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.

Differential Temporal Dynamics of Axial and Appendicular Ataxia in SCA3

“…The latter cut‐off value was chosen because only 8 out of 231 patients in the cohort had sum scores between 30 and 40, precluding robust inferences for this late disease stage. Longitudinal results are derived from patients with a complete set of SARA ratings at baseline and 1‐year follow‐up (± 3 months), which matches the duration of several previous or ongoing trials and the expected duration of (initial) future therapeutic trials 14‐16 …”

“…Longitudinal results are derived from patients with a complete set of SARA ratings at baseline and 1-year follow-up (AE 3 months), which matches the duration of several previous or ongoing trials and the expected duration of (initial) future therapeutic trials. [14][15][16] The study was approved by the ethics committees of contributing centers and written informed consent was obtained from each participant at enrolment.…”

Cerebellar transcranial direct current stimulation modulates timing but not acquisition of conditioned eyeblink responses in SCA3 patients

“…The primary objective of this randomized controlled study was to examine whether repeated sessions of cerebellar tDCS induce a decrease in ataxia severity in individuals with SCA3 [25]. Changes in eyeblink conditioning parameters were secondary endpoints.…”

“…Taken together, modulation of Purkinje cell spiking may offer a possible explanation for the shift of CR onset and peak latencies following cerebellar tDCS in healthy controls and SCA3 patients. Furthermore, we hypothesize that a lack of modulation of deep nuclear excitability, either due to neuronal degeneration at these sites or insufficient penetration of currents, explains why cerebellar tDCS, on average, did not affect CR acquisition and overall ataxia severity in SCA3 patients [25].…”

“…Furthermore, baseline eyeblink conditioning parameters of SCA3 patients were compared with previously collected data by our group from unrelated controls of comparable age and sex without a history of neurological or psychiatric disorders [22e24]. The effects of cerebellar tDCS on ataxia severity and other clinical outcome measures are described in a separate paper [25].…”