Abstract
This thesis illustrates the development of a neuroinflammatory paradigm for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), applicable to Long-COVID related “Post-COVID-19 Fatigue Syndrome” (PCFS). The brain being devoid of nociceptors, in combination with neuroimaging technology lacking sufficient sensitivity, helps to explain why the chronic but low-level neuroinflammation purported to be present in the brains of ME/CFS (and PCFS) sufferers has gone unreported by patients, and has been largely undetected by scientists, until more recently. Over-activation of microglia and astrocytes is increasingly being proposed to be at the heart of ME/CFS (and PCFS) pathophysiology. A key Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) study (2014) provided evidence of glial-cell over-activity, implicating neuroinflammation within the brain’s limbic system, of ME/CFS patients. Other cerebral spinal fluid and neuroimaging studies, including a more recent Magnetic Resonance Spectroscopy (MRS)/MRI Thermometry study (2019), have added support to this concept. Resultant dysfunction of the limbic system and its closely-connected hypothalamus, which in turn leads to a disturbed autonomic nervous system (ANS) and dysfunctional hypothalamic-pituitary-adrenal-axis (HPA-axis) could then account for the diverse range of symptoms reported in ME/CFS (and PCFS). These symptoms include chronic fatigue, flu-like malaise, mood, memory and cognitive problems (limbic system), sleep, taste, visual and thermostatic-control problems (hypothalamus), gastro-intestinal disturbance, cardiovascular problems and hypotension (ANS), as well as increased frequency of urination and lower blood cortisol levels (HPA-axis). A dysfunctional hypothalamic paraventricular nucleus (PVN), a potentially vulnerable site, within the brains of genetically susceptible people, which functions normally as a stress-control integrator, is proposed to be at the core of ME/CFS (and PCFS) aetiology and pathophysiology. It is proposed that all triggers of ME/CFS, be they viral (Epstein-Barr Virus is the most common trigger), or non-viral; including other infectious diseases, multiple vaccinations, emotional trauma or chemical toxin shock, share a common triggering mechanism. They are each proposed to manifest themselves as severe physiological stressors, which by a combination of humoral and neural routes, target, the hypothalamic PVN, of genetically susceptible individuals. By exceeding an intrinsic stress-threshold pertaining to the complex neurological circuitry, within the hypothalamic PVN, the triggering stressor is proposed to overload it into a (permanently) dysfunctional state. Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which causes Coronavirus Disease 2019 (COVID-19), in common with the triggering stressors of ME/CFS, also manifests itself as a severe physiological stressor, due to a cytokine surge at the site of the primary infection (the lungs). This particular stressor is, also, proposed to target the hypothalamic PVN, in genetically susceptible people, thus triggering PCFS. Life’s ongoing physiological stressors, such as physical, mental overexercise, chemical toxin exposure, emotional and financial stress, all of which are known to exacerbate and perpetuate ME/CFS (as well as PCFS) could do so by then targeting a now “compromised” (possibly inflamed) stress-sensitive hypothalamic PVN, by similar routes. Then if an alternative, but variable (according to fluctuating neuroinflammation of the hypothalamic PVN, itself) stress threshold was exceeded, commonly reported post-exertional malaise (PEM) episodes, more problematic flare-ups, and even more severe prolonged and characteristic relapses could ensue. It is proposed that a dysfunctional hypothalamic PVN, thereby, acts as an epicentre to a radiating neuroinflammatory response within the brains of ME/CFS (and PCFS) sufferers. A neuroinflammatory pathway, as proposed to be shared by the early-onset stages of several progressive neuroinflammatory (neurodegenerative) diseases could also be shared by ME/CFS, and PCFS. Indeed, this pathway could be shared by other potentially non-progressive neuroinflammatory disorders, such as the closely-related fibromyalgia, mental health disorders, epilepsy, and migraines. Might then the “drivers” of the inflammatory process, which sustain glial-cell activation (and neuroinflammation), in ME/CFS (and PCFS), be the perpetuating stressors, themselves, acting in combination with a now “compromised” and stress-sensitive hypothalamic PVN? If so, what then might be the mechanistic detail linking a stressor-targeted hypothalamic PVN and microglial activation in ME/CFS (and PCFS)? One attractive scenario requiring further investigation involves the release of corticotrophin releasing hormone (CRH), which is released naturally by the hypothalamic PVN due to stress. The chronic release of CRH from a stress-sensitive, dysfunctional hypothalamic PVN might induce microglia activation, leading to chronic neuroinflammation, via the stimulation of mast-cells. Two papers were published in relation to this neuroinflammatory paradigm for ME/CFS (2018, 2019), followed by another paper (2021), in which a paradigm was presented to explain the more recently emergent, but equally perplexing, Long-COVID related “Post-COVID-19 Fatigue Syndrome” (PCFS). The neuroinflammatory model presented is both coherent and unifying for all triggering stressors and perpetuating stressors of ME/CFS (& PCFS), without the need for subtypes (as many other models require), but it does require validation. To this effect, it is hoped that this neuroinflammatory model will be both thought-provoking, as well as providing a framework for scientific researchers to test, critique, modify, and develop, into the future. More brain-focussed research, using increasingly sophisticated neuroimaging technology (especially enhanced PET/MRI) is recommended. Then, a brain-signature for both ME/CFS (and PCFS) might even become attainable, within the next decade, perhaps. Long-COVID related PCFS, affecting millions of people worldwide, presents a golden opportunity for in-depth longitudinal neuroimaging studies (following patients through relapse-recovery cycles) to develop a better understanding of PCFS (and ME/CFS) pathophysiology.