Neurovascular-Endocrine Dysfunction as a Core Axis in POTS, Long COVID, and Fibromyalgia

The interplay between intracranial venous congestion, brainstem hypoperfusion, and HPA axis dysfunction

Dr Graham Exelby May 2025

Abstract

Dysfunction of the neurovascular-endocrine axis—comprising intracranial venous congestion, brainstem hypoperfusion, and hypothalamic-pituitary-adrenal (HPA) axis disruption—forms a central pathophysiological framework in POTS, Long COVID, and fibromyalgia.

This paper synthesizes anatomical, metabolic, and neuroimmune mechanisms to explain how impaired cerebral venous outflow (notably at the internal jugular, vertebral plexus, and thoracic outlet) elevates intracranial pressure, reduces brainstem and limbic perfusion, and disrupts baroreceptor signalling. These changes impair autonomic regulation and destabilize the HPA axis via glutamate excitotoxicity, GABA depletion, and neuroinflammation.

The Nucleus Tractus Solitarius (NTS) and Locus Coeruleus (LC) are shown to mediate bidirectional communication between the brainstem, limbic system, and hypothalamus, coordinating autonomic tone, cortisol regulation, and stress responses. Chronic brainstem hypoxia and glutamate excess overstimulate NMDA receptors and promote microglial activation, RAGE signalling, and mitochondrial dysfunction—fuelling a self-perpetuating loop of neuroendocrine collapse.

This model reframes HPA axis dysfunction not as primary, but as a downstream consequence of upstream neurovascular and metabolic impairment.

Therapeutic implications include venous decompression, glutamate clearance, NMDA modulation, and restoration of GABAergic and mitochondrial function. Recognition of this integrated neurovascular-endocrine failure clarifies overlapping symptom constellations in dysautonomia syndromes and supports a precision medicine approach to diagnosis and intervention.

​ Introduction

In the advancing framework of post-viral and postural autonomic syndromes, a pivotal convergence point has emerged at the intersection of intracranial venous hypertension, brainstem hypoperfusion, and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. These interdependent domains form a neurovascular-endocrine triad that increasingly appears central to the symptom clusters seen in POTS, Long COVID, and fibromyalgia—including orthostatic intolerance, fatigue, hyperalgesia, and cognitive impairment.

This section explores how venous outflow obstruction, glutamate-driven neuroinflammation, and impaired limbic regulation collectively disrupt HPA axis signalling. Special focus is placed on the Nucleus Tractus Solitarius (NTS) and Locus Coeruleus (LC), their interaction with hypothalamic centres, and the feedback loops driving stress-inflammation-circulatory collapse. We propose an integrated model in which amino acid, vascular, and neurotransmitter dysfunction coalesce into a state of neurovascular-endocrine decompensation, with implications for systems-based intervention.

The hypothalamic-pituitary-adrenal (HPA) Axis

The hypothalamic-pituitary-adrenal (HPA) axis plays a pivotal role in the body's response to stress, regulating various physiological processes, including immune function and cardiovascular dynamics. Dysfunction of the HPA axis has been implicated in several conditions, notably POTS.  Factors such as glutamate-induced neuroinflammation, intracranial hypertension (ICH), and dural sinus/intracranial venous backflow pressure may contribute to HPA axis dysregulation and are relevant in the pathophysiology of POTS, Long COVID, and Fibromyalgia.

The interrelation between HPA axis dysregulation, intracranial hypertension (ICH), venous outflow obstruction, and neuroinflammatory signalling adds a crucial neuroendocrine dimension to the broader pathophysiological model of POTS, Long COVID, and fibromyalgia. These syndromes, long characterized by autonomic instability, exertion intolerance, and neurocognitive symptoms, appear to converge upon a central axis of brainstem hypoperfusion, glutamate excitotoxicity, and hypothalamic dysfunction—all of which are magnified by postural venous congestion and impaired cerebrospinal fluid (CSF) clearance.

From Wikipedia (1): “ “The HPA axis is a major neuroendocrine system  that controls reactions to stress  and regulates many body processes, including digestion, the immune system, mood and emotions, sexuality, and energy storage and expenditure.  There is bi-directional communication and feedback between the HPA axis and the immune system.   A number of cytokines such as IL-1, IL-6, IL-10 and TNF-alpha can activate the HPA axis, although IL-1 is the most potent.”

