Locus Coeruleus Hypoperfusion and Noradrenergic Vasospasm: A Central Mechanism in Dysautonomia and Cerebral Hypoperfusion

Dr Graham Exelby May 2025

Abstract

Brainstem hypoperfusion is increasingly recognized as a unifying feature in dysautonomic syndromes such as Postural Orthostatic Tachycardia Syndrome (POTS), Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Long COVID, and Gulf War Syndrome.

This paper proposes a specific, under-recognized mechanism: hypoperfusion of the locus coeruleus (LC) in the dorsal pons triggers a compensatory surge in noradrenaline release, which paradoxically induces vasoconstriction of cerebral vessels through α2-adrenergic receptor activation.

This maladaptive response, while initially protective, may perpetuate widespread cerebral hypoperfusion and cognitive dysfunction.

The LC acts as both a perfusion sensor and effector, linking mechanical, postural, and inflammatory stressors to neurovascular dysregulation. Integration of imaging, physiological, and neurochemical evidence supports the existence of a feedforward vasospasm loop that originates in the brainstem but manifests as transcortical dysfunction.

Recognizing LC-centered autoregulatory failure offers a pathophysiological bridge between posture-induced venous congestion, orthostatic intolerance, and the diffuse cerebral symptoms seen in dysautonomia.

Introduction

Dysautonomia syndromes such as POTS, ME/CFS, and Long COVID share a characteristic constellation of cognitive dysfunction, orthostatic intolerance, and neurovascular instability. Central to their pathophysiology is brainstem hypoperfusion, particularly involving the medulla and rostral ventrolateral medulla (RVLM).

However, one structure within the dorsal pons has received insufficient attention: the locus coeruleus (LC), the brain's principal source of noradrenaline.The LC plays a dual role as both an autonomic regulator and a neurovascular modulator. It receives blood supply from small pontine branches of the basilar artery and is thus highly susceptible to dynamic perfusion deficits induced by upright posture, forward head posture (FHP), vertebrobasilar anomalies, and jugular venous obstruction.

In this paper, we propose that hypoperfusion of the LC activates a maladaptive reflex loop: increased noradrenaline release designed to restore perfusion leads instead to regional and global cerebral vasoconstriction, worsening cortical hypoxia.This model integrates high-impact findings from imaging studies, animal research, and human cognitive challenge paradigms, providing a framework to understand the feedforward loop of vasospasm, sympathetic overactivity, and cognitive dysfunction.

Moreover, it aligns with clinical observations where cognitive exertion and orthostatic stress induce symptom exacerbation even in the absence of systemic hypotension. The LC hypothesis links mechanical and metabolic dysfunction with dynamic cerebrovascular failure.

Forward Head Posture, Orthostatic Stress, and Locus Coeruleus Hypoperfusion in Dysautonomia

1. Posture and Brainstem Perfusion (Dorsal Pons/Locus Coeruleus)

Forward Head Posture (FHP) and Mechanical Factors: 

Emerging evidence links musculoskeletal posture to regional cerebral blood flow deficits. FHP – the anterior translation of the head relative to the torso – can compromise both arterial inflow and venous outflow to the brain. In particular, an excessively forward head position compresses structures at the upper cervical spine (around C1) where critical vessels and nerves pass. This posture can impinge the internal jugular veins (IJVs) and vertebral venous plexus, reducing venous drainage from the cranium. Impaired jugular/vertebral outflow raises intracranial venous pressure and thereby lowers the effective cerebral perfusion pressure, contributing to brainstem hypoperfusionfile.  FHP also increases strain on cervical muscles (scalenes, suboccipitals) which can narrow the thoracic outlet and compress the subclavian vessels, compounding circulatory impediments.

Notably, the superior cervical sympathetic ganglia lie in this region; FHP-related tension may irritate the sympathetic chain, provoking vasoconstrictive reflexes that further limit blood supply to posterior fossa structures. In essence, poor head/neck posture creates a “dual-hit” on brainstem circulation: elevated venous pressure plus sympathetic-mediated arterial constriction. Clinically, these effects can manifest as dizziness or syncope with certain neck positions. For example, dynamic head extension or rotation in individuals with a hypoplastic vertebral artery can acutely reduce basilar artery flow, sometimes causing orthostatic hypotension or vertigo.

