Brainstem Hypoperfusion in POTS,CFS, Fibromyalgia, Long COVID and GWS -a Key Role

Dr Graham Exelby May 2025

Abstract

Brainstem hypoperfusion represents a unifying and upstream pathophysiological mechanism in postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), fibromyalgia, Long COVID, and Gulf War Syndrome (GWS).

Through multimodal imaging, particularly brain SPECT, evidence consistently reveals regional hypoperfusion in the brainstem, cerebellum, and frontal cortices of affected individuals, correlating with autonomic dysregulation, cognitive dysfunction, and fatigue. Central to this process is the medulla and rostral ventrolateral medulla (RVLM), where compromised perfusion impairs baroreflex integrity, triggers sympathetic overdrive, and disrupts respiratory rhythmogenesis.

Mechanistically, chronic hypoxia stabilizes hypoxia-inducible factor 1α (HIF-1α), activates pyruvate dehydrogenase kinase (PDK), and promotes mitochondrial dysfunction, amplifying neuroinflammation via the RAGE/TLR4/NF-κB/CCL2 axis. These molecular cascades reinforce central sensitization, post-exertional malaise, and metabolic exhaustion—hallmarks of these syndromes.

This review synthesizes the overlapping structural, metabolic, immunological, and fascial mechanisms underpinning brainstem hypoperfusion, proposing a precision framework for diagnosis and intervention.    We highlight the role of postural and mechanical triggers, lymphatic dysfunction, and fascia–neuroimmune crosstalk as integral amplifiers of chronic autonomic disease.

Emerging SPECT/CT findings in Long COVID demonstrate hypoperfusion in prefrontal–limbic–brainstem circuits, underscoring the role of dynamic glial–vascular uncoupling and astrocytic dysfunction in cognitive impairment and dysautonomia. Reversibility with HBOT and rTMS suggests modifiable neurovascular coupling mechanisms

A paradigm shift is needed, recognizing brainstem hypoxia not as an epiphenomenon but as a primary driver of dysautonomia, amenable to targeted metabolic, structural, and immune-based therapies.

Introduction

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 stabilization of 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.    The varying patterns of hypoperfusion and hyperperfusion are demonstrated in brain SPECT scan changes described in Brain SPECT changes in POTS, CFS, FMS and Long COVID.(1) 

Emerging evidence suggests astrocytic dysfunction via aquaporin-4 downregulation, alongside endothelial barrier breakdown, contributes to this immune activation. In Long COVID, these changes may reflect a glial–vascular uncoupling process that is dynamically reversible—supported by clinical improvements in cerebral perfusion following rTMS and hyperbaric oxygen therapy (HBOT), highlighting a potential target for therapeutic revascularization.

Figure 1: SPECT Scans showing brainstem hypoperfusion and hyperperfusion

These SPECT scans demonstrate the typical 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

Source: Mermaid Molecular Scanning

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

Source: 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 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.

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

Locus Coeruleus Hypoperfusion and Noradrenergic Vasospasm: A Central Vasoregulatory Loop

The locus coeruleus (LC), situated in the dorsal pons, plays a central role in autonomic regulation, arousal, and cerebrovascular tone. Due to its location in the vertebrobasilar territory and reliance on penetrating pontine branches of the basilar artery, the LC is uniquely susceptible to hypoperfusion under upright stress, venous congestion, or mechanical impingement—such as forward head posture (FHP), vertebral artery hypoplasia, or internal jugular vein obstruction.

Compromised perfusion in the LC appears to initiate a compensatory increase in noradrenaline (NA) release, both systemically and locally. While initially protective, excess NA induces vasoconstriction of cerebral vessels via α₂-adrenergic receptors, particularly affecting cortical microcirculation through pericyte and smooth muscle contraction (Korte et al., 2023 (33); Goadsby et al., 1985 (34). This phenomenon—termed protective vasospasm—may reduce perfusion to higher-order regions in an attempt to preserve brainstem viability, but with detrimental long-term effects in dysautonomia syndromes.

