Brain-clinical signatures of basal ganglia-related dysfunctional reorganisation in Parkinson's disease.

Background: The hierarchical organisation of functional networks is crucial for integration and segregation, and its dysregulation is implicated in neurodegenerative progression. The basal ganglia (BG) is the communication hub of the BG-thalamo-cortical circuit, and its dysfunction drives the progression of clinical symptoms in Parkinson's disease (PD). However, network-level functional reorganisation of BG disruption remains unclear.

Methods: In this cross-sectional study, we applied functional gradient analysis based on a diffusion map embedding algorithm to delineate macroscale functional architectures of BG in 102 PD patients and 88 healthy controls (HCs). Partial least squares correlation analysis was employed to investigate the relationship between gradient alterations and clinical symptoms in PD.

Findings: The first functional gradient of BG extended from caudate nucleus to putamen, whereas second gradient was anchored at dorsal and ventral caudate nucleus. In PD patients, the first gradient showed significant global compression with the progression from unilateral to bilateral motor symptoms. The second gradient exhibited local disruptions in nucleus accumbens and putamen, driven by reduced connectivity with multiple functional systems. Gradient scores of these two nuclei displayed significant lateralisation in PD, regardless of motor deficit dominance. Dysfunctional gradients in PD are associated with motor deficits and emotional symptoms.

Interpretation: Our findings reveal that functional gradient reorganisation is a network-level signature of early-stage PD, linking functional reorganisation in BG circuit to clinical symptoms. The hemispheric asymmetry of gradient patterns may inform ongoing research on PD lateralisation.

Funding: National Natural Science Foundation of China (Nos. 82071423 and 82021004) and Beijing Natural Science Foundation (No. JQ23033).