CLINICAL TRIAL published: 12 February 2019 doi: 10.3389/fneur.2019.00073 Repetitive Transcranial Magnetic Stimulation in Spinocerebellar Ataxia: A Pilot Randomized Controlled Trial Brad Manor 1,2,3† , Patricia E. Greenstein 1,2*† , Paula Davila-Perez 1,2 , Seth Wakefield 1,2 , Junhong Zhou 2,3 and Alvaro Pascual-Leone 1,2,4 1 Berenson-Allen Center for Noninvasive Brain Stimulation and Division for Cognitive Neurology, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United States, 2 Harvard Medical School, Boston, MA, United States, 3 Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Roslindale, MA, United States, 4 Institut Guttman de Neurorehabilitació, Universitat Autonoma de Barcelona, Barcelona, Spain Spinocerebellar ataxia (SCA) is a neurodegenerative disorder caused by dysfunction of the cerebellum and its connected neural networks. There is currently no cure for SCA and symptomatic treatment remains limited. We aimed here to examine the effects of a repetitive transcranial magnetic stimulation (rTMS) targeting the cerebellum on clinical impression, postural control and gait in patients with SCA. In this randomized, double-blinded and sham-controlled study, 20 individuals aged 18–75 years with SCA confirmed by genetic testing completed rTMS or sham intervention comprising 20 sessions of MRI-guided stimulation over the cerebellum. Baseline Edited by: assessments included the Standard Ataxia Rating Assessment (SARA), the 9-hole peg Oscar Arias-Carrión, Hospital General Dr. Manuel Gea test of manual dexterity, the Timed Up-and-Go (TUG) test, standing postural control Gonzalez, Mexico with eyes-open and eyes-closed, and gait. Immediate (within 1-week) and 1-month Reviewed by: follow-ups were completed. Intervention compliance was high (19 ± 2 of 20 sessions) Matteo Bologna, Sapienza University of Rome, Italy and no rTMS-related adverse events were reported. rTMS, compared to sham, was Silmar Teixeira, associated with greater percent improvement in SARA total score from baseline to the Federal University of Piauí, Brazil 1-month follow-up (p = 0.008). Secondary analyses of individual SARA items revealed *Correspondence: that rTMS improved performance within the “stance” sub-score only (p = 0.002). This Patricia E. Greenstein pgreenst@bidmc.harvard.edu functional change was accompanied by improvement to several objective metrics of † These postural sway during eyes-open and eyes-closed standing (p < 0.008). rTMS did not authors share co-first authorship influence the 9-hole peg test, TUG, or gait kinematics. A 20-session rTMS intervention is safe and feasible for those with SCA. Additional research is warranted to confirm the Specialty section: observed longer-term benefits of this intervention on standing postural control. This article was submitted to Movement Disorders, a section of the journal Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT01975909 Frontiers in Neurology Keywords: rTMS, spinocerebellar ataxia, cerebellum, Standard Ataxia Rating Assessment, standing postural Received: 14 September 2018 control Accepted: 18 January 2019 Published: 12 February 2019 Citation: INTRODUCTION Manor B, Greenstein PE, Davila-Perez P, Wakefield S, Zhou J Autosomal dominant spinocerebellar ataxia (SCA) is associated with degeneration of the and Pascual-Leone A (2019) cerebellum and its efferent and/or afferent cerebello-thalamocortical tracts (1, 2). Patient with Repetitive Transcranial Magnetic Stimulation in Spinocerebellar Ataxia: SCA often present with a host of motor symptoms, including deficits to the control of both A Pilot Randomized Controlled Trial. standing posture and gait (3–5). Such deficits are progressive in nature and greatly increase one’s Front. Neurol. 