Dr Graham Exelby February 2024
Looking at other research areas
1. Vagal Activity and Baroreceptors
Bonaz et al (106) describe: “The vagus nerve (VN) is a key element of the autonomic nervous system and a fundamental component of the parasympathetic branch of the autonomic nervous system. This branch of the nervous system is not under conscious control and is largely responsible for the regulation of several body compartments at rest, overseeing a vast range of crucial functions, communicating motor and sensory impulses to every organ in your body. It is essential for regulation of the body’s immune response, and research is looking at the vagus in treatment of chronic diseases.”
“Vagal activity results in various effects including heart rate reduction, vasodilation/constriction of vessels, glandular activity in the heart, lungs and digestive tract as well as control of gastrointestinal sensitivity, motility and inflammation.” (106)
“As a mixed nerve, the VN contributes to the bidirectional interactions between the brain and the gut, i.e., the brain-gut axis. In particular, after integration in the central autonomic network of peripheral sensations such as inflammation and pain via vagal and spinal afferents, an efferent response through modulation of preganglionic parasympathetic neurons of the dorsal motor nucleus of the vagus and/or preganglionic sympathetic neurons of the spinal cord is able to modulate gastrointestinal nociception, motility, and inflammation.” (106)
Vagal tone specifically refers to the continual nature of baseline parasympathetic action that the vagus nerve exerts. While baseline vagal input is constant, the degree of stimulation it exerts is regulated by a balance of inputs from sympathetic and parasympathetic divisions of the autonomic nervous system, with parasympathetic activity generally being dominant. (107) Measurements of vagal tone rely mainly on heart rate and heart rate variability.
The vagus helps keep anxiety and depression at bay, and opposes the body’s reaction to stress. Over-compensation for a strong sympathetic nervous system response can cause syncope from a sudden drop in cardiac output, and can also lead to temporary loss of bladder control.(107)
The baroreflex or baroreceptor reflex is one of the body's homeostatic mechanisms that helps to maintain blood pressure at nearly constant levels. The baroreflex provides a rapid negative feedback loop in which an elevated blood pressure reflexively causes the heart rate to decrease and also causes blood pressure to decrease. Decreased blood pressure decreases baroreflex activation and causes heart rate to increase and to restore blood pressure levels. The baroreflex can begin to act in less than the duration of a cardiac cycle (fractions of a second) and thus baroreflex adjustments are key factors in dealing with postural hypotension, the tendency for blood pressure to decrease on standing due to gravity. (108)
The system relies on specialized neurons, known as baroreceptors chiefly in the aortic arch and carotid sinuses to monitor changes in blood pressure and relay them to the medulla oblongata. Baroreceptors are stretch receptors and respond to the pressure induced stretching of the blood vessel in which they are found. Baroreflex induced changes in blood pressure are mediated by both branches of the autonomic nervous system; the parasympathetic and sympathetic nerves. Baroreceptors are active even at normal blood pressures so that their activity informs the brain about both increases and decreases in blood pressure.(108)
The baroreceptors are stretch-sensitive mechanoreceptors. At low pressures, baroreceptors become inactive. When blood pressure rises, the carotid and aortic sinuses are distended further, resulting in increased stretch and, therefore, a greater degree of activation of the baroreceptors. At normal resting blood pressures, many baroreceptors are actively reporting blood pressure information and the baroreflex is actively modulating autonomic activity. Active baroreceptors fire action potentials ("spikes") more frequently. The greater the stretch the more rapidly baroreceptors fire action potentials. Many individual baroreceptors are inactive at normal resting pressures and only become activated when their stretch or pressure threshold is exceeded.(108)
Baroreceptor action potentials are relayed to the solitary nucleus, which uses frequency as a measure of blood pressure. Increased activation of the solitary nucleus inhibits the vasomotor centre and stimulates the vagal nuclei. The end-result of baroreceptor activation is inhibition of the sympathetic nervous system and activation of the parasympathetic nervous system.(108)
The sympathetic and parasympathetic branches of the autonomic nervous system have opposing effects on blood pressure. Sympathetic activation leads to an elevation of total peripheral resistance and cardiac output via increased contractility of the heart, heart rate and arterial vasoconstriction, which tends to increase blood pressure. Conversely, parasympathetic activation leads to decreased cardiac output via decrease in heart rate, resulting in a tendency to lower blood pressure.(108)
Geddes et al (72) describe heart rate and blood pressure oscillations with heads-up tilting, demonstrating these to be from baroreflex signalling modulating sympathetic and parasympathetic signalling, simulating neuropathic and hyperadrenergic POTS. Baroreceptors and mechanoreceptors respond to changes in pressure or stretch in blood vessels within the aortic arch and carotid sinus. The baroreceptors of the aortic arch transmit signals via the vagus nerve to the solitary nucleus of the medulla. The baroreceptors of the carotid sinus, where the common carotids bifurcate, transmit signals via the glossopharyngeal nerve to the solitary nucleus of the medulla.(72) Dilatation of the internal jugular vein in the carotid sheath thus has the potential to be a major “driver” through direct pressure on the carotid baroreceptors.
