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. Schroeder; Jeffrey 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

doi:10.1038/s41398-021-01622-1

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 journal › Article › peer-review

38 Scopus citations

Abstract

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 language	English
Article number	502
Journal	Translational Psychiatry
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41398-021-01622-1
State	Published - Dec 2021
Externally published	Yes

Funding

Funders	Funder number
Robert and Janice McNair Foundation
Fresenius Medical Care North America
Federal State of Mecklenburg-West Pomerania
Kairos Venture Capital, Inc.
FIPE-HCPA
Social Ministry of the Federal State of Mecklenburg-West Pomerania
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Fundação de Amparo à Pesquisa do Estado de São Paulo
Ministry of Cultural Affairs
Agenzia di Ricerca per la Sclerosi Laterale Amiotrofica
Allergan Foundation
European Research Council
Biogen, Inc.
SA MRC
National Institute of Mental Health	R01MH065413, K23MH086686, K23MH100259, K99MH117274, R01MH108509, T32MH014654, T32MH100019, R01MH116147, R01MH117600, R01MH117601, ZIA-MH-002782, K23MH109983, K23MH114023, R01MH101486, R01MH101497, K24MH064122
National Science Foundation	CBET0954643
U.S. Department of Veterans Affairs	VHA5I01CX000994, I01CX000994
Hartford HealthCare Research Funding Initiative	129522
ENIGMA World Aging Center	R56 AG058854
Deutsche Forschungsgemeinschaft	BE 3809/8-1, 44541416 – TRR 58, R01MH101486-04, R01MH117601, C0, SFB/TRR 58: C06
ENIGMA Sex Differences Initiative	R01 MH116147
Developmental Neuroscience and Child Psychopathology	K23MH109983, T32 MH100019
National Institute on Drug Abuse	U01DA041117, U01DA041106, U01DA041028, U01DA041148, U24DA041147, U01DA041048, U01DA041025, U24DA041123, U01DA041156, U01DA041134, U01DA041089, U01DA041022, U01DA041120, U01DA041174, U01DA041093
Ministero della Salute	K23MH100259, GR-2018-12367789, R01 MH 108509, C06, K23 MH 086686, RF-2016-02364582
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	019.201SG.022
Office of Naval Research	GR-2010-2312442, K99MH117274, T32 MH014654, K23MH114023, N000140410051
National Institutes of Health	R01MH11760
National Institute of Biomedical Imaging and Bioengineering	U54EB020403
Bundesministerium für Bildung und Forschung	01ZZ0403, and 01ZZ0403, 01ZZ0103, 01ZZ9603
Conselho Nacional de Desenvolvimento Científico e Tecnológico	304829/2013-7, ZIA-MH-002798, 475293/2012-6
Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul	R01MH101497
National Institute on Aging	R56AG058854

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10.1038/s41398-021-01622-1

Cite this

Harrewijn, A., Cardinale, E. M., Groenewold, N. A., Bas-Hoogendam, J. M., Aghajani, M., Hilbert, K., Cardoner, N., Porta-Casteràs, D., Gosnell, S., Salas, R., Jackowski, A. P., Pan, P. M., Salum, G. A., Blair, K. S., Blair, J. R., Hammoud, M. Z., Milad, M. R., Burkhouse, K. L., Phan, K. L., ... Pine, D. S. (2021). Cortical and subcortical brain structure in generalized anxiety disorder: findings from 28 research sites in the ENIGMA-Anxiety Working Group. Translational Psychiatry, 11(1), Article 502. https://doi.org/10.1038/s41398-021-01622-1

@article{b8d7e3856fac45cda8e3e3c665e0e451,

title = "Cortical and subcortical brain structure in generalized anxiety disorder: findings from 28 research sites in the ENIGMA-Anxiety Working Group",

