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

ENIGMA Antisocial Behavior, Anxiety, ADHD, and MDD Working Groups

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

ENIGMA Antisocial Behavior, Anxiety, ADHD, and MDD Working Groups

University of Bath
University of Birmingham
University of Marburg
University of Münster
Central Institute of Mental Health, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany.
Monash University
National Institute of Mental Health and Neurosciences
University of Copenhagen
Barcelona
Department of Neurology
Curtin University
University Hospital of Psychiatry Zürich and University of Zürich
Department of Psychiatry
Radboud University Medical Center
The Scripps Research Institute
University of Pennsylvania
Sant Pau Mental Health Research Group
The Second Xiangya Hospital of Central South University
University of Melbourne
Ghent University
Florida State University
King's College London
University of Minnesota Medical School
The University of Melbourne
University of Groningen
Goethe University Hospital
University Hospital RWTH
Maastricht University
University of Bergen
Independent researcher
University of Greifswald
University Hospital Würzburg
University of California
Yale University School of Medicine
Østfold University College
South China Normal University
Department of Psychology
German Center for Mental Health (DZPG)
Dalhousie University
School of Medicine
SWPS University of Social Sciences and Humanities
The First Affiliated Hospital of Soochow University
University Hospital Münster
State University of New York at Stony Brook
Center of Excellence on Mood Disorders
Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
Oregon Health ad Science University
University of Zurich
Baylor College of Medicine
University of Cambridge
University of La Laguna
The Ohio State University
Lausanne University Hospital CHUV and University of Lausanne
Hospital del Mar
Facultad de Ciencias de la Salud Eugenio Espejo
Child Mind Institute
Penn Lifespan Informatics and Neuroimaging Center (PennLINC)
University of Graz
Fudan University
Deakin University
Norwegian University of Science and Technology
Center for Genomic Medicine
Universitäre Psychiatrische Kliniken Basel
Department of Psychiatry and Psychotherapy
National Human Genome Research Institute
University of Southampton
Washington University in St. Louis
University of Rome Tor Vergata
Leiden University Medical Center
University of Potsdam
University of Würzburg
The University of Texas Rio Grande Valley
Hospital of the Ludwig-Maximilians-University (LMU) Munich
University of California San Fransisco
University of Hildesheim
National Institutes of Health (NIH)
University of Southern California
Health and Medical University Erfurt
Yale University
National Institute of Mental Health Intramural Research Program (NIMH-IRP)
University of Cape Town
Institute of Psychology

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Journal	Biological psychiatry
DOIs	https://doi.org/10.1016/j.biopsych.2025.08.003
Publication status	E-pub ahead of print - 12 Aug 2025

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10.1016/j.biopsych.2025.08.003

Shared-and-distinct-alterations-in-brain-structure-of-youth-with-internalizing-or-externalizing-disorders.pdfFinal published version, 2.17 MBLicence: Taverne

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@article{90cdc17df26d4deb807f73ea0c2e3790,

