Breaking the Norm: Population-Scale Normative Modeling of Brain Structure in Depression and Anxiety

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Riedel-Heller , View ORCID Profile Kerstin Ritter , View ORCID Profile Annette Peters , View ORCID Profile Tobias Pischon , View ORCID Profile Stephanie Witt , View ORCID Profile Johannes Nitsche , View ORCID Profile Joonas Naamanka , View ORCID Profile Sebastian Volkmer , View ORCID Profile Antonia Mai , View ORCID Profile Amrou Abas , Xiuzhi Li , View ORCID Profile Andreas Meyer-Lindenberg , View ORCID Profile Tobias Gradinger , View ORCID Profile Fabian Streit , View ORCID Profile Urs Braun , View ORCID Profile Emanuel Schwarz doi: https://doi.org/10.1101/2025.09.26.25336528 Julius Wiegert 1 Hector Institute for Artificial Intelligence in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Julius Wiegert Sebastian Marty-Lombardi 1 Hector Institute for Artificial Intelligence in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sebastian Marty-Lombardi Jailan Oweda 1 Hector Institute for Artificial Intelligence in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jailan Oweda Esra Lenz 1 Hector Institute for Artificial Intelligence in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Esra Lenz Peter Ahnert 2 Leipzig University, Institute for Medical Informatics, Statistics and Epidemiology; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Peter Ahnert Klaus Berger 3 Institute of Epidemiology and Social Medicine, Muenster University, Muenster, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Klaus Berger Hermann Brenner 4 German Cancer Research Center (DKFZ), Heidelberg, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Hermann Brenner Josef Frank 5 Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Josef Frank Hans Grabe 6 Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Hans Grabe Karin Halina Greiser 7 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Karin Halina Greiser Johanna Klinger-Koenig 6 Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Johanna Klinger-Koenig Andre Karch 8 Institute of Epidemiology and Social Medicine, University of Muenster, Muenster, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Andre Karch Michael Leitzmann 9 Department of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Michael Leitzmann Claudia Meinke-Franze 10 Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Claudia Meinke-Franze Rafael Mikolajczyk 11 Institute for Medical Epidemiology, Biometrics, and Informatics, Medical Faculty of the Martin Luther University Halle-Wittenberg, Halle (Saale); Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Rafael Mikolajczyk Frauke Nees 12 Institute of Medical Psychology and Medical Sociology, University Medical Center Schleswig-Holstein, Kiel University, Kiel, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Frauke Nees Thoralf Niendorf 13 Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrueck Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Thoralf Niendorf Oliver Sander 14 Clinic for Rheumatology and Hiller Research Center, University Hospital, Heinrich-Heine-University Duesseldorf, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Oliver Sander Carsten Oliver Schmidt 10 Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Carsten Oliver Schmidt Steffi G. Riedel-Heller 15 Institute of Social Medicine, Occupational Health and Public Health (ISAP), Leipzig University, Leipzig, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Steffi G. Riedel-Heller Kerstin Ritter 16 Department of Psychiatry and Neurosciences, Charite - University Medicine Berlin (corporate member of Freie University Berlin, Humboldt-University zu Berlin, and Berlin Institute of Health), Berlin, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Kerstin Ritter Annette Peters 17 Institute of Epidemiology, Helmholtz Zentrum Munich- German Research Center for Environmental Health (GmbH), Neuherberg, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Annette Peters Tobias Pischon 18 Max Delbrueck Center for Molecular Medicine in the Helmholtz Association (MDC), Molecular Epidemiology Research Group, Berlin, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Tobias