Mark A. Rice

A role for homeostatic drive in the perpetuation of complex chronic illness: Gulf War Illness and chronic fatigue syndrome.

A key component in the bodys stress response, the hypothalamic-pituitary-adrenal (HPA) axis orchestrates changes across a broad range of major biological systems. Its dysfunction has been associated with numerous chronic diseases including Gulf War Illness (GWI) and chronic fatigue syndrome (CFS). Though tightly coupled with other components of endocrine and immune function, few models of HPA function account for these interactions. Here we extend conventional models of HPA function by including feed-forward and feedback interaction with sex hormone regulation and immune response. We use this multi-axis model to explore the role of homeostatic regulation in perpetuating chronic conditions, specifically GWI and CFS. An important obstacle in building these models across regulatory systems remains the scarcity of detailed human in vivo kinetic data as its collection can present significant health risks to subjects. We circumvented this using a discrete logic representation based solely on literature of physiological and biochemical connectivity to provide a qualitative description of system behavior. This connectivity model linked molecular variables across the HPA axis, hypothalamic-pituitary-gonadal (HPG) axis in men and women, as well as a simple immune network. Inclusion of these interactions produced multiple alternate homeostatic states and sexually dimorphic responses. Experimental data for endocrine-immune markers measured in male GWI subjects showed the greatest alignment with predictions of a naturally occurring alternate steady state presenting with hypercortisolism, low testosterone and a shift towards a Th1 immune response. In female CFS subjects, expression of these markers aligned with an alternate homeostatic state displaying hypocortisolism, high estradiol, and a shift towards an anti-inflammatory Th2 activation. These results support a role for homeostatic drive in perpetuating dysfunctional cortisol levels through persistent interaction with the immune system and HPG axis. Though coarse, these models may nonetheless support the design of robust treatments that might exploit these regulatory regimes.

Succumbing to the laws of attraction

Feedback mechanisms throughout the immune and endocrine systems play a significant role in maintaining physiological homeostasis. Specifically, the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes contribute important oversight of immune activity and homeostatic regulation. We propose that these components form an overarching regulatory system capable of supporting multiple homeostatic regimes. These emerge as a result of the extensive feedback mechanisms involving cytokine and hormone signaling. Here we explore the possible role of such alternate regulatory programs in perpetuating chronic immune and endocrine dysfunction in males. To do this we represent documented interactions within and between components of the male HPA-HPG-immune system as a set of discrete logic circuits. Analysis of these regulatory circuits indicated that even in the absence of external perturbations this model HPA-HPG-immune network supported three distinct and stable homeostatic regimes. To investigate the relevance of these predicted homeostatic regimes, we compared them to experimental data from male subjects with Gulf War illness (GWI) and chronic fatigue syndrome (CFS), two complex chronic conditions presenting with endocrine and immune dysregulation. Results indicated that molecular profiles observed experimentally in male GWI and CFS were both distinct from the normal resting state. Profile alignments suggests that regulatory circuitry is largely intact in male GWI and that the persistent immune dysfunction in this illness may at least in part be facilitated by the body’s own homeostatic drive. Conversely the profile for male CFS was distant from all three stable states suggesting the continued influence of an exogenous agent or lasting changes to the regulatory circuitry such as epigenetic alterations.

Succumbing to the laws of attraction Exploring the sometimes pathogenic versatility of discrete immune logic

Feedback mechanisms throughout the immune and endocrine systems play a significant role in maintaining physiological homeostasis. Specifically, the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes contribute important oversight of immune activity and homeostatic regulation. We propose that these components form an overarching regulatory system capable of supporting multiple homeostatic regimes. These emerge as a result of the extensive feedback mechanisms involving cytokine and hormone signaling. Here we explore the possible role of such alternate regulatory programs in perpetuating chronic immune and endocrine dysfunction in males. To do this we represent documented interactions within and between components of the male HPA-HPG-immune system as a set of discrete logic circuits. Analysis of these regulatory circuits indicated that even in the absence of external perturbations this model HPA-HPG-immune network supported three distinct and stable homeostatic regimes. To investigate the relevance of these predicted homeostatic regimes, we compared them to experimental data from male subjects with Gulf War illness (GWI) and chronic fatigue syndrome (CFS), two complex chronic conditions presenting with endocrine and immune dysregulation. Results indicated that molecular profiles observed experimentally in male GWI and CFS were both distinct from the normal resting state. Profile alignments suggests that regulatory circuitry is largely intact in male GWI and that the persistent immune dysfunction in this illness may at least in part be facilitated by the body’s own homeostatic drive. Conversely the profile for male CFS was distant from all three stable states suggesting the continued influence of an exogenous agent or lasting changes to the regulatory circuitry such as epigenetic alterations.

