Meta-Analysis

. 2022 Sep;7(9):935-948.

doi: 10.1016/j.bpsc.2022.02.008. Epub 2022 Mar 15.

Remodeling of the Cortical Structural Connectome in Posttraumatic Stress Disorder: Results From the ENIGMA-PGC Posttraumatic Stress Disorder Consortium

Delin Sun¹, Gopalkumar Rakesh¹, Emily K Clarke-Rubright¹, Courtney C Haswell¹, Mark W Logue², Erin N O'Leary³, Andrew S Cotton³, Hong Xie³, Emily L Dennis⁴, Neda Jahanshad⁵, Lauren E Salminen⁵, Sophia I Thomopoulos⁵, Faisal M Rashid⁵, Christopher R K Ching⁵, Saskia B J Koch⁶, Jessie L Frijling⁷, Laura Nawijn⁸, Mirjam van Zuiden⁷, Xi Zhu⁹, Benjamin Suarez-Jimenez¹⁰, Anika Sierk¹¹, Henrik Walter¹¹, Antje Manthey¹¹, Jennifer S Stevens¹², Negar Fani¹², Sanne J H van Rooij¹², Murray B Stein¹³, Jessica Bomyea¹³, Inga Koerte¹⁴, Kyle Choi¹⁵, Steven J A van der Werff¹⁶, Robert R J M Vermeiren¹⁷, Julia I Herzog¹⁸, Lauren A M Lebois¹⁹, Justin T Baker²⁰, Kerry J Ressler²¹, Elizabeth A Olson²², Thomas Straube²³, Mayuresh S Korgaonkar²⁴, Elpiniki Andrew²⁵, Ye Zhu²⁶, Gen Li²⁶, Jonathan Ipser²⁷, Anna R Hudson²⁸, Matthew Peverill²⁹, Kelly Sambrook³⁰, Evan Gordon³¹, Lee A Baugh³², Gina Forster³³, Raluca M Simons³⁴, Jeffrey S Simons³⁴, Vincent A Magnotta³⁵, Adi Maron-Katz³⁶, Stefan du Plessis³⁷, Seth G Disner³⁸, Nicholas D Davenport³⁸, Dan Grupe³⁹, Jack B Nitschke⁴⁰, Terri A deRoon-Cassini⁴¹, Jacklynn Fitzgerald⁴², John H Krystal⁴³, Ifat Levy⁴³, Miranda Olff⁴⁴, Dick J Veltman⁷, Li Wang²⁶, Yuval Neria⁹, Michael D De Bellis⁴⁵, Tanja Jovanovic⁴⁶, Judith K Daniels⁴⁷, Martha E Shenton⁴⁸, Nic J A van de Wee¹⁶, Christian Schmahl¹⁸, Milissa L Kaufman⁴⁹, Isabelle M Rosso²², Scott R Sponheim³⁸, David Bernd Hofmann²³, Richard A Bryant⁵⁰, Kelene A Fercho⁵¹, Dan J Stein²⁷, Sven C Mueller⁵², K Luan Phan⁵³, Katie A McLaughlin⁵⁴, Richard J Davidson⁵⁵, Christine Larson⁵⁶, Geoffrey May⁵⁷, Steven M Nelson⁵⁷, Chadi G Abdallah⁴³, Hassaan Gomaa⁵⁸, Amit Etkin⁵⁹, Soraya Seedat³⁷, Ilan Harpaz-Rotem⁴³, Israel Liberzon⁶⁰, Xin Wang³, Paul M Thompson⁵, Rajendra A Morey⁶¹