“The HPA axis in turn modulates the immune response, with high levels of cortisol resulting in a suppression of immune and inflammatory reactions. This helps to protect the organism from a lethal overactivation of the immune system, and minimizes tissue damage from inflammation.  During an immune response, p[proinflammatory cytokines are released into the peripheral circulation system and can pass through the blood brain barrier where they can interact with the brain and activate the HPA axis. Interactions between the proinflammatory cytokines and the brain can alter the metabolic activity of neurotransmitters and cause symptoms such as fatigue, depression and mood changes.”(1)

The HPA stress response is driven primarily by neural mechanisms, invoking corticotrophin releasing hormone (CRH) release from hypothalamic paraventricular nucleus (PVN) neurons.   Pathways activating CRH release are stressor dependent: reactive responses to homeostatic disruption frequently involve direct noradrenergic or peptidergic drive of PVN neurons by sensory relays.

Hindbrain neurons in the nucleus of the NTS are critical for regulation of the hypothalamo-pituitary-adrenocortical (HPA) responses to stress. Research highlights the importance of the Nucleus Tractus Solitarius (NTS) as a key regulatory node for coordination of acute and chronic stress.   It is well-known that noradrenergic (as well as adrenergic) neurons in the NTS send direct projections to hypophysiotrophic corticotropin-releasing hormone (CRH) neurons and control activation of HPA axis responses to acute systemic (but not psychogenic) stressors.  Noradrenergic signalling via alpha1 receptors is primarily excitatory, working either directly on CRH neurons or through presynaptic activation of glutamate release.

Figure 1. The hypothalamic-pituitary-adrenal axis, or HPA axis

The interaction between the hypothalamus, pituitary gland, and adrenal glands; it plays an important role the body’s response to stress. The pathway of the axis results in the production of cortisol.

Source: Guy-Evans, O. (2021, Sept 27). Hypothalamic-Pituitary-Adrenal Axis. Simply Psychology. www.simplypsychology.org/hypothalamic–pituitary–adrenal-axis.html (2)

Chronic stress-induced activation of the HPA axis takes many forms (chronic basal hypersecretion, sensitized stress responses, even adrenal exhaustion), with manifestation dependent upon factors such as stressor chronicity, intensity, frequency and modality.  Neural mechanisms driving chronic stress responses can be distinct from those controlling acute reactions, including recruitment of novel limbic, hypothalamic and brainstem circuits. (3)

The Limbic System

The Limbic system lies on both sides of the thalamus, beneath the medial temporal lobe of the cerebrum, between the cerebral hemispheres and the brainstem, supports a variety of functions including emotion, behaviour, long-term memory and olfaction.  It is currently considered one of the many parts of the brain regulating visceral autonomic processes.(4)   The limbic system is vital for one's normal functioning. 

This system acts as the centre of emotions, behaviour, and memory. It is also a contributor to the control of reactions to stress, attention, and sexual instincts. It comprises a set of complex structures anatomically divided into the limbic cortex, cingulate gyrus, parahippocampal gyrus, hippocampal formation, dentate gyrus, hippocampus, subauricular complex, septal area, hypothalamus, and amygdala (5)

Perfusion scans of the Limbic system show hypoperfusion in POTS,  with prefrontal and cerebellar hypoperfusion contributing to cognitive/autonomic symptoms. Studies utilizing brain imaging techniques have identified cerebral hypoperfusion in POTS patients, even while supine, suggesting that impaired blood flow is not solely due to postural changes.(Seeley et al 2025 (7))  In POTS, cerebral hypoperfusion predominantly affects regions responsible for autonomic regulation and cognitive function. Seeley et al 2025 (7) showed that the prefrontal cortex and limbic system, including structures such as the hippocampus and amygdala, exhibit reduced blood flow.  This reduction may contribute to the cognitive impairments and emotional dysregulation observed in POTS patients.

The limbic system’s role in memory and emotion makes it susceptible to hypoperfusion and microstructural changes in post-viral/post-vaccine state. (8)(9)(10)

Figure 2: The Limbic System

Source: Blausen.com staff (2014). "Medical gallery of Blausen Medical 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436 (6)

The 4 main structures of the Limbic System:

1.     Hypothalamus- governs a wide range of physiological processes, including circadian rhythm, homeostasis, and stress response, as well as growth and development. Regulation of these activities is achieved, in part, via the activities of the hypothalamic-pituitary-adrenal axis (HPA).  The supraoptic nucleus is a collection of magnocellular neurosecretory cells (MNCs) located within the anterior hypothalamus that participate in the HPA axis. The primary function of these cells is to produce and secrete the peptide hormone vasopressin, also known as antidiuretic hormone (ADH) and oxytocin. Vasopressin serves to maintain the body's osmotic balance and regulate the body's blood pressure by instigating aquaporin expression in the kidney's distal tubule and collecting duct to increase water absorption. (11)

