Shared and distinct alterations in brain structure of youth with internalizing or externalizing disorders: Findings from the ENIGMA Antisocial Behavior, ADHD, MDD, and Anxiety Working Groups

doi:10.1016/j.biopsych.2025.08.003

. 2025 Aug 12:S0006-3223(25)01405-2.

doi: 10.1016/j.biopsych.2025.08.003. Online ahead of print.

Shared and distinct alterations in brain structure of youth with internalizing or externalizing disorders: Findings from the ENIGMA Antisocial Behavior, ADHD, MDD, and Anxiety Working Groups

Sophie Townend¹, Marlene Staginnus², Yidian Gao³, Nina Alexander⁴, Volker Arolt⁵, Tobias Banaschewski⁶, Mark A Bellgrove⁷, Vivek Benegal⁸, Robert J Blair⁹, Laura Blanco-Hinojo¹⁰, Ole Jonas Boeken¹¹, Joscha Böhnlein⁵, Sven Bölte¹², Linda M Bonnekoh¹³, Daniel Brandeis¹⁴, Rodrigo A Bressan¹⁵, Fabian Breuer⁵, Willem B Bruin¹⁶, Jan K Buitelaar¹⁷, Katie L Burkhouse¹⁸, Monica E Calkins¹⁹, Marta Cano²⁰, Narcis Cardoner²⁰, Hui Chen²¹, Xianliang Chen²¹, David R Coghill²², Olivier F Colins²³, Colm G Connolly²⁴, Michael C Craig²⁵, Kathryn R Cullen²⁶, Udo Dannlowski⁵, Christopher G Davey²⁷, Andrea Dietrich²⁸, Daifeng Dong²⁹, Christine M Freitag³⁰, Thomas Frodl³¹, Liesbet Goossens³², Dominik Grotegerd⁵, Raquel E Gur³³, Ruben C Gur³⁴, Jan Haavik³⁵, Cindy C Hagan³⁶, Tim Hahn⁵, Alfons O Hamm³⁷, Ben J Harrison²⁷, Catharina A Hartman³⁸, Martin J Herrmann³⁹, Tiffany C Ho⁴⁰, Pieter J Hoekstra²⁸, Bharath Holla⁴¹, Karim Ibrahim⁴², Andrea Jackowski⁴³, Hamidreza Jamalabadi⁴⁴, Yali Jiang⁴⁵, Tilo Kircher⁴⁴, Kerstin Konrad⁴⁶, Anna Kraus⁵, Jonna Kuntsi⁴⁷, Till Langhammer⁴⁸, Luisa Lazaro⁴⁹, Elisabeth J Leehr⁵, Ulrike Lueken⁵⁰, Ren Ma⁵¹, Frank P MacMaster⁵², Gisele G Manfro⁵³, Anne Martinelli⁵⁴, Hannah Meinert⁵, Susanne Meinert⁵⁵, Jarosław M Michałowski⁵⁶, Qingsen Ming⁵⁷, Robert Moeck⁵⁸, Lilianne R Mujica-Parodi⁵⁹, Benson Mwangi⁶⁰, Janina Neufeld⁶¹, Joel T Nigg⁶², Ruth L O'Gorman Tuura⁶³, Hyuntaek Oh⁶⁴, Jaap Oosterlaan⁶⁵, Yannis Paloyelis⁶⁶, Pedro M Pan¹⁵, Luca Passamonti⁶⁷, Wenceslao Peñate⁶⁸, K Luan Phan⁶⁹, Kerstin J Plessen⁷⁰, Jesus Pujol⁷¹, Karl Lundin Remnélius⁷², Francisco Rivero⁷³, Katya Rubia⁷⁴, Ramiro Salas⁷⁵, Giovanni A Salum⁷⁶, Theodore D Satterthwaite⁷⁷, Anne Schienle⁷⁸, Elisabeth Schrammen⁵, Koen R J Schruers⁷⁹, Gunter Schumann⁸⁰, Arjun Sethi²⁵, Tim Silk⁸¹, Norbert Skokauskas⁸², Jordan Smoller⁸³, Jair C Soares⁶⁰, Lin Sørensen⁸⁴, Christina Stadler⁸⁵, Michael C Stevens⁸⁶, Benjamin Straube⁴⁴, Thomas Straube⁵⁸, Andreas Ströhle⁸⁷, Gustavo Sudre⁸⁸, Denis G Sukhodolsky⁴², Kate Sully⁸⁹, Xiaoqiang Sun⁵¹, Chad M Sylvester⁹⁰, Nicola Toschi⁹¹, Steven J A van der Werff⁹², Alasdair Vance⁹³, Robert Vermeiren⁹⁴, Albert Wabnegger⁷⁸, Xiaoping Wang²¹, Julia Wendt⁹⁵, Sarah Whittle⁹⁶, Julian Wiemer⁹⁷, Anderson M Winkler⁹⁸, Hans U Wittchen⁹⁹, Mon-Ju Wu⁶⁰, Qiong Wu¹⁰⁰, Tony T Yang¹⁰¹, Yunbo Yang¹⁰², Shuqiao Yao⁵¹, Jibiao Zhang⁵¹, Jiansong Zhou²¹, Andre Zugman¹⁰³, Giovana B Zunta-Soares⁶⁰, Peter M Zwanzger¹⁰⁴, Sophia I Thomopoulos¹⁰⁵, Neda Jahanshad¹⁰⁵, Paul M Thompson¹⁰⁵, Kevin Hilbert¹⁰⁶, Arielle Baskin-Sommers¹⁰⁷, Charlotte A M Cecil¹⁰⁸, Moji Aghajani¹⁶, Daniel S Pine¹⁰⁹, Nic J A van der Wee⁹², Dan J Stein¹¹⁰, Nynke A Groenewold¹¹¹, Janna Marie Bas-Hoogendam¹¹², Laura K M Han¹¹³, Elena Pozzi⁹⁶, Lianne Schmaal⁹⁶, Barbara Franke¹¹⁴, Martine Hoogman¹¹⁵, Esther Walton², Stephane A De Brito¹¹⁶, Graeme Fairchild²; ENIGMA Antisocial Behavior, Anxiety, ADHD, and MDD Working Groups

