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[Preprint]. 2025 Mar 18:2025.03.17.643677.

doi: 10.1101/2025.03.17.643677.

Dissecting heterogeneity in cortical thickness abnormalities in major depressive disorder: a large-scale ENIGMA MDD normative modelling study

J M M Bayer^{1

2

3

4}, L S van Velzen^{2

3}, E Pozzi^{2

3}, C Davey⁵, L K M Han⁶, S E E C Bauduin⁷, J Bauer⁸, F Benedetti⁹, K Berger¹⁰, L M Bonnekoh^{11

12}, K Brosch¹³, R Bülow¹⁴, B Couvy-Duchesne^{15

16

17

18}, K R Cullen¹⁹, U Dannlowski¹¹, D Dima^{20

21}, K Dohm¹¹, J W Evans²², C H Y Fu²³, P Fuentes-Claramonte²⁴, B R Godlewska^{25

26}, J Goltermann¹¹, A Gonul²⁷, R Goya-Maldonado²⁸, H J Grabe²⁹, N A Groenewold³⁰, D Grotegerd¹¹, O Gruber³¹, T Hahn¹¹, G B Hall³², J Hamilton³³, B J Harrison⁵, S N Hatton³⁴, M Hermesdorf¹⁰, I B Hickie³⁴, T C Ho³⁵, N Jahanshad³⁶, A Jansen¹³, A J Jamieson⁵, T Kamishikiryo³⁷, T Kircher¹³, B Klimes-Dougan¹⁹, B Krämer³¹, A Kraus¹¹, A Krug³⁸, E J Leehr¹¹, R Leenings¹¹, M Li³⁹, A McIntosh⁴⁰, S E Medland⁴¹, S Meinert^{11

42}, E Melloni⁹, B Mwangi⁴³, I Nenadić¹³, G Okada⁴⁴, M Oudega^{6

45

46

47}, M J Portella⁴⁸, E Rodríguez²⁴, L Romaniuk⁴⁰, P G Rosa⁴⁹, M D Sacchet⁵⁰, R Salvador²⁴, P G Sämann⁵¹, H Shinzato⁵², K Sim^{53

54

55}, E Simulionyte⁵⁶, J C Soares⁴³, D J Stein⁵⁷, F Stein¹³, A Stolicyn⁴⁰, B Straube^{13

58}, L T Strike⁵⁹, L Teutenberg¹³, F Thomas-Odenthal¹³, S I Thomopoulos⁶⁰, P Usemann¹³, N J A van der Wee⁶¹, H Völzke⁶⁰, M Wagenmakers^{62

45}, M Walter^{63

39

64

65}, H C Whalley⁴⁰, S Whittle^{2

3}, N R Winter¹¹, K Wittfeld⁶⁶, M Wu⁴³, T T Yang⁶⁷, C A Zarate⁶⁸, G B Zunta-Soares⁴³, P M Thompson⁶⁹, D J Veltman⁷⁰, A F Marquand^{1

