Yes @forestglip sleep is a massive factor for me and I think it needs properly investigating why PEM affects people’s sleep
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What could it mean biologically that both physical and cognitive exertion can cause PEM?
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Utsikt
Senior Member (Voting Rights)
@Jonathan Edwards
Some googling told me that FFI results in an accumulation of misfolded cellular prion proteins (PrPc).
I found a couple of papers that mention PrPc, ME/CFS and LC. I have no idea if they contribute anything, and it’s way beyond my understanding.
https://www.sciencedirect.com/org/science/article/pii/S1470872823000401
https://pmc.ncbi.nlm.nih.gov/articles/PMC6288442/
https://pmc.ncbi.nlm.nih.gov/articles/PMC6288442/
Ctrl+F «prpc»:
https://growthzonesitesprod.azureed...1/IACFS-ME-Conference-Abstracts-Fall-2011.pdf
Some googling told me that FFI results in an accumulation of misfolded cellular prion proteins (PrPc).
I found a couple of papers that mention PrPc, ME/CFS and LC. I have no idea if they contribute anything, and it’s way beyond my understanding.
https://www.sciencedirect.com/org/science/article/pii/S1470872823000401
https://pmc.ncbi.nlm.nih.gov/articles/PMC6288442/
https://pmc.ncbi.nlm.nih.gov/articles/PMC6288442/
Ctrl+F «prpc»:
https://growthzonesitesprod.azureed...1/IACFS-ME-Conference-Abstracts-Fall-2011.pdf
I agree. As sleep is the ultimate 'recovery process' and it feels that is where at least one significant issue is then it will either be affected by having more work to do because other processes that happen in normal people aren't and it's picking up the slack or/and is affected by the same thing.
And researchers starting to see sleep as a canary in the coalmine symptom, and like other things being prepared to listen to the intricacies of those patients who can describe quite detailed differences in 'what happens' to their sleep, because there are different things going on here.
For example I'm pretty sure that as some point I described at least to myself that something closer to an equation of what I'd done for the day was the amount of sleep I needed, rather than what normal people have of this regular amount and maybe they can slowly catch up if they'd had a big whatever with a little bit extra here or there.
And I can tell for sure (my body was always creaking at the seams and in pain when I was trying to hold down a job) that I was cumulatively not just beyond my limit where I was getting slowly iller (that was a given I was stuck with for years) but likely to 'burst' (ie even the week off to recover wasn't going to work) when my sleep which was basically having to not have an evening after I got home in the weekdays was starting to be more unrefreshing and go all over the place
Although before that it was all over the place anyway because of the jobs I was trying to do and not having good knowledge of that PEM paradigm so had no control.
I think my point is that surely as apps are now getting better surely the shameful position of those who call themselves sleep experts but got away with just talking about sleep hygiene and soothing baths have no excuse but to start acknowledging there is more to it than just looking at it like an isolated behaviour from the rest of the body and timetable (picking it up hr before bed) or 'about routine'. I mean they should always have known that most healthy people when they get an illness find it changes their sleep so...
I realised / was reminded of the other day how with laypersons, and I suspect HCPs who allow themselves to think similarly, how 'on the nose' /functionally fixed many people are to seeing an issue in a specific area and assuming the issue is behavioural because they are trying to fix 'the symptom' and why the phrase 'treat the symptoms' is so dangerous.
It allows someone to make someones overall health permanently deteriorate whilst claiming a medal for their now being unable to sleep to recover themselves.
Because they try and fix the sleep pattern rather than see sleep as a medication needed in itself ie it might also be an indicator but the body if it is doing it more is doing so because it both needs it, and might find it is less 'efficient'.
eg sleep the issue is 'train the sleep', not that most often the cause is illness, or something external such as a situation - certainly if it has changed to be bad at any point. Tackle those and the sleep is just the symptom.
similar thing with lots of psychology in those trained badly in it and believing in behavioural without bothering to understand the big picture. So they assume all OCD could be about telling someone not to wash their hands instead of realising that when stress increases for other reasons can be the cause for many, just as someone else might be picking up a beer and another person might have another crutch or impact.
None of which focusing obsessively on stressing that person out about and making them self-conscious of the 'downstream effect' will help with what is actually going on and causing it. They like to BS and cover their back when found wrong by talking about 'coping mechanisms' through CBT, which is all well if it is the very few who know what is really meant by that and how short-term / a bridge that is ie the situation still needs to be tackled but that isn't what they mean. It's the 'people need to be more resilient' cover-all there seems to be a slight talk-back on for now about eg toxci organisations.
the bps tend to treat sleep like a cause and one that is behavioural (the wrong sleep is morally bad), rather than as a symptom and a signal of how things are going either in maintaining threshold vs committments or even better in the long run if there are treatments. And it isn't just about making people sleep at the right time eg with tablets, or restricting naps and hailing that as an achievement, as there is something about it being needed when someone has hypersomnia particularly seems to be linked to when recovery is needed. Hence why sleep hygiene is so dangerous because it might be the one form of recovery someone has.