Pischon Stephanie Witt 5 Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Stephanie Witt Johannes Nitsche 1 Hector Institute for Artificial Intelligence in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Johannes Nitsche Joonas Naamanka 1 Hector Institute for Artificial Intelligence in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Joonas Naamanka Sebastian Volkmer 1 Hector Institute for Artificial Intelligence in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sebastian Volkmer Antonia Mai 1 Hector Institute for Artificial Intelligence in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Antonia Mai Amrou Abas 1 Hector Institute for Artificial Intelligence in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Amrou Abas Xiuzhi Li 1 Hector Institute for Artificial Intelligence in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Andreas Meyer-Lindenberg 19 Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Andreas Meyer-Lindenberg Tobias Gradinger 19 Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Tobias Gradinger Fabian Streit 1 Hector Institute for Artificial Intelligence in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Fabian Streit Urs Braun 1 Hector Institute for Artificial Intelligence in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Urs Braun Emanuel Schwarz 1 Hector Institute for Artificial Intelligence in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Emanuel Schwarz For correspondence: emanuel.schwarz{at}zi-mannheim.de Abstract Info/History Metrics Supplementary material Data/Code Preview PDF 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 Competing Interest Statement HJG has received travel grants and speakers honoraria from Neuraxpharm, Servier, Indorsia and Janssen Cilag. 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-Roentgen-Stiftung, The LOOP Zuerich, ECNP, Teva, Medical Research Council/UKRI, Heinrich-Lanz-Stiftung, Johnson & Johnson, Lundbeckfonden, and the Wellcome Trust. He has receivedvlecture honoraria from pro Mente Akademie GmbH, Schoen Klinik, Janssen-Cilag, Evangelische Hochschule Ludwigsburg, Landesaerztekammer Baden-Wuerttemberg, Klinikum Ingolstadt, PSY (Psychiatrie und Psychotherapie Update Refresher, FOMF), Consorcio Mexicano de Neuropsico-farmacologia (MCNP), Universitaet Klagenfurt, and Universitaet 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. Funding Statement The project was conducted with data (NAKO-711) from the German National Cohort (NAKO) (http://www.nako.de/). The NAKO is funded by the Federal Ministry of Education and Research (BMBF) [project funding reference numbers: 01ER1301A/B/C, 01ER1511D, and 01ER1801A/B/C/D and 01ER2301A/B/C], federal states of Germany and the Helmholtz Association, the participating universities, and the institutes of the Leibniz Association. We thank all participants who took part in the NAKO study and the staff of this research initiative. We also thank the participants and scientists involved in making the UK Biobank resource available (http://www.ukbiobank.ac.uk/). This study was conducted under UK Biobank application number 162313. The project was supported by the DZPG (German Centre for Mental Health Research) and by the BMBF (German Ministry of Education and Research) grant 01EE2303E. Fabian Streit is supported by a 2023 NARSAD Young Investigator Grant (#31537) from the Brain & Behavior Research Foundation with support from the Families for Borderline Personality Disorder Research. This work was supported by the Hector foundation II and was endorsed by German Center for Mental Health (DZPG). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics Committee II of Ruprecht-Karls-Universitaet Heidelberg (Medizinische Fakultaet Mannheim) gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes The revised manuscript improves readability and clarifies the interpretation of the normative modeling pipeline, especially the MoCo-based embedding approach, autoencoder-based deviation estimates, and Mahalanobis distance analyses. The authors revised wording throughout to avoid implying global brain-volume effects, added clearer explanations of cohort-specific reference distributions, and emphasized that cross-cohort deviation magnitudes are descriptive rather than directly comparable. They also expanded discussion of methodological choices, site/scanner handling, clinical interpretation, regional neuroanatomical mapping, and limitations related to healthy-control definitions and MRI questionnaire timing. Reviewer-requested updates were added to the main text, figure captions, Results, Discussion, and Supplementary Material. Data Availability Access to and use of NAKO data and biosamples can be obtained via the electronic application portal (https://transfer.nako.de). Access to UK Biobank data requires application through the registration and application portal (http://ukbiobank.ac.uk/register-apply). http://ukbiobank.ac.uk/register-apply Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . View the discussion thread. Back to top Previous Next Posted May 21, 2026. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Breaking the Norm: Population-Scale Deviations of Brain Structure in Depression and Anxiety Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Breaking the Norm: Population-Scale Deviations of Brain Structure in Depression and Anxiety Julius Wiegert , Sebastian Marty-Lombardi , Jailan Oweda , Esra Lenz , Peter Ahnert , Klaus Berger , Hermann Brenner , Josef Frank , Hans Grabe , Karin Halina Greiser , Johanna Klinger-Koenig , Andre Karch , Michael Leitzmann , Claudia Meinke-Franze , Rafael Mikolajczyk , Frauke Nees , Thoralf Niendorf , Oliver Sander , Carsten Oliver Schmidt , Steffi G. Riedel-Heller , Kerstin Ritter , Annette Peters , Tobias Pischon , Stephanie Witt , Johannes Nitsche , Joonas Naamanka , Sebastian Volkmer , Antonia Mai , Amrou Abas , Xiuzhi Li , Andreas Meyer-Lindenberg , Tobias Gradinger , Fabian Streit , Urs Braun , Emanuel Schwarz medRxiv 2025.09.26.25336528; doi: https://doi.org/10.1101/2025.09.26.25336528 Share This Article: Copy Citation Tools Breaking the Norm: Population-Scale Deviations of Brain Structure in Depression and Anxiety Julius Wiegert , Sebastian Marty-Lombardi , Jailan Oweda , Esra Lenz , Peter Ahnert , Klaus Berger , Hermann Brenner , Josef Frank , Hans Grabe , Karin Halina Greiser , Johanna Klinger-Koenig , Andre Karch , Michael Leitzmann , Claudia Meinke-Franze , Rafael Mikolajczyk , Frauke Nees , Thoralf Niendorf , Oliver Sander , Carsten Oliver Schmidt , Steffi G. Riedel-Heller , Kerstin Ritter , Annette Peters , Tobias Pischon , Stephanie Witt , Johannes Nitsche , Joonas Naamanka , Sebastian Volkmer , Antonia Mai , Amrou Abas , Xiuzhi Li , Andreas Meyer-Lindenberg , Tobias Gradinger , Fabian Streit , Urs Braun , Emanuel Schwarz medRxiv 2025.09.26.25336528; doi: https://doi.org/10.1101/2025.09.26.25336528 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Areas All Articles Addiction Medicine (568) Allergy and Immunology (863) Anesthesia (300) Cardiovascular Medicine (4435) Dentistry and Oral Medicine (444) Dermatology (382) Emergency Medicine (608) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1509) Epidemiology (15229) Forensic Medicine (30) Gastroenterology (1124) Genetic and Genomic Medicine (6600) Geriatric Medicine (668) Health Economics (997) Health Informatics (4536) Health Policy (1368) Health Systems and Quality Improvement (1613) Hematology (541) HIV/AIDS (1264) Infectious Diseases (except HIV/AIDS) (15916) Intensive Care and Critical Care Medicine (1103) Medical Education (623) Medical Ethics (146) Nephrology (667) Neurology (6599) Nursing (346) Nutrition (998) Obstetrics and Gynecology (1144) Occupational and Environmental Health (957) Oncology (3332) Ophthalmology (974) Orthopedics (369) Otolaryngology (420) Pain Medicine (436) Palliative Medicine (130) Pathology (663) Pediatrics (1693) Pharmacology and Therapeutics (691) Primary Care Research (711) Psychiatry and Clinical Psychology (5447) Public and Global Health (9232) Radiology and Imaging (2198) Rehabilitation Medicine and Physical Therapy (1370) Respiratory Medicine (1196) Rheumatology (593) Sexual and Reproductive Health (712) Sports Medicine (530) Surgery (712) Toxicology (99) Transplantation (289) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a00bdd02ba441640',t:'MTc3OTYyMTEyNQ=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();