Onset, timing, and exposure therapy of stress disorders: mechanistic insight from a mathematical model of oscillating neuroendocrine dynamics

TL;DR

This paper presents a mathematical model of the HPA axis revealing how stress timing influences stress disorder states and suggesting exposure therapy mechanisms to restore normal function.

Contribution

The study introduces a dynamical systems model of the HPA axis that incorporates physiological features and explains how stress timing affects disease transitions and therapy outcomes.

Findings

Stress timing impacts transitions between healthy and diseased HPA states.

Model predicts exposure therapy can normalize HPA axis dysregulation.

Ultradian cortisol oscillations are key to understanding stress responses.

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis is a neuroendocrine system that regulates numerous physiological processes. Disruptions in the activity of the HPA axis are correlated with many stress-related diseases such as post-traumatic stress disorder (PTSD) and major depressive disorder. In this paper, we characterize "normal" and "diseased" states of the HPA axis as basins of attraction of a dynamical system describing the inhibition of peptide hormones such as corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) by circulating glucocorticoids such as cortisol (CORT). In addition to including key physiological features such as ultradian oscillations in cortisol levels and self-upregulation of CRH neuron activity, our model distinguishes the relatively slow process of cortisol-mediated CRH biosynthesis from rapid trans-synaptic effects that regulate the CRH secretion process. Crucially, we find that the slow regulation mechanism mediates external stress-driven transitions between the stable states in novel, intensity, duration, and timing-dependent ways. These results indicate that the timing of traumatic events may be an important factor in determining if and how patients will exhibit hallmarks of stress disorders. Our model also suggests a mechanism whereby exposure therapy of stress disorders such as PTSD may act to normalize downstream dysregulation of the HPA axis.