A Thought Experiment on Muscles

Utsikt said:
Maybe there are some clues in MS?

I keep coming back to my uncle with severe MS, he’s the only one that understands PEM. And he seemingly has many of the same cognitive difficulties that I experience in PEM.

Edit: I’m not sure I can claim he has delayed symptom worsening. But he understood it immediately.
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I would guess the problem with MS would be that it is also a neurodegenerative disease so a cross comparison to understand cognitive problems in ME/CFS might not be naively possible.
 
EndME said:
I would guess the problem with MS would be that it is also a neurodegenerative disease so a cross comparison to understand cognitive problems in ME/CFS might not be naively possible.
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It still has the fluctuating symptoms due to ‘exertion’ outside the attacks. So that can’t be caused only by the irreversible neurodegeneration - something else must be going on.
 
EndME said:
And perhaps equally important doing something less cognitively demanding doesn't require more energy (in the sense of ATP) than doing something less cognitively demanding, so from that point of view listening
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Please don’t take that as fact—there is very little consensus in the field about that claim. There is not even consensus on how much ATP is used for non-cognitive maintenance tasks across the whole brain in any given circumstance.

There certainly is relevant fluctuation. And very very little is known about how the brain allocates ATP production and usage across itself. Even if global ATP usage maintains constant, there will be dynamic regulation and allocation between circuits that varies wildly.

The observations Jonathan mentions are not remotely enough to conclude that there is no substantial difference in cellular metabolism—especially at the cellular level, which is what’s relevant here—across different cognitive tasks.
 
jnmaciuch said:
Please don’t take that as fact—there is very little consensus in the field about that claim. There is not even consensus on how much ATP is used for non-cognitive maintenance tasks across the whole brain in any given circumstance.

There certainly is relevant fluctuation. And very very little is known about how the brain allocates ATP production and usage across itself. Even if global ATP usage maintains constant, there will be dynamic regulation and allocation between circuits that varies wildly.

The observations Jonathan mentions are not remotely enough to conclude that there is no substantial difference in cellular metabolism—especially at the cellular level, which is what’s relevant here—across different cognitive tasks.
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Yes, I agree that local arguments can still make sense but then I see no reason to keep on talking about global energy consumption as is commonly done. Even healthy people have to take breaks from cognitive tasks, because they become taxing, I doubt anybody can give a precise explanation why that is so.
 
Jonathan Edwards said:
But they are the best we have. Anything beyond that is surely speculation to suit the hypothesis?
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It relies on the false assumption that global ATP usage across the organ provides any valuable correlate to metabolism on the cellular level. It's like saying "well the total electrical usage in the house stays pretty constant during the day so all lights in each room must be used equally at the same time."

The contradictory evidence actually has to be contradictory to negate an assumption.

We already have evidence of dynamic changes in different regions of the brain corresponding to cognitive tasks from observing blood flow changes.
 
jnmaciuch said:
It relies on the false assumption that global ATP usage across the organ provides any valuable correlate to metabolism on the cellular level. It's like saying "well the total electrical usage in the house stays pretty constant during the day so all lights in each room must be used equally at the same time."

The contradictory evidence actually has to be contradictory to negate an assumption.

We already have evidence of dynamic changes in different regions of the brain corresponding to cognitive tasks from observing blood flow changes.
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But how large are those changes?

Isn’t most of the brain active to some degree most of the time?
 
Utsikt said:
@jnmaciuch I have not been able to follow the entire thread so you might have described this already. But do you have any thoughts on why your hypothesis happens?

Why and how would someone that were previously healthy go into the state that you describe?

And why and how would someone get out of it seemingly on their own, but not most?
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That's a great question--and I think it's precisely the million dollar question.

Unfortunately we're barely able to answer that in diseases where the pathology is well understood.

