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  • Writer's pictureGraham Exelby

Migraine

Discussion document Dr Graham Exelby May 2023

Revised by Roger O'Toole, Melbourne Headache Centre


This revision by Roger O'Toole is presented as Roger and fellow research physiotherapist Craig Phillips assist developing management strategies for the tsunami of LongCovid patients, who, sensitized from the microglial activation from Covid, are presenting in large numbers, but finding current programs often ineffective.


Migraine headaches are characterized by a throbbing or pounding pain, and are classically located on one side of the head, although they can occur all over. The pain is usually severe, and is usually accompanied by sensitivity to bright lights, sounds as well as nausea and vomiting. The pain may last for hours or even days. Some migraines are preceded by an “aura” 10-30 minutes before the headache. Typically, auras can be flashing lights, cracked glass visual change, motor/ speech difficulty, weakness of an arm or leg, or it can be sensory such as with tingling of the face or hands. Certain foods that are “vasoactive” such as red wine, chocolate and aged cheese are well-known triggers. In women, hormonal changes at the times of menstruation can be a trigger. Sometimes it can be weather changes, or glare while driving, and the triggers can be obvious, but sometimes they can be very difficult to determine.


Mungoven et al (2) describe a classical migraine as having 3 phases:

  1. The Premonitory Phase (the feeling something is about to happen)-“This occurs 24–48 h prior to the headache phase and is typically characterized by symptoms such as mood alterations, fatigue and neck discomfort. In addition, approximately one third of migraineurs experience an aura, comprised of transient focal neurological symptoms of visual, sensory or motor disturbances, which may occur simultaneously with the premonitory or migraine headache phases.

  2. The Migraine Headache

  3. A Postdrome Phase “which lasts for 72 h and is characterized by non-headache symptoms including tiredness, difficulties concentrating and a stiff neck”(2)

Chronic migraine is a disabling neurological disorder ,defined as “headaches occurring on at least 15 days per month with at least eight of these fulfilling the criteria for migraine.”(2) Chronic migraine typically evolves from episodic migraine as a result of increasing attack frequency and/or several other risk factors that have been implicated with migraine chronification. Chronic migraine is characterized with higher disability and incidence of comorbidities in comparison to episodic migraine.(2)


Migraine is about inflammation and sensitization. Successful management of migraine is really about “turning off” the processes that are driving the inflammation, while reducing the reliance on medication to manage symptoms. The continuing research into Long Covid has provided quite a few answers in migraine. Migraine, fibromyalgia, POTS and Long Covid share the same cause with sensitization of microglial cells by inflammatory chemicals Cytokines. There are “activators” and “drivers” which are discussed in depth in the Long Covid papers.


Glymphatic System (or glymphatic clearance pathway or paravascular system)


Migraine generally remains a poorly managed disease, although with the increasing awareness that the newly discovered “Glymphatic System” and how this is implicated in migraine, plus newly developed monoclonal antibodies and neuromodulation techniques that treat the symptoms more effectively provides welcome news to the migraine sufferer.


Several studies support the role of the Glymphatic System in headaches, with the demonstration by Schain et al(1) that “Cortical Spreading Depression (CSD)” the neural event underlying migraine aura results in temporary impairment of glymphatic flow by closing paravascular spaces inducing CSD, accompanied by a transient increase in the extracellular concentration of substances that can activate pain receptors (nocireceptors)-including potassium, glutamate and ATP and an inflammatory cascade producing nitric oxide synthase and COX-2 in the brain parenchyma activating microglial and astrocytic cells.(4)


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. The use of other mast cell blockers, especially those in use in Long Covid, mostly fexofenadine and famotidine are currently being investigated in management of chronic migraine.


The glymphatic system, first described in 2013, is a macroscopic system for waste clearance in the brain, or in simple terms, the brain’s sewer. 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.(24)


“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.(24)(23)


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(8) 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.”(8)


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.(7) Glymphatic dysfunction has been shown in animal models of traumatic brain injury, Alzheimer's disease, and stroke.(12) 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.(10)


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(21)


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



Source: Mogensen et al. The Glymphatic System (en)during Inflammation(21)


Natale et al(20) 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.”(20)


Schain et al demonstrated “ that cortical spreading depression (CSD), an animal model of migraine aura, closes the paravascular space (PVS) and impairs glymphatic flow, which also implicates the glymphatic system in the altered cortical and endothelial functioning of the migraine brain.” CSD, a known instigator of migraine, produced a dramatic alteration in both the structure and function of the glymphatic system.