2.     Amygdala- is responsible for the control of emotions and behaviour besides memory formation. It also functions in regulating anxiety, aggression, fear conditioning, emotional memory, and social cognition.  There is a bilateral reduction of the hippocampus and amygdala functioning in PTSD (5)

3.     Thalamus is composed of different nuclei that each serve a unique role, ranging from relaying sensory and motor signals, as well as regulation of consciousness and alertness. Generally, the thalamus acts as a relay station filtering information between the brain and body.  The thalamus is made up of a series of nuclei formed mainly by neurons of excitatory and inhibitory nature. The thalamocortical neurons receive sensory or motor information from the rest of the body and present selected information via nerve fibres (thalamocortical radiations) to the cerebral cortex. The connection of limbic system structures to the anterior nuclei of the thalamus allows the thalamus to be involved in learning and episodic memory.  The thalamus is also involved in the regulation of sleep and wakefulness. (5) 

4.     Hippocampus  The hippocampus, parahippocampal region of the medial temporal lobe, and the neocortical association have been shown to be essential for memory processing. Impairment of short-term memory leading up to an inability to form new memories occurs when there is bilateral damage to the above mention regions.  The hippocampus is closely associated with the amygdala, hypothalamus, septum, and mammillary bodies such that any stimulation of the nearby parts also marginally stimulates the hippocampus. There are also high outgoing signals from the hippocampus, especially through the fornix into the anterior thalamus, hypothalamus, and greater limbic system. The hippocampus is also very hyperexcitable, meaning it can sustain weak electrical stimulation into a long, sustained stimulation that helps in encoding memory from olfaction, visual, auditory, and tactile senses.   it has a mechanism to convert short-term memory into long-term memory, consolidating verbal and symbolic thinking into information that can be accessed when needed for decision-making. (12)

Solitary Nucleus (Nucleus Tractus Solitarius).

The nucleus tractus solitarius (NTS) plays a crucial role in the sympathetic nervous system as a key integrative centre for cardiovascular and respiratory control in maintaining autonomic homeostasis.  It integrates multiple inputs, coordinates responses and modulates sympathetic outflow. 

The tract is composed of fibres from the trigeminal and facial nerves rostrally, the glossopharyngeal nerve  in the intermediate region and the vagus nerve caudally.  Evidence from animal studies revealed the solitary nucleus (Sol) as the initial relay for baroreceptor, cardiac, pulmonary chemoreceptor, and other vagal and glossopharyngeal afferents.  The Sol neurons are activated by baroreceptor afferents, while Sol projections to ventrolateral medulla are essential for baroreflex-induced sympathoinhibition and cardiovascular stimulation. (13)

As the implications of Internal Jugular Vein dilatation in the carotid sheath in the neck, thought to trigger the carotid baroreceptors, the NTS becomes important as a major relay point, especially when there is brainstem hypoperfusion.   It is also possible the carotid baroreceptor activation may cause/contribute to the hypoperfusion through sympathetic vasoconstriction of the inferior cerebellar arteries.

Glutamate is the primary neurotransmitter in the NTS for baroreflex signalling, activating receptors to mediate baroreflex responses.    Glutamatergic transmission in the NTS interacts with other neurotransmitter systems eg GABA to fine-tune cardiovascular responses.   Neurotransmitters eg nor-adrenalin and serotonin can inhibit bradycardic responses. Neuropeptides eg opioids, galanin, substance P neuropeptide Y and angiotensin 11 modulate cardiovascular function.  

Other amino acids also play a role.  Aspartic acid is an excitatory neurotransmitter in the central nervous system, along with glutamate.  It is synthesized in the brain from glucose and other precursors, as it does not cross the blood-brain barrier, is involved in the malate-aspartate shuttle, which is important for maintaining NADH delivery to mitochondria and redox balance, and plays a role in neurotransmission, the urea cycle, purine nucleotide cycle, and gluconeogenesis.

Glutamate and Substance P have been associated with increased pain perception in conditions especially fibromyalgia, although clinic studies in fibromyalgia using amino acid assays suggest that aspartic acid dysfunction may underpin the increased pain.