Affiliations

¹ Brain Imaging and Analysis Center, Duke University, Durham, North Carolina; Department of Veteran Affairs Mid-Atlantic Mental Illness Research, Education and Clinical Center, Durham, North Carolina.
² National Center for PTSD, VA Boston Healthcare System, Boston, Massachusetts; Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts; Biomedical Genetics, Boston University School of Medicine, Boston, Massachusetts; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
³ Department of Psychiatry, University of Toledo, Toledo, Ohio.
⁴ Psychiatry Neuroimaging Laboratory, Brigham & Women's Hospital, Boston, Massachusetts; Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of USC, Marina del Rey, California; Stanford Neurodevelopment, Affect, and Psychopathology Laboratory, Stanford, California; Department of Neurology, University of Utah, Salt Lake City, Utah.
⁵ Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of USC, Marina del Rey, California.
⁶ Department of Psychiatry, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Donders Institute for Brain, Cognition and Behavior, Centre for Cognitive Neuroimaging, Radboud University Nijmegen, Nijmegen, the Netherlands.
⁷ Department of Psychiatry, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
⁸ Department of Psychiatry, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Psychiatry, Amsterdam University Medical Centers, VU University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
⁹ Department of Psychiatry, Columbia University Medical Center, New York, New York; New York State Psychiatric Institute, New York, New York.
¹⁰ Department of Psychiatry, Columbia University Medical Center, New York, New York; New York State Psychiatric Institute, New York, New York; University of Rochester Medical Center, Rochester, New York.
¹¹ University Medical Centre Charité, Berlin, Germany.
¹² Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia.
¹³ Department of Psychiatry, University of California San Diego, San Diego, California.
¹⁴ Psychiatry Neuroimaging Laboratory, Brigham & Women's Hospital, Boston, Massachusetts; Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Ludwig-Maximilians-Universität, Munich, Germany.
¹⁵ Health Services Research Center, University of California San Diego, San Diego, California.
¹⁶ Department of Psychiatry, Leiden University Medical Center, Leiden, the Netherlands; Leiden Institute for Brain and Cognition, Leiden, the Netherlands.
¹⁷ Department of Psychiatry, Leiden University Medical Center, Leiden, the Netherlands.
¹⁸ Department of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
¹⁹ Department of Psychiatry, Harvard Medical School, Boston, Massachusetts; Division of Depression and Anxiety Disorders, McLean Hospital, Harvard University, Belmont, Massachusetts.
²⁰ Institute for Technology in Psychiatry, McLean Hospital, Harvard University, Belmont, Massachusetts.
²¹ Department of Psychiatry, Harvard Medical School, Boston, Massachusetts; Division of Depression and Anxiety Disorders, McLean Hospital, Harvard University, Belmont, Massachusetts; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia.
²² Department of Psychiatry, Harvard Medical School, Boston, Massachusetts; Center for Depression, Anxiety, and Stress Research, McLean Hospital, Harvard University, Belmont, Massachusetts.
²³ Institute of Medical Psychology and Systems Neuroscience, University of Münster, Münster, Germany.
²⁴ Brain Dynamics Centre, Westmead Institute of Medical Research, Westmead, New South Wales, Australia.
²⁵ Department of Psychology, University of Sydney, Westmead, New South Wales, Australia.
²⁶ Laboratory for Traumatic Stress Studies, Chinese Academy of Sciences Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China; Department of Psychology, University of Chinese Academy of Sciences, Beijing, China.
²⁷ SA MRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
²⁸ Department of Experimental Clinical and Health Psychology, Ghent University, Ghent, Belgium.
²⁹ Department of Psychology, University of Washington, Seattle, Washington.
³⁰ Department of Radiology, University of Washington, Seattle, Washington.
³¹ Veterans Integrated Service Network-17 Center of Excellence for Research on Returning War Veterans, Waco, Texas; Department of Psychology and Neuroscience, Baylor University, Waco, Texas; Center for Vital Longevity, School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, Texas; Washington University School of Medicine, St. Louis, Missouri.