Schain et al’s key findings were that CSD produces:

  1. a rapid closure of the PVS around both arteries and veins on the pial surface of the cerebral cortex lasting several minutes, and gradually recovering over 30 min. They found a mismatch between the constriction or dilation of the blood vessel lumen and the closure of the PVS suggesting that this closure is not likely to result from changes in vessel diameter.

  2. this closure is accompanied by a reduction in the outflow of interstitial fluid from the parenchyma into the PVS, reducing glymphatic flow.(1)

Their finding of decreased glymphatic flow is potentially of significance for understanding the long-term effects of migraine aura on brain health. Clinically, indications for impaired glymphatic functions after occurrence of CSD raise the possibility that migraine aura can facilitate localized degenerative processes. It appears to provide a new framework for understanding the variety of structural and functional alterations seen in the migraine brain.(1)


“Another potential risk to the migraine brain arises from our observation that CSD causes a transient spike in the concentration of interstitial solutes in the space between the smooth muscle and endothelial wall. Given that some of these solutes may include inflammatory molecules, the repeated occurrence of such events could contribute to endothelial dysfunction in pial and cortical arteries.”(1)

“Migraine aura patients exhibiting elevated levels of biomarkers of coagulation activity, fibrinolysis, inflammation, and oxidative stress, as well as enhanced arterial stiffness and vascular tone call for further attempts to delineate CSD's impact on the endothelium.”(1)


Glymphatics and Gut-Brain Axis.


Figure 3. Glymphatic System as a Gateway to Connect Neurodegeneration from Periphery to CNS.



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


Natale et al(10) 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.”


Figure 4. Glymphatic Pathway in Pathological conditions.



Source: Natale,G et al. Glymphatic System as a Gateway to Connect Neurodegeneration From Periphery to CNS. Front. Neurosci. 15:639140. doi: 10.3389/fnins.2021.639140(20)


Lymphatic anatomy


Natale et al(20) 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.


The ongoing research into glymphatics could shed light on migraine, as well as POTS and long COVID. At present, we 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.(22)


When a POTS or Long COVID patient is being assessed to look at the cause of their brain fog, there are a number of areas to be considered- the same protocols have been commenced in ongoing research at this clinic. This area is covered in “The Glymphatic System with loss of Cervical Lordosis and association with Thoracic Outlet and Jugular Outlet Syndromes”


Central Sensitization


Most migraine appears to be driven by cervical nerve root sensitivity. Physio researcher from Adelaide, Dean Watson, found “The cervical afferents of C1-3 are the reason we get increased sensitization of the brainstem. The common pathway with the Trigeminal nerve will present as the head pain or facial pain plus associated symptoms of dizziness and nausea etc (C2/3). The head pain is a representation of the input from the cervical afferent nerves C1-3. This constant input will reduce the latency period (ie someone will get symptoms earlier than the normal person). This constant input then causes the brainstem to become sensitized and effectively “ready to go” with small input. This is why small variations (small C2 rotation perhaps from bad posture) or triggers will bring on large changes so quickly. The changes of this C2 rotation can very subtle and hard to find unless therapists are experienced and delicate in assessing these. It is not a forceful technique as we are looking for subtle changes." (25)


From a management viewpoint, it is the skillset of the therapist that usually determines outcomes. Roger O'Toole believes this C2 rotation is something most of us have, creating the potential for a significant stress on the brainstem. He believes it is how well our brainstem manages the stress, which is often determined by the presence or absence of other stressors that determines how well we maintain the re-calibrated system. Adding the inflammatory activation of microglia form Covid or other stressors, may cause the already stressed system (from C2) to become overloaded resulting in an array of symptoms observed in many "functional" disorders.


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,(26) 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.(27) 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.(27)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.(26)


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.(34) 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,(27) in his work on migraine, found that stimuli applied to some hypersensitive areas of the spine can provoke symptoms of autonomic dysfunction.


Roger O'Toole views migraine "as one 'output' of dysregulation or 'overload' of this system (along with the Raphe nuclei as part of the ARAS)." (The ARAS or "Ascending Reticular Activating System" is responsible for the achievement of consciousness.) He describes that "it is fundamentally a 'brainstem stress response' disorder, of which there are many related variants. Symptomatic expression is determined to some degree by the 'weakest link' with the upper cervical spine afferents having the 'fingers in many pies'."