4}, L Schmaal^{2

3}

Affiliations

¹ Donders Institute for Brain, Cognition and Behaviour, the Netherlands.
² Centre for Youth Mental Health, University of Melbourne, Melbourne, VIC, Australia Australia.
³ Orygen, Parkville, VIC.
⁴ Radboudumc, Nijmegen, the Netherlands.
⁵ Department of Psychiatry, The University of Melbourne, Australia.
⁶ Amsterdam UMC, location Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, the Netherlands.
⁷ Leiden University Medical Center, Leiden, the Netherlands.
⁸ University Clinic for Radiology, University of Muenster, Germany.
⁹ Division of Neuroscience, IRCCS Sar Raffaele Scientific Institute, Milan, Italy.
¹⁰ Institute of Epidemiology and Social Medicine, University of Münster, Germany.
¹¹ Institute for Translational Psychiatry, University of Münster, Münster, Germany.
¹² Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy University of Münster, Germany.
¹³ Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Germany.
¹⁴ University Medicine Greifswald Institute for Radiology and Neuroradiology, Germany.
¹⁵ Institute for Molecular Bioscience, the University of Queensland, St Lucia, QLD, Australia.
¹⁶ Sorbonne University, Paris Brain Institute - ICM, France.
¹⁷ CNRS, Inria, Inserm, AP-HP, France.
¹⁸ Hôpital de la Pitié Salpêtrière, F-75013, Paris, France.
¹⁹ University of Minnesota, Minneapolis, Minnesota, USA.
²⁰ Department of Psychology, School of Health and Psychological Sciences, City, University of London, London.
²¹ UK Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
²² NIMH/NIH, USA.
²³ Centre for Affective Disorders, King's College London Department of Psychology, University of East London.
²⁴ FIDMAG Germanes Hospitalaries Research Foundation, Barcelona, Spain CIBERSAM, ISCIII, Madrid, Spain.
²⁵ Departement of Psychiatry, University of Oxford, UK.
²⁶ Oxford Health NHS Foundation Trust, Oxford, UK.
²⁷ Ege University School of Medicine Department of Psychiatry, Turkey.
²⁸ Laboratory of Systems Neuroscience and Imaging in Psychiatry (SNIP-Lab), Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
²⁹ University Medicine Greifswald, Germany.
³⁰ Department of Psychiatry & Mental Health, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
³¹ Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Germany.
³² Dept of Psychology, Neuroscience & Behaviour, McMaster University, Ontario, USA.
³³ Department of Biological and Medical Psychology; University of Bergen; Bergen, Norway.
³⁴ University of Sydney, Australia.
³⁵ Department of Psychology, University of California, Los Angeles Brain Research Institute and Interdepartmental Graduate Program in Neuroscience, University of California, Los Angeles, USA.
³⁶ Mark and Mary Stevens Neuroimaging and Informatics Institute Department of Biomedical Engineering, USA.
³⁷ Hiroshima University.
³⁸ Department of Psychiatry and Psychotherapy, University Hospital Bonn, Germany.
³⁹ Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.
⁴⁰ Division of Psychiatry, Centre for Clinical Brain Science, University of Edinburgh.
⁴¹ Queensland Institute of Medical Research, Queensland, Australia.
⁴² Institute for Translational Neuroscience, University of Münster, Münster, Germany.
⁴³ Center of Excellence on Mood Disorders, Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, the University of Texas Health Science Cetner at Houston, USA.
⁴⁴ Department of Psychiatry and Neurosciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan.
⁴⁵ GGZinGeest, Specialized Mental Health Care, Amsterdam, the Netherlands.
⁴⁶ Amsterdam Neuroscience, Mood Anxiety Psychosis Sleep & Stress program, Amsterdam, the Netherlands.
⁴⁷ Amsterdam Public Health, Mental Health program, Amsterdam, the Netherlands.
⁴⁸ Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau) Universitat Autònoma de Barcelona (UAB) Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain.
⁴⁹ PLaboratory of Psychiatric Neuroimaging (LIM-21), Departamento e Instituto de Psiquiatria, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Bazil.
⁵⁰ Meditation Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁵¹ Max Planck Institute of Psychiatry, Munich, Germany.
⁵² Department of Psychiatry and Neurosciences, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan Department of Neuropsychiatry, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
⁵³ Institute of Mental Health, Singapore.
⁵⁴ Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁵⁵ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
⁵⁶ Section for Experimental Psychopathology and Neuroimaging, Department of Psychiatry, University of Heidelberg, Heidelberg, Germany.
⁵⁷ SAMRC Unit on Risk & Resilience in Mental Disorders, Dept of Psychiatry & Neuroscience Institute, University of Cape Town. South Afrika.
⁵⁸ Germany Center for Mind, Brain and Behavior - CMBB, Marburg, Germany.
⁵⁹ Brain and Mental Health, QIMR Berghofer Medical Research Institute, Brisbane, Australia School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Australia.
⁶⁰ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA,USA.
⁶¹ Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands Leiden Institute for Brain and Cognition, Leiden University Medical Center, The Netherlands.
⁶² Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, Noord Holland 1081 HV, The Netherlands.
⁶³ Insititute for Community Medicine, University Medicine Greifswald, Germany.
⁶⁴ Germany German Center for Mental Health (DZPG), partner site Halle-Jena-Magdeburg, Germany.
⁶⁵ Germany Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health (C-I-R-C), Halle-Jena-Magdeburg, Germany.
⁶⁶ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
⁶⁷ Department of Psychiatry and Behavioral Sciences Division of Child and Adolescent Psychiatry University of California at San Francisco (UCSF), USA.
⁶⁸ National Institute of Mental Health, USA.
⁶⁹ University of Southern California, USA.
⁷⁰ Dept. Psychiatry, Amsterdam UMC, Amsterdam, the Netherlands.