Many of the POTS and FMS patients exhibit wild oscillations in their heart rate variability studies seen in out 24 hr Holter HRV studies. There is a high likelihood that this represents increased pressure in the carotid sheath that encloses the carotid artery (with the carotid bulb, Internal Jugular Vein (IJV) and vagus nerve. Our research at present is evaluating whether the Internal Jugular Vein obstruction at the venous angle (junction of subclavian and internal jugular veins) and subsequent IJV dilatation puts sufficient volume pressure in the carotid sheath to trigger the baroreceptors and probably the vagus, with subsequent autonomic oscillations as the body tries to deal with this mechanical threat.
Figure 32: Carotid Sheath
Source: Wikipedia. Carotid Sheath https://en.wikipedia.org/wiki/Carotid_sheath
Figure 33: The Carotid Space
Illustration demonstrating the contents and configuration of the left carotid space, including cranial nerves glossopharyngeus (IX), vagus (X), accessory (XI), and (XII hypoglossal) with proximity of the Cervical Sympathetic Chain
Source: Chengazi, H.U., Bhatt, A.A. Pathology of the carotid space. Insights Imaging 10, 21 (2019). https://doi.org/10.1186/s13244-019-0704-z
Changes in blood pressure are mediated by the parasympathetic and the sympathetic branches of the autonomic nervous system. Sympathetic activation raises blood pressure by increasing heart rate and contractility, as well as increasing arterial vasoconstriction. Conversely, parasympathetic activation leads to a reduced heart rate (bradycardia) and reduced cardiac contractility, which reduces cardiac output and blood pressure. The baroreflex can produce a rapid and profound decrease in blood pressure by inhibiting the sympathetic branch while activating the parasympathetic branch. Conversely, the baroreflex can also elevate blood pressure by inhibiting the parasympathetic branch while activating the sympathetic branch.
The importance of this linking to the inflammatory triggering can be seen in the work by Yang et al (109) in their study on famotidine activating the vagal inflammatory reflex to attenuate the cytokine storm providing a tantalizing look at the role of the vagus in POTS and Long Covid symptoms.
The vagus nerve is frequently implicated in POTS. It is almost impossible to prove its presence, and there are no reliable tests to perform for this clinically except heart rate variability. Using heart rate variability, you can often differentiate sympathetic overactivity from parasympathetic overactivity -Case studies in POTS. Clinically the vagal activity can originate from compression intra-abdominal “drivers” such as Nutcracker, May-Thurner and rarer intra-abdominal causes affecting a vagal pathway or from the head and neck.
Vagal neuropathy is sometimes seen in the Thoracic Outlet Syndrome/Jugular Outlet Syndrome/ impaired cervical lordosis and flexion kyphosis. The vagal nerves pass between the anterior scalene and clavicular head of the sternocleidomastoid muscles, and in Jugular Outlet Syndrome it can be impinged between the C1 transverse process and the stylohoid process. Clinically, symptoms here include hoarseness, voice changes and dry cough.
The vagus is also closely related to the Internal Jugular Vein, the Carotid artery (with the associated baroreceptors in the Carotid bulb) in the carotid sheath. While the vagus is within the carotid sheath, it gives off the superior cardiac nerve and is associated with parasympathetic fibres and impact on cardiac function. With the Jugular nerve and Cervical Sympathetic Chain in close proximity, all are potentially affected by the dilation of the Internal Jugular Vein, which we have visualized in dynamic ultrasounds to assess IJV flow. This has a close association with the Subclavian vein compression found in the Venous Thoracic Outlet, and providing a second anatomical position for potential vagal dysfunction. This was a small study but sufficient to warrant formal studies, as it is very likely to link the chaotic autonomic dysfunction seen on Heart Rate Variability studies.
