The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure, 2022, Renz-Polster et al

[Creekside]

https://osf.io/ef3n4/

The newsbrief posting reminded me that this paper wasn't mentioned. I think it may be a pretty important hypothesis for ME's root cause. It fits what I believe is the root cause of ME: that neuroglia are involved. I'm not sure whether there are any ME symptoms that can't be explained by improperly functioning neuroglia.

 

[Andy]

Preprint. See published abstract and link here

Abstract

In spite of decades of research, the pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is still poorly understood. Several pathomechanisms have been identified - including immune abnormalities, inflammatory activation, mitochondrial dysfunction, endothelial dysfunction, muscular dysfunction, cardiovascular dysfunction, and dysfunction of the autonomous nervous system. Yet, it remains unclear how these pathways are related, which of them may be upstream or downstream, and which ones may be explanatory of the symptomatology of ME/CFS (and thus possibly targets for therapeutic interventions). A similar uncertainty is currently experienced by thousands of researchers who struggle to understand Postacute Sequelae of Covid (PASC, "Long Covid"), a condition with many similarities to ME/CFS.

In this paper, we present a theoretical strategy that may help clarify the causal chain of pathophysiological events in ME/CFS. We propose to focus on the common final
histological pathway of ME/CFS. I.e., we suggest to ask: Which cellular compartment may explain the pathological processes and clinical manifestations observed in ME/CFS? Any functional unit consistently identified through this search may then be a plausible candidate for further exploration. For this "histological" approach we have compiled a list of 22 undisputed clinical and pathophysiological features of ME/CFS that need to be plausibly and most directly explained by the dysfunctional cellular unit in question. For each feature we have searched the literature for pathophysiological explanations and analyzed if they may point to the same functional cellular unit.

Through this search we have identified the CNS neuroglia - microglia and astroglia - as the one functional unit in the human body which may best explain all and any of the clinical and pathological features, dysfunctions and observations described for ME/CFS. While this points to neuroinflammation as the central hub in ME/CFS, it also points to a novel understanding of the neuroimmune basis of ME/CFS. After all, the neuroglial cells are now understood as the functional matrix of the human brain connectome which operates beyond and above specific brain centers, receptor units or neurotransmitter systems and integrates innate immune functions with CNS regulatory functions pertaining to autonomous regulation, cellular metabolism and the stress response.

Of note, this is not a unifying theory about the etiology, the triggers or the inception process of ME/CFS. This approach is focused solely on finding the final pathogenetic pathway(s) which may underlie the clinical manifestations of ME/CFS. It does not question existing theories about the inception of ME/CFS, be they based on autoimmunity, persistent infection, mitochondrial or metabolic failure or any other assumption.

 

[Jonathan Edwards]

Through this search we have identified the CNS neuroglia - microglia and astroglia - as the one functional unit in the human body which may best explain all and any of the clinical and pathological features, dysfunctions and observations described for ME/CFS.

I don't really follow this. Astroglia and microglia do not have much in common other than the name and being in the brain. The text is very long and seems to accept large amounts of preliminary findings in ME as fact. The inferences from those findings are also very dubious.

 

[borko2100]

Some things we know about ME/CFS support his hypothesis. Namely how you could get PEM from cognitive exertion alone implies that something is wrong in the brain. But others suggest a systemic problem. For example abnormal results from cardiovascular challenges (eg. CPET). Quite a few of those studies suggest that muscle cells of people with ME are switching to anaerobic energy production when stressed. I don't see how a problem rooted in the brain could impact far away muscle cells in this way.

 

[Shadrach Loom]

Without the scientific or medical background to tell duff arguments from good ones, the kicker for me was when the author mentioned near the end that he was himself an ME sufferer. When the perfect research paper is written, which ties together all the symptoms and potentially involved factors into a unifying whole, the odds are that it will come from someone whose interest in finding a plausible narrative is less personal. Pity. It zipped along authoritatively and the prose was clear, so I found it very gripping while only understanding one word in three.

 

[duncan]

A lot of good stuff in here, "abnormal sickness response" references notwithstanding.