³² Division of Basic Biomedical Sciences, Sanford School of Medicine, Vermillion, South Dakota; Center for Brain and Behavior Research, University of South Dakota, Vermillion, South Dakota; Sioux Falls VA Health Care System, Sioux Falls, South Dakota.
³³ Division of Basic Biomedical Sciences, Sanford School of Medicine, Vermillion, South Dakota; Center for Brain and Behavior Research, University of South Dakota, Vermillion, South Dakota; Brain Health Research Centre, Department of Anatomy, University of Otago, Dunedin, New Zealand.
³⁴ Center for Brain and Behavior Research, University of South Dakota, Vermillion, South Dakota; Department of Psychology, University of South Dakota, Vermillion, South Dakota.
³⁵ Department of Radiology, Psychiatry, and Biomedical Engineering, University of Iowa, Iowa City, Iowa.
³⁶ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California.
³⁷ Department of Psychiatry, Stellenbosch University, Cape Town, South Africa.
³⁸ Minneapolis VA Health Care System, University of Minnesota, Minneapolis, Minnesota; Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota.
³⁹ Center for Healthy Minds, University of Wisconsin-Madison, Madison, Wisconsin.
⁴⁰ Department of Psychiatry, University of Wisconsin-Madison, Madison, Wisconsin.
⁴¹ Division of Trauma and Acute Care Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin.
⁴² Department of Psychology, Marquette University, Milwaukee, Wisconsin.
⁴³ Division of Clinical Neuroscience, National Center for PTSD, West Haven, Connecticut; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
⁴⁴ Department of Psychiatry, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; ARQ National Psychotrauma Centre, Diemen, the Netherlands.
⁴⁵ Healthy Childhood Brain Development Developmental Traumatology Research Program, Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina.
⁴⁶ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia; Department of Psychiatry and Behavioral Neuroscience, Wayne State University School of Medicine, Detroit, Michigan.
⁴⁷ Department of Clinical Psychology, University of Groningen, Groningen, the Netherlands.
⁴⁸ Psychiatry Neuroimaging Laboratory, Brigham & Women's Hospital, Boston, Massachusetts; VA Boston Healthcare System, Brockton Division, Brockton, Massachusetts.
⁴⁹ Department of Psychiatry, Harvard Medical School, Boston, Massachusetts; Division of Women's Mental Health, McLean Hospital, Harvard University, Belmont, Massachusetts.
⁵⁰ School of Psychology, University of New South Wales, Sydney, New South Wales, Australia.
⁵¹ Division of Basic Biomedical Sciences, Sanford School of Medicine, Vermillion, South Dakota; Center for Brain and Behavior Research, University of South Dakota, Vermillion, South Dakota; Sioux Falls VA Health Care System, Sioux Falls, South Dakota; Civil Aerospace Medical Institute, US Federal Aviation Administration, Oklahoma City, Oklahoma.
⁵² Department of Experimental Clinical and Health Psychology, Ghent University, Ghent, Belgium; Department of Personality, Psychological Assessment and Treatment, University of Deusto, Bilbao, Spain.
⁵³ Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois; Mental Health Service Line, Jesse Brown VA Chicago Health Care System, Chicago, Illinois.
⁵⁴ Department of Psychology, Harvard University, Cambridge, Massachusetts.
⁵⁵ Center for Healthy Minds, University of Wisconsin-Madison, Madison, Wisconsin; Department of Psychiatry, University of Wisconsin-Madison, Madison, Wisconsin; Department of Psychology, University of Wisconsin-Madison, Madison, Wisconsin.
⁵⁶ Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin.
⁵⁷ Veterans Integrated Service Network-17 Center of Excellence for Research on Returning War Veterans, Waco, Texas; Department of Psychology and Neuroscience, Baylor University, Waco, Texas; Center for Vital Longevity, School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, Texas; Department of Psychiatry and Behavioral Science, Texas A&M University Health Science Center, Bryan, Texas.
⁵⁸ Department of Psychiatry, Pennsylvania State University, State College, Pennsylvania.
⁵⁹ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California; VA Palo Alto Health Care System, Palo Alto, California.
⁶⁰ Department of Psychiatry, University of Michigan, Ann Arbor, Michigan.
⁶¹ Brain Imaging and Analysis Center, Duke University, Durham, North Carolina; Department of Veteran Affairs Mid-Atlantic Mental Illness Research, Education and Clinical Center, Durham, North Carolina. Electronic address: rajendra.morey@duke.edu.

