Autonomic Dysregulation: A Systems-Level Integration of Brainstem Hypoperfusion, Plexus Dysfunction, and Immune-Metabolic Crosstalk in Dysautonomia

Dr Graham Exelby May 2025

Abstract:

Dysautonomia encompasses a diverse spectrum of syndromes marked by disordered autonomic nervous system regulation, most notably seen in Postural Orthostatic Tachycardia Syndrome (POTS), Long COVID, and chronic fatigue syndromes. This paper proposes a unifying systems-level model of autonomic dysregulation, where persistent brainstem hypoperfusion, TLR4-driven neuroinflammation, and dysfunction in the cardiac and coeliac plexuses form a pathophysiological continuum.

Central to this model is the activation of Toll-Like Receptor 4 (TLR4) by pathogen- and damage-associated molecular patterns (PAMPs and DAMPs), leading to chronic microglial priming and astroglial crosstalk within autonomic regulatory nuclei, notably the nucleus tractus solitarius (NTS), rostral ventrolateral medulla (RVLM), and dorsal motor nucleus.

Vagal withdrawal and sympathetic hyperactivation propagate downstream to disrupt cardiac and splanchnic plexus dynamics, resulting in preload failure, gastrointestinal dysmotility, and vascular dysregulation. These dysfunctions are compounded by structural and mechanical factors such as venous outflow obstruction, vertebral rotation, and thoracic outlet syndrome.

The framework integrates immune, metabolic, anatomical, and neurovascular domains into a coherent model of dysautonomia, underscoring the need for multidisciplinary diagnostic and therapeutic approaches.

Introduction

Dysautonomia refers to a heterogeneous group of syndromes characterized by impaired autonomic nervous system (ANS) regulation, manifesting in cardiovascular, gastrointestinal, thermoregulatory, and neurological dysfunction. Traditional classifications divide dysautonomia into primary (e.g., multiple system atrophy) and secondary forms (e.g., diabetic autonomic neuropathy, autoimmune overlap), yet this reductionist schema fails to accommodate a growing cohort of patients—particularly those with Postural Orthostatic Tachycardia Syndrome (POTS), Long COVID, and ME/CFS—who present with multisystem dysfunction absent clear structural pathology. These cases are frequently misattributed to psychosomatic or functional disorders, despite mounting evidence of a shared neuroimmune and metabolic basis.

Central to this emerging paradigm is the sustained activation of Toll-Like Receptor 4 (TLR4), a pattern recognition receptor that integrates exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs). Persistent TLR4 signalling within the brainstem—particularly in the nucleus tractus solitarius (NTS), dorsal motor nucleus of the vagus, and rostral ventrolateral medulla (RVLM)—leads to chronic microglial priming and astroglial crosstalk, disrupting baroreflex integration, cardiovagal tone, and sympathetic regulation.

Hypoperfusion of these brainstem regions, often driven by venous outflow obstruction, preload failure, or systemic hypovolemia, perpetuates this inflammatory milieu. Neurotransmission becomes dysregulated through GABA and ethanolamine depletion, resulting in sympathetic dominance and parasympathetic withdrawal. This sets the stage for a self-amplifying circuit involving receptor for advanced glycation end products (RAGE) activation and CCL2-mediated glial inflammation—hallmarks of central autonomic dysregulation seen in POTS and related syndromes.

Crucially, this central dysfunction extends into the periphery through descending autonomic pathways and local neuroimmune activation, notably targeting the cardiac and coeliac plexuses. The cardiac plexus, integrating sympathetic fibres from the cervical and upper thoracic chain with parasympathetic input from the vagus, modulates heart rate, contractility, and coronary tone. Under conditions of vagal withdrawal and sympathetic overdrive, this plexus contributes to orthostatic tachycardia, chronotropic incompetence, and impaired diastolic filling—core features of POTS.

In parallel, the coeliac plexus—responsible for splanchnic perfusion, gut motility, and adrenal output—becomes dysregulated through a combination of immune activation (e.g., CCL2, IL-6), ischaemia, and mechanical factors such as median arcuate ligament compression. The resulting splanchnic vasodilation, venous pooling, and gastrointestinal dysmotility further deplete effective circulating volume and intensify orthostatic intolerance.