Consistently, imaging and clinical studies in patients with dysautonomia-associated condition especially POTS report brainstem hypoperfusion. One resting-state EEG study found that adopting a forward head position (vs. neutral posture) altered brain activity, increasing high-frequency (gamma) waves in frontal and parietal regions. (Jung et al 2024 (1)) The authors suggested that FHP imposes stress on the cervical spine and nervous system, which may disrupt normal cerebrospinal fluid flow or neural signaling. Although EEG changes are indirect, they align with the concept that FHP can modulate brain function by mechanical strain.

Upright Postural Stress (Orthostasis): 

Beyond static head posture, simply being upright (standing or head-up tilt) places gravitational stress on circulation, and in susceptible individuals leads to cerebral hypoperfusion. Healthy persons compensate via autoregulation and venous return mechanisms, but patients with conditions like POTS, ME/CFS, or Long COVID often cannot maintain adequate brainstem and cortical perfusion upon standing. (Campen et al 2021 (2)) Tilt-table tests and NASA lean tests (a standardized orthostatic challenge) consistently show that dysautonomia patients experience a greater drop in cerebral blood flow (CBF) than controls for a given upright posture. (2)  For instance, in a comparative study, all Long COVID patients tested developed POTS on tilt, and their mean cerebral blood flow reduction was significantly larger (~40% reduction in flow) than in healthy  individuals.(2)

Notably, even ME/CFS patients without tachycardia (normal heart rate/BP on tilt) showed marked CBF reductions, indicating that cerebral hypoperfusion can occur independently of overt orthostatic hypotension. (2)  An abnormal cerebral flow decrement on tilt is seen in ~90% of ME/CFS patients, correlating with the severity of orthostatic symptoms (lightheadedness, “brain fog”). (Khan et al 2015 (3))   

Brain imaging supports these physiologic findings, both in clinic SPECT scans and other research: SPECT scans of POTS and ME/CFS patients in upright vs. supine positions demonstrate reduced perfusion in the dorsal brainstem (pons/medulla) as well as cerebellar and cortical areas when upright. Even in the supine state, a substantial subset of POTS patients show chronically low cerebral perfusion on SPEC.  (Seeley et al 2025 (4))

Together, these data indicate that upright posture – especially when combined with predisposing anatomical factors (like FHP or venous outlet obstruction) – can precipitate regional hypoperfusion in the dorsal pons (where the locus coeruleus resides) and related brainstem structures. The locus coeruleus (LC) itself, located in the dorsal pons, is perfused by branches of the basilar artery; thus, any compromise of vertebrobasilar flow (due to posture or anatomy) could directly diminish LC blood supply.

In summary, both forward head carriage and orthostatic stress are linked to brainstem hypoperfusion in susceptible individuals, through a combination of mechanical vascular compression and failure of normal cerebrovascular compensation.

2. Locus Coeruleus Hypoperfusion, Noradrenaline Release, and Vasospasm

Locus Coeruleus as a Perfusion Sensor and Sympathetic Driver: 

The locus coeruleus is the brain’s chief noradrenergic nucleus, with extensive projections regulating arousal, autonomic tone, and vascular dynamics. Intriguingly, the brainstem contains “intracranial baroreceptors” – recently identified as astrocytes and neurons in regions like the ventrolateral medulla – that sense decreases in local perfusion and trigger reflexive increases in sympathetic outflow.   

Researchers showed that astrocytes provide neurons with essential metabolic and structural support, modulate neuronal circuit activity and may also function as versatile surveyors of brain milieu, tuned to sense conditions of potential metabolic insufficiency, and that theydetect falling cerebral perfusion pressure and activate CNS autonomic sympathetic control circuits to increase systemic arterial blood pressure and heart rate with the purpose of maintaining brain blood flow and oxygen delivery.

Lowering cerebral perfusion pressure (by raising intracranial pressure in rats) activated astrocytes in brainstem autonomic centres, which in turn increased sympathetic nerve activity and blood pressure to compensate. (Marina et al 2020 (5))  Notably, even moderate perfusion drops (on the order of those during postural changes) elicited this response, with sympathetic activation occurring within ~30 seconds and persisting long after the initial insult (5)

Extrapolated to humans, this suggests that brainstem hypoperfusion (including in the LC region) rapidly triggers central sympathetic drive as a protective mechanism to maintain cerebral blood flow. In conditions of chronic brainstem under-perfusion (as posited in POTS/ME/CFS), the LC and related nuclei may be chronically hyperactive, releasing norepinephrine in an attempt to stabilize brain perfusion. Indeed, neurogenic hypertension models indicate that ischaemia in brainstem autonomic nuclei provokes sustained sympathetic overactivity.  

