Illness progression, recent stress, and morphometry of hippocampal subfields and medial prefrontal cortex in major depression

Abstract

Background: Longitudinal studies of illness progression in patients with major depressive disorder (MDD) indicate that the onset of subsequent depressive episodes becomes increasingly decoupled from external stressors. A possible mechanism underlying this phenomenon is that multiple episodes induce long-lasting neurobiological changes that confer increased risk for recurrence. Prior morphometric studies have frequently reported volumetric reductions in patients with MDD--especially in medial prefrontal cortex (mPFC) and the hippocampus--but few studies have investigated whether these changes are exacerbated by prior episodes.

Methods: In a sample of 103 medication-free patients with depression and control subjects with no history of depression, structural magnetic resonance imaging was performed to examine relationships between number of prior episodes, current stress, hippocampal subfield volume and cortical thickness. Volumetric analyses of the hippocampus were performed using a recently validated subfield segmentation approach, and cortical thickness estimates were obtained using vertex-based methods. Participants were grouped on the basis of the number of prior depressive episodes and current depressive diagnosis.

Results: Number of prior episodes was associated with both lower reported stress levels and reduced volume in the dentate gyrus. Cortical thinning of the left mPFC was associated with a greater number of prior depressive episodes but not current depressive diagnosis.

Conclusions: Collectively, these findings are consistent with preclinical models suggesting that the dentate gyrus and mPFC are especially vulnerable to stress exposure and provide evidence for morphometric changes that are consistent with stress-sensitization models of recurrence in MDD.

Keywords: Dentate gyrus; Hippocampus; MAGeT brain; MRI; Major depression; mPFC.

Figure 1

Linear and quadratic relationship between recent stress levels and number of prior episodes. A. Across all subjects, a quadratic model had a significantly better fit (R² = 0.68, p < 0.001) than the linear model (R² = 0.41, p <0.001). Error bars represent ±95% confidence interval. B. Within currently depressed patients, PSS showed a significant inverse relationship to with number of episodes (b = −0.24, p < 0.05 (one-tailed)).

Figure 2

Examples of representative hippocampal subfield segmentations for MDD and Control subjects.

Figure 3

Effects of number of episodes on volume of hippocampal subfields and amygdala (averaged across hemisphere). X-axis shows number of prior depressed episodes with “C” denoting never-depressed controls. Y-axis shows residualized volume after controlling for sex, age, and total brain volume. Error bars represent ± standard error of the mean.

Figure 4

Areas showing an association between cortical thickness and number of depressive episodes across all subjects, cluster-corrected. Regions shown include the left medial prefrontal cortex (A) as well as bilateral parahippocampal gyrus and medial temporal cortex (B).