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.

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.