Transcranial magnetic stimulation recalibrates levodopa response by attenuating neuroinflammation and glial reactivity in experimental parkinsonism.

In experimental models of Parkinson's disease (PD), chronic Levodopa (L-DOPA) induces abnormal involuntary movements (AIMs) similar to L-DOPA-induced dyskinesias (LIDs) and psychiatric disturbances associated with a lack of homeostatic synaptic downscaling in striatal spiny projection neurons (SPNs) and dysfunctional neuroimmune responses. Continuous Theta-Burst Stimulation (cTBS), a transcranial magnetic stimulation protocol that inhibits neuronal activity, is a promising non-invasive brain stimulation treatment for LIDs and addiction, whose mechanisms are still unclear. In this study, we investigated the subcortical effects of chronic cTBS during a two-week pulsatile L-DOPA treatment in 6-hydroxydopamine-lesioned rats, a well-established PD model. Six weeks post-lesion, axial, limb, and orolingual AIMs were measured using a validated scoring scale. Synaptic depotentiation of striatal SPNs was investigated ex vivo using the whole-cell patch-clamp recording technique in the dorsolateral striatum. Cytokine levels in the cerebrospinal fluid (CSF) were quantified with magnetic Luminex multiplex assays. Glial reactivity was assessed by immunofluorescence and confocal microscopy, while RNAscope in situ hybridization identified cytokine-expressing glial cells. Chronic cTBS reduced L-DOPA-induced AIMs incidence and intensity, restored long-term potentiation and synaptic depotentiation in striatal SPNs, and prevented excessive increases in glial reactivity associated with pulsatile L-DOPA. In CSF, proinflammatory cytokines were downregulated, with the most substantial reduction observed for Interleukin-1β (IL-1β), while the anti-inflammatory cytokine IL-10 was increased. RNAscope shows that IL-1β upregulation mainly originated from dysregulated microglia. These findings highlight the critical role of microglial activation and IL-1β signaling in LIDs development and support cTBS as an effective strategy to mitigate L-DOPA-induced motor complications while preserving corticostriatal synaptic integrity.