PMID: 35307575
PMCID: PMC9835553
DOI: 10.1016/j.bpsc.2022.02.008

Meta-Analysis

Remodeling of the Cortical Structural Connectome in Posttraumatic Stress Disorder: Results From the ENIGMA-PGC Posttraumatic Stress Disorder Consortium

Delin Sun et al. Biol Psychiatry Cogn Neurosci Neuroimaging. 2022 Sep.

. 2022 Sep;7(9):935-948.

doi: 10.1016/j.bpsc.2022.02.008. Epub 2022 Mar 15.

Authors

Affiliations

¹ Brain Imaging and Analysis Center, Duke University, Durham, North Carolina; Department of Veteran Affairs Mid-Atlantic Mental Illness Research, Education and Clinical Center, Durham, North Carolina.
² National Center for PTSD, VA Boston Healthcare System, Boston, Massachusetts; Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts; Biomedical Genetics, Boston University School of Medicine, Boston, Massachusetts; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
³ Department of Psychiatry, University of Toledo, Toledo, Ohio.
⁴ Psychiatry Neuroimaging Laboratory, Brigham & Women's Hospital, Boston, Massachusetts; Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of USC, Marina del Rey, California; Stanford Neurodevelopment, Affect, and Psychopathology Laboratory, Stanford, California; Department of Neurology, University of Utah, Salt Lake City, Utah.
⁵ Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of USC, Marina del Rey, California.
⁶ Department of Psychiatry, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Donders Institute for Brain, Cognition and Behavior, Centre for Cognitive Neuroimaging, Radboud University Nijmegen, Nijmegen, the Netherlands.
⁷ Department of Psychiatry, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
⁸ Department of Psychiatry, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Psychiatry, Amsterdam University Medical Centers, VU University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
⁹ Department of Psychiatry, Columbia University Medical Center, New York, New York; New York State Psychiatric Institute, New York, New York.
¹⁰ Department of Psychiatry, Columbia University Medical Center, New York, New York; New York State Psychiatric Institute, New York, New York; University of Rochester Medical Center, Rochester, New York.
¹¹ University Medical Centre Charité, Berlin, Germany.
¹² Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia.
¹³ Department of Psychiatry, University of California San Diego, San Diego, California.
¹⁴ Psychiatry Neuroimaging Laboratory, Brigham & Women's Hospital, Boston, Massachusetts; Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Ludwig-Maximilians-Universität, Munich, Germany.
¹⁵ Health Services Research Center, University of California San Diego, San Diego, California.
¹⁶ Department of Psychiatry, Leiden University Medical Center, Leiden, the Netherlands; Leiden Institute for Brain and Cognition, Leiden, the Netherlands.
¹⁷ Department of Psychiatry, Leiden University Medical Center, Leiden, the Netherlands.
¹⁸ Department of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
¹⁹ Department of Psychiatry, Harvard Medical School, Boston, Massachusetts; Division of Depression and Anxiety Disorders, McLean Hospital, Harvard University, Belmont, Massachusetts.
²⁰ Institute for Technology in Psychiatry, McLean Hospital, Harvard University, Belmont, Massachusetts.
²¹ Department of Psychiatry, Harvard Medical School, Boston, Massachusetts; Division of Depression and Anxiety Disorders, McLean Hospital, Harvard University, Belmont, Massachusetts; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia.
²² Department of Psychiatry, Harvard Medical School, Boston, Massachusetts; Center for Depression, Anxiety, and Stress Research, McLean Hospital, Harvard University, Belmont, Massachusetts.
²³ Institute of Medical Psychology and Systems Neuroscience, University of Münster, Münster, Germany.
²⁴ Brain Dynamics Centre, Westmead Institute of Medical Research, Westmead, New South Wales, Australia.
²⁵ Department of Psychology, University of Sydney, Westmead, New South Wales, Australia.
²⁶ Laboratory for Traumatic Stress Studies, Chinese Academy of Sciences Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China; Department of Psychology, University of Chinese Academy of Sciences, Beijing, China.
²⁷ SA MRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
²⁸ Department of Experimental Clinical and Health Psychology, Ghent University, Ghent, Belgium.
²⁹ Department of Psychology, University of Washington, Seattle, Washington.
³⁰ Department of Radiology, University of Washington, Seattle, Washington.
³¹ Veterans Integrated Service Network-17 Center of Excellence for Research on Returning War Veterans, Waco, Texas; Department of Psychology and Neuroscience, Baylor University, Waco, Texas; Center for Vital Longevity, School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, Texas; Washington University School of Medicine, St. Louis, Missouri.