After processing incoming signals, glutamatergic NTS neurons activate sympathetic and parasympathetic pathways, regulating heart rate and blood pressure.   Glutamateric release in the NTS is involved in the vestibulo-sympathetic reflex pathway contributing to blood pressure maintenance during postural changes.(14)(15)

The effect of hypoperfusion of brainstem on Solitary Nucleus / vagal functioning

 The NTS/solitary nucleus serves as a primary relay centre for sensory  information carried by the vagus nerve, and the close relationship between the solitary nucleus and vagal function allows for the coordination of complex physiological responses to maintain homeostasis.  It receives General visceral and special visceral inputs from 3 major cranial nerves- Facial N (CN VII), Glossopharyngeal N (CN IX), Vagus N (CN X) which carry sensory information related to taste, visceral sensation, gut wall stretch, lung stretch, dryness of mucous membranes.

An overview of the information received: (16)   

• Sensory integration with sensory input from:

  • Chemoreceptors and mechanoreceptors in heart, lungs, airways and GI tract

  • Baroreceptors in aorta and carotid artery

  • Chemoreceptors in aorta sensing blood oxygen

• Visceral sensory relay, processing and integrating sensory information from the vagus nerve

• Reflex coordination

  • Gag reflex

  • Carotid sinus reflex

  • Aortic reflex

  • Baroreflex

  • Chemoreceptor reflexes

  • Gastrointestinal reflexes regulating motility and secretion

• Autonomic regulation, coordinating autonomic responses based on vagal input

• Cardiovascular control , the dorsomedial part of the solitary nucleus is the primary convergence point for cardiovascular sensory fibres

• Respiratory regulation, with input from stretch receptors and bronchopulmonary nerve fibres via the vagus, and relayed to the respiratory control centres in the medulla.

An overview of the solitary nucleus involvement as seen in POTS:

• It receives afferent inputs from cardiovascular, respiratory and visceral receptors.

• It integrates multiple neurotransmitters and neuromodulators including glutamate, GABA, noradrenaline, serotonin and various neuropeptides to modulate sympathetic flow

• It mediates reflex tachycardia and is active in central cardiovascular regulation

• NTS neurons coordinate respiratory and sympathetic adjustments in response to peripheral afferent inputs

• After processing incoming signals, the NTS activates specific sympathetic pathways to generate appropriate autonomic responses.

• It modulates other autonomic centres in the brain to influence broader autonomic functions

• Alterations in NTS function can contribute to sympathetic overactivity. (14)(17)

Functional relationship between the Locus Coeruleus (LC) and NTS

 The Solitary Nucleus receives sensory information from visceral organs, then integrates this information to modulate autonomic functions which can influence blood pressure and heart rate indirectly affecting lymphatic flow.

The Locus Coeruleus, the main source of nor-adrenalin in the brain, involved in arousal, attention and stress responses, when activated can increase sympathetic tone which can affect lymphatic vessel contractility.

The sympathetic trunk’s pathway to the NTS and LC involves complex neural circuits that integrate autonomic and sensory information.   The integration of sympathetic and sensory information occurs through the connections of the NTS and LC.     The NTS processes sensory inputs from baroreceptors and other visceral afferents, which the LC modulates arousal and autonomic responses based on this sensory information.   This integrated pathway is designed to ensure a coordinated response to physiological and environmental stimuli, maintaining homeostasis and adaptive behaviours.(18)

The connections between the locus coeruleus and nucleus tractus solitarius (NTS) are bidirectional and plays a significant role in various physiological processes.   The functional relationship between the locus and NTS applies in several contexts:

• Chemosensitivity and respiratory control, responding to changes in CO2 and ph levels (19)

• Autonomic regulation, the connection crucial for integrating and modulating autonomic functions including cardiovascular, respiratory and gastrointestinal processes (20)

• Emotional arousal and memory formation (21)

• Pain processing, as evidenced by changes in their functional connectivity during noxious stimulation (22)

• Interoception, relaying interoceptive information from the periphery to higher brain centres (20)

• Stress response, the interaction appears important in coordinating physiological responses to stress

• Coordinated activation of NTS and LC are activated in parallel in various stress situations including restraint, shock, audiogenic stress and social stress, allowing for integrated processing of stress responses (20)

• The increased NTS to LC connectivity during stimulation indicates pathways contributing to updating sensory information

• There is bi-directional connectivity between them, with the LC potentially modulating the NTS activity and sensory processing

• The NTS-LC pathway contributes to the integration of neuroendocrine responses to stress, as evidenced by changes in plasma catecholamines and corticosterone levels.(23)(24)(25)

Interaction Between the NTS to Locus Coeruleus Pathway with the HPA Axis

The interactions occur in several important ways:

• HPA axis modulation, where the NTS modulates HPA axis activity mainly through noradrenergic and adrenergic projections to the paraventricular nucleus (PVN) of the hypothalamus (20)

• Neuroendocrine integration, where the NTS-LC pathway contributes to the integration of neuroendocrine responses to stress, with changes seen in plasma catecholamines and corticosterone during stress (20)