As such "it offers the best explanation for some of the continuous imaging studies, triggers, efficacy of many prophylactic medications and symptoms eg depression/anxiety, sleep disruption, memory, brain fog, and is a key regulator of BBB (blood brain barrier) permeability." "Very commonly after assessment we see dramatic changes in brain fog, sleep and mood disorders, which I simply cannot explain any other way."


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 sensitization.

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 sensitization, 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.


Roger believes that "there are parts of cervical muscle function that impact a mechanical impact on the upper cervical spine, most notably the neural response to alterations in these muscles that is felt across areas related to blood pressure (feed forward response to lifting the weight of the head) and vestibular function where sub-occipital muscles cancel 75% of vestibular apparatus sensory inflow to provide difference between whole body falling or spinning versus "head on trunk information."


"The attachment of Obliquus Capitis Inferior and Rectus Capitis to the dura between C1 and C2 and its implications for CSF flow, and possibly glymphatics, as well as a potential contribution to the pathogenesis and sensitization in 'pressure-based' presentations is an active area of interest, and the cervical contribution is potentially very significant, but relatively unknown."


Figure 5: Obliquus Capitis Inferior


Source: By Anatomography - en:Anatomography (setting page of this image), CC BY-SA 2.1 jp, https://commons.wikimedia.org/w/index.php?curid=27152860







Impact of Peripheral Inflammation


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 defense 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.


Mungoven et al (2) In addition to central sensitization, it is likely that the activation and sensitization of the trigeminal pathway and related pain circuits within the brain become persistent with disease chronification. This may further contribute to the structural and functional reorganization of pain related circuits in chronic migraineurs, increasing susceptibility to the development of more frequent attacks, thus bypassing the interictal phase in most instances .(2)


Figure 5: Central vs Peripheral Mechanism of Migraine.


Source: Mungoven TJ, Henderson LA and Meylakh N (2021) Chronic Migraine Pathophysiology and Treatment: A Review of Current Perspectives. Front. Pain Res. 2:705276.doi: 10.3389/fpain.2021.705276(2)


Sensitization of the Trigeminal System and Neurogenic Inflammation


The fifth cranial nerve, the Trigeminal nerve, is the common denominator for many headaches and facial pain pathologies currently known. It connects to the brainstem and supplies various parts of the head and face with sensory innervation.(3) In migraine, intracranial vasculature is innervated by trigeminal fibres. Intracranial sensory receptors cover the rich plexus of meningeal perivascular nerves of pial and dural blood vessels. (3)

Mungoven et al (2) suggest that “sensitization of trigeminal afferents is critical for the development of chronic migraine. People with chronic migraine express significant increases of transient receptor vanilloid type-1 receptor (TRPV1) immunoreaction in nerve fibres innervating the walls of scalp arteries. Expressed in small diameter sensory neurons, TRPV1 receptors promote excitation of the trigeminovascular pathway and mediate the release of calcitonin gene related peptide (CGRP) and substance P leading to sensitization." “There is some evidence that the trigeminal nerve is structurally altered in episodic migraine with histological evidence of altered fibre arrangement and MRI data showing altered trigeminal nerve anatomy.”(2)


Figure 6. The Trigeminal Nerve



Source: Btarski, Trigeminal Nerve Gray778.png. Creative Commons Attribution-Share Alike 3.0 Unported license.


Mungoven et al further describe similar MRI changes occur in the trigeminal nerve of other forms of chronic orofacial pain and that that migraine is comorbid with orofacial pain conditions such as temporomandibular disorders.(2)


Mungoven et al on CGRP


Mungoven et al(2) explain “CGRPergic nociceptor neurons can secrete CGRP in the trigeminal ganglion which can then interact with CGRP receptors on satellite glia to release nitric oxide. This release can hen enhance neural activity and may also induce additional CGRP release and ultimately evoke increased production of inflammatory mediators which then sensitize trigeminal ganglion neurons further. CGRP secretion from the trigeminal ganglion likely regulates sensory processing and evokes peripheral vasodilation by acting on CGRP receptors on smooth muscle cells of the meningeal vasculature, leading to the release of other neuropeptides that together mediate meningeal neurogenic inflammation.”(2)


Roger comments that " injection of CGRP into people with migraine produces mild to moderate headache in minutes. It seems to be a step in the path to headache in migraine rather than the point of origin, given that brainstem changes have been documented 24 hours before onset of headache with symptoms reflecting changes in homeostatic regulatory mechanism in the ARAS and hypothalamus. The modest effect of CGRP would support this.