Figure 34. Carotid sinus and carotid body.
Afferent nerve fibers travel from the baroreceptors located in the wall of the carotid sinus and chemoreceptors located in the carotid body via the glossopharyngeal nerve to the solitary nucleus of the medulla in the brainstem.
Groenland,E, Splering,W. Baroreflex Amplification and Carotid Body Modulation for the Treatment of Resistant Hypertension. Current Hypertension Reports. 2020
Figure 33: Baroreflex
“Baroreflex activation is distinct from vagal stimulation. It works through an afferent limb which has the double effect of stimulating vagal output and attenuating global sympathetic outflow.”
Source: By Darrel Francis - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=68442403Wikipedia. Baroreflex. https://en.wikipedia.org/wiki/Baroreflex: (108)
By coupling sympathetic inhibition and parasympathetic activation, the baroreflex maximizes blood pressure reduction. Sympathetic inhibition leads to a drop in peripheral resistance, while parasympathetic activation leads to a depressed heart rate (reflex bradycardia) and contractility. The combined effects will dramatically decrease blood pressure. In a similar manner, sympathetic activation with parasympathetic inhibition allows the baroreflex to elevate blood pressure.(108)
2. Microembolic processes
Compression of the popliteal and axillary/subclavian veins are known to produce emboli. In the extreme, people with TOS can get recurrent pulmonary emboli (Paget-Schroetters Syndrome,) most commonly seen in sportspeople. Again, surgery to remove the first rib may remove the embolus risk but not necessarily the accompanying autonomic symptoms.
In research from USA in 2016, Prandoni et al (110) found looking at people seen at emergency departments after syncope or sudden collapse, 20% have been found to have had pulmonary emboli. Dyspnoea in patients with known chronic obstructive pulmonary disease (COPD) can be a clinical challenge due to the nonspecific nature of atypical presentations. Typical features of fever, productive cough, and wheezing on presentation support COPD exacerbation, while absence of such findings may warrant further evaluation for underlying aetiologies, including pulmonary embolism (PE). It is suspected that one in four patients with atypical COPD exacerbation may have PE as an underlying or concomitant cause of acute dyspnoea.(111)
The lungs should filter out any microscopic emboli from the compression areas. I strongly suspect many of the people with “asthma” not confirmed on formal lung function testing, sometimes presenting at emergency departments with chest pain and shortness of breath, have had microscopic cascades. Sometimes there is a positive D-Dimer test suggesting a pulmonary embolus, but with no sign of DVT or embolus in the usual tests, they are discharged.
The microembolic risk is so important to sort out in migraine, especially if there are hyperintensities seen on brain MRI. When a patent foramen ovale is present between the atria of the heart, microemboli from the vascular compression syndromes shunting through this into the brain may be responsible for cerebral damage particularly dementia, and certainly the “stroke-like” symptoms that affect some migraine sufferers.
In the brain MRI, migraine sufferers may have white spots, FLAIR hyperintensities. Often labelled as small vessel disease they can also reflect microembolic damage from the compression syndromes, but can also be inflammatory, reflect small vessel disease, and from the ongoing work in craniovascular perfusion, perfusion abnormality. Small vessel disease is easily excluded using retinal photography. Differentiation from astrocyte /perivascular space dysfunction is very difficult.
The presence of a patent foramen ovale when there is migraine with “risk” co-symptoms eg prolonged aura, or vertebrobasilar migraine can create a management dilemma as it is wise to occlude the PFO if there is a stroke risk from microemboli. Dementia is a real risk in these patients.
Figure 34. Patent Foraman Ovale (PFO) and Gore Helex Septal Occluder being inserted for PFO repair.
Source: PFO Research Foundation: https://pfofoundation.org/ (112)
3. Acetylcholine (Ach)
Griffith University researchers found acetylcholine to be associated with chronic fatigue by affecting ion channels in mitochondria, which produce the energy in our cells. Impaired mitochondrial exchange – with calcium signalling at an intracellular level could be a common denominator in fatigue-related diseases that have some autoimmune aetiology. Fatigue seems to be a constant even when genetic implications vary from one form of autoimmune disease to another.
