White Matter Microstructure Alterations in Social Anxiety Disorder: A Mega-Analysis Across Twelve Cohorts in the ENIGMA-Anxiety Working Group

Authors

• Eline F Roelofs
• Nynke A Groenewold
• Kinga Farkas
• Alyssa H Zhu
• Si Gao
• Tiana Borgers
• Udo Dannlowski
• Kira Flinkenflügel
• Dominik Grotegerd
• Tim Hahn
• Andreas Jansen
• Elisabeth J Leehr
• Tilo T J Kircher
• Hannah Meinert
• Igor Nenadić
• Frederike Stein
• Benjamin Straube
• Tamer Demiralp
• Raşit Tükel
• P Michiel Westenberg
• Jochen Bauer
• Anna Kraus
• Alexander G G Doruyter
• Christine Lochner
• David Hofmann
• Thomas Straube
• André Zugman
• Monica E Calkins
• Raquel E Gur
• Ruben C Gur
• Bart S Larsen
• Theodore D Satterthwaite
• Theresa M Slump
• Roman A Vogler
• Suzanne N Avery
• Jennifer U Blackford
• Jacqueline A Clauss
• Su Lui
• Sophia I Thomopoulos
• Robert R J M Vermeiren
• Neda Jahanshad
• Peter V Kochunov
• Paul M Thompson
• Daniel S Pine
• Dan J Stein
• Nic J A van der Wee
• Janna Marie Bas-Hoogendam

Language

English

Publication Date

4-1-2026

Journal

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

DOI

10.1016/j.bpsc.2025.11.007

PMID

41338325

Abstract

Background: Studies investigating social anxiety disorder (SAD) have reported inconsistent alterations in white matter (WM) microstructure. The ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis)-Anxiety Working Group investigated differences in the microstructure of 25 WM tracts between individuals with SAD and healthy control (HC) participants in a mega-analysis.

Methods: We analyzed data from 487 individuals with SAD and 1604 HC participants (ages 8-65 years) from 12 cohorts worldwide. Analyses and quality control were performed using standardized ENIGMA diffusion tensor imaging protocols. We primarily examined fractional anisotropy (FA) as the main parameter of WM microstructure. Linear mixed-effects analyses were conducted to compare individuals with SAD with HC participants in the total sample. Next, adult (age >21) and adolescent (age ≤21) samples were analyzed separately. In sensitivity analyses, additional effects of sex, medication, symptom severity, and comorbid psychiatric disorders were investigated.

Results: In the total sample, individuals with SAD showed lower FA in several tracts, including the corpus callosum and fornix, compared with HC participants. Widespread sex × diagnosis interactions were observed, mostly driven by lower FA in females with SAD. Adults with SAD showed lower FA in multiple tracts, while age × diagnosis interactions were observed in adolescents.

Conclusions: Using a mega-analytic approach, several differences in WM microstructure were found between individuals with SAD and HC participants, both in the full sample and in age group-specific sensitivity analyses. Some neurobiological changes in WM tracts in individuals with SAD may vary with age and sex, whereas others may relate to broader transdiagnostic neurobiological features underlying psychopathology. Further research should investigate these issues in more detail.

Keywords

Humans, White Matter, Male, Female, Adult, Adolescent, Phobia, Social, Child, Middle Aged, Young Adult, Diffusion Tensor Imaging, Aged, Cohort Studies, Anisotropy, Brain, Diffusion tensor imaging, ENIGMA, Mega-analysis, Neuroimaging, Social anxiety disorder, White matter microstructure

Published Open-Access

yes

Recommended Citation

Roelofs, Eline F; Groenewold, Nynke A; Farkas, Kinga; et al., "White Matter Microstructure Alterations in Social Anxiety Disorder: A Mega-Analysis Across Twelve Cohorts in the ENIGMA-Anxiety Working Group" (2026). Faculty, Staff and Student Publications. 4403.
https://digitalcommons.library.tmc.edu/uthmed_docs/4403