Cerebello-cortical inhibition underlies the effects of cerebellar magnetic stimulation on spinocerebellar ataxia type 3: A randomized controlled trial

Background: Repetitive transcranial magnetic stimulation (rTMS) over the cerebellum has shown therapeutic potential for spinocerebellar ataxia type 3 (SCA3). However, the underlying electrophysiological mechanisms remain unclear. Here, we aimed to utilize single-pulse TMS combined with electroencephalography co-registration (TMS-EEG) to probe cerebellar projections underlying the effects of rTMS in SCA3 patients. Methods: A group of 38 SCA3 patients and 35 healthy controls underwent baseline TMS-EEG to assess cerebellar projections. Patients were evaluated using the International Cooperative Ataxia Rating Scale (ICARS) and then randomized to receive either a 3-week course of active intermittent theta burst stimulation (iTBS) or sham iTBS applied to the cerebellum. ICARS assessments were then performed at post-treatment and 3-month follow-up, with additional TMS-EEG performed post-treatment. Results: ICARS scores were improved by iTBS treatment than the Sham stimulation at post-treatment (2.67 [95 %CI, 0.53–4.81]; p = 0.016) and 3-month follow-up (4.11 [95 %CI, 1.02–7.20]; p = 0.011). iTBS restored cerebello-cortical inhibition over the contralateral motor cortex as reflected by enhanced N45 amplitude (1.31 [95 %CI, 0.08–2.53]; p = 0.038), which covaried with better clinical improvement (p = 0.005). iTBS also reorganized beta band oscillation, that potentially underlies the cerebello-cortical inhibition in SCA3 individuals. At the source level, cerebellar rTMS normalized the impaired cerebello-cortical inhibition characterized by the evoked current density over the motor cortex. Conclusions: Our findings indicate that cerebellar iTBS alleviates clinical ataxia severity in SCA3 potentially by restoring cerebello-cortical inhibition and reorganizing beta-band activity. N45 amplitude may serve as a potential biomarker for treatment response in SCA3.