Affiliations

¹ Department of Psychology, University of Bath, Bath, United Kingdom. Electronic address: st2325@bath.ac.uk.
² Department of Psychology, University of Bath, Bath, United Kingdom.
³ Centre for Human Brain Health, School of Psychology, University of Birmingham, Birmingham, United Kingdom.
⁴ Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany; Center for Mind, Brain and Behavior (CMBB), University of Marburg, Marburg, Germany.
⁵ Institute for Translational Psychiatry, University of Münster, Münster, Germany.
⁶ Department of Child and Adolescent Psychiatry and Psychotherapy, Medical Faculty Mannheim, Heidelberg University Central Institute of Mental Health, Mannheim, Germany.
⁷ School of Psychological Sciences, Monash University, Melbourne, VIC, Australia.
⁸ Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India.
⁹ Child and Adolescent Psychiatric Center, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
¹⁰ MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain; ISGlobal Barcelona Institute for Global Health, Barcelona, Spain.
¹¹ Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
¹² Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet & Region Stockholm, Stockholm, Sweden; Child and Adolescent Psychiatry, Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden; Curtin Autism Research Group, Curtin School of Allied Health, Curtin University, Perth, Australia.
¹³ Institute for Translational Psychiatry, University of Münster, Münster, Germany; Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Münster, Münster, Germany.
¹⁴ Department of Child and Adolescent Psychiatry and Psychotherapy, Medical Faculty Mannheim, Heidelberg University Central Institute of Mental Health, Mannheim, Germany; Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital Zürich, University of Zürich, Zürich, Switzerland.
¹⁵ Department of Psychiatry, Interdisciplinary Lab for Clinical Neurosciences (LiNC), Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, Brazil.
¹⁶ Section Forensic Family & Youth Care, Institute of Education & Child Studies, Leiden University, Leiden, The Netherlands.
¹⁷ Department of Medical Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁸ The Research Institute, Nationwide Children's Hospital, Columbus, OH, United States.
¹⁹ Neurodevelopment and Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
²⁰ Sant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain; Network Centre for Biomedical Research on Mental Health (CIBERSAM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
²¹ Department of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
²² Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia.
²³ Department of Special Needs Education, Faculty of Psychology and Educational Sciences, Ghent University, Gent, Belgium.
²⁴ Department of Biomedical Sciences, Florida State University, Tallahassee, FL, United States.
²⁵ Department of Forensic and Neurodevelopmental Sciences, The Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom.
²⁶ Department of Psychiatry and Behavioural Sciences, University of Minnesota Medical School, Minneapolis, MN, United States.
²⁷ Department of Psychiatry, The University of Melbourne, Melbourne, VIC, Australia.
²⁸ Department of Child and Adolescent Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Accare Child Study Center, Groningen, The Netherlands.
²⁹ Medical Psychological Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China; China National Clinical Research Center for Mental Disorders (Xiangya), Changsha, Hunan, China.
³⁰ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt am Main, Goethe University, Frankfurt am Main, Germany.
³¹ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital RWTH, Aachen, Germany.
³² Department of Psychiatry & Neuropsychology, Maastricht University, Maastricht, The Netherlands.
³³ Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Lifespan Brain Institute, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
³⁴ Brain Behavior Laboratory, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, United States.
³⁵ Department of Biomedicine, University of Bergen, Bergen, Norway; Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
³⁶ Independent researcher.
³⁷ Department of Biological and Clinical Psychology/Psychotherapy, University of Greifswald, Greifswald, Germany; Department of Psychology, University of Greifswald, Greifswald, Germany.
³⁸ Interdisciplinary Center Psychopathology and Emotion regulation (ICPE), Department of Psychiatry, University Medical Center Groningen, University of Groningen, The Netherlands.
³⁹ Center for Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany.
⁴⁰ Department of Psychology, University of California, Los Angeles, CA, United States.
⁴¹ Department of Integrative Medicine, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India.
⁴² Child Study Center, Yale University School of Medicine, New Haven, CT, United States.
