What could it mean biologically that both physical and cognitive exertion can cause PEM?

hotblack said:
That’s definitely something I’m interested in.
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There is a phenomena known as sympathetic sprouting, post neurological injury, there is coupling of afferent (sensory) nerves with downstream efferent sympathetic nerves. This helps aid neurological recovery but can also lead to altered sensitisation of those nerves.

Obviously this requires actual nerve injury in the DRG as a pathological mechanism. This is one of my working hypotheses and there is evidence of DRG involvement in autopsy cases in the UK for example.

"Sympathetic sprouting near sensory neurons after nerve injury occurs preferentially on spontaneously active cells and is reduced by early nerve block"

Sympathetic sprouting near sensory neurons after nerve injury occurs preferentially on spontaneously active cells and is reduced by early nerve block - PMC

Some chronic pain conditions are maintained or enhanced by sympathetic activity. In animal models of pathological pain, abnormal sprouting of sympathetic fibers around large- and medium-size sensory neurons is observed in dorsal root ganglia (DRG). ...
pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
 
Sasha said:
I've always wondered how come both physical and cognitive exertion can cause PEM. I'd have thought that moving around would have used very different biological mechanisms and energy expenditures than thinking, on the whole.

There has been talk of 'emotional exertion' causing PEM, even though emotions don't really seem to fit the bill as 'exertion'.

I also wonder whether PwME who have OI and simply remain upright for too long can have PEM (I suspect I can).

Does it indicate anything about the mechanism of ME/CFS that both physical and cognitive exertion can cause PEM?

Is it worth trying to clearly identify other possible triggers of PEM to help point at mechanism?

@Jonathan Edwards (As always!)
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Is it really that different in what is needed for cognitive vs physical exertion?

Most tasks involve some overlap eh sitting up to type or thinking where to run

Talking and the different levels of conversation depth and mediums is the classic both one. It’s pretty physical when you get iller it’s obvious how physical it is. And the word finding feels like an activity in itself vs thinking if your considered answer to the point it becomes impossible to do both at first (so you can’t consideration want to answer with words in good time), then both so you end up just saying whatever words have been out in your moth. Intuitively manybonlookers know this, see it and use it which is why I’m puzzled when the same nefarious types who take advantage that way obviously see our buttons to push but are the worst fir then claiming they don’t see them exist.

And both systems need an energy supply.

With physical exertion you have more muscles involved yes but different exertions it is different muscles.

I note I can get localized impacts eg fatigue ability in arms. But there is something central which sometimes is as much to do with being upright as well, and still now in the moment if no chair then moving is better than just standing even though both leave me harmed.

Doesn’t most ‘work’ involve certain common things in physiology?

And yes maybe there’s some interesting stuff to be had if you take the experience/knowledge of those who’ve been more severe so learned how to eg read or think whilst minimising other physical things like sitting up most would naturally do at the same time , but train some of those less ill to do those. Because that less ill group might then be able to see the difference if those activities are ‘almost pure cognitive’ where even that 10% from typing or moving a mouse is a lot for more severe. And the discomfort they might be carrying anyway etc.

And then see if their symptoms specifically to just that vary significantly vs physical but somehow with no music and no thinking. But what do you do about the orthostatic and temperature etc there - I guess just starting is a start (but noting those other factors so if someone in another part of the world gets a different result we can see that it was 10C hotter)
 
bobbler said:
And yes maybe there’s some interesting stuff to be had if you take the experience/knowledge of those who’ve been more severe so learned how to eg read or think whilst minimising other physical things like sitting up most would naturally do at the same time , but train some of those less ill to do those. Because that less ill group might then be able to see the difference if those activities are ‘almost pure cognitive’ where even that 10% from typing or moving a mouse is a lot for more severe. And the discomfort they might be carrying anyway etc.
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I wonder about this too, usually cognitive activity can have additional physical/orthostatic demands at the same time so there sort of needs to be a control (doing the same activity but without the cognitive demand).