Research from Professor Sonya Marshall-Gradisnik and her team at Griffith University (102) on the role of Ach and dysfunction cell receptors in TRPM3 in chronic fatigue may explain much of the fatigue that incapacitates many POTS and FMS patients. The transient receptor potential melastatin subfamily 3 (TRPM3) is one of the most primitive receptors in the body, activated by a wide variety of agents, from bacteria and viruses to temperature and environmental factors such as perfumes. This diversity made it a logical suspect for a condition like CFS that has so many different triggers in different people.
TRPM3 is an ion channel, controlling the way calcium ions are transmitted between cells and carrying instructions in the process. Calcium is a major signalling molecule in the cell so any impairment is potentially disruptive…although there are some compensatory mechanisms.
Increased acetylcholine responds best to slow graded exercise, as doctors treating fibromyalgia have found, and POTS becomes worse when patients are confined to bed, but experience has also shown the older concepts of pushing exercise even though it increases symptoms is counter-productive. Programs have to be specific for each patient and graded very slowly.
4. Dietary factors (food intolerance as a “driver”)
Food intolerance and its consequent problems appear to be present in almost all patients with FMS, and many researchers feel this is caused by the activated mast cells as the immune system struggles to contain the perceived threats. The, when you eat food the body sees as a threat, there is again an immune response and cytokines IL2, IL6, IL8 (45) are released.(113) Dealing with the intolerance can be vital in controlling the fatigue and pain.
Recent studies confirm that the most important mechanisms in IBS include visceral sensitivity, abnormal gut motility and autonomous nervous system dysfunction. The interactions between these three mechanisms make bowel's function susceptible to many exogenous and endogenous factors like gastrointestinal flora, feeding and psychosocial factors. The influence of genetic factors and polymorphisms of human DNA in the development of IBS is equally important.(114)
Chronic life event stress is a powerful predictor of symptom intensity in irritable bowel syndrome. The psychophysiological responses to such chronic stress should include alterations in cardiosympathetic and abdominal parasympathetic function. Autonomic dysregulation, consistent with the effects of chronic stress is a feature of IBS. Studies by Leach et al (115) on patients with constipation predominant constipation IBS demonstrated enhanced cardiosympathetic, and attenuated abdominal parasympathetic tone.(44)
“Most of IBS symptoms are directly related to specific abnormalities of autonomic nervous system. The main characteristic of IBS patients is the increased activity of Sympathetic Nervous System (SNS) and the decreased activity of Parasympathetic Nervous System (PNS).”(114)
The pathophysiology of irritable bowel syndrome (IBS) is complex and not fully understood. Liu et al (116) studied whether visceral and somatic hypersensitivity, autonomic cardiovascular dysfunction, and low-grade inflammation of the gut wall are associated with diarrhoea-predominant IBS. They had a significantly higher systolic blood pressure and heart rate after a cold stimulus, indicative of autonomic cardiovascular dysfunction. They also had a significantly higher level of calprotectin. They also found significant correlations between visceral and somatic hypersensitivity, visceral hypersensitivity and autonomic cardiovascular dysfunction, and somatic hypersensitivity and autonomic cardiovascular dysfunction. (117)
There is evidence that interactions within the brain and gut axis (BGA) that involves both, the afferent- ascending and the efferent-descending pathways as well as the somatosensory cortex, insula, amygdala, anterior cingulate cortex and hippocampus are deranged in IBS showing both the activation and inactivation.(118) Alterations in the bi-directional signaling between the enteric nervous system and the central nervous system and consequently between the brain and the gut may play a significant role in the pathophysiology of IBS.(118)
Low grade inflammation has been implicated as one of the underlying mechanisms of IBS. Variations in the circulating pro-inflammatory interleukin-6 (IL-6) levels and IL-6 gene polymorphisms have been demonstrated in IBS. Basasharti et al (113) found levels of pro-inflammatory interleukins 2,6 and 8 have been found to be elevated in IBS, especially in the post-infectious IBS (against non-post-infectious IBS) and reduction of anti-inflammatory IL-10 in both.
