Transcranial alternating current stimulation for treating spinocerebellar ataxia type 3: A randomized controlled trial

Abstract

There are no specific treatments for spinocerebellar ataxia type 3 (SCA3), a neurodegenerative disease causing cerebellar dysfunction. Transcranial alternating current stimulation (tACS) can improve cerebellar motor functions, and it has been shown to be safe and effective in treating neurological diseases. This randomized controlled trial (RCT) explored the effects of tACS on SCA3 patients. Participants received either 40-min, 70 Hz, 2 mA tACS or sham stimulation daily for 2 weeks. The primary outcome was met by 80% of the active-tACS group (32/40) and 10% of the sham group (4/40). The active group also showed significantly greater reductions in the Scale for Assessment and Rating of Ataxia (SARA) scores. No serious adverse events occurred, indicating high safety. Therefore, tACS is effective, safe, and feasible for treating SCA3. The study is registered at ClinicalTrials.gov (NCT05557786).

Keywords: functional connectivity; non-invasive brain stimulation; randomized sham-controlled trial; spinocerebellar ataxia type 3; transcranial alternating current stimulation.

Graphical abstract

Figure 1

The CONSORT flow diagram Flow diagram detailing the progress, from screening through study completion, of participants in the double-blind randomized sham-controlled trial testing a 2-week active treatment versus sham control in adults with SCA3. A total of 158 prospective participants were screened. Seventy-six of the 158 individuals enrolled in the study were not randomized because they either did not meet eligibility criteria or declined to participate. All 82 participants who were randomized were included in intention-to-treat (ITT) statistical analyses, independent of whether they completed the study.

Figure 2

Change in SARA at different time points (A) depicts the Scale for the Assessment and Rating of Ataxia (SARA; range 0–40, with higher scores indicating greater ataxic impairment) at baseline, 2 weeks, 6 weeks, and 14 weeks in participants receiving either A-tACS or S-tACS. Across all time points, A-tACS led to a significantly greater reduction in SARA scores compared with S-tACS. (B) shows the adjusted mean change from baseline in SARA scores, with error bars indicating 95% confidence intervals. The adjusted mean changes were adjusted for baseline. The minimal clinically important difference (MCID) of 1.5 points for the SARA score is considered. (A) The SARA score was analyzed using a GEE model with normal distribution and identity link function. The GEE model had treatment group (2 levels: A-tACS and S-tACS), time (3 levels: T1, T2, and T3), and group-by-time interaction as fixed effects; the baseline measurement of an outcome variable as the covariate; and subject as cluster effect. (B): The clinical improvement rate was analyzed using a GEE model with binomial distribution and logit link function. The GEE model had treatment group (2 levels: A-tACS and S-tACS), time (3 levels: T1, T2, and T3), and group-by-time interaction as fixed effects; the baseline measurement of an outcome variable as the covariate; and subject as cluster effect.

Figure 3

Changes in quality of life and gait analysis at different time points (A) Quality of life measured by EQ-5D showed significantly better improvement in A-tACS compared with S-tACS at all time points. (B-C) For gait variability, both stride time standard deviation (STSD) and double support-time standard deviation (DSSD), showed significantly better improvement in the A-tACS group compared with the S-tACS group at each time point. (D-E) The A-tACS group had also demonstrated greater improvement in Toe Out Angle Standard Deviation (Toe-Out SD) and Toe Off Angle Standard Deviation (Toe-Off SD) compared with the S-tACS group at each time point. Outcome scores are shown for the A-tACS group (circles) and the S-tACS group (squares). The values shown are unadjusted means; error bars indicate SEM. Measurements were obtained at T0, T1, T2, and T3, but data points are slightly offset for clarity. The secondary outcomes were analyzed using a GEE model with normal distribution and identity link function. The GEE model had treatment group (2 levels: A-tACS and S-tACS), time (3 levels: T1, T2, and T3), and group-by-time interaction as fixed effects; the baseline measurement of an outcome variable as the covariate; and subject as cluster effect.

Figure 4

Effect of treatment on ReHo and FC (A and B) Significantly increased ReHo values in the A-tACS group compared with the S-tACS group (AlphaSim-corrected p < 0.05, voxel-level p < 0.001). Color bar represents the F-value of the flexible-factorial design between the two groups. (C and D) Results of FC analysis selecting right DLPFC as seed point. A-tACS decreased FC in the right DLPFC with right cerebellar compared with the S-tACS group as well as compared with the baseline A-tACS value. Color bar represents the F-value of the flexible-factorial design between the two groups. Abbreviations: ReHo, regional homogeneity; FC, functional connectivity; DLPFC, dorsolateral prefrontal cortex.

Figure 5

Changes in intra-network FC Decreased FC in the visual network in the right fusiform gyrus was observed in the A-tACS group compared with the S-tACS group. The color bar corresponds to the t value of the two-sample t test, with cold colors indicating lower intra-network FC in the treatment group (Bonferroni correction).