Functional imaging studies reveal that cognitive stress (without orthostatic challenge) provokes measurable cerebral blood flow reductions in POTS patients (Wells et al., 2020 (35)), supporting the concept of neurovascular uncoupling driven by LC dysfunction. Animal models further confirm that even modest reductions in brainstem perfusion activate astrocytes and sympathetic neurons to elevate systemic blood pressure, reinforcing the feedforward loop of central sympathetic overactivation (Marina et al., 2020 (36)).

This noradrenergic vasospasm hypothesis provides a mechanistic link between brainstem hypoxia, autonomic imbalance, and downstream cortical hypoperfusion, and may explain why tilt table testing, cognitive exertion, or poor posture leads to symptom exacerbation even in the absence of overt hypotension. The LC thus acts as both a perfusion sensor and a vasoconstrictive effector, amplifying a cycle of neurovascular instability that characterizes POTS, ME/CFS, and Long COVID.

Comparative Cerebral Perfusion and Pathophysiological Overlap in POTS and Long COVID

Both POTS and Long COVID exhibit shared cerebral hypoperfusion patterns, particularly in the brainstem, prefrontal cortex, and limbic system. SPECT imaging has delineated overlapping involvement of the nucleus tractus solitarius (NTS) and dorsal vagal complex, affecting autonomic tone and respiratory rhythms. Cognitive symptoms (“brain fog”) in both conditions associate with reduced perfusion in prefrontal and limbic networks.

Key distinctions include the extent and mechanisms of hypoperfusion. In Long COVID, diffuse network dysfunction encompasses the insula, cerebellum, and thalamus—likely driven by viral persistence, RAGE/TLR4 activation, and aquaporin-4-mediated astrocyte disintegration. In contrast, non-COVID POTS tends to show more focal deficits, often limited to prefrontal–limbic areas, with a stronger emphasis on hypovolemia and peripheral sympathetic overdrive. Small fibre neuropathy appears in up to 40% of POTS cases, while Long COVID exhibits a more pronounced central glial–vascular dysregulation.

Reversibility of perfusion deficits in Long COVID through rTMS and HBOT further supports a dynamic, rather than fixed, mechanism of neurovascular uncoupling—distinct from structural or degenerative hypoperfusion models.

Structural- Mechanical and Hydraulic Dysfunction

Vertebral Artery Hypoplasia as a Structural Contributor

Vertebral artery hypoplasia (VAH) is a frequently overlooked anatomical variant that may have significant haemodynamic consequences in the context of autonomic and cerebrovascular instability. Defined as a vertebral artery diameter of less than 2.0–2.5 mm (typically at the V2 segment), VAH occurs in 15–25% of the population, often affecting the right side. While typically benign in healthy individuals, its relevance becomes substantial when coupled with inadequate collateral flow, vertebrobasilar insufficiency, or structural venous obstruction, as diameter asymmetry ratios (≤1:1.7) correlate with reduced flow volumes. (Thierfelder et al. 2014 (2)) (  Dinç et al 2021 (3)) 

VAH compromises perfusion to the posterior fossa, particularly the medulla, pons, and cerebellum—regions involved in baroreflex arcs, vestibular integration, vagal regulation, and respiratory control. In cases where the contralateral vertebral artery is hypoplastic or compromised by atherosclerosis, dolichoectasia, or dynamic flow restriction, the perfusion deficit can become symptomatic.

Dynamic head rotation or extension can further reduce flow in the dominant vertebral artery, unmasking latent deficits and precipitating symptoms such as syncope, orthostatic hypotension, vertigo, and exertional fatigue.   VAH patients exhibit focal flow turbulence and reduced time-averaged wall shear stress, predisposing to dissection or transient ischaemia during positional changes. (Bao et al 2023 (4)) (Morales-Roccuzzo et al 2024 (5))

