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

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
, Marlene Staginnus
, Yidian Gao
, Nina Alexander
, Volker Arolt
, Tobias Banaschewski
, Katja Beesdo-Baum
, Mark A. Bellgrove
, Vivek Benegal
, Robert J. Blair
, Laura Blanco-Hinojo
, Ole Jonas Boeken
, Joscha Böhnlein
, Sven Bölte
, Linda M. Bonnekoh
, Daniel Brandeis
, Rodrigo A. Bressan
, Fabian Breuer
, Willem B. Bruin
, Jan K. Buitelaar

Katie L. Burkhouse, Monica E. Calkins, Marta Cano, Narcis Cardoner, Hui Chen, Xianliang Chen, David R. Coghill, Olivier F. Colins, Colm G. Connolly, Michael C. Craig, Kathryn R. Cullen, Udo Dannlowski, Christopher G. Davey, Andrea Dietrich, Daifeng Dong, Christine M. Freitag, Thomas Frodl, Liesbet Goossens, Dominik Grotegerd, Raquel E. Gur, Ruben C. Gur, Jan Haavik, Cindy C. Hagan, Tim Hahn, Alfons O. Hamm, Ben J. Harrison, Catharina A. Hartman, Martin J. Herrmann, Tiffany C. Ho, Pieter J. Hoekstra, Bharath Holla, Karim Ibrahim, Andrea Jackowski, Hamidreza Jamalabadi, Yali Jiang, Tilo Kircher, Kerstin Konrad, Anna Kraus, Jonna Kuntsi, Till Langhammer, Luisa Lazaro, Elisabeth J. Leehr, Ulrike Lueken, Ren Ma, Frank P. MacMaster, Gisele G. Manfro, Anne Martinelli, Hannah Meinert, Susanne Meinert, Jarosław M. Michałowski, Qingsen Ming, Robert Moeck, Markus Muehlhan, Lilianne R. Mujica-Parodi, Benson Mwangi, Janina Neufeld, Joel T. Nigg, Ruth L. O’Gorman Tuura, Hyuntaek Oh, Jaap Oosterlaan, Yannis Paloyelis, Pedro M. Pan, Luca Passamonti, Wenceslao Peñate, K. Luan Phan, Kerstin J. Plessen, Jesus Pujol, Karl Lundin Remnélius, Francisco Rivero, Katya Rubia, Ramiro Salas, Giovanni A. Salum, Theodore D. Satterthwaite, Anne Schienle, Elisabeth Schrammen, Koen R.J. Schruers, Gunter Schumann, Arjun Sethi, Tim Silk, Norbert Skokauskas, Jordan W. Smoller, Jair C. Soares, Lin Sørensen, Christina Stadler, Michael C. Stevens, Benjamin Straube, Thomas Straube, Andreas Ströhle, Gustavo Sudre, Denis G. Sukhodolsky, Kate Sully, Xiaoqiang Sun, Chad M. Sylvester, Nicola Toschi, Steven J.A. van der Werff, Alasdair Vance, Robert Vermeiren, Albert Wabnegger, Xiaoping Wang, Julia Wendt, Sarah Whittle, Julian Wiemer, Anderson M. Winkler, Hans U. Wittchen, Mon-Ju Wu, Qiong Wu, Tony T. Yang, Yunbo Yang, Shuqiao Yao, Jibiao Zhang, Jiansong Zhou, Andre Zugman, Giovana B. Zunta-Soares, Peter M. Zwanzger, Sophia I. Thomopoulos, Neda Jahanshad, Paul M. Thompson, Kevin Hilbert, Arielle Baskin-Sommers, Charlotte A.M. Cecil, Moji Aghajani, Daniel S. Pine, Nic J.A. van der Wee, Dan J. Stein, Nynke A. Groenewold, Janna Marie Bas-Hoogendam, Laura K.M. Han, Elena Pozzi, Lianne Schmaal, Barbara Franke, Martine Hoogman, Esther Walton, Stephane A. De Brito, Graeme Fairchild

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

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
Early online date	12 Aug 2025
DOIs	https://doi.org/10.1016/j.biopsych.2025.08.003
Publication status	Published - 12 Aug 2025

Data Availability Statement

Data supporting the findings of this study are not publicly available due to privacy or ethical considerations, but can be requested from the corresponding authors or the ENIGMA working group in question (contact details can be found on the ENIGMA Consortium website: https://enigma.ini.usc.edu). Requested data can only be shared if approved by the working group in question and the principal investigators of the individual cohorts. Some of the included datasets (e.g., ABCD study, FemNAT-CD, IMAGEN, and cVEDA) have additional data sharing requirements.

Funding

The first author (ST) was supported by a PhD studentship from the Economic and Social Research Council. See acknowledgments section for all relevant funding sources. The funders had no role in the study design, data collection, management, analysis or interpretation, manuscript writing, reviewing, or decision to submit the paper.