• Corticotropin-releasing hormone appears to coordinate the communication between the NTS and LC systems during stress responses, crucial for integrating autonomic and behavioural aspects of stress (20)

• Cognitive processing- the LC-noradrenergic pathway receives input from the NTS, and plays a major role in cognitive processing of the stress response, affecting limbic system, hippocampus and cortex (20)

• Glucocorticoid feedback, the NTS rich in mineralocorticoid and glucocorticoid receptors, participates in the negative feedback regulation of the HPA axis by glucocorticoids (23)

• Excitatory role- the NTS, including its connections to the LC plays a largely excitatory role on ACTH and corticosterone release, signalling systemic dyshomeostasis eg hypoperfusion to the HPA axis (23)

• Glutamatergic signalling- the NTS sends glutamatergic projections to the paraventricular nucleus (PVN) driving ACTH release further modulating the HPA axis.

• Chronic stress integration- the NTS neurons appear to play a major role in chronic stress integration.  Control of the HPA stress response is mediated by the coordinated activity of numerous limbic brain regions, including the prefrontal cortex, hippocampus and amygdala, the hippocampus generally inhibiting HPA axis responses, and the amygdala activating the stress reaction. (26)(27)

Venous Outflow Obstruction

Venous outflow obstruction—particularly at the internal jugular vein (C1 level), vertebral plexus, and thoracic outlets—leads to chronic venous hypertension, which elevates intracranial pressure, reduces CSF absorption, and impairs glymphatic and lymphatic clearance. These vascular-lymphatic derangements converge at the foramen magnum and brainstem, where pressure dysregulation triggers limbic-hypothalamic dysfunction, impairing the HPA axis and autonomic centres (e.g., PVN, NTS). This anatomical vulnerability is further exacerbated in connective tissue disorders like hEDS, where impaired compliance amplifies the biomechanical strain on venous and lymphatic structures.

In parallel, glutamate-induced neuroinflammation, likely potentiated by EAAT dysfunction, microglial activation, and mast cell degranulation, disrupts hypothalamic regulation of the HPA axis. This leads to maladaptive stress responses, altered cortisol signalling, and further destabilization of autonomic tone. Such feedback loops between hypoperfusion, inflammation, and neuroendocrine failure underlie the core symptomatology of brain fog, orthostatic intolerance, postural head pressure, and cognitive dysfunction seen across these conditions.

Critically, these mechanisms are not isolated but synergistically connected to mitochondrial and amino acid dysregulation:

• Low GABA and aspartate impair inhibitory tone and bioenergetic recovery;

• Elevated glutamate sustains excitotoxic stress, impairs vagal modulation, and activates the HPA axis;

• RAGE signalling and oxidative stress further impair neurovascular stability and mitochondrial function.

  
  

This neurovascular-endocrine hypothesis provides a unifying explanation for the heterogeneous yet overlapping manifestations of POTS, Long COVID, and fibromyalgia, offering several implications:

• The HPA axis may be a secondary victim of upstream venous-CSF-lymphatic derangements and excitotoxic neuroinflammation.

• Orthostatic head pressure, pulsatile tinnitus, and cognitive fog may reflect dynamic cerebral perfusion instability, not solely psychiatric or functional disturbances.

• Interventions targeting venous decompression, CSF flow, glymphatic enhancement, glutamate clearance, and HPA modulation could yield synergistic therapeutic benefit.

Intracranial venous congestion and HPA axis collapse represent central, targetable nodes in the dysautonomia network, linking biomechanical, immune-metabolic, and neuroendocrine dysfunction into a coherent, multifactorial disease model. This model emphasizes the need for multi-axis diagnostics (vascular imaging, amino acid profiling, HPA/cortisol testing) and integrated therapeutic strategies to restore cerebral perfusion, autonomic resilience, and endocrine homeostasis in affected patients.

Lymphatic–ECM Clearance as a Modulator of Neurovascular-Immune Dysfunction

Recent clinical observations suggest that manual lymphatic therapy (MLT), when precisely applied to cervical, axillary, parasternal, and thoracoabdominal fascial sheaths, can acutely reverse post-exertional malaise (PEM) in patients with POTS and Long COVID. This rapid resolution suggests that hypoxic and inflammatory metabolites accumulate within the extracellular matrix (ECM), and that ECM clearance through lymphatic-venous mobilization is a critical bottleneck in recovery.