Chronic hypoperfusion due to VAH activates HIF-1α and NF-κB signalling, promoting a metabolic shift toward anaerobic glycolysis, mitochondrial inefficiency, and lactate accumulation. This metabolic environment promotes excitotoxicity, glial priming, and inflammation in autonomic nuclei, particularly the nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMV).  Chronic low flow in hypoplastic vertebral arteries may induce arterial remodelling, exacerbating perfusion deficits.  (  Dinç et al 2021 (3)) (Bao et al 2023 (4))

These structures are dysregulated in POTS and Long COVID and may underlie symptoms such as orthostatic tachycardia, gastrointestinal dysmotility, and respiratory irregularity. VAH may also exacerbate cerebral venous congestion when paired with internal jugular vein (IJV) compression at C1, forming a dual inflow-outflow perfusion bottleneck.

Beyond VAH- Mechanical and Postural Contributions: vTOS, FHP, and Scalene Dysfunction

Beyond VAH, a constellation of mechanical and postural abnormalities plays a critical role in brainstem hypoperfusion. These include venous thoracic outlet syndrome (vTOS), first rib elevation, scalene muscle hypertonicity, and forward head posture (FHP). Each of these can compromise arterial inflow, venous outflow, or sympathetic regulation of cerebral blood flow.

In vTOS, the subclavian vein is compressed between the first rib and clavicle, especially during shoulder depression, poor posture, or muscular hypertrophy. This impairs venous return from the arm and propagates venous congestion into the IJV and vertebral plexus, which are major drainage routes for the posterior fossa. The resulting elevation in cerebral venous pressure reduces the arterial-venous gradient required for effective perfusion, particularly in upright posture. When combined with VAH, this sets the stage for reductions in brainstem oxygenation.

The anterior and middle scalene muscles insert onto the first rib and scalene insertions on the first rib directly influence thoracic outlet dimensions.  Tight scalenes elevate the first rib, narrowing the thoracic outlet and compressing neurovascular structures.  Hypertrophic scalenes correlate with neurovascular compression in TOS. (Golden et al. 2020 (6))

Much of the knowledge on forward neck posture and Thoracic Outlet Syndrome pathology has been through Norwegian researcher Kjetil Larsen.(Larsen,K. 2018 (7))  Mechanical stress from elevated ribs may affect cervical sympathetic ganglia (C3–C5), though direct evidence is limited.  TOS-associated dysautonomia is linked to brachial plexus-sympathetic interactions. (Larsen,K. 2018 (7))    Neurogenic hypertension models show brainstem hypoperfusion activates sympathetic pathways. (Guyenet et al. 2020. (8)) (Koeers et al. 2016. (9))

FHP increases cervical spine loading and scalene tension, exacerbating thoracic outlet narrowing.  It  reduces craniovertebral angle, increasing neck muscle tension and compressing neurovascular bundles.   Postural slouching activates scalenes, worsening TOS.   FHP alters gamma wave activity in frontal/parietal lobes, suggesting disrupted sensorimotor integration that could affect autonomic control. (Jung et al. 2024 (10))

Impaired jugular/vertebral drainage elevates intracranial pressure, reducing perfusion efficiency. Scalene-mediated changes may transmit mechanical stress superiorly to C3–C5, potentially irritating the cervical sympathetic chain and superior cervical ganglion (SCG). Increased venous compression may provoke cerebral vasoconstriction via perivascular sympathetic fibres, reducing perfusion in vertebrobasilar territories. While scalene C3–5 interactions are anatomically sound (Golden et al., 2020 (6)), direct evidence of superior cervical ganglion involvement is lacking. This creates a dual-hit mechanism of venous hypertension and arterial constriction, which is particularly detrimental to brainstem perfusion.