It is often difficult to work out which gut/ bladder symptom for example is driven by the autonomic activation or the food intolerance making the boundaries very blurred. Most people with food intolerances also have specific vitamin deficiencies associated with metabolic defects so ideally these need to be sorted and treated. These often include vitamin B12, vitamin D, Zinc, and Iodine. The research by Dr Valerio Vittone (119) into DNA mutations and the impact from diet has provided a picture of mutations in POTS and Long Covid. It is expected they will be very similar in FMS.
Research from the allergist Dr David Freed implicates lectins as a major dietary factor. (120) This is particularly relevant if there is accompanying arthritis, especially rheumatoid arthritis, but the sensitivities can be to many different products. The DNA from Dr Vittone answers more of these dietary/inflammatory questions with the finding of mutations for example STAT3 which has a critical factor in IL-6 regulation.
It is well to remember here that a single mutation, by itself, is insufficient to cause the symptoms of FMS, POTS or Long Covid. It is recognition of DNA patterns so as the sensitization from microglial activation is reduced, we can work with management protocols based on DNA mutations to counter residual problems and look for patterns that may impact on future health. Dr Vittone’s DNA panels he has available includes specific panels that test for gluten, dairy, histamine, oxalate, salicylates, and sulphites.
I believe that the food industry is partly responsible for the increase in FMS, with heightened immune systems reacting to the modifications of our foods. Gluten is traditionally always the “fall-guy”, but in my experience, unless there is coeliac disease, it usually starts with cow dairy, fructose, wheat, as well as sulphites, amines salicylates and others.
5. Impact of Stress on mast cells
Psychological stress has been shown to cause mast cell degranulation in several different tissues. Stress, working through the sympathetic nervous system, or the hypothalamus-pituitary-adrenal axis, stimulates peripheral nerves to release neuropeptides that bind to receptors on the mast cells, causing them to degranulate. (121)
The inflammatory mediators cause increased blood-brain barrier permeability, recruitment of immune and inflammatory cells into the brain and neuroinflammation. Corticotropin-releasing hormone (CRH) from the paraventricular nucleus of hypothalamus and mast cells activates glial cells and mast cells to release further neuroinflammatory mediators.
Mast cells play a crucial role in the peripheral inflammation as well as in neuroinflammation due to brain injuries, stress, depression, and PTSD, and thought to accelerate the pathogenesis of neuroinflammatory and neurodegenerative diseases.(122)
6. Underlying DNA Mutations
Thanks to the work of epigeneticist Dr Valerio Vittone in decoding the DNA mutations in POTS and Long Covid patients, we can now “see” the underlying genetic processes in individual patients with POTS and PASC/Long Covid. These are detailed in- Underlying DNA Mutations in POTS and Long Covid. Dr Vittone’s work, along with neuroimmunological and genetic research from Professors Sonya Marshall-Gradisnik, Pete Smith, Lionel Barnden, and their team at Griffith University, as well as research by Afrin, Weinstock and others in mast-cell activation, provides an outline of the genetic problems that drive the sensitization and chaos that result in POTS and PASC, and increasingly apparent in fibromyalgia.
The Critical Mutations in FMS
A single mutation, by itself, may be insufficient to cause the symptoms of fibromyalgia. The DNA studies by molecular biologist Dr Valerio Vittone in POTS and Long Covid has provided valuable insights into dysfunctional metabolic and immune pathways in FMS We have recognized mutations that provide valuable patterns appropriate in fibromyalgia, starting from Toll-Like Receptor 4 (TLR4) which triggers the cytokines that ultimately lead to small fibre neuropathy, and the autonomic dysfunctional symptoms of fibromyalgia.
Even when looking at DNA many practitioners might attribute everything to “methylation,” but this for example would discount “glycation” and similarly attempts to reduce the impact of DNA mutations in vital areas eg PEMT, COMT and STAT3 can in reality be potentially harmful if one is singled out without a clear knowledge of underlying metabolic pathways and how they interact.
This section provides basic information on some of the DNA mutations in Fibromyalgia Syndrome. These are described in greater detail in DNA Mutations in POTS and Long Covid.
TLR4 mutations:
Multiple mutations in the Toll-Like Receptors (especially “first responders” TLR2 and TLR4) play a large role in the individual immune response, and associated with “downstream” mutations can create a domino effect responsible for the individual symptoms and future risk.
