Dopaminergic modulation and dosage effects on brain state dynamics and working memory component processes in Parkinson’s disease

Byeongwook Lee (), Christina B. Young, Weidong Cai, Rui Yuan, Sephira Ryman, Jeehyun Kim, Laurice Yang, Victor W. Henderson, Kathleen L. Poston and Vinod Menon ()
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Byeongwook Lee: Stanford University School of Medicine
Christina B. Young: Stanford University School of Medicine
Weidong Cai: Stanford University School of Medicine
Rui Yuan: Stanford University School of Medicine
Sephira Ryman: Stanford University School of Medicine
Jeehyun Kim: Stanford University School of Medicine
Laurice Yang: Stanford University School of Medicine
Victor W. Henderson: Stanford University School of Medicine
Kathleen L. Poston: Stanford University School of Medicine
Vinod Menon: Stanford University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Parkinson’s disease (PD) is primarily diagnosed through its characteristic motor deficits, yet it also encompasses progressive cognitive impairments that profoundly affect quality of life. While dopaminergic medications are routinely prescribed to manage motor symptoms in PD, their influence extends to cognitive functions as well. Here we investigate how dopaminergic medication influences aberrant brain circuit dynamics associated with encoding, maintenance and retrieval working memory (WM) task-phases processes. PD participants, both on and off dopaminergic medication, and healthy controls, performed a Sternberg WM task during fMRI scanning. We employ a Bayesian state-space computational model to delineate brain state dynamics related to different task phases. Importantly, a within-subject design allows us to examine individual differences in the effects of dopaminergic medication on brain circuit dynamics and task performance. We find that dopaminergic medication alters connectivity within prefrontal-basal ganglia-thalamic circuits, with changes correlating with enhanced task performance. Dopaminergic medication also restores engagement of task-phase-specific brain states, enhancing task performance. Critically, we identify an “inverted-U-shaped” relationship between medication dosage, brain state dynamics, and task performance. Our study provides valuable insights into the dynamic neural mechanisms underlying individual differences in dopamine treatment response in PD, paving the way for more personalized therapeutic strategies.

Date: 2025
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DOI: 10.1038/s41467-025-56660-w

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