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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\u2014a mediolateral and a posteroanterior\u2014each showing distinct transcriptomic, behavioural, and pathological associations. Specifically, the mediolateral gradient was related to motor and executive functions, aging and \u03b1-synuclein pathology in both PD and Alzheimer\u2019s 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.<\/jats:p>","DOI":"10.1038\/s41380-026-03803-0","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T14:51:40Z","timestamp":1788879100000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mapping the dual functional organization of the substantia nigra"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2077-5252","authenticated-orcid":false,"given":"D\u00e1niel","family":"Ver\u00e9b","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7756-630X","authenticated-orcid":false,"given":"Blanca","family":"Zufiria-Gerbol\u00e9s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Passaretti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9844-4413","authenticated-orcid":false,"given":"Mite","family":"Mijalkov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattia","family":"Veronese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joana B.","family":"Pereira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"3803_CR1","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1093\/brain\/122.8.1437","volume":"122","author":"P Damier","year":"1999","unstructured":"Damier P, Hirsch EC, Agid Y, Graybiel AM. 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No participants were recruited and no new data were collected by the authors. All methods were performed in accordance with the relevant guidelines and regulations and with the principles of the Declaration of Helsinki. The Cam-CAN study was approved by the Cambridgeshire 2 Research Ethics Committee (reference\n                      \n                      \/H0308\/50). The HCP study protocol, \u201cMapping the Human Connectome: Structure, Function, and Heritability,\u201d was approved by the Washington University in St. Louis Institutional Review Board (IRB number 201204036). The PPMI study was approved by the Research Subjects Review Board at the University of Rochester and by the institutional review board or independent ethics committee at each participating site; the study is registered at ClinicalTrials.gov (NCT01141023). The ADNI3 protocol was approved by the institutional review board or research ethics board at each participating institution (protocol ATRI-001; ClinicalTrials.gov identifier NCT02854033). Written informed consent was obtained from all participants by the investigators responsible for the original data collection or, where applicable, from their legally authorized representatives. All data were accessed and analysed in accordance with the respective data-use agreements.","order":3,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Ethics"}}]}}