Bradykinesia is the major cardinal motor sign of Parkinson's disease (PD), but its neural underpinnings are unclear. Although impairment in PD has been linked to heightened synchrony within the beta band (13-30 Hz) in the subthalamic nucleus (STN), bradykinesia appears to be the manifestation of a network-level dysfunction including the basal ganglia, motor cortex, and possibly cerebellum. The goal of this study was to examine whether changes in bradykinesia over time following long-term STN deep brain stimulation (DBS) are linked to local STN beta dynamics or a wider bilateral network dysfunction. Twenty-one individuals with Parkinson's disease chronically implanted with sensing neurostimulators (Activa PC+S, Medtronic, PLC) in the STN participated in a longitudinal 'washout' therapy study every three to six months for an average of three years. At each visit, participants were withdrawn from medication (12/24/48 hours) and had DBS turned off (>60 minutes) prior to completing a repetitive wrist-flexion extension task, a validated quantitative assessment of bradykinesia. Synchronized local field potentials and kinematic data were recorded. Local STN beta dynamics were investigated via STN beta power and burst duration, while interhemispheric beta synchrony was assessed with STN beta coherence. Higher beta power and interhemispheric STN beta coherence, but not burst duration, were significantly associated with worse bradykinesia. Bradykinesia was found to worsen off therapy over time. Interhemispheric STN beta coherence also increased over time, whereas beta power and burst duration remained stable. The observed percent change in bradykinesia was related to the percent change in interhemispheric beta coherence, with greater increases in synchrony associated with further worsening of bradykinesia. Together, these findings implicate interhemispheric beta synchrony as a neural correlate of the progression of bradykinesia following chronic STN DBS. This could imply the existence of a pathological bilateral network contributing to bradykinesia in PD.

Dr. Bronte-Stewart serves on a clinical advisory board for Medtronic PLC which supplied investigative sensing neurostimulators.

This work was supported in part by the following: NINDS UH3NS107709, NINDS R21 NS096398-02, Michael J. Fox Foundation (9605), Parkinson's Foundation - Postdoctoral Fellowship PF-FBS-2024 and PF-FBS-1899, Robert and Ruth Halperin Foundation, John A. Blume Foundation, John E Cahill Family Foundation, and Medtronic PLC who provided the devices used in this study but no additional financial support.

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The IRB of Stanford University gave ethical approval for this work.

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