Over time, this brainstem-to-plexus dysfunction becomes entrenched, sustained by central hypoperfusion, neuroimmune feedback loops, and progressive sensitization. The result is a multi-nodal, immune-metabolic form of dysautonomia, with overlapping central and peripheral manifestations that define the complex phenotype of conditions such as POTS, ME/CFS, and Long COVID.

This paper presents a systems-level framework that integrates these disparate elements—brainstem hypoperfusion, TLR4-driven neuroinflammation, and plexus-level dysfunction—into a coherent pathophysiological model. It offers a mechanistic basis for the multisystem symptoms observed in dysautonomia and a foundation for therapeutic strategies that go beyond symptom management to target the underlying drivers of autonomic instability.

Drivers of TLR4 Activation in Dysautonomia and POTS

Increasing evidence supports the role of Toll-Like Receptor 4 (TLR4) as a central immune-metabolic hub in the pathogenesis of dysautonomia, particularly in Postural Orthostatic Tachycardia Syndrome (POTS) and Long COVID. TLR4 is capable of integrating both exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs), triggering sustained microglial activation and inflammatory signalling through nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and downstream inflammasome pathways.

Once activated, TLR4 signalling in the brainstem impairs the function of the nucleus tractus solitarius (NTS), rostral ventrolateral medulla (RVLM), and dorsal motor nucleus, regions that govern the integration of vagal and sympathetic tone.

At the hub of this process lies microglial activation, which serves as a key effector mechanism linking peripheral and central immune stimuli to autonomic dysfunction. TLR4 activation on microglia triggers the release of pro-inflammatory cytokines (e.g., IL-1β, TNF-α, IL-6), reactive oxygen species (ROS), and nitric oxide, which in turn disrupt neuronal function and synaptic transmission within autonomic regulatory nuclei such as the nucleus tractus solitarius (NTS), dorsal motor nucleus, and rostral ventrolateral medulla (RVLM).

This inflammatory milieu impairs baroreflex sensitivity, blunts vagal tone, and promotes sympathetic excitation. Activated microglia also interact with astrocytes and mast cells, amplifying neuroimmune signalling and lowering the threshold for subsequent TLR4 reactivation. The persistence of this glial priming state—even after removal of the initial trigger—may account for the chronicity and reactivity seen in POTS and related dysautonomias.

I. Infectious and Post-Infectious Triggers

• Viral Pathogens: SARS-CoV-2 spike protein directly activates TLR4, as do EBV, CMV, and enteroviruses. These infections generate residual DAMPs that maintain microglial activation long after viral clearance.

• Bacterial Dysbiosis: Gram-negative bacteria-derived lipopolysaccharide (LPS) is a canonical TLR4 ligand. Increased gut permeability, common in post-infectious and inflammatory bowel phenotypes, permits translocation of LPS into systemic circulation, sustaining hepatic and central TLR4 activation.

II. Endogenous DAMPs and Metabolic Stress

• Oxidized Lipids and HMGB1: Persistent oxidative stress leads to accumulation of DAMPs such as oxidized LDL, HMGB1, and heat-shock proteins, which activate TLR4 across multiple tissues.

• Amyloid Fibrin: Amyloidogenic fibrin persists in Long COVID and some POTS cohorts, engaging TLR4 on monocytes and endothelial cells. This promotes a hypercoagulable and inflammatory milieu.

• Hypoxia and Mitochondrial Dysfunction: Hypoxia-inducible factor 1α (HIF-1α) enhances TLR4 transcription. PDH inhibition, ROS accumulation, and excitotoxic glutamate signalling contribute to a feedforward inflammatory loop.

III. Genetic and Epigenetic Sensitization

• TLR4 Polymorphisms: These, identified in subsets of POTS and Long COVID patients alter ligand sensitivity and cytokine response thresholds.

• Epigenetic Changes: Histone modifications and methylation patterns following infection or trauma may render TLR4 transcriptionally active, even in the absence of acute stimuli.

• miRNA Dysregulation: Disruption of regulatory miRNAs (e.g., miR-146a, miR-155) prolongs TLR4-mediated inflammatory signalling.

