Cortical and subcortical brain structure in generalized anxiety disorder: Findings from 28 research sites in the ENIGMA-Anxiety Working Group

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

9 Citations (Scopus)


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.

Original languageEnglish
Article number502
JournalTranslational Psychiatry
Issue number1
Publication statusPublished - 1 Oct 2021
Externally publishedYes

Bibliographical note

Funding Information:
PMP has received speakers honoraria from Daiichi Sankyo, Libbs, Sandoz, Novartis, and Abbot. NJ is MPI of a research-related grant from Biogen Inc, for work unrelated to this manuscript. JCS is consultant for PFIZER, SUNOVIAN, SANOFI, JOHNSON & JOHNSON, Livanova, and Boehringer Ingelheim. FA is Section Editor of NeuroImage: Clinical; has received speaker honoraria from Philips, Novartis, and Biogen Idec; and receives or has received research supports from the Italian Ministry of Health, AriSLA (Fondazione Italiana di Ricerca per la SLA), and the European Research Council. EC has received research support from the Italian Ministry of Health. MF is Editor-in-Chief of the Journal of Neurology; received compensation for consulting services and/or speaking activities from Biogen Idec, Merck-Serono, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Novartis, Teva Pharmaceutical Industries, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). HJG has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier, and Janssen Cilag as well as research funding from Fresenius Medical Care. GAF owns equity in Alto Neuroscience. MPP is an advisor to Spring Care, Inc., a behavioral health startup, he has received royalties for an article about methamphetamine in UpToDate. MBS has in the past 3 years been a consultant for Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, Epivario, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, Roche/Genentech, and Oxeia Biopharmaceuticals; and has stock options in Oxeia Biopharmaceuticals and Epivario. PMT received partial grant support from Biogen, Inc., for research unrelated to this manuscript; consulted for Kairos Venture Capital, Inc., on projects unrelated to this manuscript. DJS has received research grants and/or consultancy honoraria from Lundbeck and Sun. Material support (for IOL site, led by MA and GJD) was provided by Neuronetics. The remaining authors declare no competing interests.

Funding Information:
Core funding for ENIGMA was provided by the NIH Big Data to Knowledge (BD2K) program under consortium grant U54 EB020403, the ENIGMA World Aging Center (R56 AG058854), and the ENIGMA Sex Differences Initiative (R01 MH116147). This research was also supported by the Intramural Research Program of the NIMH (ZIA-MH-002782 for DSP). Data collection at the individual sites and individual researchers were supported by: Dutch Research Council NWO Rubicon fellowship 019.201SG.022 (for JMBH); McNair Medical Foundation and VHA5I01CX000994 (for SG and RS); Brazilian government institutions CNPq, CAPES and FAPESP (for PMP); Brazilian government institutions CNPq, CAPES, FIPE-HCPA, FAPERGS and FAPESP (for GAS); NIH grant R01MH101497 (for KLP); German Research Foundation (DFG), grant number: BE 3809/8-1 (for KB); NIH grant R01MH117601 (for NJ); NIH grant R01MH101486-04 (for JWS and RB); Research grants from COMPASS, ALKERMES, ALLERGAN (for JCS); Hartford HealthCare Research Funding Initiative grant #129522 (for GJD); Italian Ministry of Health, RF-2016-02364582 (for PB); Italian Ministry of Health, GR-2018-12367789 (for EM); German Research Foundation (DFG) SFB/TRR 58: C06, C07 (for DH and TS); NIH grants K23 MH 086686 and R01 MH 108509 (for CA); NIMH grant K23MH100259 (for RBP); National Council for Scientific and Technological Development CNPq 475293/2012-6 and 304829/2013-7 (for GGM); NIH intramural research program ZIA-MH-002798 (for CG); NSF CBET0954643 and ONR N000140410051 (for LRM); Italian Ministry of Health Young Researcher Grant GR-2010-2312442 (for CO); NIMH grant K23MH114023 (for GAF); NIMH grants MH65413 and MH64122 (for MBS); NIMH grant K99MH117274 (for ANK); NIH grant T32 MH014654 (for BL); Developmental Neuroscience and Child Psychopathology T32 MH100019 (for MTP); NIMH grant K23MH109983 (for CMS); German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) Projektnummer 44541416 – TRR 58 (for UL); SA MRC (for DJS). SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. MRI scans in SHIP have been supported by a joint grant from Siemens Healthineers, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. Part of the data has been collected at the Neuroimaging Center, Faculty of Psychology, Technische Universität Dresden (for Dresden). Data used in the preparation of this article were obtained from the Adolescent Brain Cognitive Development (ABCD) Study (, held in the NIMH Data Archive (NDA). This is a multisite, longitudinal study designed to recruit more than 10,000 children age 9–10 and follow them over 10 years into early adulthood. The ABCD Study is supported by the National Institutes of Health and additional federal partners under award numbers U01DA041022, U01DA041025, U01DA041028, U01DA041048, U01DA041089, U01DA041093, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, and U24DA041147. A full list of supporters is available at A listing of participating sites and a complete listing of the study investigators can be found at principal-investigators.html. ABCD consortium investigators designed and implemented the study and/or provided data but did not necessarily participate in the analysis or writing of this report. This manuscript reflects the views of the authors and may not reflect the opinions or views of the NIH or ABCD consortium investigators.

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© 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.


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