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[Preprint]. 2025 Jun 8:2025.06.04.657717.
doi: 10.1101/2025.06.04.657717.

Childhood Maltreatment and Deviations from Normative Brain Structure: Results from 3,711 Individuals from the ENIGMA MDD and ENIGMA PTSD

ENIGMA MDD Working Group; ENIGMA PTSD Working Group

Childhood Maltreatment and Deviations from Normative Brain Structure: Results from 3,711 Individuals from the ENIGMA MDD and ENIGMA PTSD

ENIGMA MDD Working Group et al. bioRxiv. .

Abstract

Childhood maltreatment (CM), encompassing abuse and neglect, affects over two-thirds of the general population and increases risk for stress-related psychopathology, including major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). The extent to which neuroanatomical alterations in MDD and PTSD are attributable to CM, however, is uncertain. Here, we analyzed CM and 3D structural brain MRI data from 3,711 participants in the ENIGMA MDD and PTSD Working Groups (25 sites; 33.3±13.0 years; 59.9% female). Normative modeling estimated deviation z-scores for 14 subcortical volumes (SV), 68 cortical thickness (CT), and 68 surface area (SA) measures, capturing differences from population norms. Transdiagnostic associations between CM and brain deviation scores were evaluated within each sex and age cohort. In young adults (ages 18-35), abuse was associated with larger volumes in thalamus and pallidum, thinner isthmus cingulate and middle frontal regions, and thicker medial orbitofrontal cortex; there were no significant effects in pediatric (≤18 years) participants. The strongest effects were observed in young female adults (∣β∣=.07-.22, q<.05): greater abuse and neglect were correlated with smaller hippocampus and putamen volumes, thinner entorhinal cortex, and smaller SA in fusiform/inferior parietal regions, and with larger SA in orbitofrontal and occipital cortices. In males, abuse had widespread effects on CT and SA (∣β∣=.1-.18, q<.05); effects for neglect were minimal. Our findings of age- and sex-specific instantiations of CM on brain morphometry highlight the importance of developmental context in understanding how adverse experiences shape neurobiological vulnerability to MDD and PTSD.

Keywords: Brain morphometry; Childhood maltreatment; Depression; Normative modeling; PTSD; Sex differences.

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Conflict of interest statement

Conflicts of Interest Disclosures CA served as a consultant and on advisory boards for Douglas Pharmaceutical, Freedom Biosciences, Aptinyx, Genentech, Janssen, Psilocybin Labs, Lundbeck, Guidepoint, and FSV7. He also received royalties from a patent for using mTORC1 inhibitors to augment the effects of antidepressants. IHR reports research funding from BI Pharma on precision psychiatry. RH is a consultant for Jazz Pharmaceuticals. LL 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 and spousal private equity in Violet Therapeutics unrelated to the present work. EAO reports employment at Crisis Text Line. KR has performed scientific consultation for Bioxcel, Bionomics, Acer, and Jazz Pharma; serves on Scientific Advisory Boards for Sage, Boehringer Ingelheim, Senseye, and the Brain Research Foundation, and he has received sponsored research support from Alto Neuroscience. AE reports salary and equity from Alto Neuroscience, equity from Mindstrong Health and Akili Interactive. TY reports a clinical trials agreement that provides funds to UCSF by NeuroQore, and a portion of these funds to UCSF have supported TTY’s effort on paper(s) with NeuroQore. None of the funds from NeuroQore supported Dr Yang's effort on this current paper. All other authors do not have any conflicts of interest to declare.

Figures

Figure 1.
Figure 1.. Deviations from Normative Subcortical Volume Associated with Childhood Trauma.
A. Normative deviations in subcortical volumes associated with abuse in males and females; B. Normative deviations in subcortical volumes associated with neglect in males and females. β represents the standardized effect size from the general linear model (GLM, FDR corrected q<.05). Results from the pediatric cohort are not displayed as there were no significant associations between CTQ and subcortical volumes in this age cohort.
Figure 2.
Figure 2.. Deviations from Normative Cortical Thickness Associated with Childhood Trauma.
A. Normative deviations in cortical thickness associated with abuse in males and females; B. Normative deviations in cortical thickness associated with neglect in males and females. β represents the standardized effect size from the GLM (FDR corrected q<.05). Results from the pediatric cohort are not displayed as there were no significant associations between CTQ and subcortical volumes in this age cohort.
Figure 3.
Figure 3.. Deviations from Normative Surface Area Associated with Childhood Trauma.
A. Normative deviations in surface area associated with abuse in males and females; B. Normative deviations in surface area associated with neglect in males and females. β represents the standardized effect size from the GLM (FDR corrected q<.05). Results from the pediatric cohort are not displayed as there were no significant associations between CTQ and subcortical volumes in this age cohort.
See this image and copyright information in PMC

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