10:73. risk of falling (6, 7) and losing functional independence (8). There is currently no cure for SCA doi: 10.3389/fneur.2019.00073 and attempts to improve the clinical symptoms of ataxia have been largely unsuccessful and/or Frontiers in Neurology | www.frontiersin.org 1 February 2019 | Volume 10 | Article 73 Manor et al. rTMS Improves Balance in SCA short-lasting (9). There is thus an urgent need to develop novel or concomitant medical condition (i.e., stroke, arthritis, etc.), therapeutic interventions for this vulnerable population. clinically-significant abnormalities on screening (e.g., basic lab Dysfunction in the cerebellar region and its connected work or EKG abnormalities), concurrent participation in another neural networks is thought to be the proximal root cause of clinical study, history of substance abuse, untreated depression, movement disorder in patients with SCA (1, 2, 10). Therapeutic dementia, psychiatric illness, subjects who were wheelchair strategies aimed at functional improvement of the cerebellum bound, Mini Mental Status Exam score <24, legal incapacity may thus lead to significant clinical benefit within this vulnerable or limited legal capacity. TMS and MRI-specific exclusions population. Repetitive transcranial magnetic stimulation (rTMS) included metal in the head, history of neurosurgical procedures, enables non-invasive modulation of cortical excitability (11). ferromagnetic bioimplants, metallic paint, history of seizure rTMS targeting cerebellar structures is capable of inducing disorder, claustrophobia, current usage of buproprion or other long-lasting changes in the excitability of cerebello-thalamo- medications that may increase risk of TMS-induced seizures. cortical pathways (12–14). Shiga et al. (15) reported that as We screened 110 individuals. Seventy-nine were ineligible and compared to a sham intervention, 21 daily sessions of rTMS 11 were uninterested (Figure 1). The remaining 20 completed targeting the cerebellum improved performance in several short baseline testing. Ten were randomized to the rTMS intervention clinical tests of gait and posture, when tested immediately after (women = 8; SCA type 3 = 8; mean ± SD age = 53 ± 9 years; the intervention was completed, in a cohort of patients with height = 164 ± 10 cm; body mass = 71 ± 13 kg) and ten to spinocerebellar degeneration. Still, the longer-term effects of sham (women = 8; SCA type 3 = 6; age = 49 ± 4 years; height rTMS on the clinical impression of symptom severity, as well = 161 ± 6 cm; body mass = 67 ± 13 kg). All 20 participants as the biomechanical control of gait and standing posture, were naïve to TMS and completed the intervention and all have not been established. We therefore conducted a small, yet study assessments. well-controlled trial to assess the effects of a four-week, 20- session rTMS intervention targeting the cerebellum, as guided by Intervention individual brain anatomy using structural MRI, on the clinical The rTMS intervention comprised 20 sessions over 4 consecutive severity of SCA and the control of standing posture and gait weeks. A Magstim 200 (UK) and 14 cm circular coil delivered using quantitative kinematic assessments, in patients with SCA stimuli at 100% of maximal stimulator output intensity with the as confirmed by genetic testing. coil centered over three regions: the inion, 4 cm lateral to the left of the inion, 4 cm lateral to the right of the inion. Participants METHODS were asked to lay their head down on a pillow placed on a table in front of them, and the handle of the TMS coil was held Trial Design facing upwards. Structural MRIs were used to locate and mark A parallel-group, randomized controlled trial was conducted each region for rTMS and neuronavigation using Brainsight R (NCT01975909). Enrolled participants completed baseline (Rogue Resolutions, Cardiff, Wales) ensured that all stimuli for assessments and a structural brain MRI. They were then assigned a given region within and across daily sessions targeted the to receive the rTMS or sham intervention via permuted block same cerebellar regions. For each region, five pulses separated randomization with stratification by sex. rTMS was administered by 6 s were delivered counter-clockwise, followed by five pulses by study personnel uninvolved in other study procedures. delivered clockwise, for a total of 10 pulses per region and session, Participants and the study staff who assessed outcomes were and a total of 30 pulses per session (15). For sham intervention, blinded to intervention arm. Immediate (i.e., within 1 week of the same parameters and procedures were used except the coil intervention completion) and 1-month follow-up assessments was angled 90 degrees from the scalp, inducing non-measurable were completed. changes of the excitability in cerebellum (17). Trial Registration Ethics This study was registered prospectively at https://clinicaltrials. This study was carried out in accordance with the gov/ (NCT01975909). recommendations of the BIDMC Institutional Review