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

Creekside said:
The brain is much less understood, so there's greater potential for clear signs to still be hidden.
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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 still think that someone should do electrostimulation of muscles of a severe patient, to see whether the muscles respond normally (proper power output, O2 consumption, lactic acid production, etc). While not an absolute test of "is it physical or neurological", it might be quite revealing.
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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.
 
Jonathan Edwards said:
I have been thinking about this. I don't think microglial activation in the brain asa primary event would fit at all. Microglial activation in brain would be expected to produce disturbances of cognition like hallucinations or irrational thought or memory or function disturbance.
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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.

One of the striking things about PWME is that however bad they feel, their minds seem to be functioning completely normally. There is brain fog but PWME do not show mental aberration. They do not have paranoid delusions etc.
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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.
 
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JemPD said:
wow in a really bad bout of PEM when my cognitive function is very bad & i feel really drunk/drugged, i often think my carer is angry with me or that people have fallen out with me, and i do cry a lot, i feel very low and somewhat paranoid about people not liking me.

After it passes i wonder what on earth i was thinking.
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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.
 
poetinsf said:
I'll have to disagree. You don't have to know what is under the hood to build a model to study or predict. This is routinely done in systems engineering. I can model a transfer function just based on the input and output to reasonably predict how the system will behave.
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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.
 
poetinsf said:
Well, I won't get into ethics of animal study. But science only can deal with what is measurable, not how one feels.
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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.
 
poetinsf said:
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.
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I do hope nobody ever lets you in a lab!!
 
poetinsf said:
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.
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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
 
poetinsf said:
And that is the point. You give mouse alcohol (input), it outputs a measurable drunken stupor, and you can reasonably conclude that drunken mouse is a proxy for alcohol effect that can be used for drinking study.
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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.

poetinsf said:
But science only can deal with what is measurable, not how one feels.
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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
 
Jonathan Edwards said:
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.
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Ah good that's what i thought you meant, thanks for clarifying.
 
JemPD said:
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.
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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.

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.
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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.
 
Jonathan Edwards said:
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.
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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.
 
JemPD said:
Assume you mean by this gross delusions - of the 'aliens have taken over the planet and are trying to kill me type delusion you would see in paranoid schizophrenia etc? I only mention it because wow in a really bad bout of PEM when my cognitive function is very bad & i feel really drunk/drugged, i often think my carer is angry with me or that people have fallen out with me, and i do cry a lot, i feel very low and somewhat paranoid about people not liking me.
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Jonathan Edwards said:
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.
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This.

At my worst I was never out of touch with reality, by any valid measure. It was often very difficult to process what was going on, and I made (and still make) a lot of errors in processing, but I always had my eye on the reality ball.

The difference to me is that I knew full well I was having those difficulties, and was able, particularly with hard earned experience, to make at least some accommodation and adaption to it.

I never lost the capacity for meta-cognition.

I think the evidence is quite clear that ME patients are anything but delusional. The opposite, in fact. We are having to deal with some truly appalling realities, from the state of our bodies through to how the world around us reacts to it, and are somehow managing to stay sane and focused. Mostly because we have no choice.

That is the shitty reality that some in medicine don't want the rest of the profession and broader society to understand and accept, because the consequences for them will, quite rightly, be brutal to their reputations and careers.
 
Jonathan Edwards said:
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.
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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.
 
poetinsf said:
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.
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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.
 
Eddie said:
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?
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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.
 
poetinsf said:
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.
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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.
 
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