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Cortical volume abnormalities in posttraumatic stress disorder: an ENIGMA-psychiatric genomics consortium PTSD workgroup mega-analysis

Molecular Psychiatry volume 26, pages 4331–4343 (2021)Cite this article

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Abstract

Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = −0.111 to −0.068, FDR corrected P values < 0.039) and were significantly negatively correlated with PTSS severity. After adjusting for depression symptoms, the PTSD findings in left and right LOFG remained significant. These findings indicate that cortical volumes in PTSD patients are smaller in prefrontal regulatory regions, as well as in broader emotion and sensory processing cortical regions.

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Fig. 1: Cortical volume differences between PTSD and control subjects.

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  • 21 November 2022

    For Author K. Luan Phan, given name and family name tagging is updated.

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Acknowledgements

The individual cohorts were supported by following grants: 1R21MH102634, 5U01AA021681-08, Academic Medical Center Research Council (110614), Anonymous Women’s Health Fund, Barlow Family Fund, BOF 01J05415, CDMRP W81XWH-08–2–0038, Center for Brain and Behavior Research Pilot Grant, CX001600 VA CDA, Dana Foundation, DoD W81XWH08-2-0159, DoD W81XWH-10-1-0925, DoD W81XWH-12-2-0012, F32MH109274, German Research Foundation (DA 1222/4-1 and WA 1539/8-2), German Research Society (Deutsche Forschungsgemeinschaft, DFG; SFB/TRR 58: C06, C07), HD071982, HD085850, K01MH118428, K23MH090366-01, K24DA028773, K24MH71434, K99NS096116, Kasparian Fund, L30MH114379, M01RR00039, MH071537, MH098212, MH101380, MJFF 14848, NARSAD- Young Investigator Grant, National Institute of Child Health and Human Development (P30-HD003352), NCATS (CTSA)- Yale Center for Clinical Investigation, The Netherlands Organization for Health Research and Development (40-00812-98-10041), NHMRC Program Grant (1073041), NIAAA (P50)- Center for the Translational Neuroscience in Alcohol, P30HD003352, P41EB015922, R01AA12479, R01AG059874, R01MH043454, R01MH096987, R01MH103291, R01MH105355, R01MH105535, R01MH110483, R01MH111671, R01MH116147, R01MH117601, R01MH61744, R01MH63407, R21MH097196, R21MH098198, R21MH112956, R56AG058854, South African Medical Research Council, South Dakota Governor’s Research Center Grant, T32MH018931, Trauma Scholars Fund, U54EB020403, UCI-LBVA Biumvirate Grant, UL1TR000153, UL1TR000454, The University of Wisconsin Institute for Clinical and Translational Research, VA CSR&D 1IK2CX001680, VA Merit Review Program, VA National Center for PTSD, VA RR&D1IK2RX000709, VA RR&D1K1RX002325, VA RR&D1K2RX002922, VA RR&DI01RX000622, VISN6 MIRECC.

Author information

Author notes

  1. These authors jointly supervised this work: Rajendra A. Morey, Israel Liberzon

Authors and Affiliations

  1. Department of Psychiatry, University of Toledo, Toledo, OH, USA

    Xin Wang, Andrew S. Cotton, Brian M. O’Leary & Marijo Tamburrino

  2. Department of Neurosciences, University of Toledo, Toledo, OH, USA

    Hong Xie & John Wall

  3. Department of Mathematics and Statistics, University of Toledo, Toledo, OH, USA

    Tian Chen

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

    Lauren E. Salminen, Emily L. Dennis, Neda Jahanshad, Faisal M. Rashid, Sophia I. Thomopoulos & Paul M. Thompson