Board with written informed consent from all subjects. All participants gave Participants written informed consent in accordance with the Declaration of Participants were recruited between 2013 and 2015 from the Helsinki. The protocol was approved by the BIDMC Institutional Neurogenetics Clinic and Movement Disorders Center at the Review Board. Beth Israel Deaconess Medical Center (BIDMC), local ataxia support organizations, the National Ataxia Foundation and Assessments clinicaltrials.gov. Assessments were conducted at the Harvard-Catalyst Clinical Inclusion criteria included SCA confirmed by genetic testing, Research Center at the BIDMC at approximately the same time age 18–75, the ability to ambulate without assistance from of day. Screening included health history, neurological exam, the another person (canes/walkers allowed), a score >3 on the Mini Mental State Examination and the SARA. A nurse recorded “gait” subsection of the Scale for the Assessment and Rating medications, resting EKG, vital signs, height and body mass. of Ataxia (SARA) (16), a negative pregnancy test and stable Hematology, pregnancy testing (if applicable), renal and liver medications. Exclusion criteria were unstable neurological illness panels were completed. A study physician reviewed screening Frontiers in Neurology | www.frontiersin.org 2 February 2019 | Volume 10 | Article 73 Manor et al. rTMS Improves Balance in SCA FIGURE 1 | Study CONSORT diagram. One hundred and ten individuals were screened. Seventy-nine were ineligible and 11 were uninterested. The remaining 20 completed baseline testing. Ten were randomized to the rTMS intervention and ten to sham. All of them completed the intervention and both follow-ups. data to determine eligibility. The SARA, nine-hole peg test, meters, turn around, walk back, and return to a seated position Timed Up-and-Go (TUG) and biomechanical assessments of was recorded. standing posture and gait were measured at baseline and at both follow-ups. Assistive devices were allowed on all tests except standing posture. Assessment of Standing Posture and Gait Standing postural control and gait were assessed using standard Scale for the Assessment and Rating of procedures. Postural control was assessed by measuring postural Ataxia (SARA) sway (i.e., center of pressure) fluctuations (240 Hz) during The clinical severity of SCA was measured using the valid and standing on a stationary force platform (AMTI, Watertown, reliable SARA scoring scale (16). This scale consists of eight MA). Participants were asked to stand barefoot on the platform items related to gait, stance, sitting, speech, finger-chase test, and complete two 30-s trials under both eyes-open and eyes- nose-finger test, fast alternating movements, and heel-shin test. closed conditions. Trial order was randomized. Tissue paper was placed on the force platform and foot placement of each participant was outlined prior to the first trial. This outline was 9-Hole Peg Test then used throughout all future assessments and trials to ensure The peg test was used to assess fine motor control hand and consistent foot placement over time. Participants were instructed manual dexterity (18). Participants were asked to remove the pegs to “stand as still as possible” prior to each trial. For eyes-open from the holes, one by one, and then replace them back into trials, participants were further instructed to visually focus on a the container. The time to complete the test was recorded, with target “X” placed on the wall approximately 3-m in front of them longer times reflecting worse performance. at eye-level. Gait was assessed by measuring the kinematics of walking Timed Up-and-Go Test (TUG) using the wireless Mobility Lab R system (APDM, Seattle WA) The TUG test was used to assess functional mobility (19). during a 90-s walk. Participants were instructed to walk at The time taken to stand from a chair, walk forward three their normal, preferred paced. The use of assistive device (e.g., Frontiers in Neurology | www.frontiersin.org 3 February 2019 | Volume 10 | Article 73 Manor et al. rTMS Improves Balance in SCA cane) was allowed and if it was used, the same device was used group decreased their 10-m walk time (from 14.3 ± 1.8 to 9.9 throughout the study. ± 0.7 s, mean ± SD) significantly more than those receiving the sham treatment (from 13.7 ± 1.2 to 13.6 ± 1.2 s). We