Cerebellar Transcranial Direct Current Stimulation in Spinocerebellar Ataxia Type 3: a Randomized, Double-Blind, Sham-Controlled Trial

Abstract

Repeated sessions of cerebellar anodal transcranial direct current stimulation (tDCS) have been suggested to modulate cerebellar-motor cortex (M1) connectivity and decrease ataxia severity. However, therapeutic trials involving etiologically homogeneous groups of ataxia patients are lacking. The objective of this study was to investigate if a two-week regimen of daily cerebellar tDCS sessions diminishes ataxia and non-motor symptom severity and alters cerebellar-M1 connectivity in individuals with spinocerebellar ataxia type 3 (SCA3). We conducted a randomized, double-blind, sham-controlled trial in which twenty mildly to moderately affected SCA3 patients received ten sessions of real or sham cerebellar tDCS (i.e., five days per week for two consecutive weeks). Effects were evaluated after two weeks, three months, six months, and twelve months. Change in Scale for the Assessment and Rating of Ataxia (SARA) score after two weeks was defined as the primary endpoint. Static posturography, SCA Functional Index tests, various patient-reported outcome measures, the cerebellar cognitive affective syndrome scale, and paired-pulse transcranial magnetic stimulation to examine cerebellar brain inhibition (CBI) served as secondary endpoints. Absolute change in SARA score did not differ between both trial arms at any of the time points. We observed significant short-term improvements in several motor, cognitive, and patient-reported outcomes after the last stimulation session in both groups but no treatment effects in favor of real tDCS. Nonetheless, some of the patients in the intervention arm showed a sustained reduction in SARA score lasting six or even twelve months, indicating interindividual variability in treatment response. CBI, which reflects the functional integrity of the cerebellothalamocortical tract, remained unchanged after ten tDCS sessions. Albeit exploratory, there was some indication for between-group differences in SARA speech score after six and twelve months and in the number of extracerebellar signs after three and six months. Taken together, our study does not provide evidence that a two-week treatment with daily cerebellar tDCS sessions reduces ataxia severity or restores cerebellar-M1 connectivity in early-to-middle-stage SCA3 patients at the group level. In order to potentially increase therapeutic efficacy, further research is warranted to identify individual predictors of symptomatic improvement.

Keywords: Cerebellar brain inhibition; Randomized controlled trial; Scale for the Assessment and Rating of Ataxia; Spinocerebellar ataxia type 3; Transcranial direct current stimulation; Transcranial magnetic stimulation.

Fig. 1

Scale for the Assessment and Rating of Ataxia (SARA) scores at different time points. Panel (A) shows trajectories of individual SCA3 patients in the real and sham tDCS group at baseline (T0) and after two weeks (T1), three months (T2), six months (T3), and twelve months (T4). The dashed black lines represent mean group scores. There were no significant differences in delta SARA score between both groups at any of the time points. Panel (B) shows SARA axial, appendicular, and speech domain scores. For SARA speech, a treatment effect of real tDCS was observed at T3, with between-group differences close to significance at T4. There were no treatment effects for axial and appendicular subscores. ^*Significant change from baseline (p < 0.05)

Fig. 2

Secondary motor outcome measures at different time points. Shown are group mean scores for the 8 m walk test (A), 9-hole peg test (9HPT) performed with the dominant hand (B), 9HPT performed with the non-dominant hand (C), PATA repetition task (D), and Inventory of Non-Ataxia Signs (INAS) count (E) at baseline (T0) and after two weeks (T1), three months (T2), six months (T3), and twelve months (T4). A treatment effect of real tDCS was observed for INAS count at T2 and T3. Between-group differences in delta PATA repetition rate were close to significance at T2 and T4. There were no treatment effects for the 8 m walk test or 9-hole peg test. ^*Significant change from baseline (p < 0.05)

Fig. 3

Patient-reported and cognitive outcomes at different time points. Panels (A) and (B) show group mean scores for the Activities of Daily Living part of the Friedreich Ataxia Rating Scale and the EQ-5D utility index, respectively, at baseline (T0) and after two weeks (T1), three months (T2), six months (T3), and twelve months (T4). Panels (C) and (D) show total score and number of failed tests at the cerebellar cognitive affective syndrome scale (CCAS-S) throughout the study. No treatment effects of real tDCS were observed for any of these outcome measures at any of the time points. ^*Significant change from baseline (p < 0.05)