Cortical excitability dynamics in Parkinson's disease: A 4.5-year longitudinal study

Abstract

Introduction: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by the gradual emergence of motor and non-motor impairments, often leading to disability and diminished quality of life. Although the Movement Disorder Society–Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is the most widely used clinical tool for monitoring disease progression, it offers limited insight into underlying neurophysiological mechanisms. Transcranial magnetic stimulation (TMS), a non-invasive technique used to assess cortical excitability, holds promise as a complementary biomarker for understanding disease dynamics. Longitudinal studies that combine clinical and neurophysiological data are needed to elucidate the progression of PD and inform rehabilitative strategies.

Objective: To characterise longitudinal changes in motor and non-motor symptoms alongside cortical excitability in individuals with PD over 4·5 years, and to explore the potential of TMS-derived parameters as biomarkers of disease progression.

Methods: A cohort of 22 patients with PD (11 men and 11 women; early-stage, n = 15; advanced-stage, n = 7) was followed between 2018 and 2023. Clinical assessments included the MDS-UPDRS, and neurophysiological measures were obtained via single-pulse TMS. Parameters included resting motor threshold (rMT), cortical silent period (CSP), motor evoked potential (MEP) amplitude and duration, and recruitment curves. Assessments were conducted across four periods—two before the COVID-19 pandemic (2018–19) and two after (2021–22)—enabling evaluation of environmental stressors on disease trajectory. Longitudinal changes were analysed using robust linear mixed-effects models, and repeated-measures correlations were used to examine associations between clinical and neurophysiological variables.

Findings: Motor scores (MDS-UPDRS Part III) demonstrated progressive deterioration over time, with a significant worsening between the pre-pandemic and post-pandemic periods. Patients with advanced PD showed more pronounced impairments, particularly in the lower limbs and on the less affected side, suggesting a need for tailored rehabilitation approaches. TMS data revealed a longitudinal decline in rMT and a bilateral increase in CSP duration, indicative of altered cortical excitability and enhanced GABAergic inhibition—most evident in early-stage PD. In this group, CSP duration in the less affected hemisphere correlated moderately with UPDRS Part III scores, supporting its potential as a marker of early motor decline. Interhemispheric asymmetry in motor symptoms corresponded with asymmetry in recruitment curves, reinforcing the clinical value of lateralised TMS assessments. No significant sex differences were identified. The pandemic period was associated with accelerated clinical and neurophysiological decline, possibly reflecting reduced physical activity and disrupted access to care.

Interpretation: These findings emphasise the value of longitudinal monitoring in PD to capture dynamic changes in motor function and cortical physiology. Disease stage emerged as a key determinant of progression, underscoring the need for stage-specific therapeutic strategies. The marked deterioration observed after the pandemic highlights the vulnerability of individuals with PD to environmental stressors and the importance of sustained rehabilitation. TMS—particularly CSP—shows promise as a neurophysiological biomarker and could enhance clinical monitoring of disease trajectory. Further research should investigate the integration of TMS into standardised longitudinal assessments to support personalised management in PD.