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1 Supplementary Online Content Chou Y-h, Hickey PT, Sundman M, Song AW, Chen N-k. Effects of repetitive transcranial magnetic stimulation on motor symptoms in Parkinson disease: a systematic review and metaanalysis. JAMA Neurol. Published online February 16, doi: /jamaneurol eappendix. Methods and Results ereferences. etable 1. Physiotherapy Evidence Database (PEDro) Scale etable 2. rtms Effects for Different Sham-rTMS Approaches etable 3. Risk of Bias Assessment in Individual Studies efigure 1. Flow Diagram efigure 2. Funnel Plot of Standard Error by Effect Size (SMD) This supplementary material has been provided by the authors to give readers additional information about their work American Medical Association. All rights reserved. 1

2 eappendix. Methods and Results Search Strategies Database PubMed Date of search Initial search April 2014, updated June 2014 Search strategy (parkinson's disease[title/abstract]) AND (((repetitive transcranial magnetic stimulation[title/abstract]) OR rtms[title/abstract]) OR repetitive TMS[Title/Abstract]) Items found 155 Database Web of Science Date of search Initial search April 2014, updated June 2014 Search strategy (TOPIC: (Parkinson's disease) OR TITLE: (Parkinson's disease)) AND TITLE: (repetitive transcranial magnetic stimulation) OR TOPIC: (repetitive transcranial magnetic stimulation) OR TITLE: (repetitive TMS) OR TOPIC: (repetitive TMS) OR TITLE: (rtms) OR TOPIC: (rtms) Items found 667 Database EMBASE Date of search Initial search April 2014, updated June 2014 Search strategy parkinsons disease and ( repetitive transcranial magnetic stimulation or rtms or repetitive TMS ) Items found 315 Database SCOPUS Date of search Initial search April 2014, updated June 2014 Search strategy (TITLE ABS KEY(parkinson's disease)) AND ((TITLE ABS KEY(repetitive transcranial magnetic stimulation)) OR (TITLE ABS KEY(repetitive tms)) OR (TITLE ABS KEY(rtms))) Items found 201 Database Cochrane Library Date of search Initial search April 2014, updated June 2014 Search strategy parkinson s disease and repetitive transcranial magnetic stimulation Items found American Medical Association. All rights reserved. 2

3 Search Results Step 1: Records identified through database searching (n = = 2203) Step 2: Additional records identified through other sources (n = 1) 1 Step 3: Full text articles assess for eligibility (n = 60) 1 60 Step 4: Among the 60 potentially eligible studies, 40 full text articles were excluded because of the following reasons: UPDRS III not included in the article as an outcome measure for the rtms effect (n = 16) 3,6,9,11,14,16,17,19,23 26,42,51,52,57 Not randomized sham controlled trials (n = 14) 1,4,28 31,35 38,48,50,56,58 Did not directly examine rtms effect (n = 4) Testing difference between active rtms + placebo drug and drug + shamrtms 44,46 Varied rtms intensity and duration of train to test safety 15 Theta burst stimulation included in the rtms treatment protocol 33 Statistical data not available for meta analysis 2,49 Single case study 10,20 Not idiopathic PD 13 Article not written in English 60 Step 5: Studied included in meta analysis (n = 20) 5,7,8,12,18,21,22,27,32,34,39 41,43,45,47,53 55, American Medical Association. All rights reserved. 3

