+1 Neuroinflammation

<p>From: <a href="https://www.ncbi.nlm.nih.gov/pubmed/24665088">Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An ¹¹C-(R)-PK11195 PET Study. - PubMed - NCBI</a></p>

<p>Neuroinflammation is present in widespread brain areas in CFS/ME patients and was associated with the severity of neuropsychologic symptoms. Evaluation of neuroinflammation in CFS/ME patients may be essential for understanding the core pathophysiology and for developing objective diagnostic criteria and effective medical treatments.</p>

<p>Activation of microglia or astrocytes is related to neuroinflammation. (11)C-(R)-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide ((11)C-(R)-PK11195) is a ligand of PET for a translocator protein that is expressed by activated microglia or astrocytes. We used (11)C-(R)-PK11195 and PET to investigate the existence of neuroinflammation in CFS/ME patients.</p>

<p>The BP(ND) values of (11)C-(R)-PK11195 in the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons were 45%-199% higher in CFS/ME patients than in healthy controls. In CFS/ME patients, the BP(ND) values of (11)C-(R)-PK11195 in the amygdala, thalamus, and midbrain positively correlated with cognitive impairment score, the BP(ND) values in the cingulate cortex and thalamus positively correlated with pain score, and the BP(ND) value in the hippocampus positively correlated with depression score.</p>

<p>From: <a id="null" class="null" href="https://www.diva-portal.org/smash/get/diva2:398436/FULLTEXT01.pdf">https://www.diva-portal.org/smash/get/diva2:398436/FULLTEXT01.pdf</a></p>

<p>It was previously believed that inflammation in the CNS was not possible because of the lack of resident immune cells and the impenetrable blood-brain barrier (BBB)86, 87. It is now known that microglia function as immune cells and that several types of immune cells can cross the BBB. The involvement of the immune system in CNS diseases is well established for multiple sclerosis88 and has been implicated in narcolepsy89, Alzheimer’s disease and Parkinson’s disease87. There are two ways in which the immune system can cause damage to the host. Surrounding tissue can be damaged when the immune system performs a functional task, for example the release of toxic substances to attack bacteria or parasites. The host can also sustain damage if the immune system mistakes endogenous or harmless proteins for pathogens and initiates an immune response against them, which occurs in autoimmune diseases and allergy90.</p>

<p>pro- and anti-inflammatory cytokines can polarize microglia to distinct activation states. Alternatively activated macrophages express cytokines and receptors that are implicated in inhibiting inflammation and restoring homeostasis. This includes production of IL-10 to downregulate inflammatory cells, extracellular matrix protecting proteins like YM1, ornithine, and polyamines for wound repair, and higher levels of receptors associated with phagocytosis, such as scavenger receptors [<a href="https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-11-98#CR18">18</a>]. Just as the Th1 cytokine IFNγ has been associated with induction of proinflammatory M1 macrophages, the Th2 cytokine IL-4 has been associated with M2, or alternative, activation. In the periphery, M2 cells are not always associated with protective functions. In addition to parasite protection, wound repair, and debris clearance, these cells are also potential key players in asthma and allergy responses [<a href="https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-11-98#CR7">7</a>]. However, these types of harmful reaction may not be relevant in the CNS, demonstrating a divergence between peripheral and central cells. Interestingly, it appears that when there is a lack of M2 cell differentiation in the CNS, problems can arise (this is discussed in detail later).</p>

<p>From: 'First Direct Evidence of Neuroinflammation – ‘Encephalitis’ – in ME/CFS' <a href="http://phoenixrising.me/archives/24936">http://phoenixrising.me/archives/24936</a></p>

<p>A <a title="Phoenx Rising Discussion thread" href="http://forums.phoenixrising.me/index.php?threads/neuroinflammation-in-patients-with-cfs-me-pet-study.29219/" target="blank">small study</a> with just nine patients has captured the attention of patients and researchers alike after reporting direct evidence of inflammation in the brain of ME/CFS patients. The finding was one of the highlights picked out by Professor Anthony Komaroff in his IACFS/ME <a href="http://forums.phoenixrising.me/index.php?threads/key-points-from-professor-komaroff%E2%80%99s-highlights-iacfsme-2014.29383/" target="blank">conference round up</a>.</p>

<h2>Back to the future</h2>

<p>What makes this study so fascinating is that it provides tantalising evidence supporting not only of current views that inflammation in the brain is central to understanding the disease, but also of Melvin Ramsay’s original name of <a title="More detail from a 1986 paper by the late Dr Ramsay" href="http://www.meactionuk.org.uk/ramsey.html" target="_blank">‘myalgic encephalomyelitis</a>‘.
<em>Encephalomyelitis</em> is inflammation of the brain <em>and</em> spinal column, and critics of the name pointed to the lack of direct evidence for inflammation of either. This study only looked at the brain, not the spinal column (so could only find encephalitis), but the immune cells found to be activated in the brain are also present in the spinal column.</p>

<h2>The study</h2>

<p><em>Dr. Yasuyoshi Watanabe</em></p>

</div>

<p>To see if there is immune activation in the brain, researchers need to look <em>inside</em> the brain — which is not so easy if you want patients to still be alive when your study is done.
The scientists in this study, led by Dr. Yasuyoshi Watanabe from the<a title="RIKEN press release on the new study" href="http://www.riken.jp/en/pr/press/2014/20140404_1/" target="blank"> RIKEN </a>institute in Japan, used <a title="MedlinePlus: PET scan" href="http://www.nlm.nih.gov/medlineplus/ency/article/003827.htm" target="blank">PET & MRI</a> imaging to peer into the brain.
What make this study work is the use of tiny quantities of a radioactive tracer that binds to specific proteins that appear on activated microglia (the main immune cells of the brain) but crucially doesn’t bind to non-activated microglia. The marker also binds to activated astrocytes, which play an immune role in the brain. The brains of nine ME/CFS patients meeting both Fukuda and International Consensus Criteria were compared with those of 10 healthy controls.
The results showed that neuroinflammation markers were higher for patients than controls across many brain areas including the thalamus, the pons and the midbrain. They also found that the severity of symptoms correlated with the degree of inflammation in multiple brain regions, particularly for cognitive functioning.
It was the correlation between a biological finding — neuroinflammation — and clinical problems that Komaroff found so exciting about this work, because it suggests a biologically plausible explanation for the symptoms of ME/CFS:</p>

