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

Taking a shower at a lower temperature helps, a bit, for me. The blood has to cool down the hotter skin and is taken away from from other duties?
Oxygen seems to get lost between arteries and tissues, what blocks it ? (vasoconstriction in me, I think)

When muscles have to work harder they don't get more oxygen, resulting in damage. Running on empty. Repairs need more energy too?

I do get PEM from cognitive exertion. My tillt table test resulted in part of my brain going offline for two days.
It felt like a preview of dementia, really traumatic. I needed answers on how to prevent that from happening again.
My PEM lasted a month. During that time my "research" was not getting anywhere.
It took me about 4 months to finally conclude oxygen deprivation during the test must have been the cause and over 12 hours of traveltime didn't help either.
How to prevent it. No tilt table test ever again, I'm not going back for seconds. No other prevention required. That put my mind at ease again.

Something beautiful happened too. I seem to have a back-up system in my brain. I had severe brainfog during my appointment, but I have a video recording of that visit, without the fog, even 4 years later it's mostly there. I could even give better answers to the questions asked during the test. (on sound, vision etc)
 
Snow Leopard said:
Can you be more specific what you mean by PEM in this context (which symptoms)?

PEM is not always experienced the same.
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Following an exertional trigger (with or without delay), worsening in functional capacity and symptoms with duration and intensity that is far higher than what would be reasonably expected for someone with a non-ME chronic illness.

If compounded, these worsenings can be permanent. They also sometimes produce new symptoms or symptoms that or only present during these worsenings, on top of exacerbating existing ones.
 
Yann04 said:
Following an exertional trigger (with or without delay), worsening in functional capacity and symptoms with duration and intensity that is far higher than what would be reasonably expected for someone with a non-ME chronic illness.
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Which symptoms though?

I get different symptoms as a result of cognitive exertion (brain fog, headache, drowsiness) than I do from muscular exertion (sore throat, persistent fatigubility, muscle cramps etc), and the onset time frame is different too.
 
Snow Leopard said:
Which symptoms though?

I get different symptoms as a result of cognitive exertion (brain fog, headache, drowsiness) than I do from muscular exertion (sore throat, persistent fatigubility, muscle cramps etc), and the onset time frame is different too.
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To me I get the exact same worsening in symptoms whether the exertion was cognitive or physical in nature. I get myalgia, cramps, sore throat etc from cognitive exertion.
 
I can think there is ample evidence that people report "cognitive PEM" from "cognitive exertion". But to me it isn't quite clear whether there are differences in onset timeframe, whether there are differences in symptoms experienced after "cognitive exertion" vs "muscular exertion" and at what percentages all these differences occur. I think another important question would be: What is the interaction between the general cognitive difficulties reported in ME/CFS and these phenomena?

As extremely unfortunate as it is that nobody has looked into this, I think we should be careful to not overinterpret some of the data from this site.

Since things don't always appear to be super homogenous in ME/CFS I wouldn't be surprised if things aren't very homogenous here either.
 
I've posted about this in another thread, but I wonder if the autonomic nervous system could be part of unifying these three types of exertion.
For me overexertion almost always involves an activation of the sympathetic nervous system (most notably sweating, frequent urination, GI issues). Sometimes this experience is positive (kind of euphoric) and sometimes it's negative (overstimulation or anxiety). I also don't always notice it very strongly. But it does always end with tired but wired / restlessness and insomnia into PEM.

Physical, cognitive and emotional exertion all seem to recruit the sympathetic nervous system, especially if you're pushing your limits. This in turn puts your body in a catabolic state, which might then trigger PEM. Or the sympathetic nervous sytem might have specific effects on the immune system.

It could also just be a downstream or unrelated effect though.
 
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Utsikt said:
My legs are the first to notice cognitive over-exertion, other than my head. They get really heavy and sluggish.
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I gradually loose sensation in my legs the more i cognitively exert. And at best I usually have patchy awareness of my body eg my left leg awareness decreases the further towards the foot it goes. There’s a medical term for that prioception. When I've met GPs, they often start would it be nice to get you out of bed or walking again and they don't seem to grasp as far as I'm concerned The awareness of the body is already disturbed and that has got to be more solid & normal before you can even use that body.
 
Jesse said:
I've posted about this in another thread, but I wonder if the autonomic nervous system could be part of unifying these three types of exertion.
For me overexertion almost always involves an activation of the sympathetic nervous system (most notably sweating, frequent urination, GI issues). Sometimes this experience is positive (kind of euphoric) and sometimes it's negative (overstimulation or anxiety). I also don't always notice it very strongly. But it does always end with tired but wired / restlessness and insomnia into PEM.

Physical, cognitive and emotional exertion all seem to recruit the sympathetic nervous system, especially if you're pushing your limits. This in turn puts your body in a catabolic state, which might then trigger PEM. Or the sympathetic nervous sytem might have specific effects on the immune system.

It could also just be a downstream or unrelated effect though.
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My hypothesis to explain this is dysfunction of the autonomic nervous system too, but I don't think it is any sort of generalised "activation of the sympathetic nervous system at all". I think it is more subtle and to do with specific types of nerves rather than the whole system.
 
Utsikt said:
Let’s assume that misfolded proteins are at the heart of this. These are more or less random thoughts:

What causes and or drives the misfolding? Can it be multiple drivers?

Can misfolded proteins in themselves lead to more misfolded proteins?

Are the misfolded proteins a precursor to something else? I read something about PrPc being converted to PrPcs (toxic) by PrPcs itself, in patients with FFI.