⁴³ Department of Psychiatry, Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, Brazil; Department of Education, ICT and Learning, Østfold University College, Halden, Norway.
⁴⁴ Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.
⁴⁵ School of Psychology, South China Normal University, GuangZhou, GuangDong, China.
⁴⁶ Child Neuropsychology Section, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital RWTH, Aachen, Germany; JARA-BRAIN Institute II, Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen, Juelich, Germany.
⁴⁷ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
⁴⁸ Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany.
⁴⁹ Department of Child and Adolescent Psychiatry and Psychology, Hospital Clínic, IDIBAPS, CIBERSAM, Barcelona, Spain; Department of Medicine, Institute of Neuroscience, University of Barcelona, Barcelona, Spain.
⁵⁰ Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany; German Center for Mental Health (DZPG), partner site Berlin/Potsdam, Germany.
⁵¹ Medical Psychological Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
⁵² IWK Health, Halifax, Nova Scotia, Canada; Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
⁵³ Department of Psychiatry, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Psychiatry Services, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
⁵⁴ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt am Main, Goethe University, Frankfurt am Main, Germany; Psychology School, Fresenius University of Applied Sciences, Frankfurt am Main, Germany.
⁵⁵ Institute for Translational Psychiatry, University of Münster, Münster, Germany; Institute for Translational Neuroscience, University of Münster, Münster, Germany.
⁵⁶ Poznan Laboratory of Affective Neuroscience, University SWPS, Poznan, Poland.
⁵⁷ Medical Psychological Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Psychiatry, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
⁵⁸ Institute of Medical Psychology and Systems Neuroscience, University Hospital Münster, Münster, Germany.
⁵⁹ Biomedical Engineering, Laufer Center for Physical and Quantitative Biology, State University of New York at Stony Brook, Stony Brook, NY, United States; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
⁶⁰ Center of Excellence on Mood Disorders, Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, UTHealth Houston, Houston, TX, United States.
⁶¹ Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet & Region Stockholm, Stockholm, Sweden; Swedish Collegium for Advanced Study (SCAS), Uppsala, Sweden.
⁶² Department of Psychiatry, Oregon Health & Science University, Portland, OR, United States.
⁶³ University Children's Hospital Zurich, Zurich, Switzerland; University of Zurich, Zurich, Switzerland.
⁶⁴ Menninger Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, United States; The Menninger Clinic, Houston, TX, United States.
⁶⁵ Clinical Neuropsychology section, Vrije Universiteit, Amsterdam, The Netherlands; Emma Children's Hospital, Amsterdam UMC location University of Amsterdam, Department of Pediatrics, Emma Children's Hospital Amsterdam UMC Follow-Me program & Emma Neuroscience Group, Amsterdam, The Netherlands; Amsterdam Reproduction and Development research institute, Amsterdam, The Netherlands.
⁶⁶ The Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom.
⁶⁷ Clinical Neuroscience Department, University of Cambridge, Cambridge, United Kingdom.
⁶⁸ Department of Clinical Psychology, Psychobiology and Methodology, University of La Laguna, La Laguna, Tenerife, Spain; University Institute of Neuroscience (IUNE), La Laguna, Tenerife, Spain.
⁶⁹ Department of Psychiatry and Behavioral Health, The Ohio State University, Columbus, OH, United States.
⁷⁰ Division of Child and Adolescent Psychiatry, Department of Psychiatry University Hospital Lausanne, CHUV and University of Lausanne, Lausanne, Switzerland.
⁷¹ MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain.
⁷² Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet & Region Stockholm, Stockholm, Sweden.
⁷³ Facultad de Ciencias de la Salud, Universidad Europea de Canarias, La Orotava, Tenerife, Spain.
⁷⁴ Department of Child Psychiatry, The Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom.
⁷⁵ The Menninger Clinic, Houston, TX, United States; Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States.
⁷⁶ Department of Psychiatry, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Psychiatry Services, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Child Mind Institute, New York, NY, United States.
⁷⁷ Penn Lifespan Informatics and Neuroimaging Center (PennLINC), Philadelphia, PA, United States; Penn-CHOP Lifespan Brain Instiute (LiBI), Philadelphia, PA, United States.
⁷⁸ Clinical Psychology, University of Graz, Graz, Austria.
⁷⁹ Research Institute for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands; Mondriaan Mental Health Center, Maastricht, The Netherlands.