<blockquote><em>“[If replicated] it would, for me, say that there is a <strong>low-grade, chronic encephalitis in these patients</strong>, that the image we clinicians have of encephalitis as an acute and often dramatic clinical presentation that can even be fatal has — may have — blinded us to the possibility that there <strong>may be that long-lasting — many years long — cyclic chronic neuroinflammation is underlying the symptoms of this illness.”</strong></em></blockquote>

<p><em>Representative PET scans showing activated microglia in a CFS/ME patient.</em>
<em><strong>Key to brain regions:</strong> AMY, amygdala; CC, cingulate cortex; HIP, hippocampus; MID, midbrain; THA, thalamus; and PON: pons.</em>
<em>Photo credit: Image courtesy of RIKEN</em></p>

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<p>Intriguingly, the midbrain, thalamus and amygdala — all regions where cognitive problems correlate with neuroinflammation — are also all part of neural circuits involved in awareness, arousal and attention. Concentration problems are typical of ME/CFS, and one of the problems <a title="Brain fog: The Research (blog)" href="http://phoenixrising.me/archives/16688" target="_blank">found most consistently in laboratory testing.</a></p>

<h2>Replication needed</h2>

<p>While tantalising, these findings are far from conclusive, as the authors acknowledge. The study has only nine patients, albeit diagnosed with ICC criteria. The tracer used to identify activated immune cells produces a very ‘noisy’ signal, giving rather indistinct readings, and the overall level of neuroinflammation was relatively low.
Although cognitive issues correlated with neuroinflammation in several areas, generally other symptoms, including fatigue, did not significantly correlate with inflammation.
There was almost no sign of inflammation in the prefrontal cortex, the region of the brain most involved in higher cognitive functions, that might be expected to be a problem in ME/CFS. And there was a potential technical weakness in the way the study was run.
Commenting on the neuroinflammation, Komaroff emphasised the need for replication:</p>

<blockquote>“If it were confirmed by multiple other investigators … these data are consistent with [encephalitis], but I would feel more strongly if other labs using same technology came up with the same result.”</blockquote>

<p>The good news is that the authors of this study are already working on a new study using the same patients but with a newer and more sensitive tracer to pick up neuroinflammation. They will address the earlier technical issue, and to make the study more powerful they will also be looking at neurotransmitter activity in the brain, following up their <a title="Reduction of serotonin transporters of patients with chronic fatigue syndrome." href="http://www.ncbi.nlm.nih.gov/pubmed/15570154" target="_blank">previous findings</a> of neurotransmitter abnormalities.
Hopefully independent groups will try to replicate this finding too – and in the U.K., Dr. Charles Shepherd of the ME Association has already said it would welcome applications to fund a replication attempt.</p>

<h2>Microglia — key to ME/CFS?</h2>

<p><em>Microglial cells (green).</em>
<em>Photo credit: <a href="http://commons.wikimedia.org/wiki/File:Microglia_and_neurons.jpg">Gary Shaw, Wikimedia</a>, <a href="http://creativecommons.org/licenses/by-sa/3.0/deed.en">CC 3.0 licence</a></em></p>

</div>

<p>So neuroinflammation — specifically activation of microglia — correlates with cognitive problems, but how might microglial activation <em>cause</em> the problem?
The most plausible answer is through what is termed ‘sickness behaviour’ — a characteristic set of responses to infection, including fatigue, malaise joint and muscle pain and problems concentrating — which might just sound familiar to ME/CFS sufferers. (‘Sickness behaviour’ is a lousy name for biological phenomenon, as <a href="http://phoenixrising.me/archives/12042" target="_blank">Dr. Dan Peterson has noted)</a>.
Microglia are known to play a key role in regulating sickness behaviour, and that’s a big reason this study has attracted so much attention in ME/CFS.
The fatigue, malaise, problems concentrating, etc., of sickness behaviour help us survive an infection by forcing us to rest so our body can devote all its resources to the energy-greedy immune system.
However, sickness behaviour is normally a short-lived response to an acute infection, designed to temporarily divert resources to ensure a swift recovery. If that doesn’t happen, e.g., if there is a chronic infection, or the process goes wrong, for instance, if microglia remain activated after an infection has been cleared, then sickness behaviour can itself be a problem. ME/CFS may be an example of this.</p>

<h3><strong>Cytokines in the spotlight</strong></h3>

<p>Cytokines are a key trigger for sickness behaviour, and researchers have often found elevated cytokines in patients, but the findings have been inconsistent and in small studies. The new studies reported on by Dr. Jose Montoya at the Stanford conference and Dr. Mady Hornig at the IACFS/ME conference are helping to firm up these findings in huge cohorts.
Probably the most important piece of work on the role of sickness behaviour — and cytokines — in ME/CFS came from the landmark “Dubbo” studies.
The researchers found that <a href="http://www.ncbi.nlm.nih.gov/pubmed/16950834" target="blank">about 11% of those with</a> glandular fever and two other infections developed CFS after six months. And crucially, what predicted the length of the illness (and chance of developing CFS) wasn’t psychological factors, but the severity of the initial ‘acute illness’, or sickness behaviour.
The researchers also <a href="http://www.ncbi.nlm.nih.gov/pubmed/18937577" target="blank">showed</a> that those with more active genes for the pro-inflammatory cytokine Interferon-gamma had a more severe sickness behaviour (and longer illness) than those with regular versions, linking cytokine response to sickness behaviour and ME/CFS.
<strong>The Dubbo study did not look at inflammation in the brain, but the authors did speculate that the cause of CFS could be long-term activation of microglia and astrocytes. And that is exactly what was found in this new PET imaging study.</strong>
As with all research findings, replication is essential, and a new version of the Dubbo study is currently under way in Sydney, Australia.
The new imaging study from Japan has found provisional evidence of activated astrocytes and microglia cells (both types of glial cell) in the brain of ME/CFS patients. This is support for the suggestion from the Dubbo team that ME/CFS develops from certain infections as a result of activation of brain microglia.
Dr. Michael VanElzakker’s recent <a title="One Theory To Explain Them All? The Vagus Nerve Infection Hypothesis for Chronic Fatigue Syndrome " href="http://simmaronresearch.com/2013/12/one-theory-explain-vagus-nerve-infection-chronic-fatigue-syndrome/" target="blank">vagus nerve infection hypothesis</a> also features glial cells heavily. And recently Professor Hugh Perry, who has studied microglial cells in neurodegenerative diseases such as Parkinson’s disease,<a href="http://www.twitlonger.com/show/n_1rt43lk" target="blank"> proposed that primed microglia</a> and sickness behaviour lie at the heart of ME/CFS.</p>