Seminal studies by Guyenet el al 2004 (6) demonstrated that inhibition of neurons in the RVLM abolished the pressor response to cerebral ischaemia, indicating the critical role of this region in mediating cardiovascular responses to ischaemic events. This finding supports the concept that the brainstem can initiate a compensatory increase in sympathetic outflow during ischaemia, a phenomenon often referred to as the "ischaemic pressor response," consistent with the idea that the brainstem “fights back” against hypoxia by dumping catecholamines (the so-called “ischaemic pressor response”).

Furthermore, Guyenet's research has elucidated the importance of C1 neurons within the RVLM in maintaining sympathetic tone and arterial pressure. Depletion of these neurons leads to significant reductions in both parameters, underscoring their pivotal role in autonomic regulation. (Guyenet & Stornetta 2022 (7))

These studies collectively reinforce the understanding that the RVLM, particularly its C1 neuronal population, is integral to the body's response to ischemic stress, orchestrating increases in sympathetic activity to preserve cerebral perfusion. (Guyenet 2006 (8))

Noradrenaline-Mediated Vasoconstriction: 

Paradoxically, while increased sympathetic output raises systemic blood pressure, noradrenalin release in the brain can cause local vasospasm of cerebral vessels.  The LC’s noradrenergic axons innervate cerebral arteries, arterioles, and even capillaries via perivascular projections.  Classic experiments by Goadsby et al 1985 (9)) showed that electrically stimulating the LC in monkeys produces frequency-dependent cerebral vasoconstriction, increasing cerebrovascular resistance (especially in the internal carotid arterial territory supplying the brain.) (Korte et al 2023 (10))

They demonstrated that, LC-derived noradrenalin can tighten brain arteries via α_2 receptors, reducing cerebral blood flow. More recent work has pinpointed the action at the microvascular level: Attwell et al. 2023 (1)) found that LC-released noradrenalin contracts capillary pericytes and arteriolar smooth muscle, creating a baseline “contractile tone” in the cerebral microcirculation. (Korte et al 2023 (10))

This tonic vasoconstriction (again via α_2-adrenoceptors) may normally serve to prevent hyperperfusion and to allow redistribution of blood to active regions (since vessels can dilate from a constricted baseline in response to local activity. (Korte et al 2023 (9))  However, in the context of chronic hypoperfusion, excessive noradrenalin(NA) release could overshoot, causing maladaptive vasospasm.

In theory, a hypoperfused locus coeruleus will fire persistently to correct perceived low flow, spilling noradrenalin both into the bloodstream and onto cerebral vessels. The result is a double-edged sword: systemic blood pressure may rise (potentially “protective” to overall brain perfusion), but regionally, the cerebral vasculature (especially in high-NA areas like the cortex) may constrict, worsening perfusion in some territories. Some authors have posited this as a central mechanism of “protective vasospasm,” where the brain sacrifices perfusion to less-critical regions in order to shunt blood to vital structures. For instance, LC stimulation in animals dilates external carotid (facial) vessels even as it constricts internal carotid flow, suggesting a redistribution of blood away from the brain in favor of the periphery at certain LC firing patterns.(Goadsby et al 1985 (9))

This could be viewed as protective against intracranial pressure surges or to prioritize brainstem perfusion over cortical perfusion in extreme cases. However, in chronic syndromes, such vasoconstriction is more likely detrimental, contributing to symptoms. Importantly, noradrenergic vasospasm has been observed in pathological states: e.g., stress-induced reversible cerebral vasoconstriction syndrome (RCVS) involves transient hyperactivation of sympathetic innervation of cerebral arteries.

While RCVS is an acute entity, it underscores how surges in NA (often due to stressors or catecholamine-releasing triggers) can precipitate diffuse cerebral artery narrowing (vasospasm) and hypoperfusion. In POTS and related conditions, one might envision a milder, chronic form of this phenomenon.

In summary, locus coeruleus hypoperfusion is likely to increase LC firing/NA release, which initially aims to restore blood flow (via systemic pressure elevation), but concurrently can induce cerebrovascular constriction via α_2-adrenoceptor mechanisms. (Goadsby et al 1985 (9))  This noradrenergic vasospasm can be “protective” in an acute reflexive sense, yet if persistent it becomes part of a vicious cycle of impaired brain perfusion.