Historical and Occupational Triggers of vTOS and Autonomic Symptoms

The role of thoracic outlet compression in autonomic dysfunction is further supported by historical observations. As early as 1943, military physicians Falconer & Weddel (11) recognized that sustained use of heavy backpacks could precipitate neurovascular symptoms consistent with “costoclavicular syndrome,” including syncope, paraesthesia, and orthostatic intolerance—symptoms now recognized within the POTS spectrum. Sustained backpack use compresses the costoclavicular space, depressing the clavicle and increasing scalene muscle activation. This exacerbates brachial plexus tension and subclavian vein compression, leading to venous congestion and sympathetic overactivation. (Larsen,K. 2018 (7))    

Similarly, De Silva in 1986 (12) documented that excessive breast weight in females can alter shoulder mechanics, depress the clavicle, and narrow the costoclavicular space, contributing to venous thoracic outlet obstruction and secondary autonomic symptoms. This mechanism parallels occupational risks in roles requiring repetitive overhead motions or heavy lifting.(Jones et al. 2019 (13)) 

Povlsen and Povlsen in 2018 (14) describe “high-level repetitive physical activity involving the upper extremity may put individuals at risk for development of thoracic outlet syndrome.”  They also evaluated high-performance string instrument musicians demonstrating abnormal ultrasound scans with vascular compressions detected in 69% of musicians versus 15% of controls. Interestingly, they also noted vascular compression were more commonly noted in violinists and viola players than cellists.  Furthermore, in violinists and viola players, the left arm, which is elevated to hold up the instrument, was more commonly affected than the right bow-holding hand.

These biomechanical forces increase compressive loading on the subclavian vein and brachial plexus, intensify scalene activation, and may ultimately provoke both vascular congestion and sympathetic overactivation. The relevance of these triggers in modern clinical cohorts—particularly those with postural collapse, connective tissue disorders, or fascial dysfunction—highlights the underappreciated contribution of external and musculoskeletal loads in precipitating or exacerbating POTS symptoms.  These biomechanical forces can be seen in teens and pre-teens struggling with heavily weighted backpacks for school, activating and driving POTS symptoms.

Importantly, the association between vTOS and thrombotic complications such as Paget-Schroetter syndrome (effort thrombosis of the subclavian vein) provides additional clinical relevance. (Illig & Doyle 2010 (15))  In such cases, microembolic phenomena and upper extremity venous hypertension may contribute to chest pain, dyspnoea, or even posterior circulation hypoperfusion, particularly after prothrombotic triggers such as COVID-19.

Inflammatory endothelial activation, venous stasis, and external compression converge to increase thrombotic risk in this anatomical corridor, suggesting that mechanical venous obstruction may be an underrecognized source of cardio-pulmonary and neurovascular symptoms in post-viral dysautonomia.

Forward Head Posture (FHP)

FHP compounds these effects by anteriorly shifting the centre of mass of the head, increasing strain on the deep cervical flexors and suboccipital muscles. This posture compresses the SCG and IJV at the C1 transverse process, where these structures lie in close fascial proximity to the longus colli. Mechanical impingement here may impair venous drainage and amplify sympathetic output, creating a self-perpetuating cycle of hypoperfusion, autonomic instability, and neuroinflammation. Clinical features include central fatigue, orthostatic lightheadedness, cognitive dysfunction, and positional headaches.

The Lymphatic Links

Detailed in: Lymphatic and CSF Canalicular Systems (16) The lymphatic system and fascial structures of the head and neck play critical roles in the regulation of fluid balance, immune function, and neurovascular health, all of which are frequently dysregulated in conditions like POTS, Chronic Fatigue Syndrome, Fibromyalgia, and Long COVID.

The relationship between lymphatic obstruction, cerebrospinal fluid (CSF) flow, and the glymphatic system in conditions like POTS and Long COVID is complex and underexplored.  It has consistently been seen in clinic physical therapy, warranting the use of manual lymphatic drainage.

Ongoing clinic research has highlighted the intricate connections between lymphatic drainage, sympathetic nervous system (SNS) activity, glymphatic function, and fascial dynamics, suggesting that lymphatic dysfunction may exacerbate the pathophysiology of these chronic illnesses, and complements the research by Raymond Perrin in 2019 (17).