<h2>Neuroinflammation and Sickness Behaviour the final common path in ME/CFS?</h2>

<p>It may prove to be that ‘neuroinflammation’ — i.e., activated microglia in the brain/spinal column — is a common endpoint of numerous triggers, including glandular fever (EBV), other infections, vaccines — or even, as Dr. Lipkin has proposed, <a href="http://phoenixrising.me/archives/21929" target="_blank">disturbances in the microbiome</a>.
Discovering if this is the case — and firming up the finding of neuroinflammation is key — could be a big step forward in understanding and then treating ME/CFS. And those it is still very early days, it is possible this approach could eventually show that Dr Ramsay was right about ‘encephalomyeltitis’.</p>

<p>From: <a id="null" class="null" href="http://jpet.aspetjournals.org/content/jpet/early/2018/08/03/jpet.118.250845.full.pdf">http://jpet.aspetjournals.org/content/jpet/early/2018/08/03/jpet.118.250845.full.pdf</a></p>

<p>The involvement of neuroinflammation of the brain has recently been suggested without any specific pathogenetic mechanism. (Glassford, 2017), (Tomas and Newton, 2018), (Morris, et al., 2018)</p>

<p>From user Nielk: <a href="https://forums.phoenixrising.me/index.php?threads/evidence-of-neurological-abnormalities-in-me-suppressed-in-the-iom-me-cfs-r.36060/">Evidence of Neurological Abnormalities in ME Suppressed in the IOM "ME/CFS" R | Phoenix Rising ME / CFS Forums</a></p>

<p>The 2014 Nakatomi et al. study "Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study" concluded:

Neuroinflammation is present in widespread brain areas in CFS/ME patients and was associated with the severity of neuropsychologic symptoms. Evaluation of neuroinflammation in CFS/ME patients may be essential for understanding the core pathophysiology and for developing objective diagnostic criteria and effective medical treatments. 
<a class="externalLink" href="http://m.jnm.snmjournals.org/content/55/6/945.full.pdf" target="blank" rel="nofollow">http://m.jnm.snmjournals.org/content/55/6/945.full.pdf</a>

<strong>It is vitally important to note that this important study used the 2011 ME-ICC to select subjects.</strong> (Reference 13 in the paper) Although the Nakatomi et al. paper used the undefined term "CFS/ME" to refer to the disease, this is solely an ME study. That the subjects also met the broader 1994 CDC Fukuda CFS criteria (Reference 12 in the paper) is irrelevant because only a portion of the Fukuda CFS subjects meet the more specific 2011 International Consensus Criteria for ME. <strong>The results of this study can be applied reliably only to ME patients – not the overly inclusive group of Fukuda-diagnosed CFS patients.</strong>

The IOM report discussed this study and others finding evidence of brain abnormalities beginning on page 88, but nevertheless the committee concluded that there was a "general lack of evidence of brain inflammation in ME/CFS patients." Nor did the IOM committee conclude there was sufficient evidence of neurological abnormalities associated with their new socially constructed fatigue illness "SEID" to justify making cognitive impairment a required symptom for diagnosing "SEID."<strong> By contrast, the 2011 ME-ICC require at least THREE symptoms indicating neurological involvement for an ME diagnosis. This is consistent with the World Health Organization's 46-year classification of ME as a neurological disease.</strong>

Inexplicably, the IOM committee did NOT mention the 2012 International Consensus Primer whatsoever in their 235-page report. The 26 highly qualified and experienced members of the ICC panel from 12 countries concluded on page ii:

<strong>Myalgic encephalomyelitis, a name that originated in the 1950s, is the most accurate and appropriate name because it reflects the underlying multi-system pathophysiology of the disease</strong>. Our panel strongly recommends that only the name ‘myalgic encephalomyelitis’ be used to identify patients meeting the ICC because a distinctive disease entity should have one name. Patients diagnosed using broader or other criteria for CFS or its hybrids (Oxford, Reeves, London, Fukuda, CCC, etc.) should be reassessed with the ICC. Those who fulfill the criteria have ME; those who do not would remain in the more encompassing CFS classification.
<a class="externalLink" href="http://l.facebook.com/l.php?u=http%3A%2F%2Fsacfs.asn.au%2Fdownload%2Fme_international_consensus_primer_for_medical_practitioners.pdf&h=1AQGAJRc2&s=1" target="blank" rel="nofollow">http://sacfs.asn.au/download/me_international_consensus_primer_for_medical_practitioners.pdf</a>

<a class="externalLink" href="http://l.facebook.com/l.php?u=http%3A%2F%2Fwww.name-us.org%2FDefintionsPages%2FDefinitionsArticles%2F2012_ICC%2520primer.pdf&h=5AQECjQZi&s=1" target="_blank" rel="nofollow">http://www.name-us.org/DefintionsPages/DefinitionsArticles/2012_ICC%20primer.pdf</a></p>

