Abstract
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.
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Funding
The study was supported by ZonMw, the Netherlands organization for Health Research and Development (40-00812-98-10041), and by a grant from the Academic Medical Center Research Council (110614) (Miranda Olff); NIMH K01 MH118428-01 (BS-J); NARSAD 27040 (XZ); R01 MH105355 (YN); RO1 MH111671 and VISN6 MIRECC (RAM); Grant 01J05415 from the Special Research Fund (BOF) at Ghent University (SCM); K01 MH118467, Julia Kasparian Fund for Neuroscience Research (LAML); R21 MH112956, R01 MH119227, McLean Hospital Trauma Scholars Fund, Barlow Family Fund, Julia Kasaparian Fund for Neuroscience Research (MLK); The Natural Science Foundation of Jiangsu Province (No. BK20221554), and the Foundation for the Social Development Project of Jiangsu (No. BE2022705) (RQ); grant no. AZV NV18-7 04-00559 from the Ministry of Health of the Czech Republic, (PŘ); NIH U54 EB020403, R01 MH116147, R01 MH129742 (CRKC); R01 MH111671, R01 MH117601, R01 AG059874, MJFF 14848 (NJ); Department of Defense award number W81XWH-12-2-0012; ENIGMA was also supported in part by NIH U54 EB020403 from the Big Data to Knowledge (BD2K) program, R56 AG058854, R01 MH116147, R01 MH111671, and P41 EB015922 (PMT); funding from the SAMRC Unit on Risk & Resilience in Mental Disorders (DJS); the South African Research Chairs Initiative in Posttraumatic Stress Disorder through the Department of Science and Technology and the National Research Foundation (SS); the South African Medical Research Council for the “Shared Roots” Flagship Project, Grant no. MRC-RFA-IFSP-01-2013/SHARED ROOTS” through funding received from the South African National Treasury under its Economic Competitiveness and Support Package (SdP); funding by the South African Medical Research Council through its Division of Research Capacity Development under the SAMRC CLINICIAN RESEARCHER (M.D PHD) SCHOLARSHIP PROGRAMME from funding received from the South African National Treasury (LLvdH); the National Natural Science Foundation of China (No. U21A20364 and No. 31971020), the Key Project of the National Social Science Foundation of China (No. 20ZDA079), the Key Project of Research Base of Humanities and Social Sciences of Ministry of Education (No.16JJD190006), and the Scientific Foundation of Institute of Psychology, Chinese Academy of Sciences (No. E2CX4115CX) (LW); German Research Foundation grant to JKD (numbers DA 1222/4-1 and WA 1539/8-2) (JKD, AS, AM, HW); R01 MH113574 (IL); VA RR&D 1IK2RX000709 (NDD); VA RR&D I01RX000622; CDMRP W81XWH-08–2–0038 (SRS); VA RR&D 1K1RX002325; 1K2RX002922 (SGD); German Research Society (Deutsche Forschungsgemeinschaft, DFG; SFB/TRR 58: C06, C07) (TS, DH); Dana Foundation (to JBN); the University of Wisconsin Institute for Clinical and Translational Research (to Dr. Emma Seppala); a National Science Foundation Graduate Research Fellowship (to DWG); the National Institute of Mental Health (NIMH) R01-MH043454 and T32-MH018931 (to RJD); and a core grant to the Waisman Center from the National Institute of Child Health and Human Development (P30-HD003352); R01 MH106574 (CL & TAdeR-C); VA CSR&D 1IK2CX001680; VISN17 Center of Excellence Pilot funding (EMG, GM, SMN); VA National Center for PTSD; The Beth K and Stuart Yudofsky Chair in the Neuropsychiatry of Military Post Traumatic Stress Syndrome (CGA); R21 MH102634 (IL); R01 MH105535 (IR);Department of Veterans Affairs via support for the National Center for PTSD, NIAAA via its support for (P50) Center for the Translational Neuroscience if Alcohol, and NCATS via its support of (CTSA) Yale Center for Clinical Investigation (JHK); and R01AG067103 (ASotiras). The content of this article is the sole responsibility of the authors and does not necessarily reflect the position, policy or official views of the Department of Veterans Affairs, the U.S. Government, the South African Medical Research Council, or any other funding sources listed here.
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Conceptualization: JY, AH, DS, RAM, and AS; methodology: JY, AH, DS, RAM, and AS; formal analysis: JY; resources:, CD, CCH, DJV, JLF, MO, MvZ, SBJK, LN, BS-J, XZ, YN, ARH, SCM, JTB, LAML, MLK, RQ, GML, PŘ, IR, ELD, CRKC, LES, NJ, PMT, DJS, SK, JCI, SS, SdP, LLvdH, LW, YZ, GL, AS, AM, HW, JKD, CS, JIH, IL, AK, MA, NDD, SRS, SGD, TS, DH, DWG, JBN, RJD, CL, TAdeR-C, JUB, BOO, EMG, GM, RAM, AS; writing—original draft: JY, AH, RAM, and AS; writing – review and edition: all authors; visualizations: JY, and AS; supervision: RAM and AS.
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LAML reports unpaid membership on the Scientific Committee for the International Society for the Study of Trauma and Dissociation (ISSTD), and spousal IP payments from Vanderbilt University for technology licensed to Acadia Pharmaceuticals unrelated to the present work. ISSTD and NIMH were not involved in the analysis or preparation of the manuscript. CRKC received partial research support from Biogen, Inc. (Boston, USA) for research unrelated to the content of this manuscript. NJ received partial research support from Biogen, Inc. (Boston, USA) for research unrelated to the content of this manuscript. PMT received partial research support from Biogen, Inc. (Boston, USA) for research unrelated to the topic of this manuscript. RJD is the founder and president of, and serves on the board of directors for, the non-profit organization Healthy Minds Innovations, Inc. CGA has served as a consultant, speaker and/or on advisory boards for Aptinyx, FSV7, Lundbeck, Psilocybin Labs, Genentech, and Janssen; served as editor of Chronic Stress for Sage Publications, Inc; and filed a patent for using mTOR inhibitors to augment the effects of antidepressants (filed on August 20, 2018). 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); has 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); and has filed a patent for using mTOR inhibitors to augment the effects of antidepressants (filed on August 20, 2018). ASotiras holds equity in TheraPanacea and has received personal compensation for serving as a grant reviewer with the BrightFocus Foundation. The remaining authors have nothing to disclose.
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Yang, J., Huggins, A.A., Sun, D. et al. Examining the association between posttraumatic stress disorder and disruptions in cortical networks identified using data-driven methods. Neuropsychopharmacol. 49, 609–619 (2024). https://doi.org/10.1038/s41386-023-01763-5
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DOI: https://doi.org/10.1038/s41386-023-01763-5