 

[duncan]

s, the kicker for me was when the author mentioned near the end that he was himself an ME sufferer. When the perfect research paper is written, which ties together all the symptoms and potentially involved factors into a unifying whole, the odds are that it will come from someone whose interest in finding a plausible narrative is less personal. Pity. It zipped along authoritatively and the prose was clear, so I found it very gripping while only understanding one w

I am reminded of that old Woody Allen quip, "I would never belong to a country club that would have me as a member" - or something along those lines.

 

[chrisb]

Wasn't that Groucho Marks?

 

[Shadrach Loom]

Wasn't that Groucho Marx?

Yep, hence the Groucho club.

 

[Jonathan Edwards]

I don't see how a problem rooted in the brain could impact far away muscle cells in this way.

I think that is an important concern. However, the brain may be as good an explanation as any. If we accept that cardiac muscle is behaving differently after a first Day 1 CPET then lots of cells are being influenced by something abnormal - which seems therefore likely to be a something circulating or spread widely by nerve signals (vagus perhaps). The brain is probably as good as any organ at orchestrating such signals. It can control hormones and it can respond to circulating cytokines to produce its own broadcast signals.

That does not make it certain that the primary problem is in brain, or certainly not for everyone with ME. But the authors are looking for a common mechanism, not primary cause. In that context brain seems to me probably the best place to look.

 

[Hoopoe]

Re. PEM and cognitive exertion. I've been told it's normal to feel generalized fatigue after mental exertion. Maybe in ME/CFS this is more pronounced. And maybe PEM is just what can happen when these pathways are activated: a kind of an emergency brake to stop what is on some level perceived by the brain as activity that is well beyond any reasonable limits, for whatever reason.

Maybe I don't have the same PEM as others. To me it feels like it could be part of a system to control my activity levels and keep them low.

 

[Jonathan Edwards]

I've been told it's normal to feel generalized fatigue after mental exertion.

In my experience it is normal to feel mental fatigue after mental exertion. So after the mental exertion of six hours writing a difficult manuscript or seeing twenty sick people in a clinic that had time for twelve I would feel mentally exhausted and desperate to have a break. (After 36 hours on call I would be desperate for a sleep but that was physical too.) But I would have no problem going for a brisk walk or windsurfing - if anything I would feel anti-fatigued physically.

On the other hand the mental exertion of trying to deal with getting medical help when feeling very ill - maybe with flu or vestibulitis would be just as generally exhausting as trying to walk to an ambulance.

My impression is that mental exertion adds in to general fatigue only when there is something wrong - some signal system is set off that wants to shut everything down to save resources for basic functions.

 

[duncan]

That does not make it certain that the primary problem is in brain, or certainly not for everyone with ME. But the authors are looking for a common mechanism, not primary cause. In that context brain seems to me probably the best place to look.

Yes.

The brain could just be one of a couple privileged sites.

How do you check, I wonder. Even in autopsy, tissue sampling has to look for something. Can one just look at neuroglial cells and see they're not structurally right? Do you have to look for some sort of signature or footprint, and if so, what - a specific pathogen for instance? Do you go in with some sort of multiplex pathogen sampler?

But if I had to start, I'd start with the brain, too.

 

[Hoopoe]

Re. mental exertion causing generalized fatigue. I notice this after spending time on the computer or sitting down to read. I tend to feel increasingly stressed and sick as time goes on. Then when standing up and walking around the house, the fatigue and weakness is so severe that it's visible in my gait. I then eat something because that helps somewhat (I often feel starved too). I am not certain that it's really the mental exertion that causes this, it could also be merely sitting (instead of lying down) or something to do with poor fasting tolerance, or some combination of all of these things. It feels very abnormal that an ordinary activity could be so draining.

PS: there is also a slowing of movement that occurs with this fatigue/weakness/sickness/stressed/hungry feeling. Is this "psychomotor slowing"?

 

[Mij]

How does mental over exertion cause calf muscle fatigue/soreness and equilibrium imbalances in pwME? I feel as though I've climbed uphill when I've gone over my mental limit.