An example from “problematic POTS activators” such as in T8 rotation combines repetitive rotation eg dental assistants, teachers, posture, breast weight (add military body armour), lymphatic obstruction,  activation of the sympathetic splenic nerve, (at T6 -9,) coeliac ganglion and greater splanchnic nerve.  T8 rotation may act as a mechanical trigger for POTS by disrupting sympathetic outflow to the splanchnic circulation, amplifying blood pooling, and compounding occupational/postural stressors.  Added weight eg military armour of 4 to 11 kg exacerbates postural strain potentially compromising lymphatic drainage near the diaphragm, worsening fluid retention and orthostatic intolerance. Chronic postural stress amplifies catecholamine release, a hallmark of hyperadrenergic POTS. (19)

In POTS, splanchnic blood flow increases by ~50%  during upright posture due to failed vasoconstriction, diverting blood to the gut and away from systemic circulation.(20)(21)  T8 rotation may exacerbate this via greater splanchnic nerve dysregulation with altered signalling to the coeliac ganglion impairing gut vasoconstriction, and linked to pelvic venous congestion, iliac vein compression and varicose veins in POTS.(20)(22)(23)

Manual lymphatic drainage and interventions targeting fascial restrictions have shown clinical utility in modulating autonomic symptoms in this cohort. Moreover, the lymphatic obstruction appears to activate mast cell populations, which release vasoactive and fibrotic mediators that remodel fascia and worsen neurovascular tethering. This establishes a feedback loop in which inflammation, mechanical stress, and autonomic dysregulation are mutually reinforcing.

Lymphatic Drainage and Venous Angles

The lymphatic system plays a critical role in draining interstitial fluids, proteins, waste products, and other solutes from tissues into the venous circulation. The lymphatic system drains into the venous angles, which are the sites where the thoracic duct and right lymphatic duct converge with venous circulation at the internal jugular vein (IJV) and subclavian veins.

 Lymphatic dysfunction in these areas could potentially lead to several issues, especially in POTS, where blood volume regulation, venous return, and autonomic regulation are already impaired.

The concept of "Perrin Points" as described by osteopath researcher Dr Raymond Perrin (17) relates to regions of lymphatic congestion that are associated with symptoms like fatigue, pain, and brain fog—often reported in chronic fatigue syndrome (CFS), fibromyalgia, and potentially POTS.  These points have been hypothesized to correlate with lymphatic obstruction or stagnation, particularly in the neck region near the venous angles and subclavian veins.  Ongoing clinic lymphatic flow studies at a preliminary stage show a strong correlation with his hypothesis.

Lymphatic obstruction at these sites might further exacerbate autonomic dysfunction, inflammation, and impact CSF circulation, considering their proximity to critical vasculature and lymphatic drainage paths.

Venous Obstruction at C1 and CSF Canalicular System

The vertebral veins and internal jugular veins (IJV) drain blood from the brain and spinal cord. The cervical spine, particularly the C1 vertebra, is a key region where venous obstruction could affect both the cerebral venous circulation and potentially the lymphatic/CSF flow.

Obstruction or retrograde flow in these veins we believe creates a pressure gradient, reducing the efficiency of venous drainage and increasing intracranial pressure. This may impair CSF reabsorption and lead to CSF stasis or congestion.  The role of the CSF Canalicular System as described by Joel Pessa 2023 (19) is at present only seen in cadaver specimens.   The path of this gravitational-driven pathway that is large enough to be more important than the lymphatic system in maintain CSF balance is potentially vulnerable both at C1 and the venous angles.  

The consistent finding of altered fascia would impact further on this pathway, as well as the lymphatics that channel through the carotid fascia to join the subclavian/IVJ confluence.   As it is gravitational, its role may be of major importance when head pressure increases with standing/sitting, complicating vertebral venous outflow obstruction.  

Lymphatic Obstruction at foramen magnum

At the level of the foramen magnum, where the spinal cord and brainstem transition, any venous obstruction or retrograde flow from vertebral veins could put pressure on the cervical lymphatic channels and impact the drainage of CSF.  CSF obstruction at this site would contribute to Intracranial Hypertension, which often overlaps with conditions like POTS and Long COVID.