⁸⁰ Centre for Population Neuroscience and Stratified Medicine (PONS), The Institute of Science and Technology for Brain-inspired Intelligence (ISTBI), Fudan University, Shanghai, China; PONS Centre, Department of Psychiatry and Neuroscience, Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁸¹ School of Psychology and the Centre for Social and Early Emotional Development (SEED), Deakin University, Geelong, VIC, Australia.
⁸² RKBU, Norwegian University of Science and Technology, Trondheim, Norway.
⁸³ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States; Center for Precision Psychiatry, Massachusetts General Hospital, Boston, MA, United States.
⁸⁴ Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway.
⁸⁵ Universitäre Psychiatrische Kliniken Basel, Basel, Switzerland.
⁸⁶ Olin Neuropsychiatry Research Center, Hartford, CT, United States; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States.
⁸⁷ Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁸⁸ National Human Genome Research Institute, Bethesda, MD, United States.
⁸⁹ School of Psychology, University of Southampton, Southampton, United Kingdom.
⁹⁰ Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States; Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States; Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis, St. Louis, MO, United States.
⁹¹ Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Rome, Italy; Martinos Center for Biomedical Imaging, Boston, MA, United States.
⁹² Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands; Leiden Institute for Brain and Cognition, Leiden, The Netherlands.
⁹³ Academic Child Psychiatry Unit, Faculty MDHS, University of Melbourne, Melbourne, VIC, Australia.
⁹⁴ LUMC Curium, Child and Adolescent Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
⁹⁵ Biological Psychology and Affective Science, University of Potsdam, Potsdam, Germany; Oberberg Clinic Potsdam, Potsdam, Germany.
⁹⁶ Orygen, The National Centre of Excellence in Youth Mental Health, Parkville, VIC, Australia; Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia.
⁹⁷ Institute of Psychology (Biological Psychology, Clinical Psychology, and Psychotherapy), University of Würzburg, Würzburg, Germany.
⁹⁸ Division of Human Genetics, The University of Texas Rio Grande Valley, Browsville, TX, United States.
⁹⁹ Department Psychiatry and Psychotherapy, Ludwig Maximilians University (LMU), Munchen, Germany.
¹⁰⁰ Medical Psychological Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
¹⁰¹ Department of Psychiatry and Behavioral Sciences, University of California San Fransisco, San Fransisco, CA, United States.
¹⁰² Institut for Psychology, University of Hildesheim, Hildesheim, Germany.
¹⁰³ Section on Development and Affective Neuroscience (SDAN), National Institute of Mental Health (NIMH), National Institutes of Health (NIH), Bethesda, MD, United States.
¹⁰⁴ Department Psychiatry and Psychotherapy, Ludwig Maximilians University (LMU), Munchen, Germany; kbo-Inn-Salzach-Hospital Clinical Center for Psychiatry, Psychotherapy and Psychosomatics, Wasserburg am Inn, Germany.
¹⁰⁵ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, United States.
¹⁰⁶ Department of Psychology, Health and Medical University Erfurt, Erfurt, Germany.
¹⁰⁷ Department of Psychology, Yale University, New Haven, CT, United States.
¹⁰⁸ Department of Child and Adolescent Psychiatry and Psychology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands; Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
¹⁰⁹ National Institute of Mental Health Intramural Research Program (NIMH-IRP), Bethesda, MD, United States.
¹¹⁰ SAMRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry & Neuroscience Institute, University of Cape Town, Cape Town, South Africa; UCT Department of Psychiatry, Groote Schuur Hospital, Cape Town, South Africa.
¹¹¹ Department of Psychiaty & Mental Health, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
¹¹² Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands; Leiden Institute for Brain and Cognition, Leiden, The Netherlands; Institute of Psychology, Leiden University, Leiden, The Netherlands.
¹¹³ Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia; Department of Psychiatry, Amsterdam UMC, location Vrije Universiteit, Amsterdam Neuroscience, Amsterdam, The Netherlands.
¹¹⁴ Department of Medical Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
¹¹⁵ Department of Medical Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Psychiatry, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
¹¹⁶ Centre for Human Brain Health, School of Psychology, University of Birmingham, Birmingham, United Kingdom; Institute for Mental Health, School of Psychology, University of Birmingham, Birmingham, United Kingdom; Centre for Developmental Science, School of Psychology, University of Birmingham, Birmingham, United Kingdom; Birmingham Centre for Neurogenetics, School of Psychology, University of Birmingham, Birmingham, United Kingdom.

