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Volume of subcortical brain regions in social anxiety disorder: mega-analytic results from 37 samples in the ENIGMA-Anxiety Working Group

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Abstract

There is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in methodological approaches across studies, including sample selection based on age and clinical characteristics. The ENIGMA-Anxiety Working Group initiated a global mega-analysis to determine whether differences in subcortical volumes can be detected in adults and adolescents with SAD relative to healthy controls. Volumetric data from 37 international samples with 1115 SAD patients and 2775 controls were obtained from ENIGMA-standardized protocols for image segmentation and quality assurance. Linear mixed-effects analyses were adjusted for comparisons across seven subcortical regions in each hemisphere using family-wise error (FWE)-correction. Mixed-effects d effect sizes were calculated. In the full sample, SAD patients showed smaller bilateral putamen volume than controls (left: d = −0.077, pFWE = 0.037; right: d = −0.104, pFWE = 0.001), and a significant interaction between SAD and age was found for the left putamen (r = −0.034, pFWE = 0.045). Smaller bilateral putamen volumes (left: d = −0.141, pFWE < 0.001; right: d = −0.158, pFWE < 0.001) and larger bilateral pallidum volumes (left: d = 0.129, pFWE = 0.006; right: d = 0.099, pFWE = 0.046) were detected in adult SAD patients relative to controls, but no volumetric differences were apparent in adolescent SAD patients relative to controls. Comorbid anxiety disorders and age of SAD onset were additional determinants of SAD-related volumetric differences in subcortical regions. To conclude, subtle volumetric alterations in subcortical regions in SAD were detected. Heterogeneity in age and clinical characteristics may partly explain inconsistencies in previous findings. The association between alterations in subcortical volumes and SAD illness progression deserves further investigation, especially from adolescence into adulthood.

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Fig. 1: Schematic overview of the seven subcortical brain regions segmented for each hemisphere.
Fig. 2: Mixed-effects d effect size and Standard Error (SE) for differences in subcortical brain volume between social anxiety disorder (SAD) and healthy control (HC) participants, obtained in mega-analyses that were adjusted for sex, age, age2, sex-by-age, sex-by-age2 and total ICV.

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Data availability

The ENIGMA-Anxiety Working Group is open to sharing the data and code from this investigation to researchers for secondary data analysis. To request access to volumetric, clinical, and demographic data, an analysis plan can be submitted to the ENIGMA-Anxiety Working Group (http://enigma.ini.usc.edu/ongoing/enigma-anxiety/). Data access is contingent on approval by PIs from contributing samples.

Code availability

Code can be requested from the corresponding author.

Notes

  1. While regions of the frontal cortex also feature in neurobiological models of SAD, the focus of the present investigation is exclusively on subcortical brain regions.

