Sensorimotor basal ganglia circuit asymmetry explains lateralized motor dysfunction in early Parkinson's disease

Abstract

Parkinsons disease (PD) is characterized by an early spatial pattern of degeneration in the basal ganglia. This pattern includes both posterior predominance and hemispheric asymmetry that correspond to lateralized motor symptoms. While these spatial features are well established in the striatum using dopaminergic imaging, it remains unclear whether they reflect local or circuit-level pathology across the broader basal ganglia system. It is also unknown whether widely available structural MRI can detect these spatial characteristics with comparable sensitivity. Here, we investigate the spatial pattern of basal ganglia pathology in harmonized clinical MRI data of 136 early-stage PD patients and 60 healthy controls from the PPMI database. Using gradient analyses, we identified anterior-posterior variations and selective posterior alterations in the putamen and external globus pallidus, revealing early subregional "PD hotspots". Hemispheric asymmetry analyses across the basal ganglia showed associations with motor symptom lateralization that were most substantial in the substantia nigra, posterior putamen, and posterior external globus pallidus, indicating preferential early involvement of the sensorimotor basal ganglia circuit in lateralized PD pathology. Joint models integrating multiple regions and MRI measurements approached the explanatory power of DaTSCAN and were consistent longitudinally. In addition, they achieved robust out-of-sample cross-validated motor asymmetry prediction across visits, providing non-redundant information beyond DaTSCAN. Together, our findings demonstrate that anatomically guided spatial analysis of routine MRI reveals subregional basal ganglia pathology that underlies motor symptom lateralization in PD. This study extends spatial characterization of the basal ganglia beyond the striatum and uncovers multiple regions and data-driven posterior "hotspots" that predict motor dysfunction asymmetry. Thus, this work advances the development of MRI-based circuit-level biomarkers of PD neurodegeneration.