 

[Hoopoe]

The author says

While muscular fatigue can indeed originate on different levels of the motor pathway and can theoretically be related to central and peripheral components, any level of muscular
fatigue can clearly happen from central dysregulation alone; muscular fatigue emanating from central pathology has been shown to be related to abnormalities in deep brain circuits involved in motor planning and execution, i.e., in a decreased neural drive to the muscle. 119–121

For ME/CFS, there is now indeed ample evidence that the motor dysfunction is mediated by a reduction in the ability of the CNS to generate motor neurotransmission. 122–125

Clinically, motor slowing in ME/CFS very consistently correlates with mental fatigue (see above). The correlation between fatigue and motor slowing may even have some anatomical-topographical correlation as both fatigue and motor slowing have been associated with basal ganglia dysfunction (and, specifically, seem to both correlate with reduced activation of the striatum).14

Conspicuously, motor slowing during a ME/CFS exacerbation seems to be clinically different from motor slowing following regular muscular exhaustion as it includes phenomena reminiscent of neurological compromise: not only is muscular strength reduced during PEM, but also gait regulation seems to be affected with individuals unable to perform normal strides and maintain effective coordination.

Similar psychomotor pictures associated with fatigue as seen in ME/CFS (i.e. fatigue, which extends to executive functions but also to "reward" circuits) is typically seen by neurologists in disorders with lesions affecting the attention and arousal system, or with lesions in the reticular activating and limbic system, or with lesions in the basal ganglia. 94 This "mental" type of "psychomotor" fatigue is also well described in MS, and here the same nuclei and regulatory centers have been implicated as in ME/CFS. 75 Similar correlations are seen in hepatitis C, which often presents as encephalopathy with a striking clinical overlap with ME/CFS. Here again similar brain structures may be involved.126

Sounds like what I've described above (I didn't read the quoted part until afterwards).

That eating helps me with this problem to me suggests that there is some metabolic deficit in the brain. This is why I'm so interested in the metabolic side of ME/CFS.

 

[borko2100]

How does mental over exertion cause calf muscle fatigue/soreness and equilibrium imbalances in pwME? I feel as though I've climbed uphill when I've gone over my mental limit.

For me it's the same. Mental exertion doesn't just trigger fatigue, but other completely unrelated symptoms, like muscle pain that you mentioned and others. Which leads me to a question I have asked before: how could an activity where the brain is involved lead to symptoms that seem to have a completely different origin (localized muscle pain being a great example)? I think having an answer to that question would give us a great lead as to where to look further.

 

[JemPD]

My impression is that mental exertion adds in to general fatigue only when there is something wrong - some signal system is set off that wants to shut everything down to save resources for basic functions.

Interesting. Makes sense to me

Re. mental exertion causing generalized fatigue. I notice this after spending time on the computer or sitting down to read. I tend to feel increasingly stressed and sick as time goes on. Then when standing up and walking around the house, the fatigue and weakness is so severe that it's visible in my gait.

Yes same for me, although eating ive not noticed it helping and i always lie in reclined position to do cognitive work so i dont think it can be that.

How does mental over exertion cause calf muscle fatigue/soreness and equilibrium imbalances in pwME? I feel as though I've climbed uphill when I've gone over my mental limit.

yes me too, it is truly bizarre. Also if i walk too far/upright too long i become terribly cognitively impaired, before any muscle pain etc the cognitive difficulties usually come first

 

[Jonathan Edwards]

Can one just look at neuroglial cells and see they're not structurally right?

For most things these days functional imaging with MRI or PET is probably going to be more sensitive than looking at structure. So with nothing much showing up on in vivo imaging I doubt much is going to be found structurally. Something like change in water or myelin content should have shown up on scans.

I think the use of the term neuroglia by the author reveals a lack of familiarity with the field. Astrocytes, microglia and oligodendrocytes are all very different types of cell. There isn't much reason to lump them together. 'Neuroglia' may be a common German term but is rarely used in my experience.

 

[DokaGirl]

How does mental over exertion cause calf muscle fatigue/soreness and equilibrium imbalances in pwME? I feel as though I've climbed uphill when I've gone over my mental limit.

When I've gone over my mental limit my brain feels strained and very tired. When I feel like this I usually can't fit one more mental task in, no matter how small. I also feel very fatigued physically, often weak, and uncoordinated.