  5. National Center for PTSD, VA Boston Healthcare System, Boston, MA, USA

    Mark W. Logue

  6. Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA

    Mark W. Logue

  7. Brain Imaging and Analysis Center, Duke University, Durham, NC, USA

    Emily K. Clarke-Rubright, Courtney C. Haswell & Rajendra A. Morey

  8. VISN 6 MIRECC, Durham VA Health Care System, Durham, NC, USA

    Emily K. Clarke-Rubright, Courtney C. Haswell & Rajendra A. Morey

  9. Department of Neurology, University of Utah, Salt Lake City, UT, USA

    Emily L. Dennis

  10. Clinical Neuroscience Division, National Center for PTSD, VA Connecticut Healthcare System, West Haven, CT, USA

    Chadi G. Abdallah, Ilan Harpaz-Rotem, John H. Krystal & Ifat Levy

  11. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Chadi G. Abdallah, Ilan Harpaz-Rotem & John H. Krystal

  12. University of Sydney, Westmead, NSW, Australia

    Elpiniki Andrew

  13. Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, USA

    Lee A. Baugh, Kelene A. Fercho & Gina L. Forster

  14. Center for Brain and Behavior Research, University of South Dakota, Vermillion, SD, USA

    Lee A. Baugh, Kelene A. Fercho & Raluca M. Simons

  15. Sioux Falls VA Health Care System, Sioux Falls, SD, USA

    Lee A. Baugh, Kelene A. Fercho & Jeffrey S. Simons

  16. Center of Excellence for Stress and Mental Health, VA San Diego Healthcare System, San Diego, CA, USA

    Jessica Bomyea

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

    Jessica Bomyea & Murray B. Stein

  18. Center for Trauma Recovery, Department of Psychological Sciences, University of Missouri-St. Louis, St. Louis, MO, USA

    Steven E. Bruce

  19. School of Psychology, University of New South Wales, Sydney, NSW, Australia

    Richard Bryant

  20. Health Services Research Center, University of California, San Diego, La Jolla, CA, USA

    Kyle Choi

  21. Department of Clinical Psychology, University of Groningen, Groningen, The Netherlands

    Judith K. Daniels

  22. Minneapolis VA Health Care System, Minneapolis, MN, USA

    Nicholas D. Davenport, Seth G. Disner & Scott R. Sponheim

  23. Department of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis, MN, USA

    Nicholas D. Davenport, Seth G. Disner & Scott R. Sponheim

  24. Center for Healthy Minds, University of Wisconsin-Madison, Madison, WI, USA

    Richard J. Davidson

  25. Department of Psychology, University of Wisconsin-Madison, Madison, WI, USA

    Richard J. Davidson & Dan Grupe

  26. Department of Psychiatry, University of Wisconsin-Madison, Madison, WI, USA

    Richard J. Davidson & Jack B. Nitschke

  27. Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA

    Michael DeBellis

  28. Department of Surgery, Division of Trauma & Acute Care Surgery, Medical College of Wisconsin, Milwaukee, WI, USA

    Terri deRoon-Cassini

  29. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA

    Negar Fani, Jennifer S. Stevens & Sanne J. H. van Rooij

  30. Civil Aerospace Medical Institute, US Federal Aviation Administration, Oklahoma City, OK, USA

    Kelene A. Fercho

  31. Department of Psychology, Marquette University, Milwaukee, WI, USA

    Jacklynn Fitzgerald

  32. Brain Health Research Centre, Department of Anatomy, University of Otago, Dunedin, New Zealand

    Gina L. Forster

  33. Department of Psychiatry, Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam Neuroscience, University of Amsterdam, Amsterdam, The Netherlands

    Jessie L. Frijling, Saskia B. J. Koch, Laura Nawijn, Miranda Olff & Mirjam van Zuiden

