Childhood maltreatment influences adult brain structure through its effects on immune, metabolic, and psychosocial factors

Abstract

Childhood maltreatment (CM) leads to a lifelong susceptibility to mental ill-health which might be reflected by its effects on adult brain structure, perhaps indirectly mediated by its effects on adult metabolic, immune, and psychosocial systems. Indexing these systemic factors via body mass index (BMI), C-reactive protein (CRP), and rates of adult trauma (AT), respectively, we tested three hypotheses: (H1) CM has direct or indirect effects on adult trauma, BMI, and CRP; (H2) adult trauma, BMI, and CRP are all independently related to adult brain structure; and (H3) childhood maltreatment has indirect effects on adult brain structure mediated in parallel by BMI, CRP, and AT. Using path analysis and data from N = 116,887 participants in UK Biobank, we find that CM is related to greater BMI and AT levels, and that these two variables mediate CM's effects on CRP [H1]. Regression analyses on the UKB MRI subsample (N = 21,738) revealed that greater CRP and BMI were both independently related to a spatially convergent pattern of cortical effects (Spearman's ρ = 0.87) characterized by fronto-occipital increases and temporo-parietal reductions in thickness. Subcortically, BMI was associated with greater volume, AT with lower volume and CPR with effects in both directions [H2]. Finally, path models indicated that CM has indirect effects in a subset of brain regions mediated through its direct effects on BMI and AT and indirect effects on CRP [H3]. Results provide evidence that childhood maltreatment can influence brain structure decades after exposure by increasing individual risk toward adult trauma, obesity, and inflammation.

Keywords: MRI; childhood maltreatment; gray matter; inflammation; metabolic.

Fig. 1.

Relationships between childhood maltreatment, adult trauma, BMI, and CRP. (A) Correlation matrix representing pair-wise Spearman’s correlations (Upper triangle) and scatterplots of the relationships between each pair of variables, with solid lines indicating fitted linear regression models (Lower triangle). The diagonal represents the probability density function for each variable. All correlations were significantly greater than zero, with FDR $\le 0.05$. (B) Path diagram representing direct effects of retrospectively ascertained CM (white) on the contemporaneously measured adult (log-transformed) variables, AT, CRP, and BMI (gray). Standardized path coefficients are given as Wald (z) statistics.

Fig. 2.

Independent effects of adult trauma, BMI, and CRP on adult cortical thickness and subcortical volumes. (A, Left column) Brain maps of independent linear relationships between adult trauma (AT), CRP or BMI, and cortical thickness (CT) and subcortical volume. Each map shows the anatomical distribution of effect sizes (t-values); for corresponding maps thresholded for FDR-corrected significance, see SI Appendix Fig. S18; for maps of standardized regression β coefficients, see SF20A&B. Negative t-values indicate a reduction in either cortical thickness or subcortical volume (red), and positive t-values indicate an increase in gray matter (blue), as a result of increase in one of these independently treated predictor variables. (A, Right column) Illustrative scatterplots of the relationship between each independent variable and the cortical area or subcortical structure most strongly associated with it. Cortical areas are labeled by their specific areal nomenclature and corresponding regional grouping, as defined by the Glasser template (35). (B, Top panel) Scatterplot of the effect size (t-value) of BMI (x-axis) versus the effect size of CRP (t-value; y-axis) on cortical thickness; each point represents one of 180 cortical areas; Spearman’s correlation $\rho =0.87,P_{\mathit{spin}}<0.0001$ over all areas; the solid line is the regression of t-values for the effect of BMI on t-values for the effect of CRP. (B, Bottom panel) Scatterplot of the effect size of BMI on CT (x-axis) versus the effect size of AT on CT (y-axis); Spearman’s $\rho =-0.41$, $P_{\mathit{spin}}=0.0009$.

Fig. 3.

Indirect effects of childhood maltreatment (CM) on cortical subcortical structures can be mediated by direct effects on body mass index (BMI), C-reactive protein (CRP) or adult trauma (AT) in two nested path models (full and sparse). (A and B) Diagrams of nested path models of indirect effects of CM on brain structure. Full model (A): contains direct effects of BMI, CRP and AT on adult brain MRI measurements (paths $c1,c2$ and $c3$, respectively); all other paths between non-MRI variables are identical to the model in Fig. 1. Sparse model (B) contains a direct effect of CRP, only, on adult brain structure; adult trauma and BMI can have indirect effects on brain MRI measurements mediated by their direct effects on CRP. (C) Comparison of full and sparse models: This pair of nested models was evaluated at each of 180 cortical areas defined by the Glasser parcellation (36) and their difference in model goodness-of-fit was measured by the likelihood-ratio. Yellow areas indicate significantly better fit by the full model at FDR $\le 0.05$; green areas indicate where the sparse model was sufficient to explain local variance. (D, left.) Brain map of BMI-mediated indirect effects (Wald z) of childhood maltreatment on brain structure, together with a schema highlighting (in bold lines) the paths whose coefficients are combined to estimate the overall magnitude of the indirect effect. Blank areas on the cortical and subcortical maps indicate non-significant results (FDR $\ge 0.05$) or locations where the model was not evaluated. Negative z-values indicate decreased grey matter (blue), and positive z-values indicate increased grey matter (red), associated with greater BMI predicted by greater CM. (D, right.) Indirect effects of childhood maltreatment on brain structure, mediated by adult trauma. Negative z-values indicate decreased grey matter (blue); positive z-values indicate increased grey matter (red), associated with greater AT predicted by greater CM. For thresholded and unthresholded maps of all paths evaluated see SI Appendix, Figs. S21 and S22; and for unstandardized coefficients see SI Appendix, Figs. S23 and S24. (E, left) Childhood maltreatment had indirect effects on adult brain structure that were mediated by a chain of paths from CM → BMI → CRP. Negative z-values indicate reduced CT was indirectly predicted by CM via its direct effects on BMI, which in turn could have effects on brain structure directly or via its effects on CRP. (E, right) There were no significant indirect effects of childhood maltreatment mediated by a chain of paths from CM to CRP via AT, i.e., CM → AT → CRP. For maps of all thresholded and unthresholded paths see SI Appendix, Figs. S25 and S26; for unstandardized coefficients SI Appendix, Figs. S27 and S28. Wald z scores represent the product of path coefficients (standardized by their standard errors) constituting each of the indirect effects of CM on brain structure evaluated by these two (full and sparse) models.