3. Validating LC-Mediated Cortical Hypoperfusion: Insights from Cognitive Challenge Studies

Brainstem Autonomic Dysfunction Spreading Upwards: 

Conditions such as Postural Orthostatic Tachycardia Syndrome (POTS), Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and Long COVID exhibit striking overlaps in neurovascular pathology. A unifying feature is dysfunction of the brainstem autonomic centres – including areas like the LC, nucleus tractus solitarius, and rostral ventrolateral medulla – which leads to systemic dysautonomia and secondary effects on higher brain region. When the dorsal medulla/pons is under-perfused, baroreflex and vagal tone are blunted, and sympathetic outflow surges.

This state has two major consequences: (1) systemic hemodynamic instability, and (2) impaired cerebral autoregulation, both of which threaten cortical perfusion. For example, an MRI arterial spin labeling study in POTS patients by Seeley et al 2025 (4) found reduced blood flow not only in the brainstem but also in cortical regions, correlating with cognitive complaints (“brain fog”.)   Brain SPECT imaging consistently shows a pattern of brainstem and frontal cortical hypoperfusion in these syndromes.   In POTS, Seeley et al. (2025) reported that 61% of patients had abnormal CBF on SPECT even while supine, with the prefrontal and sensorimotor cortices most commonly affected.  This suggests a baseline cortical under-perfusion potentially driven by chronic dysautonomia.

The “spread” of hypoperfusion likely reflects both direct and indirect mechanisms. Directly, as discussed, LC projections to the cortex release NA which can reduce cortical vessel calibre. (Goadsby et al 1985 (9))    Indirectly, chronic brainstem dysfunction means cerebral blood flow is not properly regulated during challenges. As an analogy, the brainstem is the command centre for keeping the brain perfused (through blood pressure control and CO₂ sensing for vasodilation); if that centre is oxygen-starved, it cannot effectively safeguard the cortex’s blood supply.

Cognitive Challenge as a Perfusion Stressor: 

Interestingly, it’s not just orthostatic stress that unmasks these deficits – cognitive exertion can also exacerbate hypoperfusion. Patients with POTS often report “brain fog” and concentration difficulties even while seated or supine.   Wells et al 2020 (11) subjected POTS patients to a 30-minute cognitive stress test without orthostatic change and found their cerebral blood flow velocity dropped by nearly 8%, comparable to the reduction seen during upright tilt.   Healthy controls had only a ~2% drop with the same cognitive task.  Moreover, the POTS group’s mental performance worsened after the cognitive load, and symptom scores (e.g. difficulty concentrating) increased.

All of this occurred with unchanged blood pressure and CO₂,suggesting a failure of neurovascular regulation rather than systemic hypotension.   The authors concluded that sustained cognitive effort can provoke cerebral hypoperfusion in POTS, likely because their baseline cerebrovascular tone is already high (due to sympathetic overactivity) and cannot relax sufficiently to meet the increased metabolic demand of cognitive processing.  This finding reinforces the concept of a feed-forward loop: brainstem dysautonomia leads to cortical under-perfusion, which then manifests as cognitive dysfunction, especially under stress.   A possible criticism of this study and its “findings,” is that the subjects in the cognitive testing while seated may have been in a head-forward position looking at laptops or similar, which the authors have declined to provide information on.  

In ME/CFS and Long COVID, similar patterns are observed. Many individuals have normal brain MRI structure, yet functional scans (SPECT, PET) show patchy cortical hypometabolism or hypoperfusion – often frontoparietal – alongside brainstem abnormalities.  Patients commonly describe that mental or physical exertion worsens their symptoms (post-exertional malaise). 

The noradrenergic overdrive originating in the brainstem may also induce a pro-inflammatory state in the brain that spreads dysfunction. Noradrenaline can activate microglia and modulate neuroinflammation; chronic LC hyperactivity might thus contribute to cortical neuroinflammation or oxidative stress, compounding perfusion issues .  While human evidence of this inflammatory cascade is still emerging, animal models of chronic brain hypoperfusion show microglial activation and white matter changes distant from the initial insult, hinting at a propagating process.

Thus, in syndromes like POTS, ME/CFS, Long COVID, we can envisage a chain-reaction: postural stress triggers brainstem hypoxia, the LC ramps up noradrenaline, cortical vessels constrict and neuroinflammation is amplified, leading to diffuse cerebral hypoperfusion and “brain fog.”  Patients end up with both brainstem symptoms (orthostatic intolerance, autonomic swings) and cortical symptoms (cognitive impairment, fatigue), rooted in this common pathophysiological cascade.

