Long Covid Part 12 The Glymphatic System and mechanical factors affecting Brain Fog

Dr Graham Exelby January 2023

THIS SECTION IS UNDERGOING A MAJOR REVISION AFTER NEW FINDINGS-EXPECTED COMPLETION MID-APRIL

This paper combines the research in multiple areas to find the driving pathology in diverse areas especially chronic fatigue and the autonomic instability associated with Long-COVID and POTS. The emergence of glymphatics in this mix where loss of cervical lordosis, internal jugular vein compression, poor posture and lifestyle provide the causes begins to help explain what is happening, and how inflammatory and autonomic problems cannot be separated, and by assessing DNA mutations, allows us to track down individual causes and provide some answers and individualized management programs. The required physiotherapy techniques for a satisfactory treatment are in its infancy and being developed, just as this paper’s content is changing in time with the rapid research that is occurring.

The combination of subclavian vein obstruction in Thoracic Outlet Syndrome and jugular vein compression when upright, the exaggerated autonomic changes in the sensitised central nervous system particularly in neck posture and arm elevation from cytokine-induced small fibre neuropathy (SFN), also affecting the flow of the cervical lymphatics (and above this the glymphatics) appears to be combining to create the “perfect storm” in the pathogenesis of POTS and Long COVID cognitive impairment.

The developing association of research with the mast-cell mutations and epigenetic changes found by Dr Valerio Vittone(44), Professors Marshall-Gradisnik, Eaton-Fitch,Smith Barnden and others from Griffith University on ME/CFS and glymphatics, and Afrin et al’s work in mast cell activation, added to the mechanical findings of Larsen(216) particularly in thoracic outlet syndrome and jugular compression provides a tantalizing look at the complex changes in POTS and Long COVID and the beginning of recovery programs for the people with this.

In 2020, a breakthrough paper from Adelaide University (164) confirmed that POTS patients have altered cerebral blood flow while they are experiencing cognitive impairment (“brain fog”), even in the absence of orthostatic symptoms. While the inflammatory change is unsurprising, as SPECT scans done in our early investigations, and currently being used in newer investigations, have already shown loss of function, it is the confirmation of altered blood flow that is so important. Similarly, Svetlana Blitshteyn’s 2021 paper (189) linking POTS to a central nervous system (CNS) disorder goes further, but again they were not looking at causes.

Brain fog, which is so common and disabling, can often be controlled through conservative measures: dietary and lifestyle alterations, non-prescription medication to stabilise mast cells, and improved posture. The effects of these simple interventions demonstrate the importance of the DNA, inflammatory and mechanical factors in both POTS and long COVID.

Brain fog is often associated with a feeling of pressure in the brain, and is seen commonly in arterial thoracic outlet syndrome (ATOS) and the more common one where venous and lymphatic obstruction appear increasingly to be a major cause with apparent impact on the glymphatic system drainage. Our current and planned vascular and SPECT studies, augmented by the ongoing studies by Kjetil Larsen that include assessment of flow rates hopefully can resolve these issues.

Glymphatic System (or glymphatic clearance pathway or paravascular system)

The glymphatic system, first described in 2013, is a macroscopic system for waste clearance in the brain. It uses a system of perivascular channels, formed by astroglial cells, to promote efficient elimination of soluble proteins and metabolites from the CNS. The name is in reference of its dependence on glial cells and the similarities to the functions of the peripheral lymphatic system. Initially thought to provide the solution to how sensitive neural tissue of the CNS functions, it has since been established there are also conventional lymphatic vessels lining dural sinuses and meningeal arteries.(210)

“Cerebrospinal fluid flows into the paravascular space around cerebral arteries, combining with interstitial fluid and parenchymal solutes, exiting down venous paravascular spaces. Exchange of solutes is driven primarily by arterial pulsation and regulated during sleep by the expansion and contraction of brain extracellular space.(210)

Besides eliminating waste, the glymphatic system may also distribute non-waste compounds, such as glucose, lipids, amino acids, and neurotransmitters, as well as permitting the flow of fluid through the brain (Figure 1.) Intriguingly, the glymphatic system functions mainly during sleep and is largely disengaged during wakefulness.