4 Results. Analysis of Quality of Individual Studies The results showed that eight studies were of excellent methodological quality (PEDro scale 11/11). Ten studies were of good methodological quality (8/11 10/11). One study was of fair methodological quality (7/11). The results were summarized in etable 3. In order to assess whether the rigor of studies would influence the overall rtms effect size, we conducted the following three different analyses: First, we removed one study with a PEDro score of 7 (i.e., keeping excellent and good quality studies), and found that the effect size (or SMD) increased from 0.46 (N = 19) to 0.48 (N = 18, standard error = 0.09, 95% CI = [0.29, 0.64]). Second, we removed 11 studies with a PEDro score less than 11 (i.e., only keeping excellent quality studies with a PEDro score of 11). The data showed that the SMD increased from 0.46 (N = 19) to 0.49 (N = 8, standard error = 0.15, 95% CI = [0.21, 0.78]). Third, we ran a meta regression with the PEDro score as a predictor. The results showed that no significant correlation between the PEDro score and the SMD was found, r = 0.06, p = The findings suggest that although better quality studies had a tendency to increase the rtms effect, the correlation between quality score and effect size was not significant American Medical Association. All rights reserved. 4

5 ereferences 1. Antczak J, Rakowicz M, Banach M, et al. The Influence of Repetitive Transcranial Magnetic Stimulation on Sleep in Parkinson's Disease. Biocybern Biomed Eng. 2011;31(3): Sayin S, Cakmur R, Yener GG, Yaka E, Ugurel B, Uzunel F. Low frequency repetitive transcranial magnetic stimulation for dyskinesia and motor performance in Parkinson's disease. J Clin Neurosci. Mar von Papen M, Fisse M, Sarfeld AS, Fink GR, Nowak DA. The effects of 1 Hz rtms preconditioned by tdcs on gait kinematics in Parkinson's disease. J Neural Transm. Feb Spagnolo F, Volonte MA, Fichera M, et al. Excitatory deep repetitive transcranial magnetic stimulation with H coil as add on treatment of motor symptoms in Parkinson's disease: an open label, pilot study. Brain Stimul. Mar Apr 2014;7(2): Nardone R, De Blasi P, Holler Y, et al. Repetitive transcranial magnetic stimulation transiently reduces punding in Parkinson's disease: a preliminary study. J Neural Transm. Mar 2014;121(3): Randhawa BK, Farley BG, Boyd LA. Repetitive transcranial magnetic stimulation improves handwriting in Parkinson's disease. Parkinsons Dis. 2013;2013: Maruo T, Hosomi K, Shimokawa T, et al. High Frequency Repetitive Transcranial Magnetic Stimulation over the Primary Foot Motor Area in Parkinson's Disease. Brain Stimul. May Shirota Y, Ohtsu H, Hamada M, Enomoto H, Ugawa Y. Supplementary motor area stimulation for Parkinson disease: a randomized controlled study. Neurology. Apr ;80(15): Eliasova I, Mekyska J, Kostalova M, Marecek R, Smekal Z, Rektorova I. Acoustic evaluation of short term effects of repetitive transcranial magnetic stimulation on motor aspects of speech in Parkinson's disease. J Neural Transm. Apr 2013;120(4): Filipovic SR, Bhatia KP, Rothwell JC. 1 Hz repetitive transcranial magnetic stimulation and diphasic dyskinesia in Parkinson's disease. Mov Disord. Feb 2013;28(2): Filipovic SR, Rothwell JC, Bhatia K. Slow (1 Hz) repetitive transcranial magnetic stimulation (rtms) induces a sustained change in cortical excitability in patients with Parkinson's disease. Clin Neurophysiol. Jul 2010;121(7): Filipovic SR, Rothwell JC, Bhatia K. Low frequency repetitive transcranial magnetic stimulation and off phase motor symptoms in Parkinson's disease. J Neurol Sci. Apr ;291(1 2): Yip CW, Cheong PW, Green A, et al. A prospective pilot study of repetitive transcranial magnetic stimulation for gait dysfunction in vascular parkinsonism. Clin Neurol Neurosurg. Jul 2013;115(7): American Medical Association. All rights reserved. 5