PMID: 40166143
PMCID: PMC11956935
DOI: 10.1101/2025.03.17.643677

Dissecting heterogeneity in cortical thickness abnormalities in major depressive disorder: a large-scale ENIGMA MDD normative modelling study

J M M Bayer et al. bioRxiv. 2025.

[Preprint]. 2025 Mar 18:2025.03.17.643677.

doi: 10.1101/2025.03.17.643677.

Authors

Affiliations

¹ Donders Institute for Brain, Cognition and Behaviour, the Netherlands.
² Centre for Youth Mental Health, University of Melbourne, Melbourne, VIC, Australia Australia.
³ Orygen, Parkville, VIC.
⁴ Radboudumc, Nijmegen, the Netherlands.
⁵ Department of Psychiatry, The University of Melbourne, Australia.
⁶ Amsterdam UMC, location Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, the Netherlands.
⁷ Leiden University Medical Center, Leiden, the Netherlands.
⁸ University Clinic for Radiology, University of Muenster, Germany.
⁹ Division of Neuroscience, IRCCS Sar Raffaele Scientific Institute, Milan, Italy.
¹⁰ Institute of Epidemiology and Social Medicine, University of Münster, Germany.
¹¹ Institute for Translational Psychiatry, University of Münster, Münster, Germany.
¹² Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy University of Münster, Germany.
¹³ Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Germany.
¹⁴ University Medicine Greifswald Institute for Radiology and Neuroradiology, Germany.
¹⁵ Institute for Molecular Bioscience, the University of Queensland, St Lucia, QLD, Australia.
¹⁶ Sorbonne University, Paris Brain Institute - ICM, France.
¹⁷ CNRS, Inria, Inserm, AP-HP, France.
¹⁸ Hôpital de la Pitié Salpêtrière, F-75013, Paris, France.
¹⁹ University of Minnesota, Minneapolis, Minnesota, USA.
²⁰ Department of Psychology, School of Health and Psychological Sciences, City, University of London, London.
²¹ UK Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
²² NIMH/NIH, USA.
²³ Centre for Affective Disorders, King's College London Department of Psychology, University of East London.
²⁴ FIDMAG Germanes Hospitalaries Research Foundation, Barcelona, Spain CIBERSAM, ISCIII, Madrid, Spain.
²⁵ Departement of Psychiatry, University of Oxford, UK.
²⁶ Oxford Health NHS Foundation Trust, Oxford, UK.
²⁷ Ege University School of Medicine Department of Psychiatry, Turkey.
²⁸ Laboratory of Systems Neuroscience and Imaging in Psychiatry (SNIP-Lab), Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
²⁹ University Medicine Greifswald, Germany.
³⁰ Department of Psychiatry & Mental Health, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
³¹ Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Germany.
³² Dept of Psychology, Neuroscience & Behaviour, McMaster University, Ontario, USA.
³³ Department of Biological and Medical Psychology; University of Bergen; Bergen, Norway.
³⁴ University of Sydney, Australia.
³⁵ Department of Psychology, University of California, Los Angeles Brain Research Institute and Interdepartmental Graduate Program in Neuroscience, University of California, Los Angeles, USA.
³⁶ Mark and Mary Stevens Neuroimaging and Informatics Institute Department of Biomedical Engineering, USA.
³⁷ Hiroshima University.
³⁸ Department of Psychiatry and Psychotherapy, University Hospital Bonn, Germany.
³⁹ Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.
⁴⁰ Division of Psychiatry, Centre for Clinical Brain Science, University of Edinburgh.
⁴¹ Queensland Institute of Medical Research, Queensland, Australia.
⁴² Institute for Translational Neuroscience, University of Münster, Münster, Germany.
⁴³ Center of Excellence on Mood Disorders, Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, the University of Texas Health Science Cetner at Houston, USA.
⁴⁴ Department of Psychiatry and Neurosciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan.
⁴⁵ GGZinGeest, Specialized Mental Health Care, Amsterdam, the Netherlands.
⁴⁶ Amsterdam Neuroscience, Mood Anxiety Psychosis Sleep & Stress program, Amsterdam, the Netherlands.
⁴⁷ Amsterdam Public Health, Mental Health program, Amsterdam, the Netherlands.
⁴⁸ Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau) Universitat Autònoma de Barcelona (UAB) Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain.
⁴⁹ PLaboratory of Psychiatric Neuroimaging (LIM-21), Departamento e Instituto de Psiquiatria, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Bazil.
⁵⁰ Meditation Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁵¹ Max Planck Institute of Psychiatry, Munich, Germany.
⁵² Department of Psychiatry and Neurosciences, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan Department of Neuropsychiatry, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
⁵³ Institute of Mental Health, Singapore.
⁵⁴ Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁵⁵ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
⁵⁶ Section for Experimental Psychopathology and Neuroimaging, Department of Psychiatry, University of Heidelberg, Heidelberg, Germany.
⁵⁷ SAMRC Unit on Risk & Resilience in Mental Disorders, Dept of Psychiatry & Neuroscience Institute, University of Cape Town. South Afrika.
⁵⁸ Germany Center for Mind, Brain and Behavior - CMBB, Marburg, Germany.
⁵⁹ Brain and Mental Health, QIMR Berghofer Medical Research Institute, Brisbane, Australia School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Australia.
⁶⁰ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA,USA.
⁶¹ Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands Leiden Institute for Brain and Cognition, Leiden University Medical Center, The Netherlands.
⁶² Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, Noord Holland 1081 HV, The Netherlands.
⁶³ Insititute for Community Medicine, University Medicine Greifswald, Germany.
⁶⁴ Germany German Center for Mental Health (DZPG), partner site Halle-Jena-Magdeburg, Germany.
⁶⁵ Germany Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health (C-I-R-C), Halle-Jena-Magdeburg, Germany.
⁶⁶ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
⁶⁷ Department of Psychiatry and Behavioral Sciences Division of Child and Adolescent Psychiatry University of California at San Francisco (UCSF), USA.
⁶⁸ National Institute of Mental Health, USA.
⁶⁹ University of Southern California, USA.
⁷⁰ Dept. Psychiatry, Amsterdam UMC, Amsterdam, the Netherlands.