A loss of-function mutation in the TLR4 gene reliably reduced microglial activation, decreasing the concentration of inflammatory mediators. TLR4 antagonism attenuated NF-κB pathways to decrease the number of inflammatory mediators secreted by astrocytes. Furthermore, TLR4 plays a crucial role in central neuroinflammation.
TLR4, NFkB and TRP mutations
TLR4 signalling and TRP are 2 separate biological pathways that can intersect in certain contexts. TLR4 signalling can activate TRP channels, such as TRPA1 and TRPV4, which are expressed on immune cells. The activation of these channels can lead to an influx of calcium ions into the cell, which can modulate downstream signaling events, including the activation of the NF-κB pathway.
NFkB is a protein complex that plays a crucial role in regulating the immune response, inflammation, and cell survival. The primary function of NFkB is to control gene expression in response to various signals, such as pro-inflammatory cytokines, bacterial or viral products, stress, and oxidative damage. NF-κB has long been considered a prototypical proinflammatory signaling pathway, largely based on the activation of NF-κB by proinflammatory cytokines such as interleukin 1 (IL-1) and tumor necrosis factor α (TNFα), and the role of NF-κB in the expression of other proinflammatory genes.(95) Dysregulation of NFkB signalling has been implicated in various health conditions, including autoimmune disorders, inflammatory diseases, cancer, and neurodegenerative diseases.
TRP refers to a family of ion channels found on a cell membrane of a variety of cells, including immune cells. These channels are involved in a wide range of intracellular processes, eg pain sensation, temperature sensing and regulation of intracellular calcium levels.
TRP mutations- TRPM3 appears critical in NK (Natural Killer) immune cell function, with implications for Ca2+ signalling and cell function. (103) The transient receptor potential melastatin subfamily 3 (TRPM3) is one of the most primitive receptors in the body, activated by a wide variety of agents, from bacteria and viruses to temperature and environmental factors such as perfumes.
Researchers, notably Prof Sonya Marshall-Gradisnik and the Griffith University Chronic Fatigue team (102)(103)(104)(105) working with TRPM3 function in chronic fatigue at Griffith University have linked mutations in this pathway with “glymphatic” function and fatigue and the therapeutic benefit of Low Dose Naltrexone, while Drs Grubb and Gunning, (123) have demonstrated chronic inflammatory changes in POTS patients.
This diversity made it a logical suspect for a condition like CFS that has so many different triggers in different people.
TRPA1 is a key ion channel that detects oxidative stress and a range of endogenous and exogenous chemicals (smoke, solvents, cold air).
TRPM3 activity is impaired in CFS/ME patients suggesting changes in intracellular Ca2+ concentration, which may impact NK cellular functions. This investigation further helps to understand the intracellular-mediated roles in NK cells and confirm the potential role of TRPM3 ion channels in the aetiology and pathomechanism of CFS/ME.
Barnden’s work in chronic fatigue syndrome (ME/CFS),(70)(71), demonstrating abnormal MRI correlations with symptom severity and autonomic measures have suggested impaired nerve signal conduction within the brainstem while seemingly unrelated, provide a tantalizing explanation for much of the fatigue, autonomic instability and cognitive impairment that link all of these.
Mast Cell mutations
The mast cell is a potent immune cell known for its functions in host defense responses and diseases, such as asthma and allergies. An abundance of mast cells reside in connective tissue that borders with the external world (the skin as well as gastrointestinal, respiratory, and urogenital tracts.)
Mast Cell Activation is a characteristic in Long Covid and POTS, and appears to play a major role in fibromyalgia. Dr Vittone has identified a number of mutations affecting mast cell function - one on the membrane and additional mutations of two critical enzymes (namely DAO & HNMT) involved in clearing histamines in different tissues in the body. Mast cell mutations affect body’s ability to respond to mast cell activation and threats mediated through mast cells.
The Dao enzyme (Diamine oxidase) is involved in the metabolism, oxidation, and inactivation of histamine and other polyamines such as putrescine or spermidine. DAO is produced in kidneys, thymus and intestinal lining that breaks down excess histamine in the body, particularly in the gut.