³² Division of Basic Biomedical Sciences, Sanford School of Medicine, Vermillion, South Dakota; Center for Brain and Behavior Research, University of South Dakota, Vermillion, South Dakota; Sioux Falls VA Health Care System, Sioux Falls, South Dakota.
³³ Division of Basic Biomedical Sciences, Sanford School of Medicine, Vermillion, South Dakota; Center for Brain and Behavior Research, University of South Dakota, Vermillion, South Dakota; Brain Health Research Centre, Department of Anatomy, University of Otago, Dunedin, New Zealand.
³⁴ Center for Brain and Behavior Research, University of South Dakota, Vermillion, South Dakota; Department of Psychology, University of South Dakota, Vermillion, South Dakota.
³⁵ Department of Radiology, Psychiatry, and Biomedical Engineering, University of Iowa, Iowa City, Iowa.
³⁶ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California.
³⁷ Department of Psychiatry, Stellenbosch University, Cape Town, South Africa.
³⁸ Minneapolis VA Health Care System, University of Minnesota, Minneapolis, Minnesota; Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota.
³⁹ Center for Healthy Minds, University of Wisconsin-Madison, Madison, Wisconsin.
⁴⁰ Department of Psychiatry, University of Wisconsin-Madison, Madison, Wisconsin.
⁴¹ Division of Trauma and Acute Care Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin.
⁴² Department of Psychology, Marquette University, Milwaukee, Wisconsin.
⁴³ Division of Clinical Neuroscience, National Center for PTSD, West Haven, Connecticut; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
⁴⁴ Department of Psychiatry, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; ARQ National Psychotrauma Centre, Diemen, the Netherlands.
⁴⁵ Healthy Childhood Brain Development Developmental Traumatology Research Program, Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina.
⁴⁶ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia; Department of Psychiatry and Behavioral Neuroscience, Wayne State University School of Medicine, Detroit, Michigan.
⁴⁷ Department of Clinical Psychology, University of Groningen, Groningen, the Netherlands.
⁴⁸ Psychiatry Neuroimaging Laboratory, Brigham & Women's Hospital, Boston, Massachusetts; VA Boston Healthcare System, Brockton Division, Brockton, Massachusetts.
⁴⁹ Department of Psychiatry, Harvard Medical School, Boston, Massachusetts; Division of Women's Mental Health, McLean Hospital, Harvard University, Belmont, Massachusetts.
⁵⁰ School of Psychology, University of New South Wales, Sydney, New South Wales, Australia.
⁵¹ Division of Basic Biomedical Sciences, Sanford School of Medicine, Vermillion, South Dakota; Center for Brain and Behavior Research, University of South Dakota, Vermillion, South Dakota; Sioux Falls VA Health Care System, Sioux Falls, South Dakota; Civil Aerospace Medical Institute, US Federal Aviation Administration, Oklahoma City, Oklahoma.
⁵² Department of Experimental Clinical and Health Psychology, Ghent University, Ghent, Belgium; Department of Personality, Psychological Assessment and Treatment, University of Deusto, Bilbao, Spain.
⁵³ Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois; Mental Health Service Line, Jesse Brown VA Chicago Health Care System, Chicago, Illinois.
⁵⁴ Department of Psychology, Harvard University, Cambridge, Massachusetts.
⁵⁵ Center for Healthy Minds, University of Wisconsin-Madison, Madison, Wisconsin; Department of Psychiatry, University of Wisconsin-Madison, Madison, Wisconsin; Department of Psychology, University of Wisconsin-Madison, Madison, Wisconsin.
⁵⁶ Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin.
⁵⁷ Veterans Integrated Service Network-17 Center of Excellence for Research on Returning War Veterans, Waco, Texas; Department of Psychology and Neuroscience, Baylor University, Waco, Texas; Center for Vital Longevity, School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, Texas; Department of Psychiatry and Behavioral Science, Texas A&M University Health Science Center, Bryan, Texas.
⁵⁸ Department of Psychiatry, Pennsylvania State University, State College, Pennsylvania.
⁵⁹ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California; VA Palo Alto Health Care System, Palo Alto, California.
⁶⁰ Department of Psychiatry, University of Michigan, Ann Arbor, Michigan.
⁶¹ Brain Imaging and Analysis Center, Duke University, Durham, North Carolina; Department of Veteran Affairs Mid-Atlantic Mental Illness Research, Education and Clinical Center, Durham, North Carolina. Electronic address: rajendra.morey@duke.edu.