estimated Study Outcomes that a sample size of 20 would provide over 80% power to detect The primary outcome of this study was the SARA total a similar effect size, after adjusting for three covariates. score. Secondary outcomes included performance within clinical functional tests (9-hole peg test, TUG) and metrics related to standing postural control and gait. Standing postural control RESULTS metrics were chosen based upon their sensitivity to change in SCA severity (3) and included average sway speed (i.e., center- The demographic, SCA and health characteristics of each of-pressure path length divided by trial duration) and area (i.e., participant are listed in Table 1. The groups receiving rTMS the area of a confidence ellipse enclosing 95% of the center- and sham intervention had similar age, height and body mass. of-pressure trajectory) during both eyes-open and eyes-closed At baseline, the rTMS group, as compared to the sham group, conditions. Gait metrics included average walking speed, stride exhibited lower SARA scores (p = 0.01), faster 9-hole peg test time variability (i.e., the coefficient of variation about the mean time (p = 0.03) and faster postural sway speed during eyes-open between consecutive heel strikes of the right foot) and double standing (p = 0.01) (Table 2). No other between-group baseline support time (i.e., the average percentage of each stride time spent differences were observed. Baseline functional outcomes did not with both feet on ground), as each has been linked to SCA severity differ by sex (p > 0.56) and were not significantly correlated and related functional decline (4, 5). with participant age (p > 0.33) or BMI (p > 0.40). Intervention compliance was high (19 ± 2 of 20 sessions) and similar between Statistical Analysis groups. The rTMS and sham interventions were well-tolerated Analyses were performed using JMP Pro 12 (SAS Institute, Cary, and no unexpected side effects or adverse events were reported. NC). Descriptive statistics summarized group demographics Primary and secondary outcomes are presented by and outcomes. Potential between-group differences in baseline intervention group in Table 2. A two-way, repeated-measures characteristics were tested with Student’s t-tests or chi-square ANOVA revealed a trend toward a main effect of group for SARA tests. Primary analyses examined the effects of rTMS on primary total score (F = 2.0, p = 0.16, Cohen’s d = 0.5, η2 = 0.06). As and secondary outcomes using two-way repeated-measures can be observed in Figure 2A, both groups exhibited relatively ANOVAs. As groups differed in several measures of functional large percent reductions (i.e., improvements) in this outcome performance at baseline, dependent variables were the percent from baseline to the immediate follow-up. Secondary analyses change in each outcome from baseline to each follow-up visit. omitting the one-week follow-up assessment revealed that the Model effects included follow-up time (within-subject: one- rTMS intervention, as compared to sham, induced a greater week, one-month), group (between-subject: rTMS, sham), and percent decrease in SARA total scores from baseline to the their interaction. Models were completed with and without 1-month follow-up (F = 9.3, p = 0.008, Cohen’s d = 1.3, η2 adjustments for age, sex, and intervention compliance. Two = 0.38) (Figure 2A). This effect was independent of age, sex, secondary analyses were complete based upon the observed and intervention compliance. Spurred by this observation, the effects of rTMS intervention on SARA performance. First, as a effects of intervention on the percent change from baseline to the potential placebo effect was observed in SARA total score at the 1-month follow-up in each of the nine SARA sub-scores were one-week follow-up, a one-way repeated-measures ANOVA was also examined. rTMS, compared to sham, improved performance completed to determine the between-subject effect of group on within the “stance” sub-score (F = 10.4, p = 0.002, Cohen’s d the percent change in SARA total score only from baseline to = 0.9; η2 = 0.24) (Figure 2B). No other item-specific changes the 1-month follow-up visit. Second, similar two-way models within the SARA exam were observed between groups. as described above were completed to examine the effects of The beneficial effect of rTMS on the clinical assessment intervention on