If you had to guess ME/CFS cause, what'd you say?

One Idea I had was to knock out all glial cells and see the MECFS patient recover. That would conclusively prove if they are directly involved in the chain of MECFS pathology. Glial cells are supposed to regenerate to full in 7 days as I understand, but I wouldn't know of ethics of such experiment.

I think they should be compared to similarly sick/deconditioned controls, not healthy ones. Unless we do know for a fact that flu patients, for example, exhibit no muscle anomaly under stress.

 

Microglial activation has been linked to concussion fatigue, age related fatigue, etc. It has also been implicated to brain fog in chemotherapy, GWI, etc. Are those proven? I have no idea. But it keeps popping up in fatigue/cognitive impairment just about everywhere I look.

I think some do. There are reports (I think there was an NYT article as well) about cases of paranoia and delusion among COVID/long-COVID patients. Bruce Campbell also reported paranoia during the depth of his MECFS sickness.

 

That I regard as very normal brain function. And you have complete insight. One hallmark of disturbed brain function with brain pathology is lack of insight. Another is phenomena outside the range you get in adverse circumstances - hallucinations for instance.

 

This completely misses the point @poetinsf. You can model certain input-output relations if you know what they are but in disease we don't. We see complex and inconsistent patterns of correlation such that there is no hope of predicting input-output relations. Once you can predict those you must have worked out the mechanism.

 

Of course, but that is because you know what causes the stupor in the human!

 

Sorry, wrong again, science has been dealing with feelings ever since. This is a bogus argument raised by philosophers of science with various axes to grind. My career was all about dealing with symptoms both qualitatively and to some degree quantitatively.

Making animals suffer in order to do bad experiments is never excusable.

 

I do hope nobody ever lets you in a lab!!

 

As bandwagons always do. Most situations are of secondary glial activation situations so not what we are interested in. Quietening down glia in a brain that has been irreversibly damaged is unlikely to do anything useful

 

but if what you are studying is 'X' condition that among other things makes people stagger, giving the mouse alcohol and then studying it, tells you nothing about 'X' condition, it tells you only about the effects of staggering caused by alcohol.

Sure... but since we dont have anything measurable in ME on which to base diagnosis yet, all diagnostic criteria are based on feelings only - ie symptoms. my point was that at least if the mouse could talk it could tell us if what it was experiencing after whatever the scientist did to it, fulfilled the diagnostic criteria for ME. Because behaving in ways that are similar isnt the same thing at all.

Edit: Cross posted with Jonathan

 

Ah good that's what i thought you meant, thanks for clarifying.

 

Nobody should! I'm not a biomedical scientist.

Could well be a case of seeing what I want to see, but most of the reports of microglial activation have been from fields unrelated to MECFS. I wouldn't call it a bandwagon unless they somehow colluded or glial theory is in vogue.

 

Not sure if the analogy stands. Monje study was specifically about brain fog of long-COVID, not long-COVID or MECFS in general. She gave COV-SARS-2 virus, which is suspected input for the long-COVID brain fog, not some random thing that can cause brain fog.

Not sure about this one either. Diagnostic criteria may be subjective, at least for now, but there are clearly measurable things. Like time spent lying down (which I'm using). Or the speed the mouse moves through a maze. Time required to solve a puzzle. Etc.

 

Engineers and physicists (I happened to pretend to be one) would disagree with you. You DON'T have to work out the underlying mechanism to model the workings of a system if you have complete set of inputs and outputs. Inputs and outputs define function, in other words. To (sorta) paraphrase Steven Wolfram, the complexity and computational limitations is only thing that stops you from reversing the 2nd law of thermodynamics, which is infinitely more complex than any biomedical systems.

 

If the PET portion of this study https://www.biorxiv.org/content/10.1101/2023.10.19.563117v1?ct= were to be replicated in ME, perhaps with a larger sample size, would that be good evidence that glial activation is somehow involved in ME?

 

This makes sense in some cases but surely it is possible to have changes in the brain that do not result in clearly apparent issues like hallucinations. For example when I had concussions playing rugby I never had hallucinations but I did have sensitivity to light, ringing in my ears, dizziness, difficulty concentrating and other issues commonly found in ME for a period of time. I don't personally think this is the entire picture, however, if the concussion did cause changes in brain function without causing hallucinations and serious lack of insight, couldn't it be possible for a pathology like glial activation to be creating similar issues in the brain in ME? These changes in brain function don't necessarily have to be on the level of grand delusion just enough to cause some general symptoms that are difficult to pick up on traditional scans.

 

If all you care about is how the system works you are correct.

If you want to intervene in a biological system you need detailed molecular mechanisms to design a new drug.

However you can repurpose an existing drug, presuming there are suitable candidates, with little knowledge of detailed mechanisms. The problem here is in selecting the drugs. Which drugs should you test? It would be sure nice to understand the detailed molecular biology to help you decide.

 

Almost anything is possible but I work on the basis of what seems to fit with all the associated predictions that a model tends to raise - particularly things like course of extended time. If glial activation was the primary cause of ME why do we not see progressive changes with disturbed mental function at least in some people over time?

In concussion there is presumably minor mechanical damage to neural dendrites throughout cortex. It is bad enough initially to produce unconsciousness. So we have a cause of injury. There may be some microglial activation during the repair process but glial activation is not the primary cause of the problem. Moreover, I don't think we have any evidence that it is responsible for symptoms like sensitivity to light. Secondary glial activation occurs in all sort of other brain disorders without producing such symptoms.

In ME we have no primary injury to blame glial activation on and so far there seems no good evidence there is any.

Biomedical science goes through fashions all the time. Currently glial activation and neuroinflammation are in fashion. Thousands of labs are working on such things, but as far as I know not solving any major puzzles. The same is true of the microbiome.

 

Would brain hypoperfusion trigger glial activation?

 

Yes, but the important word there is "complete". For an electrical circuit, the model might match the real-life device perfectly with inputs ranging from 0 to 12V, but provide completely unexpected results outside that range. We don't know the range of inputs for ME. We don't even know what all the inputs are. So, you can make a model that works well on a very limited range of inputs, but be very different from the real thing. Like any tool, models can't be trusted beyond their designed limits.