Recent clinical data further suggest that the severity and persistence of PEM may not solely reflect mitochondrial dysfunction or neurovascular dysregulation but also impaired clearance of metabolic endproducts retained in the extracellular matrix (ECM).

 Observations of near-immediate PEM resolution following targeted manual lymphatic drainage (MLD)—notably through the cervical, parasternal, and thoracic channels—support a model in which exertion-induced hypoxic metabolites and neuroinflammatory byproducts accumulate within the ECM due to impaired glymphatic-lymphatic outflow.

This stagnation likely amplifies brainstem and cortical sensitization. Restoration of lymphatic patency appears to facilitate rapid symptomatic reversal, particularly in cognitive fatigue, suggesting that PEM may in part be a detoxification failure secondary to autonomic, fascial, and venous congestion.”

This aligns with earlier findings that LC-driven vasospasm and elevated noradrenaline levels impair glymphatic function via astrocytic AQP4 modulation and reduced perivascular clearance. Taken together, the data reinforce the model of PEM as a clearance failure—one that may be rapidly modifiable via lymphatic mobilisation techniques.

4. Neurovascular Autoregulatory Dysfunction in Orthostatic Syndromes

Impaired Autoregulation: 

Under normal circumstances, cerebral autoregulation maintains relatively stable blood flow to the brain across changes in posture or blood pressure. In POTS, ME/CFS, and related conditions, autoregulation appears blunted or delayed, especially during orthostatic challenge. (Khan et al 2025 (3))   Khan et al (3)) noted that in ME/CFS patients, cerebral blood flow remained low even after tilt-back to supine, suggesting a sluggish recovery of autoregulation compared to healthy individuals, which we have noted in dynamic studies of vertebral arteries and veins in clinic studies.  

Many forms of orthostatic intolerance involve “impaired regulation of cerebral blood flow in the upright posture, which results in disabling symptoms. (3)   Mechanistically, this could stem from both neurogenic and vascular causes. On the neurogenic side, chronic sympathetic overactivation can desensitize or damage the baroreflex and small vessels.

Normally, cerebral arterioles dilate when BP drops or CO₂ rises; in dysautonomia patients, transcranial Doppler studies show an excessive drop in flow with standing that is not fully compensated by vasodilation. Stewart et al 2015 (13) noted some POTS patients exhibit oscillatory blood flow on tilt, reflecting an unstable vasomotor tone. 

Using 24 hr heart rate variability studies in clinic, we have found this oscillatory pattern in a number of patients where the perceived origin is from IJV obstruction at the base of the neck associated with a venous Thoracic Outlet Syndrome (vTOS), and a dilated IJV impacting on the carotid baroreceptor in a confines of the carotid sheath.  We have described this as the Modified Geddes Baroreceptor Hypothesis.(Exelby 2025. (14))

On the vascular side, endothelial dysfunction or reduced vascular compliance (perhaps from oxidative stress or inflammation) could limit the arterioles’ ability to respond. There is evidence of neurovascular uncoupling in these conditions – i.e. the usual link between neural activity and local blood flow is disrupted.

Autonomic Reflex Instability: 

The locus coeruleus and ventrolateral medulla are integral to autonomic reflexes (like the baroreflex). Hypoperfusion in these areas impairs their function, causing feed-forward instability. For example, a hypoxic brainstem cannot properly sense blood pressure swings or coordinate heart rate, leading to exaggerated heart rate responses (tachycardia) but inadequate vascular responses.

POTS patients often have a hyperadrenergic state (elevated plasma noradrenaline on standing) as the body’s desperate attempt to maintain cerebral perfusion. Yet this high noradrenaline appears to overshoot, triggering systemic vasoconstriction that raises blood pressure unevenly and perhaps paradoxically reducing cerebral blood flow (if peripheral resistance shoots up without improving cardiac output).

Studies have documented elevated sympathetic nerve activity in POTS and ME/CFS, and interestingly, interventions that modulate this (like low-dose propranolol or clonidine, an α_2 agonist) can sometimes improve cerebral blood flow and cognitive symptoms – suggesting the issue is partly one of neurogenic overcompensation.

Another facet is vascular sensitivity where chronic noradrenaline exposure might upregulate α-adrenergic receptors or induce smooth muscle hyper-reactivity, making cerebral arteries prone to spasm. This could explain why even mild upright stress yields an outsized reduction in CBF in patients. In Long COVID POTS, van Campen et al 2021 (15)) showed patients who were very fit pre-illness (ruling out deconditioning) still develop severe orthostatic cerebral hypoperfusion,  pointing toward an acquired dysautonomia and autoregulatory failure rather than simply being out of shape.