each of the nine SARA items. Significance level of posture was corroborated by improvements within several for all statistical tests within this pilot study was set to p < 0.05. objective kinematic metrics of standing postural sway. As Effect sizes of significant models was measured using Cohen’s d compared to sham, those who completed the rTMS intervention and the partial eta square metric (η2 ). exhibited a greater percent decrease in postural sway speed when Sample size considerations: To our knowledge, this was the standing with eyes open (group effect: F = 9.5, p = 0.004, Cohen’s first pilot study to systematically test the effects of MRI- d = 1.0; η2 = 0.28) and eyes closed (group effect: F = 11.4, guided cerebellar rTMS on the SARA and other functional and p = 0.002, Cohen’s d = 1.0, η2 = 0.26) (Figures 2C,D). rTMS, biomechanics outcomes over a 1-month follow-up period in as compared to sham, also reduced sway area during eyes-closed patients with genetically-confirmed SCA. While the primary standing (F = 8.5, p = 0.007, Cohen’s d = 0.9, η2 = 0.17). Each objective of this study was to provide the data needed to of these observed group effects were independent of age, sex, and appropriately power more definitive trials in the future, we intervention compliance. No main effects of time, nor group by conducted a priori sample size calculations based upon Shiga time interactions, were observed for any metric. et al. (15). That study reported the immediate after-effects of a Participant-level results of intervention on postural sway non-MRI-guided, 21-day cerebellar rTMS intervention on 10- speed are presented in Figure 3. Seven of ten participants who m walking speed in 74 patients with suspected SCA. The rTMS received rTMS exhibited slower sway speed (i.e., better standing Frontiers in Neurology | www.frontiersin.org 4 February 2019 | Volume 10 | Article 73 Manor et al. rTMS Improves Balance in SCA TABLE 1 | Demographics and baseline functional performance of each participant. Participant ID Age (years) Sex BMI SCA-type rTMS SARA 9-hole peg test (s) TUG time (s) P001 61 Male 29.3 3 Real 22.5 78.0 65.0 P002 52 Female 21.7 3 Sham 13.5 39.5 22.1 P003 45 Female 25.8 3 Sham 24 45.8 68.8 P004 45 Female 21.9 3 Sham 15.5 51.7 49.7 P005 47 Male 27.1 1 Sham 13.5 41.8 20.4 P006 38 Male 19.8 3 Real 10 34.8 42.6 P007 47 Male 24.5 3 Sham 24.5 76.9 119.9 P008 52 Male 27.3 3 Real 14 37.2 24.4 P009 44 Female 28.3 3 Real 11 32.4 21.2 P010 54 Female 18.1 6 Sham 19.5 61.0 51.3 P011 65 Female 30.2 3 Real 14.5 40.5 39.3 P012 47 Female 29.3 2 Sham 19 55.2 33.5 P013 54 Female 28.7 3 Real 16.5 28.6 36.0 P014 56 Female 32.9 8 Sham 12 29.9 31.3 P015 46 Female 22.5 3 Sham 16 37.9 35.3 P016 49 Female 20.1 3 Real 15 30.4 24.9 P017 49 Female 32.3 14 Sham 13.5 18.3 20.6 P018 50 Male 25.6 6 Real 13 27.7 18.8 P019 47 Female 22.9 3 Real 11 21.1 14.3 P020 68 Female 25.6 6 Real 18.5 32.4 18.8 TABLE 2 | SCA severity, postural control and gait outcomes (mean ± SD) at baseline and follow-up. rTMS Sham Baseline Follow up Follow-up Baseline Follow up Follow-up (immediate) (1 month) (immediate) (1 month) SARA (total) 13.7 ± 2.8 10.7 ± 3.4 9.8 ± 2.6 17.1 ± 4.5 12.9 ± 4.9 14.7 ± 4.0 TUG 26.7 ± 10.1 22.5 ± 7.8 20.2 ± 5.6 32.0 ± 16.6 30.5 ± 11.6 31.5 ± 13.9 9-hole peg test (sec) 31.6 ± 5.7 30.6 ± 5.6 30.8 ± 5.4 42.3 ± 13.1 42.3 ± 14.3 41.0 ± 13.5 POSTURAL SWAY Eyes-open Speed (mm/s) 41.2 ± 15.9 27.0 ± 10.2 24.8 ± 10.7 21.5 ± 9.0 20.3 ± 8.9 22.9 ± 7.1 Area (mm2 ) 639 ± 376 467 ± 228 436 ± 173 602 ± 636 479 ± 303 674 ± 249 Eyes-closed Speed (mm/s) 81.4 ± 46.5 51.0 ± 24.3 55.0 ± 30.0 61.0 ± 17.1 63.0 ± 40.4 68.4 ± 40.3 Area (mm2 ) 1992 ± 1337 824 ± 404 1303 ± 839 868 ± 780 1156 ± 938 1517 ± 1382 GAIT Speed (m/s) 1.0 ± 0.3 1.0 ± 0.4 1.0 ± 0.4 0.9 ± 0.4 0.9 ± 0.4 0.9 ± 0.4 Variability (%) 7.0 ± 3.3 5.9 ± 2.3 5.6 ± 3.8 8.0 ± 5.8 7.8 ± 6.2 8.3 ± 5.9 Double support (%) 27.9 ± 6.9 25.2 ± 7.8 24.2 ± 11.3 27.6 ± 15.2 30.0 ± 14.2 31.2 ± 14.5 SCA, spinocerebellar ataxia; rTMS, repetitive transcranial direct current stimulation; SARA, scale for the assessment and rating of ataxia; TUG, Timed Up-and-Go. postural control) during eyes-open standing at the 1-month performance (i.e., walking speed, stride time variability, double follow-up assessment as compared to baseline. In contrast, only support time). two sham participants demonstrated such improvements. Nine rTMS participants