IV. Mechanical and Structural Inputs

• Venous and Lymphatic Obstruction: Impaired drainage from the internal jugular or vertebral veins leads to regional hypoxia and DAMP accumulation, particularly in the brainstem and cervical spinal cord. These changes compromise glymphatic clearance and raise interstitial pressure near brainstem autonomic centres, potentiating microglial activation and vagal dysfunction.

• Fascial and Plexus Compression: Chronic mechanical irritation of the cardiac or coeliac plexuses (e.g., T8 vertebral rotation, thoracic outlet syndrome, MALS) contributes to sterile neuroinflammation via local TLR4 activation. Compression of autonomic ganglia disrupts afferent-efferent relay and promotes sympathetic hyperactivity, contributing to orthostatic intolerance and gastrointestinal dysmotility. 

• Backpack Strain and Cervical Trauma: Sustained use of heavy backpacks, particularly during growth phases or occupational repetition, imposes compressive load on the cervical and upper thoracic spine. This leads to fascial tension, venous congestion, and microvascular shear injury that provoke DAMP release and TLR4 activation in spinal and paraspinal autonomic circuits. When combined with pre-existing craniocervical instability or vertebral venous congestion, these inputs further impair brainstem perfusion, perpetuating a cycle of autonomic dysregulation.  Impaired drainage from the internal jugular or vertebral veins leads to regional hypoxia and DAMP accumulation, particularly in the brainstem and cervical spinal cord.

V. Environmental, Psychological, and Hormonal Factors

• Mould Exposure: Mycotoxins such as ochratoxin and trichothecenes activate TLR4 and compromise epithelial barriers, leading to systemic immune activation.

• Psychological Stress and PTSD: Chronic stress and trauma rewire central autonomic circuits and upregulate TLR4 expression via glucocorticoid receptor resistance, increased oxidative stress, and microglial priming. PTSD-associated neuroinflammation further exacerbates autonomic dysregulation.

• Diet-Derived Ligands: Advanced glycation end-products (AGEs), saturated fats, and LPS absorbed with chylomicrons postprandially contribute to TLR4 stimulation.

• Hormonal Modulation: Cortisol and oestrogen dysfunction, common post-COVID or in stress-induced amenorrhea, reduce NF-κB inhibition, enhancing TLR4-driven inflammation.

• Environmental Exposures: Air pollutants and nanoparticles are potent TLR4 agonists and exacerbate barrier dysfunction.

Taken together, these diverse inputs converge on TLR4 to drive a sustained neuroinflammatory state, particularly within autonomic control centres in the brainstem. This promotes a cascade of vagal withdrawal, sympathetic excess, and plexus dysfunction (cardiac and coeliac), creating the multisystem autonomic phenotype observed in POTS and related dysautonomias.

Importantly, many of these triggers also contribute to a state of central and peripheral sensitization, in which inflammatory signalling, neuroglial activation, and altered neurotransmission lower the threshold for autonomic reactivity. In such states, even minimal stimuli—mechanical, emotional, or metabolic—can elicit exaggerated autonomic responses. Sensitization becomes deeply embedded in the autonomic framework, making separation of cause from perpetuation nearly impossible. It is this blurred boundary between immune activation, central processing, and neural circuit plasticity that underlies the refractory and multifactorial nature of dysautonomia in this population.

Brainstem Hypoxia as a Central Driver of Dysautonomia

Persistent hypoxia is increasingly recognized as a central mechanism in the chronic neuroimmune dysfunction seen in Postural Orthostatic Tachycardia Syndrome (POTS), Long COVID, and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).  

The brainstem—particularly the medulla and rostral ventrolateral medulla (RVLM)—is critical for autonomic, cardiovascular, and respiratory homeostasis.  Hypoperfusion in these regions triggers a cascade of maladaptive responses: excessive sympathetic activation, impaired baroreflex sensitivity, parasympathetic withdrawal, and altered respiratory rhythmogenesis. These features form the clinical core of many overlapping syndromes within the dysautonomia spectrum.

In parallel, neuropeptides such as Substance P, CGRP, and VIP—released from sensory and autonomic neurons—exacerbate inflammation by activating mast cells, glial cells, and endothelial cells. Together, these pathways promote blood-brain barrier breakdown, neuroinflammation, and autonomic instability.

