Internal capsule microstructure mediates the relationship between childhood maltreatment and PTSD following adulthood trauma exposure - PubMed (original) (raw)

. 2023 Dec;28(12):5140-5149.

doi: 10.1038/s41380-023-02012-3. Epub 2023 Mar 17.

Lauren A M Lebois 1 2, Timothy D Ely 3, Sanne J H van Rooij 3, Steven E Bruce 4, Vishnu P Murty 5, Tanja Jovanovic 6, Stacey L House 7, Francesca L Beaudoin 8 9, Xinming An 10, Donglin Zeng 11, Thomas C Neylan 12, Gari D Clifford 13 14, Sarah D Linnstaedt 10, Laura T Germine 2 15 16, Kenneth A Bollen 17, Scott L Rauch 2 15 18, John P Haran 19, Alan B Storrow 20, Christopher Lewandowski 21, Paul I Musey Jr 22, Phyllis L Hendry 23, Sophia Sheikh 23, Christopher W Jones 24, Brittany E Punches 25 26, Michael C Kurz 27 28 29, Robert A Swor 30, Lauren A Hudak 31, Jose L Pascual 32 33, Mark J Seamon 33 34, Claire Pearson 35, David A Peak 36, Roland C Merchant 37, Robert M Domeier 38, Niels K Rathlev 39, Brian J O'Neil 40, Paulina Sergot 41, Leon D Sanchez 37 42, Mark W Miller 43 44, Robert H Pietrzak 45 46, Jutta Joormann 47, Deanna M Barch 48, Diego A Pizzagalli 1 2, Steven E Harte 49 50, James M Elliott 51 52 53, Ronald C Kessler 54, Karestan C Koenen 55, Samuel A McLean 56 57, Kerry J Ressler 1 2, Jennifer S Stevens # 58, Nathaniel G Harnett # 59 60

Affiliations

Internal capsule microstructure mediates the relationship between childhood maltreatment and PTSD following adulthood trauma exposure

Samantha A Wong et al. Mol Psychiatry. 2023 Dec.

Abstract

Childhood trauma is a known risk factor for trauma and stress-related disorders in adulthood. However, limited research has investigated the impact of childhood trauma on brain structure linked to later posttraumatic dysfunction. We investigated the effect of childhood trauma on white matter microstructure after recent trauma and its relationship with future posttraumatic dysfunction among trauma-exposed adult participants (n = 202) recruited from emergency departments as part of the AURORA Study. Participants completed self-report scales assessing prior childhood maltreatment within 2-weeks in addition to assessments of PTSD, depression, anxiety, and dissociation symptoms within 6-months of their traumatic event. Fractional anisotropy (FA) obtained from diffusion tensor imaging (DTI) collected at 2-weeks and 6-months was used to index white matter microstructure. Childhood maltreatment load predicted 6-month PTSD symptoms (b = 1.75, SE = 0.78, 95% CI = [0.20, 3.29]) and inversely varied with FA in the bilateral internal capsule (IC) at 2-weeks (p = 0.0294, FDR corrected) and 6-months (p = 0.0238, FDR corrected). We observed a significant indirect effect of childhood maltreatment load on 6-month PTSD symptoms through 2-week IC microstructure (b = 0.37, Boot SE = 0.18, 95% CI = [0.05, 0.76]) that fully mediated the effect of childhood maltreatment load on PCL-5 scores (b = 1.37, SE = 0.79, 95% CI = [-0.18, 2.93]). IC microstructure did not mediate relationships between childhood maltreatment and depressive, anxiety, or dissociative symptomatology. Our findings suggest a unique role for IC microstructure as a stable neural pathway between childhood trauma and future PTSD symptoms following recent trauma. Notably, our work did not support roles of white matter tracts previously found to vary with PTSD symptoms and childhood trauma exposure, including the cingulum bundle, uncinate fasciculus, and corpus callosum. Given the IC contains sensory fibers linked to perception and motor control, childhood maltreatment might impact the neural circuits that relay and process threat-related inputs and responses to trauma.

© 2023. The Author(s).

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Conflict of interest statement

Conflict of Interest:

Dr. Lebois reports unpaid membership on the Scientific Committee for the International Society for the Study of Trauma and Dissociation (ISSTD), grant support from the National Institute of Mental Health (NIMH), K01 MH118467, and the Julia Kasparian Fund for Neuroscience Research. Dr. Lebois also reports spousal IP payments from Vanderbilt University for technology licensed to Acadia Pharmaceuticals unrelated to the present work. Dr. Neylan has received research support from NIH, VA, and Rainwater Charitable Foundation, and consulting income from Jazz Pharmaceuticals. In the last three years Dr Clifford has received research funding from the NSF, NIH and LifeBell AI, and unrestricted donations from AliveCor Inc, Amazon Research, the Center for Discovery, the Gates Foundation, Google, the Gordon and Betty Moore Foundation, MathWorks, Microsoft Research, Nextsense Inc, One Mind Foundation, the Rett Research Foundation, and Samsung Research. Dr. Clifford has financial interest in AliveCor Inc and Nextsense Inc. He also is the CTO of MindChild Medical and CSO of LifeBell AI and has ownership in both companies. These relationships are unconnected to the current work. Dr. Rauch reports grants from NIH during the conduct of the study; personal fees from SOBP (Society of Biological Psychiatry) paid role as secretary, other from Oxford University Press royalties, other from APP (American Psychiatric Publishing Inc.) royalties, other from VA (Veterans Administration) per diem for oversight committee, and other from Community Psychiatry/Mindpath Health paid board service, including equity outside the submitted work; other from National Association of Behavioral Healthcare for paid Board service; and Leadership roles on Board or Council for SOBP, ADAA (Anxiety and Depression Association of America), and NNDC (National Network of Depression Centers). Dr. Sheikh has received funding from the Florida Medical Malpractice Joint Underwriter’s Association Dr. Alvin E. Smith Safety of Healthcare Services Grant; Allergan Foundation; the NIH/NIA-funded Jacksonville Aging Studies Center (JAX-ASCENT; R33AG05654); and the Substance Abuse and Mental Health Services Administration (1H79TI083101–01); and the Florida Blue Foundation. Dr. Jones has no competing interests related to this work, though he has been an investigator on studies funded by AstraZeneca, Vapotherm, Abbott, and Ophirex. Dr. Joormann receives consulting payments from Janssen Pharmaceuticals. Dr. Barch has received function from the NIMH, NIDA, and the American Foundation for Suicide Prevention, and consults for Boehringer-Ingelheim. Over the past 3 years, Dr. Pizzagalli has received consulting fees from Albright Stonebridge Group, Boehringer Ingelheim, Compass Pathways, Concert Pharmaceuticals, Engrail Therapeutics, Neumora Therapeutics (former BlackThorn Therapeutics), Neurocrine Biosciences, Neuroscience Software, Otsuka Pharmaceuticals, and Takeda Pharmaceuticals; honoraria from the Psychonomic Society (for editorial work) and Alkermes, and research funding from NIMH, Dana Foundation, Brain and Behavior Research Foundation, and Millennium Pharmaceuticals. In addition, he has received stock options from Neumora Therapeutics (former BlackThorn Therapeutics), Compass Pathways, Engrail Therapeutics, and Neuroscience Software.

Dr. Harte has no competing interests related to this work, though in the last three years he has received research funding from NIH, Aptinyx, and Arbor Medical Innovations, and consulting payments from Aptinyx, Heron Therapeutics, and Memorial Sloan Kettering Cancer Center. Dr. Elliott reports support from the National Institutes of Health (NIH) through Grant Numbers R01HD079076 & R03HD094577: Eunice Kennedy Shriver National Institute of Child Health & Human Development; National Center for Medical Rehabilitation Research. He also reports funding from New South Wales Health, Spinal Cord Injury Award (2020–2025) and consulting fees (< $15,000 per annum) from Orofacial Therapeutics, LLC. In the past 3 years, Dr. Kessler was a consultant for Cambridge Health Alliance, Canandaigua VA Medical Center, Holmusk, Partners Healthcare, Inc., RallyPoint Networks, Inc., and Sage Therapeutics. He has stock options in Cerebral Inc., Mirah, PYM, and Roga Sciences. Dr. Koenen’s research has been supported by the Robert Wood Johnson Foundation, the Kaiser Family Foundation, the Harvard Center on the Developing Child, Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, the National Institutes of Health, One Mind, the Anonymous Foundation, and Cohen Veterans Bioscience. She has been a paid consultant for Baker Hostetler, Discovery Vitality, and the Department of Justice. She has been a paid external reviewer for the Chan Zuckerberg Foundation, the University of Cape Town, and Capita Ireland. She has had paid speaking engagements in the last three years with the American Psychological Association, European Central Bank. Sigmund Freud University – Milan, Cambridge Health Alliance, and Coverys. She receives royalties from Guilford Press and Oxford University Press. Dr. McLean serves as a consultant for Walter Reed and for Arbor Medical Innovations. Dr. Ressler has performed scientific consultation for Bioxcel, Bionomics, Acer, Takeda, and Jazz Pharma; serves on Scientific Advisory Boards for Sage and the Brain Research Foundation, and he has received sponsored research support from Takeda, Brainsway and Alto Neuroscience. Dr. Harnett reports grant support from the National Institute of Mental Health, K00 MH119603.

Figures

Figure 1.

Figure 1.. The relationship between childhood maltreatment load and Internal Capsule FA values at 2-Weeks and 6-months.

The internal capsule and its subcomponents are displayed on 3D rendering of human white matter tracts (a) Standardized residual plot of the regression of Childhood Maltreatment Load on 2-Week Internal Capsule FA Values depicts the significant negative effect (b). Standardized residual plot of Childhood Maltreatment Load on 2-Week Posterior-Limb of the Internal Capsule FA Values depicts the significant negative effect (c). Standardized residual plot of the regression of Childhood Maltreatment Load on Internal Capsule FA Values indexed 6-months post-trauma depicts the significant negative effect (d).

Figure 2.

Figure 2.. Mediation model of the effect of childhood maltreatment load on 6-month PCL-5 through Internal Capsule FA values indexed 2-weeks post-trauma.

The indirect effect is significant based on a 5000 permutation, bootstrapped 95% confidence interval (b=0.37, Boot SE=0.18, 95% CI=[0.05, 0.76]), completely mediating the effect of childhood maltreatment load on PCL-5 scores (b=1.37, SE=0.79, 95% CI=[−0.18, 2.93]).

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