Cerebellar magnetic stimulation decreaseslevodopa-induced dyskinesias inParkinson disease

G. Koch, MD, PhDL. Brusa, MD, PhDF. Carrillo, MDE. Lo Gerfo, PsyDS. Torriero, PsyDM. Oliveri, MD, PhDP. Mir, MD, PhDC. Caltagirone, MDP. Stanzione, MD

ABSTRACT

Background: The neural mechanisms and the circuitry involved in levodopa-induced dyskinesia(LID) are still partially obscure. LID can be considered the consequence of an abnormal pattern orcode of activity that originates and is conveyed from the basal ganglia to the thalamus and thecortical motor areas. However, not only striatothalamocortical motor circuits but also other inter-connected pathways could be implicated in its pathogenesis.

Methods: In a series of experiments, we applied repetitive transcranial magnetic stimulation(rTMS) over the lateral cerebellum in a group of patients with advanced Parkinson disease, toinvestigate whether modulation of cerebellothalamocortical circuits by means of rTMS may resultin a modification of a dyskinetic state induced by levodopa ingestion.

Results: We found that a single session of cerebellar continuous theta burst stimulation (cTBS)was capable of transiently reducing LID. In the same patients, we observed that cerebellar cTBSchanged the profile of activation of intracortical circuits in the contralateral primary motor cortex.Cerebellar cTBS reduced short intracortical inhibition and increased long intracortical inhibition,inducing a cortical reorganization that is associated with a reduction of LID. Furthermore, in an-other experiment, we observed that a 2-week course of bilateral cerebellar cTBS induced persis-tent clinical beneficial effects, reducing peak-dose LID for up to 4 weeks after the end of the dailystimulation period.

Conclusions: Our study demonstrates that cerebellar continuous theta burst stimulation has anantidyskinetic effect in Parkinson disease patients with levodopa-induced dyskinesia, possiblydue to modulation of cerebellothalamocortical pathways. Neurology® 2009;73:113–119

GLOSSARYAMT � active motor threshold; ANOVA � analysis of variance; CAPSIT � Core Assessment Program for Surgical Interven-tional Therapies; CS � conditioning stimulus; cTBS � continuous theta burst stimulation; FDI � first dorsal interosseousmuscle; GABAB � �-aminobutyric acid type B; ISI � interstimulus interval; LICI � long intracortical inhibition; LID � levodopa-induced dyskinesia; M1 � primary motor cortex; MEP � motor evoked potential; MSO � maximum stimulator output; PD �Parkinson disease; RMT � resting motor threshold; rTMS � repetitive transcranial magnetic stimulation; SICI � shortintracortical inhibition; SMA � supplementary motor area; TBS � theta burst stimulation; TS � test stimulus; UPDRS �Unified Parkinson’s Disease Rating Scale.

Long-term levodopa therapy in patients with Parkinson disease (PD) is commonly complicatedby the development of fluctuations in motor response, such as levodopa-induced dyskinesia(LID).1,2 LID can be considered the consequence of an abnormal pattern or code of activitythat originates and is conveyed from the basal ganglia to the thalamus and the cortical motorareas.3-5 The net effect of these imbalances would be excessive disinhibition of thalamocorticalneurons and overactivation of cortical motor and premotor areas.6-10

Recent studies suggested that there are also changes in cerebellothalamocortical networksoccurring in PD and in some cases in LID.11-14 Functional or metabolic changes in the cerebel-lum have been reported in patients with PD treated with procedures known to alleviate dyski-nesias, such as deep brain stimulation or pallidotomy of the globus pallidus.15,16 Furthermore, arecent PET study showed that in patients with PD who underwent stereotactic pallidotomy,

From the Clinica Neurologica (G.K., M.O., C.C., P.S.), Dipartimento di Neuroscienze, Universita di Tor Vergata, Rome, Italy; Fondazione SantaLucia IRCCS (G.K., E.L.G., S.T., C.C., P.S.), Rome, Italy; UOC Neurologia (L.B.), Ospedale S. Eugenio, Rome, Italy; and Unidad de Trastornosdel Movimiento (F.C., P.M.), Servicio de Neurología y Neurofisiología Clínica, Hospital Universitario Virgen del Rocío, CIBERNED, Seville, Spain.