HNMT Histamine N-methyltransferase) catalyzes the methylation of histamine in the presence of S-adenosylmethionine (SAM-e) forming N-methylhistamine. HNMT is involved in metabolism of intracellular histamine, mainly in kidneys and liver, but also in bronchi, large intestine, ovary, prostate, spinal cord, spleen, trachea. and peripheral tissue.
Mast cells- with mutations in membrane, HNMT, Dao enzyme function. Activation triggers include
o TLR activation
o Oxidative stress (Reactive Oxygen Species)
o Extracellular mitochondrial components from damaged mitochondria
o Glutathione depletion (compromised clearance of free radicals)
COMT mutations
Catechol-O-Methyltransferase (COMT) is one of several enzymes that degrade catecholamines eg dopamine, adrenaline, nor-adrenaline, catecholestrogens and various drugs, and is a critical mutation in fibromyalgia.
The COMT gene is found on chromosome 22, which is the second smallest human chromosome, spanning more than 51 million DNA building blocks (base pairs) and representing between 1.5 and 2 percent of the total DNA in cells. This is sometimes called the “warrior gene,”as those with the G/G:Val/Val with fast COMT activity have higher pain threshholds. The COMT gene has many variants, but one of the most well-studied is a single nucleotide polymorphism (SNP) called rs4680. The COMT gene codes for the COMT enzyme, which breaks down dopamine in the brain's prefrontal cortex.(124)
The most common genotype in Caucasians with intermediate pain sensitivity is the A/G:Val/Met, while the slow COMT with 40% lower COMT activity has lower pain threshold, higher dopamine, and they experience more pain, and this is more common in fibromyalgia patients.
COMT gene production is itself influenced by methylation. (125) Usually, methylation shuts down gene production.
COMT (impaired processing of catecholamines, 2 types, fast and slow COMT- clue is family history breast cancer, autism, ADHD, POTS/dysautonomia, fibromyalgia, Parkinson’s disease).
Methylation mutations eg MTHFR
The 677 MTHFR mutation typically is associated with increased homocysteine, and affects collagen function via SAMe and other molecules as well as increased thrombotic risk, and plaque formation in different tissues. Elevated plasma levels of homocysteine are a metabolic risk factor for atherosclerotic vascular disease, as shown in numerous clinical studies that linked elevated homocysteine levels to de novo and recurrent cardiovascular events.
High levels of homocysteine promote oxidative stress in vascular cells and tissue because of the formation of reactive oxygen species (ROS), which have been strongly implicated in the development of atherosclerosis.
BHMT, PEMT and CHKA are connected to MTHFR and the folate and methylation cycle so mutations in genes like MTR and MTFHR indirectly affect them too, eg in the BHMT-catalyzed reaction, betaine, also known as trimethylglycine, acts as a methyl donor, transferring one of its methyl groups to homocysteine. This transfer results in the conversion of homocysteine to methionine and betaine to dimethylglycine.
PEMT mutations
Phosphatidylethanolamine N-methyltransferase (PEMT) catalyses phosphatidylcholine synthesis. PEMT and similar mutations are involved in vascular complications, neurodegeneration and thrombo-inflammation. It is thought that PEMT gene polymorphisms are associated with non-alcoholic fatty liver disease (NAFLD.)(126)
Fatigue is a common symptom of PEMT mutations and its associated mitochondrial dysfunction, and is thought to be involved in neurodegenerative disease. PEMT is involved in the biosynthesis of phosphatidylcholine (PC) from phosphatidylethanolamine (PE), and likely to be the underlying culprit in persistent D-Dimer tests in Long Covid. At present, only DNA can reveal whether this is present as there are no biomarkers for this.
CCL2 (monocyte chemoattractant protein-1)
CCL2, also known as monocyte chemoattractant protein-1 (MCP-1), is a chemokine that is involved in the recruitment and activation of monocytes and other immune cells. The CCL2 chemokine is also expressed by neurons, astrocytes and microglia.(127)
Genetic variations in the CCL2 gene are associated with an increased risk of developing diseases such as rheumatoid arthritis and multiple sclerosis. Dysregulation of CCL2 expression has been implicated in the pathogenesis of various other health conditions, including atherosclerosis, asthma, cancer, IBS, MCAS, breast cancer, fibromyalgia, chronic fatigue, chronic pain syndromes, POTS, connective tissue disease, Raynaud’s disease, pelvic congestion, ADHD, and autism. For example, high levels of CCL2 expression in tumour cells have been shown to promote tumour growth and metastasis by attracting immune cells to the tumour microenvironment.(128)
Fibromyalgia: Some studies have suggested that CCL2 may play a role in the pathogenesis of fibromyalgia, as elevated levels of CCL2 have been found in the cerebrospinal fluid of patients with fibromyalgia.