A key feature of this model is the persistence of inflammation in brain regions critical to autonomic control (e.g., the brainstem), even after systemic recovery.  Hypoxia and its downstream immune and neurovascular effects form a self-sustaining loop—one that explains the chronicity of symptoms across multiple systems.

Postural and Mechanical Drivers of Hypoxia

Head-forward posture and mechanical compressions (e.g., internal jugular vein [IJV] obstruction at C1, thoracic outlet syndrome [TOS]-mediated vascular compression) are increasingly recognized as contributors to cerebral hypoperfusion.

The superior cervical sympathetic chain (SCSC) is intimately connected to vascular regulation in the brainstem and upper spinal cord. Compression or dysregulation of this structure especially at the C1 region could perpetuate neurovascular dysautonomia.

Thoracic outlet compression could induce sympathetic overactivity via mechanoreceptor activation in the stellate ganglia, exacerbating vasoconstriction and worsening hypoperfusion in the brainstem.

Functional Continuum with Cardiac and Coeliac Plexuses

The medulla oblongata and rostral ventrolateral medulla (RVLM) in the brainstem coordinate cardiovascular, respiratory, and autonomic function. Chronic or dynamic hypoperfusion compromises neuronal viability and reflex integration.- discussed in Brainstem Hypoperfusion in POTS, CFS, Fibromyalgia, Long COVID and GWS.

The downstream consequences of brainstem hypoxia extend beyond central autonomic nuclei and permeate peripheral autonomic relay systems. Given the longitudinal continuity of the sympathetic chain and shared parasympathetic pathways, disturbances originating in the rostral medulla and nucleus tractus solitarius (NTS) can propagate functionally through spinal intermediolateral columns, ultimately manifesting as aberrant signalling in downstream plexuses.

A critical but often overlooked concept is the gastro-cranial hydraulic continuum, which links abdominal venous and lymphatic congestion to central neurovascular dysfunction. In this model, mechanical or vascular compression syndromes such as Nutcracker Syndrome (NCS) cause venous outflow dysfunction left renal vein and affecting splanchnic venous congestion (Pelvic Congestion Syndrome.)

 Given the valveless architecture of the vertebral and paravertebral venous systems, this venous congestion may propagate cranially, contributing to cerebrospinal fluid impedance, intracranial hypertension (ICH), and impaired glymphatic clearance.

The cardiac and coeliac plexii are functionally intertwined via both direct sympathetic chain continuity and shared central regulatory nuclei, making them susceptible to common dysautonomic insults in syndromes such as POTS, Long COVID, and functional GI disorders.

Dysfunction in one plexus can propagate dysregulation through both neuroanatomical pathways and autonomic feedback loops, particularly under conditions of central hypoperfusion, neuroinflammation, and mechanical thoracic or abdominal impedance. Recognizing this interdependence enhances the interpretation of multi-system symptoms and opens avenues for integrated therapeutic approaches, including vagal stimulation, anti-inflammatory strategies, and mechanical decompression.

The coeliac plexus, anatomically and functionally proximal to these vascular bottlenecks, becomes a critical relay in this continuum—subjected to mechanical stress, neuroinflammation, and sympathetic overdrive.

This gastro-cranial pathway provides a plausible mechanistic link between abdominal autonomic dysfunction, impaired venous return, and brainstem hypoperfusion observed in POTS, ME/CFS, and Long COVID. Recognition of this continuum underscores the need for integrated imaging approaches and orthostatic haemodynamic assessments when evaluating these patients.

The cardiac and coeliac plexuses serve as principal nodal points within this distributed autonomic hierarchy. They relay centrally-derived signals into somato-visceral outputs—regulating cardiac contractility, vascular tone, splanchnic perfusion, adrenal output, and gastrointestinal motility.

Importantly, the structural and functional integrity of these plexuses is susceptible to both central influences (e.g., hypoperfusion-induced parasympathetic withdrawal) and regional mechanical perturbations (e.g., MALS, SMA compression, thoracic vertebral dysfunction).

