Resting-state functional connectivity patterns associated with childhood maltreatment in a large bicentric cohort of adults with and without major depression

Abstract

Background: Childhood maltreatment (CM) represents a potent risk factor for major depressive disorder (MDD), including poorer treatment response. Altered resting-state connectivity in the fronto-limbic system has been reported in maltreated individuals. However, previous results in smaller samples differ largely regarding localization and direction of effects.

Methods: We included healthy and depressed samples [n = 624 participants with MDD; n = 701 healthy control (HC) participants] that underwent resting-state functional MRI measurements and provided retrospective self-reports of maltreatment using the Childhood Trauma Questionnaire. A-priori defined regions of interest [ROI; amygdala, hippocampus, anterior cingulate cortex (ACC)] were used to calculate seed-to-voxel connectivities.

Results: No significant associations between maltreatment and resting-state connectivity of any ROI were found across MDD and HC participants and no interaction effect with diagnosis became significant. Investigating MDD patients only yielded maltreatment-associated increased connectivity between the amygdala and dorsolateral frontal areas [p_FDR < 0.001; η²_partial = 0.050; 95%-CI (0.023-0.085)]. This effect was robust across various sensitivity analyses and was associated with concurrent and previous symptom severity. Particularly strong amygdala-frontal associations with maltreatment were observed in acutely depressed individuals [n = 264; p_FDR < 0.001; η²_partial = 0.091; 95%-CI (0.038-0.166)). Weaker evidence - not surviving correction for multiple ROI analyses - was found for altered supracallosal ACC connectivity in HC individuals associated with maltreatment.

Conclusions: The majority of previous resting-state connectivity correlates of CM could not be replicated in this large-scale study. The strongest evidence was found for clinically relevant maltreatment associations with altered adult amygdala-dorsolateral frontal connectivity in depression. Future studies should explore the relevance of this pathway for a maltreated subgroup of MDD patients.

Keywords: adverse childhood experiences; amygdala; childhood maltreatment; depression; emotion regulation; resting-state functional connectivity.

Fig. 1.

Clusters with altered connectivity to the right amygdala associated with CTQ sum in lifetime MDD participants. (a) Right amygdala seed region of interest (ROI) presented in red. (b) Significant clusters (before Bonferroni correction) with altered connectivity associated with maltreatment. Slice position is displayed using MNI-coordinates. (c) Scatter plots with individual CTQ sum scores and connectivity values between seed ROI and significant clusters.

Fig. 2.

Clusters with altered connectivity to the scACC associated with CTQ sum in healthy controls. (a) Right scACC seed region of interest (ROI) presented in red. (b) Significant clusters (before Bonferroni correction) with altered connectivity associated with maltreatment. Slice position is displayed using MNI-coordinates. (c) Scatter plots with individual CTQ sum scores and connectivity values between seed ROI and significant clusters.

Fig. 3.

Clusters with altered connectivity to the left hippocampus associated with CTQ sum in healthy controls. (a) Left hippocampus seed region of interest (ROI) presented in red. (b) Significant clusters (before Bonferroni correction) with altered connectivity associated with maltreatment. Slice position is displayed using MNI-coordinates. (c) Scatter plot with individual CTQ sum scores and connectivity values between seed ROI and significant cluster.

Fig. 4.

Scatter plots of associations between individual amygdala-frontal connectivity and clinical measures within the MDD sample. Individual amygdala seed connectivities with frontal cluster significantly associated with childhood maltreatment are displayed on the y-axis. BDI, Beck depression inventory; GAF, global assessment of functioning.