Origin of Brainstem Hypoperfusion in POTS and Long COVID: A Dual-Gate Hypothesis Linking Mechanical and Molecular Initiation

Dr. Graham Exelby June 2025- a Preliminary Paper

Abstract

Postural Orthostatic Tachycardia Syndrome (POTS) frequently presents after viral or mechanical triggers, but its pathophysiological origins remain poorly defined. This paper proposes a dual-gate hypothesis—an integrated model in which either mechanical disruption or immunometabolic injury initiates brainstem hypoperfusion, ultimately leading to autonomic dysfunction.

Mechanical compression at the cervicomedullary junction or activation of the superior cervical sympathetic ganglion (SCG) creates a flow-restrictive state; in parallel, viral agents such as SARS-CoV-2 engage the RAGE–TLR4–HIF-1α axis, destabilizing endothelial and glial function. Both pathways converge on the locus coeruleus and nucleus tractus solitarius, initiating a vicious cycle of sympathetic dominance, vagal withdrawal, and chronic neuroimmune dysregulation. This hypothesis reframes POTS as an anatomically-primed, hypoxia-triggered condition.

Recent clinical insights suggest that the extracellular matrix (ECM) may function as a reservoir of retained hypoxic and inflammatory ligands, sustaining neuroinflammation and post-exertional malaise (PEM). Resolution of PEM via manual lymphatic drainage (MLD) highlights the potential for physical detoxification to reverse neuroimmune feedback loops, particularly those driven by RAGE activation. This introduces a dynamic and reversible component to brainstem hypoxia and positions ECM clearance as a therapeutic frontier.

I. Introduction

Despite the wide array of clinical triggers, the first physiological abnormality in many POTS cases is regional hypoperfusion of the brainstem. Yet, no model has comprehensively defined whether this originates mechanically, immunologically, or both. This paper advances a dual-gate hypothesis: that brainstem hypoperfusion can be initiated either by anatomical/mechanical disruption or by molecular signalling cascades following viral, toxic, or metabolic insult. These two routes—mechanical and molecular—interact and potentiate one another.

The findings from Griffith University about brainstem changes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and hypoxia when scrutinized against the pathophysiological changes in dilatation of the ascending aorta suggest a common biological pathways involving RAGE, TLR4, and HIF-1a.

Brainstem Changes and Hypoxia in ME/CFS

Griffith University found that ME/CFS patients have larger brainstem volumes, which might be linked to symptoms like fatigue and breathing difficulties. While their studies don’t explicitly mention hypoxia as a cause, other research shows ME/CFS involves cerebral hypoperfusion, potentially leading to reduced oxygen supply (hypoxia) in brain tissues. 

Brainstem hypoxia represents a common pathway in a wide spectrum of neurocardiovascular and neuroimmune syndromes including POTS, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Long COVID, fibromyalgia, and Gulf War Syndrome (GWS). 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.

Neuroimaging studies, including brain SPECT as used in clinic investigations, MRI, and PET imaging, have consistently demonstrated hypoperfusion in the brainstem, cerebellum, and frontal subcortical circuits in affected individuals. The molecular footprint of this hypoperfusion includes the hypoxia-inducible factor 1-alpha (HIF-1α), activation of pyruvate dehydrogenase kinase (PDK), mitochondrial dysfunction, and neuroinflammation driven by RAGE/NF-κB/CCL2 signalling.

These processes contribute to the characteristic metabolic exhaustion, post-exertional malaise (PEM), and central sensitization seen in POTS, ME/CFS, and Long COVID.   

In Long COVID and vaccine injuries, the function of the clearance system in the brain, the Glymphatic system is impaired, reducing the body’s ability to remove toxic end products.   The astrocytic dysfunction via aquaporin-4 downregulation, alongside endothelial barrier breakdown, contributes to the accumulation of the excitotoxic glutamate. In Long COVID, these changes may reflect a glial–vascular uncoupling process that is dynamically reversible.