In syndromes like POTS and ME/CFS, the combined effect of descending sympathetic hyperactivation and vagal suppression precipitates a multilevel dysautonomia, where both cardiac and coeliac plexus dysfunction converge to shape the systemic phenotype—characterized by preload failure, postprandial hypotension, and central-peripheral mismatched autonomic tone.

There is descending sympathetic continuity along the thoracic sympathetic chain from T1–T12, with inter-ganglionic communication. The cardiac plexus governs chronotropy, inotropy, and coronary vascular tone.  It receives sympathetic innervation from T1–T4 via cervical and stellate ganglia.  Parasympathetic fibres arise from the vagus, converging near the base of the heart.

The coeliac plexus receives preganglionic sympathetic fibres from T5–T12 via greater, lesser, and least splanchnic nerves, Integrates vagal efferents and phrenic input, and modulates mesenteric, renal, and adrenal perfusion and gut motility.

Overactivity or dysfunction in the upper thoracic ganglia (affecting cardiac plexus) can propagate signals caudally, influencing the splanchnic sympathetic outflow.  This becomes highly relevant in central autonomic syndromes such as POTS, where a spinal or brainstem signal may be amplified and relayed across both cardiac and coeliac levels.

The sympathetic chain continuity permits vertical signal propagation from upper thoracic segments to abdominal plexuses.  The loss of vagal tone (from brainstem hypoperfusion) concurrently depresses parasympathetic output to both plexuses.

Anatomical Continuity and Overlapping Sympathetic Pathways.

Cardiac Plexus

In POTS, blunted baroreflex sensitivity and vagal withdrawal can be partially explained by dysfunction in the deep cardiac plexus:   This plexus directly integrates aortic baroreceptor afferents, vagal efferents, and sympathetic chronotropic nerves.

• Chronic central activation (via NTS-LC-PVN circuits) in high cortisol/IL-6 states can inhibit parasympathetic ganglia, further destabilizing heart rate control.

• In Long COVID, elevated IL-6 and TNF-α correlate with persistent baroreflex suppression, possibly mediated through this plexus.

• Located at the base of the heart, this plexus integrates sympathetic input (T1–T5) from the cervical and upper thoracic ganglia (stellate and thoracic sympathetic chain), and parasympathetic input via the vagus nerve.

• Sympathetic fibres from T1–T4/5 project to the heart, affecting rate, rhythm, and vascular tone.

• It communicates with both deep and superficial components, connecting with the pulmonary and thoracic sympathetic pathways.

The thoracic outlet syndrome (TOS) offers a compelling anatomical and mechano-neurovascular interface that could impair the cardiac plexus through mechanical, ischaemic, and inflammatory mechanisms, thereby contributing to preload failure, dysautonomia, and POTS—especially in the venous pooling subtype. Even subclinical dynamic compression may:

• Disrupt neural communication to autonomic centres

• Alter venous return and thoracic lymphatic drainage

• Induce localized ischaemia and inflammation that could compromise the cardiac plexus, particularly its sympathetic inputs from the cervical ganglia

• Impair intrathoracic pressure–preload coupling

Coeliac Plexus

The largest autonomic plexus, the coeliac plexus is a reflex integration hub.   It governs mesenteric, splanchnic, adrenal, renal, and gastric function, forming the abdominal sympathetic outflow.  Chronic compression may lead to:

• Imbalanced sympathetic-parasympathetic tone, with predominant sympathetic drive.

• Reduced baroreflex sensitivity via vagal withdrawal and overactivation of splanchnic vasoconstriction (low-flow gut states, impaired gut motility).

• Potentiation of coeliac ganglionopathy and dysfunctional feedback loops into the hypothalamic–pituitary–adrenal axis.

 The coeliac plexus receives input from:

• Preganglionic sympathetic input from the greater splanchnic nerves (T5–T9), lesser (T10–T11), and least splanchnic nerves (T12).

• Parasympathetic vagal branches and fibres from the phrenic nerve.

• Afferents from gut, pancreas, adrenals, kidneys, and liver

T6–T9 vertebral rotation may directly irritate sympathetic splanchnic roots and their ganglionic convergence in the coeliac plexus.   Fascial/lymphatic congestion around the diaphragm may amplify this via:

• Impaired drainage from the thoracic duct (which runs posterior to the plexus).

