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Achieving Remission in Gulf War Illness: A Simulation-Based Approach to Treatment Design.

Craddock TJ, Del Rosario RR, Rice M, Zysman JP, Fletcher MA, Klimas NG, Broderick G - PLoS ONE (2015)

Bottom Line: 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%).

View Article: PubMed Central - PubMed

Affiliation: Institute for Neuro Immune Medicine, Nova Southeastern University, Ft. Lauderdale, FL, United States of America; Center for Psychological Studies, Nova Southeastern University, Ft. Lauderdale, FL, United States of America; Graduate School for Computer and Information Sciences, Nova Southeastern University, Ft. Lauderdale, FL, United States of America; College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL, United States of America.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Average values of simulated Th1Cyt—GR inhibition treatment course.
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pone.0132774.g007: Average values of simulated Th1Cyt—GR inhibition treatment course.

Mentions: Due to the limited availability of detailed kinetic data, the models used in this work strictly enforce the direction and sequence of regulatory control actions but do not represent the response time. Although the intervals described in Figs 6 and 7 are reported as simulation time steps, the actual timescale of these treatments courses can nonetheless be extracted in the form of landmark states. To provide a more robust approximation of the rate of success and to glimpse the intermediate transitory states occupied by the system, a minimally invasive single treatment cycle of Th1Cyt/ GR inhibition was simulated 1000 times. The value of each node variable was averaged for each time-point and plotted as a function of the time-step for all simulations leading to the HHM (Fig 7). These simulation results indicate that Th1Cyt inhibition alone causes the system to move from the GWI illness state characterized by high CORT, low TEST and a Th1 shift towards one of the other alternate homeostatic modes (AHM) predicted in our previous work [16], with high GRD, GR and low ACTH. Treatment of this second alternate mode with inhibition of GR pushes the system towards normal homeostasis. Importantly these simulations suggest that the second intervention involving GR blockade should not be applied until ACTH levels reach a stable minimum. Only then should a GR blockade be attempted. As HPA dynamics may be expected to vary from one individual to the next, these intervals will fluctuate and such landmark states might in reality prove to be more useful than a standardized time period. Simulations also showed that subsequent cycles of Th1Cyt and GR inhibition produce similar responses and serve to redirect those trajectories that did not respond to the first two-step treatment course, thus increasing the overall percentage of trajectories reaching health.


Achieving Remission in Gulf War Illness: A Simulation-Based Approach to Treatment Design.

Craddock TJ, Del Rosario RR, Rice M, Zysman JP, Fletcher MA, Klimas NG, Broderick G - PLoS ONE (2015)

Average values of simulated Th1Cyt—GR inhibition treatment course.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4508058&req=5

pone.0132774.g007: Average values of simulated Th1Cyt—GR inhibition treatment course.
Mentions: Due to the limited availability of detailed kinetic data, the models used in this work strictly enforce the direction and sequence of regulatory control actions but do not represent the response time. Although the intervals described in Figs 6 and 7 are reported as simulation time steps, the actual timescale of these treatments courses can nonetheless be extracted in the form of landmark states. To provide a more robust approximation of the rate of success and to glimpse the intermediate transitory states occupied by the system, a minimally invasive single treatment cycle of Th1Cyt/ GR inhibition was simulated 1000 times. The value of each node variable was averaged for each time-point and plotted as a function of the time-step for all simulations leading to the HHM (Fig 7). These simulation results indicate that Th1Cyt inhibition alone causes the system to move from the GWI illness state characterized by high CORT, low TEST and a Th1 shift towards one of the other alternate homeostatic modes (AHM) predicted in our previous work [16], with high GRD, GR and low ACTH. Treatment of this second alternate mode with inhibition of GR pushes the system towards normal homeostasis. Importantly these simulations suggest that the second intervention involving GR blockade should not be applied until ACTH levels reach a stable minimum. Only then should a GR blockade be attempted. As HPA dynamics may be expected to vary from one individual to the next, these intervals will fluctuate and such landmark states might in reality prove to be more useful than a standardized time period. Simulations also showed that subsequent cycles of Th1Cyt and GR inhibition produce similar responses and serve to redirect those trajectories that did not respond to the first two-step treatment course, thus increasing the overall percentage of trajectories reaching health.

Bottom Line: 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%).

View Article: PubMed Central - PubMed

Affiliation: Institute for Neuro Immune Medicine, Nova Southeastern University, Ft. Lauderdale, FL, United States of America; Center for Psychological Studies, Nova Southeastern University, Ft. Lauderdale, FL, United States of America; Graduate School for Computer and Information Sciences, Nova Southeastern University, Ft. Lauderdale, FL, United States of America; College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL, United States of America.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus