Achieving remission in Gulf War Illness: A simulation-based approach to treatment design

Gulf War Illness (GWI) is a chronic multi-symptom disorder affecting up to one-third of the 700,000 returning veterans of the 1991 Persian Gulf War and for which there is no known cure. GWI symptoms span several of the body's principal regulatory systems and include debilitating fatigue, severe musculoskeletal pain, cognitive and neurological problems. Using computational models, our group reported previously that GWI might be perpetuated at least in part by natural homeostatic regulation of the neuroendocrine-immune network. In this work, we attempt to harness these regulatory dynamics to identify treatment courses that might produce lasting remission. Towards this we apply a combinatorial optimization scheme to the Monte Carlo simulation of a discrete ternary logic model that represents combined hypothalamic-pituitary-adrenal (HPA), gonadal (HPG), and immune system regulation in males. In this work we found that no single intervention target allowed a robust return to normal homeostatic control. All combined interventions leading to a predicted remission involved an initial inhibition of Th1 inflammatory cytokines (Th1Cyt) followed by a subsequent inhibition of glucocorticoid receptor function (GR). These first two intervention events alone ended in stable and lasting return to the normal regulatory control in 40% of the simulated cases. Applying a second cycle of this combined treatment improved this predicted remission rate to 2 out of 3 simulated subjects (63%). These results suggest that in a complex illness such as GWI, a multi-tiered intervention strategy that formally accounts for regulatory dynamics may be required to reset neuroendocrine-immune homeostasis and support extended remission.