PEM discussion thread - post-exertional malaise

[Kitty]

Does @poetinsf have something with the idea of tolerance?

To me, none of it seems like inputs and outputs. It's a substantial, often variable, and sometimes devastating reduction in tolerance to almost everything—perhaps caused by some kind of biological brake being applied.

 

[Jesse]

Is there evidence that MECFS causes dysregulated cortisol, or that the arrow of causality is reversed? Or if other systems eg immune are involved?

I don't think so but I do think cortisol is heavily involved in stress and energy production and thus could relate to (over)exertion.

 

[Mij]

It appears that normal cortisol response is lost in over training syndrome here

 

[bobbler]

I talked about it here

Post in thread 'What could it mean biologically that both physical and cognitive exertion can cause PEM?'

Jun 28, 2025

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+...

• Hutan

• 

Exercise/being upright/heat/ mental exertion >adrenalin > activates t-cells >
activated T cells produce interferon, among other things that might contribute to PEM

There's a study in mice.

I'm happy to have it explained why it can't be a mechanism for PEM.

one thing I've been increasingly conscious of, both (I think) in creating PEM and when in PEM, is that there is the orthostatic and there is the just supporting one's own body - and in that the more upright but also if for example you have a supportive chair which supports arms, neck, back. My car seat for example is a pretty good fit, and is a best fit for supporting everything I need it to support if it is pretty upright, and stops doing so once recline and so I'd find I was better off with it being upright evne though orthostatic is sort of a big thing for me too.

I think* that this was a thing when I was less ill as by the end of a day in the office it was that desperate feeling of needing to rest my head on the back of the chair (and I mean longingly wanting to turn around and put my cheek on the back of it so head would be horizontal), and when I got home getting head and face supported by a pillow. I mention this because I'm conscious these days so many would assume it is just me 'being ill but having to be out of bed' or of course that ole deconditioning assumptions. But it was there, just slower to catch up with me, when I was having to live a life where noone sensible could have claimed it was a vicious circle of deconditioning because I was having to 'act normal' so claiming other healthy people who did the same as me were somehow free of this because they did more was nonsense because they didn't 'do more' (unless you were the type who assumed I was wrong in what I was saying)

I will say though that I definitely used 'momentum' (a term I'm stealing from @Sean because it was spot on) in getting through any day where I wasn't at home. Whether that was adrenaline specifically I don't know but certainly I'd feel better walking that bit fast to get it done, and schzuzz it up vs doing it slowly sometimes, 'throw myself' to places when I didn't have anything left but somehow had to get onto a train or from x to y, and if I couldn't sit I'd have to move (orthostatic issues) and that probably doesn't help that it was pushing through a sense of exhuastion and maybe sleepiness so keeping a bit focused if I could.

On the other hand I'm not sure in creating PEM that did me much good - hence why these trying to be clever 'how to manage fatigue' type documents we've started seeing that are giving out exactly this same advice I know is just making the problem worse/denying it (complete misunderstanding of what the issue is and using that short-term coerce people into performing x and 'see it's better' even though you know in your body what you are doing) longer-term.

So I'm kind of intrigued what kind of measures an app type thing could come up with that can distinguish the change in whatever it is that happens due to orthostatic and how some of us are having to then compensate it and the above (body wanting to slump and lie down) with things that stop us collapsing when we are in situations when we can't. And how if we can control for things and isolate these different scenarios and reactions how they relate to what PEM /later effect someone gets on another day.

And now of course when I'm more ill it is a case of when in PEM I might be able to eventually get a little bit less than flat if I can get pillows supporting my whole body and limbs, and if on a better day then the clock starts when out of bed and it feels it runs down much much faster if I'm sitting and not supported vs maybe just a little reclined (but not enough to really make a difference to orthostatic, just gravity/weight) and very supported in all the areas I need.

As it would be quite likely to be correlated with these situations also happenning on days where I'm having to do more of 'something else' on this list, eg obviously this automatically interacts with orthostatic because I'm also 'more upright' (although slumped by the end of it) but might be having to do it to speak to someone or do an appointment it is hard to unpick.

 

[Hutan]

I don't think so but I do think cortisol is heavily involved in stress and energy production and thus could relate to (over)exertion.

Yes. I don't think there is any good evidence of cortisol levels that are abnormal (given the average lifestyle of people with ME/CFS - waking later, no morning rush) or that the production of cortisol in response to stressors is abnormal. I see that @arnoble has been directed to our thread on cortisol here already, on another thread, but link it here again for completeness.

I suppose bursts of cortisol may contribute to the effect of adrenalin in activating t-cells - I haven't looked to see if it does cortisol does that too.