exhibited slower sway speed during eyes- DISCUSSION closed standing 1 month following the intervention, as compared to only three sham participants. This randomized sham-controlled pilot clinical trial provided rTMS did not have significant effects on performance within preliminary evidence that cerebellar rTMS intervention is safe the 9-hole peg test, the TUG test of mobility, or on metrics of gait and feasible for patients with SCA who vary considerably in Frontiers in Neurology | www.frontiersin.org 5 February 2019 | Volume 10 | Article 73 Manor et al. rTMS Improves Balance in SCA FIGURE 2 | The effects of cerebellar rTMS on the clinical assessment of ataxia and standing postural control (mean ± SE). Both groups exhibited relatively-large improvement (i.e., percent reduction) in SARA total score from baseline to the immediate follow-up (A). The rTMS group, however, exhibited greater percent improvement in this outcome, as compared to the sham group, at the 1-month follow-up. Secondary analyses revealed that compared to sham, the rTMS group exhibited greater improvements specifically within the SARA “stance” sub-score (B), yet no other SARA item (outcomes not pictured). Moreover, rTMS improved postural sway speed (i.e., sway speed decreased) during both eyes-open (C) and eyes-closed (D) standing. *Indicates significant main effects of group within two-way, repeated-measures ANCOVAs adjusted for age, sex, and intervention compliance. age and disease progression. Participants who completed the by Shiga et al. (15), who reported that an rTMS intervention 4-week rTMS intervention exhibited significant improvements targeting the cerebellum improved the capacity to stand with to both clinical and kinematic outcomes of standing postural different bases of support (i.e., foot placements), when tested control, over a 1-month follow-up period, as compared to those soon after completion of the intervention. The current results who received the sham intervention. rTMS did not influence further suggest that rTMS may enhance standing balance by manual dexterity, functional mobility or gait kinematics during improving the capacity to control (i.e., minimize) the speed the follow-up period. Still, the potential benefits of rTMS on and magnitude of postural sway, and that such improvements posture warrant larger, more definitive trials to establish the may persist for at least 1 month. Future large-scale studies effects of MRI-guided cerebellar rTMS on postural control, as are thus needed to confirm these results, and, to establish the well as activities of daily living and quality of life in SCA. mechanisms through which cerebellar stimulation may improve rTMS intervention improved the clinical impression of standing posture. The regulation of posture when standing relies standing posture (i.e., the SARA “stance” sub-score), along with upon a complex control system that utilizes and integrates multiple metrics of postural sway when standing with eyes multiple sources of sensory input within spinal and supra-spinal open and closed. In each case, the value of Cohen’s d was networks to generate both automatic and volitional corrective greater than 0.8, indicating a large effect size of intervention on muscular actions (20–22). Neuroimaging studies indicate that the this important functional domain. These results are supported task of standing, as compared to sitting, activates a distributed Frontiers in Neurology | www.frontiersin.org 6 February 2019 | Volume 10 | Article 73 Manor et al. rTMS Improves Balance in SCA FIGURE 3 | Individual effects of cerebellar rTMS intervention on standing postural control. The average speed of standing postural sway fluctuations for each participant when standing with eyes open (top) and eyes closed (bottom) at baseline and at the immediate and 1-month follow-up assessments. Two participants with extremely high sway speed values at baseline (out of the mean ± 2XS.D.) were excluded from the figure for better visual effects. network of brain regions including the cerebellum, primary Cooperative Ataxia Rating Scale (ICARS) over the follow-up motor cortex, and other regions involved in sensory integration period (27). Additionally, in the current study, a proportion and/or cognitive-motor control (22, 23). SCA causes postural of participants within each intervention arm stayed within the disturbances, at least