But I think there is something there with regards to autonomic symptoms, those who report cognitive activity causing physical PEM seem to have more severe autonomic symptoms in general, I think this is something that needs studying.
 
jnmaciuch said:
I have known someone who administered epinephrine as a "false alarm" (had a very severe peanut allergy and mistakenly believed they ate something contaminated) and they didn't get any PEM-like symptoms after the initial effect wore off
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Given endogenous vs epipen adrenalin have different dosages, release patterns, delivery routes, associated hormones (epipen would have no associated cortisol or norepinephrine, etc ... is epipen response PEM-relevant?
 
arnoble said:
Given endogenous vs epipen adrenalin have different dosages, release patterns, delivery routes, associated hormones (epipen would have no associated cortisol or norepinephrine, etc ... is epipen response PEM-relevant?
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Perhaps it’s not 1:1, though I would expect them to overlap somewhat. I’ve also watched scary movies with plenty of jump scares that sent my heart rate spiking, or accidentally taken too much of my stimulant, and had no PEM either time. Though like I said, perhaps it’s a concentration/duration dependent phenomenon.

Just from personal experience, a beta blocker did nothing to prevent PEM for me when I was taking them around the clock for supposed “anxiety”, though I found that they did help specifically with lessening PEM insomnia. I guess I’m just more inclined to see Adrenalin as a secondary rather than causative factor in PEM based on all those things cumulatively, but I’m happy to be proven wrong!
 
I used to think heart rate or blood pressure had something to do with PEM. It's easy to fit either into "physical" or emotional induced PEM. It's not as easy when purely cognitive PEM is on the table. But I think I can differentiate cognition when laying flat vs cognition when sitting up. I read most studies when doing the latter, same with math and such. It is these higher level cognitions that seem - I think - to induce PEM in me. So maybe the autonomic system plays a role?

I clearly think a lot when laying flat, often invoking complex thoughts - but I seldom associate PEM with such. Perhaps I am wrong. I am laying flat when I dream, and dreams can trigger PEM, but then HR is involved.

Is it easier to fall into cognitive PEM when you're at your sharpest time of the day? Harder?

It's all so non linear and complex.
 
jnmaciuch said:
I’ve also watched scary movies with plenty of jump scares that sent my heart rate spiking
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But pwME allegedly have dampend/dysregulated cortisol feedback (prolonged, stuck in overdrive) vs scary-movie would involve more normal negative feedback (transient). Also pwME allegedly may have immune system cross-talk eg HHV reactivation. I don't know any of this, just floating the questions - it's likely not so much the adrenalin as a) its dosage, release-patterns, other sympathetic/para factors ... and b) different responses from other systems eg immune.
 
arnoble said:
But pwME allegedly have dampend/dysregulated cortisol feedback (prolonged, stuck in overdrive) vs scary-movie would involve more normal negative feedback (transient).
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I've looked into the literature on this, I don't think there actually is good evidence of dysregulated cortisol feedback. We have tons of studies with directly contradictory findings, and cortisol measurements are notorious for being influenced by confounders. There may well be something wrong, but existing studies don't really confirm it in my opinion.
 
jnmaciuch said:
I've looked into the literature on this, I don't think there actually is good evidence of dysregulated cortisol feedback.
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Thanks very much - so hard to sort out fact from fiction, especially for a non-scientist like me. Could you point me to a study that concludes there is NO cortisol dysregulation? Is there a better way to find relevant papers than just ask Gemini or ChatGPT?
 
arnoble said:
Thanks very much - so hard to sort out fact from fiction, especially for a non-scientist like me. Could you point me to a study that concludes there is NO cortisol dysregulation? Is there a better way to find relevant papers than just ask Gemini or ChatGPT?
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There might not be any one paper that «disproves» X or Y. But if there are multiple paper with inconsistent or contradictory findings, that is in itself fairly strong evidence that you’re probably just looking at noise.

