Long-term continuous theta burst stimulation ameliorates L-DOPA-induced dyskinesia in Parkinsonian rats through modulation of the cerebello-thalamo-striatal circuit

Abstract

Levodopa-induced dyskinesia (LID) is a debilitating complication of Parkinson's disease therapy. Emerging evidence suggests that the cerebellum is involved via cerebello -thalamo-striatal pathways.We first performed dual viral tracing to confirm cerebello-thalamo-striatal connectivity in a unilateral 6- hydroxydopamine rat model of LID. We then compared the efficacy of two cerebellar continuous theta burst stimulation (cTBS) protocols: a 2block protocol (14 days) and an intensified 3block protocol (10 days). Behavioral outcomes were assessed using the abnormal involuntary movement scale (AIMs). Local field potentials were recorded from the cerebellar dentate nucleus (DN) to characterize oscillatory variations. Striatal FosB expression was quantified as the molecular endpoint. Viral tracing confirmed the anatomical connectivity from the DN to the dorsolateral striatum via the parafascicular thalamus. Both the two protocols alleviated orolingual dyskinesia, with the 3block cTBS protocol demonstrated superior therapeutic efficacy (p < 0.001). Electrophysiological analysis revealed that LID was associated with reduced δ-band power and enhanced low-γ power in DN. Notably, cTBS normalized these aberrant oscillatory patterns by increasing δ power and decreasing pathological low-γ activity. The magnitude of δ power was negatively correlated with orolingual AIMs scores (r = −0.467, p = 0.021), whereas low-γ power was positively correlated with total dyskinesia severity (r = 0.551, p = 0.005) and orolingual AIMs scores (r = 0.581, p = 0.003). At the molecular level, cTBS normalized pathologically elevated striatal FosB expression in LID rats (p < 0.001). Collectively, these findings suggest that long-term cerebellar cTBS selectively ameliorates orolingual dyskinesia by modulating the cerebello-thalamo-striatal circuit.