Individualized cortico-basal ganglia-thalamo-cortical circuit dysfunction links striatal dopaminergic loss to motor symptom severity in Parkinson's disease

Motor impairment in Parkinson's disease (PD) is classically attributed to striatal dopaminergic degeneration, yet dopamine loss alone does not fully explain symptom severity, suggesting a key role for circuit-level mechanisms. The cortico-basal ganglia-thalamo-cortical (CBGTC) system is central to dopaminergic motor modulation, but whether dysfunction within individualized CBGTC circuits mediates motor severity across disease stages remains unclear. Here, we studied 76 PD patients (40 mild, 36 moderate-to-severe) who underwent ¹⁸F-FP-CIT PET and multimodal MRI. Individualized long and short CBGTC loops were reconstructed using connectivity profile-based segmentation and probabilistic tractography, with functional connectivity (FC) quantified alongside striatal dopaminergic integrity. Compared with mild PD, moderate-to-severe PD showed a global reduction in striatal dopamine binding, most pronounced in the bilateral caudate. Critically, FC between the caudate and premotor cortex in the more-affected hemisphere was selectively reduced with increasing disease severity in both CBGTC loops (p-FDR = 0.027). The cross-sectional mediation models demonstrated that caudate-premotor FC statistically accounted for the association between caudate dopaminergic loss and motor symptom severity. These findings position individualized cortico-basal ganglia circuit connectivity as a potential mechanistically grounded biomarker linking molecular pathology to motor impairment in PD, with potential relevance for future circuit-guided therapeutic strategies.