Motor Cortex Disinhibition Is Dissociated from Clinical Motor Features in Parkinson's Disease: Longitudinal Evidence

Abstract Background In Parkinson's disease, motor dysfunction largely reflects dopamine‐dependent pathophysiological alterations and compensatory mechanisms that progress over time and are partially reversible with dopaminergic treatment. Our recent cross‐sectional observations suggest that disinhibition of the primary motor cortex—assessed with short‐interval intracortical inhibition (SICI) using transcranial magnetic stimulation—does not correlate with clinical motor features, does not progress across disease stages, and instead correlates with olfactory dysfunction, a common prodromal and dopamine‐independent feature. Objective We aimed to provide longitudinal evidence for or against the hypothesis that motor cortex disinhibition is dissociated from clinical motor features in Parkinson's disease. Methods We compared SICI across three cohorts (total n = 95 patients): (1) baseline and 2‐year follow‐up (n = 43), with concurrent motor assessment and 18 F‐DOPA positron emission tomography (PET) imaging (n = 24); (2) before and after levodopa administration (n = 30); and (3) before and after focused ultrasound subthalamotomy (n = 22). We also included a pooled healthy control group (n = 75) from two previously published studies. Bayesian statistics was applied to formally assess evidence for the presence or the absence of an effect. Results SICI was expectedly reduced, with very strong to extreme Bayesian evidence, in patients compared with control subjects. We found evidence that cortical disinhibition did not worsen with clinically evident disease progression confirmed with 18 F‐DOPA PET and did not improve following a clinically effective dose of levodopa or subthalamotomy. Moreover, changes in SICI did not correlate with changes in motor features across cohorts. Conclusions These findings provide longitudinal evidence that motor cortex disinhibition is largely dissociated from clinical motor features in Parkinson's disease. © 2026 International Parkinson and Movement Disorder Society.