PMID: 35307575
PMCID: PMC9835553
DOI: 10.1016/j.bpsc.2022.02.008

Abstract

Background: Posttraumatic stress disorder (PTSD) is accompanied by disrupted cortical neuroanatomy. We investigated alteration in covariance of structural networks associated with PTSD in regions that demonstrate the case-control differences in cortical thickness (CT) and surface area (SA).

Methods: Neuroimaging and clinical data were aggregated from 29 research sites in >1300 PTSD cases and >2000 trauma-exposed control subjects (ages 6.2-85.2 years) by the ENIGMA-PGC (Enhancing Neuro Imaging Genetics through Meta Analysis-Psychiatric Genomics Consortium) PTSD working group. Cortical regions in the network were rank ordered by the effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2-148) regions with the largest effect size for PTSD > non-PTSD formed hypertrophic networks, the largest effect size for PTSD < non-PTSD formed atrophic networks, and the smallest effect size of between-group differences formed stable networks. The mean structural covariance (SC) of a given n-region network was the average of all positive pairwise correlations and was compared with the mean SC of 5000 randomly generated n-region networks.

Results: Patients with PTSD, relative to non-PTSD control subjects, exhibited lower mean SC in CT-based and SA-based atrophic networks. Comorbid depression, sex, and age modulated covariance differences of PTSD-related structural networks.

Conclusions: Covariance of structural networks based on CT and cortical SA are affected by PTSD and further modulated by comorbid depression, sex, and age. The SC networks that are perturbed in PTSD comport with converging evidence from resting-state functional connectivity networks and networks affected by inflammatory processes and stress hormones in PTSD.

Keywords: Brain network; Cortical thickness; Depression; PTSD; Structural covariance; Surface area.

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Conflict of interest statement

Conflicts of Interest

Dr. Abdallah 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. Davidson is the founder and president of, and serves on the board of directors for, the non-profit organization Healthy Minds Innovations, Inc. Dr. Jahanshad received partial research support from Biogen, Inc. (Boston, USA) for research unrelated to the content of this manuscript. Dr. Krystal 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); and filed a patent for Intranasal Administration of Ketamine to Treat Depression. U.S. Application No. 14/197,767 (filed on March 5, 2014); US application or Patent Cooperation Treaty international application No. 14/306,382 (filed on June 17, 2014). Filed a patent for using mTOR inhibitors to augment the effects of antidepressants (filed on August 20, 2018). Dr. Schmahl is consultant for Boehringer Ingelheim International GmbH. Dr. Stein has received research grants and/or consultancy honoraria from Lundbeck and Sun. Dr. Thompson received partial research support from Biogen, Inc. (Boston, USA) for research unrelated to the topic of this manuscript. All other authors have no conflicts of interest to declare.

Figures

**Figure 1.. Analyses pipelines.**
(A) Anatomical neuroimaging data from 29 research sites was aggregated by the ENIGMA PGC PTSD working group. Regional estimates of cortical thickness (CT) and surface area (SA) extracted from 148 cortical regions based on the Destrieux atlas (Destrieux, Fischl, Dale, & Halgren, 2010) were harmonized to remove site effects with *ComBat* approach and entered into a linear model to adjust for effects of age, age², sex, and whole-brain mean CT (or SA). The residuals were used to compute Pearson correlation coefficients for each pair of cortical regions across subjects within groups. The correlation coefficients were r-to-z transformed to improve normality and yielded a structural covariance (SC) matrix for each participant group. The cortical regions were rank ordered according to the magnitude of effect size when contrasting CT (or SA) between PTSD and non-PTSD groups. The top-n (n = 2 to 148) regions with the largest effect size of differences for PTSD > non-PTSD constituted atrophic networks, PTSD < non-PTSD constituted hypertrophic networks, while the smallest effect size stable networks. The mean SC of a given n-region network measured by the mean of positive correlations between all possible pairs of regions were compared to 5,000 randomly generated n-region networks matched for hemisphere and distance. Both global and individual tests were employed to compute statistical significance based on the proportion of mean SC values from randomly chosen sets of n regions that exceeded or equaled the mean SC of the actual top-n network. As illustrated in (B), the top-n (n = 5, 10, and 20) regions showed (i) the largest effect size in CT (or SA) for PTSD < non-PTSD (atrophic networks); (ii) the largest effect size of PTSD > non-PTSD (hypertrophic networks); or (iii) the smallest effect size of PTSD vs. non-PTSD (stable networks). (C) CT-based hypertrophic networks for top-3, top-*10 and* top-50 regions.

**Figure 2.. The top-20 regions showing PTSD-related differences.**
The top-20 regions that (A) PTSD < non-PTSD and (B) PTSD > non-PTSD in cortical thickness. The top-20 regions that (C) PTSD < non-PTSD and (D) PTSD > non-PTSD in surface area. Node size represents the magnitude of effect size for between-group differences per region. Warm color denotes PTSD > non-PTSD, and cool color denotes PTSD < non-PTSD. Regions names are listed in Supplementary Table S4. Two examples are shown on the right to denote the node size and the corresponding effect size (Cohen’s d). The directions of the brain maps (axial view) are also shown.