Xie et al in 2013(211)(210) described that the biological need for sleep across all species may therefore reflect that the brain must enter a state of inactivity that enables elimination of potentially neurotoxic waste products, including β-amyloid.”(38)(211)

The glymphatics also play an important role in the paravascular transport of lipids and impairment of glymphatic circulation results in intracellular lipid accumulation and pathological signalling among astrocytes.(210) Glymphatic dysfunction has been shown in animal models of traumatic brain injury, Alzheimer's disease, and stroke.(123) It is also potentially involved in haemorrhagic and ischaemic neurovascular disorders and other acute degenerative processes such as normal pressure hydrocephalus and traumatic brain injury.(213)

Figure 1. The Glymphatic System

The glymphatic systems in the brain and eye export fluid and solutes from metabolically active neural tissue. Fluids from both the brain and the eye drain via the cervical lymph vessels, which empty into the venous system at the level of the subclavian veins.

Source: Mogensen et al. The Glymphatic System (en)during Inflammation(124)

Figure 2. Neuroinflammation impairs glymphatic function and exacerbates the inflammatory response.

Source: Mogensen et al. The Glymphatic System (en)during Inflammation(124)

Natale et al(213) describe “the glymphatic pathway is connected to a classic lymphatic network, associated with dural meninges covering the brain, as well as sheaths of cranial nerves, or drains via the olfactory route, then exiting through cranial foramina. This drains ultimately to deep and superficial lymph nodes.” They explain that “during ageing meningeal lymphatic vessels exhibit decreased vessel diameter and reduced drainage to cervical lymph nodes. Experimental studies in mice showed that ablated or ligated meningeal lymphatics led to an increase in b-amyloid deposition and macrophage recruitment to plaque sites, with a reduced extracellular clearance of altered proteins.”(213)

Natale et al(213) continue that disruption of the glymphatic system plays a crucial role in age-related brain dysfunction, and there is strong evidence documenting the clearance of b-amyloid and tau via this system, as well as potentially harmful metabolites. In obstructive sleep apnoea they describe increasing cerebral aggregation and increased neurodegeneration. In haemorrhagic stroke, fibrin and other blood products occlude perivascular spaces, while “in ischaemic stroke there is an impaired CSF inflow and the release of several pro-inflammatory cytokines.” They also describe how an altered glymphatic function may account for idiopathic normal pressure hydrocephalus. “These pathological conditions are associated with a decrease in CSF influx to the glymphatic pathway or reduced clearance efficacy.”(213)

Glymphatics and Gut-Brain Axis.

Natale et al(213) further describe that a “large body of evidence shows how gastrointestinal pathologies can affect the CNS bypassing or altering blood-brain barrier (BBB) and related pathways, including the glymphatic system.

In a novel experimental study a- synuclein fibrils injected into the duodenal and pyloric muscularis layer can spread in the brain, first in the dorsal motor nucleus, and then in the locus coeruleus” and then further. Furthermore, “via the microbiota-gut-brain axis, triggering Receptors Expressed on Myeloid cells (TREM)-positive activated macrophages along with inflammatory mediators may reach the brain through blood, glymphatic system, circumventricular organs, or the vagus nerve. This may foster pro-inflammatory reactions in the brain, bridging inflammatory bowel disease and neurological disorders.” This is thought to occur from the SARS-CoV-2 viral infection. This topic is well covered by Natale et al.(213) This linking with the gut and the importance of the microbiome is currently being revised in the website.

Figure 3. The Glymphatic System, neurovascular unit (NVU) and blood-brain barrier

Source: Natale,G et al. Glymphatic System as a Gateway to Connect Neurodegeneration from Periphery to CNS. 2021. Glymphatic System as a Gateway to Connect Neurodegeneration From Periphery to CNS. Front. Neurosci. 15:639140. doi: 10.3389/fnins.2021.639140(213)

Figure 4: Glymphatic Pathway in Pathological conditions.

Source: Natale,G et al. Glymphatic System as a Gateway to Connect Neurodegeneration from Periphery to CNS. 2021. Glymphatic System as a Gateway to Connect Neurodegeneration From Periphery to CNS. Front. Neurosci. 15:639140. doi: 10.3389/fnins.2021.639140(213)

Lymphatic anatomy

Natale et al(213) describe how “not only the level of consciousness, but also body posture contributes to drainage.”

