Early Life Adversity and Deviations in Normative Brain Structure: An ENIGMA Mega-Analysis

Introduction: Early life adversity (ELA), encompassing abuse and neglect, affects more than two-thirds of the general population and substantially increases risk for stress-related psychopathology, including major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). While neuroanatomical abnormalities are frequently observed in both MDD and PTSD, the extent to which these alterations are attributable to ELA exposure remains uncertain. Methods: We analyzed ELA and structural MRI data from 3,711 participants (1,389 patients [872 MDD, 517 PTSD] and 2,322 healthy controls) across 25 international cohorts from the ENIGMA MDD and PTSD Working Groups (mean age 33±12.98 years; 59.82% female). Using the Childhood Trauma Questionnaire, we calculated separate composite scores for abuse (emotional, physical, and sexual) and neglect (emotional and physical) subscales. Leveraging normative modeling based on an independent reference population of 37,407 healthy individuals, we quantified deviation scores in subcortical volumes, cortical thickness, and surface area, evaluating transdiagnostic associations between ELA and brain deviation scores separately within each sex across three age groups: pediatric (≤18 years), young adult (>18 and <35 years), and older adult (≥35 years). Results: We observed heterogeneous effects of ELA on brain deviation scores that varied by exposure type, age, and sex, with the strongest effects emerging in young adult females. In this group, childhood abuse was associated with widespread alterations in volumes of the hippocampus and pallidum and cortical thickness of medial temporal and frontal regions (|r |= 0.12-0.18, q < 0.01), while childhood neglect was associated with larger surface area of frontal and temporal pole regions (r = 0.19-0.21, q < 0.01). Notably, no significant associations were observed in the pediatric cohort, and effects were most pronounced in association cortices showing protracted developmental trajectories. These patterns remained robust after controlling for diagnosis, site effects, and clinical variables. Conclusions: Our findings support incubation models of ELA, suggesting that the neurobiological consequences of early adversity may not manifest immediately but rather emerge more prominently during young adulthood, particularly in females. This work highlights the importance of considering age- and sex-specific effects when studying the impact of early adversity on brain development and emphasizes the potential value of targeted interventions during young adulthood, especially for females with histories of childhood trauma.