Long-term effect of childhood trauma: Role of inflammation and white matter in mood disorders

Abstract

Bipolar disorder (BD) and major depressive disorder (MDD) are severe psychiatric illnesses that share among their environmental risk factors the exposure to adverse childhood experiences (ACE). Exposure to ACE has been associated with long-term changes in brain structure and the immune response. In the lasts decades, brain abnormalities including alterations of white matter (WM) microstructure and higher levels of peripheral immune/inflammatory markers have been reported in BD and MDD and an association between inflammation and WM microstructure has been shown. However, differences in these measures have been reported by comparing the two diagnostic groups. The aim of the present study was to investigate the interplay between ACE, inflammation, and WM in BD and MDD. We hypothesize that inflammation will mediate the association between ACE and WM and that this will be different in the two groups. A sample of 200 patients (100 BD, 100 MDD) underwent 3T MRI scan and ACE assessment through Childhood Trauma Questionnaire. A subgroup of 130 patients (75 MDD and 55 BD) underwent blood sampling for the assessment of immune/inflammatory markers. We observed that ACE associated with higher peripheral levels of IL-2, IL-17, bFGF, IFN-γ, TNF-α, CCL3, CCL4, CCL5, and PDGF-BB only in the BD group. Further, higher levels of CCL3 and IL-2 associated with lower FA in BD. ACE were found to differently affect WM microstructure in the two diagnostic groups and to be negatively associated with FA and AD in BD patients. Mediation analyses showed a significant indirect effect of ACE on WM microstructure mediated by IL-2. Our findings suggest that inflammation may mediate the detrimental effect of early experiences on brain structure and different mechanisms underlying brain alterations in BD and MDD.

Keywords: Bipolar disorder; Early stress; Interleukin 2; White matter.

Fig. 1

WM tracts where ACE negatively associated with FA.

Fig. 2

WM areas where CCL3 peripheral levels significantly correlated with lower fractional anisotropy in BD. Voxels of significant negative correlation are mapped on the mean FA template of the studied sample, and are shown in glass-brain images. The colorbar refers to 1-p values for the observed differences. Numbers are z coordinates in the standard Montreal Neurological Institute (MNI) space.

Fig. 3

WM areas where IL-2 peripheral levels significantly correlated with lower fractional anisotropy in BD. Voxels of significant negative correlation are mapped on the mean FA template of the studied sample, and are shown in glass-brain images. The colorbar refers to 1-p values for the observed differences. Numbers are z coordinates in the standard Montreal Neurological Institute (MNI) space.

Fig. 4

Mediation model for the effect of ACE through IL-2 for FA measures of WM tracts. a, b, c and c’ are path coefficients representing unstandardized regression weights. * Significant confidence intervals at 95%.