• Venous congestion, contributing to intermittent hypoxia and mechanosensitive afferent firing.

This may explain why patients with post-surgical POTS, dental assistant spinal posture, or body armour use (military) develop POTS phenotypes via chronic sympathetic upregulation at the splenic/coeliac interface.

Reflexogenic viscera-sympathetic patterns may occur, where stimulation of splenic capsule, pancreas, mesenteric vessels, or diaphragm may lead to reflex cardiac and vascular instability through coeliac–cardiac plexus convergence.

Mechanical Compression & Ischaemia

The coeliac plexus lies directly adjacent to the coeliac trunk and superior mesenteric artery—a known compression point in Median Arcuate Ligament Syndrome (MALS.).  Compression by the median arcuate ligament (especially during expiration) results in:

• Ischaemia of splanchnic autonomic nerves.

• Mechanical neuropathic irritation or chronic afferent barrage from plexal afferents.

• Coactivation of adrenal medullary output (via splanchnic nerves), triggering catecholamine surges and sympathetic overdrive.

Chronic nerve irritation likely initiates central sensitization in brainstem–hypothalamic circuits, including:

• Nucleus of the Solitary Tract (NTS)

• Paraventricular Nucleus (PVN)

• Locus Coeruleus (LC) → These circuits are heavily connected to the coeliac-cardiac axis through both afferent vagal and efferent sympathetic links.

Coeliac Plexus Dysfunction (Network-Level)

Occurs due to regional vascular compression, venous hypertension, or neuroinflammation adjacent to the plexus:

• Mechanisms:

  • Perineural inflammation or oedema from LRV hypertension

  • Sympathetic afferent overactivation (from gut, adrenals, kidney)

  • Parasympathetic-vagal input disruption due to stretch/inflammation

• Clinical manifestations:

  • Gut dysmotility (delayed gastric emptying, postprandial bloating)

  • Orthostatic intolerance (via maladaptive splanchnic vasoconstriction)

  • Pancreatic-type pain syndromes (without pathology)

  • Emotional-autonomic feedback loops (due to vagal-cortical disintegration)

Coeliac Ganglia Dysfunction (Nodal-Level)

Involves cellular or neurotransmitter-level dysregulation within the ganglia, potentially driven by:

• Neuroimmune activation: IL-1β, TNF-α, and CCL2 expression upregulating neuronal excitability.

• Hypoxia and oxidative stress from venous congestion increasing sympathetic ganglion firing.

• Autoantibodies or RAGE-mediated sensitization interfering with sympathetic neuronal integrity.

• Clinical features more typical of ganglia dysfunction:

  • Localized visceral pain unrelieved by vagal manoeuvres

  • Profound sympathetic vasoconstriction, especially during stress or upright posture

  • Adrenal dysregulation (as output is downstream of the ganglia)

  • Episodic hypertension, tachycardia, or catecholamine-like syndromes in POTS

Functional Continuum

There is descending sympathetic continuity along the thoracic sympathetic chain from T1–T12, with inter-ganglionic communication. Thus:

• Overactivity or dysfunction in the upper thoracic ganglia (affecting cardiac plexus) can propagate signals caudally, influencing the splanchnic sympathetic outflow.

• This becomes highly relevant in central autonomic syndromes such as POTS, where a spinal or brainstem signal may be amplified and relayed across both cardiac and coeliac levels.

Physiological Independence and Shared Autonomic Tone

1.     Sympathetic Coupling

During sympathetic activation (e.g., orthostasis), there is parallel activation of the cardiac and splanchnic vasculature:

• Cardiac plexus modulates chronotropy, inotropy, and coronary tone.

• Coeliac plexus governs splanchnic vasoconstriction, modulating venous reservoir recruitment, a vital component of preload compensation.

• If cardiac sympathetic tone is dysregulated, e.g., in inappropriate sinus tachycardia, this may destabilize baroreflex integration, leading to maladaptive splanchnic vascular responses via the coeliac plexus (e.g., pooling, vasodilation, mesenteric angina).