  34. Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands

    Elbert Geuze & Tim Varkevisser

  35. Brain Research and Innovation Centre, Ministry of Defence, Utrecht, The Netherlands

    Elbert Geuze & Tim Varkevisser

  36. Department of Psychiatry and Behavioral Health, Penn State College of Medicine, Hershey, PA, USA

    Hassaan Gomaa

  37. Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA

    Evan M. Gordon

  38. Department of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany

    Julia I. Herzog & Christian Schmahl

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

    David Hofmann & Thomas Straube

  40. Program for Traumatic Stress, Tibor Rubin VA Medical Center, Long Beach, CA, USA

    Michael Hollifield

  41. Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA

    Bobak Hosseini & K. Luan Phan

  42. Department of Experimental Clinical and Health Psychology, Ghent University, Ghent, Belgium

    Anna R. Hudson & Sven C. Mueller

  43. Department of Psychiatry, University of Cape Town, Cape Town, South Africa

    Jonathan Ipser

  44. Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, MI, USA

    Tanja Jovanovic

  45. Division of Women’s Mental Health, McLean Hospital, Belmont, MA, USA

    Milissa L. Kaufman

  46. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    Milissa L. Kaufman, Lauren A. M. Lebois, Elizabeth A. Olson, Kerry Ressler, Isabelle M. Rosso & Martha E. Shenton

  47. Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA

    Anthony P. King

  48. Donders Institute for Brain, Cognition and Behavior, Centre for Cognitive Neuroimaging, Radboud University Nijmegen, Nijmegen, The Netherlands

    Saskia B. J. Koch

  49. Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, MA, USA

    Inga K. Koerte & Martha E. Shenton

  50. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Ludwig-Maximilians-Universität, Munich, Germany

    Inga K. Koerte

  51. Brain Dynamics Centre, Westmead Institute of Medical Research, University of Sydney, Westmead, NSW, Australia

    Mayuresh S. Korgaonkar

  52. Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, USA

    Christine Larson

  53. Division of Depression and Anxiety Disorders, McLean Hospital, Belmont, MA, USA

    Lauren A. M. Lebois & Kerry Ressler

  54. Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA

    Ifat Levy

  55. Institute of Psychology, Chinese Academy of Sciences, Beijing, China

    Gen Li & Ye Zhu

  56. Department of Psychology, University of Chinese Academy of Sciences, Beijing, China

    Gen Li, Li Wang & Ye Zhu

  57. Departments of Radiology, Psychiatry, and Biomedical Engineering, University of Iowa, Iowa City, IA, USA

    Vincent A. Magnotta

  58. Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

    Antje Manthey, Anika Sierk & Henrik Walter

  59. VISN 17 Center of Excellence for Research on Returning War Veterans, Doris Miller VA Medical Center, Waco, TX, USA

    Geoffrey May & Steven M. Nelson

  60. Center for Vital Longevity, School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, TX, USA

    Geoffrey May & Steven M. Nelson

  61. Department of Psychology and Neuroscience, Baylor University, Waco, TX, USA

    Geoffrey May & Steven M. Nelson

  62. Department of Psychiatry and Behavioral Science, Texas A&M University College of Medicine, College Station, TX, USA

    Geoffrey May & Israel Liberzon

  63. Department of Psychology, Harvard University, Boston, MA, USA

    Katie A. McLaughlin

  64. Department of Personality, Psychological Assessment and Treatment, University of Deusto, Bilbao, Spain

    Sven C. Mueller

  65. Department of Psychiatry, Amsterdam University Medical Centers, Location VU University Medical Center, VU University, Amsterdam, The Netherlands