<p>From: <a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full">Frontiers | The Neuroinflammatory Etiopathology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | Physiology</a></p>

<h1>The Neuroinflammatory Etiopathology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)</h1>

<div class="authors"><a href="https://www.frontiersin.org/image/user/167190/24">https://www.frontiersin.org/image/user/167190/24</a><a class="user-id-167190" href="http://www.frontiersin.org/people/u/167190">Julian A. G. Glassford</a><sup>*</sup></div>

<li class="pl0">Independent Health Researcher and Consultant, Shrewsbury, UK</li>

</ul>

<p>Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multi-systemic chronic illness of unknown etiology, classified as a neurological disorder by the World Health Organization (WHO). The symptomatology of the condition appears to emanate from a variety of sources of chronic neurological disturbance and associated distortions, and chronicity, in noxious sensory signaling and neuroimmune activation. This article incorporates a summary review and discussion of biomedical research considered relevant to this essential conception perspective. It is intended to provide stakeholders with a concise, integrated outline disease model in order to help demystify this major public health problem. The primary etiopathological factors presented are: (A) Postural/biomechanical pain signaling, affecting adverse neuroexcitation, in the context of compression, constriction, strain, or damage of vertebral-regional bone and neuromuscular tissues; (B) Immune mediated inflammatory sequelae, in the context of prolonged immunotropic neurotrophic infection—with lymphotropic/gliotropic/glio-toxic varieties implicated in particular; (C) A combination of factors A and B. Sustained glial activation under such conditions is associated with oxidative and nitrosative stress, neuroinflammation, and neural sensitivity. These processes collectively enhance the potential for multi-systemic disarray involving endocrine pathway aberration, immune and mitochondrial dysfunction, and neurodegeneration, and tend toward still more intractable synergistic neuro-glial dysfunction (gliopathy), autoimmunity, and central neuronal sensitization.</p>

</div>

<h2>Introduction</h2>

<p class="mb15">Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an idiopathic, heterogeneous condition involving distortion of homeostasis across multiple organ systems. It is chiefly characterized by myalgia, fatigue, neurocognitive dysfunction, and, critically, delayed muscle recovery (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B83">Paul et al., 1999</a>) and the intensification of symptoms following physical exertion: “Post Exertional Malaise” (PEM), or “Post Exertional Neuroimmune Exhaustion” (PENE) (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B107">VanNess et al., 2010</a>).</p>

<p class="mb15">This highly intrusive disease involves varying degrees of physical disability and cognitive deficits, associated psychosocial difficulties, and significantly reduced quality of life (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B112">Winger et al., 2015</a>) and life expectancy (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B49">Jason et al., 2006</a>), across a patient population numbering in the millions worldwide. Complete/spontaneous recovery is extremely rare and conventional treatment strategies rarely deliver even modest direct, objective and, sustained symptomatic improvement. Thus, ME/CFS constitutes a particularly enigmatic, debilitating, and costly major public health issue, and the advancement of our understanding of its essence, hence, a pressing area of biomedical enquiry (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B3">Arroll, 2014</a>).</p>

<p class="mb0">The central focus of this work is the proposition that ME/CFS constitutes the symptomatic manifestation of enhanced nervous sensitivity attributable to a neuroinflammatory etiopathology associated with abnormal nociceptive and neuroimmune activity. The article reviews, highlights, and interconnects numerous relevant disease features, processes, and concepts from the biomedical literature, the ultimate aim of which is to provide stakeholders with an instructive pathophysiological conceptual framework.</p>

<h2>Discussion</h2>

<h3 class="pt0">Neuroanatomical Input</h3>

<p class="mb15">Postural and biomechanically induced neuroexcitatory neuroinflammation has been posited as a partial explanation for PEM/PENE (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B98">Rowe et al., 2013</a>), and sustained muscle activity and associated cortical excitability have been observed in ME/CFS (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B17">Brouwer and Packer, 1994</a>).</p>

<p class="mb15">A number of clinical and physical therapy researchers have, over the course of recent decades, variously formed associations between ME/CFS, orthostatic intolerance, and Ehlers-Danlos syndrome (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B95">Rowe et al., 1999</a>), ME/CFS and joint hypermobility (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B8">Barron et al., 2002</a>), and ME/CFS and innate (flat thoracic spine), osteochondritis, or trauma-linked vertebral defects (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B84">Perrin, 2007</a>). These issues, along with other connective tissue disorders, fractures, and other factors that reduce range of motion (ROM), a physical impediment common among ME/CFS patients (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B96">Rowe et al., 2014</a>), plus lengthy periods of reduced movement of neuromuscular tissues, may be associated with diminished neural motility and increased neuromuscular tension/strain. Both during and 24 h following strain-inducing experimental physical maneuvers, ME/CFS patients report significantly greater symptom intensity elevation than do sham exposed patient and healthy control cohorts (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B97">Rowe et al., 2016</a>). Along with neuropathies and peri-neural adhesions, these issues represent potential ongoing sources of nociceptive input and glial activation, resulting in enhanced peripheral and central nervous sensitivity (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B98">Rowe et al., 2013</a>). Peri-neural adhesions are fibrous bonds proximal to nerve tissues, often formed during post-operative/injury healing.</p>

<p class="mb0">Any residual central sensitivity may, in turn, effect heightened sensitivity of relevant portions of the peripheral nervous system (PNS) to further input (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B96">Rowe et al., 2014</a>). Furthermore, neurons may continue to fire after the initiating stimulation has ceased (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B59">Löscher and Ebert, 1996</a>): a phenomenon observed in relation to persistent, relatively low threshold stimulation, colloquially referred to as “kindling” (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B50">Jason et al., 2011</a>). Thus, the potential exists for the emergence of an insidious peripheral-central neurogenic sensitization loop, which would conceivably have the power to modulate the impact of symptom worsening events in ME/CFS. Hypothesized pathological products of these processes include increased resting muscle tone, affected by enhanced tension in/stimulation from proximal peri-neural fibers subject to sensitization, and aggravation of vascular and autonomic tone (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B98">Rowe et al., 2013</a>).</p>

