Mapping the dual functional organization of the substantia nigra.

Abstract

The human substantia nigra (SN) is a central hub for dopaminergic signalling and a key site of pathology in Parkinson's disease (PD). However, its internal functional organization in human individuals is not well understood. To fill this knowledge gap, here we applied connectopic mapping to the SN in more than 1000 participants from four independent datasets. We identified two main gradients or axes of functional organization within the SN-a mediolateral and a posteroanterior-each showing distinct transcriptomic, behavioural, and pathological associations. Specifically, the mediolateral gradient was related to motor and executive functions, aging and α-synuclein pathology in both PD and Alzheimer's disease (AD). In contrast, the posteroanterior gradient was linked to memory, anxiety, depression and other neuropsychiatric symptoms in all cohorts. We found gradient-specific associations with gene expression profiles, neurotransmitter maps and cerebrospinal fluid biomarkers that further supported their neurobiological differences. Together, these results reveal a dual-gradient architecture that reflects the functional heterogeneity of the SN and offers new markers, grounded in behaviour and pathology, for stratifying neurodegenerative disease risk in aging, PD and AD.