Objective: We applied connectopic mapping to the internal functional organisation of the substantia nigra (SN) in independent cohorts.

Background: The human SN is a central hub for dopaminergic signalling and a key site of pathology in Parkinson’s disease (PD). However, its internal functional organisation in humans remains poorly understood.

Method: We applied a connectomic mapping approach based on functional connectivity gradients, which decompose whole-brain connectivity matrices into principal axes of functional connectivity. We integrated resting-state fMRI, clinical data, neurodegeneration biomarkers (including α-synuclein SAA, Aβ1-42) and proteomic analysis.

Results: We identified two main gradients or axes of functional organisation 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 contrast, the posteroanterior gradient was linked to memory, anxiety, depression and other neuropsychiatric symptoms. We found gradient-specific associations with brain gene expression profiles, neurotransmitter maps and cerebrospinal fluid biomarkers supporting their neurobiological differences.

Conclusion: Together, these results reveal a dual-gradient architecture that reflects the functional heterogeneity of the SN, grounded in its cellular organisation and offers new markers, based on behaviour and pathology, for stratifying neurodegenerative disease risk.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-dual-functional-organization-of-the-substantia-nigra-in-parkinsons-disease/