6 14. Srovnalova H, Marecek R, Kubikova R, Rektorova I. The role of the right dorsolateral prefrontal cortex in the Tower of London task performance: repetitive transcranial magnetic stimulation study in patients with Parkinson's disease. Exp Brain Res. Nov 2012;223(2): Benninger DH, Lomarev M, Wassermann EM, et al. Safety study of 50 Hz repetitive transcranial magnetic stimulation in patients with Parkinson's disease. Clin Neurophysiol. Apr 2009;120(4): Minks E, Marecek R, Pavlik T, Ovesna P, Bares M. Is the Cerebellum a Potential Target for Stimulation in Parkinson's Disease? Results of 1 Hz rtms on Upper Limb Motor Tasks. Cerebellum. Dec 2011;10(4): Srovnalova H, Marecek R, Rektorova I. The Role of the Inferior Frontal Gyri in Cognitive Processing of Patients with Parkinson's Disease: A Pilot rtms Study. Movement Disord. Jul 2011;26(8): Gonzalez Garcia N, Armony JL, Soto J, Trejo D, Alegria MA, Drucker Colin R. Effects of rtms on Parkinson's disease: a longitudinal fmri study. Journal of Neurology. Jul 2011;258(7): Kimura H, Kurimura M, Kurokawa K, et al. A comprehensive study of repetitive transcranial magnetic stimulation in Parkinson's disease. ISRN Neurol. 2011;2011: Kodama M, Kasahara T, Hyodo M, et al. Effect of Low Frequency Repetitive Transcranial Magnetic Stimulation Combined with Physical Therapy on L Dopa Induced Painful Off Period Dystonia in Parkinson's Disease. Am J Phys Med Rehab. Feb 2011;90(2): Pal E, Nagy F, Aschermann Z, Balazs E, Kovacs N. The impact of left prefrontal repetitive transcranial magnetic stimulation on depression in Parkinson's disease: a randomized, double blind, placebo controlled study. Mov Disord. Oct ;25(14): Arias P, Vivas J, Grieve KL, Cudeiro J. Controlled trial on the effect of 10 days lowfrequency repetitive transcranial magnetic stimulation (rtms) on motor signs in Parkinson's disease. Mov Disord. Sep ;25(12): Kang SY, Wasaka T, Shamim EA, et al. Characteristics of the sequence effect in Parkinson's disease. Mov Disord. Oct ;25(13): Hartelius L, Svantesson P, Hedlund A, Holmberg B, Revesz D, Thorlin T. Short term effects of repetitive transcranial magnetic stimulation on speech and voice in individuals with Parkinson's disease. Folia Phoniatr Logop. 2010;62(3): Gruner U, Eggers C, Ameli M, Sarfeld AS, Fink GR, Nowak DA. 1 Hz rtms preconditioned by tdcs over the primary motor cortex in Parkinson's disease: effects on bradykinesia of arm and hand. J Neural Transm. Feb 2010;117(2): Jacobs JV, Lou JS, Kraakevik JA, Horak FB. The supplementary motor area contributes to the timing of the anticipatory postural adjustment during step initiation in participants with and without Parkinson's disease. Neuroscience. Dec ;164(2): Sedlackova S, Rektorova I, Srovnalova H, Rektor I. Effect of high frequency repetitive transcranial magnetic stimulation on reaction time, clinical features and cognitive 2015 American Medical Association. All rights reserved. 6