Emotional is different to cognitive and I'm not sure on the emotional one. Anger for example is something we have to control because it does make us over-exert. I'm more likely to need to distract myself or the situation more likely to need to do something if something bad or sad is going on.
One thing for sure on the 'emotional' front is someone shouting at me, talking loudly and fast to force me eventually into that (which whether it is grumpy or not is bad too), and playing sophist rhetoric interrupting me when I speak and making me repeat things and jump through hoops is exhausting (basically mental gynmnastics for the disabled person), but it's not due to my emotions but their toying with my disability and pressing buttons on the illness, and if it was a stroke patient someone was saying 'ah but...' anyone else would normally say that's apalling to watch someone do, but hey we've had a lot reframed onto us.
It can sometimes be difficult for me to separate cognitive from sensory and even physical because talking takes it out of me and involves perhaps more being distracted about length of time sitting up vs the warning symptoms, if face to face the social pressure of feet down with that too, and of course the physical act of talking as well as thinking to talk.
I certainly got worse PEM from the days I was in the office at work than those working from home. Depending on the role and time of year the tasks were different and how I could manage them at home were different though as you would try and use those precious hours out of the office and disturbance to get work that you needed to concentrate on done vs lots of multi-tasking and sensory disturbances in some office days in certain roles.
I can tell the difference between cognitive/sensory PEM and PEM that has been mostly physical for that reason - and the latter gave me both physical and cognitive/sensory symptoms where the cognitive/sensory just cognitive/sensory - although these days if I have my feet on the floor for too long when sitting that changes that. I think because of those old days where I could definitely tell the difference I would say there is 'central PEM' ie which relates to the malaise bit and then added bits.
I slightly suspect that whilst the physical PEM now hits 36hrs later I used to think cognitive PEM hits faster (because it would be the not being able to wake my brain and body the next day). But when I'm talking physical PEM I'm talking about appointments really so the exertion of travelling to and talking at / sensory stuff etc. and being more upright.
Anyway I guess my point I've realised is that this stuff is really hard. Certainly would take me another time of bit by bit thinking to unpick and think on. Because we can't even really do controlled experiments on ourselves, because there is always somehow some amount of a cumulative and overlapping element.
Kitty
Senior Member (Voting Rights)
Me too.
It worries me that it might contribute to the effects of PEM, because being awake all night fidgeting—not to mention needing a wee every half hour—probably uses up at least as much capacity as whatever set it off in the first place.
these are scrappy bits of thoughts but I've just remembered there is something in the 'load' aspect regarding size of immediate cognitive fatiguability/egg-timer issue and I'm realising that I'm assuming this relates in a straight line to cognitive PEM (but I'm actually not sure)
With regards the load this is where it certainly crosses over with the sensory, and indeed if you were having to stand on one leg or in an uncomfortable sitting positions etc (relevant when eg you look at things like the EEfrt test done in Walitt's study/paper). And I think we are talking about executive function load there. Which I almost think of like a through-gate trying to balance all of the different things going on at one.
Which makes me think of the term 'intensity' and I think it is @poetinsf (?) who has tended to use and underline this term and its relevance for the physical PEM side?
I'm basically drawn by instinct to thinking that intensity has something to do with cognitive PEM
And I've learned over the years that with me often instinct and insight actually do come from somewhere I just need to think it out.
I'll also have a think because I did for example have work from home days when I was moderate where I was doing cognitive work that wasn't untaxing, but was routine in the sense that it was a similar set of tasks with a similar level of difficulty for many months at certain times of years. eg things like reading and assessing. Thinking back I was sort of fortunate that because of the nature of work from home days often being chosen to split the office days I was actually also alternating the type of tasks and probably aspects it was hitting. So it reduced that issue of cumulative load.
There is also the concepts of 'deep' and complexity eg when I used to have to try and do uni work then you'd wait for that day when the brain was fully on and could suddenly lightbulb with things coming together and having great thoughts across papers or seeing issues with something. Other days I could theoretically try and read paragraphs but it wasn't going in, even if I wasn't having to read them 20 times and not remembering what I read at the start of the paragraph.
AliceLily
Senior Member (Voting Rights)
I can only glance over this thread at the moment as I am trying not to provoke worsening symptoms. Feeling better today though.
For me, I think reading and scrolling affect the muscles in the eye, causing PEM?. I remember in my severer years scrolling was just awful, so something about movement as well. I would separate this from cognitive use which is another PEM inducer as well. I'm not sure whether there should be separation though.
Emotions, I try to keep subdued. I often tell people to excuse me from empathizing for too long because it just takes too much out of me due to my illness. I've found I have to be repetitive about this so they will remember.