2.     Vagal Tone Interdependence

Vagal input to both plexuses originates from the dorsal motor nucleus of the vagus and nucleus ambiguus, which receive central input from the hypothalamus, paraventricular nucleus (PVN), and nucleus tractus solitarius (NTS).    Loss of vagal tone centrally (e.g., from brainstem hypoperfusion) may cause concurrent parasympathetic withdrawal in both plexuses, amplifying sympathetic dominance.

Pathophysiological Hypotheses Linking the Cardiac and Coeliac Plexuses

1. Shared Hypoxic Vulnerability

Brainstem hypoperfusion, particularly affecting the NTS, may disrupt both cardiac and abdominal autonomic outflow.  Low cerebral perfusion may decouple baroreflex pathways, destabilizing both cardiac and coeliac autonomic control.

2.     Thoracic Outlet Syndrome (TOS) or Vertebral Obstruction

Mechanical obstruction at the thoracic inlet may compress sympathetic fibres destined for both plexii.  Compression of venous return (e.g., IJV, azygous) can lead to central congestion, reducing preload, increasing sympathetic drive at both plexus levels.

3. Mast Cell Activation & Neuroimmune Crosstalk

Cardiac and coeliac plexii are both highly innervated and mast cell-rich zones.

• RAGE/NF-κB/CCL2 activation may create regional inflammatory loops that disinhibit sympathetic activity and impair parasympathetic feedback.

• Local or systemic DAMPs could affect both regions, contributing to splanchnic dysmotility, cardiac dysrhythmias, and preload instability.

Table 1. Effects of the Parasympathetic and Sympathetic Divisions on Various Organs

Target organ or system	Parasympathetic effects	Sympathetic effects
Eye (iris)	Stimulates sphincter pupillary muscles, constricts pupil	Stimulates dilator pupillae muscles; dilates pupils
Eye (ciliary muscle)	Stimulates muscle, resulting bulging of lens for close vision	Weakly inhibits muscle, flattening lens for far vision
Glands (nasal, lacrimal, gastric, pancreas)	Stimulates secretory activity	Inhibits secretory activity, causes vasoconstriction of blood vessels to glands
Salivary glands	Stimulates watery saliva	Stimulates thick, viscous saliva
Sweat glands	No effect (no innervation)	Stimulates copious sweating (cholinergic fibres)
Adrenal medulla	No effect (no innervation)	Stimulates medulla cells to secrete adrenalin and noradrenalin
Arrector pili muscles attached top hair follicles	No effect (no innervation)	Stimulates contraction which erects hairs and produces goosebumps
Heart (muscle)	Decreases heart rate	Increases heart rate and force of contraction
Heart (coronary blood vessels)	No effect (no innervation)	Causes vasodilation *
Urinary bladder/urethra	Contraction of smooth muscle of bladder wall, relaxes urethral sphincter, promotes voiding	Relaxation of smooth muscle of bladder wall, constricts urethral sphincter, inhibits voiding
Lungs	Constricts bronchioles	Dilates bronchioles *
Digestive tract organs	Increases motility (peristalsis) and amount of secretion by digestive organs, relaxes sphincters to allow movement of food along tract	Decreases activity of glands and muscles and constricts sphincters (eg anal sphincter)
Liver	Increases glucose uptake from blood	Stimulates secretion of glucose to blood *
Gallbladder	Excites (gallbladder contracts to expel bile)	Inhibits function, gallbladder is relaxed
Kidney	No effect (no innervation)	Promotes renin release, causes vasoconstriction, decreases urine output
Penis	Causes erection (vasodilation)	Causes ejaculation
Vagina/clitoris	Causes erection (vasodilation of clitoris), increases vaginal lubrication	Causes contraction of vagina
Blood vessels	Little or no effect	Constricts most vessels and increases blood pressure, constricts vessels of abdominal viscera and skin to divert blood to muscles, brain, and heart when necessary: Noradrenalin constricts most vessels, Adrenalin dilates vessels of the skeletal muscles during exercise *
Blood coagulation	No effect (no innervation)	Increases coagulation *
Cellular metabolism	No effect (no innervation)	Increases metabolic rate *
Adipose tissue	No effect (no innervation)	Stimulates lipolysis (fat breakdown)

•  Effects mediated by adrenalin release into bloodstream from adrenal medulla

Source: Marieb,H.,Hoehn,K. Human Anatomy & Physiology, 8th Ed, Pearson International, 2010, p 538

Figure 2.   ANS overall anatomy.