Lymphatics of the face and head drain inferiorly into the pericervical lymphatic collar. This collar consists of a series of connected lymph nodes, which form a chain that encircles the junction of the head and the neck. The collar consists of the following groups of nodes (from posterior to anterior): occipital, postauricular (retroauricular), preauricular, submandibular, and submental. These lymph nodes are drained by lymphatic channels that eventually drain into the deep cervical lymph nodes, located along the internal jugular vein. The deep cervical lymph nodes empty into the thoracic duct on the left side and the right lymphatic duct on the right side. It is an easy leap of faith to see that when the jugular and/or subclavian vein is compressed, then these lymphatics are also affected.

Clinical Review of possible causes of Lymphatic/Glymphatic and Vascular Obstruction

The ongoing research into glymphatics is shedding shed light not only on POTS and long COVID., but also likely on Alzheimers and Parkinsons Diseases.

At present, we clinically confirm Natale et al’s assertion that poor posture impairs glymphatic flow. There are number of areas currently being assessed, including impaired jugular return flow, that may be the cause of the cognitive impairment described by Jenssen et al.(122)

When a Long COVID patient is being assessed to look at the cause of their brain fog, there are a number of areas to be considered, and where we have targeted our research:

1. Glymphatic flow (dysfunction) is likely to be very important when fatigue and cognitive impairment are present. The cause is often very difficult to pin-point without good imaging and physical assessment looking at:

• Intracerebral obstruction eg tumours, microembolic trauma (including PFOs), physical and vascular trauma eg strokes

• Impaired function especially Apo E4, TRP mutations, sleep disorder (including sleep apnoea)

2. Cervical lymph obstruction -an area where research is continuing given the complexity and difficulty in confirming specific causes

• Jugular vein compression

• Thoracic Outlet Syndrome

3. Craniovascular perfusion dysfunction. This includes a potential risk for thrombosis in the venous sinuses which may need angiography. The dysfunction often improves with diet change, H1/H2 blockade, and attention to posture, (especially with computer and sustained phone usage.) Backpacks can contribute to symptoms by compression at the thoracic outlet.

• Diet change may improve this – mechanism not entirely clear, possibly as described above by Natale et al(213), inflammatory, autonomic or even vascular. Identification of foods the body reacts to reduces inflammatory responses, and appears, especially with keto, to improve mitochondrial dysfunction

• Variability in brain fog. Lau, Wells et al(164) demonstrated impaired intracerebral vascular flow. We are also seeing what clinically is hyperperfusion with typical severe “pressure” headaches.

• Arterial thoracic outlet syndrome from subclavian artery compression is believed to increase pressure as blood is diverted into the cranial circulation

• Potentially venous obstruction from neck pathology, particularly seen in loss of normal lordosis, as well as subclavian, vertebral and jugular venous compression.

• The effect of scalene pull on the cervical vertebrae, especially at C2/3

• Vertebral arterial compression

Amyloid at present not measurable- depends on radiologist skill in interpretation -if risk contact radiology for formal Alzheimers study as may need specialist referral

The possible neurogenerative changes from APO E4, LPa and PEMT and similar mutations where no formal diagnostic test except DNA exists.

Retinal arterial photography if camera adequate can give a clear picture of cerebral vasculature.

LDN in Glymphatic Function

The research from Griffith University has shown the effectiveness of Low Dose Naltrexone (H4 blocker) in improving glymphatic function. At times it is difficult to ascertain exactly what is happening when multiple problems are in place. When LDN is effective against the fatigue and brain fog, it suggests this area is where investigations should be focussed. Posture is a major concern in most brain fog and needs attention, especially in computer and phone use.

Figure 5: Lymphatic system of head and neck and association with Internal Jugular Vein

Source: https://www.britannica.com/science/lymph-node

Figure 6: Entry of Lymphatic duct into Subclavian Vein

Source: Tewfik,T. Thoracic Duct Anatomy. https://emedicine.medscape.com/article/1970145-overview

1. The Thoracic Outlet (TOS) / Neck/ Craniovenous outlet Connection

Thoracic outlet syndrome (TOS) is known to be associated with diffuse craniological comorbidities (CCM), such as occipital headaches, migraines, vestibular dysfunction, tinnitus and fatigue. Angiography tends to be normal in TOS sufferers, however, and doppler ultrasonography of the vertebral artery fails to demonstrate severe flow reduction. TOS is attributed to the brachial plexus and subclavian artery being compressed in the interscalene triangle, costoclavicular or subpectoral passages. Larsen et al (29) postulate that the blood, prevented from entering the brachium due to distal subclavian compression, retrogrades to the brain via the carotid and vertebral arteries, resulting in craniovascular hyperperfusion and congestion.(29)

The mechanical drivers that are found in all POTS are extremely difficult to address until the sensitisation from glial inflammation eg from COVID-19 is controlled. Increasingly, our research into mechanical drivers has been drawn to the TOS in its various forms and its association with neck pathology as a major cause of symptoms in most POTS patients.

