Human Genetics Publications
Document Type
Article
Publication Date
8-12-2025
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 (Enhancing NeuroImaging 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 ds = -0.07 to -0.24) as well as total SA and intracranial volume (ds = -0.11 to -0.25). Externalizing-specific reductions in SA were observed in frontoparietal 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 novel findings can guide future research targeting common biological processes across youth psychiatric disorders as well as features unique to individual disorders.
Recommended Citation
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., Buitelaar, J. K., … ENIGMA Antisocial Behavior, Anxiety, ADHD, and MDD Working Groups (2025). Shared and Distinct Alterations in Brain Structure of Youth With Internalizing or Externalizing Disorders: Findings From the ENIGMA Antisocial Behavior, ADHD, Major Depressive Disorder, and Anxiety Working Groups. Biological psychiatry, S0006-3223(25)01405-2. Advance online publication. https://doi.org/10.1016/j.biopsych.2025.08.003
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Publication Title
Biological Psychiatry
DOI
10.1016/j.biopsych.2025.08.003
Comments
Copyright © 2025 Society of Biological Psychiatry. All rights reserved.