Hippocampal atrophy in major depression: a function of childhood maltreatment rather than diagnosis?

Abstract

Reduced hippocampal volumes are probably the most frequently reported structural neuroimaging finding associated with major depressive disorder (MDD). However, it remains unclear whether altered hippocampal structure represents a risk factor for or a consequence of MDD. Reduced hippocampal volumes were consistently reported in subjects affected by childhood maltreatment. As the prevalence of childhood maltreatment is highly elevated in MDD populations, previous morphometric findings regarding hippocampal atrophy in MDD therefore might have been confounded by maltreatment experiences. The aim of this study was to differentiate the impact of childhood maltreatment from the influence of MDD diagnosis on hippocampal morphometry. Depressed patients (85) as well as 85 age- and sex-matched healthy controls underwent structural MRI. The Childhood Trauma Questionnaire was administered to estimate experiences of childhood maltreatment. Hippocampal volume and surface structure was examined by the use of two independent methods, automated segmentation (FSL-FIRST) and voxel-based morphometry (VBM8). In line with existing studies, MDD patients showed reduced hippocampal volumes, and childhood maltreatment was consistently associated with hippocampal volume loss in both, patients and healthy controls. However, no analysis revealed significant morphological differences between patients and controls if maltreatment experience was regressed out. Our results suggest that hippocampal alterations in MDD patients may at least partly be traced back to higher occurrence of early-life adverse experiences. Regarding the strong morphometric impact of childhood maltreatment and its distinctly elevated prevalence in MDD populations, this study provides an alternative explanation for frequently observed limbic structural abnormalities in depressed patients.

Figure 1

Results of FSL-FIRST vertex analysis of group differences in left hippocampal shape (dorsal and ventral view). The color bar indicates the values of the F-statistics: an increase from red to blue means transition from lower to higher statistical significance, whereas the length of the vectors displays mean differences between groups. For display reasons, unthresholded values are presented. The vectors indicate the direction of change: vectors pointing inwards represent local atrophy. (a) Major depressive disorder patients show significant local atrophy in fronto-temporal and temporal areas of the left hippocampus compared with healthy controls. (b) Significant differences in hippocampal shape between patients and healthy controls (blue areas) vanish if Childhood Trauma Questionnaire score is included as a covariate.

Figure 2

Results of FSL-FIRST vertex analysis of correlation of Childhood Trauma Questionnaire (CTQ)-scores with left hippocampal shape (dorsal and ventral view). The color bar indicates the values of the F-statistics: an increase from red to blue means transition from lower to higher statistical significance, whereas the length of the vectors displays means strength of correlation. For display reasons, unthresholded values are presented. The vectors indicate the direction of change: vectors pointing inwards represent local atrophy. (a) High CTQ-scores correlate significantly with local atrophy in fronto-temporal and occipito-temporal areas of the left hippocampus in major depressive disorder patients. (b) High CTQ-scores correlate significantly with local atrophy in fronto-temporal, occipito-medial, and occipito-temporal areas of the left hippocampus in the whole-sample analysis.

Figure 3

Effect of childhood maltreatment on hippocampal gray matter volume in the entire study sample. Left: coronal view (x=−14) depicting gray matter volume negatively associated with Childhood Trauma Questionnaire (CTQ)-scores; color bar, negative correlation coefficient r. Right: scatter plot depicting gray matter volume at x=−14, y=−10, z=−24 correlated with CTQ-scores within the entire sample. Dotted lines: regression slopes of patients and controls separately; continuous line: regression slope in the entire sample.