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.

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Publication Details

Journal
Molecular Psychiatry
Published
2026-07-18
DOI
https://doi.org/10.1038/s41380-026-03691-4
Primary Topic
Functional Brain Connectivity Studies
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Xiuzhi Li, Karin Halina Greiser, Urs Braun, Peter Ahnert et al.
Molecular Psychiatry
Functional Brain Connectivity Studies
article

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

Xiuzhi Li, Karin Halina Greiser, Urs Braun, Peter Ahnert, Josef Frank, Oliver Sander, Claudia Meinke‐Franze, Emanuel Schwarz, Carsten Oliver Schmidt, A Meyer-Lindenberg, Sebastian Volkmer, Stephanie H. Witt, Tobias Pischon, Steffi Gerlinde Riedel-Heller, Tobias Gradinger, Sebastián Marty-Lombardi, Frauke Nees, Joonas Naamanka, Hermann Brenner, Thoralf Niendorf, Johanna Klinger-König, Fabian Streit, André Karch, Annette Peters, Johannes Nitsche, Amrou Abas, Rafael Mikolajczyk, Julius Wiegert, Esra Lenz, Michael Leitzmann, Klaus Berger, Kerstin Ritter, Antonia Mai, Hans J. Grabe, Jailan Oweda
article en

Abstract

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.

Molecular Psychiatry
Halle Institute for Economic Research (DE), University of Helsinki (FI), German Cancer Research Center (DE), Max Delbrück Center (DE), Heidelberg University (DE), University of Münster (DE), Universitätsmedizin Greifswald (DE), University Hospital Heidelberg (DE), Helmholtz Zentrum München (DE), Christian-Albrechts-Universität zu Kiel (DE), Humboldt-Universität zu Berlin (DE), Düsseldorf University Hospital (DE), Central Institute of Mental Health (DE), German Center for Infection Research (DE), German Centre for Cardiovascular Research (DE), Bernstein Center for Computational Neuroscience Tübingen (DE), Hertie Institute for Clinical Brain Research (DE), Tübingen AI Center, Heinrich Heine University Düsseldorf (DE), University of Regensburg (DE), Martin Luther University Halle-Wittenberg (DE), Freie Universität Berlin (DE), Charité - Universitätsmedizin Berlin (DE), Ludwig-Maximilians-Universität München (DE), Leipzig University (DE)
National Alliance for Research on Schizophrenia and Depression, Bundesministerium für Bildung und Forschung, Hector Stiftung, Hector Stiftung II, Leibniz-Gemeinschaft
Good health and well-being
Openalex Percentile: Top 7%
Functional Brain Connectivity Studies
DOIOpen Access PDFOpenAlex
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