We know many characteristics of cancer cells. We know that cancerous mutations happen constantly but there is some level of immune surveillance that often steps in. We even know that certain cancerous mutations only really thrive in certain tissues. And we have a lot of effective treatments. But the question of why someone got cancer at that moment--and why they may or may not go into remission in the future--is a black box.

Honestly I'm quite skeptical of any theory which claims to neatly give an answer to this, especially in ME/CFS--at most, it can only point to a relevant regulatory mechanism, but probably can't explain why different triggers lead to ME/CFS in some but not others.

I'm hoping it's something that can be elucidated by first understanding the mechanism, though. I'm hesitant to speculate much at this point just because there's so little information to base my speculation on in that specific regard.

Thanks for the question!
 
jnmaciuch said:
It relies on the false assumption that global ATP usage across the organ provides any valuable correlate to metabolism on the cellular level.
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No it doesn't. I was talking about changes in oxygen or glucose usage in quite small domains. The shifts are small.

jnmaciuch said:
We already have evidence of dynamic changes in different regions of the brain corresponding to cognitive tasks from observing blood flow changes.
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Yes, they are small.

If brain cells were really short on ATP in ME/CFS then there ought to be some severe cases where you can measure specific mental deficits of the sort you can clearly identify in people with TIAs for instance. I have myself had a brief episode of what I suspect was loss of metabolic function in my left parietal lobe. For about an hour I could not remember any numbers - my house or phone or my age or anything. That evening I could remember it all. And there was no signalling to make me feel as if I had 'PEM'. If specific bits of brain got short on ATP from usage we should be able to show some people with ME/CFS cannot remember any numb era if they have been asked to remember numbers for ten minutes - or something like that. I appreciate that people have brain fog but nobody seems to be able to find specific defects.
 
jnmaciuch said:
Thanks for the question!
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Thanks for the answer! I have no idea about any of this, so all I can do is ask.

@Jonathan Edwards you mentioned 55 steps or something like that in your publication on RA. How many unknowns are there left in RA? I’m mostly asking to get a better understanding of how well we understand diseases in general. Which is probably an impossible question to answer..
 
jnmaciuch said:
But the question of why someone got cancer at that moment--and why they may or may not go into remission in the future--is a black box.
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Not really. We have very good evidence that it is stochastic, as expected from the nature of cellular chemistry - the law of mass action. It might even be ROS in some cases! It is certainly radiation in some cases, which is stochastic. It is very likely also due to action of activation induced deaminase (AID) in some cases - which again is stochastic at this level.

But cancer is clonal and ME/CFS doesn't look as if it can be driven by clones - unless of course they are B or T cell clones and in the case of B having properties due to the action of AID. I find it hard to see how a systemic metabolic response shift comes about without something like that.
 
Jonathan Edwards said:
No it doesn't. I was talking about changes in oxygen or glucose usage in quite small domains. The shifts are small.



Yes, they are small.

If brain cells were really short on ATP in ME/CFS then there ought to be some severe cases where you can measure specific mental deficits of the sort you can clearly identify in people with TIAs for instance. I have myself had a brief episode of what I suspect was loss of metabolic function in my left parietal lobe. For about an hour I could not remember any numbers - my house or phone or my age or anything. That evening I could remember it all. And there was no signalling to make me feel as if I had 'PEM'. If specific bits of brain got short on ATP from usage we should be able to show some people with ME/CFS cannot remember any numb era if they have been asked to remember numbers for ten minutes - or something like that. I appreciate that people have brain fog but nobody seems to be able to find specific defects.
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small does not mean irrelevant especially in the brain.
 