The main drivers are usually the upper cervical spine, with loss of lordosis from posture and loss of conditioning (or injury) aggravated by EDS/hypermobility, (which increasingly is seen as part of the inflammatory process that is POTS and Long Covid.) TOS(3)(4) and the scalene pull at C3 to C6 aggravates the problem. Arterial TOS changes intracranial vascular pressure, as shown in the extensive work by Kjetil Larsen.(112)(216) He also demonstrates that the scalene compressive component is source of the head symptoms in most patients. The close relationship of the cranial nerves and brachial plexus provides many of the answers to symptoms when there is neural sensitization.

Figure 7: Thoracic Outlet Syndrome

Source: http://sportmedschool.com/thoracic-outlet-syndrome/ (22)- an excellent resource of information for clinician.

The brachial plexus directly anastomoses with the central sympathetic chain via the ventral ramus. This can derange autonomic function and result in various strange and seemingly unrelated disorders, and with the developing understanding of the glymphatics, the diffuse headaches, poor concentration, low energy levels and visual focus / blurriness -all are potential symptoms of craniovenous outlet obstruction affecting the glymphatics and cervical lymph drainage.

Larsen et al(216) describe: “The name thoracic outlet syndrome suggests chronic irritation (compression) of the brachial plexus and the subclavian vessels. The cause of the compression is mainly tightness of the surrounding muscles and clavicular depression, strangulating the thoracic outlet vascular and nervous structures.”(216)

“In turn, the main cause of the muscle tightness and clavicular depression, is faulty movement and postural strategies. This can be rooted in habits alone, or triggered by injuries such as a clavicular fracture, whiplash injury or similar. Slouching of the neck (forward head posture) and shoulder, belly-(only)-breathing and lack of diverse movement will cause the scalenes that form the interscalene triangle of which the brachial plexus pass through, to inhibit/deactivate. This in turn may cause severe tightening of the scalenes, compressing all of the thoracic outlet’s structures and may thus (potentially) cause all of the initially mentioned symptoms.” (216)

“The (anterior and medial) scalenes are involved in many actions. They elevate the ribs during inspiration (inhalation), ipsilaterally rotate, cause lateral translation, laterally flex and forward flex (bend) the neck. In normal breathing patterns, the ribs and clavicle should elevate slightly during inspiration, and this is done in syncronization by the scalenes, trapezius and several other muscles. Severe slouching habits will inhibit this pattern as well as proper cervical (axial) rotation, causing degeneration of the involved muscles. In turn, severe inhibition of the scalenes will often develop over time.” (216)

Larsen describes that additionally, because the scalenes attach to the ribs, they may elevate the first rib, greatly increasing the potential of secondary compression between the 1st rib and the clavicle. Compression within the scalenes often attribute to between 60-80% of the patients’ direct symptoms in his experience” (216)

In 1986, da Silva’s research showed that TOS (or costoclavicular syndrome) resulting from tight, narrow brassiere straps was a common cause of neck, shoulder, and arm pain in obese, heavy-breasted middle aged or elderly women. The costoclavicular syndrome was first described in 1943 as occurring in soldiers, who developed pain, numbness, and fatiguability of the arms as they stood at attention with loaded knapsacks. The mechanisms of compression involved downward movement of the clavicle against the first rib, with a resultant tendency toward shearing of the neurovascular bundle.(70)

This same mechanism is thought to explain subclavian vein thrombosis often precipitated by prolonged heavy exercise of the upper extremities—the Paget-Schroetter syndrome. This research is important in the understanding of the pathogenesis of fibromyalgia syndrome.(70) Just as POTS is often triggered by the use of heavy backpacks, the subclavian compression resulting from increased breast weight may exacerbate the autonomic instability associated with menopause. I believe that subclavian vein thrombosis is a major factor in the production of microemboli, a significant part of the pathology of long COVID.