7 functions in patients with Parkinson's disease. J Neural Transm. Sep 2009;116(9): van Dijk KD, Most EI, Van Someren EJ, Berendse HW, van der Werf YD. Beneficial effect of transcranial magnetic stimulation on sleep in Parkinson's disease. Mov Disord. Apr ;24(6): Baumer T, Hidding U, Hamel W, et al. Effects of DBS, premotor rtms, and levodopa on motor function and silent period in advanced Parkinson's disease. Mov Disord. Apr ;24(5): Brusa L, Finazzi Agro E, Petta F, et al. Effects of inhibitory rtms on bladder function in Parkinson's disease patients. Mov Disord. Feb ;24(3): Furukawa T, Izumi S, Toyokura M, Masakado Y. Effects of low frequency repetitive transcranial magnetic stimulation in Parkinson's disease. Tokai J Exp Clin Med. Sep 2009;34(3): Hamada M, Ugawa Y, Tsuji S. High frequency rtms over the supplementary motor area for treatment of Parkinson's disease. Mov Disord. Aug ;23(11): Rothkegel H, Sommer M, Rammsayer T, Trenkwalder C, Paulus W. Training effects outweigh effects of single session conventional rtms and theta burst stimulation in PD patients. Neurorehabil Neural Repair. May 2009;23(4): Filipovic SR, Rothwell JC, van de Warrenburg BP, Bhatia K. Repetitive transcranial magnetic stimulation for levodopa induced dyskinesias in Parkinson's disease. Mov Disord. Jan ;24(2): Rektorova I, Sedlackova S, Telecka S, Hlubocky A, Rektor I. Dorsolateral prefrontal cortex: a possible target for modulating dyskinesias in Parkinson's disease by repetitive transcranial magnetic stimulation. Int J Biomed Imaging. 2008;2008: Kim JY, Chung EJ, Lee WY, et al. Therapeutic effect of repetitive transcranial magnetic stimulation in Parkinson's disease: analysis of [11C] raclopride PET study. Mov Disord. Jan ;23(2): Epstein CM, Evatt ML, Funk A, et al. An open study of repetitive transcranial magnetic stimulation in treatment resistant depression with Parkinson's disease. Clin Neurophysiol. Oct 2007;118(10): Khedr EM, Rothwell JC, Shawky OA, Ahmed MA, Foly N, Hamdy A. Dopamine levels after repetitive transcranial magnetic stimulation of motor cortex in patients with Parkinson's disease: preliminary results. Mov Disord. May ;22(7): Khedr EM, Rothwell JC, Shawky OA, Ahmed MA, Hamdy A. Effect of daily repetitive transcranial magnetic stimulation on motor performance in Parkinson's disease. Mov Disord. Dec 2006;21(12): del Olmo MF, Bello O, Cudeiro J. Transcranial magnetic stimulation over dorsolateral prefrontal cortex in Parkinson's disease. Clin Neurophysiol. Jan 2007;118(1): Brusa L, Versace V, Koch G, et al. Low frequency rtms of the SMA transiently ameliorates peak dose LID in Parkinson's disease. Clin Neurophysiol. Sep 2006;117(9): American Medical Association. All rights reserved. 7