Mungoven et al on Chronic Migraine


“Sensitization of the ascending trigeminal pathways within the brain itself is likely involved in chronic migraine. Such central sensitization is thought to underpin the presence of cutaneous allodynia in chronic migraine that is more common and severe than that seen in individuals with episodic migraine. Cutaneous allodynia may also underpin migraine chronification and as a consequence, the prevention or reversal of central sensitization may therefore reduce migraine pain and the rate of chronic migraine transformation. In conjunction with observations of reduced pain thresholds in chronic migraineurs compared with episodic migraineurs, it is apparent that altered central processing of noxious information may contribute significantly to prolonged pain

and hypersensitivity in chronic migraine.”(2)


Figure 7: Brain Regions involved in Underlying Mechanisms of Migraine




Source: Mungoven TJ, Henderson LA and Meylakh N (2021) Chronic Migraine Pathophysiology and Treatment: A Review of Current Perspectives. Front. Pain Res. 2:705276.doi: 10.3389/fpain.2021.705276(2)


Brainstem and Dysregulation of Noradrenaline/ Locus Coeruleus Axis


Ioachim et al(30) 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 9), 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 sensitize the brainstem. Clinically, as the sensitization 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.(31)


Figure 8. Locus coeruleus


Source : Wikipedia. Locus Coeluleus. https://en.wikipedia.org/wiki/Locus_coeruleus (32)


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.(31) 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, and this it is expected to be part of the migraine. 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.


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.(33) 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.(33) 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).


DNA Mutations in Migraine


Genetic information points to the involvement of transient receptor potential (TRP) channels in pain mechanism. The other DNA mutations we believe exist in migraine are as below. At this stage we have data in POTS and Long Covid patients who have migraine as a co-morbidity. Further research by Dr Valerio Vittone PH.D(6) should provide the relevant information.


Among the genes implicated in the pathogenesis of this disease, including genes involved in regulating the vascular system, of particular importance is the methylenetetrahydrofolate reductase (MTHFR) gene and the role it plays in migraine with aura. Migraine with aura has previously been shown to have a significant comorbidity with stroke, making the vascular class of genes a priority for migraine studies. (13)


Mast cell mutations that affect body’s ability to respond to mast cell activation and threats mediated through mast cells. These are major mutations in POTS and thus far in Long Covid. The primary ones are on the mast cell membranes and in the function of Dao enzyme. The mast cell is a potent immune cell known for its functions in host defense responses and diseases, such as asthma and allergies. “Mast cells play a key role in homeostatic mechanisms and surveillance, recognizing and responding to different pathogens, and tissue injury. 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.)


Oxidative stress eNOS, SOD2. NO metabolism- associated with the development of FMS and pain sensitization.


Inflammatory mutations- various mutations in interleukins producing impaired inflammatory responses.


Methylation mutations (especially 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. When in Covid infections amyloid is added to the fibrin clot the plaques become very dangerous. These become very significant when we find cerebral hyperintensities on MRI, especially in post-Covid, and may be relevant in migraine where MRI brain hyperintensities are present in excess numbers.


TRP mutations- TRPM3 appears critical in NK (Natural Killer) immune cell function, with implications for Ca2+ signalling and cell function.(15) 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. TRPA1, an ion channel on the trigeminal (and most other sensory) nerves is the major oxidative threat sensor. It is activated by various irritants and agents releasing the pro-migraine peptide, calcitonin gene-related peptide through this nerve pathway. TRPA1 agonists release chemicals that cause vascular dilation.

  • Prof Sonya Marshall-Gradisnik and the Griffith University Chronic Fatigue team working with TRPM3 function in the research into chronic fatigue at Griffith University(14) have linked mutations in this pathway with “glymphatic” function with consequent reduced clearance of waste solutes from the brain with production of fatigue and brain fog and the therapeutic benefit of Low Dose Naltrexone

  • 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 natural killer cell (NK) 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.(15)

APO E4 - The Apolipoprotein E allele 4 is a major genetic risk factor for Alzheimer's disease, as this lipid carrier is important for maintaining homeostasis necessary for a healthy environment of the brain. This mutation is seen in around 15 to 20% of the general population, with 2-3% being homozygous with the increased risks that are associated. Miao et al(5) found that the APOE e4 allele is not associated with migraine susceptibility, but is positively related to migraine.