Funders
Economic and Social Research Council

Access to Document

10.1016/j.biopsych.2025.08.003Licence: CC BY

BrainHealth - Decoding life course pathways of mental ageing - Frontier Research Guarantee
Walton, E. (PI) & Ward, A. (CoI)
EPSRC
1/10/23 → 30/09/28
Project: EU Commission

Cite this

Sophie Townend, Staginnus, M., Gao, Y., Alexander, N., Arolt, V., Banaschewski, T., Beesdo-Baum, K., Bellgrove, M. A., Benegal, V., Blair, R. J., Blanco-Hinojo, L., Boeken, O. J., Böhnlein, J., Bölte, S., Bonnekoh, L. M., Brandeis, D., Bressan, R. A., Breuer, F., Bruin, W. B., ... Fairchild, G. (2025). 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. Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2025.08.003

Sophie Townend, Staginnus, M, Gao, Y, Alexander, N, Arolt, V, Banaschewski, T, Beesdo-Baum, K, Bellgrove, MA, Benegal, V, Blair, RJ, Blanco-Hinojo, L, Boeken, OJ, Böhnlein, J, Bölte, S, Bonnekoh, LM, Brandeis, D, Bressan, RA, Breuer, F, Bruin, WB, Buitelaar, JK, Burkhouse, KL, Calkins, ME, Cano, M, Cardoner, N, Chen, H, Chen, X, Coghill, DR, Colins, OF, Connolly, CG, Craig, MC, Cullen, KR, Dannlowski, U, Davey, CG, Dietrich, A, Dong, D, Freitag, CM, Frodl, T, Goossens, L, Grotegerd, D, Gur, RE, Gur, RC, Haavik, J, Hagan, CC, Hahn, T, Hamm, AO, Harrison, BJ, Hartman, CA, Herrmann, MJ, Ho, TC, Hoekstra, PJ, Holla, B, Ibrahim, K, Jackowski, A, Jamalabadi, H, Jiang, Y, Kircher, T, Konrad, K, Kraus, A, Kuntsi, J, Langhammer, T, Lazaro, L, Leehr, EJ, Lueken, U, Ma, R, MacMaster, FP, Manfro, GG, Martinelli, A, Meinert, H, Meinert, S, Michałowski, JM, Ming, Q, Moeck, R, Muehlhan, M, Mujica-Parodi, LR, Mwangi, B, Neufeld, J, Nigg, JT, O’Gorman Tuura, RL, Oh, H, Oosterlaan, J, Paloyelis, Y, Pan, PM, Passamonti, L, Peñate, W, Phan, KL, Plessen, KJ, Pujol, J, Remnélius, KL, Rivero, F, Rubia, K, Salas, R, Salum, GA, Satterthwaite, TD, Schienle, A, Schrammen, E, Schruers, KRJ, Schumann, G, Sethi, A, Silk, T, Skokauskas, N, Smoller, JW, Soares, JC, Sørensen, L, Stadler, C, Stevens, MC, Straube, B, Straube, T, Ströhle, A, Sudre, G, Sukhodolsky, DG, Sully, K, Sun, X, Sylvester, CM, Toschi, N, van der Werff, SJA, Vance, A, Vermeiren, R, Wabnegger, A, Wang, X, Wendt, J, Whittle, S, Wiemer, J, Winkler, AM, Wittchen, HU, Wu, M-J, Wu, Q, Yang, TT, Yang, Y, Yao, S, Zhang, J, Zhou, J, Zugman, A, Zunta-Soares, GB, Zwanzger, PM, Thomopoulos, SI, Jahanshad, N, Thompson, PM, Hilbert, K, Baskin-Sommers, A, Cecil, CAM, Aghajani, M, Pine, DS, van der Wee, NJA, Stein, DJ, Groenewold, NA, Bas-Hoogendam, JM, Han, LKM, Pozzi, E, Schmaal, L, Franke, B, Hoogman, M, Walton, E, De Brito, SA & Fairchild, G 2025, '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', Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2025.08.003

@article{88181c180bcb4d6b8b12f25c466384e3,

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{\textquoteright}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 = "\{Sophie Townend\} and Marlene Staginnus and Yidian Gao and Nina Alexander and Volker Arolt and Tobias Banaschewski and Katja Beesdo-Baum 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 Markus Muehlhan and Mujica-Parodi, \{Lilianne R.\} and Benson Mwangi and Janina Neufeld and Nigg, \{Joel T.\} and \{O{\textquoteright}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 Smoller, \{Jordan W.\} 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",

year = "2025",

month = aug,

day = "12",

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

language = "English",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier",

}

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 - Sophie Townend, null

AU - Staginnus, Marlene

AU - Gao, Yidian

AU - Alexander, Nina

AU - Arolt, Volker

AU - Banaschewski, Tobias

AU - Beesdo-Baum, Katja

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 - Muehlhan, Markus

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 W.

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

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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BrainHealth - Decoding life course pathways of mental ageing - Frontier Research Guarantee

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