Intermittent Theta-Burst Stimulation (iTBS) Improves Motor Coordination and Modulates Neuroinflammation and Autophagy...

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is an autosomal dominant neurodegenerative disorder characterized by misfolded ataxin-3 aggregation and neuronal intranuclear inclusions. Its primary symptom is progressive ataxia, progressively restricting daily living activities. While repetitive transcranial magnetic stimulation (rTMS) may alleviate symptoms, the effects and mechanisms of specific rTMS paradigms, particularly intermittent and continuous theta burst stimulation (iTBS/cTBS), remain unclear in SCA3. This study therefore aimed to investigate the impacts of iTBS and cTBS on motor coordination, cerebellar neuroinflammation, and autophagy in SCA3 transgenic mice. Thirty 14-week-old SCA3 transgenic mice were randomly divided into sham, cTBS, and iTBS groups. Cerebellar stimulation was delivered at 30% maximum output (600 pulses/session, once daily, 5 days/week for 2 weeks). Motor coordination was assessed via rotarod and CatWalk gait analysis. Pathological changes were evaluated by measuring ataxin-3 protein and ubiquitin-positive inclusions. Cerebellar neuroinflammation was analyzed using Iba-1, CD206, and a cytokine array, while autophagy was assessed via Beclin-1 and LC3B expression. iTBS significantly improved motor coordination in SCA3 mice, reducing rotarod falls (vs. sham P < 0.001, vs. cTBS P < 0.05) and improving gait symmetry (vs. sham P < 0.05) and regularity index (vs. sham P < 0.01, vs. cTBS P < 0.01). It also alleviated cerebellar pathology, lowering ataxin-3 expression (vs. sham P < 0.01, vs. cTBS P < 0.01) and ubiquitin-positive inclusions (vs. sham P < 0.01, vs. cTBS P < 0.05). While both iTBS and cTBS increased Iba-1-positive cells (P < 0.05 and P < 0.05, respectively, vs. sham), only iTBS raised CD206-positive cells (vs. sham P < 0.05) and downregulated pro-inflammatory cytokines. Furthermore, iTBS activated autophagy, enhancing Beclin-1 (vs. sham P < 0.05) and LC3B expression (vs. sham P < 0.0001, vs. cTBS P < 0.001). iTBS improved motor coordination and alleviated core cerebellar pathology in SCA3 mice. This effect may be mediated through the downregulation of cerebellar neuroinflammation and the activation of autophagy. Furthermore, the therapeutic efficacy of iTBS was superior to that of cTBS across multiple dimensions, demonstrating distinct paradigm specificity.