  • APO E is particularly concentrated in astrocytic processes at the pial surface and around the blood vessels. In addition, the choroid plexus and tanycytes in the wall of the third ventricle also produce Apolipoprotein E. Thus, Apolipoprotein E production is co-localized with CSF production sites and transport pathways suggesting that lipids are transported by the glymphatic system.

  • The glymphatic system is thought to play a central role in macroscopic distribution of lipids in the brain and that medium to large lipid soluble molecules might require carrier particles in order to be delivered via the CSF. 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.

  • APO E4 mutation also affects arteries, significantly increasing coronary artery disease risk ,decreased mitochondrial function, decreased insulin sensitivity, increased insulin resistance, fatty liver and progression to cirrhosis (APO E4 contributing to altered VLDL metabolism and increased atherosclerosis).

COMT mutations (= reduced ability to process catecholamines and implications in malignancy, rheumatoid arthritis and SLE) are expected, but not yet confirmed. Catechol-O-Methyltransferase (COMT) is one of several enzymes that degrade catecholamines eg dopamine, adrenaline, nor-adrenaline, catecholestrogens and various drugs. COMT introduces a methyl group to the catecholamines which is donated by S-adenosylmethionine (SAM).(16) Therefore you need adequate SAM for COMT to work.


Having too little SAM and too much SAH (s-adenosylhomocysteine) from undermethylation results in COMT inhibition as well.(17) For this reason, MTHFR SNPs that cause undermethylation and COMT SNPs that lower COMT levels are a bad combination.(18) COMT gene production is itself influenced by methylation.(19) Usually, methylation shuts down gene production. The association of COMT mutations with malignancy and auto-immune disease is discussed in another paper.

Patent Foramen Ovale (PFO)


The link between migraine and PFO was identified some years ago. Getting accurate trials has been very difficult to achieve, but when the patient selection criteria are correct, researchers provide a 50 to 80% cure rate from migraine with the closure of the PFO. The other inflammatory processes discussed above also need to be addressed, as closure of the PFO does not guarantee control of the migraines.(8)


The PFO is a remnant of the foetal circulation, that normally closes in the first year of life to form a solid wall (called a septum) between the chambers. It is estimated to be present in 20 to 30% of adults, and provides a passageway between the 2 atria. to If the PFO does not close, the opening can permit venous blood, normally filtered by the lungs, to pass unfiltered into the left atrium and out to the body, including the brain. Usually the blood pressure of the left atrium is higher than that of the right atrium, which will not cause right-to-left shunt (RLS). RLS via the PFO may occur when the pressure in the right atrium exceeds the left to give rise to structural changes in the heart, pulmonary hypertension, coughing, sneezing, and laughing.(9)(10)


PFO is more common in migraine patients than in the general population- approximately 40 to 60% of people with migraine with auras have PFOs.(10)


Assessment for the presence of a PFO is useful for:

  • patients who have suffered a TIA/stroke or heart attack from a blood clot that cannot be explained

  • sufferers of severe migraine with or without aura (with life disabling symptoms)

  • commercial, military or advanced recreational divers.(10)

Figure 9: Patent Foramen Ovale


Source: Cleveland Clinic: Patent Foramen Ovale. http://my.clevelandclinic.org/heart/disorders/congenital/pfo.aspx


Figure 10: Gore Helex Septal Occluder being inserted for PFO repair.


Source: PFO Research Foundation: https://pfofoundation.org/(82)


Research implicates PFOs as a cause of migraine “auras” and again PFOs cause an inflammatory response, complicated by the potential passage of microemboli into the cerebral circulation, with consequent hyperintensities seen on MRI, which need to be separated from small vessel disease changes.


It does not mean though, that if you have auras you have a PFO and will get dementia. At present, the current thinking is that they are both common, and that a percentage of people with migraine who also have PFOs, which puts them in the risk for vascular disease, and should be assessed correctly. Even if you have demonstable hyperintensities in MRI brains does not necessarily mean you have small vessel disease, or even that these are the result of microemboli passing through the PFO.We have found these MRI changes also may represent increased fluid in the perivascular spaces resulting from pressure in the dysfunctional lymphatic system.


At present, as the knowledge is expanding we must review these periodically to see where the understanding of the condition has progressed and whether changed are required in management. We also believe now, that if we can eliminate the migraines, especially the auras, we probably need to do no further investigation at present.