in part, by impairing functional activation hospital’s Clinical Research Center for the duration of the study of cerebellar Purkinje cells. This in turn inhibits cortical motor and thus received ongoing clinical research staff supervision activation via a complex neural pathway involving the dentate that was likely greater than their normal care. The possibility nucleus (10). Several recent studies have demonstrated that that this increased attention confounded the initial effects of cerebellar rTMS is capable of facilitating motor cortical activation intervention, together with the potential for a significant placebo via modulation of Purkinje cell excitability (24–26). Future effect within this population, are thus important factors to studies employing paired-pulse TMS methodology are thus consider when designing future trials of rTMS or other therapies needed to examine the effects of cerebellar rTMS intervention in SCA. on motor cortex excitability, and its links to postural control, in While the effects of rTMS on outcomes related to postural those individuals with SCA. control were independent of age, sex, and intervention Both the rTMS and sham groups demonstrated improved compliance, the small sample size of this pilot study limited performance in the SARA total score at the immediate follow- our capacity to statistically control for additional, important up assessment, as compared to baseline (Figure 2A). However, covariates such as SCA subtype. Considerable between-subject within the sham group, this initial improvement was attenuated variance in symptom severity and functional status was present, at the 1-month follow-up assessment. This short-lasting positive and despite random assignment to intervention arm, the rTMS effect of rTMS in the sham group was only present for the group exhibited better functional performance at baseline. SARA total score, and may have reflected a placebo effect Nevertheless, the observations that the rTMS intervention was of the intervention. Such placebo effects have been reported well-attended and not associated with any unexpected side in several other studies in those with cerebellar degeneration effects or adverse events, together with preliminary evidence (27, 28). For example, in a multi-center study of patients with of improved postural control, highlight the potential for this cerebellar ataxia, ondansetron and placebo interventions resulted form of non-invasive brain stimulation to serve as a therapeutic in a similar improvement in performance on the International rehabilitative strategy for SCA. Frontiers in Neurology | www.frontiersin.org 7 February 2019 | Volume 10 | Article 73 Manor et al. rTMS Improves Balance in SCA AUTHOR CONTRIBUTIONS FUNDING BM, PG, and AP-L designed the study. BM, PG, SW, and PD-P This study was supported by grants from the NIH (R21 collected the data. BM, PD-P, and JZ analyzed the data and NS085491-01; 1-K01-AG044543-01A1), the Sidney R. Baer Jr. performed statistical analyses. BM, PG, PD-P, JZ, and AP-L Foundation and the Harvard Catalyst | The Harvard Clinical and drafted the manuscript. All authors contributed to and approved Translational Science Center (NCRR and the NCATS NIH, UL1 the final version. RR025758). REFERENCES induction of motor-evoked potentials. Biol Psychiat. (2001) 49:460–3. doi: 10.1016/S0006-3223(00)01110-0 1. Diener HC, Dichgans J. Pathophysiology of cerebellar ataxia. Mov Disord. 18. Oxford GK, Vogel KA, Le V, Mitchell A, Muniz S, Vollmer MA. 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This is an open-access article distributed under the terms of the Creative Depondt C, et al. Scale for the assessment and rating of ataxia: Commons Attribution License (CC BY). The use, distribution or reproduction in development of a new clinical scale. Neurology (2006) 66:1717–1720. other forums is permitted, provided the original author(s) and the copyright owner(s) doi: 10.1212/01.wnl.0000219042.60538.92 are credited and that the original publication in this journal is cited, in accordance 17. Lisanby SH, Gutman D, Luber B, Schroeder C, Sackeim HA. Sham with accepted academic practice. No use, distribution or reproduction is permitted TMS: intracerebral measurement of the induced electrical field and the which does not comply with these terms. Frontiers in Neurology | www.frontiersin.org 8 February 2019 | Volume 10 | Article 73