Let’s say that there’s a genetic component: is WASf relevant here? I vaguely remember a discussion about that a week ago @Jonathan Edwards

Maybe there’s a critical limit to how much you can accumulate before something goes wrong (you get ME/CFS)?
Remission = below the threshold on a systemic level
Relapse = something caused you to cross the threshold again

I also have a vague memory of reading that ROS is usually good for you in normal levels, but that very high levels of ROS makes it bad for you.

There’s also the BH4 and BH2 theory that I don’t know enough about:
https://pubmed.ncbi.nlm.nih.gov/39161795/
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@mariovitali

Pretty sure misfolded proteins have been run in one of your network analyses
 
We've circled around adrenalin (epinephrine I think is usually the term for exogenous adrenalin) as a possible cause of PEM. I can't remember how much of this has been said before.

Exercise definitely increases adrenalin. Cognitive effort can too, especially if it is demanding or there is time pressure. Hot temperatures do. Being upright and not getting enough blood to the brain increases adrenalin.

And adrenalin activates CD8+ t-cells. It seems to result in an increase of them in the blood, followed by them going into tissues. I think we haven't quite worked out how the CD8+ t-cells could cause PEM.

Exercise accelerates recruitment of CD8+ T cell to promotes anti-tumor immunity in lung cancer via epinephrine, 2024
(in mice)
Overall, these data suggest that exercise promotes the expression of Ccl5, Cxcl10, Cxcl9, and Cxcl11, further promoting the recruitment of CD8+ T cells. Specifically, the expression of Ccl5 and Cxcl10 is dramatically higher compared to other chemokines.
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T cell infiltration also requires the help of cytokines. Such as IFN-γ and TNF-α, both produced by NK cells and activated T cells, further enhancing the proliferation of T cells and slowing down the proliferation of cancer cells [43,44,45]. The ability of T cells to express IFN-γ and TNF-α plays an important role in anti-tumor immune response [46]. In our model, both IFN-γ and TNF-α were upregulated after exercise
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C-X-C motif chemokine ligand 10 (CXCL10) also known as Interferon gamma-induced protein 10 (IP-10) or small-inducible cytokine B10 is an 8.7 kDa protein that in humans is encoded by the CXCL10 gene

We could test the idea that adrenaline causes PEM by injecting people with epinephrine. Has anyone looked at that?
 
Hutan said:
We could test the idea that adrenaline causes PEM by injecting people with epinephrine. Has anyone looked at that?
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I guess it happens often enough when people have dental treatment? A small quantity of epinephrine, used to help confine local anaesthetic to the area where it's needed, may be ingested.

There seem to be several responses, including a steep drop in blood pressure that leads to fainting, uncontrollable shaking and nausea, and no ill-effects at all.

I suspect the adverse reactions aren't confined to people with ME/CFS, though. I've heard people unwell with other conditions describing similar experiences to mine (I seem to favour No. 1).
 
I tried having dental work with the adrenaline free jab but had to wave my hands to get a second jab as it wore off really quickly so I just go with the normal one now. I do definitely worse PEM after dental treatment than going out for other reasons but I’m lucky that I don’t get any fainting or nausea, but then I have hypertension so probably less affected by drop in bp.
think adrenaline definitely worth looking into as I wonder about the link with tired but wired as I’ve experienced the thing of feeling like a flow round my body of something switching off and then falling asleep.
 
I've seen adverse reactions in a few patients injected with local anesthetic and epinephrine for foot surgery too.

Some patients inform the doctor in advance that they had adverse reactions in the past. It was most likely due to an allergic reaction. to amides or ester(or both) in the local anesthetic and not the epinephrine.
 
Hutan said:
We could test the idea that adrenaline causes PEM by injecting people with epinephrine. Has anyone looked at that?
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Not in ME/CFS but it doesn't do that much in healthy people - it doesn't actually improve exercise performance.

Studies of catecolamine levels in circulation in adults with ME/CFS largely show nothing abnormal. The only exercise study I know of was immediately after (lower adrenaline) and no difference the next day. https://pubmed.ncbi.nlm.nih.gov/11150897/

Pharmacolgical stimulation also had normal or attenuated responses. https://pubmed.ncbi.nlm.nih.gov/23770415/

An increase in adrenergic receptors in PBMCs post exercise was found maybe suggesting the opposite, a reduction or catecolamines or maybe no difference.

Generally speaking more highly trained people have a much stronger adrenaline response to exercise.
 
From my own experiences I do think the sympathetic nervous system is involved, though my instinct is that it is more involved as a compensatory reaction than anything. Throughout the past few years I've been able to incorporate a bit of exercise into my routine without triggering PEM that definitely elevated my heart rate to a greater intensity that PEM-causing activity. On the other hand, if it is causative, maybe the key is a prolonged sympathetic nervous system response.

As for PEM after injecting epinephrine--I don't think people report PEM after an epipen injection for allergic reaction. In that case there is the confounding factor of an initial allergic reaction, though. 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.

Though perhaps it's a matter of differential responses to epinephrine as well in pwME.
 
Snow Leopard said:
Studies of catecolamine levels in circulation in adults with ME/CFS largely show nothing abnormal.
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Levels of adrenaline could be entirely normal, it's just that adrenalin activates CD8+ t-cells that perhaps then go on to do something unusual in people with ME/CFS. I wouldn't expect a dose of adrenalin to cause PEM in healthy people.

jnmaciuch said:
Though perhaps it's a matter of differential responses to epinephrine as well in pwME.
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I don't think people with ME/CFS would need to have a different initial response to adrenalin for the idea to work. It's the downstream response that could be different, and account for PEM in people with ME/CFS.
 
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