This finding reframes PEM not solely as a mitochondrial or redox failure but also as a drainage-dependent phenomenon. The malate-aspartate shuttle, implicated in redox homeostasis and GABAergic tone, may become depleted as aspartate is diverted toward metabolite detoxification. Restoration of lymphatic outflow may normalize aspartate and GABA, explaining clinical improvements post-MLT.

This also supports a three-compartment model of toxic stress accumulation—intravascular, interstitial, and ECM—where only MLT reaches the third compartment. Combined with evidence of low urinary GABA and aspartate and elevated glutamate in these cohorts, lymphatic-ECM dysfunction should be considered a primary therapeutic target.

Glutamate-Induced Neuroinflammation and HPA Axis Dysfunction

Glutamate, the primary excitatory neurotransmitter in the central nervous system, is integral to neuronal communication. However, excessive glutamate levels can lead to excitotoxicity, triggering neuroinflammation and potentially disrupting the HPA axis. Studies have demonstrated that chronic disruption of the HPA axis alters the expression of genes related to glutamate signalling in brain regions such as the medial prefrontal cortex, hippocampus, and amygdala. This dysregulation may result in heightened neural responses to stress, contributing to a maladaptive stress response.(Kinlein et al. 2022 (28))

Intracranial Hypertension (ICH), Dural Sinus Obstruction, and Venous Backflow Pressure

Intracranial hypertension, characterized by elevated intracranial pressure (ICP), can result from impaired cerebral venous outflow. Obstructions or stenoses in the dural venous sinuses can impede venous drainage, leading to increased venous pressure and reduced cerebrospinal fluid (CSF) absorption. This venous hypertension has been implicated in conditions such as idiopathic intracranial hypertension (IIH) . The resulting elevated ICP can disrupt normal brain function, potentially affecting the HPA axis and contributing to neuroendocrine dysregulation.(Tuta 2022 (29))

Midtlien et al (30) observed a significant association between POTS and conditions involving cerebral venous outflow impairment. In a study examining co-existing conditions, POTS was present in 55.8% of patients with cerebral venous disorders, suggesting a potential link between impaired venous drainage, increased ICP, and autonomic dysfunction.  This links to the impaired cerebral venous outflow seen in clinic, with obstruction in Internal Jugular Veins and Vertebral Veins, providing an explanation for the postural component for the positional head pressure and pulsatile sensation in tinnitus and “whooshing.”

Conclusion: The Neurovascular-Endocrine Model—A Systems-Based Paradigm in Dysautonomia

The mechanistic interplay between intracranial venous congestion, brainstem hypoperfusion, and HPA axis dysfunction creates a neurovascular-endocrine bottleneck in POTS, Long COVID, and fibromyalgia. Disruption of venous outflow—via jugular stenosis, vertebral reflux, or thoracic outlet compromise—elevates intracranial pressure, compromising perfusion to the NTS, LC, and limbic structures. This initiates or perpetuates glutamate-driven excitotoxicity, dysautonomia, and aberrant cortisol feedback.

Functionally, this manifests as:

• Cognitive fog, intracranial pressure and pulsatile tinnitus, reflecting impaired cerebral vascular flow, CSF clearance and cerebral perfusion.

• Emotional lability and stress intolerance, from limbic hypoperfusion and HPA dysregulation.

• Orthostatic symptoms and fatigue, driven by impaired baroreflex signalling, excitatory neurotransmitter overload (e.g. glutamate), and inhibitory deficits (e.g. GABA, aspartate).

These processes are further compounded by mitochondrial dysfunction, oxidative stress (e.g. RAGE activation), and amino acid imbalance—specifically low GABA and aspartate with elevated glutamate, as seen in your cohort.

The HPA axis is not an isolated dysfunction, but rather a downstream casualty of upstream anatomical and metabolic injury. This necessitates a shift in therapeutic targeting: decompressive strategies (e.g. for venous hypertension), modulators of glutamatergic tone (e.g. NMDA antagonists, EAAT enhancers), and interventions restoring mitochondrial bioenergetics and inhibitory neurotransmission (e.g. GABA, aspartate supplementation, NAD+ axis support).

Ultimately, the recognition of intracranial venous hypertension as a root biomechanical stressor—amplified by excitotoxicity, impaired CSF/glymphatic clearance, and limbic-HPA axis fragility—offers a comprehensive systems biology framework for understanding dysautonomia. Rather than isolated syndromes, POTS, Long COVID, and fibromyalgia represent phenotypic variants of a shared failure in neurovascular-endocrine homeostasis.

