Environmental adversities significantly increase the risk of developing psychiatric disorders in adulthood. Individuals cope with adversity through adaptations in emotional, cognitive, and behavioral processes, but these adaptations can be maladaptive and increase psychopathology risk. Despite this clear link, the underlying neurobiological mechanisms remain elusive due to several factors: 1. **Focus on regions of interest:** Studies focusing on specific brain regions (e.g., limbic system) may neglect interindividual differences in brain organization and overlook substantial whole-brain changes. 2. **Inconsistent findings:** Inconsistent findings may result from the dominance of studies focused on group means, obscuring individual-level variability. Contradictory results (e.g., increased or decreased brain volume) may arise from this averaging effect. 3. **Ignoring typical brain development:** Studies often fail to account for typical brain growth and development, making it difficult to identify true neurobiological alterations amidst age and sex-specific trajectories. 4. **Correlated adversities:** The correlation between various adversities makes it difficult to isolate the effects of a single adversity in adulthood. 5. **Limited longitudinal studies:** Longitudinal studies investigating the enduring effects of adversity on brain structure are limited, hindering the understanding of stability in neurobiological correlates. This study addresses these limitations by using a voxel-wise normative modeling approach to quantify the centiles of variation in adversity effects across the population. The researchers leveraged data from the well-phenotyped "Mannheim Study of Children at Risk" (MARS) cohort, building a spatially precise normative model capturing long-term neural adaptation to adversities. The stability of the model was tested over time in the MARS cohort and replicated in an independent sample from the IMAGEN cohort.

Meta-analyses have shown a convergence of developmental risk factors in key regions of affective and cognitive regulatory processing, both within and beyond the limbic system. However, these studies suffer from between-study heterogeneity in assessments, participants, and analyses. Previous research has inconsistently linked specific adversities to specific brain outcomes, potentially due to the focus on group means rather than individual variability. Studies have not adequately considered typical brain development patterns when investigating the impact of adversity. The correlation of different adversities adds complexity. Longitudinal studies are scarce, with limited evidence for the stability of adversity-related neurobiological correlates over time. Thus, the need for predictive mechanistic models to account for the long-lasting effects of lifespan adversity at a whole-brain level, while accommodating interindividual neurobiological heterogeneity, was apparent.

This study utilized data from the Mannheim Study of Children at Risk (MARS) cohort, a well-phenotyped adult at-risk cohort followed since birth. The MARS cohort underwent 11 assessment waves, prospectively acquiring developmental risk factors (prenatal, perinatal, and psychosocial adversities) up to adulthood. A voxel-wise normative modeling approach was applied. Brain structure was quantified using Jacobian determinants (JDs) of deformation fields derived from nonlinear registration. Voxel-wise normative models predicted these measures based on a broad panel of adversities (prenatal maternal smoking and stress, obstetric risks at birth, lower early maternal care, adverse family environment, childhood traumatic events, and stressful life events). Seven adversities were considered. The normative model was built on data from participants at age 25 and replicated at age 33 in the MARS cohort and in an independent sample (IMAGEN cohort) at age 22. A normative model of age-related volumetric changes across development was estimated using a large compilation of data to serve as a reference for interpreting adversity-related effects as acceleration or delay of development. Finally, individual deviations from normative brain trajectories were investigated for their association with psychopathology. The researchers used Bayesian linear regression under tenfold cross-validation for the normative models. Structure coefficients were used to capture the unique impact of each adversity. Principal component analysis was used to summarize the primary sources of variance within the set of adversities. Linear mixed models were used to assess the association between individual deviations from the normative model and psychopathological symptoms.

The study revealed a widespread morphometric signature of adversity at age 25, extending beyond previously identified regions of interest (hippocampus, amygdala, basal ganglia, vmPFC, ACC) to include the thalamus, frontal gyri, occipital gyrus, and precentral gyrus. This signature was stable over time, evident in the same participants at age 33 and replicated in an independent sample. Structure coefficients revealed adversity- and region-specific volumetric expansions or contractions. The highest whole-brain overlap was observed for psychosocial risks (family adversity, trauma, stressful life events). Principal component analysis (PCA) revealed distinct morphometric patterns associated with different adversity factors (PCs). For example, PC1 (lifespan psychosocial family adversities and prenatal smoking) was related to cortical and subcortical volume contractions, while PC2 (obstetric risk and prenatal maternal stress) showed a more balanced picture of expansions and contractions. Sensitivity analyses confirmed the robustness of the findings. Individual negative deviations from the normative model (more volume contractions than predicted) at age 25 predicted current and later anxiety, even when controlling for other psychopathology and adversities. No relationship was found for positive deviations.

The study provides compelling evidence for a persistent neurobiological signature of lifespan adversity exposure in the adult brain. This signature is stable over time and replicable across independent samples. The findings highlight region-specific accelerated or delayed development related to specific adversities. Individual heterogeneity in the expression of this adversity signature is clinically meaningful, as negative deviations from the normative model are predictive of anxiety. The study's design allowed investigating the independent and combined effects of multiple adversities, revealing distinct trajectories associated with specific adversity profiles (e.g., vmOFC volume contractions after psychosocial adversities and expansions after obstetric risks). This suggests that psychosocial adversities may accelerate development in some regions, while obstetric risks may delay it. The stable neurobiological pattern may indicate reduced neural adaptability in adulthood, although further research is needed to explore this. The association between negative deviations and anxiety may be linked to heightened cortisol reactivity and increased vigilance, potentially leading to neurotoxic effects.

This study demonstrates a stable and replicable neural signature of lifespan adversity exposure in the adult brain. This signature is widespread, region-specific, and related to the timing and type of adversity. Individual-level deviations from normative trajectories predict anxiety. Future research should investigate the impact of timing of adverse experiences during critical brain development periods, explore cause-and-effect relationships, and validate findings in larger samples and clinical populations. Further investigation of the interplay between subjective experience of adversity and objective adversity exposure is also crucial.

The study's limitations include the availability of imaging data only in adulthood, the potential for bidirectional relationships between adversity and brain structure, and the need for further replication in larger and more diverse samples. The reliance on self-reported measures of adversity and the lack of distinction between threat and deprivation as dimensions of adversity also pose limitations. Future studies should collect neuroimaging data across the lifespan, incorporate multimodal data, and refine adversity assessments to improve understanding of this complex relationship.