Disclosure: Author disclosures are provided at the end of the article.

Supplemental data atwww.neurology.org

Address correspondence andreprint requests to Dr. GiacomoKoch, Laboratorio di NeurologiaClinica e ComportamentaleFondazione Santa Lucia, IRCCSVia Ardeatina 306 00179 Roma,Italyg.koch@hsantalucia.it; giakoch@libero.it

Copyright © 2009 by AAN Enterprises, Inc. 113

the level of binding potential of cerebellarsigma receptors did not correlate with Hoehnand Yahr stages and the Unified Parkinson’sDisease Rating Scale (UPDRS), but a positivecorrelation was seen between the binding po-tential and the preoperative LID severityscore, suggesting that the cerebellum may po-tentially involve the genesis of LID.17

In a recent study, we found that in healthysubjects, a novel repetitive transcranial mag-netic stimulation (rTMS) protocol, the thetaburst stimulation (TBS),18 was effective inmodulating the excitability of the cerebello-thalamocortical circuits. Changes in the inter-connected primary motor cortex (M1) wereobserved when continuous theta burst stimula-tion (cTBS) was applied over the lateral cerebel-lum.19 Namely, cTBS induced a reduction ofshort intracortical inhibition (SICI)20,21 and anincrease of long intracortical inhibition (LICI)22

circuits. Interestingly, these effects resemble thechanges induced by pallidotomy on the M1 ex-citability of dyskinetic patients with PD.23-25

Here, we used cerebellar cTBS to investi-gate whether modulation of excitability of thecerebellothalamocortical circuits may result inmodification of LID in patients with PD.

METHODS Experiment 1: Effects of a single sessionof cerebellar cTBS on LIDs. Ten patients with advancedPD who had disabling peak-dose dyskinesias after levodopa in-gestion were enrolled during 1 year (mean age 64.2 � 5.4 years,mean disease duration 11.2 � 3.3 years; table e-1 on the Neurology®

Web site at www.neurology.org). Diagnosis of idiopathic PDwas made according to Brain Bank criteria.26 Antiparkinsonianmedications producing the best control of PD and LID symp-toms were fixed for at least 1 month before and during the study.Inclusion criteria were stable medication dose for 4 weeks, andLID �25% of waking hours (item 32 of UPDRS �2) and both-ersome (item 33 � 2). Exclusion criteria were previous PD sur-gery and contraindications to rTMS. Patients took regularmedications during the study except on days of levodopa chal-lenge test. Informed consent (describing the procedure and pos-sible beneficial effects on LID) and ethics board approval wereobtained for all 3 experiments.

Patients were in withdrawal of therapy (Core AssessmentProgram for Surgical Interventional Therapies [CAPSIT]) andhad been fasting since the night before. After 12 hours of over-night medication withdrawal, patients received 125% of theirusual morning levodopa equivalent dose as immediate releaselevodopa/carbidopa. The assessment in each video-recorded ses-sion consisted of a complete UPDRS III and CAPSIT dyskinesiascale.27 LID was assessed individually in the face, neck, trunk,and right and left upper and lower limbs, and was scored asfollows: 0, none; 1, mild; 2, moderate; 3, severe; and 4, extreme(0–28). After levodopa administration, UPDRS III and CAPSIT

were calculated every 15 minutes for 1 hour (t0, t15, t30, t45,t60). Two blinded raters experts in the field of movement disor-ders rated videotapes independently to provide CAPSIT andUPDRS scores. Both video raters were blinded to rTMS, and thescores were generated after a consensus was reached comparingthe individual scores.7,8

In 2 separate sessions, performed at least 1 week apart, cere-bellar cTBS and sham cerebellar cTBS were applied immediatelyafter levodopa administration (immediately after t0) over thelateral cerebellum ipsilateral to each individual patient’s side inwhich dyskinesias were predominant. The order of the sessionswas pseudorandomized across patients.7,8