ECM congestion and impaired lymphatic drainage appear to trap hypoxic and inflammatory byproducts, contributing directly to PEM. Techniques that mobilize lymphatic and fascial flow—such as targeted MLT—may restore inhibitory neurotransmitter profiles, relieve head pressure, and accelerate metabolic recovery, thus representing a foundational, non-pharmacological intervention.

Multimodal diagnostics—spanning venographic imaging, amino acid assays, and cortisol profiling—combined with integrative therapeutics (e.g., glutamatergic modulators, mitochondrial restoration, veno-lymphatic decompression) may unlock precision-targeted care for these patients.

References

1.     HPA Axis. Wikipedia. https://en.wikipedia.org/wiki/Hypothalamic%E2%80%93pituitary%E2%80%93adrenal_axis

2.     Guy-Evans, O. (2021, Sept 27). Hypothalamic-Pituitary-Adrenal Axis. Simply Psychology. www.simplypsychology.org/hypothalamic–pituitary–adrenal-axis.html

3.     Torrico TJ, Munakomi S. Neuroanatomy, Thalamus. In: StatPearls [Internet]. Treasure Island (FL): updated 2023 https://www.ncbi.nlm.nih.gov/books/NBK542184/

4.     Fogwe LA, Reddy V, Mesfin FB. Neuroanatomy, Hippocampus. [Updated 2023] StatPearls [Internet]. Treasure Island (FL): https://www.ncbi.nlm.nih.gov/books/NBK482171/

5.     AbuHasan Q, Reddy V, Siddiqui W. Neuroanatomy, Amygdala. [Updated 2023]. In: StatPearls Treasure Island (FL): StatPearls Publishing; 2024 https://www.ncbi.nlm.nih.gov/books/NBK537102/

6.     Blausen.com staff (2014). "Medical gallery of Blausen Medical 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436

7.     Seeley, MC., O’Brien, H., Wilson, G. et al. Novel brain SPECT imaging unravels abnormal cerebral perfusion in patients with postural orthostatic tachycardia syndrome and cognitive dysfunction. Sci Rep 15, 3487 (2025). https://doi.org/10.1038/s41598-025-87748-4

8.     Mishra SS, Pedersini CA, Misra R, Gandhi TK, Rokers B, Biswal BB. Tracts in the limbic system show microstructural alterations post COVID-19 recovery. Brain Commun. 2024 May 7;6(3):fcae139. doi: 10.1093/braincomms/fcae139. PMID: 38715715; PMCID: PMC11074789.

9.     Ajčević M, Iscra K, Furlanis G, et al. Cerebral hypoperfusion in post-COVID-19 cognitively impaired subjects revealed by arterial spin labeling MRI. Sci Rep. 2023;13(1):5808. Published 2023 Apr 10. doi:10.1038/s41598-023-32275-3

10.  Douaud, G., Lee, S., Alfaro-Almagro, F. et al. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature 604, 697–707 (2022). https://doi.org/10.1038/s41586-022-04569-5

11.  Invernizzi A, Renzetti S, van Thriel C, Rechtman E, Patrono A, Ambrosi C, Mascaro L, Cagna G, Gasparotti R, Reichenberg A, Tang CY, Lucchini RG, Wright RO, Placidi D, Horton MK. Covid-19 related cognitive, structural and functional brain changes among Italian adolescents and young adults: a multimodal longitudinal case-control study. medRxiv [Preprint]. 2023 Jul 23:2023.07.19.23292909. doi: 10.1101/2023.07.19.23292909. PMID: 37503251; PMCID: PMC10371098.

12.  Klein R, Soung A, Sissoko C, Nordvig A, Canoll P, Mariani M, Jiang X, Bricker T, Goldman J, Rosoklija G, Arango V, Underwood M, Mann JJ, Boon A, Dowrk A, Boldrini M. COVID-19 induces neuroinflammation and loss of hippocampal neurogenesis. Res Sq [Preprint]. 2021 Oct 29:rs.3.rs-1031824. doi: 10.21203/rs.3.rs-1031824/v1. Update in: Brain. 2022 Dec 19;145(12):4193-4201. doi: 10.1093/brain/awac270. PMID: 34729556; PMCID: PMC8562542.

13.  Talman WT. Glutamatergic transmission in the nucleus tractus solitarii: from server to peripherals in the cardiovascular information superhighway. Braz J Med Biol Res. 1997 Jan;30(1):1-7. doi: 10.1590/s0100-879x1997000100001. PMID: 9222396.

14.  Baker E, Lui F. Neuroanatomy, Vagal Nerve Nuclei. [Updated 2023 Jul 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK545209/

15.  Neff RA, Mihalevich M, Mendelowitz D. Stimulation of NTS activates NMDA and non-NMDA receptors in rat cardiac vagal neurons in the nucleus ambiguus. Brain Res. 1998 May 11;792(2):277-82. doi: 10.1016/s0006-8993(98)00149-8. PMID: 9593939.

