Exercise-Induced modulation of molecular-enriched functional connectivity in Parkinson's disease

Parkinson's disease (PD) involves degeneration of dopaminergic neurons and dysfunction across multiple neurotransmitter systems, contributing to both motor and cognitive impairments. Aerobic exercise improves clinical outcomes; however, its underlying neural mechanisms remain unclear. Using conventional resting-state fMRI combined with Receptor-Enriched Analysis of functional Connectivity by Targets (REACT), we examined molecular-enriched motor network changes following six months of supervised aerobic training in PD. Exercise-related connectivity changes were inversely correlated with baseline PD–healthy control differences, reflecting a partial normalization of PD-altered motor networks. Molecular-enriched analyses revealed selective effects on dopaminergic (FDOPA-enriched) and cholinergic (VAChT-enriched) related networks, with no changes observed in networks associated with serotonergic or noradrenergic systems. These findings provide supporting evidence for potential mechanistic links between aerobic exercise and network reorganization in PD, highlight multisystem effects, and illustrate the utility of molecular-enriched fMRI for probing neurotransmitter-specific interventions.