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Neuroanatomical normative modeling (NM) can quantify person-specific deviations from healthy variability, yet it remains unknown whether pre-trained, large-scale NM features support site-held-out classification and mechanistic brain\u2013behavior mapping in SSD. Here, we applied a publicly available PCNtoolkit model (trained on ~57,000 healthy controls from 82 sites) to six independent cohorts (N\u2009=\u2009831) to derive individual deviations in cortical thickness (CT) and subcortical volumes from T1-weighted MRI. Employing a random forest classifier with leave-site-out cross-validation, we achieved a balanced accuracy of 65%, which underscores the inherent complexity of SSD. Feature importance analysis identified total gray matter volume, mean CT, and CT changes in limbic and sensorimotor regions as key predictive features. Relative to healthy controls, SSD participants showed a higher burden of extreme negative deviations, which related to reduced attention and processing speed and to elevated neurological soft signs (NSS). Finally, canonical correlation analysis revealed a robust multivariate relationship linking structural deviationsparticularly CT changes in limbic and sensorimotor cortices, to cognition and NSS. Together, these results demonstrate that NM features transferred from a large external reference can generalize across sites and elucidate clinically relevant brain\u2013behavior associations in SSD, supporting the integration of multimodal, large-scale datasets to advance biomarker discovery and inform earlier, more targeted interventions.<\/jats:p>","DOI":"10.1038\/s41398-026-03956-0","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T15:34:31Z","timestamp":1774020871000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Normative age-related structural brain deviations underlying psychopathology, cognitive impairment and neurological soft signs in schizophrenia spectrum disorders"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4489-9125","authenticated-orcid":false,"given":"Sebastian","family":"Volkmer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina M.","family":"Kubera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Fritze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geva","family":"Brandt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5172-3303","authenticated-orcid":false,"given":"Dilsa Cemre","family":"Akkoc Altinok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0638-6213","authenticated-orcid":false,"given":"Jonas","family":"Daub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Kukovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kent-Tjorben","family":"B\u00f6ttcher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oksana","family":"Berhe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchen","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7339-7569","authenticated-orcid":false,"given":"Heike","family":"Tost","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5903-203X","authenticated-orcid":false,"given":"Andre F.","family":"Marquand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Meyer-Lindenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0261-5063","authenticated-orcid":false,"given":"Emanuel","family":"Schwarz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1226-9800","authenticated-orcid":false,"given":"Dusan","family":"Hirjak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,20]]},"reference":[{"key":"3956_CR1","doi-asserted-by":"publisher","first-page":"1228","DOI":"10.1038\/mp.2012.23","volume":"17","author":"JL Rapoport","year":"2012","unstructured":"Rapoport JL, Giedd JN, Gogtay N. 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AM-L has received consultant fees from: Agence Nationale de la Recherche, Brain Mind Institute, Brainsway, CISSN (Catania International Summer School of Neuroscience), Daimler und Benz Stiftung, Fondation FondaMental, Hector Stiftung II, Janssen-Cilag GmbH, Lundbeck A\/S, Lundbeckfonden, Lundbeck Int. Neuroscience Foundation, MedinCell, Sage Therapeutics, Techspert.io, The LOOP Z\u00fcrich, University Medical Center Utrecht, von Behring R\u00f6ntgen Stiftung. AM-L has received speaker fees from: Arztekammer Nordrhein, BAG Psychiatrie Oberbayern, Biotest\u00a8 AG, Forum Werkstatt Karlsruhe, International Society of Psychiatric Genetics, Brentwood, Klinik f\u00fcr Psychiatrie und Psychotherapie Ingolstadt, Lundbeck SAS France, med Update GmbH, Merz-Stiftung, Siemens Healthineers, Society of Biological Psychiatry. AM-L has received editorial fees from: American Association for the Advancement of Science, Elsevier, Thieme Verlag. ES received speaker fees from bfd buchholz-fachingormationsdienst GmbH and Lundbeckfonden as well as editorial fees from Lundbeckfonden and the Wellcome Trust. The other authors have declared that there are no conflicts of interest in relation to the subject of this study.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"197"}}