PMID: 40812743
DOI: 10.1016/j.biopsych.2025.08.003

Shared and distinct alterations in brain structure of youth with internalizing or externalizing disorders: Findings from the ENIGMA Antisocial Behavior, ADHD, MDD, and Anxiety Working Groups

Sophie Townend et al. Biol Psychiatry. 2025.

. 2025 Aug 12:S0006-3223(25)01405-2.

doi: 10.1016/j.biopsych.2025.08.003. Online ahead of print.

Authors

Affiliations

¹ Department of Psychology, University of Bath, Bath, United Kingdom. Electronic address: st2325@bath.ac.uk.
² Department of Psychology, University of Bath, Bath, United Kingdom.
³ Centre for Human Brain Health, School of Psychology, University of Birmingham, Birmingham, United Kingdom.
⁴ Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany; Center for Mind, Brain and Behavior (CMBB), University of Marburg, Marburg, Germany.
⁵ Institute for Translational Psychiatry, University of Münster, Münster, Germany.
⁶ Department of Child and Adolescent Psychiatry and Psychotherapy, Medical Faculty Mannheim, Heidelberg University Central Institute of Mental Health, Mannheim, Germany.
⁷ School of Psychological Sciences, Monash University, Melbourne, VIC, Australia.
⁸ Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India.
⁹ Child and Adolescent Psychiatric Center, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
¹⁰ MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain; ISGlobal Barcelona Institute for Global Health, Barcelona, Spain.
¹¹ Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
¹² Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet & Region Stockholm, Stockholm, Sweden; Child and Adolescent Psychiatry, Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden; Curtin Autism Research Group, Curtin School of Allied Health, Curtin University, Perth, Australia.
¹³ Institute for Translational Psychiatry, University of Münster, Münster, Germany; Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Münster, Münster, Germany.
¹⁴ Department of Child and Adolescent Psychiatry and Psychotherapy, Medical Faculty Mannheim, Heidelberg University Central Institute of Mental Health, Mannheim, Germany; Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital Zürich, University of Zürich, Zürich, Switzerland.
¹⁵ Department of Psychiatry, Interdisciplinary Lab for Clinical Neurosciences (LiNC), Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, Brazil.
¹⁶ Section Forensic Family & Youth Care, Institute of Education & Child Studies, Leiden University, Leiden, The Netherlands.
¹⁷ Department of Medical Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁸ The Research Institute, Nationwide Children's Hospital, Columbus, OH, United States.
¹⁹ Neurodevelopment and Psychosis Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
²⁰ Sant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain; Network Centre for Biomedical Research on Mental Health (CIBERSAM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
²¹ Department of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
²² Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia.
²³ Department of Special Needs Education, Faculty of Psychology and Educational Sciences, Ghent University, Gent, Belgium.
²⁴ Department of Biomedical Sciences, Florida State University, Tallahassee, FL, United States.
²⁵ Department of Forensic and Neurodevelopmental Sciences, The Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom.
²⁶ Department of Psychiatry and Behavioural Sciences, University of Minnesota Medical School, Minneapolis, MN, United States.
²⁷ Department of Psychiatry, The University of Melbourne, Melbourne, VIC, Australia.
²⁸ Department of Child and Adolescent Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Accare Child Study Center, Groningen, The Netherlands.
²⁹ Medical Psychological Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China; China National Clinical Research Center for Mental Disorders (Xiangya), Changsha, Hunan, China.
³⁰ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt am Main, Goethe University, Frankfurt am Main, Germany.
³¹ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital RWTH, Aachen, Germany.
³² Department of Psychiatry & Neuropsychology, Maastricht University, Maastricht, The Netherlands.
³³ Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Lifespan Brain Institute, Children's Hospital of Philadelphia, Philadelphia, PA, United States.
³⁴ Brain Behavior Laboratory, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, United States.
³⁵ Department of Biomedicine, University of Bergen, Bergen, Norway; Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
³⁶ Independent researcher.
³⁷ Department of Biological and Clinical Psychology/Psychotherapy, University of Greifswald, Greifswald, Germany; Department of Psychology, University of Greifswald, Greifswald, Germany.
³⁸ Interdisciplinary Center Psychopathology and Emotion regulation (ICPE), Department of Psychiatry, University Medical Center Groningen, University of Groningen, The Netherlands.
³⁹ Center for Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany.