Figure 1: SPECT Scans showing brainstem hypoperfusion and hyperperfusion

These SPECT scans demonstrate the mixed hyperperfusion and brainstem hypoperfusion typical of POTS, and the variation in SPECT patterns in CFS, POTS and  Long COVID

Green represents normal perfusion. The blue areas reflect hypoperfusion, green normal, yellow, red then white increased metabolic activity/ hyperperfusion.  The hyperperfusion is thought to be from endotheiliitis and blood barrier disruption allowing neurotoxins into the brain. 

a.     Chronic Fatigue Syndrome with brainstem hypoperfusion

b.     POTS with extensive hyperperfusion and significant cognitive dysfunction, labelled as “Functional Neurological Disorder.”

c.     Long COVID demonstrating significant hypoperfusion

d.     Vaccine Injury

Source: Mermaid Molecular Scanning (now CRT)

e.     Brainstem hypoperfusion changes spreading across the cerebral cortex with postural change using NASA Protocol

Source: Courtesy Dr Kevin Lee

Table 1: Cerebral Perfusion Patterns by Brain Region

At the present time, there is no available direct comparison data demonstrating the mix of hypoperfusion and hyperperfusion seen in POTS, Long COVID, Covid Vaccine Reactions, Fibromyalgia.  This data is extracted from multiple sources to provide the comparative table. 

The author recognizes the innate flaws in this comparison, but until comparative data from a single imaging modality becomes available, this table may be modified. The data collection for this is underway.

The techniques employed include:

 SPECT - for frontal cortex hypoperfusion, particularly in conditions like POTS, where autonomic dysfunction and cognitive symptoms are present

PET- Applied to temporal lobe hypoperfusion, useful for assessing memory and verbal recall issues

PCT -  for cerebellar hypoperfusion, often linked to dyscoordination and dizziness

Doppler ultrasound- for brainstem regions to evaluate autonomic control disruptions and middle cerebral flow studies

ASL MRI – non-invasive alternative for temporal lobe epilepsy

  🔵 Light blue for hypoperfusion

 🌸 Light pink for hyperperfusion

💛 Light yellow for variable perfusion

Brain Region	POTS	Long COVID	Fibromyalgia	Post-COVID Vaccine
Frontal cortex	HypoperfusionAutonomic dysregulation, executive dysfunction, and fatigue (29)	HypoperfusionCognitive dysfunction (“brain fog”), reduced attention span, and fatigue	HypoperfusionCognitive dysfunction and fatigue	HypoperfusionPost-vaccine cognitive complaints (“brain fog”), fatigue, mood changes
Temporal lobes	HypoperfusionMemory disturbances and difficulty with verbal fluency (30)	-	HypoperfusionImpaired memory and verbal fluency	-
Cerebellum	HypoperfusionDyscoordination and dizziness, consistent with autonomic instability (30)(31)	-	-	-
Brainstem (medulla, pons)	HypoperfusionAutonomic control disruption, baroreflex dysfunction, and orthostatic intolerance (32)	HypoperfusionDysautonomia, respiratory irregularities, and orthostatic intolerance	-	HypoperfusionAutonomic dysfunction, baroreflex failure, postural tachycardia
Limbic structures (amygdala)	HyperperfusionHeightened anxiety, emotional lability, and sympathetic overactivation	-	-	HyperperfusionEmotional volatility, anxiety, sympathetic overactivation (includes hippocampal involvement)
Parietal lobes	-	HypoperfusionSensory processing issues and impaired visuospatial functions	-	-
Basal ganglia	-	HypoperfusionMotor symptoms (e.g., weakness, tremors) and fatigue	HyperperfusionChronic pain processing and heightened central nervous system sensitization	Variable (hypo-/hyper-)Motor disturbances (e.g., tremors, rigidity), fatigue
Thalamus	-	HyperperfusionAltered sensory processing, fatigue, and central sensitization	-	-
Insular cortex	-	-	HypoperfusionAltered pain perception, associated with hyperalgesia and allodynia	HypoperfusionDysregulated interoception and pain perception, FM-like symptoms
Cingulate cortex	-	-	HyperperfusionHeightened emotional processing, central sensitization, and catastrophizing tendencies	-

Brainstem Hypoxia as a Unifying Pathophysiological Driver- Summary

The brainstem, particularly the medulla and rostral ventrolateral medulla (RVLM), plays a crucial role in autonomic regulation. Hypoxia in these regions is known to trigger maladaptive autonomic responses, including excessive sympathetic activation, baroreflex dysfunction, and vascular dysregulation—hallmarks of POTS and related conditions.

Hypoxia-inducible factor (HIF-1α) activation in chronic hypoxia could drive secondary metabolic disturbances, affecting mitochondrial efficiency, pyruvate dehydrogenase (PDH) function, and lactate accumulation, reinforcing a persistent energy crisis seen in CFS and fibromyalgia.

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.

Integration with Mitochondrial and Metabolic Dysfunctions

• PDH dysfunction: Hypoxia inhibits PDH via activation of pyruvate dehydrogenase kinase (PDK), shifting metabolism toward anaerobic glycolysis, lactate buildup, and inefficient ATP generation.

• Malate-Aspartate Shuttle Dysfunction: A hypoxic brainstem would suffer impaired oxidative phosphorylation, reducing the ability to shuttle electrons efficiently across the mitochondrial membrane, further compounding energy deficits.

• Lactate Shuttle Defects: The inability to clear lactate from hypoxic regions creates a pro-inflammatory state that may contribute to neuroinflammation and symptom chronicity.

  
  

Immune and Inflammatory Pathways as Downstream Mediators

• The TLR4/NF-κB/RAGE/CCL2 pathways are key drivers of neuroinflammation, perpetuating the hypoxia-inflammatory loop.

• RAGE activation by hypoxia-induced glycation end-products (AGEs) in the brainstem may contribute to persistent oxidative stress and neurovascular dysfunction.

• RAGE directly activates STAT3 and CCL2 as well as via NF-κB.   With the impaired function of the Natural Killer Cells (NK cells) by COVID, these are likely to be responsible for much of the increased malignancy that is being seen but poorly reported.

• CCL2 and leukocyte infiltration into the brainstem are implicated in post-viral and autoimmune dysautonomia, further sustaining sympathetic hyperactivity and central sensitization.

Glymphatic and Lymphatic Dysfunction: A Missing Link in PEM and Neuroimmune Sensitization

In Long COVID and vaccine injuries, the function of the clearance system in the brain—particularly the glymphatic and peripheral lymphatic systems—is impaired. Astrocytic dysfunction via aquaporin-4 downregulation, alongside endothelial barrier breakdown, reduces clearance of toxic end products such as glutamate, HMGB1, and other RAGE ligands. These findings converge with clinical observations that mechanical lymphatic clearance through Vodder-style MLD produces rapid resolution of PEM in POTS and Long COVID patients.

This suggests that hypoxic and inflammatory metabolites accumulate within the ECM, where they continuously stimulate RAGE, sustaining the neuroimmune loop. Without ECM clearance, mitochondrial and amino acid-based recovery strategies may be delayed or ineffective. In contrast, resolution of PEM following MLD supports a model in which physical removal of these ligands can reset the RAGE–NF-κB axis and rapidly reverse autonomic destabilization.

The metabolic timeline observed clinically shows early restoration of GABA and ethanolamine with NAD+ repletion, while aspartate levels—diverted for detoxification and urea cycling—lag behind. Aspartate normalization only occurs after ECM clearance, supporting its role as a biomarker for exertional resilience.

Hypoxia-Driven HIF-1α Activation and Ascending Aortic Dilatation: A Mechanistic Cascade- a clue to the origin of brainstem hypoxia in Long COVID.

In the ascending aorta, a central pathophysiological mechanism involves chronic sympathetic vasoconstriction impairing vasa vasorum perfusion, particularly in the setting of autonomic dysregulation or persistent stellate ganglion overactivation. The vasa vasorum, essential for nourishing the aortic media and adventitia, becomes functionally ischaemic under sympathetic tone, especially in segments with poor collateral supply.

This regional hypoxia stabilizes HIF-1α, which transcriptionally upregulates VEGF, IL-6, CCL2, and matrix metalloproteinases (MMPs). Simultaneously, hypoxia and oxidative stress trigger release of RAGE ligands—such as HMGB1, S100 proteins, and advanced glycation end products (AGEs)—from stressed endothelium, VSMCs, and immune cells.

HIF-1α and RAGE co-activation drives a feedforward loop: RAGE ligation enhances NF-κB and STAT3 signalling, sustaining inflammation and recruiting monocytes via CCL2, while MMP-2 and MMP-9 degrade elastin and collagen, weakening the aortic wall. Over time, this leads to aneurysmal remodelling, medial degeneration, and in some cases, calcification or dissection.

This mechanism parallels what is observed in inflammatory aortopathies, but may also underlie non-syndromic dilatation in POTS, Long COVID, and post-viral autonomic dysfunction where chronic sympathetic tone and impaired ECM repair dominate.

This positions this model as a convergent axis of neurovascular and immunometabolic injury that is likely to provide the underlying cause of the brainstem changes and matches the brain SPECT scan findings both in clinic and elsewhere.   RAGE/CCL2 activation serves as a final common pathway across these pathologies—but the crux lies in the localized, reproducible source of hypoxia that initiates it.  