While direct evidence is limited, tracers injected into spinal CSF pathways drain into paravertebral lymph nodes and mediastinal lymph nodes.  Vertebral venous hypertension may obstruct these routes, trapping inflammatory mediators in cervicomedullary regions. Xu et al, 2023 (25))

Jacob, Boisserand et al (26) confirmed in mice studies that “vertebral lymph vessels connect to peripheral sensory and sympathetic ganglia and form similar vertebral circuits connecting to lymph nodes and the thoracic duct.   They showed that the connection between lymph vessels and sympathetic ganglia occurred at the surface of the ganglia revealing a hitherto unknown anatomical interaction between the autonomous nervous system and vertebral lymphatic vessels.   They are closely apposed around the chains of sensory and sympathetic nervous ganglia, so lymphatic vessels may provide molecular signals to the sympathetic neurons that control vascular tone of lymphatic ducts and cerebral arteries and arterioles.”

“Previous observations by the authors also showed that adrenergic fibres connect to the thoracic lymphatic duct and also innervate the wall of lymph node arterioles.   The crosstalk between spine LVs and the sympathetic system is thus likely relevant for the regulation of peripheral lymph and glymphatic drainage and may coordinate them with the activity of brain and spine tissues. The authors speculate that a regulatory loop may link meningeal lymph vessels, sympathetic chain neurons and both CNS and peripheral fluid drainage.”(26)

Albayram et al (27) showed “dural lymphatic structures along the dural venous sinuses in dorsal regions and along cranial nerves in the ventral regions in the human brain and they detected direct connections between lymphatic fluid channels along the cranial nerves and vascular structures and the cervical lymph nodes.  They also identified age-related cervical lymph node atrophy and thickening of lymphatics channels in both dorsal and ventral regions, findings which reflect the reduced lymphatic output of the aged brain.”(27) 

“Macromolecules, waste products, and excess fluid from most tissues are known to drain into the systemic lymphatic system.   Classically, absorption of CSF occurred through arachnoid granulations and villi of the intracranial and spinal venous sinuses.   More recent animal studies have demonstrated CSF-ISF drainage via meningeal lymphatic vessels and along the cranial nerves into deep cervical lymph nodes.”  According to their study result, the vascular-carotid space in the neck is very important for the CSF-ISF drainage from the brain.”(27) 

Glymphatic System Dysfunction and COVID-19

The glymphatic system is a recently discovered pathway for clearing metabolic waste from the brain, operating predominantly during sleep. It is a perivascular system that facilitates CSF movement along the walls of the arteries, around the brain, and back to the venous system. The glymphatic system is especially vulnerable to disruptions in the blood-brain barrier, CSF flow, or venous drainage, all of which are implicated in POTS and Long COVID.

COVID-19 has been shown to contribute to blood-brain barrier disruption, inflammation, and microvascular changes, all of which could impact glymphatic function. Additionally, viral-induced cytokine storms could cause neuroinflammation, which may disrupt CSF flow and glymphatic clearance.

CSF obstruction due to lymphatic dysfunction or venous congestion could lead to an accumulation of neurotoxic metabolites like amyloid beta, which has been implicated in neurodegenerative diseases and cognitive dysfunction. This would align with the cognitive symptoms seen in Long COVID and POTS, including brain fog, cognitive impairment and fatigue.

Lymphatic Obstruction and Mast Cell Activation

Lymphatic obstruction can trigger a cascade of immune responses, particularly through the mast cell activation pathway. Mast cells are widely distributed in the skin, mucosal tissues, and other organs, including those around the cervical spine, venous angles, and fascia. They are key players in allergic responses, inflammation, and immune modulation.

1. Lymphatic Congestion and Immune Activation:

   • Lymphatic vessels are responsible for draining immune cells, inflammatory mediators, and waste products from the tissues. When lymphatic drainage is compromised, inflammatory mediators can accumulate, leading to localized or systemic immune activation.