Around 20 to 25% of the population in general have foramen ovales that do not close at birth, but only a small percentage of patients with a PFO suffer with migraine and certainly not all migraine sufferers have a PFO.


Approximately 40% of all strokes have no obvious cause, and this is more common in the under 60’s. In this group there is a higher percentage of PFO. The risk is higher if there is any medical condition that raises the pressure in the right side of the heart eg lung disease, pulmonary hypertension, pulmonary embolus, Obstructive Sleep Apnoea, DVT, cancer or any severe acute or chronic illness. The presence of an atrial septal aneurysm (mobile atrial septum) associated with a PFO or atrial septal defect also increases the risk of TIA/ stroke to 5% yearly.(11)


Those who should be referred for assessment for a PFO include:

  • The severe migraine with aura non responsive or intolerant to usual therapy.

  • Blindness, hemiplegia or other significant neurological events would be a strong indicator for assessment (especially those whose employment is at risk or these events would place them or others in physical danger ie commercial pilots and divers).

  • Anyone who we feel may have had a TIA (mini-stroke). Generally neurological symptoms lasting more than 20 mins in a migraine event could be TIA

  • Migraine or anyone with unexplained changes in the brain MRI

  • Migraine with aura who feel they have cognitive decline

  • Severe migraine variants eg vestibular, abdominal, hemiplegic

  • The other masquerader is multiple sclerosis. If it’s obviously MS so be it but some just don’t behave clinically like it and the follow up MRIs don’t fit.(11)

PFOs cannot be reliably diagnosed on an echocardiogram, the test most doctors use. They may need a Transcranial Doppler . The actual PFOs are often very small, and may be only the size of a pinhead so there are no functional problems occurring in the heart. In the Transcranial Doppler, saline is shaken to produce tiny bubbles. The saline is then injected into a vein, and a doppler is used on the head to listen for “pinging” which should not occur unless there is a PFO or pulmonary issue allowing transfer of venous to arterial blood systems. If positive, the definitive test is usually an Transoesophageal echocardiogram, which requires an anaesthetic.


Treatment


Successful management of migraine is really about “turning off” the processes that are driving the inflammation. In most people I see they are significantly driven by the neck, sometimes the thoracic outlet syndrome, which in turn affects the C2/3 region (see Thoracic Outlet Syndrome for details on this very complex and controversial problem).


Certain foods that are “vasoactive” such as red wine, chocolate and aged cheese are well-known triggers. In women, hormonal changes at the times of menstruation can be a trigger. Sometimes it can be weather changes, or glare while driving, and the triggers can be obvious, but sometimes they can be very difficult to determine.


The relevance of loss of cervical lordosis and impaired glymphatic function and is discussed in the POTS and Long Covid papers. It is my opinion that the first part of managing migraine should be working out the causes of the sensitization, and removing the “drivers” wherever possible, and in migraine and its variants such as cluster headache and visual snow, it means current management of the upper cervical spine.


Roger comments "I view migraine, and related disorders as dysregulation of the stress response, the symptoms of which in some cases will fit migraine, other cases cyclic vomiting syndrome, while other cases may fit IBS. While there are reasons why the triggers are able to produce a response, why is the system so sensitive to it? Not everyone with flat feet gets shin splints, and the current argument against the cervical spine would equate to this, therefore flat feet cannot cause shin splints or we would see it in anyone."


The information below is extracted from the excellent paper:

Mungoven TJ, Henderson LA and Meylakh N (2021) Chronic Migraine Pathophysiology and Treatment: A Review of Current Perspectives. Front. Pain Res. 2:705276.doi: 10.3389/fpain.2021.705276


Mungoven et al (2) report “Acute therapies include analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) or migraine specific agents with vasoconstrictive properties such as triptans and ergot derivatives. Chronic migraineurs exhibit a less robust response to triptans and the addition of further triptans or NSAIDs to an existing triptan based regimen is not associated with improvements in chronic migraine associated disability.”