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Acknowledgements

ENIGMA acknowledges the NIH Big Data to Knowledge (BD2K) award for foundational support and consortium development (U54 EB020403 to PMT). For a complete list of ENIGMA-related grant support please see here: http://enigma.ini.usc.edu/about-2/funding/. NAG was supported by a Developing Emerging Academic Leaders Fellowship. This work was made possible in part by a grant from Carnegie Corporation of New York. JMBH was supported by a Rubicon grant from the Dutch Research Council NWO (019.201SG.022). ARA, CL, and DJS were supported by the South African Medical Research Council (SA-MRC). DJS and NJAW were supported by the EU7th Frame Work Marie Curie Actions International Staff Exchange Scheme grant “European and South African Research Network in Anxiety Disorders” (EUSARNAD). NJAW was also supported by the Anxiety Disorders Research Network European College of Neuropsychopharmacology. The Leiden Family Lab study on Social Anxiety Disorder (LFLSAD) was funded by Leiden University Research Profile ‘Health, Prevention and the Human Life Cycle’. The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (ZonMw, grant number 10-000-1002) and financial contributions by participating universities and mental health care organizations (VU University Medical Center, GGZ inGeest, Leiden University Medical Center, Leiden University, GGZ Rivierduinen, University Medical Center Groningen, University of Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Rob Giel Onderzoekscentrum). SHIP is part of the Community Medicine Research Network of the University Medicine Greifswald, which is supported by the German Ministry of Education and Research (BMBF) and a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. This work was supported by multiple grants from the German Research Foundation (DFG): FOR5187 grant (HI 2189/4-1) - KH; grant BE 3809/8-1 - KBB, grants (JA 1890/7-1, JA 1890/7-2) - AJ; grants FOR2107 (KI588/14-1, KI588/14-2) - TK; grants (KR 3822/7-1, KR 3822/7-2) -AK; grants (NE2254/1-2, NE2254/3-1, NE2254/4-1) - IN; grants (DA1151/5-1, DA1151/5-2) - UD; FOR5187 grant (KR 4398/5-1) - BK; (SFB/TRR 58: C06, C07) - TS; grants (LU 1509/9-1, LU 1509/10-1, LU 1509/11-1) - UL. UD was additionally supported by the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD). This work was further supported by the NIH through multiple grants. MPP, MBS, TMB and AS were supported by NIMH MH65413. GAF was supported by NIMH K23MH114023 and JUB was supported by NIMH K01MH083052. JAC was supported by NIMH 5T32MH112485. BF was supported by NIMH T32MH018921. CMS was supported by NIMH K23MH109983 and R01MH122389. NJ was supported by R01MH117601. DSP was supported by ZIA-MH-002781. In addition, GAF received support from the One Mind – Basczucki Brain Research Fund. JAC was additionally supported by the Louis V. Gerstner III Research Scholar Award. HO was supported by the American Foundation for Suicide Prevention (YIG-1-141-20). RS was supported by the McNair Foundation (MIND-MB), VHA (CX000994, CX001937). PMP was supported by the foundation for Research Support of the State of São Paulo (FAPESP 2014 / 50917-0), Brazil and the National Council for Scientific and Technological Development CNPq 465550/2014-2), Brazil. AT was supported by NARSAD/Brain and Behavioral Research Foundation. KR was supported by the European Research Council (grant# ERC_CoG-2017_772337). QG was supported by the National Natural Science Foundation of China (Project Nos. 82120108014 and 81621003). SL acknowledges the support from Humboldt Foundation Friedrich Wilhelm Bessel Research Award. AH (Louvain) was supported by the F.R.S.-FNRS Belgian Science Foundation (Grant ”1.C.059.18 F”) and by the Belgian Fund for Scientific Research (F.R.S.-FNRS, Belgium) as Research Associate. AGGD was funded by the SA-MRC under the MRC Clinician Researcher Programme; the National Technologies in Medicine and the Biosciences Initiative (NTeMBI), managed by the South African Nuclear Energy Corporation (Necsa) and funded by the Department of Science and Innovation; and Harry Crossley Foundation. TF was supported by the Swedish Research Council, the Swedish Brain Foundation, and Riksbankens Jubileumsfond. KNTM was supported by the Swedish Research Council (2018-06729).

Author information

Authors and Affiliations

  1. Neuroscience Institute, Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa

    Nynke A. Groenewold, Alyssa R. Amod & Dan J. Stein

  2. South African Medical Research Council (SA-MRC) Unit on Child and Adolescent Health, Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital, University of Cape Town, Cape Town, South Africa

    Nynke A. Groenewold

  3. Department of Psychiatry, Leiden University Medical Center, Leiden, Netherlands

    Janna Marie Bas-Hoogendam & Nic J. A. Van der Wee

  4. Department of Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, Netherlands

    Janna Marie Bas-Hoogendam & P. Michiel Westenberg

  5. Leiden Institute for Brain and Cognition, Leiden, Netherlands

    Janna Marie Bas-Hoogendam, P. Michiel Westenberg & Nic J. A. Van der Wee

  6. Department of Anatomy & Neurosciences, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands

    Max A. Laansma

  7. Orygen & Centre for Youth Mental Health, The University of Melbourne, Melbourne, VIC, Australia

    Laura S. Van Velzen

  8. Leiden University, Institute of Education & Child Studies, Section Forensic Family & Youth Care, Leiden, Netherlands

    Moji Aghajani

  9. Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany

    Kevin Hilbert & Ulrike Lueken

  10. Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA

    Hyuntaek Oh & Ramiro Salas

  11. Michael E DeBakey VA Medical Center, Center for Translational Research on Inflammatory Diseases, Houston, TX, USA

    Ramiro Salas

  12. LiNC, Department of Psychiatry, Federal University of São Paulo, São Paulo, SP, Brazil

    Andrea P. Jackowski & Pedro M. Pan

  13. Section on Negative Affect and Social Processes, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Giovanni A. Salum

  14. Child and Adolescent Mental Health Centre, Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark

    James R. Blair

  15. Center for Neurobehavioral Research, Boys Town National Research Hospital, Boys Town, NE, USA

    Karina S. Blair

  16. Departments of Psychiatry & Neurobiology, Yale School of Medicine, New Haven, CT, USA

    Joy Hirsch

  17. Department of Psychiatry, Columbia University Medical Center, New York, NY, USA

    Spiro P. Pantazatos, Franklin R. Schneier & Ardesheer Talati

  18. New York State Psychiatric Institute, New York, NY, USA

    Spiro P. Pantazatos, Franklin R. Schneier & Ardesheer Talati

  19. Donders Institute for Brain, Cognition and Behavior, Radboud University Behavioral Science Institute, Radboud University, Nijmegen, Netherlands

