Posttraumatic stress disorder (PTSD) is associated with lower cortical thickness (CT) in prefrontal, cingulate, and insular cortices in diverse trauma-affected samples. However, some studies have failed to detect differences between PTSD patients and healthy controls or reported that PTSD is associated with greater CT. Using data-driven dimensionality reduction, we sought to conduct a well-powered study to identify vulnerable networks without regard to neuroanatomic boundaries. Moreover, this approach enabled us to avoid the excessive burden of multiple comparison correction that plagues vertex-wise methods. We derived structural covariance networks (SCNs) by applying non-negative matrix factorization (NMF) to CT data from 961 PTSD patients and 1124 trauma-exposed controls without PTSD. We used regression analyses to investigate associations between CT within SCNs and PTSD diagnosis (with and without accounting for the potential confounding effect of trauma type) and symptom severity in the full sample. We performed additional regression analyses in subsets of the data to examine associations between SCNs and comorbid depression, childhood trauma severity, and alcohol abuse. NMF identified 20 unbiased SCNs, which aligned closely with functionally defined brain networks. PTSD diagnosis was most strongly associated with diminished CT in SCNs that encompassed the bilateral superior frontal cortex, motor cortex, insular cortex, orbitofrontal cortex, medial occipital cortex, anterior cingulate cortex, and posterior cingulate cortex. CT in these networks was significantly negatively correlated with PTSD symptom severity. Collectively, these findings suggest that PTSD diagnosis is associated with widespread reductions in CT, particularly within prefrontal regulatory regions and broader emotion and sensory processing cortical regions.

1st Department of Neurology St Anne's University Hospital and Faculty of Medicine Masaryk University Brno Czech Republic

ARQ National Psychotrauma Centre Diemen The Netherlands

CEITEC Central European Institute of Technology Multimodal and Functional Neuroimaging Research Group Masaryk University Brno Czech Republic

Center for Healthy Minds University of Wisconsin Madison Madison WI USA

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

Comprehensive Injury Center Medical College of Wisconsin Milwaukee WI USA

Del Monte Institute for Neuroscience University of Rochester Medical Center Rochester NY USA

Department of Clinical Psychology University of Groningen Groningen The Netherlands

Department of Comparative Medicine Yale University New Haven CT USA

Department of Experimental Clinical and Health Psychology Ghent University Ghent Belgium

Department of Medical Imaging Jinling Hospital Medical School of Nanjing University Jiangsu China

Department of Neurology University of Utah Salt Lake City UT USA

Department of Neuroscience Yale University New Haven CT USA

Department of Psychiatry Amsterdam University Medical Center Amsterdam The Netherlands

Department of Psychiatry and Behavioral Science Texas A and M University College Station TX USA

Department of Psychiatry and Behavioral Science Texas A and M University Health Science Center Bryan TX USA

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

Department of Psychiatry and Neuroscience Institute University of Cape Town Cape Town South Africa

Department of Psychiatry Columbia University Medical Center New York NY USA

Department of Psychiatry Harvard Medical School Boston MA USA

Department of Psychiatry of Behavioral Sciences Baylor College of Medicine Houston TX USA

Department of Psychiatry Stellenbosch University Cape Town South Africa

Department of Psychiatry University of Michigan Ann Arbor MI USA

Department of Psychiatry University of Minnesota Minneapolis MN USA

Department of Psychiatry University of Wisconsin Madison Madison WI USA

Department of Psychiatry Yale University School of Medicine New Haven CT USA

Department of Psychology and Neuroscience Baylor University Waco TX USA

Department of Psychology The Education University of Hong Kong Hong Kong China

Department of Psychology University of Chinese Academy of Sciences Beijing China

Department of Psychology University of Wisconsin Madison Madison WI USA

Department of Psychology University of Wisconsin Milwaukee Milwaukee WI USA

Department of Psychology Vanderbilt University Nashville TN USA

Department of Psychology Yale University New Haven CT USA

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

Department of Radiology Washington University in St Louis St Louis MO USA

Division of Clinical Neuroscience National Center for PTSD West Haven CT USA

Division of Depression and Anxiety Disorders McLean Hospital Belmont MA USA

Division of Trauma and Acute Care Surgery Department of Surgery Medical College of Wisconsin Milwaukee WI USA

Division of Women's Mental Health McLean Hospital Belmont MA USA

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

Duke UNC Brain Imaging and Analysis Center Duke University Durham NC USA

George E Wahlen Veterans Affairs Medical Center Salt Lake City UT USA

Imaging Genetics Center Mark and Mary Stevens Neuroimaging and Informatics Institute Keck School of Medicine of USC Marina del Rey CA USA

Institute for Informatics Data Science and Biostatistics Washington University in St Louis St Louis MO USA

Institute for Technology in Psychiatry McLean Hospital Harvard University Belmont MA USA

Institute of Medical Psychology and Systems Neuroscience University of Münster Münster Germany

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

Mid Atlantic Mental Illness Research Education and Clinical Center Durham VA Medical Center Durham NC USA

Minneapolis VA Health Care System Minneapolis MN USA

Munroe Meyer Institute University of Nebraska Medical Center Omaha NE USA

New York State Psychiatric Institute New York NY USA

University Medical Centre Charité Berlin Germany

Veterans Integrated Service Network 17 Center of Excellence for Research on Returning War Veterans Waco TX USA

Wu Tsai Institute Yale University New Haven CT USA

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