Furthermore “Opioid and barbiturate containing medications are not recommended due to their strong association with medication overuse. Acute treatment should be limitedto 2 days per week.”(2)


Prophylactic Treatments


Mungoven et al further describe: “With limited clinical prophylactic treatment options, there remains an unmet need for more effective, tolerable preventative therapeutic targets in chronic migraine. To date, the only currently available pharmacotherapies that have demonstrated efficacy in chronic migraine prophylaxis are onabotulinumtoxin A (BoNT-A), topiramate and newly approved CGRP targeted monoclonal antibodies.” “It is proposed that injection of BoNT-A (botox) inhibits the release of several neurotransmitters such as CGRP, substance P and glutamate from peripheral trigeminal

nociceptive neurons and disrupts TRP channels, thereby reducing neuronal hyperexcitability and peripheral and central sensitization.(2)


“Topiramate may exert its effect in chronic migraine prevention through the reduction of nociceptive transmission via trigeminovascular modulation, which inhibits neuronal hyperexcitability and suppresses the initiation and development of cortical spreading depression (CSD).”(2)


“Recently developed as the first fully humanized monoclonal antibody treatments specifically for chronic migraine, fremanezumab (164), galcanezumab (165) and eptinezumab (166) target the CGRP ligand, while erenumab (167) targets the CGRP receptor. These novel antibody treatments are postulated to neutralize the effects of excessive CGRP released in the trigeminal sensory nerve fibres during migraine attacks. Each of these anti-CGRP monoclonal antibodies have been proven effective, tolerable and safe as chronic migraine prophylactic treatments in clinical trials”(2)


Additional chronic migraine prophylactic agents shown to be effective in limited studies include valproate, gabapentin, pregabalin, tizanidine, zonisamide and amitriptyline.”


Non-pharmacological Emerging Treatments


“A promising emerging treatment for pharmacologically non-responsive or intractable chronic migraine is neuromodulation. Demonstrating promising results, noninvasive neurostimulation modalities include supraorbital transcutaneous stimulation, transcranial magnetic stimulation, transcranial direct current stimulation and non-invasive vagus nerve stimulation.(2)


Personal observation on evolving research


With the evolving pathogenesis of Long Covid with the triggered threat receptors, mast cell activation and consequent cytokine storm causing microglial activation, it appears that it is microglial activation that is the missing piece of the puzzle, whether this be CIFS/ME, POTS, fibromyalgia, migraine, IBS or migraine.


Background on Roger O'Toole and Craig Phillips:


Roger opened the Melbourne Headache Centre in 2012 and predominantly treats chronic migraine and headache disorders. Operating in a niche area in manual therapy has paved the way for clinical research into primary headache disorders (migraine with aura), vestibular migraine and nausea and vomiting syndromes, and is now expanding to encompass concussion and post-concussion syndromes.



Craig’s career working with the performing arts & sporting worlds, firstly as a professional dancer with the Australian Ballet where he developed what was to become a lifelong interest in Pilates, then medical coordinator & consultant to performing arts companies, forged links with the sporting world, Defence Forces & universities on validating outcome driven patient classification models. Craig enjoys his work as a consultant treating patients, continuing his passion of developing and overseeing research projects into the Clinical Pilates programme.He now uses this passion to liaise with Roger and work towards planning recovery programs.


References:


1. Aaron J. Schain,1,2 Agustin Melo-Carrillo,1,2 Andrew M. Strassman,1,2 and Rami Burstein Cortical Spreading Depression Closes Paravascular Space and Impairs Glymphatic Flow: Implications for Migraine Headache. J Neurosci. 2017 Mar 15; 37(11): 2904–2915. doi: 10.1523/JNEUROSCI.3390-16.2017

2. Mungoven TJ, Henderson LA and Meylakh N (2021) Chronic Migraine Pathophysiology and Treatment: A Review of Current Perspectives. Front. Pain Res. 2:705276.doi: 10.3389/fpain.2021.705276

3. Edvinsson et al. The Journal of Headache and Pain (2020) 21:65 https://doi.org/10.1186/s10194-020-01134-1

4. María Toriello, PhD, Vicente González-Quintanilla, PhD, Sara Pérez-Pereda, MD, Noelia Fontanillas, PhD, Julio Pascual, PhD, The Potential Role of the Glymphatic System in Headache Disorders, Pain Medicine, Volume 22, Issue 12, December 2021, Pages 3098–3100, https://doi.org/10.1093/pm/pnab137

5. Miao, J. et al. Association of the Apolipoprotein E polymorphism with Migraine: a meta-analysis. MNC Neurology 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534059/

6. Vittone,V.: Epigenetics. https://www.drvaleriovittone.com/

8. Zhang,Y, Wang, H and Liu, L. Patent Foramen Ovale Closure for Treating Migraine: a Meta-Analysis. 2022 J Interv Cardiol. doi: 10.1155/2022/6456272

