Altered white matter microstructural organization in posttraumatic stress disorder across 3047 adults: results from the PGC-ENIGMA PTSD consortium

Abstract

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1426 individuals with PTSD and 1621 controls (2174 males/873 females) between ages 18–83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen’s d = −0.11, p = 0.0055). The tapetum connects the left and right hippocampus, for which structure and function have been consistently implicated in PTSD. Results were consistent even after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.

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Fig. 1: Results from the group comparisons.
Fig. 2: Site effects for tapetum result.
Fig. 3: Tapetum displayed on the ENIGMA template FA.
Fig. 4: Linear association with CAPS-4 across the whole sample (left) and within the PTSD cases only (right).

Code availability

All analyses were conducted using generalizable scripts available on the ENIGMA-GitHub https://github.com/ENIGMA-git/ENIGMA/tree/master/WorkingGroups/EffectSize_and_GLM. Individual ROI level data were shared with the central site and processed using a set of R scripts with regressions customized for the current PGC-ENIGMA-PTSD dMRI analysis, publicly available on a set of Google Spreadsheet configuration files.

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K99NS096116 to ELD; CIHR, CIMVHR; 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); R01MH043454 and T32MH018931 (to RJD); and a core grant to the Waisman Center from the National Institute of Child Health and Human Development (P30HD003352); Defense and Veterans Brain Injury Centers, the U.S. Army Medical Research and Materiel Command (USAMRMC; W81XWH-13-2-0025) and the Chronic Effects of Neurotrauma Consortium (CENC; PT108802-SC104835); Department of Defense award number W81XWH-12-2-0012; ENIGMA was also supported in part by NIH U54EB020403 from the Big Data to Knowledge (BD2K) program, R56AG058854, R01MH116147, R01MH111671, and P41EB015922; 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; DoD W81XWH-10-1-0925; Center for Brain and Behavior Research Pilot Grant; South Dakota Governor’s Research Center Grant; F32MH109274; Funding from the Bill & Melinda Gates Foundation; Funding from the SAMRC Unit on Risk & Resilience in Mental Disorders; German Research Foundation grant to JKD (numbers DA 1222/4-1 and WA 1539/8-2).; German Research Society (Deutsche Forschungsgemeinschaft, DFG; SFB/TRR 58: C06, C07); I01-CX000715 & I01-CX001542; K01MH118428; K23MH090366; K2CX001772, Clinical Science Research and Development Service, VA Office of Research and Development; MH098212; MH071537; M01RR00039; UL1TR000454; HD071982; HD085850; MH101380; NARSAD 27040; NARSAD Young Investigator, K01MH109836, Young Investigator Grant, Korean Scientists and Engineers Association; NHMRC Program Grant # 1073041; R01AG050595, R01AG022381; R01AG058822; R01EB015611; R01MH105355; R01MH105355, R01DA035484; R01MH111671, R01MH117601, R01AG059874, MJFF 14848; R01MH111671; VISN6 MIRECC; R21MH112956, Anonymous Women's Health Fund, Kasparian Fund, Trauma Scholars Fund, Barlow Family Fund; 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. The work by LLvdH reported herein was made possible through 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.; South African Research Chairs Initiative in Posttraumatic Stress Disorder through the Department of Science and Technology and the National Research Foundation.; the National Natural Science Foundation of China (No. 31271099, 31471004), the Key Research Program of the Chinese Academy of Sciences (No. ZDRW-XH-2019-4); 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) both awarded to MO.; Translational Research Center for TBI and Stress Disorders (TRACTS), a VA Rehabilitation Research and Development (RR&D) Traumatic Brain Injury Center of Excellence (B9254-C) at VA Boston Healthcare System.; VA CSR&D 1IK2CX001680; VISN17 Center of Excellence Pilot funding; VA CSR&D 822-MR-18176 and Senior Career Scientist Award; VA National Center for PTSD; VA RR&D 1IK2RX000709; VA RR&D 1K1RX002325; 1K2RX002922; VA RR&D I01RX000622; CDMRP W81XWH-08–2–0038; W81XWH08-2-0159 (PI: MBS) from the US Department of Defense. The views reflected here are strictly those of the authors and do not constitute endorsement by any of the funding sources listed here.

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ELD, SGD, NF, LES, ML, EKC, NJ, and RAM wrote the initial draft, all authors reviewed and edited the manuscript. All authors contributed data to the analyses.

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Correspondence to Emily L. Dennis.

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Conflict of interest

CGA has served as a consultant, speaker and/or on advisory boards for FSV7, Lundbeck, 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). RJD is the founder and president of, and serves on the board of directors for, the nonprofit organization Healthy Minds Innovations, Inc. JK 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). NJ received partial research support from Biogen, Inc. (Boston, USA) for research unrelated to the content of this paper. PMT received partial research support from Biogen, Inc. (Boston, USA) for research unrelated to the topic of this paper.

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Dennis, E.L., Disner, S.G., Fani, N. et al. Altered white matter microstructural organization in posttraumatic stress disorder across 3047 adults: results from the PGC-ENIGMA PTSD consortium. Mol Psychiatry (2019). https://doi.org/10.1038/s41380-019-0631-x

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