Integrated Model: 

Tying these pieces together, forward head posture and upright stress can initiate brainstem hypoperfusion; an immediate reflex via astrocytes and LC neurons cranks up sympathetic outflow to compensate in the short term this raises blood pressure (protecting against fainting), but also causes cerebral vasoconstriction via NE (risking localized ischaemia)- Marina et al 2020 (5))  If this cycle repeats frequently or continuously – as in chronic orthostatic intolerance – the normal neurovascular regulatory mechanisms become dysregulated.

Over time, one sees a pattern of persistent brainstem hypoperfusion with secondary cortical hypoperfusion, sustained by a combination of mechanical factors (e.g. venous congestion from FHP or connective tissue laxity), and neurochemical factors (excess noradrenaline, neuroinflammation). High-impact studies support various links in this chain: SPECT and PET scans from clinics and research labs document the brainstem and cortical blood flow deficits, while  animal experiments in Nature (5) show astrocyte-mediated sympathetic reflexes to low brain perfusion.   Pharmacologic studies demonstrate α_2-driven vasospasm from LC activity- Goadsby et al 1985 (9)  

In conditions like POTS, ME/CFS, and Long COVID, we now recognize neurovascular autoregulatory dysfunction as a core contributor to symptoms. Rather than being a mere downstream effect, brainstem hypoperfusion could be a driving lesion – setting off noradrenergic surges and cerebrovascular dysregulation that propagate a state of widespread cerebral hypoxia.

This paradigm shift has important implications: it suggests that therapies aiming to improve brainstem perfusion (e.g. enhancing venous drainage, correcting posture, or using vasodilators that cross the blood-brain barrier) and to calm the locus coeruleus might break the cycle of hypoperfusion and sympathetic overdrive.

Persistent noradrenergic vasospasm and sympathetic overdrive are not only vasoconstrictive but also suppress lymphatic contractility and glymphatic-ECM flow. Clinical studies and pilot interventions in POTS and Long COVID patients have now demonstrated that PEM can be significantly reduced or eliminated via MLD techniques aimed at decompressing the cervical lymphatics and opening the subclavian and thoracic ducts. This suggests that ECM congestion—driven by vascular, autonomic, and postural failure—becomes a reservoir for hypoxic waste that sustains post-exertional dysfunction.

Restoration of interstitial drainage via physical mobilisation may represent a key therapeutic frontier, directly targeting the metabolic-autonomic feedback loops described throughout this paper.

In conclusion, the literature increasingly supports that forward head posture and orthostatic stress can induce locus coeruleus hypoperfusion, inciting a compensatory noradrenergic response that may lead to cerebral vasospasm – a sequence that helps explain the cranial hypoperfusion seen from the brainstem to the cortex in POTS, ME/CFS, Long COVID and related syndrome . This integrative neurovascular pathophysiology is shaping new approaches to diagnose and treat these often misunderstood conditions.

Conclusion

Locus coeruleus hypoperfusion represents a pivotal and underappreciated driver of cerebral dysfunction in dysautonomia. Its unique position within the brainstem's vascular and autonomic landscape allows it to act both as a sentinel and executor of neurovascular tone. When deprived of adequate perfusion—whether due to upright posture, venous congestion, or anatomical compression—the LC initiates a noradrenergic response that, while aimed at restoring homeostasis, paradoxically induces vasospasm through α2-receptor activation.

The emerging ability to resolve PEM through lymphatic therapy strongly supports the model of central congestion and impaired metabolic clearance as a downstream effect of locus coeruleus vasospasm and brainstem hypoxia. This therapeutic window opens a new domain of targeted intervention—lymphatic clearance—for syndromes previously thought to be refractory to acute reversal.

This response becomes maladaptive when chronic, spreading hypoperfusion from the brainstem to cortical and limbic areas. The resulting cognitive dysfunction, fatigue, and autonomic instability form the clinical phenotype seen in POTS, ME/CFS, and Long COVID. Future work must validate LC perfusion dynamics through targeted imaging and investigate the potential of therapeutic modulation using centrally acting α2 agonists, postural correction, and venous decompression. Recognizing LC-driven vasospasm as a central mechanism offers a crucial path toward integrated and mechanistically targeted interventions in complex autonomic syndromes

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