PMID: 40166143
PMCID: PMC11956935
DOI: 10.1101/2025.03.17.643677

Abstract

Importance: Major depressive disorder (MDD) is highly heterogeneous, with marked individual differences in clinical presentation and neurobiology, which may obscure identification of structural brain abnormalities in MDD. To explore this, we used normative modeling to index regional patterns of variability in cortical thickness (CT) across individual patients.

Objective: To use normative modeling in a large dataset from the ENIGMA MDD consortium to obtain individualised CT deviations from the norm (relative to age, sex and site) and examine the relationship between these deviations and clinical characteristics.

Design setting and participants: A normative model adjusting for age, sex and site effects was trained on 35 CT measures from FreeSurfer parcellation of 3,181 healthy controls (HC) from 34 sites (40 scanners). Individualised z-score deviations from this norm for each CT measure were calculated for a test set of 2,119 HC and 3,645 individuals with MDD. For each individual, each CT z-score was classified as being within the normal range (95% of individuals) or within the extreme range (2.5% of individuals with the thinnest or thickest cortices).

Main outcome measures: Z-score deviations of CT measures of MDD individuals as estimated from a normative model based on HC.

Results: Z-score distributions of CT measures were largely overlapping between MDD and HC (minimum 92%, range 92-98%), with overall thinner cortices in MDD. 34.5% of MDD individuals, and 30% of HC individuals, showed an extreme deviation in at least one region, and these deviations were widely distributed across the brain. There was high heterogeneity in the spatial location of CT deviations across individuals with MDD: a maximum of 12% of individuals with MDD showed an extreme deviation in the same location. Extreme negative CT deviations were associated with having an earlier onset of depression and more severe depressive symptoms in the MDD group, and with higher BMI across MDD and HC groups. Extreme positive deviations were associated with being remitted, of not taking antidepressants and less severe symptoms.