abstract = "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.",

author = "Anita Harrewijn and Cardinale, {Elise M.} and Groenewold, {Nynke A.} and Bas-Hoogendam, {Janna Marie} and Moji Aghajani and Kevin Hilbert and Narcis Cardoner and Daniel Porta-Caster{\`a}s and Savannah Gosnell and Ramiro Salas and Jackowski, {Andrea P.} and Pan, {Pedro M.} and Salum, {Giovanni A.} and Blair, {Karina S.} and Blair, {James R.} and Hammoud, {Mira Z.} and Milad, {Mohammed R.} and Burkhouse, {Katie L.} and Phan, {K. Luan} and Schroeder, {Heidi K.} and Strawn, {Jeffrey R.} and Katja Beesdo-Baum and Neda Jahanshad and Thomopoulos, {Sophia I.} and Randy Buckner and Nielsen, {Jared A.} and Smoller, {Jordan W.} and Soares, {Jair C.} and Benson Mwangi and Wu, {Mon Ju} and Zunta-Soares, {Giovana B.} and Michal Assaf and Diefenbach, {Gretchen J.} and Paolo Brambilla and Eleonora Maggioni and David Hofmann and Thomas Straube and Carmen Andreescu and Rachel Berta and Erica Tamburo and Price, {Rebecca B.} and Manfro, {Gisele G.} and Federica Agosta and Elisa Canu and Camilla Cividini and Massimo Filippi and Milutin Kosti{\'c} and {Munjiza Jovanovic}, Ana and Alberton, {Bianca A.V.} and Brenda Benson and Freitag, {Gabrielle F.} and Filippi, {Courtney A.} and Gold, {Andrea L.} and Ellen Leibenluft and Ringlein, {Grace V.} and Werwath, {Kathryn E.} and Hannah Zwiebel and Andr{\'e} Zugman and Grabe, {Hans J.} and {Van der Auwera}, Sandra and Katharina Wittfeld and Henry V{\"o}lzke and Robin B{\"u}low and Balderston, {Nicholas L.} and Monique Ernst and Christian Grillon and Mujica-Parodi, {Lilianne R.} and {van Nieuwenhuizen}, Helena and Critchley, {Hugo D.} and Elena Makovac and Matteo Mancini and Frances Meeten and Cristina Ottaviani and Ball, {Tali M.} and Fonzo, {Gregory A.} and Paulus, {Martin P.} and Stein, {Murray B.} and Gur, {Raquel E.} and Gur, {Ruben C.} and Kaczkurkin, {Antonia N.} and Bart Larsen and Satterthwaite, {Theodore D.} and Jennifer Harper and Michael Myers and Perino, {Michael T.} and Sylvester, {Chad M.} and Qiongru Yu and Ulrike Lueken and Veltman, {Dick J.} and Thompson, {Paul M.} and Stein, {Dan J.} and {Van der Wee}, {Nic J.A.} and Winkler, {Anderson M.} and Pine, {Daniel S.}",

note = "Publisher Copyright: {\textcopyright} 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",

year = "2021",

month = dec,

doi = "10.1038/s41398-021-01622-1",

language = "אנגלית",

volume = "11",

journal = "Translational Psychiatry",

issn = "2158-3188",

publisher = "Nature Publishing Group",

number = "1",

}

Harrewijn, A, Cardinale, EM, Groenewold, NA, Bas-Hoogendam, JM, Aghajani, M, Hilbert, K, Cardoner, N, Porta-Casteràs, D, Gosnell, S, Salas, R, Jackowski, AP, Pan, PM, Salum, GA, Blair, KS, Blair, JR, Hammoud, MZ, Milad, MR, Burkhouse, KL, Phan, KL, Schroeder, HK, Strawn, JR, Beesdo-Baum, K, Jahanshad, N, Thomopoulos, SI, Buckner, R, Nielsen, JA, Smoller, JW, Soares, JC, Mwangi, B, Wu, MJ, Zunta-Soares, GB, Assaf, M, Diefenbach, GJ, Brambilla, P, Maggioni, E, Hofmann, D, Straube, T, Andreescu, C, Berta, R, Tamburo, E, Price, RB, Manfro, GG, Agosta, F, Canu, E, Cividini, C, Filippi, M, Kostić, M, Munjiza Jovanovic, A, Alberton, BAV, Benson, B, Freitag, GF, Filippi, CA, Gold, AL, Leibenluft, E, Ringlein, GV, Werwath, KE, Zwiebel, H, Zugman, A, Grabe, HJ, Van der Auwera, S, Wittfeld, K, Völzke, H, Bülow, R, Balderston, NL, Ernst, M, Grillon, C, Mujica-Parodi, LR, van Nieuwenhuizen, H, Critchley, HD, Makovac, E, Mancini, M, Meeten, F, Ottaviani, C, Ball, TM, Fonzo, GA, Paulus, MP, Stein, MB, Gur, RE, Gur, RC, Kaczkurkin, AN, Larsen, B, Satterthwaite, TD, Harper, J, Myers, M, Perino, MT, Sylvester, CM, Yu, Q, Lueken, U, Veltman, DJ, Thompson, PM, Stein, DJ, Van der Wee, NJA, Winkler, AM & Pine, DS 2021, 'Cortical and subcortical brain structure in generalized anxiety disorder: findings from 28 research sites in the ENIGMA-Anxiety Working Group', Translational Psychiatry, vol. 11, no. 1, 502. https://doi.org/10.1038/s41398-021-01622-1

