Cortical and subcortical brain structure in generalized anxiety disorder: findings from 28 research sites in the ENIGMA-Anxiety Working Group
Authors: Harrewijn Anita , Cardinale Elise M. , Groenewold Nynke A. , Bas-Hoogendam Janna Marie , Aghajani Moji , Hilbert Kevin , Cardoner Narcis , Porta-Casteràs Daniel , Gosnell Savannah , Salas Ramiro , Jackowski Andrea P. , Pan Pedro M. , Salum Giovanni A. , Blair Karina S. , Blair James R. , Hammoud Mira Z. , Milad Mohammed R. , Burkhouse Katie L. , Phan K. Luan , Schroeder Heidi K. , Strawn Jeffrey R. , Beesdo-Baum Katja , Jahanshad Neda , Thomopoulos Sophia I. , Buckner Randy , Nielsen Jared A. , Smoller Jordan W. , Soares Jair C. , Mwangi Benson , Wu Mon-Ju , Zunta-Soares Giovana B. , Assaf Michal , Diefenbach Gretchen J. , Brambilla Paolo , Maggioni Eleonora , Hofmann David , Straube Thomas , Andreescu Carmen , Berta Rachel , Tamburo Erica , Price Rebecca B. , Manfro Gisele G. , Agosta Federica , Canu Elisa , Cividini Camilla , Filippi Massimo , Kostić Milutin , Munjiza Jovanovic Ana , Alberton Bianca A. V. , Benson Brenda , Freitag Gabrielle F. , Filippi Courtney A. , Gold Andrea L. , Leibenluft Ellen , Ringlein Grace V. , Werwath Kathryn E. , Zwiebel Hannah , Zugman André , Grabe Hans J. , Van der Auwera Sandra , Wittfeld Katharina , Völzke Henry , Bülow Robin , Balderston Nicholas L. , Ernst Monique , Grillon Christian , Mujica-Parodi Lilianne R. , van Nieuwenhuizen Helena , Critchley Hugo D. , Makovac Elena , Mancini Matteo , Meeten Frances , Ottaviani Cristina , Ball Tali M. , Fonzo Gregory A. , Paulus Martin P. , Stein Murray B. , Gur Raquel E. , Gur Ruben C. , Kaczkurkin Antonia N. , Larsen Bart , Satterthwaite Theodore D. , Harper Jennifer , Myers Michael , Perino Michael T. , Sylvester Chad M. , Yu Qiongru , Lueken Ulrike , Veltman Dick J. , Thompson Paul M. , Stein Dan J. , Van der Wee Nic J. A. , Winkler Anderson M. , Pine Daniel S. 
Published: October 2021

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5–90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.