<h3>Glial Activation</h3>

<p class="mb15">Nociceptive afferent input excites post-synaptic neurons and may also be read by glia, triggering cellular responses e.g., via the stimulated neuronal release of chemical mediators that bind to glial receptors (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B91">Ren and Dubner, 2008</a>). Calcium ion (Ca(2+)) influx into astrocytes following stimulation causes central terminals of the nociceptor to release a host of neuroactive signal molecules. These include the primary neuroexcitatory neurotransmitter, glutamate, nitric oxide (NO), and pro-inflammatory cytokines: Tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B94">Ricci et al., 2009</a>).</p>

<p class="mb15">Activated microglia behave similarly in responding to immune challenge/inflammation (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B92">Renno et al., 1995</a>), also inducing superoxide production. Superoxide and NO are free radical substrates of the potent, toxic oxidant peroxynitrite (ONOO–), and hence sources of oxidative and nitrosative (O+NS) damage, both individually and, particularly, when combined (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B6">Barger et al., 2007</a>). Along with the abovementioned stimuli, glia may also be primed to respond more harshly by exposure to toxins and electromagnetic fields (EMF), including non-ionizing, radio frequency (RFR) electromagnetic radiation (EMR) (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B38">Hao et al., 2010</a>), autoimmune processes (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B22">Colton, 2009</a>), and the effects of aging (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B77">Norden and Godbout, 2012</a>).</p>

<p class="mb15">Glia propagate inflammatory signals and may cause chronic pain e.g., involving allodynia and hyperalgesia (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B116">Yasui et al., 2014</a>), via the impact of bidirectional neuro-glial signaling; glia may be activated by way of neuronal stimulation (as described above) and the inflammatory cytokines that they release may, in turn, couple to neuronal glutamate receptors, thereby enhancing neuroexcitation (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B91">Ren and Dubner, 2008</a>). Synergistic interactions may result, prompting the dysregulation of glial functions (gliopathy) and associated maladaptive hyper-activation (microgliosis) (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B51">Ji et al., 2013</a>). Magnetic resonance imaging (MRI) reveals changes in the structure of the brain in ME/CFS that may indeed be attributable to astrocyte dysfunction (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B7">Barnden et al., 2011</a>).</p>

<p class="mb15">Gliopathy can come about following exposure to “glio-toxins”: Immunosuppressive mycotoxins produced by certain species of fungi, including house mold (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B1">Aikawa and Suzuki, 1985</a>). In one study, 93% of ME/CFS patients tested positive for mycotoxins (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B15">Brewer et al., 2013</a>), compared with 0% of controls at similar detection thresholds (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B44">Hooper et al., 2009</a>).* Gliopathies are also believed to be initiated, more broadly, by concurrent increases in extracellular glutamate and cytokine production (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B45">Hulsebosch, 2008</a>).</p>

<p class="mb0">Enhanced glial activation results in neuroexcitation, neuroinflammation and neurodegeneration, indicated by significantly reduced white and gray matter in ME/CFS (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B88">Puri et al., 2012</a>), and hence (additional) glial multiplication subject to neuronal damage; at the symptomatic level it is associated with cognitive deficits, common in ME/CFS (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B103">Shanks et al., 2013</a>), and depressive-like behavior (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B77">Norden and Godbout, 2012</a>), also fairly common in the condition (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B60">Maes and Twisk, 2010</a>). Widespread low-level neuroinflammation has been detected in the brains of ME/CFS patients, with neuropsychological symptom severity associated with the level of neuroinflammation in one study (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B72">Nakatomi et al., 2014</a>), and with self-reported chronic pain in another (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B46">Ickmans et al., 2015</a>). Furthermore, animal testing appears to indicate that microglial induction of IL-1β may be a prerequisite for immunologically induced fatigue (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B47">Ifuku et al., 2014</a>), and that gender-specific relationships may exist concerning suppression of T cell contact-mediated glial activation (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B14">Brahmachari and Pahan, 2010</a>) and relative prolongation of glial responses following neurotoxin exposure (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B21">Ciesielska et al., 2009</a>). These findings accord with numerous human studies highlighting relatively high prevalence of ME/CFS among females (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B93">Reyes et al., 2003</a>).</p>

<p>* Elevated levels of pro-inflammatory cytokines paired with O+NS stress are suspected as being behind mitochondrial dysfunction in the disease (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B69">Morris and Maes, 2012</a>). Associated depletion of antioxidants may account for some of the damage to fatty acids, proteins, and mitochondrial DNA and membranes associated with ME/CFS, via the activity of reactive oxygen and nitrogen species (ROS/RNS) (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B60">Maes and Twisk, 2010</a>). The anomalous presence of mycotoxins may play a role here too (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B15">Brewer et al., 2013</a>), and EMR exposure represents a complicating factor within this thematic e.g., given its capacity to influence fungal activity/biotoxicity (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B109">Velizarov et al., 1999</a>) and lipid peroxidation (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B61">Mailankot et al., 2009</a>).</p>

<p> IL-1β mediates substances that may induce excitotoxicity (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B67">Mohebiany and Schneider, 2013</a>), and inflammatory cytokine activity could play an important role in the aberration of endocrine (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B50">Jason et al., 2011</a>) and mitochondrial dysfunction (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B71">Myhill et al., 2009</a>).</p>

<h3>Central Sensitivity</h3>

<p class="mb15">Peripheral pain can contribute to “central sensitization,” or “wind-up”: The enhancement of nociceptive pathways in the central nervous system (CNS), a process arguably manifest in hyperalgesia in ME/CFS (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B76">Nijs et al., 2012</a>) and sister condition Fibromyalgia Syndrome (FMS) (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B114">Woolf, 2011</a>), and one which has been used to theoretically elucidate aspects of ME/CFS symptomatology (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B64">Meeus and Nijs, 2007</a>). Wind-up takes place under long-term potentiation (LTP), in the context of temporal summation effected by repetitive nociceptive stimulation (which may be low/subclinical in intensity) (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B113">Woolf, 1991</a>).</p>

