Warfighter Neuroendocrinology: modeling stress response, PTSD, and TBI

Physiological response to stress is an important determinant of performance and health. Although there have been many experimental, biological studies about stress and the physiological responses it elicits, there have been few mechanistically-based mathematical models. Existing models describe the dynamics of the hypothalamus-pituitary-adrenal system (HPA) in terms of cortisol output. Such neuroendocrine models have not been fully developed to include interactions with other stress-related brain regions, nor have they been used to help define possible biomarkers for stress. Moreover, with few exceptions, there have been few attempts to use mathematical models to describe conditions such as post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI), and mechanisms of their treatment. In this study, the investigators will develop comprehensive mathematical models to better understand the neuroendocrine system and to to better address these shortcomings. The proposal will focus on achieving the following three aims: Aim 1: Develop dynamical models for neuroendocrine systems - Mathematical models of the HPA axis will be extended to include additional interactions with brain structures (such as the locus coeruleus and amygdala), the effects of neuromodulation, and coupling to processes mediated by direct activation by action potentials. Particular attention will be paid to multi-stationarity and oscillatory behavior of these models. One goal will be to motivate and use delays to develop reduced models that exhibit oscillatory and/or multiple basins of attraction. Aim 2: Explore time-dependent parameters and forcing of the models - The models developed in Aim 1 will be further explored to identify and describe diseased states that can be identified as PTSD or TBI, as well as their treatment. Different parameters and driving terms (e.g., sources of stress) will be explored to determine the response of the our models to both adverse events and treatments. One specific goal will be to explore whether dysfunction such as PTSD can be described as alternative stable state and its onset as?first order? transition between basins of attraction or by continuous ?second order? changes in the models. Aim 3: Model coupling between neuroendocrine system with measurable biomarkers - Our final aim will be to analyze, within our mathematical models, neuroendocrine response to stress might be detected through biomarkers such as heart rate, sweat gland activity, vascular constriction, etc. We will develop models to study the coupling between various neuroendocrine systems and the autonomic nervous system that couples stress response in the brain to other physiological observables. This coupling is fundamental since it leads to variations in observable physiological responses. Our models will be analyzed to provide guidance for the development of useful biomarkers. Research plan and timeline - The research team will consist of Prof. M. R. D?Orsogna (Math, Calstate Northridge) and Prof. T. Chou (Biomathematics, UCLA) who will each supervise a graduate student on this project. In year 1, the investigators will focus on Aim 1 by culling the clinical and experimental observations and developing self-consistent mathematical models. Year 2 will focus on analysis of these models in the context of disease and treatment, while year 3 will largely explore the quantification of readouts or biomarkers for the neuroendocrine system.