Utsikt said:
How many unknowns are there left in RA?
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The unknowns in RA can be reasonably well delineated. There is the unknown of where disease memory resides - memory B cells, plasma cells or T cells. The answer to that will be fairly simple once known. But we also have unknowns relating to the fact that each individual person's RA will be driven by a spectrum of antibody species of which there may be a billion or more types to choose from. And every antibody will have more or less ability to function badly in some of the various 55 steps. So we will never know exactly what the dynamics are even for one person's RA. The interactions are just way too complicated. But generalities can be made that look to make sense.
 
jnmaciuch said:
https://www.frontiersin.org/journals/psychology/articles/10.3389/fpsyg.2014.00552/full
Here's an interesting study I discussed in class that might provide a bit of insight into the complexity of that question!
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I only looked at the figures because everything else is way outside my understanding. The figures are as well for that matter.

But as far as I can tell, they only show a change in mean cerebral blood flow of somewhere between 3-5 %.

If that indicates an increase in oxygen consumption through the proxy of oxygen delivery through the blood, and oxygen consumption is a proxy for energy consumption, then I don’t see how the paper supports substantial differences in energy consumption in relation to the level of mental exertion.
 
Utsikt said:
I only looked at the figures because everything else is way outside my expertise. The figures are as well for that matter.

But as far as I can tell, they only show a change in mean cerebral blood flow of somewhere between 3-5 %.

If that indicates an increase in oxygen consumption through the proxy of oxygen delivery through the blood, and oxygen consumption is a proxy for energy consumption, then I don’t see how the paper supports substantial differences in energy consumption in relation to the level of mental exertion.
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I think it's best explained by what @EndME noted earlier: even healthy people will face fatigue doing cognitive tasks. The changes are small to our eyes, but we already know from healthy populations that they'll be correlated with fatigue, otherwise healthy people could spend 20 hours a day on spreadsheets with no problems. To me, it's a sign that the small changes are extremely relevant. But as with all neuroscience, there's a huge lack of understanding on the how. The discussion my class had with neuroscientists around this paper was extremely interesting in that regard--we're barely scratching the surface
 
EndME said:
Yes, I agree that local arguments can still make sense but then I see no reason to keep on talking about global energy consumption as is commonly done. Even healthy people have to take breaks from cognitive tasks, because they become taxing, I doubt anybody can give a precise explanation why that is so.
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I agree, I think it's an oversimplification. You said it very well
 
jnmaciuch said:
The changes are small to our eyes, but we already know from healthy populations that they'll be correlated with fatigue, otherwise healthy people could spend 20 hours a day on spreadsheets with no problems.
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I’m assuming there are probably multiple causes of the experience of fatigue. It doesn’t have to be caused by over-consumption of energy.

And that doesn’t explain the delay of the fatigue as a part of PEM. If it used the same mechanism as fatigue in healthy people, PEM-fatigue would have to be instant.
 
jnmaciuch said:
I think it's best explained by what @EndME noted earlier: even healthy people will face fatigue doing cognitive tasks. The changes are small to our eyes, but we already know from healthy populations that they'll be correlated with fatigue, otherwise healthy people could spend 20 hours a day on spreadsheets with no problems. To me, it's a sign that the small changes are extremely relevant. But as with all neuroscience, there's a huge lack of understanding on the how. The discussion my class had with neuroscientists around this paper was extremely interesting in that regard--we're barely scratching the surface
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But do we have any indication that "cognitive fatigue" would arise from a lack of local ATP? Does it not seem more likely that it would be consequence of other neurological processes?

Whenever I used to experience cognitive fatigue after a long day at uni, I would still be perfectly fine to do physical sports for hours aftwards, in fact that provided the best distraction for me. For pwME a different phenomenon seems to occur on top of that, they also often develop physical symptoms that seem to have consequences across different body parts. On the other hand there may be some indications that "cognitive PEM" in ME/CFS might often be more instantaneous, who knows what that means when it's unclear what "cognitive PEM" is supposed to mean...
 
Utsikt said:
I’m assuming there are probably multiple causes of the experience of fatigue. It doesn’t have to be caused by over-consumption of energy.
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Probably a semantic point, but even if it were the over-consumption of energy there would have to be some signal for that to be perceived as fatigue by the brain.
 
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