Conclusions and relevance: Our study illustrates a large heterogeneity in the spatial location of CT abnormalities across patients with MDD and confirms a substantial overlap of CT measures with HC. We also demonstrate that individualised extreme deviations can identify protective factors and individuals with a more severe clinical picture.

Keywords: ENIGMA; Normative modelling; cortical thickness; depression; individualised predictions; neuroimaging.

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Conflict of interest statement

K.B has received research funding as principal or coordinating investigator from the German Ministry of Education and Research (BMBF). HJG has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm and Janssen Cilag as well as research funding from Fresenius Medical Care. IBH is the Co-Director, Health and Policy at the Brain and Mind Centre (BMC) University of Sydney. The BMC operates an early-intervention youth services at Camperdown under contract to headspace. He is the Chief Scientific Advisor to, and a 3.2% equity shareholder in, InnoWell Pty Ltd which aims to transform mental health services through the use of innovative technologies. J.C.S states that within the last twelve (12) months of the date set forth below, neither h nor, to the best of my knowledge, any member of his family has any interest in or has taken any action which would violate the Conflict of Interest Policy, except such interest or action as he has fully disclosed below: ALKERMES, ALLERGAN, ASOFARMA, ATAI, BOEHRINGER Ingelheim, COMPASS, JOHNSON & JOHNSO, LIVANOVA, PFIZER, PULVINAR NEURO LLC, RELMADA, SANOFI, SUNOVIAN. G.B.S-Z is a full-time U.S government employee. He is listed as a coinventor on a patent for the use of ketamine in major depression and suicidal ideation. Dr. Zarate is listed as a coinventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain. G.B.S-Z is listed as co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation and post-traumatic stress disorders. G.B.S-Z has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. The views expressed are his own and do not necessarily represent the views of the National Institutes of Health, the Department of Health and Human Services, or the United States Government.

Figures

**Figure 1.**
Distribution of age and sex for the three partitions of the data used in this study. A) Training set, healthy controls. B) Test set, healthy controls. M= male, F=female C) Test set, MDD. D) Illustrated Pre-Processing pipeline. The sample consisted of 34 regional features and one whole brain measure from 5300 healthy controls and 3645 individuals with MDD from the ENIGMA MDD consortium.

**Figure 2.**
**A, B, C:** Distributional overlap between individuals with MDD and HCs (HC) for the A. fusiform gyrus, B: the pars opercularis of the inferior frontal gyrus and C: average CT, showing the lowest distributional overlap between MDD and HC groups. **D, E:** Cohen’s d effect sizes of differences in z-scores between MDD and HCs for each significant cortical region (FDR corrected, only significant regions are displayed). Red: Individuals with MDD have lower z-scores (thinner cortices) on average than HCs. An overview of Cohen’s d effect sizes for z-score differences in different cortical regions is provided in Table S1.7 in the supplementary material. D) medial view. E) lateral view. F: Spider plot showing the average z-scores for individuals with MDD and HCs for all cortical regions. All regions that show significant differences are plotted in bold.

**Figure 3.**
**A. B:** Heterogeneity in cortical thickness deviations in depression. Percentage of individuals with MDD with an infra-normal z-scores (extreme negative deviations; z < −1.96) and supra-normal z-scores (extreme positive deviations; z >1.96) per cortical region. **(A)** infra-normal z-scores; **(B)** supra-normal z-scores. C: Distribution of positive load score (number of extreme negative deviation; z > 1.96) **(C, top)** and negative load score (number of extreme positive deviations; z < −1.96) **(C, bottom)** in individuals with MDD and healthy controls.

See this image and copyright information in PMC

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This is a preprint.

Dissecting heterogeneity in cortical thickness abnormalities in major depressive disorder: a large-scale ENIGMA MDD normative modelling study

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Dissecting heterogeneity in cortical thickness abnormalities in major depressive disorder: a large-scale ENIGMA MDD normative modelling study

Authors

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Abstract

Conflict of interest statement

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