⁴⁰ Department of Psychology, University of California, Los Angeles, CA, United States.
⁴¹ Department of Integrative Medicine, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India.
⁴² Child Study Center, Yale University School of Medicine, New Haven, CT, United States.
⁴³ Department of Psychiatry, Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, Brazil; Department of Education, ICT and Learning, Østfold University College, Halden, Norway.
⁴⁴ Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.
⁴⁵ School of Psychology, South China Normal University, GuangZhou, GuangDong, China.
⁴⁶ Child Neuropsychology Section, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital RWTH, Aachen, Germany; JARA-BRAIN Institute II, Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen, Juelich, Germany.
⁴⁷ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
⁴⁸ Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany.
⁴⁹ Department of Child and Adolescent Psychiatry and Psychology, Hospital Clínic, IDIBAPS, CIBERSAM, Barcelona, Spain; Department of Medicine, Institute of Neuroscience, University of Barcelona, Barcelona, Spain.
⁵⁰ Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany; German Center for Mental Health (DZPG), partner site Berlin/Potsdam, Germany.
⁵¹ Medical Psychological Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
⁵² IWK Health, Halifax, Nova Scotia, Canada; Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
⁵³ Department of Psychiatry, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Psychiatry Services, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
⁵⁴ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt am Main, Goethe University, Frankfurt am Main, Germany; Psychology School, Fresenius University of Applied Sciences, Frankfurt am Main, Germany.
⁵⁵ Institute for Translational Psychiatry, University of Münster, Münster, Germany; Institute for Translational Neuroscience, University of Münster, Münster, Germany.
⁵⁶ Poznan Laboratory of Affective Neuroscience, University SWPS, Poznan, Poland.
⁵⁷ Medical Psychological Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Psychiatry, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
⁵⁸ Institute of Medical Psychology and Systems Neuroscience, University Hospital Münster, Münster, Germany.
⁵⁹ Biomedical Engineering, Laufer Center for Physical and Quantitative Biology, State University of New York at Stony Brook, Stony Brook, NY, United States; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
⁶⁰ Center of Excellence on Mood Disorders, Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, UTHealth Houston, Houston, TX, United States.
⁶¹ Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet & Region Stockholm, Stockholm, Sweden; Swedish Collegium for Advanced Study (SCAS), Uppsala, Sweden.
⁶² Department of Psychiatry, Oregon Health & Science University, Portland, OR, United States.
⁶³ University Children's Hospital Zurich, Zurich, Switzerland; University of Zurich, Zurich, Switzerland.
⁶⁴ Menninger Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, United States; The Menninger Clinic, Houston, TX, United States.
⁶⁵ Clinical Neuropsychology section, Vrije Universiteit, Amsterdam, The Netherlands; Emma Children's Hospital, Amsterdam UMC location University of Amsterdam, Department of Pediatrics, Emma Children's Hospital Amsterdam UMC Follow-Me program & Emma Neuroscience Group, Amsterdam, The Netherlands; Amsterdam Reproduction and Development research institute, Amsterdam, The Netherlands.
⁶⁶ The Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom.
⁶⁷ Clinical Neuroscience Department, University of Cambridge, Cambridge, United Kingdom.
⁶⁸ Department of Clinical Psychology, Psychobiology and Methodology, University of La Laguna, La Laguna, Tenerife, Spain; University Institute of Neuroscience (IUNE), La Laguna, Tenerife, Spain.
⁶⁹ Department of Psychiatry and Behavioral Health, The Ohio State University, Columbus, OH, United States.
⁷⁰ Division of Child and Adolescent Psychiatry, Department of Psychiatry University Hospital Lausanne, CHUV and University of Lausanne, Lausanne, Switzerland.
⁷¹ MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain.
⁷² Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet & Region Stockholm, Stockholm, Sweden.
⁷³ Facultad de Ciencias de la Salud, Universidad Europea de Canarias, La Orotava, Tenerife, Spain.
⁷⁴ Department of Child Psychiatry, The Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom.
⁷⁵ The Menninger Clinic, Houston, TX, United States; Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States.
⁷⁶ Department of Psychiatry, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Psychiatry Services, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Child Mind Institute, New York, NY, United States.
⁷⁷ Penn Lifespan Informatics and Neuroimaging Center (PennLINC), Philadelphia, PA, United States; Penn-CHOP Lifespan Brain Instiute (LiBI), Philadelphia, PA, United States.
⁷⁸ Clinical Psychology, University of Graz, Graz, Austria.