TY - JOUR

T1 - Cortical and subcortical brain structure in generalized anxiety disorder

T2 - findings from 28 research sites in the ENIGMA-Anxiety Working Group

AU - Harrewijn, Anita

AU - Cardinale, Elise M.

AU - Groenewold, Nynke A.

AU - Bas-Hoogendam, Janna Marie

AU - Aghajani, Moji

AU - Hilbert, Kevin

AU - Cardoner, Narcis

AU - Porta-Casteràs, Daniel

AU - Gosnell, Savannah

AU - Salas, Ramiro

AU - Jackowski, Andrea P.

AU - Pan, Pedro M.

AU - Salum, Giovanni A.

AU - Blair, Karina S.

AU - Blair, James R.

AU - Hammoud, Mira Z.

AU - Milad, Mohammed R.

AU - Burkhouse, Katie L.

AU - Phan, K. Luan

AU - Schroeder, Heidi K.

AU - Strawn, Jeffrey R.

AU - Beesdo-Baum, Katja

AU - Jahanshad, Neda

AU - Thomopoulos, Sophia I.

AU - Buckner, Randy

AU - Nielsen, Jared A.

AU - Smoller, Jordan W.

AU - Soares, Jair C.

AU - Mwangi, Benson

AU - Wu, Mon Ju

AU - Zunta-Soares, Giovana B.

AU - Assaf, Michal

AU - Diefenbach, Gretchen J.

AU - Brambilla, Paolo

AU - Maggioni, Eleonora

AU - Hofmann, David

AU - Straube, Thomas

AU - Andreescu, Carmen

AU - Berta, Rachel

AU - Tamburo, Erica

AU - Price, Rebecca B.

AU - Manfro, Gisele G.

AU - Agosta, Federica

AU - Canu, Elisa

AU - Cividini, Camilla

AU - Filippi, Massimo

AU - Kostić, Milutin

AU - Munjiza Jovanovic, Ana

AU - Alberton, Bianca A.V.

AU - Benson, Brenda

AU - Freitag, Gabrielle F.

AU - Filippi, Courtney A.

AU - Gold, Andrea L.

AU - Leibenluft, Ellen

AU - Ringlein, Grace V.

AU - Werwath, Kathryn E.

AU - Zwiebel, Hannah

AU - Zugman, André

AU - Grabe, Hans J.

AU - Van der Auwera, Sandra

AU - Wittfeld, Katharina

AU - Völzke, Henry

AU - Bülow, Robin

AU - Balderston, Nicholas L.

AU - Ernst, Monique

AU - Grillon, Christian

AU - Mujica-Parodi, Lilianne R.

AU - van Nieuwenhuizen, Helena

AU - Critchley, Hugo D.

AU - Makovac, Elena

AU - Mancini, Matteo

AU - Meeten, Frances

AU - Ottaviani, Cristina

AU - Ball, Tali M.

AU - Fonzo, Gregory A.

AU - Paulus, Martin P.

AU - Stein, Murray B.

AU - Gur, Raquel E.

AU - Gur, Ruben C.

AU - Kaczkurkin, Antonia N.

AU - Larsen, Bart

AU - Satterthwaite, Theodore D.

AU - Harper, Jennifer

AU - Myers, Michael

AU - Perino, Michael T.

AU - Sylvester, Chad M.

AU - Yu, Qiongru

AU - Lueken, Ulrike

AU - Veltman, Dick J.

AU - Thompson, Paul M.

AU - Stein, Dan J.

AU - Van der Wee, Nic J.A.

AU - Winkler, Anderson M.

AU - Pine, Daniel S.

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

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ER -

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

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