This is one of the things I find the most challenging as a non-scientist - knowing all of the ways you can get something to show up in your data without it actually being there, or being of any importance.

But Gemini or any other LLM will not be a very reliable source of info. I strongly suspect you end up knowing less if you rely on them because so much of what is written in research papers is wrong to some degree, and LLMs don’t know how to judge it. For ME/CFS, your best bet is probably asking here or looking at threads.
 
Utsikt said:
This is one of the things I find the most challenging as a non-scientist - knowing all of the ways you can get something to show up in your data without it actually being there, or being of any importance.
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Yup. Unfortunately most scientists aren't much better off--they'll get that specific level of knowledge in their particular subfield, but then be completely clueless more than 2 steps removed from that niche. I've learned the hard way that an immunologist talking about biochemistry or metabolism is usually more wrong than they are right (a former mentor had some truly bizarre opinions about mitochondria that I'm glad I didn't take at face value...). And the same is true in the other direction.

The only reason I knew that the findings in this paper were suspect, for example, was because I've done integration of single cell data sets repeatedly. Even another bioinformatician might not have caught that if they didn't specifically have transcriptomic experience, because they wouldn't know what part of the method to look for. I only know the issues with cortisol measurements because I've collaborated with several clinical researchers, and my knowledge on that is still minimal.

The best way to get around this is simply to have a critical concentration of people with different expertise all assessing the same thing, but of course that doesn't often happen in an organized way. This is what reviewers are supposed to be for, and yet that subfornical organ paper somehow passed peer review and got published in Nature.
 
Sorry, I'm too fatigued to go through the past 5 pages to see if anybody brought up a potential mechanistic link between PEM and exercise/stress induced leukocytosis?

I remember Dr Puta mentioning leukocytosis in connection with catecholamine release during his presentation at the ME/CFS conference this year.

Leukocytosis, from what I can see, is an increase of leukocytes in circulation. This seems to be driven by epinephrine and norepinephrine via agonism of beta 2 adrenergic receptors. It's been observed as an effect of exercise but it's also been connected to other types of stressors such as emotional stress (as these also affect catecholamine release).

A small double-blind crossover trial could see a differential effect of propanolol on stress and exercise induced leukocytosis. I haven't read the full text.
One week of ingesting propranolol modestly elevated the numbers of CD62L+ (P<0.019) but not CD62L– T-lymphocytes. Moreover, propranolol preferentially blunted-psychological stress-induced increases in naïve T-helper (CD4+CD62L+; P<0.049) and naïve T-cytotoxic lymphocytes (CD8+CD62L+; P<0.003), as well as activated T-cytotoxic lymphocytes (CD8+CD29+; P<0.005). However, exercise-induced increases in leukocyte numbers were enhanced following propranolol treatment (P<0.04).
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I am wondering whether this doesn't fit nicely with the concept of PEM?
Exertion or emotional stress causes leukocytosis which then (due to whatever misguided reactivity of the leukocytes) causes PEM.
The disliked agonistic beta 2 receptor autoantibodies might even play a role :D
 
forestglip said:
Lately, I've been thinking more that it's related to sleep in ME/CFS as well. It seems so strange that exertion causes insomnia. I think this is common in ME/CFS but I'm not sure.
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Grateful to this discussion as am experiencing more issues with exertion(cognitive and/or physical) equalling insomnia , or what I call “fall out” ,as I get older.

For example a medical apt out with required travel (obviously being upright for longer), ends in worsening symptoms (not being able to regulate temperature, leaden legs, that woozy unstable feeling when needing to stand, nausea etc., and being unable to rest the brain or sleep. Similar to the feeling of being on steroids for a few days…youd expect the stimuli would worsen exhaustion (and it does) , that stimuli and exertion would, at the end of the day, lead to better sleep but it does the exact opposite for me cognitively.
The longer the day out and about the worse the insomnia (regardless of that overall feeling of depletion).
 
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