⁷⁹ Research Institute for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands; Mondriaan Mental Health Center, Maastricht, The Netherlands.
⁸⁰ Centre for Population Neuroscience and Stratified Medicine (PONS), The Institute of Science and Technology for Brain-inspired Intelligence (ISTBI), Fudan University, Shanghai, China; PONS Centre, Department of Psychiatry and Neuroscience, Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁸¹ School of Psychology and the Centre for Social and Early Emotional Development (SEED), Deakin University, Geelong, VIC, Australia.
⁸² RKBU, Norwegian University of Science and Technology, Trondheim, Norway.
⁸³ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States; Center for Precision Psychiatry, Massachusetts General Hospital, Boston, MA, United States.
⁸⁴ Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway.
⁸⁵ Universitäre Psychiatrische Kliniken Basel, Basel, Switzerland.
⁸⁶ Olin Neuropsychiatry Research Center, Hartford, CT, United States; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States.
⁸⁷ Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁸⁸ National Human Genome Research Institute, Bethesda, MD, United States.
⁸⁹ School of Psychology, University of Southampton, Southampton, United Kingdom.
⁹⁰ Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States; Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States; Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis, St. Louis, MO, United States.
⁹¹ Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Rome, Italy; Martinos Center for Biomedical Imaging, Boston, MA, United States.
⁹² Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands; Leiden Institute for Brain and Cognition, Leiden, The Netherlands.
⁹³ Academic Child Psychiatry Unit, Faculty MDHS, University of Melbourne, Melbourne, VIC, Australia.
⁹⁴ LUMC Curium, Child and Adolescent Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
⁹⁵ Biological Psychology and Affective Science, University of Potsdam, Potsdam, Germany; Oberberg Clinic Potsdam, Potsdam, Germany.
⁹⁶ Orygen, The National Centre of Excellence in Youth Mental Health, Parkville, VIC, Australia; Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia.
⁹⁷ Institute of Psychology (Biological Psychology, Clinical Psychology, and Psychotherapy), University of Würzburg, Würzburg, Germany.
⁹⁸ Division of Human Genetics, The University of Texas Rio Grande Valley, Browsville, TX, United States.
⁹⁹ Department Psychiatry and Psychotherapy, Ludwig Maximilians University (LMU), Munchen, Germany.
¹⁰⁰ Medical Psychological Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
¹⁰¹ Department of Psychiatry and Behavioral Sciences, University of California San Fransisco, San Fransisco, CA, United States.
¹⁰² Institut for Psychology, University of Hildesheim, Hildesheim, Germany.
¹⁰³ Section on Development and Affective Neuroscience (SDAN), National Institute of Mental Health (NIMH), National Institutes of Health (NIH), Bethesda, MD, United States.
¹⁰⁴ Department Psychiatry and Psychotherapy, Ludwig Maximilians University (LMU), Munchen, Germany; kbo-Inn-Salzach-Hospital Clinical Center for Psychiatry, Psychotherapy and Psychosomatics, Wasserburg am Inn, Germany.
¹⁰⁵ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, United States.
¹⁰⁶ Department of Psychology, Health and Medical University Erfurt, Erfurt, Germany.
¹⁰⁷ Department of Psychology, Yale University, New Haven, CT, United States.
¹⁰⁸ Department of Child and Adolescent Psychiatry and Psychology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands; Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
¹⁰⁹ National Institute of Mental Health Intramural Research Program (NIMH-IRP), Bethesda, MD, United States.
¹¹⁰ SAMRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry & Neuroscience Institute, University of Cape Town, Cape Town, South Africa; UCT Department of Psychiatry, Groote Schuur Hospital, Cape Town, South Africa.
¹¹¹ Department of Psychiaty & Mental Health, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
¹¹² Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands; Leiden Institute for Brain and Cognition, Leiden, The Netherlands; Institute of Psychology, Leiden University, Leiden, The Netherlands.
¹¹³ Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia; Department of Psychiatry, Amsterdam UMC, location Vrije Universiteit, Amsterdam Neuroscience, Amsterdam, The Netherlands.
¹¹⁴ Department of Medical Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
¹¹⁵ Department of Medical Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Psychiatry, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
¹¹⁶ Centre for Human Brain Health, School of Psychology, University of Birmingham, Birmingham, United Kingdom; Institute for Mental Health, School of Psychology, University of Birmingham, Birmingham, United Kingdom; Centre for Developmental Science, School of Psychology, University of Birmingham, Birmingham, United Kingdom; Birmingham Centre for Neurogenetics, School of Psychology, University of Birmingham, Birmingham, United Kingdom.