 

[MeSci]

Years ago a friend with ME did the ACTH stimulation test and it came back normal. She didn't have insomnia either.

I've done the ACTH stimulation test which came back normal, but I do (often) have insomnia. Also, during the test, my gut swelled up severely, I think because I was told to sit still, and it was very uncomfortable.

 

[Mij]

I've done the ACTH stimulation test which came back normal, but I do (often) have insomnia. Also, during the test, my gut swelled up severely, I think because I was told to sit still, and it was very uncomfortable.

Yes, it can make some people feel nauseated too.

 

[poetinsf]

But if it is the basis of a symptom that patients are expected to recognise it has to be subjective.

Why? A symptom being subjective doesn't mean that the cause of the symptom has to be subjective as well. Your feeling pain because a car ran over you does not mean the weight of the car is subjective. Or the sound of the backfire from the passing vehicle that triggered the PTSD symptom.

We should talk of power (calories per time would be power) or of total energy usage. So far I don't think we have established even which of those is relevant - and they are very different in implications.

Calories by itself does not cause enough stress/damage. For healthy people anyway. Just living and breathing consumes about 1 cal/min, which means over 1000 cal/day. But you will surely feel the next day the damage from 1000 cal spent in an hour.

The stress from burnt calories gets relieved/cleared at a certain rate. It accumulates rapidly as the arrival rate approaches/exceeds the clearance rate if we view it as an MM1 queue. This is probably why slowing down by 5-10% allows athletes run/skate/swim twice as far. My theory is that the accumulated stress, or working against it, is what causes damage and subsequent PEM. This model could explain things like pacing (slowing down and incorporating rest) letting you walk much further without triggering PEM and the illusion of lowered threshold from accumulation effect in rolling PEM, etc.

I've modeled it mathematically using R and fitbit minute-by-minute data and had some success with it. Then Google deprecated the authentication API and replaced it with OAUTH2 protocol which R did not support then. I couldn't find ways to improve the model anyway, so I shelved it at that time. I've been meaning to resurrect it, but I haven't so far. Now I'm too distracted with making up for what I've missed now that I have my life back. But it's still on my list of things to do...

 

[poetinsf]

Subjectively it feels that a simple measure like calories per unit of time does not correspond to what ever culminates in triggering PEM. Other things interact like the novelty of the activity, additional sensory stimuli or orthostatic issues.

There could be several triggers for PEM, with physical exertion being but one. Mental exertion or sensory stimuli could be other. We could take just the physical exertion portion, of it, since that is the simplest to objectify, and then establish the relationship between physical exertion and PEM. There could be other factors like emotion, but we could treat them as noises in the model that lowers correlation.

 

[poetinsf]

Meaning that if PEM has something to do with the processes which increase utilization of different fuel sources (be that AMPK phosphorylation, increased glucose uptake, fatty acid mobilization, etc), this will look different between tissues.

But you do need recovery from mental exertion (I know how my mental ability degrades after 1 hour of thinking), and there is no reason to preclude such stress/damage as the possible trigger for PEM. And how hard you think, and how tired you are afterward, got to be proportional to the amount of expended for thinking within the given time period.

 

[Jonathan Edwards]

Why? A symptom being subjective doesn't mean that the cause of the symptom has to be subjective as well. Your feeling pain because a car ran over you does not mean the weight of the car is subjective. Or the sound of the backfire from the passing vehicle that triggered the PTSD symptom.

Those examples are not equivalent. PEM is defined as a worsening following exertion. Whether or not it is caused by exertion is a different issue. It is elicited as a temporal symptom profile in which the apparent trigger is a subjective sense of having done a lot or 'exerted' and the time relation is nearly always subjective in that when PEM is elicited by a physician in clinic or in a questionnaire nobody really knows whether any particular exertion was what the worsening followed.

As to what causes PEM, that is a biological issue that would do well to keep well away from terms like 'exertion'.

But you will surely feel the next day the damage from 1000 cal spent in an hour.

Maybe but from what members say, the length of time at that rate is also relevant. So we seem to need a complex measure of a high work rate for a certain length of time. I agree that total work done is not going to cut it but nor is just work rate. So we are likely to need some new measure that so far nobody has calculated. And if nobody has calculated it I do not see how anyone can know what it is from experience to be honest. People may get very good at predicting what will cause trouble but so far no formal measure that reflects that has been devised.

 

[Jonathan Edwards]

My theory is that the accumulated stress, or working against it, is what causes damage and subsequent PEM.

What would 'stress' be here? It is another lay term that may not help I suspect.

I continue to think that what may trigger PEM is some cumulative tissue response to microtrauma - like the response to using your hands that leads to calluses on your palm. It is partly the intensity of force involved and partly the duration, but not a simple multiplication of the two.

