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, Major Depressive Disorder, and Anxiety Working Groups
AU - ENIGMA Antisocial Behavior, Anxiety, ADHD, and MDD Working Groups
AU - Sophie Townend, Townend
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 - Mujica-Parodi, Lilianne R.
N1 - Publisher Copyright:
© 2025 Society of Biological Psychiatry.
PY - 2026/8/15
Y1 - 2026/8/15
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 (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium, we conducted a mega-analysis to identify shared and distinct cortical and subcortical brain alterations across internalizing (anxiety disorders and depression) and externalizing (attention-deficit/hyperactivity disorder [ADHD] and conduct disorder [CD]) disorders in youth. Methods 3D T1-weighted magnetic resonance imaging data from youths (age range 4–21 years) with anxiety disorders ( n = 1044), depression ( n = 504), ADHD ( n = 1317), and CD ( n = 1172) along with healthy control participants ( n = 4743) were analyzed. We assessed group differences in regional cortical thickness, surface area (SA), and subcortical volume using linear models, adjusted for site, age, and sex, as well as total intracranial volume in the SA and subcortical volume models. Results We observed transdiagnostic associations, with both internalizing and externalizing disorders characterized by lower SA in the insula, entorhinal cortex, and middle temporal gyrus and lower amygdala volume (Cohen’s d s = −0.07 to −0.24) as well as total SA and intracranial volume ( d s = −0.11 to −0.25). Externalizing-specific reductions in SA were observed in frontoparietal regions ( d s = −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 novel 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 (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium, we conducted a mega-analysis to identify shared and distinct cortical and subcortical brain alterations across internalizing (anxiety disorders and depression) and externalizing (attention-deficit/hyperactivity disorder [ADHD] and conduct disorder [CD]) disorders in youth. Methods 3D T1-weighted magnetic resonance imaging data from youths (age range 4–21 years) with anxiety disorders ( n = 1044), depression ( n = 504), ADHD ( n = 1317), and CD ( n = 1172) along with healthy control participants ( n = 4743) were analyzed. We assessed group differences in regional cortical thickness, surface area (SA), and subcortical volume using linear models, adjusted for site, age, and sex, as well as total intracranial volume in the SA and subcortical volume models. Results We observed transdiagnostic associations, with both internalizing and externalizing disorders characterized by lower SA in the insula, entorhinal cortex, and middle temporal gyrus and lower amygdala volume (Cohen’s d s = −0.07 to −0.24) as well as total SA and intracranial volume ( d s = −0.11 to −0.25). Externalizing-specific reductions in SA were observed in frontoparietal regions ( d s = −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 novel findings can guide future research targeting common biological processes across youth psychiatric disorders as well as features unique to individual disorders.
KW - Child and adolescent psychiatry
KW - ENIGMA
KW - Meta-analysis
KW - Structural MRI
KW - Transdiagnostic
KW - Youth
UR - https://www.scopus.com/pages/publications/105044960736
U2 - 10.1016/j.biopsych.2025.08.003
DO - 10.1016/j.biopsych.2025.08.003
M3 - Article
C2 - 40812743
AN - SCOPUS:105044960736
SN - 0006-3223
VL - 100
SP - 399
EP - 413
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 4
ER -