PMID: 40812743
DOI: 10.1016/j.biopsych.2025.08.003

Abstract

Background: Externalizing and internalizing disorders are common in youth but are often studied separately, preventing researchers from identifying shared (i.e., transdiagnostic) alterations in brain structure. Using data from the ENIGMA Consortium, we conducted a mega-analysis to identify shared and distinct cortical and subcortical brain alterations across internalizing (anxiety disorders and depression) and externalizing disorders (attention-deficit/hyperactivity disorder [ADHD] and conduct disorder [CD]) in youth.

Methods: 3D T1-weighted MRI data from youth (aged 4-21 years) with anxiety disorders (n=1,044), depression (n=504), ADHD (n=1,317), and CD (n=1,172), along with healthy controls (n=4,743) were analyzed. We assessed group differences in regional cortical thickness, surface area, and subcortical volume using linear models, adjusted for site, age, and sex, and total intracranial volume in the surface area and subcortical volume models.

Results: We observed transdiagnostic associations, with both internalizing and externalizing disorders characterized by lower surface area in the insula, entorhinal cortex, and middle temporal gyrus, and lower amygdala volume (Cohen's ds=-0.07 to -0.24), as well as total surface area and intracranial volume (ds=-0.11 to -0.25). Externalizing-specific reductions in surface area were observed in fronto-parietal regions (ds=-0.08 to -0.13), but no internalizing-specific associations were identified. Disorder-specific alterations were identified for ADHD, CD, and anxiety disorders, but not depression.

Conclusions: Both common and disorder-specific alterations were identified, with regions involved in salience attribution and emotion processing implicated across internalizing and externalizing disorders. These findings can guide future research targeting common biological processes across youth psychiatric disorders as well as features unique to individual disorders.

Keywords: Child and adolescent psychiatry; ENIGMA; Meta-analysis; Structural MRI; Transdiagnostic; Youth.

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Shared and distinct alterations in brain structure of youth with internalizing or externalizing disorders: Findings from the ENIGMA Antisocial Behavior, ADHD, MDD, and Anxiety Working Groups

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Shared and distinct alterations in brain structure of youth with internalizing or externalizing disorders: Findings from the ENIGMA Antisocial Behavior, ADHD, MDD, and Anxiety Working Groups

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Abstract

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