 

[poetinsf]

Does @poetinsf have something with the idea of tolerance?

To me, none of it seems like inputs and outputs. It's a substantial, often variable, and sometimes devastating reduction in tolerance to almost everything—perhaps caused by some kind of biological brake being applied.

I wouldn't be surprised if the tolerance/sensitivity is highly variable in some cases. Some people report oscillation between remission and relapse after all. That's an ultimate case of tolerance variability. Your guess is as good as mine as to why. I'm mainly interested in a steady state response to physical exertion though, mainly because that is the easiest to establish, and that will probably help the most since PEM from physical exertion is universal in ME/CFS.

 

[poetinsf]

Those examples are not equivalent. PEM is defined as a worsening following exertion. Whether or not it is caused by exertion is a different issue. It is elicited as a temporal symptom profile in which the apparent trigger is a subjective sense of having done a lot or 'exerted'

This is what I meant by "the idea of subjective exertion can be positively dismissed by the typical delay of 12-48 hours". I'm not aware of any psychological process that a perceptual "apparent trigger" can actually worsen the symptoms, subjectively or otherwise, after 12-48 hours.

and the time relation is nearly always subjective in that when PEM is elicited by a physician in clinic or in a questionnaire nobody really knows whether any particular exertion was what the worsening followed.

So, are you questioning PEM being a delayed response to exertion? Or even a response to an actual exertion at all? That would be easy to settle, I think. Do a CPET test, and measure VAS every hour. The symptom response may be subjective, but the exertion there will be objectively objective and there would be no question what particular exertion proceeded.

Maybe but from what members say, the length of time at that rate is also relevant. So we seem to need a complex measure of a high work rate for a certain length of time. I agree that total work done is not going to cut it but nor is just work rate. So we are likely to need some new measure that so far nobody has calculated.

Well, I did. It's something like integral over time of the difference between the arrival and clearance in exponential form. I don't have the notebook with me here in NYC, but it was borrowed from queuing model.

 

[poetinsf]

What would 'stress' be here? It is another lay term that may not help I suspect.

I don't know why you are so allergic to abstract terms. Can we call it a concept, build a model for it and test?

I continue to think that what may trigger PEM is some cumulative tissue response to microtrauma - like the response to using your hands that leads to calluses on your palm. It is partly the intensity of force involved and partly the duration, but not a simple multiplication of the two.

We can always build a model and test.

 

[jnmaciuch]

But you do need recovery from mental exertion (I know how my mental ability degrades after 1 hour of thinking), and there is no reason to preclude such stress/damage as the possible trigger for PEM. And how hard you think, and how tired you are afterward, got to be proportional to the amount of expended for thinking within the given time period.

I don’t think what you’re quoting from me is in opposition to what you’re saying here, it could well be that a failure to upregulate one of those mechanisms may substantially lower the time or activity it takes to get to whatever biological state needs to be recovered from

 

[Jonathan Edwards]

Responding to a deleted post about learning by experience how much you can do.

I think you are quoting out of context. I agree that people can get to know what will be problematic. I am saying that nobody has got to know what that means in biological terms like calories per hour..

 

[Jesse]

I continue to think that what may trigger PEM is some cumulative tissue response to microtrauma - like the response to using your hands that leads to calluses on your palm. It is partly the intensity of force involved and partly the duration, but not a simple multiplication of the two.

Maybe thinking too much outside of the box but would there any non-exertion things that should also trigger PEM if that's the case?
It would be interesting if we could reliably trigger PEM without (over)exertion.

 

[Jonathan Edwards]

Maybe thinking too much outside of the box but would there any non-exertion things that should also trigger PEM if that's the case?

Passive movement would be the obvious thing, but that isn't easy. If it is necessary for internal forces to be generated in muscle you might need electrical stimulation and that is pretty nasty over an extended period.

A 'non-exertion' thing that gives me serious fatigue is maintaining posture when in a moving vehicle or on a boat. But that involves muscle work, despite one not being aware of it.

People with ME/CFS talk of PEM being precipitated by having to travel in an ambulance, even if lying down. Goodness knows what calories are involved there.

I think the whole thing is wide open.

 

[Jesse]

Passive movement would be the obvious thing, but that isn't easy. If it is necessary for internal forces to be generated in muscle you might need electrical stimulation and that is pretty nasty over an extended period.

A 'non-exertion' thing that gives me serious fatigue is maintaining posture when in a moving vehicle or on a boat. But that involves muscle work, despite one not being aware of it.

People with ME/CFS talk of PEM being precipitated by having to travel in an ambulance, even if lying down. Goodness knows what calories are involved there.

I think the whole thing is wide open.

I was more so thinking about non-muscle microtrauma.