title = "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",

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.",

author = "\{ENIGMA Antisocial Behavior, Anxiety, ADHD, and MDD Working Groups\} and Sophie Townend and Marlene Staginnus and Yidian Gao and Nina Alexander and Volker Arolt and Tobias Banaschewski and Bellgrove, \{Mark A\} and Vivek Benegal and Blair, \{Robert J\} and Laura Blanco-Hinojo and Boeken, \{Ole Jonas\} and Joscha B{\"o}hnlein and Sven B{\"o}lte and Bonnekoh, \{Linda M\} and Daniel Brandeis and Bressan, \{Rodrigo A\} and Fabian Breuer and Bruin, \{Willem B\} and Buitelaar, \{Jan K\} and Burkhouse, \{Katie L\} and Calkins, \{Monica E\} and Marta Cano and Narcis Cardoner and Hui Chen and Xianliang Chen and Coghill, \{David R\} and Colins, \{Olivier F\} and Connolly, \{Colm G\} and Craig, \{Michael C\} and Cullen, \{Kathryn R\} and Udo Dannlowski and Davey, \{Christopher G\} and Andrea Dietrich and Daifeng Dong and Freitag, \{Christine M\} and Thomas Frodl and Liesbet Goossens and Dominik Grotegerd and Gur, \{Raquel E\} and Gur, \{Ruben C\} and Jan Haavik and Hagan, \{Cindy C\} and Tim Hahn and Hamm, \{Alfons O\} and Harrison, \{Ben J\} and Hartman, \{Catharina A\} and Herrmann, \{Martin J\} and Ho, \{Tiffany C\} and Hoekstra, \{Pieter J\} and Bharath Holla and Karim Ibrahim and Andrea Jackowski and Hamidreza Jamalabadi and Yali Jiang and Tilo Kircher and Kerstin Konrad and Anna Kraus and Jonna Kuntsi and Till Langhammer and Luisa Lazaro and Leehr, \{Elisabeth J\} and Ulrike Lueken and Ren Ma and MacMaster, \{Frank P\} and Manfro, \{Gisele G\} and Anne Martinelli and Hannah Meinert and Susanne Meinert and Micha{\l}owski, \{Jaros{\l}aw M\} and Qingsen Ming and Robert Moeck and Mujica-Parodi, \{Lilianne R\} and Benson Mwangi and Janina Neufeld and Nigg, \{Joel T\} and \{O'Gorman Tuura\}, \{Ruth L\} and Hyuntaek Oh and Jaap Oosterlaan and Yannis Paloyelis and Pan, \{Pedro M\} and Luca Passamonti and Wenceslao Pe{\~n}ate and Phan, \{K Luan\} and Plessen, \{Kerstin J\} and Jesus Pujol and Remn{\'e}lius, \{Karl Lundin\} and Francisco Rivero and Katya Rubia and Ramiro Salas and Salum, \{Giovanni A\} and Satterthwaite, \{Theodore D\} and Anne Schienle and Elisabeth Schrammen and Schruers, \{Koen R J\} and Gunter Schumann and Arjun Sethi and Tim Silk and Norbert Skokauskas and Jordan Smoller and Soares, \{Jair C\} and Lin S{\o}rensen and Christina Stadler and Stevens, \{Michael C\} and Benjamin Straube and Thomas Straube and Andreas Str{\"o}hle and Gustavo Sudre and Sukhodolsky, \{Denis G\} and Kate Sully and Xiaoqiang Sun and Sylvester, \{Chad M\} and Nicola Toschi and \{van der Werff\}, \{Steven J A\} and Alasdair Vance and Robert Vermeiren and Albert Wabnegger and Xiaoping Wang and Julia Wendt and Sarah Whittle and Julian Wiemer and Winkler, \{Anderson M\} and Wittchen, \{Hans U\} and Mon-Ju Wu and Qiong Wu and Yang, \{Tony T\} and Yunbo Yang and Shuqiao Yao and Jibiao Zhang and Jiansong Zhou and Andre Zugman and Zunta-Soares, \{Giovana B\} and Zwanzger, \{Peter M\} and Thomopoulos, \{Sophia I\} and Neda Jahanshad and Thompson, \{Paul M\} and Kevin Hilbert and Arielle Baskin-Sommers and Cecil, \{Charlotte A M\} and Moji Aghajani and Pine, \{Daniel S\} and \{van der Wee\}, \{Nic J A\} and Stein, \{Dan J\} and Groenewold, \{Nynke A\} and Bas-Hoogendam, \{Janna Marie\} and Han, \{Laura K M\} and Elena Pozzi and Lianne Schmaal and Barbara Franke and Martine Hoogman and Esther Walton and \{De Brito\}, \{Stephane A\} and Graeme Fairchild",

note = "Copyright {\textcopyright} 2025. Published by Elsevier Inc.",

year = "2025",

month = aug,

day = "12",

doi = "10.1016/j.biopsych.2025.08.003",

language = "English",

journal = "Biological psychiatry",

issn = "0006-3223",

publisher = "Elsevier USA",

}

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. / ENIGMA Antisocial Behavior, Anxiety, ADHD, and MDD Working Groups.
In: Biological psychiatry, 12.08.2025.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Shared and distinct alterations in brain structure of youth with internalizing or externalizing disorders

T2 - Findings from the ENIGMA Antisocial Behavior, ADHD, MDD, and Anxiety Working Groups

