Autonomic Biomarkers and Treatment for Gulf War Illness

Principal Investigator: MORRIS, MARIANA
Institution Receiving Award: WRIGHT STATE UNIVERSITY
Program: GWIRP
Proposal Number: GW060050
Award Number: W81XWH-07-1-0622
Funding Mechanism: Investigator-Initiated Research Award
Partnering Awards:
Award Amount: $687,530.00


Gulf War Illness (GWI) is a syndrome suffered by veterans of the Persian Gulf War. It is characterized by problems in neuropsychological, muscular, and autonomic neural function. Even with the passage of time, it remains a debilitating problem for a group of veterans who were involved in this military theater. One idea given to explain the syndrome is the environmental exposure to potentially toxic substances, such as chemical warfare agents, pesticides, and drugs to protect against the warfare agents.

The objective of this new research initiative is to shed light on the mechanisms of GWI and to test drugs that might lead to effective treatments. One of the issues of concern in the study of GWI is the difficulty in finding an appropriate animal model. For this reason, we set out to develop an animal model that would simulate the autonomic disabilities and underlying neural changes noted in persons with GWI. The autonomic nervous system is one that regulates automatic bodily functions, such as breathing, heart rate, blood pressure, stomach movement, and others. Autonomic balance, as related to the heart, refers to the complementary input of the parasympathetic (cholinergic) and sympathetic (adrenergic) branches of the nervous system, which originates in the brainstem.

A keystone study by a clinical investigative team at a major medical center showed that GWI is associated with changes in heart rate variability and autonomic balance as well as cell damage in specific brain regions involved in regulating autonomic and central nervous system control of cardiovascular function. We developed a mouse model that reproduces these symptoms. The model is based on the fact that low-dose exposure to the chemical warfare agent sarin produces long-term autonomic and brain anatomical changes in mice. For the study, special pressure sensors were implanted in a blood vessel to measure blood pressure and heart rate over long periods. Results showed that sarin at a dose that caused no detectable symptoms produced delayed, pronounced changes in heart rate variance. Sarin also caused changes in the pattern of cell expression in brain centers controlling the heart. Data indicate that the chemically induced syndrome in mice is similar to GWI. The objective of this research program is to use the newly developed animal model for GWI to examine: (1) the utility of heart rate variance and autonomic balance as biological makers for GWI, and (2) to assess the effectiveness of treatments of the proposed GWI animal syndrome. The treatments will focus on commercially available drugs that either enhance or inhibit autonomic outflow from the brain. Thus, we will attempt to increase the parasympathetic or cholinergic system and inhibit the sympathetic adrenergic system. The drugs are ones that are currently used for the treatment of a brain-degenerative disease, Alzheimer's disease. Along with the behavioral deficits, persons with Alzheimer's also show changes in autonomic neural balance and changes in heart rate variance.

Diagnostic markers in the animals will be cardiovascular function, brain neural activation, indices of stress hormone levels, and behavioral responses to stress. The project has direct relevance to the objectives of the GWI Research Program because it will evaluate treatment strategies and identify pathophysiological mechanisms in an appropriate animal model. The pathway from animal experiments to clinical trials will be accelerated by the use of drugs that are already approved for clinical use.