2. Jugular outlet syndrome

Larsen(233) describes how compression of the internal jugular veins, especially in patients who have a poor secondary-drainage system (via the vertebral, suboccipital, cavernous and pterygoid plexuses), may result in cerebral venous hypertension, with or without raised cerebrospinal fluid levels. Venous hypertension will slow the arterial to venous transfer at the capillaries due to venous side congestion, and may thus also affect arterial resting pressures. Research from Ozen et al(120) showed that normal drainage volumes in the internal jugular veins is between 700-1200 mililiters per minute, although Larsen found that drainage must be quite low before serious symptoms occur, usually as low as 300mL/min. But fatigue and headache can be seen as high as 500mL/min, especially in patients whose optimal drainage rate is high (this is impossible to know in advance).

“As venous hypertension raises, a raise in CSF pressure will also tend to occur. But, it can be hard to identify, because as several researchers have shown CSF leaks, chronic elevation in CSF tends to cause secondary CSF leaks which causes a quite diffuse and equivocal constellation of symptoms as well as imaging findings that may seem paradoxical.”(233)

Kosugi et al (217) described “In a supine position, the internal jugular veins (IJVs) are the primary venous drain for the brain . Several studies have recently reported that the jugular veins are collapsed and the main venous outflow from the brain occurs via the vertebral venous systems (VVS) in an upright position. The vertebral venous system contains veins, venous plexuses, and venous sinuses that course along the entire length of the spine, and it is regarded as a unique, large capacity, valveless plexiform venous network in which the flow is bidirectional. The condylar veins (anterior, lateral, and posterior) and the anterior condylar confluence (ACC), which is located extracranially in front of the aperture of hypoglossal canal, represent the most important connections between the intracranial cerebral venous circulation and the VVS, and have been suggested to contribute to the main outflow tract for encephalic drainage in the upright position.”

Figure 8: Summary of the positional changes in craniocervical venous structure between supine and upright posture.

Source: Kosugi,K et al Posture-Induced Changes in the Vessels of the Head and Neck: Evaluation using conventional Supine CT and Upright CT. Nature (Scientific reports) 2020. https://doi.org/10.1038/s41598-020-73658-0 (217)

Kosugi et al, using CT angiography,showed that Internal and External Jugular Veins collapsed in an upright posture. Craniocervical junction venous structures, which flow just downstream of the outlet of the intracranial space and connect to the VVS, became more prominent in the upright position, in contrast to the more anteriorly located jugular system. Thirdly, intracranial vessels, including arteries, veins, and venous sinuses, did not show major postural changes in contrast to venous structures in the neck and craniocervical junction. The pressure in the Internal Jugular Veins is negative in this posture because they are positioned above the heart, which causes these thin-walled vessels to collapse. Similar postural changes are also observed in the superior vena cava, which is also located above the heart. They found that the vertebral venous plexus, which courses along the entire length of the spine, plays a role in the main venous outflow or large-capacity venous reservoir in an upright posture. (217)

Larsen believes, as confirmed in our studies, that contrary to common belief, craniovenous outlet insufficiency is a common disorder. Jayaraman et al(218) showed that up to 70% of patients undergoing angiographies demonstrated concurrent venous outlet obstruction at the skull base, either uni or bilateral. Ding et al.(210) found that 75% of patients with cervical spondylosis also had internal jugular venous stenosis at the skull base. Fifty percent of the stenotic vessels were compressed by the transverse process of C1, and 45% by the transverse process of C1 combined with the styloid process. The transverse process of C1 compression was more common in unilateral Internal Jugular Vein Syndrome while the transverse process of C1 combined with the styloid process compression had a higher propensity to occur in bilateral form. (210)

Larsen describes that jugular venous stenosis is a common cause of craniovenous outlet insufficiency and carries insidious and diffuse symptoms that are often misdiagnosed as a stress or diet problem. In reality, commonly it is a postural problem and can be treated by postural correctives in most circumstances.

Frydrychowski et al(219) demonstrated that bilateral jugular vein compression leads to a hyperkinetic cerebral circulation and direct transmission of pulse pressure into the brain microcirculation. Clinical studies at our clinic looking at this were quite conclusive, triggering tachycardia, brain fog, and other symptoms suggestive of increased intracranial vascular pressure, which a number of patients recognised as being identical to the pressure feeling they were having.