    Karin Roelofs

  20. Wellcome Centre for Integrative Neuroimaging Neuroimaging (WIN), Centre for Functional MRI of the Brain (FMRIB), Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK

    Inge Volman

  21. MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain

    Laura Blanco-Hinojo & Jesus Pujol

  22. Centro Investigación Biomédica en Red de Salud Mental, CIBERSAM G21, Barcelona, Spain

    Laura Blanco-Hinojo & Jesus Pujol

  23. Department of Mental Health, University Hospital Parc Taulí-I3PT, Barcelona, Spain, Barcelona, Spain

    Narcís Cardoner

  24. Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain

    Narcís Cardoner

  25. Centro de Investigación Biomédica en Red de Salud Mental, Carlos III Health Institute, Madrid, Spain

    Narcís Cardoner

  26. Behavioral Epidemiology, Institute of Clinical Psycholog and Psychotherapy, Technische Universität Dresden, Dresden, Germany

    Katja Beesdo-Baum

  27. Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA

    Christopher R. K. Ching, Sophia I. Thomopoulos, Neda Jahanshad & Paul M. Thompson

  28. Core-Facility Brainimaging, Faculty of Medicine, University of Marburg, Marburg, Germany

    Andreas Jansen

  29. Department of Psychiatry, University of Marburg, Marburg, Germany

    Tilo Kircher, Axel Krug, Igor Nenadić & Frederike Stein

  30. Department of Psychiatry, University Hospital of Bonn, Bonn, Germany

    Axel Krug

  31. Institute for Translational Psychiatry, University of Münster, Münster, Germany

    Udo Dannlowski, Dominik Grotegerd, Hannah Lemke, Susanne Meinert, Alexandra Winter, Joscha Böhnlein, Katharina Dohm, Elisabeth Schrammen & Elisabeth J. Leehr

  32. Institute for Translational Neuroscience, University of Münster, Münster, Germany

    Susanne Meinert

  33. Department of Biomedical Magnetic Resonance, University of Tübingen, Tübingen, Germany

    Michael Erb

  34. Department of Psychiatry and Psychotherapy, Tübingen Center for Mental Health (TüCMH), University of Tübingen, Tübingen, Germany

    Benjamin Kreifelts

  35. Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, Department of Radiology, West China Hospital of Sichuan University, Chengdu, China

    Qiyong Gong, Su Lui & Fei Zhu

  36. Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, China

    Qiyong Gong, Su Lui & Fei Zhu

  37. Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Benson Mwangi, Jair C. Soares & Mon-Ju Wu

  38. Department of Neuroscience, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey

    Ali Bayram

  39. Department of Physiology, Istanbul University, Istanbul, Turkey

    Mesut Canli

  40. Department of Psychiatry, Istanbul University, Istanbul, Turkey

    Raşit Tükel

  41. Psychological Science Research Institute, Université Catholique de Louvain, Louvain-la-Neuve, Belgium

    Alexandre Heeren

  42. Department of Clinical Psychology, University of Amsterdam, Amsterdam, Netherlands

    Henk R. Cremers

  43. Institute of Medical Psychology and Systems Neuroscience, University of Münster, Münster, Germany

    David Hofmann & Thomas Straube

  44. Division of Nuclear Medicine, Stellenbosch University, Stellenbosch, South Africa

    Alexander G. G. Doruyter

  45. SA-MRC Unit on Risk and Resilience in Mental Disorders, Stellenbosch University, Stellenbosch, South Africa

    Christine Lochner

  46. Institute of Systems Medicine and Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, Germany

    Jutta Peterburs

  47. Cognitive Neuroscience Center, University Medical Center Groningen, University of Groningen, Groningen, Netherlands

    Marie-José Van Tol

  48. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA

    Raquel E. Gur, Bart Larsen & Theodore D. Satterthwaite

  49. Department of Psychology, Vanderbilt University, Nashville, TN, USA

    Antonia N. Kaczkurkin

  50. Emotion and Development Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

    Courtney A. Filippi, Anita Harrewijn, André Zugman, Anderson M. Winkler & Daniel S. Pine