A MagStim Super Rapid magnetic stimulator (Magstim Com-pany, Whitland, Wales, UK), connected with a figure-of-eight coilwith a diameter of 70 mm was used to deliver cTBS. Three-pulsebursts at 50 Hz repeated every 200 msec for 40 s were delivered at80% of the active motor threshold (AMT) over the lateral cerebel-lum (600 pulses).18 cTBS was applied over the lateral cerebellumusing the same scalp coordinates (1 cm inferior and 3 cm left/rightto the inion) adopted in previous MRI studies showing that this sitetargets the posterior and superior lobules of the lateral cerebellum.28

Although cerebellar stimulation has been originally performed witha double cone coil,29 we used the figure-of-eight coil because thisapproach has been adopted in previous investigations in which cere-bellar rTMS was shown to be effective in modulating the excitabilityof the contralateral motor cortex.28 The coil was positioned tangen-tially to the scalp, with the handle pointing superiorly.28

Sham stimulation was delivered with the coil angled at 90°,with only the edge of the coil resting on the scalp. Stimulusintensity, expressed as a percentage of the maximum stimulatoroutput, was set only at 40% AMT for the first dorsal interosse-ous muscle (FDI).

Furthermore, to control for possible effects induced by stim-ulation of afferent fibres from the neck, cTBS was applied overthe neck muscles (3.5 cm inferior and 3 cm lateral to the inion)immediately after levodopa administration. This session was per-formed in the same subjects 3 months later.

Experiment 2: Effects of a single session of cerebellarcTBS on intracortical circuits of contralateral motorcortex. This experiment was performed in the same group ofpatients with PD at least 1 week apart from experiment 1. Re-cordings were performed in the morning with patients receivingtheir usual morning levodopa equivalent dose. We chose not toincrease the dosage of levodopa administration to prevent for thedevelopment of abnormal movements that would have interferedwith EMG recordings. Paired TMS of the motor cortex wasperformed with a 7-cm figure-of-eight coil and 2 Magstim 200stimulators connected via 2 Bistim modules. The magnetic stim-uli had a nearly monophasic pulse configuration. The coil wasplaced at the optimal position for eliciting motor evoked poten-tials (MEPs) from the left contralateral FDI. SICI was testedusing paired TMS with a conditioning stimulus (CS) precedinga test stimulus (TS) by 1 to 15 msec.20,21 CS was set at 80%AMT21 while the intensity of TS was adjusted to evoke a MEP ofapproximately 1 mV peak to peak in the relaxed FDI. ForLICI,21,22 the CS preceded the TS by 80, 100, and 120 msec. Theintensity of CS was set at 120% resting motor threshold (RMT)and the intensity of TS was adjusted to evoke a MEP of approx-imately 1 mV peak to peak in the left FDI. Ten responses werecollected for each condition. The amplitude of the conditionedMEP at each interstimulus interval (ISI) was expressed as a per-centage of the mean peak-to-peak amplitude size of the uncondi-tioned TS in that block.

114 Neurology 73 July 14, 2009

SICI and LICI were tested in the morning 1 hour after theindividual dose of levodopa/carbidopa. On 2 different days, sep-arate by at least 1 week, real or sham cTBS was applied over theleft lateral cerebellum. SICI and LICI measures were again taken10 minutes after cerebellar cTBS. The order of presentation ofthe blocks was pseudorandomized across subjects. Before andafter cTBS, the intensity of TS was adjusted to evoke a MEP ofapproximately 1 mV peak to peak in the left FDI.

Experiment 3: Effects of repetitive sessions of cerebel-lar cTBS on LIDs. In this experiment, patients with PD un-derwent a 2-week course of bilateral cerebellar cTBS. Thecerebellum was stimulated bilaterally to have a clinical effect onboth body sides. In total, 20 patients with advanced PD (10 ofwhom participated in experiment 1) with peak-dose dyskinesiaswere enrolled (mean age 64.7 � 6.9 years, mean disease duration10.4 � 4.3 years; see table e-1 and figure 1 for a flow diagram).Antiparkinsonian medications producing the best control of PDand LID symptoms were fixed for at least 1 month before andduring the study. Patients with PD were randomly assigned toreal or sham cerebellar cTBS. Ten patients were assigned to realcTBS, and 10 patients were assigned to sham cTBS.