    Laura Nawijn & Dick J. Veltman

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

    Yuval Neria, Benjamin Suarez-Jimenez & Xi Zhu

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

    Yuval Neria, Benjamin Suarez-Jimenez & Xi Zhu

  68. ARQ National Psychotrauma Centrum, Diemen, The Netherlands

    Miranda Olff

  69. Center for Depression, Anxiety, and Stress Research, McLean Hospital, Belmont, MA, USA

    Elizabeth A. Olson & Isabelle M. Rosso

  70. Department of Psychology, University of Washington, Seattle, WA, USA

    Matthew Peverill

  71. The Ohio State University Wexner Medical Center, Columbus, OH, USA

    K. Luan Phan

  72. Mental Health Service Line, Jesse Brown VA Medical Center, Chicago, IL, USA

    K. Luan Phan

  73. Department of Radiology, University of Washington, Seattle, WA, USA

    Kelly Sambrook

  74. Department of Psychiatry, University of Western Ontario, London, ON, Canada

    Christian Schmahl

  75. Department of Psychiatry, VA Boston Healthcare System, Brockton, MA, USA

    Martha E. Shenton

  76. Department of Radiology, Harvard Medical School, Boston, MA, USA

    Martha E. Shenton

  77. Institute of Cognitive Neuroscience, University College London, London, United Kingdom

    Anika Sierk

  78. Department of Psychology, University of South Dakota, Vermillion, SD, USA

    Jeffrey S. Simons & Raluca M. Simons

  79. Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA, USA

    Murray B. Stein

  80. SAMRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa

    Dan J. Stein

  81. Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands

    Nic J. A. van der Wee & Steven J. A. van der Werff

  82. Leiden Institute for Brain and Cognition, Leiden, The Netherlands

    Nic J. A. van der Wee & Steven J. A. van der Werff

  83. Clinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA, USA

    Theo G. M. van Erp

  84. Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, CA, USA

    Theo G. M. van Erp

  85. Child and Adolescent Psychiatry, Leiden University Medical Center, Leiden, The Netherlands

    Robert R. J. M. Vermeiren

  86. Youz-Parnassia Group, Leiden, The Netherlands

    Robert R. J. M. Vermeiren

  87. Laboratory for Traumatic Stress Studies, CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China

    Li Wang

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Corresponding author

Correspondence to Xin Wang.

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Conflict of interest

Dr CGA has served as a consultant, speaker and/or on advisory boards for FSV7, Lundbeck, Psilocybin Labs, Genentech and Janssen, and editor of Chronic Stress for Sage Publications, Inc.; he has filed a patent for using mTOR inhibitors to augment the effects of antidepressants (filed on August 20, 2018). Dr RJD is the founder and president of, and serves on the board of directors for, the non-profit organization Healthy Minds Innovations, Inc. Dr NJ received partial research support from Biogen, Inc. (Boston, USA) for research unrelated to the content of this paper. Dr JHK is a consultant for AbbVie, Inc., Amgen, Astellas Pharma Global Development, Inc., AstraZeneca Pharmaceuticals, Biomedisyn Corporation, Bristol-Myers Squibb, Eli Lilly and Company, Euthymics Bioscience, Inc., Neurovance, Inc., FORUM Pharmaceuticals, Janssen Research & Development, Lundbeck Research USA, Novartis Pharma AG, Otsuka America Pharmaceutical, Inc., Sage Therapeutics, Inc., Sunovion Pharmaceuticals, Inc., and Takeda Industries; is on the Scientific Advisory Board for Lohocla Research Corporation, Mnemosyne Pharmaceuticals, Inc., Naurex, Inc., and Pfizer; is a stockholder in Biohaven Pharmaceuticals; holds stock options in Mnemosyne Pharmaceuticals, Inc.; holds patents for Dopamine and Noradrenergic Reuptake Inhibitors in Treatment of Schizophrenia, US Patent No. 5,447,948 (issued September 5, 1995), and Glutamate Modulating Agents in the Treatment of Mental Disorders, U.S. Patent No. 8,778,979 (issued July 15, 2014); filed a patent for Intranasal Administration of Ketamine to Treat Depression. U.S. Application No. 14/197,767 (filed on March 5, 2014); filed US application or Patent Cooperation Treaty international application No. 14/306,382 (filed on June 17, 2014); and filed a patent for using mTOR inhibitors to augment the effects of antidepressants (filed on August 20, 2018). Dr PMT received partial research support from Biogen, Inc. (Boston, USA) for research unrelated to the topic of this paper. No other authors reported conflicts of interest.

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Wang, X., Xie, H., Chen, T. et al. Cortical volume abnormalities in posttraumatic stress disorder: an ENIGMA-psychiatric genomics consortium PTSD workgroup mega-analysis. Mol Psychiatry 26, 4331–4343 (2021). https://doi.org/10.1038/s41380-020-00967-1

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