  51. Department of Psychiatry and Human Behavior, Brown University Warren Alpert Medical School, Providence, RI, USA

    Andrea L. Gold

  52. Department of Psychology, Education and Child Studies, Erasmus University Rotterdam, Rotterdam, Netherlands

    Anita Harrewijn

  53. Institute for Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany

    Robin Bülow

  54. Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany

    Hans J. Grabe & Katharina Wittfeld

  55. German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany

    Hans J. Grabe & Katharina Wittfeld

  56. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany

    Henry Völzke

  57. University Clinic for Radiology, University of Münster, Münster, Germany

    Harald Kugel

  58. KBO-Inn-Salzach-Klinikum, Munich, Germany

    Peter Zwanzger

  59. Department of Psychiatry and Psychotherapy, Ludwig Maximilians University of Munich, Munich, Germany

    Peter Zwanzger

  60. Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany

    Lisa Sindermann

  61. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA

    Tali M. Ball

  62. Department of Psychiatry and Behavioral Sciences, The University of Texas at Austin Dell Medical School, Austin, TX, USA

    Gregory A. Fonzo

  63. Laureate Institute for Brain Research, Tulsa, OK, USA

    Martin P. Paulus

  64. Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA

    Alan Simmons

  65. Departments of Psychiatry & School of Public Health, University of California, San Diego, La Jolla, CA, USA

    Murray B. Stein

  66. Departments of Psychology & Psychiatry, University of Illinois at Chicago, Chicago, IL, USA

    Heide Klumpp

  67. Department of Psychiatry & Behavioral Health, the Ohio State University, Columbus, OH, USA

    K. Luan Phan

  68. Department of Psychology, Uppsala University, Uppsala, Sweden

    Tomas Furmark

  69. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Kristoffer N. T. Månsson & Amirhossein Manzouri

  70. Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA

    Suzanne N. Avery & Brandee Feola

  71. Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA

    Jennifer Urbano Blackford

  72. Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Jacqueline A. Clauss

  73. Department of Psychiatry, Washington University, St. Louis, MO, USA

    Jennifer C. Harper & Chad M. Sylvester

  74. Department of Psychiatry, Amsterdam UMC location VUMC, Amsterdam, Netherlands

    Dick J. Veltman

  75. SA-MRC Unit on Risk & Resilience in Mental Disorders, University of Cape Town, Cape Town, South Africa

    Dan J. Stein

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Contributions

NAG: conceptualization, methodology, data curation, formal analysis, visualization, project administration, writing—original draft; JMBH: conceptualization, methodology, data curation, visualization, project administration, writing—review & editing; ARA: methodology, data curation, formal analysis, project administration, writing—review & editing; MAL, CRKC, NJ: methodology, writing—review & editing; LSV: data curation, methodology, writing—review & editing; MA: conceptualization, writing—review & editing; HO, SPP, IV, LBH, FS, DG, HL, SM, AW, ME, SL, FZ, BM, MJW, AB, MC, HRC, DH, JPe, ANK, BL, CAF, ALG, AHa, AZ, KW, KD, HKl, ES, LS, TMB, GAF, KNTM, AM, SNA, JAC, BF, JCH, AMW: data curation, writing—review & editing; RS, APJ, PMP, GAS, JRB, JH, FRS, KR, NC, JPu, KBB, AJ, TK, AK, IN, UD, QG, JCS, RT, PMW, TS, CL, MJVT, REG, TDS, RB, HJG, HV, JB, PZ, MPP, AS, MBS, HKu, KLP, TF, JUB, CMS, UL, DJV: investigation, writing—review & editing; KH, KSB, AT, BK, AHe, AGGD, EJL: data curation, investigation, writing—review & editing; SIT: project administration, writing—review & editing; DSP: conceptualization, resources, investigation, writing—review & editing; PMT: funding acquisition, conceptualization, methodology, supervision, writing—review & editing; DJS: funding acquisition, conceptualization, resources, investigation, supervision, writing—review & editing; NJAW: funding acquisition, conceptualization, methodology, investigation, supervision, writing—review & editing.

Corresponding author

Correspondence to Nynke A. Groenewold.

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Competing interests

PMP received payment or honoraria for lectures and presentations in educational events for Sandoz, Daiichi Sankyo, Eurofarma, Abbot, Libbs, Instituto Israelita de Pesquisa e Ensino Albert Einstein, Instituto D’Or de Pesquisa e Ensino. 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. PMT and NJ received a research grant from Biogen, Inc., unrelated to the topic of this paper. DJS received research grants and/or consultancy honoraria from Lundbeck and Sun.

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Groenewold, N.A., Bas-Hoogendam, J.M., Amod, A.R. et al. Volume of subcortical brain regions in social anxiety disorder: mega-analytic results from 37 samples in the ENIGMA-Anxiety Working Group. Mol Psychiatry 28, 1079–1089 (2023). https://doi.org/10.1038/s41380-022-01933-9

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