9. Liu, K et al. The Correlation Between Migraine and Patent Foramen Ovale. 2020. Frontiers in Neurology. doi: 10.3389/fneur.2020.543485

12. Cleveland Clinic: Patent Foramen Ovale. http://my.clevelandclinic.org/heart/disorders/congenital/pfo.aspx

13. Stuart,S., Cox, H., Lea,R.,Griffith,l.: The role of the MTHFR gene in migraine. 2012. Headache. https://www.ncbi.nlm.nih.gov/pubmed/22375693

14. Marshall-Gradisnik et al. Examination of Single Nucleotide Polymorphisms (SNPs) in Transient Receptor Potential (TRP) Ion Channels in Chronic Fatigue Syndrome Patients. Immunology and Immunogenetics Insights 2015:7 1–6 doi:10.4137/III.S25147.

15. Eaton‑Fitch et al. Impaired TRPM3‑dependent calcium influx and restoration using Naltrexone in natural killer cells of myalgic encephalomyelitis/chronic fatigue syndrome patients Journal of Translational Medicine https://doi.org/10.1186/s12967‑022‑03297‑8

16. Wikipedia. Catechol-O-methyltransferase .https://en.wikipedia.org/wiki/Catechol-O-methyltransferase

17. Zhu BT, Liehr JG. Inhibition of catechol O-methyltransferase-catalyzed O-methylation of 2- and 4-hydroxyestradiol by quercetin. Possible role in estradiol-induced tumorigenesis. J Biol Chem. 1996 Jan 19;271(3):1357-63. doi: 10.1074/jbc.271.3.1357. PMID: 8576124.

18. Tahara T, Shibata T, Arisawa T, Nakamura M, Yamashita H, Yoshioka D, Okubo M, Maruyama N, Kamano T, Kamiya Y, Fujita H, Nagasaka M, Iwata M, Takahama K, Watanabe M, Hirata I. Impact of catechol-O-methyltransferase (COMT) gene polymorphism on promoter methylation status in gastric mucosa. Anticancer Res. 2009 Jul;29(7):2857-61. PMID: 19596974

19. Van der Knaap LJ, Schaefer JM, Franken IH, Verhulst FC, van Oort FV, Riese H. Catechol-O-methyltransferase gene methylation and substance use in adolescents: the TRAILS study. Genes Brain Behav. 2014 Sep;13(7):618-25. doi: 10.1111/gbb.12147. Epub 2014 Jun 24. PMID: 24902721.

20. 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

21. Mogensen, F.L.-H.; Delle, C.; Nedergaard, M. The Glymphatic System (En)during Inflammation. Int. J. Mol. Sci. 2021, 22, 7491. https://doi.org/10.3390/ijms2214749

22. Jenssen,N et al. The Glymphatic System- A Beginners’s Guide. Neurochem Res. 2015 December ; 40(12): 2583–2599. doi:10.1007/s11064-015-1581-6.

23. Xie, L et al. Sleep Drives Metabolite Clearance from the Adult Brain. 2013. Science. https://doi.org/10.1126%2Fscience.1241224

24. Wikipedia Contributors. Glymphatic System. 2022. Wikipedia, the Free Encyclopedia. https://en.wikipedia.org/w/index.php?title=Glymphatic_system&oldid=1096466284

26. Dong H, Zhang X, Wang Y, Zhou X, Qian Y, Zhang S. Suppression of Brain Mast Cells Degranulation Inhibits Microglial Activation and Central Nervous System Inflammation. Mol Neurobiol. 2017 Mar;54(2):997-1007. doi: 10.1007/s12035-016-9720-x. Epub 2016 Jan 21. PMID: 26797518

27. Low, J et al. Neuropathology of COVID-19 (neuro-COVID): clinicopathological update. Free Neuropathol. 2021 January 18; 2: . doi:10.17879/freeneuropathology-2021-2993.

29. Wells,R, Malik,V.,Lau,D. et al, : Cerebral Blood Flow and Cognitive Performance in Postural Tachycardia Syndrome: Insights from Sustained Cognitive Stress Test. Journal of the American Heart Association, 2020

30. Ioachim, G et al. Altered Pain in the Brainstem and Spinal Cord of Fibromyalgia Patients During the Anticipation and Experience of Experimental Pain. Front. Neurol., 06 May 2022. https://doi.org/10.3389/fneur.2022.862976

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