There were 10 days of stimulation (5 days per week, Monday toFriday). Cerebellar cTBS was applied daily at the same hour in the

morning (9 AM) for each patient. Two trains of cTBS (80% AMT,600 pulses, duration 40 s) were applied over the left and right lateralcerebellum with a pause of 2 minutes between the 2 trains. Theorder of stimulation was pseudorandomized in each subject in everysession. Sham stimulation was performed as in experiment 1.

Evaluation of dyskinesia and CAPSIT was performed byblinded raters (as in experiment 1) 1 hour before staring the firstsession of stimulation (pre-cTBS), the Monday after the 2 weeksof stimulation (post-cTBS) and again after 4, and 6 weeks afterthe beginning of the stimulation period (i.e., 2 and 4 weeks afterthe end of the stimulation period).

Patients completed an hourly on–dyskinesia–off diary 1 weekbefore the cTBS treatment, during the all stimulation period and 2weeks after the end of the cTBS treatment, to calculate the percent-age of the 24-hour day spent on with dyskinesia.30 Before the begin-ning of the study, all patients were instructed in the identification of4 motor states; no or worst mobility (complete off), moderate mo-bility (partial off), good mobility without dyskinesia (complete on),and mobility with dyskinesia (on with dyskinesia).

Data analysis. In experiment 1, nonparametric Friedmananalysis of variance (analysis of variance) was performed between

Figure 1 Flow diagram of patients enrolled for a 2-week course of bilateralcerebellar continuous theta burst stimulation (cTBS)

Figure 2 Comparison of cerebellar cTBS withsham and neck cTBS

(A) When compared with sham and neck stimulation, a singlesession of continuous theta burst stimulation (cTBS) over thelateral cerebellum significantly ameliorated global abnormalinvoluntary movement score 30 and 45 minutes after the in-gestion of levodopa. (B) No changes were observed measuringUnified Parkinson’s Disease Rating Scale (UPDRS) score in allconditions. *p � 0.05. Errors bars indicate SEM.

Neurology 73 July 14, 2009 115

the values of CAPSIT or those of UPDRS at each time point (t0,t15, t30, t45, and so on). If a significant effect was observed,single comparisons were performed by Wilcoxon tests, Bonfer-roni corrected (accepted p level �0.016), as post hoc test. Inexperiment 2, repeated-measures ANOVAs were performed onmean percentage of change in respect to TS with cTBS condi-tion (cTBS vs sham), time (pre vs post), and ISI as main factors.When a significant main effect was reached, post hoc t tests withBonferroni correction were used to characterize the different ef-fects of the specific ISIs (Bonferroni corrected accepted p level�0.009). In experiment 3, nonparametric Friedman ANOVAwas performed between the values of CAPSIT or those ofUPDRS obtained before and after 2, 4, and 6 weeks after cTBSat each time point (t0, t15, t30, t45, and so on). The same posthoc analysis as in experiment 1 was preformed (Bonferroni cor-rected accepted p level �0.012). For all statistical analyses, ap value �0.05 was considered to be significant.

RESULTS Experiment 1. The procedure was welltolerated by all subjects. The mean patients’ AMTtaken with the MagStim Super Rapid magnetic stim-ulator was 46.2 � 8.5% maximum stimulator out-put (MSO). After lateral cerebellar cTBS, globalCAPSIT dyskinesia scale scores were decreased incomparison with both sham and neck cTBS. Thiswas evident at t30 (Friedman ANOVA �2 � 9,80;p � 0.007; cerebellum vs sham: Z � �2.55, p �0.011; cerebellum vs neck: Z � �2.55, p � 0.011)and at t45 (Friedman ANOVA �2 � 10,30; p �

0.005; cerebellum vs sham: Z � �2.65, p � 0.008;cerebellum vs neck: Z � �2.55, p � 0.011) (figure2A) after L-dopa administration. Motor abilitiesscored by the mean UPDRS section III were notmodified by any cTBS condition as revealed by Wil-coxon test (figure 2B).

Experiment 2. Cerebellar stimulation with cTBSmodified the SICI circuits over contralateral M1 (ISImain factor: F � 25,40; p � 0.001; condition �

time � ISI interaction: F � 4.83; p � 0.05). Posthoc analysis Bonferroni correction showed thatchanges occurred after real and not sham cerebellarcTBS at ISI � 3 and 5 msec (all p � 0.05) in whichSICI was reduced (figure 3, A and B).

