Modeling Cortisol Dynamics in the Neuro-endocrine Axis Distinguishes Normal, Depression, and Post-traumatic Stress Disorder (PTSD) in Humans

Abstract

Cortisol, secreted in the adrenal cortex in response to stress, is an informative biomarker that distinguishes anxiety disorders such as major depression and post-traumatic stress disorder (PTSD) from normal subjects. Yehuda et al. proposed a hypothesis that, in humans, the hypersensitive hypothalamus-pituitary-adrenal (HPA) axis is responsible for the occurrence of differing levels of cortisol in anxiety disorders. Specifically, PTSD subjects have lower cortisol levels during the late subjective night in comparison to normal subjects, and this was assumed to occur due to strong negative feedback loops in the HPA axis. In the present work, to address this hypothesis, we modeled the cortisol dynamics using nonlinear ordinary differential equations and estimated the kinetic parameters of the model to fit the experimental data of three categories, namely, normal, depressed, and PTSD human subjects. We concatenated the subjects (n = 3) in each category and created a model subject (n = 1) without considering the patient-to-patient variability in each case. The parameters of the model for the three categories were simultaneously obtained through global optimization. Bifurcation analysis carried out with the optimized parameters exhibited two supercritical Hopf points and, for the choice of parameters, the oscillations were found to be circadian in nature. The fitted kinetic parameters indicate that PTSD subjects have a strong negative feedback loop and, as a result, the predicted oscillating cortisol levels are extremely low at the nadir in contrast to normal subjects, albeit within the endocrinologic range. We also simulated the phenotypes for each of the categories and, as observed in the clinical data of PTSD patients, the simulated cortisol levels are consistently low at the nadir, and correspondingly the negative feedback was found to be extremely strong. These results from the model support the hypothesis that high stress intensity and strong negative feedback loop may cause hypersensitive neuro-endocrine axis that results in hypocortisolemia in PTSD.

Hypothalamic-pituitary-adrenal axis dysregulation and cortisol activity in obesity: A systematic review

“…Borrowing from the field of systems engineering, robustness theory describes how architectural features of a system (in this case, negative cortisol feedback loops, adrenal/non-adrenal interactions, and 11␤-HSD and other enzymatic interactions) give rise to system functioning. Dynamic systems modeling has been used successfully within the context of HPA function (Aschbacher et al, 2012;Sriram et al, 2012;Vinther et al, 2011), as well as in predicting metabolic health (Aschbacher et al, 2014). This approach to modeling HPA activity in obesity may be more appropriate and is a promising avenue for future research.…”

Concerns Over Divergent Approaches in the Diagnostics of Posttraumatic Stress Disorder

“…Rather, investigations will more likely identify or model dynamics of different biomarkers or biosignatures that indicate the presence of clinically significant PTSD symptoms, associate with risk for PTSD after trauma exposure, and predict or identify recovery. 97 Protein, metabolic, as well as genetic and genomic candidate biomarkers are being sought, but none so far has been discovered that shows sufficient sensitivity for PTSD diagnosis as well as specificity (ie, little overlap with other psychiatric diagnoses). 40,98 The most replicated biomarker so far is a hypothalamic-pituitary-adrenal axis finding of low plasma cortisol (especially at the nadir), and increased glucocorticoid receptor sensitivity, a finding opposite that of MDD, despite commonalities that include central nervous system hyperarousal, increased amygdalar reactivity, and diminished parasympathetic outflow.…”

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

“…Authors Recommendations: The validity of this model can be more clearly demonstrated by comparing the model solution with the previously published data of cortisol dynamics in normal and post-traumatic stress disorder (PTSD) in references ( [53] and [16]). …”

“…These models [13,14,16] incorporate positive self-regulation of glucocorticoid receptor expression in the pituitary, which may generate bistability in the dynamical structure of the model [17]. Of the two stable equilibrium states, one is characterized by higher levels of cortisol and is identified as the "normal" state.…”