<p class="mb0">ME/CFS patients have demonstrably low nociceptive thresholds of the muscle tissues (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B108">Vecchiet et al., 1996</a>), and many have significant cerebral (brain) hypoperfusion (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B37">Hamre, 1995</a>), including in the parahippocampus (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B33">Gay et al., 2016</a>) and brain stem (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B23">Costa et al., 1995</a>), which may contribute to abnormal function of the locus ceruleus, involved in the control of descending inhibitory nociceptive pathways (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B64">Meeus and Nijs, 2007</a>). Along with NO and pro-inflammatory cytokine activity, excitotoxicity may play a role in migraine pathogenesis (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B58">Longoni and Ferrarese, 2006</a>). Migraines have been detected in 82% of ME/CFS cases and factors implicated in migraine pathology likely contribute to the type of headaches and cognitive impairments seen in the disease. Consistent with the above, the cortical spreading depression (CSD) model of migraine describes dysfunction in brain energetics, the brainstem, and thalamocortical tracts associated with changes in cerebrovascular dynamics and ischemia affecting loss of descending inhibitory nociceptive processes (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B90">Rayhan et al., 2013</a>).</p>

<h3>Aberration of Endocrine Pathways</h3>

<p class="mb0">Pro-inflammatory cytokines can alter the metabolism of serotonin (5-HT) and dopamine (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B30">Felger and Miller, 2012</a>),* effecting dysregulation of associated neurotransmitters, including glutamate, norepinephrine (NE, noradrenalin), and corticosteroids. 5-HT and NE are the major neurotransmitters involved in descending nociceptive modulation, and NE increases blood flow/pressure by increasing vascular tone, triggers glucose release, and can suppress neuroinflammation. Glucocorticoid deficiencies are associated with interrupted nociceptive modulation, for example via the disruption of neuroendocrine-mediated glial activation mechanisms (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B102">Schwartzman, 2012</a>).</p>

<p>* Serotonin status fluctuation (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B4">Badawy et al., 2005</a>) and dopaminergic modulation abnormalities (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B34">Georgiades et al., 2003</a>) have been observed in ME/CFS.</p>

<p> Both increased resistance to glucocorticoid-immune signaling (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B53">Kavelaars et al., 2000</a>) and increased glucocorticoid receptor sensitivity have been implicated in ME/CFS (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B110">Visser et al., 2001</a>).</p>

<p class="mb0">Adenosine triphosphate (ATP) activity influences glutamate and gamma-Aminobutyric acid (GABA) release, and hence the glutamate:GABA ratio. GABA is the primary neuroinhibitory neurotransmitter in the CNS. ATP depletion is observed in ME/CFS (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B70">Morris and Maes, 2013</a>), and is associated with N-methyl-D-aspartate (NMDA) stimulation and hypersensitivity (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B80">Pall, 2003</a>). Furthermore, low neuronal energy production markedly increases sensitivity to glutamate excitotoxicity (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B11">Blaylock and Maroon, 2012</a>). NMDA receptor activation results in increased levels of ONOO– (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B80">Pall, 2003</a>) and triggers loss of mitochondrial membrane potential and apoptosis (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B39">Hardingham et al., 2002</a>).</p>

<h3>Circulatory Abnormalities</h3>

<p class="mb0">ME/CFS patients tend to have low cardiac output and the vast majority experience orthostatic intolerance (OI) (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B66">Miwa, 2015</a>), a manifestation of dysautonomia relating to inadequate blood circulation and attributable to hypovolemia/blood pooling in the extremities. Various regulatory neurotransmitter/(neuro)endocrine abnormalities (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B81">Pall, 2007</a>), as well as (related) sympathetic nervous system (SNS) dominance (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B32">Freeman and Komaroff, 1997</a>), and diminished cardiac mass (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B43">Hollingsworth et al., 2012</a>), may account for such features. Additionally, cerebral vascular control appears closely related to skeletal muscle pH, found to be elevated in ME/CFS at rest (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B52">Jones et al., 2010</a>), and it has been hypothesized that compromised skeletal muscle cellular membrane function may lead to a degree of acidity equalization between the skeletal muscle intracellular environment (raised pH) and the blood (lowered pH). Consistent with these relations, abnormally prolonged cerebral vasoconstriction following orthostatic challenge is routinely observed in ME/CFS (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B40">He et al., 2013</a>); this has ramifications for neural health, as per the links outlined in the previous section, plus other deleterious effects including cerebral hypoxia and neurocognitive deficits (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B78">Ocon, 2013</a>).</p>

<h3>Gene Activity</h3>

<p class="mb15">General statistical surveys are suggestive of a heritable aspect to ME/CFS, with the relative risk of disease development among first degree relatives almost 3 times the norm (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B2">Albright et al., 2011</a>). It is worth noting that inflammatory reactivity is of course a function of genetic variation in cytokine genotypes, which underpin the severity of “sickness behavior” in ME/CFS (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B111">Vollmer-Conna et al., 2008</a>) e.g., in the context of chronic neurotropic infection (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B106">VanElzakker, 2013</a>).</p>