Figure 9: Head and Neck Veins

Source: Wikipedia: Head and Neck Veins. https://commons.wikimedia.org/wiki/File:2133_Head_and_Neck_Veins.jpg (220)

3. Loss of cervical lordosis and spine injuries

Katz et al (221) demonstrated that correction of cervical lordosis was associated with an immediate increase in cerebral blood flow. Bulut et al (222) showed that loss of cervical lordosis was associated with decreased diameter, flow volume, and peak systolic velocity in the vertebral arteries.

When migraine is present, physiotherapy researcher Dean Watson(223) described the cervical afferents of C1-3 as causing increased sensitisation of the brainstem. Neck trauma, especially in the C2/3 region, is a fairly common activator of POTS. Detailed histories usually reveal significant neck or other spine injury in most POTS patients.

The role of the cervical spine in the pathogenesis of POTS is still not straightforward because baroreceptors also regulate cerebral blood flow. There is convincing evidence for arterial baroreflex function playing an important role in maintaining brain homeostasis (e.g., cerebral metabolism, cerebral haemodynamics, and cognitive function).(224)

Anatomically, the spine has a greater range of motion and a greater incidence of non-physiological curves in females than in males. The correspondingly greater distraction/ stretch of the posterior upper spine in females has been implicated in suboccipital headaches.

Yoganandan et al(225) showed that a forward location of the head’s centre of gravity along the anteroposterior axis had the greatest influence on the curve of the neck and the motion of the upper and lower spine and that any increased load may pose a greater risk of injuries to the neck. The sex differences in the structure of the cervical spine may explain why POTS is so much more common in females than in males; thus, it is an area for future research.

Prolonged use of computers for work and recreation is often cited as a cause of neck pain. Individuals who use smartphones for prolonged durations tend to have poorer posture (head-forward posture and rounded shoulders) than do subjects who spent less time on smartphones, as well as partly impaired respiratory function.

Forward head posture is one of the most common cervical abnormalities that predisposes individuals to pathological conditions, such as headache, neck pain, temporomandibular disorders, vertebral body disorders, alterations in the length and strength of soft-tissue, and scapula and shoulder dyskinesia. Many studies have proven that people who use computers heavily have a higher incidence of head-forward posture. When people concentrate on watching the relatively small screen of a smartphone, they tend to bend their neck while looking at the screen. Thus, they may develop more serious problems.(226)

Neck injuries and poor posture (especially from computer and smartphone use) and even the increasingly heavy backpacks our schoolchildren are forced to carry are major factors in this mix of shoulder and neck pathology. For a child with hypermobile Ehlers-Danlos syndrome (hEDS) or a neck injury, POTS may be triggered by something as simple as a backpack or constant use of a laptop. The pull of the scalenes on an unstable hypermobile or injured neck requires gentle attention, as the usual physiotherapy or manual therapy approach is often too aggressive.

4. Brainstem and Dysregulation of Noradrenaline/ Locus Coeruleus Axis

Ioachim et al(227) found significant differences between fibromyalgia patients and control patients in the connectivity of the brainstem/spinal cord network, involving the regions of the hypothalamus, thalamus, hypothalamus, locus coeruleus (Figure 10), and other areas. This network and the nucleus solitarius provide ample scope for ongoing research into the exact mechanism that occurs in the brainstem, and the manner in which physical problems sensitise the brainstem. Clinically, as the sensitisation is reduced and the mechanical problems better managed, symptoms subside.

The locus coeruleus (from the Latin for “blue spot,”) communicates closely with the amygdala. The locus coeruleus is a cluster of noradrenergic neurons in the upper dorsolateral pontine tegmentum and is the brain’s main source of the neurotransmitter norepinephrine. This chemical is released in response to pain or stress, stimulating what is referred to as the “fight-or-flight” mechanism. In the brain, norepinephrine is a neurotransmitter; but in the rest of the body, it acts as a hormone and is released by the adrenal glands.(228)

Figure109. Locus coeruleus

Source: https://en.wikipedia.org/wiki/Locus_coeruleus#/media/File:Locus-coeruleus.gif

The LC-NE (norepipinephrine) system has a major role in arousal, attention, and stress response. In the brain, NE may also contribute to long-term synaptic plasticity, pain modulation, motor control, energy homeostasis, glymphatic regulation and control of local blood blow. The LC is severely affected in neurodegenerative disorders such as Alzheimer disease and Parkinson disease.

