Cortical Effects of Dopamine Replacement Account for Clinical Response Variability in Parkinson's Disease

Abstract

Background

Individual variability in clinical response to dopamine replacement therapy (DRT) is a key barrier to efficacious treatment for patients with Parkinson's disease (PD). A better understanding of the neurobiological sources of such interindividual differences is necessary to personalize DRT prescribing, inform future clinical interventions, and motivate translational research.

Objective

One potential source of this variability is an unintended secondary activation of extra-nigrostriatal dopamine systems by DRT, particularly in the neocortex. Our goal was to determine the clinical effects of cortical dopamine system activation by DRT in patients with PD.

Methods

We used pharmaco-magnetoencephalography data collected from patients with PD (N_PD = 17, N_HC = 20) before and after DRT to map their cortical neurophysiological responses to dopaminergic pharmacotherapy. By combining these DRT response maps with normative atlases of cortical dopamine system densities, we linked the variable enhancement of rhythmic cortical activity by DRT to dopamine-rich cortical regions and determined its clinical relevance.

Results

We found beta-rhythmic responses to DRT in dopamine-rich regions of the cortex that are expressed variably across individuals. Importantly, patients who exhibited a larger dopaminergic beta cortical enhancement showed a smaller clinical improvement from DRT, indicating a potential source of individual variability in medication response for patients with PD.

Conclusions

We conclude that these findings inform our understanding of the dopaminergic basis of neurophysiological variability often seen in patients with PD, and indicate that our methodological approach may be useful for data-driven contextualization of medication effects on cortical neurophysiology in future research and clinical applications. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.