Linking the Extended Autonomic System with the Homeostat Theory: New Perspectives about Dysautonomias, 2024, David S Goldstein

Abstract
Dysautonomias are conditions in which altered functions of one or more components of the autonomic nervous system (ANS) adversely affect health. This essay is about how elucidating mechanisms of dysautonomias may rationalize personalized treatments.

Emphasized here are two relatively new ideas—the “extended” autonomic system (EAS) and the “homeostat” theory as applied to the pathophysiology and potential treatments of dysautonomias. The recently promulgated concept of the EAS updates Langley’s ANS to include neuroendocrine, immune/inflammatory, and central components. The homeostat theory builds on Cannon’s theory of homeostasis by proposing the existence of comparators (e.g., a thermostat, glucostat, carbistat, barostat) that receive information about regulated variables (e.g., core temperature, blood glucose, blood gases, delivery of blood to the brain).

Homeostats sense discrepancies between the information and response algorithms. The presentation links the EAS with the homeostat theory to understand pathophysiological mechanisms of dysautonomias. Feed-forward anticipatory processes shift input–output curves and maintain plaCteau levels of regulated variables within different bounds of values—“allostasis”. Sustained allostatic processes increase long-term wear-and-tear on effectors and organs—allostatic load. The decreasing thresholds for destabilizing and potentially fatal positive feedback loops. The homeostat theory enables mathematical models that define stress, allostasis, and allostatic load.

The present discussion applies the EAS and homeostat concepts to specific examples of pediatric, adolescent/adult, and geriatric dysautonomias—familial dysautonomia, chronic orthostatic intolerance, and Lewy body diseases. Computer modeling has the potential to take into account the complexity and dynamics of allostatic processes and may yield testable predictions about individualized treatments and outcomes.

Application Adult Dysautonomias: POTS

Dysautonomias in adolescents or adults often involve complex, multi-system disorders of regulation of components of the ANS, where the effectors have developed normally. Chronic orthostatic intolerance in POTS and repeated episodes of neurocardiogenic syncope (NCS) involve many symptoms, such as fatigue, exercise and heat intolerance, presyncope, impaired concentration and memory, headache, coat hanger pain, early satiety, bloating or vomiting, tremulousness, and pallor.

Both POTS and NCS are far more common in women than men, for reasons that remain poorly understood. Among vigorously healthy astronauts re-exposed to the earth’s gravity after prolonged space flight, orthostasis intolerance is far more prevalent in females. Application of a computer model of cardiovascular function has indicated that simple differences in physiognomy such as the longitudinal center of gravity can explain the greater prevalence of post-reentry orthostatic intolerance in women than men. For the same orthostatic gravitational stress, women might have a greater shift in blood volume to pelvic veins and therefore a larger fall in venous return to the heart and cardiac stroke volume.

The schema in Figure 7 offers a concept for how neurocirculatory dyshomeostasis might result in persistent fatigue, a tendency to faint, excessive orthostatic tachycardia, and brain fog in POTS.
The red arrows indicate afferent input to the central autonomic network from “high pressure” arterial baroreceptors that respond to alterations in systemic blood pressure, “low pressure” baroreceptors that respond to alterations in pulmonary venous pressure, and signals from the immune/inflammatory system. The numerous inter-relationships, most of which are bi-directional, seem dauntingly complex, yet they are derived from two relatively simple ideas, the EAS and the homeostat theory.

Figure 7. Concept diagram relating the EAS to intervening variables to symptoms of brain fog, a tendency to faint, and orthostatic intolerance in post-infectious POtS.
Red arrows indicate afferent input to the brain from high-pressure and low-pressure mechanoreceptors.
Grayed out boxes indicate variables for which objective data in POTS are incomplete or inconsistent.
Pink filling indicates variables with abnormal values in POTS. Imbalance between sympathetic noradrenergic system (SNS) and sympathetic adrenergic system (SAS) outflows produces a tendency to faint.

Other abbreviations: AVP = arginine vasopressin; Autoreg. = cerebrovascular autoregulation; BV = blood volume; BP = arterial blood pressure; CBF = cerebral blood flow; Endothel. = endothelial dysfunction; Neurotransm. = central neurotransmitters; POTS = postural tachycardia syndrome; PVP = pulmonary venous pressure; RAS = renin-angiotensin-aldosterone; SV = cardiac stroke volume; Tend. to faint = tendency to faint; TPR = total peripheral vascular resistance; Ven. Compl. = splanchnic venous compliance.

In general, chronic orthostatic intolerance syndromes do not evolve to lethal neurodegenerative diseases, and in a substantial proportion of cases, the overall clinical status improves over time. Therapeutic interventions in which patients actively participate, such as graded exercise or counter-maneuvers, meditation, or yoga, might improve symptoms because of SNS activation in the setting of active coping.

Conclusions
The EAS expands on the ANS by including neuroendocrine systems, immune/inflammatory systems, and the central autonomic network. The four components interact complexly and bi-directionally and determine clinical manifestations of dysautonomias.

The homeostat theory enables objective, non-circular definitions of stress, allostasis, and allostatic load. Computer modeling has the potential to take into account the complexity and dynamics of allostatic processes and may yield testable predictions about individualized treatments and outcomes.

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