8 42. Strafella AP, Ko JH, Grant J, Fraraccio M, Monchi O. Corticostriatal functional interactions in Parkinson's disease: a rtms/[11c]raclopride PET study. Eur J Neurosci. Dec 2005;22(11): Lomarev MP, Kanchana S, Bara Jimenez W, Iyer M, Wassermann EM, Hallett M. Placebocontrolled study of rtms for the treatment of Parkinson's disease. Mov Disord. Mar 2006;21(3): Boggio PS, Fregni F, Bermpohl F, et al. Effect of repetitive TMS and fluoxetine on cognitive function in patients with Parkinson's disease and concurrent depression. Mov Disord. Sep 2005;20(9): Lefaucheur JP, Drouot X, Von Raison F, Menard Lefaucheur I, Cesaro P, Nguyen JP. Improvement of motor performance and modulation of cortical excitability by repetitive transcranial magnetic stimulation of the motor cortex in Parkinson's disease. Clin Neurophysiol. Nov 2004;115(11): Fregni F, Santos CM, Myczkowski ML, et al. Repetitive transcranial magnetic stimulation is as effective as fluoxetine in the treatment of depression in patients with Parkinson's disease. J Neurol Neurosurg Psychiatry. Aug 2004;75(8): Khedr EM, Farweez HM, Islam H. Therapeutic effect of repetitive transcranial magnetic stimulation on motor function in Parkinson's disease patients. Eur J Neurol. Sep 2003;10(5): Ikeguchi M, Touge T, Nishiyama Y, Takeuchi H, Kuriyama S, Ohkawa M. Effects of successive repetitive transcranial magnetic stimulation on motor performances and brain perfusion in idiopathic Parkinson's disease. J Neurol Sci. May ;209(1 2): Okabe S, Ugawa Y, Kanazawa I. 0.2 Hz repetitive transcranial magnetic stimulation has no add on effects as compared to a realistic sham stimulation in Parkinson's disease. Mov Disord. Apr 2003;18(4): Dragasevic N, Potrebic A, Damjanovic A, Stefanova E, Kostic VS. Therapeutic efficacy of bilateral prefrontal slow repetitive transcranial magnetic stimulation in depressed patients with Parkinson's disease: an open study. Mov Disord. May 2002;17(3): Gilio F, Curra A, Inghilleri M, Lorenzano C, Manfredi M, Berardelli A. Repetitive magnetic stimulation of cortical motor areas in Parkinson's disease: implications for the pathophysiology of cortical function. Mov Disord. May 2002;17(3): Sommer M, Kamm T, Tergau F, Ulm G, Paulus W. Repetitive paired pulse transcranial magnetic stimulation affects corticospinal excitability and finger tapping in Parkinson's disease. Clin Neurophysiol. Jun 2002;113(6): Shimamoto H, Takasaki K, Shigemori M, Imaizumi T, Ayabe M, Shoji H. Therapeutic effect and mechanism of repetitive transcranial magnetic stimulation in Parkinson's disease. J Neurol. Sep 2001;248 Suppl 3:III Boylan LS, Pullman SL, Lisanby SH, Spicknall KE, Sackeim HA. Repetitive transcranial magnetic stimulation to SMA worsens complex movements in Parkinson's disease. Clin Neurophysiol. Feb 2001;112(2): American Medical Association. All rights reserved. 8

9 55. Siebner HR, Rossmeier C, Mentschel C, Peinemann A, Conrad B. Short term motor improvement after sub threshold 5 Hz repetitive transcranial magnetic stimulation of the primary motor hand area in Parkinson's disease. J Neurol Sci. Sep ;178(2): Mally J, Stone TW. Therapeutic and "dose dependent" effect of repetitive microelectroshock induced by transcranial magnetic stimulation in Parkinson's disease. J Neurosci Res. Sep ;57(6): Siebner HR, Mentschel C, Auer C, Conrad B. Repetitive transcranial magnetic stimulation has a beneficial effect on bradykinesia in Parkinson's disease. Neuroreport. Feb ;10(3): Mally J, Stone TW. Improvement in Parkinsonian symptoms after repetitive transcranial magnetic stimulation. J Neurol Sci. Jan ;162(2): Benninger DH, Iseki K, Kranick S, Luckenbaugh DA, Houdayer E, Hallett M. Controlled study of 50 Hz repetitive transcranial magnetic stimulation for the treatment of Parkinson disease. Neurorehabil Neural Repair. Nov Dec 2012;26(9): de Groot M, Hermann W, Steffen J, Wagner A, Grahmann F. [Contralateral and ipsilateral repetitive transcranial magnetic stimulation in Parkinson patients]. Nervenarzt. Dec 2001;72(12): Franssen M, Winward C, Collett J, Wade D, Dawes H. Interventions for fatigue in Parkinson's disease: A systematic review and meta analysis. Mov Disord. Nov 2014;29(13): Moher D, Liberati A, Tetzlaff J, Altman DG, Group P; PRISMA Group. Preferred reporting items for systematic reviews and meta analyses: the PRISMA statement. PLoS Med. 2009;6(7):e doi: /journal.pmed American Medical Association. All rights reserved. 9