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.

A case matched study examining the reliability of using ImPACT to assess effects of multiple concussions.

BackgroundApproximately 3.8 million sport and recreational concussions occur per year, creating a need for accurate diagnosis and management of concussions. Researchers and clinicians are exploring the potential dose-response cumulative effects of concussive injuries using computerized neuropsychological exams, however, results have been mixed and/or contradictory. This study starts with a large adolescent population and applies strict inclusion criteria to examine how previous mild traumatic brain injuries affect symptom reports and neurocognitive performance on the Immediate Post-concussion Assessment and Cognitive Testing (ImPACT) computerized tool.MethodsAfter applying exclusion criteria and case matching, 204 male and 99 female participants remained. These participants were grouped according to sex and the number of previous self-reported concussions and examined for overall differences on symptoms reported and scores obtained on the ImPACT neurocognitive battery composites. In an effort to further reduce confounding factors due to the varying group sizes, participants were then case matched on age, sex, and body mass index and analyzed for differences on symptoms reported and scores obtained on the ImPACT neurocognitive battery composites.ResultsCase matched analysis demonstrated males with concussions experience significantly higher rates of dizziness (p = .027, η2 = .035), fogginess (p = .038, η2 = .032), memory problems (p = .003, η2 = .055), and concentration problems (p = .009, η2 = .046) than males with no reported previous concussions. No significant effects were found for females, although females reporting two concussions demonstrated a slight trend for experiencing higher numbers of symptoms than females reporting no previous concussions.ConclusionsThe results suggest that male adolescent athletes reporting multiple concussions have lingering concussive symptoms well after the last concussive event; however, these symptoms were found to be conflicting and better explained by complainer versus complacent attitudes in the population examined. Our results conflict with a significant portion of the current literature that uses relatively lenient inclusion and exclusion criteria, providing evidence of the importance of strict inclusion and exclusion criteria and examination of confounding factors when assessing the effects of concussions.

Gulf War Illness: Is there lasting damage to the endocrine-immune circuitry?

We reported previously that the persistence of complex immune, endocrine and neurological symptoms that afflict up to one third of veterans from the 1990-91 Gulf War might be supported by a misdirected regulatory drive. Here we use a detailed model of immune signaling in concert with an overarching circuit model of known sex and stress hormone co-regulation to explore how the failure of regulatory elements may further establish a self-perpetuating imbalance that closely resembles Gulf War Illness (GWI). Defects to the model were imparted iteratively and the stable regulatory modes supported by these altered immune-endocrine circuits were identified using repeated simulation experiments. In each case the predicted homeostatic regimes were compared to experimental data collected in male GWI (n=20 ) and matched healthy veterans (n=22 ). We found that alignment of GWI with a new homeostatic regime improved significantly when cortisols normal anti-inflammatory activity was interrupted. Alignment improved further when this cortisol insensitivity was compounded by the loss of the normal antagonistic effects of Th1 cytokines on Th2 lymphocyte activation. Together these simulation results suggest altered glucocorticoid gene regulation compounded by possible changes in IGF-1 regulation of Th1:Th2 immune balance may be key underlying features of GWI.

Breaking Away: The Role of Homeostatic Drive in Perpetuating Depression

We propose that the complexity of regulatory interactions modulating brain neurochemistry and behavior is such that multiple stable responses may be supported, and that some of these alternate regulatory programs may play a role in perpetuating persistent psychological dysfunction. To explore this, we constructed a model network representing major neurotransmission and behavioral mechanisms reported in literature as discrete logic circuits. Connectivity and information flow through this biobehavioral circuitry supported two distinct and stable regulatory programs. One such program perpetuated a depressive state with a characteristic neurochemical signature including low serotonin. Further analysis suggested that small irregularities in glutamate levels may render this pathology more directly accessible. Computer simulations mimicking selective serotonin reuptake inhibitor (SSRI) therapy in the presence of everyday stressors predicted recidivism rates similar to those reported clinically and highlighted the potentially significant benefit of concurrent behavioral stress management therapy.