Continuous theta burst stimulation delays L-DOPA-induced dyskinesia progression and ameliorates orolingual dyskinesia with concomitant reduction of striatal FosB/ΔFosB and neuroinflammation.

Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) administration in patients with Parkinson's disease (PD) inevitably leads to L-DOPA-induced dyskinesia (LID), which can be more disabling than PD itself. Therefore, finding ways to prevent or delay LID progression is crucial. Continuous theta burst stimulation (cTBS), a patterned form of repetitive transcranial magnetic stimulation, shows promise to alleviate LID. However, whether it can prevent or delay LID progression and the underlying mechanisms remain largely unknown. In this study, we administered L-DOPA daily with or without concurrent cTBS to hemiparkinsonian rats for 3 weeks. Electromagnetic simulation confirmed that the dorsolateral striatum is within the electromagnetic field generated by cTBS. Prolonged L-DOPA administration deteriorated LID progressively, whereas cTBS significantly delayed the development of axial, limb, and total dyskinesia, with orolingual dyskinesia even improving over time. Additionally, L-DOPA administration significantly increased the number of FosB/ΔFosB⁺ cells and CD68⁺/Iba1⁺ cells, with elevated iNOS, IL-1β, TNF-α, and IL-6 levels, without altering total microglial numbers in the dorsolateral striatum. cTBS reversed all these changes, reducing FosB/ΔFosB⁺ cells, CD68⁺/Iba1⁺ cells, and all 4 pro-inflammatory markers. Furthermore, FosB/ΔFosB⁺ cell numbers and pro-inflammatory marker levels positively correlated with the severity of total, axial, limb, and orolingual dyskinesia. Collectively, cTBS treatment delays the progression of LID and improves orolingual dyskinesia, which is closely associated with the reduction of FosB/∆FosB+ cells and alleviation of microglia-related inflammation in the striatum.