Moreover, cerebellar cTBS was also effective inmodulating LICI circuits in contralateral M1.ANOVA analysis performed on mean percentage ofchange in respect to TS showed that there was a con-dition � time interaction (F � 3,87; p � 0.05) butnot a condition � time � ISI interaction (F � 0,49;p � not significant), showing that LICI was in-creased after real and not sham cerebellar cTBS at allthe ISIs explored (figure 3, C and D).

For SICI and LICI measures, the intensity of TSwas adjusted to evoke an MEP of approximately 1mV peak to peak in the FDI before and after TBS;therefore, the observed effects cannot be ascribed tochanges in the amplitude of the MEP at differenttimes. For unconditioned TS, MEP amplitudes be-fore and after TBS were 0.98 � 0.28 and 1.11 �

0.33 mV. Stimulus intensities for TS were 58.3 �

7.4% and 59.2 � 8.8%. RMT were 45.6 � 6.3%and 44.5 � 4.8%.

Experiment 3. The procedure was well tolerated bythe patients with PD. No adverse effect was reported.The mean patients’ AMT taken with the MagStimSuper Rapid magnetic stimulator was 44.2 � 8.6%MSO for the real cTBS group and 43.3 � 9.1%MSO for the sham group.

Bilateral cerebellar cTBS was effective in reducingpersistently LIDs when applied with repeated ses-sions during 2 weeks. Global CAPSIT dyskinesiascales scores were decreased in comparison with base-line pre-cTBS evaluation at t30 (Friedman ANOVA�2 � 21,90; p � 0.0001) and t45 (FriedmanANOVA �2 � 13,92; p � 0.003) after L-dopa ad-ministration. The Wilcoxon test revealed that thiseffect was observable 2 weeks (at t30: Z � �2.65,p � 0.008; at t45: Z � �2.65, p � 0.008), 4 weeks(at t30: Z � �2.81, p � 0.005; at t45: Z � �2.56,p � 0.01), and 6 weeks (at t45: Z � �2.59, p �

0.009) after the beginning of the cTBS treatment(figure 4A). No changes were observed in the shamcTBS group (figure 3B). Motor abilities scored by

Figure 3 Effects of a single session of real or sham continuous theta burststimulation on intracortical circuits tested over the contralateralmotor cortex

Real but not sham continuous theta burst stimulation (cTBS) reduced short intracorticalinhibition at 3 and 5 msec (A and B) and increased long intracortical inhibition (C and D). *p �

0.05. Errors bars indicate SEM. MEP � motor evoked potential; ISI � interstimulus interval.

116 Neurology 73 July 14, 2009

the mean UPDRS section III were not modified byany cTBS condition as revealed by Wilcoxon test(figure 5).

Analysis of the diaries kept by the patients con-firmed that bilateral cerebellar cTBS was able to reducethe amount of dyskinesia, with an appreciable impacton the subjective self-evaluation performed by the pa-tients (figure e-1). Waking time (hours) spent as ONwith dyskinesias was decreased in comparison with thepretreatment self-evaluation during the first week ofcTBS (5.8 � 1.8 vs 8.2 � 2.1 hours; p � 0.02 at t testanalysis), during the second week after treatment(4.3 � 2.1 vs 8.2 � 2.1 hours; p � 0.01 at t test analy-sis), and during the first week after the end of the cTBS(5.1 � 2.5 vs 8.2 � 2.1 hours; p � 0.03 at t test analy-sis). No difference was reported in the sham group(baseline: 7.8 � 2.6 hours; first week during treatment:7.1 � 2.1 hours; second week during treatment 6.8 �2.2 hours; after treatment: 6.6 � 2.7 hours; all compar-isons: p � not significant).