   • Mast cells, which reside in close proximity to the lymphatic system, may become activated in response to this fluid and immune overload. This can result in the release of pro-inflammatory mediators such as histamine, prostaglandins, cytokines, and serotonin, all of which are involved in vasodilation, oedema, and recruitment of other immune cells.

   • Lymphatic obstruction at the venous angle or C1, where the lymphatic vessels drain into the venous system, can particularly exacerbate mast cell activation. The failure to adequately drain inflammatory products could lead to chronic low-grade inflammation, which contributes to the development of symptoms like brain fog, fatigue, headaches, and autonomic dysfunction.

2. Mast Cell Activation Syndrome (MCAS):

   • MCAS is characterized by inappropriate activation and degranulation of mast cells, which release a variety of inflammatory mediators that can contribute to vascular permeability, neuropathic pain, autonomic dysfunction, and gastrointestinal symptoms. In the context of cervical lymphatic obstruction, it is probable that the local accumulation of immune cells and inflammatory mediators might trigger mast cell activation, leading to an exacerbation of symptoms related to neuroinflammation and vascular dysfunction.

     
     

Fascia and Its Role in the System

The fascia is a connective tissue structure that surrounds muscles, bones, and organs, providing structural support and contributing to fluid dynamics. Fascia is deeply connected with lymphatic drainage and can influence venous flow, neurovascular regulation, and inflammation. Fascial restrictions around the C1 vertebra, venous angles, and jugular veins could exacerbate the effects of lymphatic obstruction.

Fascia plays a role in regulating the movement of lymphatic fluid and venous blood, acting as a conduit for these fluids to flow toward the venous angles and lymph nodes. Changes in the fascia, especially when it becomes tight or restricted, can impair the movement of lymph and increase pressure on cervical lymphatic structures.

C1 Fascial Compression and Neurovascular Structures

Tight or restricted fascia surrounding the C1 vertebra, especially involving the alar and transverse ligaments, can exert compressive forces on adjacent structures including the internal jugular vein (IJV), carotid sheath, and superior cervical ganglion. This anatomical convergence may explain the prevalence of headaches, neck pain, cervical instability, and vagally-mediated autonomic symptoms in patients with dysautonomia.

Fascial tension in this region may impair cerebral venous return and glymphatic clearance, elevating intracranial pressure and promoting neuroinflammation. Moreover, mechanical stress near the superior cervical ganglion may enhance sympathetic output, feeding into a vicious cycle of autonomic instability and hypoperfusion.

Myofascial Trigger Points and Sensitization

Chronic tension in the neck and upper thoracic fascia, particularly in the trapezii and suboccipital muscles, is often associated with myofascial trigger points. These zones of contracture may be compounded by lymphatic congestion, mast cell degranulation, and local ischemia. Such microenvironmental disturbances can drive nociceptor sensitization and glial activation, leading to central sensitization—a core feature of chronic pain and dysautonomia.

Notably, these trigger points often localize to the trapezius ridge where “coat-hanger pain” occurs, a hallmark of hypoperfusion-related myofascial ischaemia. Collagen remodelling and altered fascial compliance under chronic inflammatory and hypoxic conditions further support the role of fascia as a dynamic integrator of neuroimmune and mechanical stress.

Biotensegrity and Fascia-Neuroimmune Crosstalk

Emerging concepts in bio-tensegrity suggest fascia transmits mechanical forces across distant anatomical compartments. Cervical fascial tension may thus impact thoracic venous angles, vertebral venous return, and even diaphragmatic lymphatic movement.

Mast cell activation within fascial tissues, particularly in hypoxic and inflamed microenvironments, potentiates fibrosis and perineural sensitization, worsening pain and autonomic symptoms. This supports a structural-inflammatory model wherein fascia acts both as a mediator and amplifier of dysautonomia in POTS and Long COVID.

Integration with Mitochondrial and Immune Dysfunction

The integration of brainstem hypoxia with mitochondrial and immune dysfunction creates a pathophysiological cascade that perpetuates autonomic dysregulation in conditions like POTS.

