Striatal dopamine depletion drives disease progression and network topology aberrations specifically by impairing left primary motor cortex network

Abstract

Abstract The understanding of pathophysiological mechanisms underlying symptom severity and brain network aberrations in Parkinson’s disease (PD) can offer objective, theoretically supported targets to develop novel interventions to prevent the onset and progression of motor and non-motor symptoms. The objective of current study is to explore how stratal dopamine depletion, a pathogenic driver of PD, shapes symptom severity and brain networks. PD participants (n = 141) undergoing functional magnetic resonance imaging from Parkinson’s Progression Markers Initiative (PPMI) database were investigated. Based on the quartiles of striatal binding ratio (SBR) in striatum, PD patients were divided into Q1 group (SBR level rank: 0%~25%), Q2-3 group (SBR level rank: 25%~75%), and Q4 group (SBR level rank: 75%~100%). The associations between stratal dopamine depletion and clinical manifestations or brain networks were characterized by integrative brain network analysis, multiple linear regression analysis, and mediation analysis. PD patients in Q1 group exhibited worsening motor and non-motor symptoms compared to Q4 group. Additionally, both structural and functional network topology significantly differ between Q1 and Q4 group. Specifically, the functional connectivity of left primary motor cortex (M1) was much lower in Q1 group, which mediated the topological disruptions of functional network. Importantly, impaired left M1 subnetwork and aberrant network topology mediated the effects of striatal dopamine depletion on motor and non-motor symptoms. These data demonstrate that striatal dopamine depletion specifically impairs left M1 subnetwork to disturb functional network topology and precipitate motor and non-motor symptoms, theoretically supporting left M1 is a realistic neuromodulation target for PD.