conduction time [105]. Application of repetitive transcranialmagnetic stimulation (rTMS) in patients with spinocerebellar de-generations (SCD) has shown reduction in ascorbate free radical(AFR) in cerebrospinal fluid (CSF), decline in ataxia severity andincrease in cerebellar hemispheric blood flow (CHBF) [106]. In pa-tients with SCD there is an inverse relationship between ataxiaseverity and CHBF, rTMS improves ataxia by decreasing oxidativestress and increasing CHBF. Cerebellar rTMS for 3 weeks hasimproved the time to walk, tandem gait steps and body balance. Anincrease in the blood flow to the cerebellar hemisphere, putamenand pons was observed that may explain its effectiveness inimproving ataxic gait [107]. This might suggest that TMS over thecerebellum may be an effective therapy for patients with SCD. Inpatients with cerebellar symptoms due to multiple sclerosis (MS),



there was an improvement in hand dexterity tested by 5 Hz rTMSover the motor cortex [108].

2.12. Limitations of rTMS

The results of various studies exploring the effects of rTMS oncortical excitability and its usefulness in movement disorders havebeen inconsistent. A novel rTMS protocol encompassing the idealstimulation parameters is yet to emerge. Further studies arerequired to address the issue. Another limitation is the small depthof penetration of the stimulus. The deeper structures are notaffected. However if the deeper structures were to be stimulatedusing high intensity stimulus, it would be epileptogenic andharmful to the surface tissue [3]. Other adverse effects like head-ache, scalp electrode burns, histotoxicity and its effect on cognitionare also reported [3]. Transient nausea has been reported as a sideeffect following a relatively high output of stimulator and900 pulses at 0.9 Hz over the cerebellum [139].

Though most of the studies of rTMS in PD have shownimprovement in motor and non-motor symptoms, these studieswere not reproduced by the same author or by others using similarrTMS parameters. Hence it is difficult to arrive at a clear consensuson optimal rTMS protocol for PD and other movement disorders.

2.13. Conclusions

In conclusion rTMS is a safe and a potential therapeutic option inmovement disorder patients. Active research in movement disor-ders is still taking place and has the potential to provide useful data.Based on these new research new therapeutic guidelines may beestablished in future. Apart from its potential clinical role, rTMS is avaluable probe of brain function that can be used to investigate theneural circuitry. This additional knowledge might help in devel-oping new treatments that may be specifically targeted.

Financial disclosure/conflict of interest

None of the authors have any financial disclosure to make orhave any conflict of interest.

Source of funding

Nil.

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Therapeutic applications of repetitive transcranial magnetic stimulation (rTMS) in movement...

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