10 etable 1. Physiotherapy Evidence Database (PEDro) Scale Item Description 1 Eligibility criteria were specified. 2 Participants were randomly allocated to groups. 3 Allocation was concealed. 4 The groups were similar at baseline regarding the most important prognostic indicators. 5 There was blinding of all participants. 6 There was blinding of all personnel who administered the intervention. 7 There was blinding of all assessors who measures at least 1 key outcome. 8 Measures of at least 1 key outcome were obtained from more than 85% of the participants initially allocated to groups. 9 All participants for whom outcome measures were available received the treatment or control condition as allocated or, where this was not the case, data for at least 1 key outcome were analyzed by intention to treat. 10 The results of between group statistical comparisons are reported for at least 1 key outcome. 11 The study provides both point measures and measures of variability for at least 1 key outcome American Medical Association. All rights reserved. 10

11 etable 2. rtms effects for different sham rtms approaches Type No. of studies SMD 95% CI p Back surface coil [0.07, 2.28] 0.04 Active rtms at occipital regions [0.08, 1.16] 0.03 Tilted coil [0.25, 0.96] Sham coil [ 0.11, 1.00] Inactive coil with stimulation sound [ 0.51, 1.36] Realistic coil [0.06, 0.61] 0.02 Active coil on top of an inactive coil [ 0.30, 0.90] American Medical Association. All rights reserved. 11

12 etable 3. Risk of bias assessment in individual studies Study Selection Performance Detection Attrition a Reporting Carry over b PEDro Siebner et al., N/A + + 9/11 Boylan et al., N/A + + 8/11 Shimamoto et al., ? c + +? d + N/A 7/11 Khedr et al., N/A 11/11 Lefaucheur et al., N/A /11 Khedr et al., N/A 11/11 Lomarev et al., N/A 10/11 Brusa et al, ? e + N/A +? f 8/11 del Olmo et al, N/A 9/11 Hamada et al, N/A 11/11 Sedlácková et al, ? g? g N/A +? f 8/11 Filipović et al, 11, , N/A +? f 8/11 Pal et al, N/A 11/11 Arias et al, N/A 11/11 Gonzalez Garcia et al, N/A 10/11 Benninger et al, N/A 11/11 Maruo et al, N/A /11 Shirota et al, N/A 11/11 Nardone et al, N/A +?f 8/11 Note. The Cochrane tool classifies studies as having low (+), high ( ), or unclear (?) risk of bias in the following domains: selection bias, performance bias, detection bias, attrition bias, reporting bias, and carry over effect. The PEDro scale was used to evaluate the number of items that met the criteria for quality assessment of RCTs. We considered a PEDro score of > 8 to represent a high quality study, a score of 6 and 7 a moderate quality study, and a score of 5 a low quality study 61. a Assessment of attrition bias is only relevant for parallel RCTs; b Assessment of carry over bias is only relevant for cross over RCTs; c Not clear whether participants were randomized into different groups; d Not clear whether there was no systematic 2015 American Medical Association. All rights reserved. 12

13 difference between groups in withdrawals; e Not clear whether patients were blinded; f Not clear whether there was a carryover effect; g Not clear whether patients, personnel, and outcome assessors were blinded American Medical Association. All rights reserved. 13

14 Records iden+fied through database searching (n = 2203) Addi+onal records iden+fied through other resources (n = 1) Full- text ar+cles assess for eligibility (n = 60) Studies included in meta- analysis (n = 20) Full- text ar+cles excluded (n = 40): UPDRS- III not included as an outcome measure (n = 16) Not randomized sham- controlled trials (n = 14) Data not available for meta- analysis (n = 2) Not idiopathic PD (n = 1) Single- case study (n = 2) Did not directly examine rtms effect (n = 4) Ar+cle not wriren in English (n = 1)

15 efigure 2. Funnel plot of standard error by effect size (SMD). The funnel plot was plotted with SMD on the X axis and the standard error on the Y axis American Medical Association. All rights reserved. 15