Dysregulation of LC-NE system has been implicated in sleep and arousal disorders, attention deficit hyperactivity disorder, and post-traumatic stress disorder. Extrasynaptic norepinephrine mediates signalling effects on neurons, glial cells, and microvessels.(228) It is also implicated in the dysregulation of “glymphatic” function.

Research on COVID-19 has suggested that brainstem involvement is a part of the pathology of long COVID. The brainstem regulates the respiratory, cardiovascular, gastrointestinal, and neurological processes that can be affected by long COVID. As neurons do not readily regenerate, brainstem dysfunction may be long-lasting. This brainstem dysfunction has been implicated in other similar disorders, such as chronic pain and migraine and myalgic encephalomyelitis or chronic fatigue syndrome. Further research into the regulatory role of TRPM3 and waste clearance will improve knowledge in these areas as well as improving management of chronic fatigue.

5. Brainstem Connectivity in Chronic Fatigue Syndrome

ME/CIFS is a common, debilitating multisystem disorder that seems to involve dysregulation of the CNS, immune system and cellular energy metabolism.(115) Research from Griffith University into chronic fatigue has implicated mitochondrial dysfunction as a significant factor, and when combined with the newer research into glymphatic dysfunction and Barnden’s findings in brainstem connectivity, pieces come together. Research continue at Griffith University.

At the 2019 conference of the Organization for Human Brain Mapping, Dr Leighton Barnden from Australia’s National Centre for Neuroimmunology and Emerging Diseases (NCNED) presented MRI data also showed that connectivity within the brainstem is impaired in patients with chronic fatigue syndrome.(115) Leighton’s research found that the connectivity within the brainstem, which consists of the midbrain, pons and medulla, was significantly different in ME/CFS, as compared with healthy controls. Impaired brainstem connectivity could explain reported autonomic and compensatory structural changes in patients with CFS as previously reported by NCNED (Barnden, 2015, 2016).

6. Central Sensitization

The concept of central sensitization, wherein pain and altered sensory states may be due to changes in nerve synapses and membrane excitability in the CNS, as opposed to processes in peripheral tissues, has been around for more than 20 years. Research into long COVID has demonstrated that glial and microglial small-fibre neuropathy are the likely source of this sensitisation, and confirms the inflammatory nature that underpins it, with primary cause from IL-6 and TNFa.

Pain itself often modifies the way the CNS works, so that a patient actually becomes more sensitive and gets more pain with less provocation. It’s called “central sensitisation” because it involves changes in the CNS in particular — the brain and the spinal cord. Sensitised patients are not only more sensitive to things that should hurt, but sometimes to ordinary touch and pressure as well. Their pain also “echoes,” fading more slowly than in other people. This is also sometimes called “amplified pain.”

In serious cases, the extreme oversensitivity is obvious. But in mild cases — which are common — patients cannot really be sure that pain is actually worse than it “should” be, because there is nothing to compare it to except their own memories of pain.

According to Dong et al,(197) brain inflammation plays a critical role in the pathophysiology of brain diseases. Microglia, the resident immune cells in the brain, play an important role in brain inflammation, while brain mast cells, rather than microglia, are the "first responders" to brain injury. He showed that site-directed injection of a “mast-cell degranulator” compound in the hypothalamus initiated the acute inflammatory response by inducing mast-cell degranulation, activating microglia, and triggering the production of inflammatory factors. The complex nature of the immune response and mast cell activation in now an integral part of Long Covid pathogenesis.

Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for 10% to 15% of all cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune defence in the CNS.(105) Inflammatory microglial activation (IL-6 and TNFa) is the most common brain pathology found in patients who died of COVID-19: 42% are affected, and another 15% have microclots in brain tissue.(105)This microglial activation causes the sensitization responsible for the majority of the symptoms of POTS-like Long COVID.