The metabolic consequences of brainstem hypoxia include:

• PDH inhibition- this disrupts pyruvate entry into the Citric Acid/ Krebs cycle, forcing reliance on anaerobic glycolysis. This elevates lactate levels while reducing ATP synthesis, exacerbating energy deficits in brainstem autonomic nuclei.( Clemente-Suárez et al. 2023 (28))

• Mitochondrial uncoupling  increases reactive oxygen species (ROS) production, further damaging electron transport chain complexes and impairing oxidative phosphorylation. ( Clemente-Suárez et al. 2023 (28))

• Lactate dysregulation arises from impaired astrocyte-endothelial shuttling, leading to neuroinflammation and metabolic rigidity.  Excess lactate inhibits histone deacetylases, promoting pro-inflammatory gene expression. ( Clemente-Suárez et al. 2023 (28))

These changes further exacerbate cellular energy failure in autonomic brainstem nuclei. Dysregulation of the malate-aspartate shuttle and lactate shuttling across astrocytes and endothelial barriers contributes to neuroinflammation and metabolic rigidity.

Hypoxia amplifies inflammatory pathways via stabilization of HIF-1α, which interacts with TLR4, RAGE, and NF-κB signalling to promote a pro-inflammatory milieu. RAGE is particularly relevant, as its ligands accumulate in hypoxic environments and perpetuate oxidative stress, monocyte recruitment, and endothelial dysfunction. Inflammatory infiltration of the brainstem via CCL2 and leukocyte trafficking may further disrupt autonomic regulation, contributing to the chronicity of POTS and related conditions.

Conclusion and Future Directions

Brainstem hypoperfusion represents a unifying, upstream pathology in POTS and related neuroimmune syndromes, integrating vascular, metabolic, and immune dysfunctions. Central to this hypothesis is the interaction between anatomical constraints (e.g., vertebral artery hypoplasia, thoracic outlet compression, forward head posture), impaired venous and lymphatic drainage, and mitochondrial insufficiency within the autonomic nuclei of the medulla and pons.

Hypoperfusion activates HIF-1α, driving mitochondrial shutdown via PDH inhibition, lactate accumulation, and oxidative stress. Simultaneously, venous congestion—particularly at the C1-IJV interface—compromises glymphatic outflow and CSF turnover, contributing to intracranial hypertension and neuroinflammation. Fascial restriction at key neurovascular chokepoints potentiates this cascade by mechanically impeding lymphatic drainage and facilitating mast cell activation.

Importantly, fascia is not merely a passive scaffold but an active regulator of neurovascular and immune homeostasis. Through its interaction with mast cells, sympathetic fibres, and lymphatic vessels, fascial dysfunction bridges mechanical and inflammatory models of autonomic disease.

These findings demand a paradigm shift in the diagnosis and treatment of POTS and allied syndromes. Future clinical strategies should integrate:

• Dynamic imaging: upright MRV/CTV, duplex ultrasound, and brainstem SPECT to evaluate perfusion and venous congestion.

• Metabolic profiling: PDH activity, lactate, amino acid balance (particularly aspartate/glutamate), and mitochondrial function.

• Mechanical assessment: postural analysis, fascial compliance, and TOS evaluation.

• Therapeutic innovation: combining metabolic support (e.g., nicotinamide, magnesium), mast cell stabilization (e.g., ketotifen, cromolyn), targeted fascial release, and lymphatic drainage techniques.

A precision medicine framework should distinguish mechanical–vascular, immunoinflammatory, and metabolic POTS phenotypes, tailoring intervention accordingly. As we move toward phenotype-based classification—distinguishing mechanical-vascular, neuroinflammatory, and metabolic subtypes—comparative perfusion mapping may serve as both a diagnostic biomarker and a treatment monitoring tool.

Ultimately, by placing brainstem hypoperfusion at the centre of a neuroimmune-metabolic network, we open the door to integrative and mechanistically-informed therapies that address the root drivers of dysautonomia—moving beyond symptomatic control to disease modification.

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