Thesis: A neuroinflammatory paradigm can explain Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome and Post-COVID-19 Fatigue Syndrome

Mackay, Angus

Date: 2023
Advisor: Tate, Warren Percy
Degree Name: Doctor of Philosophy
Degree Discipline: Biochemistry
Publisher: University of Otago

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.

https://ourarchive.otago.ac.nz/handle/10523/15089

 

Also: A Paradigm for Post-Covid-19 Fatigue Syndrome Analogous to ME/CFS

https://www.s4me.info/threads/a-par...ndrome-analogous-to-me-cfs-2021-mackay.21994/

 

The full thesis is available as a pdf - open the Show full item record on the https://ourarchive.otago.ac.nz/handle/10523/15089 page - lower right. Direct pdf: https://ourarchive.otago.ac.nz/bits...MackayAngus2021PhD.pdf?sequence=1&isAllowed=y

 

I agree with the general aspects of the theory, and agree with the need for more focus on neuroimaging of patients before, during, and after episodes of worsening. I disagree with the concept of the PVN "overloading" permanently. I see ME as a feedback loop that gets witched on by a stressor and then gets stuck in that state. It could be as simple as a neuron forming a synaptic link to another neuron, which then gets strengthened with each new stressor. Maybe a glial cell grows in a certain location, blocking the normal "reset" signal from a certain cell. Lots of possibilities; we need more data.

 

Interesting, and perhaps promising.

Although waiting another 10 years for a brain model of neuroinflammation is too long.

I hope these researchers are aware of Jarrad Younger's research on neuroimflammation
in ME.

 

Well, it's better than waiting ten years before someone decides it's worth starting such a study. If it does take ten years to get enough data to identify the problem, the sooner we start, the sooner we succeed.

 

I agree with the sooner we start the sooner we get somewhere. However, researchers have been doing brain imaging of pwME since the early 1990s, and perhaps earlier. Abnormalities have been found, such as hypoperfusion, reduced grey matter, edema, and demyelination, but no one seems to have the funds, the will, and/or technology to continue. Those in opposition just brush these findings off as inconsequential, and this research keeps spinning its wheels.

 

No, at least it limits where funding should go. Right now there's funding going to mitochondrial dysfunction, blood vessel dysfunction, blood cell abnormalities, probably liver and other organs, and of course: psychological problems. If this theory is plausible enough, it will convince more researchers to follow that path, and fund managers to consider those projects. If someone really wants funding for "ME is caused by toenail fungus", they would have to work extra hard to convince the fund managers.

 

Another cocktail napkin full of wild speculation?
Sure, just put it on the shelf over there with the other 127 hypotheses that no one has the interest or funding to pursue.

Seriously, what is the point of publishing any more hypotheses?
Unless, of course, you offer a testable mechanism that will either prove or refute the hypothesis.
Because, we need to cull the herd.

 

"Then, a brain-signature for both ME/CFS (and PCFS) might even become attainable, within the next decade, perhaps."
F U.

 

Their comment: "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."

Provoking thought and discussion is important, rather than repeating old already disproven theories. We've got plenty of researchers who continue to push their failed hypotheses because admitting failure would be bad for their careers. In this case, they can't provide a simple test of the hypothesis, since it requires "increasingly sophisticated neuroimaging technology" which not many have access to.

Here's a suggestion: when a new medical technology, such as a stronger field MRI, becomes available, there should be government funding for scanning patients with still-mysterious disease such as ME, with the data available for all researchers. Add in free access to some scans of normal, healthy people (they have to test the machines on someone during development). Then researchers can look for abnormalities and see whether they fit or discredit some hypotheses. Patients scanned for other reasons can volunteer their scans for the open-access databank.

Back to your question, publishing more hypotheses is communication and idea-sharing, which is far more useful than each potential researcher working in isolation. It's up to research fund managers to decide which hypotheses should get funding. Open discussion of all those hypotheses would be helpful too (maybe someone will point out flaws in a hypothesis, saving the need to fund testing of it).

 

I'm bitter as hell - there is no question about that. And my comments reflect that. I don't wish to drag this discussion out, but I'll add two more things.

I agree with Hutan. There have been countless hypotheses proposing neuroinflammation. Each one involves an Abracadabra hand wave at the end that potentially explains away a dozen symptoms.

And some studies have shown neuroinflammation, or hypoperfusion, or miscommunication between elements of the brain, or whatever - wherever someone chooses to look, they see a problem - but they don't connect the observation to prove or disprove a hypothesis.

I want to read, "Here's our hypothesis. And if you insert an electrode here and another one there, then measure the potential and find it's greater than X, our hypothesis is wrong."

What theories have been disproven? In my decades of following ME/CFS research, I've never heard a researcher call BS on another researcher or their theories. I've never read a paper that says, "Well, we now know that hypothesis B is utterly wrong and it should should be tossed onto the scrap heap of history." Never. And I've never witnessed a conference where one scientist said to another, "Your presentation was cute, but here's why your idea will never work..."

And so, they all continue to get a piece of the pie, they all drag this out for years beyond any reasonable projection, we all continue to suffer - or, perhaps worse, decide that we cannot continue to suffer and opt out.

 

This is very true, and it's because the incentives are misaligned. Researchers have every reason to drag things out forever and no reason to reach a conclusion. They have no stake in the game.

 

That is a very fair critique of the biomedical science scene. I learnt early on how uncritical they are. A famous immunologist called Av Mitchison said to me I was foolish to think that there was any rational debate - I could see that that meant that only he could diss other people's stuff - when he was on advisory boards. It is a cesspit really. Which is why S4ME is so good.

 

I've seen something like 50 doctors and was hospitalized (neurology, infectivology, rheumatology departments) a few times. Sometimes during outpatient visits doctors had med students sitting about. So I've seen doctors interacting with eachother and with med students a lot. Every time I had the impression i was witnessing a political power game of sorts rather than a team of people working together to find the true answer to a difficult problem. I have to say, if i didn't have severe ME and could actually work, i wouldn't last more than a few days in that kind of environment.

 

Okay, "disproven" is a bit too extreme, since it implies that everyone accepts it. "Failed to provide supporting evidence" is more common. Various theories were tested out using drugs (or psychological quackery) and failed to produce the predicted levels of success, convincing most people that the theory was wrong.

Yes, there are lots of problems with the present research and publication system, and that makes it harder for ME research to actually progress. Silencing papers about hypotheses, even if they don't offer a quick and easy test, doesn't seem like a good way to improve the system. Can you offer some constructive criticism of the system? Journals could require a clear test for the hypothesis, but the bad researchers would somehow work that for their benefits, perhaps by presenting a test that can't be done yet ("It's not our fault that a 39 Tesla MRI machine isn't available."). That requirement might prevent some good observations and ideas from being communicated to someone who could think of a way to test it.

There's been discussion lately about how AI might affect the world. It might not be too long before AIs can take over medical research, doing it far more effectively than humans. Developing suitable AIs actually seems like an easier problem now than fixing human greed, or even just the flaws in the research system.

 

Neuroinflammatory model, as published by Marvel Entertainment:

Virus* make brain angry!
Brain SMASH!

Okay, now give brain funding and brain fill in blanks for you.

*: or bacteria, or mold, or stress, or a really bad stumble.