**Figure 3.. Mean SC of patients with PTSD.**
Global tests showed that PTSD patients have higher mean SC in both CT- (p < 0.001) and SA-based (p = 0.017) atrophic networks, both CT- (p = 0.029) and SA-based (p = 0.017) hypertrophic networks, and CT-based (p < 0.001) but not SA-based (p > 0.5) stable networks than the corresponding random networks. The curves of networks with up to 50 nodes are shown for illustrative purposes, given that the mean SC of actual networks and the mean SC of the average of random networks were very similar for large network sizes. Red curve, mean SC of the actual networks; Blue curve, mean SC of the average of 5,000 random networks; light blue ribbon, 95% confidence interval (CI) of the 5,000 random networks.

**Figure 4.. Mean SC of trauma-exposed participants without PTSD.**
Global tests showed that participants without PTSD had higher mean SC in both CT- (p < 0.001) and SA-based (p < 0.001) atrophic networks, SA-based (p = 0.014) but not CT-based (p = 0.139) hypertrophic networks, and neither CT- (p = 0.264) nor SA-based (p = 0.732) stable networks than in corresponding random networks. The curves for networks with up to 50 nodes are shown for illustrative purpose, given that the mean SC of actual networks and the mean SC of the average of random networks were very similar for large network sizes. Red curve, mean SC of the actual networks; Blue curve, mean SC of the average of 5,000 random networks; light blue ribbon, 95% confidence interval (CI) of the 5,000 random networks.

**Figure 5.. Mean SC of PTSD vs. non-PTSD.**
Global tests showed that patients with PTSD versus non-PTSD participants had lower mean SC in both CT- (p = 0.014) and SA-based (p = 0.024) atrophic networks, but no significant difference in CT- (p = 0.098) and SA-based (p > 0.5) hypertrophic networks as well as CT- (p > 0.5) and SA-based (p > 0.5) stable networks. The curves of networks with up to 50 nodes are shown for illustrative purpose, given that the mean SC of actual networks and the mean SC of the average of random networks were very similar for large network sizes. Red curve, mean SC of the actual networks; Blue curve, mean SC of the average of 5,000 random networks; light blue ribbon, 95% confidence interval (CI) of the 5,000 random networks.

**Figure 6.. Replication analyses results.**
The global-tests results shown in Figures 3, 4, and 5 are reliable as underscored by the area under curve (AUC) of mean SC for the results based on all 29 sites (represented by the red vertical line) was always located within the 95% confidence interval (represented by two blue vertical dashed lines) of the AUC of mean SC from 5,000 iterations leaving out 3 sites at each iteration across all types of networks.

**Figure 7.. Interaction effects of PTSD and depression.**
Global tests showed that patients with depression alone had higher mean SC in **(A)** CT-based (p < 0.001) and **(B)** SA-based (p < 0.001) atrophic networks, and lower mean SC in **(D)** SA-based hypertrophic networks (p = 0.029), than patients with both PTSD and depression. Patients with depression alone also showed higher mean SC in both **(A)** CT-based (p < 0.001) and **(B)** SA-based (p < 0.001) atrophic networks, and lower mean SC in **(D)** SA-based hypertrophic networks (p < 0.001), than patients with neither PTSD nor depression. Patients with PTSD alone showed lower mean SC in **(A)** CT-based atrophic networks than patients with depression alone (p < 0.001), and higher mean SC in **(B)** SA-based atrophic networks than patients with both PTSD and depression (p < 0.001) as well as participants with neither PTSD nor depression (p = 0.014). No significant PTSD x depression interaction effect (global p-values > 0.2) was found in the other types of networks shown in **(C)**, **(E)** and **(F)**. The curves of networks with up to 30 nodes were shown for illustrative purposes. Error bar denotes 95% confidence interval of 5,000 random networks. * represents p < 0.05; *** represents p < 0.001.

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References

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Remodeling of the Cortical Structural Connectome in Posttraumatic Stress Disorder: Results From the ENIGMA-PGC Posttraumatic Stress Disorder Consortium

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Remodeling of the Cortical Structural Connectome in Posttraumatic Stress Disorder: Results From the ENIGMA-PGC Posttraumatic Stress Disorder Consortium

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