Breaking the norm: population-scale deviations of brain structure in depression and anxiety

Structural brain alterations associated with depression and anxiety are subtle, heterogeneous, and difficult to characterize. We applied autoencoder-based normative modeling to contrastively learned structural MRI representations from two large population-based cohorts (German National Cohort, N ≈ 29,000; UK Biobank, N ≈ 25,000) to quantify individual deviations from normative brain structure across symptom dimensions of depression, anxiety, and, for contextualization, alcohol use. 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. 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. Contact emanuel.schwarz@zi-mannheim.de