Perturbing the Hypothalamic–Pituitary–Adrenal Axis: A Mathematical Model for Interpreting PTSD Assessment Tests

Abstract

We use a dynamical systems model of the hypothalamic–pituitary–adrenal (HPA) axis to understand the mechanisms underlying clinical protocols used to probe patient stress response. Specifically, we address dexamethasone (DEX) and ACTH challenge tests, which probe pituitary and adrenal gland responses, respectively. We show that some previously observed features and experimental responses can arise from a bistable mathematical model containing two steady-states, rather than relying on specific and permanent parameter changes due to physiological disruption. Moreover, we show that the timing of a perturbation relative to the intrinsic oscillation of the HPA axis can affect challenge test responses. Conventional mechanistic hypotheses supported and refuted by the challenge tests are reexamined by varying parameters in our mathematical model associated with these hypotheses. We show that (a) adrenal hyposensitivity can give rise to the responses seen in ACTH challenge tests and (b) enhanced cortisol-mediated s...