Parasympathetic pathways represented by blue and the sympathetic pathways in red. The interrupted red lines indicate post-ganglionic rami to the cranial and spinal nerves. This image is from the 20th US edition of Gray's Anatomy of the Human Body and is in the public domain.

POTS as an example of a Fragmented Traditional Approach- The Traditional Physician Viewpoint- (Especially in general practice, cardiology, psychiatry, gastroenterology, immunology)

Traditional medicine is trained to diagnose based on discrete symptom clusters and align those with organ-based pathology. When patients present with multisystem symptoms—fatigue, palpitations, abdominal pain, bloating, brain fog, heat intolerance, food sensitivity, sleep disturbance—they often fall through the cracks.

When test results are non-revealing and symptoms fluctuate, clinicians often revert to biopsychosocial frameworks.  Diagnoses like “somatic symptom disorder,” “anxiety disorder,” “functional neurological disorder” may be applied.  Especially if the patient is young, female, and articulate, there's a bias toward psychogenic explanations.

In many fatigue or POTS-like presentations, deconditioning is seen as both cause and consequence.. Recommendations lean toward exercise, CBT, and lifestyle modification — even though many patients report worsening with exertion.

Food intolerance without IgE positivity or eosinophilia is considered either functional or psychogenic, and mast cell activation is viewed sceptically unless tryptase is high.

Many physicians (especially in psychiatry, primary care, and women’s health) consider a central sensitization framework that the brain becomes hypersensitized due to trauma, chronic stress, or inflammatory priming.  This results in “amplified pain perception,” fatigue, dysautonomia, and hypersensitivity.  This is often taught as part of understanding fibromyalgia or functional GI disorders.

• Fatigue → Sent to psychology or rheumatology (e.g., CFS or somatization).

• Palpitations → Cardiology (often normal ECGs, Holters).

• GI complaints → Gastroenterology (often labelled as IBS).

• Heat/cold intolerance or flushing → Endocrinology or dermatology (often dismissed unless extreme).

• Neurological symptoms → Neurology (MRI often normal, sent back).

• "Allergic" symptoms → Immunology or allergy clinics, often no IgE finding.

They may document "possible autonomic dysfunction" or "subjective intolerance" or "functional overlay", but without a unifying diagnosis that fits a textbook mould, fragmentation persists.

Conclusion:

The traditional compartmentalization of dysautonomia into discrete organ systems has obscured the unifying pathophysiological processes that underpin syndromes like POTS, Long COVID, and ME/CFS. This paper proposes a comprehensive model that integrates central neuroimmune sensitization, brainstem hypoperfusion, and peripheral autonomic plexus dysfunction into a coherent systems-level framework.

At its core lies a TLR4-mediated inflammatory cascade that begins with peripheral immune triggers and culminates in central autonomic dysregulation via microglial priming, vagal suppression, and sympathetic hyperactivation.

This dysfunctional cascade does not terminate at the brainstem. Instead, it propagates to peripheral nodes—specifically the cardiac and coeliac plexuses—whose functional integrity is compromised by both descending signals and local environmental or mechanical factors. These plexuses represent critical relay stations through which the central nervous system exerts control over cardiovascular and gastrointestinal homeostasis. Their dysregulation contributes to hallmark symptoms of dysautonomia, including orthostatic intolerance, postprandial hypotension, and adrenergic instability.

Recognition of this neuroimmune–vascular–mechanical continuum reframes our understanding of complex multisystem syndromes. It demands a shift in clinical practice—from organ-based management toward integrated evaluation of autonomic networks, including advanced imaging, orthostatic hemodynamic assessments, and recognition of mechanical compressive syndromes. Therapeutically, it highlights the potential for interventions targeting glial priming, vagal tone restoration, and structural decompression. Only by embracing this complexity can we begin to provide accurate diagnosis, mechanism-based treatment, and scientific clarity for patients long misunderstood by the prevailing medical paradigm.