<p class="mb0">Polymorphism in the TNF-α promoter gene <em>TNF-857</em> and significant decrease of <em>interferon-gamma</em> (IFNγ) <em>low producershave</em> been observed in ME/CFS (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B18">Carlo-Stella et al., 2006</a>), implying an inherent pro-inflammatory immunomodulatory disposition. Patients have also been found to have polymorphisms of transient receptor potential channels (TRPs): TRPM1 and TRPM3 (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B62">Marshall-Gradisnik et al., 2015</a>), affecting mechanoreceptor nociceptive and mood-linked neurological status, and appear to have peculiar genes and gene activity relating more specifically to aspects of central nociception and stress mediation (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B19">CDC, 2006</a>). Abnormally high expression of P2X purinoceptor 7 protein encoding <em>P2RX7</em>, a gene that regulates nociception (and inflammatory pain in particular), has been noted (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B57">Light et al., 2013</a>) and there is also evidence of an array of serotonergic genetic abnormalities; these include differences in genes responsible for 5-HT production (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B73">Narita et al., 2003</a>) as well as distinct genotypic and allelic frequencies of the 5-HT receptor 2A (5-HT2A) encoding <em>HTR2A</em> gene (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B12">Bozzinia et al., 2012</a>). 5-HT2A receptors are believed to mediate neuronal excitation and anxiety, their expression appears to be up-regulated post-infection (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B24">Couch et al., 2015</a>), and their antagonists have been shown to mitigate chronic pain (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B5">Bardin, 2011</a>).</p>

<h3>Evolution of Encumbrance Disorders</h3>

<p class="mb15">The term “encumbrance” is used in this article to denote the constriction, strain, or damage of neuromuscular tissues, as well as associated compression of proximal osseous tissues.</p>

<p class="mb0">Core intensive/high neuro-dynamic intensity physical activity increases the risk of encumbrance-linked health problems, particularly during spinal development. Related risk factors also include acute neuromuscular strains, neuropathies,* and peri-neural adhesions, as well as relatively indirect processes such as the evolution of connective tissue, hypermobility, and inflammatory disorders. Such issues may be underpinned by genetic vulnerability concerning/the epigenetic impact of psychological trauma (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B41">Heim et al., 2009</a>) and psychosocial stress (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B86">Prins et al., 2008</a>), together with a broader array of neurotoxic (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B35">Giordano and Costa, 2012</a>)/immunotoxic stressors (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B27">Dietert, 2014</a>), on the development and functioning of (neuro)anatomic, (neuro)endocrine, and (neuro)immune systems.</p>

<p>* Animal testing reveals that peripheral nerve injury may alter blood-spinal cord barrier (BSCB) integrity (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B28">Echeverry et al., 2011</a>), and viruses, inflammatory cytokines, RFR EMR, ONOO–, O+NS stress, and psychological stress may similarly compromise the blood-brain barrier (BBB) (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B10">Bested et al., 2001</a>). This renders the central nervous system (CNS) relatively vulnerable to the permeation of pollutants from the blood.</p>

<p class="mb15">Common postural risk factors associated with constriction/biomechanical strain of neuromuscular tissues subject to abnormal tension and related sensitivity may include: (1) Flexion of the hip or ankle beyond 70 degrees; (2) Flexion of the neck/arching of the back associated with tucking of the chin and forward/stooped head positions; (3) Lower back slumping/jamming/immobilization e.g., in the absence of sufficient ischial support (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B97">Rowe et al., 2016</a>). Factor 3 is a potential source of decreased lumbar lordosis, and constriction/compression of proximal dorsal root ganglia (DRG) and osseous tissues, and hence of (enhanced) nociceptive stimulation (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B68">Mörl and Bradl, 2013</a>).</p>

<p class="mb15">Relative inactivity may also have ramifications for the health of neuromuscular tissues, for example via heightened nociceptive/neuroinflammatory responses in the context of enhanced neuromuscular tension/strain resulting from diminished neurodynamic and neuromuscular motility/flexibility (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B98">Rowe et al., 2013</a>).</p>

<p class="mb0">Chronic sleep deficiencies in ME/CFS influence insulin-like growth factor 1 (IGF-1) synthesis, neural sensitivity (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B101">Schuh-Hofer et al., 2013</a>), and neurotoxin clearance (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B115">Xie et al., 2013</a>). IGF-1 is a hormone stimulated by growth hormone, particularly during deeper “slow-wave” sleep; ME/CFS patients typically experience little sleep at stages III and IV (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B31">Fischler et al., 1997</a>) and have lower serum levels of IGF-1 (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B9">Berwaerts et al., 1998</a>), with quality of sleep correlated with circulating levels of pro-inflammatory cytokines, and severity and frequency of symptoms, in the disease (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B65">Milrad et al., 2017</a>). Additionally, pro-inflammatory cytokines appear to directly dampen IGF-1 pathways (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B87">Puche and Castilla-Cortázar, 2012</a>). IGF-1 plays an important role in many biological processes, notably including: Myelination (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B56">Liang et al., 2007</a>) and early recovery from demyelination (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B63">Mason et al., 2000</a>), and mitochondrial nutrient and inhibitory neurotransmitter synthesis.</p>

<h3>Neuroinflammatory Etiopathogenesis</h3>

<p class="mb0">The picture that emerges from the literature indicates that disease pathogenesis is a function of the following primary etiopathologies: (A) Chronic peripheral nociception/neuroinflammation associated with encumbrance of neuromuscular/osseous tissues (Figure <a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#F1">1</a>); (B) Chronic immune activation associated with marked antigenic activity; (C) A combination of factors A and B.</p>

<p>A) Under postural/biomechanical challenge, sensitive neuromuscular tissues subject to encumbrance trigger noxious nociceptive input and glial activity. Responding glial cells propagate inflammatory signals, releasing pro-inflammatory cytokines and effecting central nociceptor terminal release of neuroactive molecules, including glutamate and NO.</p>

<p>B) Persistent neuroimmune stimulation, above systemic tolerance thresholds, associated with inadequate immunological responses to neurotrophic infection, often involving lymphotropic/gliotropic microorganisms (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B42">Hickie et al., 2006</a>), may lead to immune suppression/exhaustion. In the context of immunological functional impairment tending toward autoimmunity (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B13">Bradley et al., 2013</a>), this may involve somewhat circular processes of initial infection, inflammation, paired with enhanced serotonin receptor expression (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B24">Couch et al., 2015</a>), and hence raised (inflammatory) pain, immunodeficiency, and progression/reactivation of opportunistic intercurrent (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B104">Smith and Thomas, 2015</a>) and latent infections (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B16">Broderick et al., 2010</a>); well represented among these pathogens (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B74">Nicolson et al., 2003</a>) are those known to target sites of autoimmune inflammation (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B85">Posnett and Yarilin, 2005</a>). Consistent with this picture, recurrent viral infections and concordant chronic systemic inflammation appear to be a hallmark of the disease (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B89">Raison et al., 2009</a>).</p>