AU - ENIGMA Antisocial Behavior, Anxiety, ADHD, and MDD Working Groups

AU - Townend, Sophie

AU - Staginnus, Marlene

AU - Gao, Yidian

AU - Alexander, Nina

AU - Arolt, Volker

AU - Banaschewski, Tobias

AU - Bellgrove, Mark A

AU - Benegal, Vivek

AU - Blair, Robert J

AU - Blanco-Hinojo, Laura

AU - Boeken, Ole Jonas

AU - Böhnlein, Joscha

AU - Bölte, Sven

AU - Bonnekoh, Linda M

AU - Brandeis, Daniel

AU - Bressan, Rodrigo A

AU - Breuer, Fabian

AU - Bruin, Willem B

AU - Buitelaar, Jan K

AU - Burkhouse, Katie L

AU - Calkins, Monica E

AU - Cano, Marta

AU - Cardoner, Narcis

AU - Chen, Hui

AU - Chen, Xianliang

AU - Coghill, David R

AU - Colins, Olivier F

AU - Connolly, Colm G

AU - Craig, Michael C

AU - Cullen, Kathryn R

AU - Dannlowski, Udo

AU - Davey, Christopher G

AU - Dietrich, Andrea

AU - Dong, Daifeng

AU - Freitag, Christine M

AU - Frodl, Thomas

AU - Goossens, Liesbet

AU - Grotegerd, Dominik

AU - Gur, Raquel E

AU - Gur, Ruben C

AU - Haavik, Jan

AU - Hagan, Cindy C

AU - Hahn, Tim

AU - Hamm, Alfons O

AU - Harrison, Ben J

AU - Hartman, Catharina A

AU - Herrmann, Martin J

AU - Ho, Tiffany C

AU - Hoekstra, Pieter J

AU - Holla, Bharath

AU - Ibrahim, Karim

AU - Jackowski, Andrea

AU - Jamalabadi, Hamidreza

AU - Jiang, Yali

AU - Kircher, Tilo

AU - Konrad, Kerstin

AU - Kraus, Anna

AU - Kuntsi, Jonna

AU - Langhammer, Till

AU - Lazaro, Luisa

AU - Leehr, Elisabeth J

AU - Lueken, Ulrike

AU - Ma, Ren

AU - MacMaster, Frank P

AU - Manfro, Gisele G

AU - Martinelli, Anne

AU - Meinert, Hannah

AU - Meinert, Susanne

AU - Michałowski, Jarosław M

AU - Ming, Qingsen

AU - Moeck, Robert

AU - Mujica-Parodi, Lilianne R

AU - Mwangi, Benson

AU - Neufeld, Janina

AU - Nigg, Joel T

AU - O'Gorman Tuura, Ruth L

AU - Oh, Hyuntaek

AU - Oosterlaan, Jaap

AU - Paloyelis, Yannis

AU - Pan, Pedro M

AU - Passamonti, Luca

AU - Peñate, Wenceslao

AU - Phan, K Luan

AU - Plessen, Kerstin J

AU - Pujol, Jesus

AU - Remnélius, Karl Lundin

AU - Rivero, Francisco

AU - Rubia, Katya

AU - Salas, Ramiro

AU - Salum, Giovanni A

AU - Satterthwaite, Theodore D

AU - Schienle, Anne

AU - Schrammen, Elisabeth

AU - Schruers, Koen R J

AU - Schumann, Gunter

AU - Sethi, Arjun

AU - Silk, Tim

AU - Skokauskas, Norbert

AU - Smoller, Jordan

AU - Soares, Jair C

AU - Sørensen, Lin

AU - Stadler, Christina

AU - Stevens, Michael C

AU - Straube, Benjamin

AU - Straube, Thomas

AU - Ströhle, Andreas

AU - Sudre, Gustavo

AU - Sukhodolsky, Denis G

AU - Sully, Kate

AU - Sun, Xiaoqiang

AU - Sylvester, Chad M

AU - Toschi, Nicola

AU - van der Werff, Steven J A

AU - Vance, Alasdair

AU - Vermeiren, Robert

AU - Wabnegger, Albert

AU - Wang, Xiaoping

AU - Wendt, Julia

AU - Whittle, Sarah

AU - Wiemer, Julian

AU - Winkler, Anderson M

AU - Wittchen, Hans U

AU - Wu, Mon-Ju

AU - Wu, Qiong

AU - Yang, Tony T

AU - Yang, Yunbo

AU - Yao, Shuqiao

AU - Zhang, Jibiao

AU - Zhou, Jiansong

AU - Zugman, Andre

AU - Zunta-Soares, Giovana B

AU - Zwanzger, Peter M

AU - Thomopoulos, Sophia I

AU - Jahanshad, Neda

AU - Thompson, Paul M

AU - Hilbert, Kevin

AU - Baskin-Sommers, Arielle

AU - Cecil, Charlotte A M

AU - Aghajani, Moji

AU - Pine, Daniel S

AU - van der Wee, Nic J A

AU - Stein, Dan J

AU - Groenewold, Nynke A

AU - Bas-Hoogendam, Janna Marie

AU - Han, Laura K M

AU - Pozzi, Elena

AU - Schmaal, Lianne

AU - Franke, Barbara

AU - Hoogman, Martine

AU - Walton, Esther

AU - De Brito, Stephane A

AU - Fairchild, Graeme

PY - 2025/8/12

Y1 - 2025/8/12

N2 - 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.

AB - 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.

U2 - 10.1016/j.biopsych.2025.08.003

DO - 10.1016/j.biopsych.2025.08.003

M3 - Article

C2 - 40812743

SN - 0006-3223

JO - Biological psychiatry

JF - Biological psychiatry

ER -

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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