The mast-cell stabiliser disodium cromoglycate (cromolyn) inhibited this effect: decreasing the production of inflammatory cytokines, reducing microglial activation, inhibiting the MAPK and AKT pathways, and repressing the expression of H1, H4, protease-activated receptor 2 (PAR2), and toll-like receptor 4 (TLR4) in microglia. These results demonstrated that in the brain, activation of mast cells triggers activation of microglia, whereas stabilisation of mast cells inhibits the CNS inflammation that would otherwise result from activation of microglia.(105)

7. Sensitization of Neural Pathways and Impact of Peripheral Inflammation

Hypersensitivity following an injury is an important self-preservation mechanism. By warning the organism to avoid further injury to the area, hypersensitivity promotes healing of the injured area. Hypersensitivity can be peripheral or central, and the 2 can be hard to tell apart.(230) Unfortunately, hypersensitivity (whether central or peripheral) can overstay its welcome. In such cases, it would cause pain that serves no useful purpose. Hypersensitivity is important to identify, as it can increase patients’ suffering and may interfere with treatment.

Physiotherapy researcher Dean Watson,(22) in his work on migraine, found that stimuli applied to some hypersensitive areas of the spine can provoke symptoms of autonomic dysfunction. In patients with sensitization of the C1-3 cervical nerve root afferents and brainstem, direct pressure on C1-2 can provoke signs of autonomic dysfunction. In contrast, injuries to the sacrum/coccyx or to the upper cervical spine can provoke parasympathetic responses as well as activating neural sensitisation.

Sensitization that occurs around T7 as a result of rotation (especially after seatbelt rotational injury or prolonged occupational activity) and around sacrococcygeal joints (again, usually a history of coccygeal injury) can result in marked adrenergic responses, consistent with the different sympathetic and parasympathetic pathways in these areas.

In patients with such sensitisation, even seemingly minor stimuli such as changes in posture can provoke autonomic symptoms. The responses can be dramatic and seemingly out of context with the activity. Craig Phillips from DMA Pilates Melbourne (231) has provided evidence of the impact of rotational and other spinal injury on autonomic dysfunction, but also a pathway to recovery by addressing these mechanical injuries.

Peripheral inflammation refers to any activation of the innate or adaptive immune system outside of the central nervous system (CNS). An initial peripheral infection can alter CNS function, with responses ranging from changes in body temperature, to severe fatigue and loss of consciousness, as can occur in systemic infections. Short-term acute inflammation does not normally affect the homeostasis of the brain, thanks to the defence afforded by an intact blood-brain barrier. However, severe peripheral inflammation can often involve the CNS and trigger neuroinflammation. There are a number of ways in which peripheral inflammation can come to involve the CNS, mostly as a result of circulating cytokines.

Peripheral inflammation can have obvious effects on behaviour, sleep, memory, and cognition. There is also abundant literature showing that peripheral inflammation, perhaps by secondary involvement of CNS, can contribute to neuronal damage and increase the risk of neurodegenerative processes.

Figure 11. Overall anatomy of the autonomic nervous system.

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

Source: Bankenahally, R., Krovvidi, H. Autonomic Nervous System: Anatomy, Physiology, and Relevance in Anaesthesia and Critical Care Medicine. BJA Education. 2016;16(11):381-387.(232)

Conclusion

Research from Wells, Lau et al at Adelaide University(164) demonstrated impaired intracranial vascular flow when “brain fog” is present. We believe there is also an increased intracranial vascular pressure that was not identified in this study, which provides a link to the typical “brain fog” in Long COVID, as both can occur, part of the evolving concepts in hypo- and hyperperfusion. SPECT scans of the brain provide a picture of the perfusion abnormality. Given the high level of mechanical involvement in the sensitized Long COVID patient, these areas need further investigation in the Long COVID patient especially with autonomic instability. We anticipate the addition of a TransCranial Doppler to measure changing intracranial vascular flow/pressure, matched up with doppler studies of arterial and venous flow in the head and neck arteries and veins and with the current electrophysiological studies in using continuing heart rate and variability, QT and PR interval change, should provide a finally resolve many of the perplexing issues in POTS.

The patient with Long COVID, typically with autonomic instability that reflects a POTS spectrum of dysfunction, and who fails to respond to our protocols and reconditioning appears to have those same mechanical “drivers” as are apparent in the POTS research. This includes the intra-abdominal compression syndromes such as Median Arcuate Ligament Syndrome. https://www.mcmc-research.com/post/median-arcuate-ligament-syndrome