The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology

Abstract

Volumetric reductions in the hippocampus and medial prefrontal cortex (mPFC) are among the most well-documented neural abnormalities in major depressive disorder (MDD). Hippocampal and mPFC structural reductions have been specifically tied to MDD illness progression markers, including greater number of major depressive episodes (MDEs), longer illness duration, and nonremission/treatment resistance. Chronic stress plays a critical role in the development of hippocampal and mPFC deficits, with some studies suggesting that these deficits occur irrespective of MDE occurrence. However, preclinical and human research also points to other stress-mediated neurotoxic processes, including enhanced inflammation and neurotransmitter disturbances, which may require the presence of an MDE and contribute to further brain structural decline as the illness advances. Specifically, hypothalamic-pituitary-adrenal axis dysfunction, enhanced inflammation and oxidative stress, and neurotransmitter abnormalities (e.g., serotonin, glutamate, gamma-aminobutyric acid) likely interact to facilitate illness progression in MDD. Congruent with stress sensitization models of MDD, with each consecutive MDE it may take lower levels of stress to trigger these neurotoxic pathways, leading to more pronounced brain volumetric reductions. Given that stress and MDD have overlapping and distinct influences on neurobiological pathways implicated in hippocampal and mPFC structural decline, further work is needed to clarify which precise mechanisms ultimately contribute to MDD development and maintenance.

Keywords: Depression; Hippocampus; Illness progression; Medial prefrontal cortex; Neuroprogression; Stress.

Figure 1.. The Role of Chronic Stress and Neurotoxic Processes on Brain Volumetric Reductions and MDD Illness Progression.

Chronic life stress can trigger the initial development of medial prefrontal cortex (mPFC) and hippocampal volume reductions. However, these reductions are neither necessary nor sufficient to produce a major depressive episode. On the other hand, stress also initiates a set of neurotoxic processes (hypothalamic pituitary adrenal (HPA) axis dysregulation, inflammation, neurotransmitter disturbances) that interact and may drive the development of a more chronic type of MDD marked by further reductions in hippocampal and mPFC volume reductions.

Figure 2.. Estimated Effect Sizes of Hippocampal and mPFC Volume Reductions in MDD.

The medial prefrontal cortex (mPFC) includes ventral portions of the mPFC (ventral medial prefrontal cortex; vmPFC, medial orbitofrontal cortex; mOFC) and dorsal portions of the mPFC (dorsal medial prefrontal cortex; dmPFC) as well as rostral anterior cingulate cortex; rACC and dorsal anterior cingulate cortex; dACC). In this figure, we provide a range, mean (standard deviation) of effect sizes calculated from individual studies for each of the mPFC subdivisions. We also provide a range, mean (standard deviation) of effect sizes for reduced hippocampal volumes in MDD calculated from three prior meta-analyses. Negative effect size values indicate that those with MDD have reduced mPFC and hippocampal volumes compared to healthy controls.

Figure 3.. A Stress-Mediated Neurotoxic Pathway Leading to Chronic MDD Hippocampal and mPFC Volume Reduction.

Chronic stress sets off a cascade of neurotoxic processes. The presence of chronic stress triggers dysregulation of the hypothalamic pituitary adrenal (HPA) axis, which can either be enhanced or blunted due to glucocorticoid resistance. This HPA axis dysregulation triggers the immune system, leading to enhanced inflammation (stress can also have a direct effect on inflammation not mediated by the HPA axis). In turn, enhanced inflammation can produce further dysregulation of the HPA axis. Pro-inflammatory cytokines then activate indoleamine 2,3-dioxygenase (IDO), an enzyme that catabolizes tryptophan, which leads to serotonin depletion and the production of kynurenine. Kynurenine can be converted to neurotoxic 3HK and quinolinic acid, which can increase glutamate release and oxidative stress, as well as reduce GABA inhibitory control. Dysregulated serotonin levels lead to further reductions in GABA inhibitory control. This reduction in GABA inhibitory control can lead to further glutamate release. With successive major depressive episodes, even minor levels of stress can trigger this pathway, leading to further hippocampal and mPFC volume decline. Genetic risk profiles can also increase vulnerability to chronic stress triggering of these neurotoxic pathways to illness progression and brain structural decline.