<p>C) Neuromuscular tissue inflaming anatomical stimuli modulate local immune responses. Equally, immune stimulation affecting altered serotonergic receptor activity, glial activation, and inflammation of neuromuscular tissues proximal to infection sites also enhances sensitivity of said tissues to postural/biomechanical stimulation. Neural excitation threshold reduction affected by select pathogenic strains may also play a role here (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B79">Oldstone, 1989</a>).</p>

<div class="Imageheaders">FIGURE 1</div>

<p><strong>Figure 1. Encumbrance pathway “A”</strong>.</p>

</div>

<p class="mt15 w100pc float_left">Sufficiently acute/sustained exposure to glio-toxins (B, C) and/or extracellular glutamate and pro-inflammatory cytokine elevation stemming from other neuroinflammatory stimuli (A, B, C) is associated with elevated, and potentially increasingly primed, glial activity and sickness behavior, as well as neuroinflammtory (excitotoxic) neurotoxicity and O+NS stress, and raised peripheral nervous sensitivity. Signal molecules released in relation to these effects act as to lower the threshold and opening characteristics of neuronal receptor channels, hence enhancing central neuronal sensitivity. See Figure <a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#F2">2</a> for a basic model of adverse products of glial activation and their downstream effects.</p>

<div class="Imageheaders">FIGURE 2</div>

<p><strong>Figure 2. Effects of sustained glial activation</strong>.</p>

</div>

<p class="mb0 w100pc float_left mt15">Sustained glial activation enhances the potential for longer lasting, more intractable multi-systemic disarray, including space for: Synergistic neuro-glial distortions (i.e., gliopathy/microgliosis), neuroendocrine pathway aberration, mitochondrial dysfunction, and immunodeficiency; hence, glial-simulative neurological activity may have the capacity to fundamentally determine disease severity and prolongation. Given that low-dose Naltrexone (LDN) inhibits glial activation, the reported efficacy of this drug in ME/CFS and FMS would appear consistent with this proposition (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B117">Younger et al., 2013</a>).</p>

<h3>Mitigation of Encumbrance Symptoms</h3>

<p class="mb15">Optimal management/treatment of the encumbrance-linked abnormalities outlined in this article and the supporting literature warrants further study (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B96">Rowe et al., 2014</a>). At a minimum, avoiding the noted “common postural risk factors” (flexion/slumping) and intense/repetitive neuro-dynamic movement of sensitive neuromuscular tissues is advisable. The use of special furniture/accessories may aid relevant behavior change e.g., rocking kneeling chairs/wobble cushions and vertebral support belts/braces.</p>

<p class="mb15">Manual physical therapy focused on mild functional exercises and gentle stretching, intended to gradually increase ROM and reduce neuromuscular tension, may prove beneficial. Physical therapists should be aware, however, that the DRG may be sensitive/inflamed and that manipulation of this region, as well as direct nerve mobilization (particularly in the direction of strain), has the capacity to exacerbate symptoms considerably (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B98">Rowe et al., 2013</a>).</p>

<p class="mb15">Overcoming physical activity avoidance and facilitating physical rehabilitation are considered important recovery goals (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B75">Nijs et al., 2013</a>). If progress here is to be optimally sustained, then related endeavors will, thus, remain within dynamic, individualized parameters, reflecting: Levels of strength and stamina (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B29">Eyskens et al., 2015</a>), peripheral sensitivity (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B105">Staud et al., 2015</a>), limited energy envelopes (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B48">Jason et al., 2009</a>), and delayed mitochondrial energy (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B54">Lengert and Drossel, 2015</a>) and muscular recovery (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B83">Paul et al., 1999</a>).</p>

<p class="mb15">Complementary dietary supplementation regimens might include: Omega-3 PUFAs (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B60">Maes and Twisk, 2010</a>), CoQ10 (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B20">Chang et al., 2012</a>), <em>Withania Somnifera</em> (<em>Ashwagandha</em>, Indian Ginseng) (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B100">Sankar et al., 2007</a>), N-acetylcysteine (NAC) (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B26">Dean et al., 2011</a>),* vitamin B12 (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B118">Zoccolella et al., 2009</a>), curcumin (contained in turmeric) (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B11">Blaylock and Maroon, 2012</a>), zinc (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B36">Hambidge and Krebs, 2007</a>), magnesium (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B25">Cox et al., 1991</a>), 2-aminoethanesulfonic acid (L-Taurine) (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B55">Leon et al., 2009</a>), and carnitine (L-Carnitine) (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B60">Maes and Twisk, 2010</a>). These substances reportedly aid healthy modulation of glutamatergic, neurotropic, and other relevant inflammatory pathways, protection against/the reversal of excitotoxicity, the rebalancing of glutamate:GABA, and mitochondrial and brain function.</p>

<p class="mb0">A precautionary approach may be considered sensible with respect to additional factors that could conceivably complicate pathophysiological processes outlined in this article. These may include: Exposure to toxicants e.g., chemical pesticides (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B27">Dietert, 2014</a>)/heavy metals (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B35">Giordano and Costa, 2012</a>), mold (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B1">Aikawa and Suzuki, 1985</a>), and both low frequency (ELF) (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B99">Rowland et al., 1998</a>) and high frequency RFR (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B82">Pall, 2016</a>) EMFs/EMR, as well as psychological stress (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B86">Prins et al., 2008</a>), dehydration (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B95">Rowe et al., 1999</a>), and exhaustion (<a href="https://www.frontiersin.org/articles/10.3389/fphys.2017.00088/full#B11">Blaylock and Maroon, 2012</a>).</p>

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