II. Mechanical Gateway: Cervico-Cranial Structural Vulnerability

A. Head Forward Posture and Cervical Instability

Forward head posture (FHP) and cervical kyphosis compress vertebral artery flow during dynamic movement. The dorsal medulla, supplied by the vertebrobasilar system, becomes selectively hypoxic. Clinic-based Doppler and imaging studies show reduced flow at C1–C2 during flexion, especially in those with connective tissue disorders.

B. Superior Cervical Sympathetic Ganglion (SCG) Activation

SCG sits adjacent to the C2 vertebra and modulates vertebral and carotid blood flow via vasoconstrictive fibres. In C1–C2 instability or trauma, aberrant activation of the SCG may lead to prolonged vasoconstriction of intracranial vessels, reducing perfusion.

C. Spinal Sympathetic Afferent Feedback

Mechanical trauma at thoracic levels (T4–T8) sends afferent signals into the central autonomic network. These afferents converge on the paraventricular nucleus (PVN) and NTS, increasing sympathetic tone systemically and locally, further worsening perfusion.

III. Molecular Gateway: RAGE–HIF-1α–TLR4 Activation

A. Viral Triggers and Endothelial Inflammation

SARS-CoV-2 spike protein, along with reactivated EBV, fungal toxins, and persistent PAMPs, upregulate RAGE and TLR4. These receptors are highly expressed on brainstem endothelium and astrocytes. Their activation initiates NF-κB and STAT3 signalling, triggering IL-6, TNFα, and CCL2 release.

B. HIF-1α Stabilization

Even modest hypoxia (from microclots or endothelial swelling) inhibits prolyl hydroxylases, stabilizing HIF-1α. This transcription factor promotes VEGF (vascular leak), PDK (PDH inhibition), and metabolic shift toward glycolysis. Lactate accumulation and redox imbalance ensue.

C. Redox Disruption and Mitochondrial Suppression

Activated NADPH oxidase generates ROS, which oxidizes iron (Fe2+ to Fe3+) and further stabilizes HIF-1α. ROS and cytokines open the blood–brain barrier, activate glia, and sensitize the brainstem’s vascular and autonomic centres.

IV. Synergistic Convergence: The Hypoxic–Neuroimmune Vortex

Both mechanical and molecular initiators converge on:

• Locus Coeruleus (LC): Noradrenergic instability, cortical dysregulation

• Nucleus Tractus Solitarius (NTS): Baroreflex suppression, vagal withdrawal

• Rostral Ventrolateral Medulla (RVLM): Sympathetic excess, BP dysregulation

The result is a self-sustaining feedback loop: reduced perfusion → HIF-1α + RAGE activation → ROS and cytokines → further perfusion loss. Once established, this “neuroimmune vortex” perpetuates POTS pathophysiology.

V. Clinical Implications

• Structural POTS (e.g., from trauma or EDS) may benefit from correction of forward head pressure, improved posture, lordosis restoration, and decompression of venous or lymphatic outlets.

• Long COVID and Vaccine Injuries: In the brainstem, RAGE activation provides the logical source of initial hypoxia that is then exaggerated and perpetuated by mechanical and other factors. These may respond better to RAGE antagonists (telmisartan), antioxidants (ALA), and mitochondrial supports (NAD+ precursors).

Crucially, lymphatic therapy (e.g., MLD) emerges as a pivotal intervention. Clinical reports show that targeted lymphatic activation enables rapid resolution of PEM, suggesting that retained RAGE ligands and hypoxic metabolites in the ECM sustain the pathophysiological loop. Lymphatic drainage appears to unburden metabolic detoxification systems and may enable more rapid normalization of aspartate, reducing post-exertional crashes.

This points toward a staged therapeutic model:

• Stage 1: Immune stabilization and ECM clearance (H1/H2 blockers, MLD, antioxidants)

• Stage 2: Mitochondrial recovery and metabolic support (NAD+, magnesium)

• Stage 3: Neuroimmune rebalancing (LDN, taurine, GABAergic agents)

Combined forms require personalized, phenotypically-informed intervention.

Conclusion

The dual-gate model explains how both structural compression and immune-metabolic dysregulation initiate brainstem hypoxia. This framework enables phenotype-driven treatment, potentially reversing the pathophysiological cascade in POTS, Long COVID, and vaccine-related autonomic syndromes.