Unraveling the Complexity of Parkinson's Disease: Insights into Pathogenesis and Precision Interventions

Abstract Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss, leading to motor and non‐motor symptoms. Early detection before symptom onset is crucial but challenging. This study presents a framework integrating circuit modeling, non‐equilibrium dynamics, and optimization to understand PD pathogenesis and enable precision interventions. Neuronal firing patterns, particularly oscillatory activity, play a critical role in PD pathology. The basal ganglia network, specifically the subthalamic nucleus‐external globus pallidus (STN‐GPe) circuitry, exhibits abnormal activity associated with motor dysfunction. The framework leverages the non‐equilibrium landscape and flux theory to identify key connections generating pathological activity, providing insights into disease progression and potential intervention points. The intricate STN‐GPe interplay is highlighted, shedding light on compensatory mechanisms within this circuitry may initially counteract changes but later contribute to pathological alterations as disease progresses. The framework addresses the need for comprehensive evaluation methods to assess intervention outcomes. Cross‐correlations between state variables provide superior early warning signals compared to traditional indicators relying on critical slowing down. By elucidating compensatory mechanisms and circuit dynamics, the framework contributes to improved management, early detection, risk assessment, and potential prevention/delay of PD development. This pioneering research paves the way for precision medicine in neurodegenerative disorders.