Other relevant mutations
Oxidative stress and mitochondrial mutations eg eNOS, SOD2. NO metabolism- associated with the development of FMS and pain sensitization
IL-6 and other Interleukins
APO E4- APO E is particularly concentrated in astrocytic processes at the pial surface and around the blood vessels. Astrocytes thus play a key role in lipid synthesis and lipid distribution by releasing lipid carrier proteins, such as Apolipoprotein E, and in maintaining the highway for distribution, the glymphatic system.
Conclusion
Fibromyalgia Syndrome (FMS) is a chronic disorder that causes pain and tenderness throughout the body, as well as fatigue and sleep disorder. The pain of fibromyalgia is typically diffuse, migratory (moves from one joint to another) and may involves both muscles (myalgia) and joints (arthralgia). It affects both sides of the body, and above and below the waist. Typically this can be associated with increased skin sensitivity even to touch.
FMS is a complex problem that requires a very detailed history to look at possible causes, the “activators” and the ongoing “drivers,” as they may be different. Environmental and genetic factors predispose individuals to develop fibromyalgia. Symptoms usually start after a precipitating event such as injury or acute stress, although in some it is a cumulative series of traumas or “activators” which can include physical trauma, especially MVAs with neck and shoulder injuries, stress, parasites such as blastocystis hominis, moulds, infections, or prolonged postural or rotational causes often occupational in origin. Initial symptoms can often be traced to childhood. Ehlers-Danlos Syndrome is a very significant factor both in increased predisposition and management.
FMS can be controlled. It takes time and patience. There is no magic “fix” but a progressive dissection of the underlying problems will allow each to be dealt with. Working out the things that are triggering the immune system -the role of activation of the body’s threat receptors (Toll-Like Receptors) and immune response via Mast Cells, affecting microglial and astrocyte function in the nervous system and the symptoms this causes, is critical to understanding and controlling fibromyalgia and its comorbidities.
But like Pandora’s Box, when you open this it can be very complicated with the multiple genetic factors, and various drivers to work out. But each one you do control can improve the quality of life in someone with this immeasurably.
The improvements start with desensitization of the central sensitization, usually achieved through mast cell blockade, and attention to posture and diet while investigations sort out “drivers.” The brain fog, and it’s altered cerebrovascular pressure is a major investigation area, as there appears to be both hypoperfusion and hyperperfusion. This latter area remains a subject of continuing research, although symptoms can be reduced or stopped with the improving physical therapy techniques and attention to lifestyle and especially posture with computers and phones.
The main physical drivers are the upper cervical spine and Thoracic Outlet Syndrome. The Internal Jugular Vein obstruction at the stylohyoid and venous angles is becoming increasingly apparent, with the combination of these vascular compression areas seen to increase intracranial vascular pressure. These are usually amenable to postural change, and usually physiotherapy/osteopathic and lymphatic techniques. For many the enemies are phones and laptops with the “forward head” position that has become a major part of our lives. Sustained poor posture has significant impacts on this complex mechanism.
The physical, infective and genetic factors impact on the glymphatic system, a macroscopic system for waste clearance in the brain, using a system of channels around blood vessels, formed by astroglial cells, that are responsible for the defense of the central nervous system.
Management remains the same – desensitize the sensitization, work out the drivers, remove the ones we can, and control the inflammatory and autonomic response. I think people can be overwhelmed by the vast array of inflammatory things that are activated, and the biochemical changes that come with the underlying genetic stuff, and try to supplement their way out of it all. There are many practitioners struggling to get on top of these problems, but seem to “fix” on one source. I have no doubt I have not worked out all the processes, but the improvement in the patients looking in these directions provides at least a light for people in whom the future has appeared very grim.
Management is discussed in Management of Fibromyalgia Syndrome.
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