DISCUSSION Cerebellar TMS is thought to inducechanges in Purkinje cells or in local interneurons,

resulting in indirect modifications in the excitabilityof the dentate nucleus, which is known to exert abackground tonic facilitatory drive onto the con-tralateral M1, through synaptic relay in the ventrallateral thalamus.29,31 In our sample of dyskinetic pa-tients with PD, a single session of cerebellar cTBSinduced a reduction of SICI and an increase of LICIcircuits in the contralateral motor cortex. These find-ings were not unexpected, resembling our previousstudy in healthy subjects.19 Recent investigati-ons showed that a single dose of the specific�-aminobutyric acid type B (GABAB) receptor ago-nist baclofen increases LICI and decreases SICI.32

Consistent with these premises, it is possible that inour patients with PD, the SICI reduction after cere-bellar cTBS may be the consequence of activation ofpresynaptic GABAB receptors, whereas LICI changesmay be due to increased GABAB receptor–mediatedinhibitory postsynaptic potentials. Moreover, our re-sults are in agreement with previous TMS investiga-tions in PD patients with LID treated withpallidotomy, a procedure known to exert profound

Figure 4 Effect of a 2-week session of bilateral cerebellar continuous theta burst stimulation on levodopa-induced dyskinesia

Real (A) but not sham (C) continuous theta burst stimulation (cTBS) ameliorated dyskinesia score obtained with an acutelevodopa challenge when tested at different time points after the end of the 2-week session. (B and D) Individual dyskine-sias scores measured at peak for each patient in the cTBS group (B) and in the sham group (D). *p � 0.05. Errors barsindicate SEM.

Neurology 73 July 14, 2009 117

and stable antidyskinetic effects.15 Pallidotomy wasfound to decrease SICI23 and to increase the TMSinduced cortical silent period,24,25 a parameter of pri-mary motor cortex excitability that is thought to re-flect the activity of populations of GABAB

interneurons. Therefore, it is likely that the above-described profile of motor cortical excitability couldrepresent the cortical reorganization that is associatedwith a reduction of LID. Alternatively, cerebellarcTBS may have expressed its antidyskinetic effectthrough direct modulation of the cerebellar cortexexcitability, of cerebellothalamic circuits, or throughdirect disynaptic connections between the cerebel-lum and the striatum,33 indirectly affecting abnormalcorticostriatal plasticity that characterizes LID.34

Beneficial and specific rTMS effects on bradyki-nesia and psychomotor speed have been reported inpatients with PD after high-frequency stimulation ofthe motor cortex.35-37 The finding that a 2-weekcourse of bilateral cerebellar cTBS was able to inducea marked and persistent reduction of LID that lastedfor up to 4 weeks after the end of the stimulationperiod is in agreement with the notion that repeatedsessions of stimulation may induce cumulativechanges leading to persistent modifications in the ex-citability of the stimulated and of the interconnectedareas.38 In a previous work, we did not induce bene-ficial effects on LID after a 5-day course of 1-Hz

rTMS of the supplementary motor area (SMA),8

whereas in the current study, the beneficial effectsdue to bilateral cerebellar cTBS were evident afterfew days of stimulation (as reported by the patients’diaries) and lasted for up to 4 weeks. This discrep-ancy could be because the cerebellum is a subcorticalstructure deputed to plastic mechanisms of motorlearning39 more than the SMA and therefore couldbe susceptible to more sustained rTMS-inducedchanges, leading to marked clinical beneficial effects.Moreover, it has to be noticed that we did not findany significant change in the UPDRS scores for bothsham and real cTBS. This finding was partially unex-pected because previous studies clearly demonstratedthat repeated session of sham rTMS led to some UP-DRS improvement.40 However, in the current study,subjects were informed that they could have less ab-normal movements and not a general improvementin motor skills as assessed by UPDRS III. Therefore,the expectation of therapeutic benefit from rTMSdiffered from previous studies.40

DISCLOSUREG.K. receives research support from Ministero della Salute (RF06.60).

P.M. receives research support from Ministerio de Educacion y Ciencia de

Espana (SAF2007–60700), Consejería de Innovacion, Ciencia y Empresa

de la Junta de Andalucía (CVI-02526), and Consejería de Salud de la

Junta de Andalucía (PI-0377/2007). L.B., F.C., E.L.G., S.T., M.O.,

C.C., and P.S. report no disclosures.

Received October 14, 2008. Accepted in final form April 3, 2009.

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