16.  Gowda SN, Munakomi S, De Jesus O. Brainstem Stroke. [Updated 2024 Feb 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560896/

17.  Howland RH. Vagus Nerve Stimulation. Curr Behav Neurosci Rep. 2014 Jun;1(2):64-73. doi: 10.1007/s40473-014-0010-5. PMID: 24834378; PMCID: PMC4017164.

18.  Kerfoot EC, Chattillion EA, Williams CL. Functional interactions between the nucleus tractus solitarius (NTS) and nucleus accumbens shell in modulating memory for arousing experiences. Neurobiol Learn Mem. 2008 Jan;89(1):47-60. doi: 10.1016/j.nlm.2007.09.005. Epub 2007 Oct 26. PMID: 17964820; PMCID: PMC2175480.

19.  Koning E, Powers JM, Ioachim G, Stroman PW. A Comparison of Functional Connectivity in the Human Brainstem and Spinal Cord Associated with Noxious and Innocuous Thermal Stimulation Identified by Means of Functional MRI. Brain Sci. 2023 May 9;13(5):777. doi: 10.3390/brainsci13050777. PMID: 37239249; PMCID: PMC10216620.

20.  Godoy LD, Rossignoli MT, Delfino-Pereira P, Garcia-Cairasco N, de Lima Umeoka EH. A Comprehensive Overview on Stress Neurobiology: Basic Concepts and Clinical Implications. Front Behav Neurosci. 2018 Jul 3;12:127. doi: 10.3389/fnbeh.2018.00127. PMID: 30034327; PMCID: PMC6043787

21.  Herman JP. Regulation of Hypothalamo-Pituitary-Adrenocortical Responses to Stressors by the Nucleus of the Solitary Tract/Dorsal Vagal Complex. Cell Mol Neurobiol. 2018 Jan;38(1):25-35. doi: 10.1007/s10571-017-0543-8. Epub 2017 Sep 11. PMID: 28895001; PMCID: PMC5918341.

22.  Herman JP, Ostrander MM, Mueller NK, Figueiredo H. Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis. Prog Neuropsychopharmacol Biol Psychiatry. 2005 Dec;29(8):1201-13. doi: 10.1016/j.pnpbp.2005.08.006. Epub 2005 Nov 4. PMID: 16271821.

23.  Teckentrup, Vanessa & Krylova, Marina & Jamalabadi, Hamidreza & Neubert, Sandra & Neuser, Monja & Hartig, Renée & Fallgatter, Andreas & Walter, Martin & Kroemer, Nils. (2021). NBrain signaling dynamics after vagus nerve stimulation. NeuroImage. 245. 118679. 10.1016/j.neuroimage.2021.118679.

24.  Herman JP, McKlveen JM, Ghosal S, Kopp B, Wulsin A, Makinson R, Scheimann J, Myers B. Regulation of the Hypothalamic-Pituitary-Adrenocortical Stress Response. Compr Physiol. 2016 Mar 15;6(2):603-21. doi: 10.1002/cphy.c150015. PMID: 27065163; PMCID: PMC4867107.

25.  Blessing WW. Inadequate frameworks for understanding bodily homeostasis. Trends Neurosci. 1997 Jun;20(6):235-9. doi: 10.1016/s0166-2236(96)01029-6. PMID: 9185301.

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

27.  Hampton,L. (Ed) Baroreceptors. Physiopedia. https://www.physio-pedia.com/Baroreceptors

28.  Kinlein SA, Wallace NK, Savenkova MI, Karatsoreos IN. Chronic hypothalamic-pituitary-adrenal axis disruption alters glutamate homeostasis and neural responses to stress in male C57Bl6/N mice. Neurobiol Stress. 2022;19:100466. Published 2022 Jun 5. doi:10.1016/j.ynstr.2022.100466

29.  Tuță S. Cerebral Venous Outflow Implications in Idiopathic Intracranial Hypertension-From Physiopathology to Treatment. Life (Basel). 2022;12(6):854. Published 2022 Jun 8. doi:10.3390/life12060854

30.  Midtlien JP, Curry BP, Chang E, Kiritsis NR, Aldridge JB, Fargen KM. Characterizing a new clinical phenotype: the co-existence of cerebral venous outflow and connective tissue disorders. Front Neurol. 2024;14:1305972. Published 2024 Jan 10. doi:10.3389/fneur.2023.1305972