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We applied autoencoder-based normative modeling to contrastively learned structural MRI representations from two large population-based cohorts (German National Cohort,\n                    <jats:italic>N<\/jats:italic>\n                    \u2009\u2248\u200929,000; UK Biobank,\n                    <jats:italic>N<\/jats:italic>\n                    \u2009\u2248\u200925,000) to quantify individual deviations from normative brain structure across symptom dimensions of depression, anxiety, and, for contextualization, alcohol use.\n                  <\/jats:p>\n                  <jats:p>Deviation magnitude increased with symptom severity for depressive and anxiety symptoms and was most pronounced in individuals with high alcohol use. Directional analyses revealed shared deviation patterns for depression and anxiety that were largely distinct from alcohol-related deviations, and these patterns generalized across cohorts. These affective-symptom-related patterns implicated distributed regional brain-structural variation. Individual deviation profiles improved classification of symptomatic status beyond demographic covariates, with gains concentrated at higher symptom severity.<\/jats:p>\n                  <jats:p>Together, these findings indicate that affective symptoms are associated with reproducible, dimensional patterns of regional brain-structural deviation that extend beyond normative population variability, supporting transdiagnostic models of internalizing psychopathology.<\/jats:p>","DOI":"10.1038\/s41380-026-03691-4","type":"journal-article","created":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T11:47:07Z","timestamp":1784375227000},"page":"6034-6045","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Breaking the norm: population-scale deviations of brain structure in depression and 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ES received speaker fees from bfd buchholz-fachinformationsdienst GmbH, Lundbeckfonden, and Janssen-Cilag GmbH, as well as editorial fees from Lundbeckfonden and the Wellcome Trust. AML has received consultancy honoraria from AbbVie, Janssen-Cilag GmbH, Boehringer-Ingelheim, Daimler und Benz Stiftung, Helmut Horten Stiftung, Neurotorium\/Lundbeckfonden, Hector Stiftung, Endosane Pharmaceuticals, Elsevier, von Behring-R\u00f6ntgen-Stiftung, The LOOP Z\u00fcrich, ECNP, Teva, Medical Research Council\/UKRI, Heinrich-Lanz-Stiftung, Johnson & Johnson, Lundbeckfonden, and the Wellcome Trust. He has received lecture honoraria from pro Mente Akademie GmbH, Sch\u00f6n Klinik, Janssen-Cilag, Evangelische Hochschule Ludwigsburg, Landes\u00e4rztekammer Baden-W\u00fcrttemberg, Klinikum Ingolstadt, PSY (Psychiatrie und Psychotherapie Update Refresher, FOMF), Consorcio Mexicano de Neuropsicofarmacologa (MCNP), Universit\u00e4t Klagenfurt, and Universit\u00e4t Norwalk\/USA. He has received editorial honoraria (as editor, etc.) from ECNP\/Neuroscience Applied and JSPS. He has received authorship honoraria from Beltz Verlag, Thieme Verlag, and Kohlhammer Verlag. He has received project funding from BMBF, DFG, Hector Stiftung, Klaus Tschira Stiftung, and MWK.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}