Regarding the eyes, there is a 'ME look' in some patients. I've recognized it in others and have seen it in my eyes. What contributes to this, I don't know.
PEM always comes with insomnia for me.
For me, I think reading and scrolling affect the muscles in the eye, causing PEM?. I remember in my severer years scrolling was just awful, so something about movement as well. I would separate this from cognitive use which is another PEM inducer as well. I'm not sure whether there should be separation though.
Emotions, I try to keep subdued. I often tell people to excuse me from empathizing for too long because it just takes too much out of me due to my illness. I've found I have to be repetitive about this so they will remember.
Regarding the eyes, there is a 'ME look' in some patients. I've recognized it in others and have seen it in my eyes. What contributes to this, I don't know.
PEM always comes with insomnia for me.
I didn't know if it was worth mentioning, but I've wondered if cognitive PEM might just be prolonged use of eye muscles. At least for me, most cognitive crashes come from activities involving long focus on a page or screen.
I also have felt like I overexert even just from focusing on an audiobook. During these times, I've noticed that my closed eyes are sometimes still tensed up, flitting back and forth, "following" the story.
I doubt this is the whole story, maybe even any of the story, for cognitive PEM, but who knows.
I get it from conversations as well
I don't know how connected this sense is to anything "real", but in the last year I've increasingly thought that the subjective experience of exerting is the most reliable indicator of whether an activity will cause PEM for me, separate from how much 'energy' is used. One example is responding to a text message - if one comes in while I'm looking at my phone and I'm able to fire off a response immediately, there's no impact even if I write hundreds of words. However, if I come to it later, and find myself thinking "I really should reply" - bam, I'm hit with brain fog, shaking of muscles, heaviness of legs, etc etc. This happens with the physical too - I'm fully bedbound, but sometimes feel compelled to press my feet against the foot board of the bed to stretch out my ankles or calves. Impromptu, that seems to be fine, but if I think "I should do this today as I haven't yet" and then go ahead and do it, I get symptoms.
Like so much about this illness, I think this sounds a bit fanciful.
Like so much about this illness, I think this sounds a bit fanciful.
With the caveat that discussions on this thread are speculation, though often backed by personal experiences, I have some ideas.
First, about exertion. Its about energy demand. Cognitive, physical and emotional exertion will increase energy needs, driving increased mitochondrial energy requirements. I strongly suspect that at some point our mitochondria do not respond adequately. This is where I put the trigger for PEM, at least with my current thinking. The debate is still raging on why this is happening though.
Further as the brain engages more and more it recruits more and more areas of the brain. So larger regions are more activated. With consequent higher energy demands.
Sleep is not a passive process. Its an active process, at least biochemically. Sleep is induced biochemically in an orchestrated sequence of chemical releases. Its heavily reliant on all sorts of chemicals, including PGD2, or prostaglandin D2, which is derived from long chain omega 6 fatty acids. A shortfall of any of these processes might leave people wired and unable to sleep. Disruptions in the regulation or duration of sleep might mean its much less restorative.
First, about exertion. Its about energy demand. Cognitive, physical and emotional exertion will increase energy needs, driving increased mitochondrial energy requirements. I strongly suspect that at some point our mitochondria do not respond adequately. This is where I put the trigger for PEM, at least with my current thinking. The debate is still raging on why this is happening though.
Further as the brain engages more and more it recruits more and more areas of the brain. So larger regions are more activated. With consequent higher energy demands.
Sleep is not a passive process. Its an active process, at least biochemically. Sleep is induced biochemically in an orchestrated sequence of chemical releases. Its heavily reliant on all sorts of chemicals, including PGD2, or prostaglandin D2, which is derived from long chain omega 6 fatty acids. A shortfall of any of these processes might leave people wired and unable to sleep. Disruptions in the regulation or duration of sleep might mean its much less restorative.
Jonathan Edwards
Senior Member (Voting Rights)
Yes, I doubt that would be directly relevant to ME/CFS but there might be a lesson in there somewhere.
On a related note, maybe 25 years ago I proposed on a science forum that mitochondrial oxidative stress, and in particular a lack of glutathione, could result in misfolded proteins. A protein encoded in the nucleus is imported unfolded into the mitochondria, and folded there. If something interferes with that the mitochondrial protein, particularly if it requires disulphide bonds, would result in accumulation of misfolded proteins. More recently it became a possibility that if mTOR is more active in some of us, we might fail to remove the misfolded proteins. Its also possible that lack of activity might drive synthesis of even more proteins, resulting in more misfolding, and without fixing the issues.
This does not fit with the spontaneous temporary remission many of us have experienced though.
Peter T
Senior Member (Voting Rights)
When I was still working, a colleague I did a lot of joint work with used to say she could see in my eyes the point in time, usually in the afternoon, when my useful contributions were about to dramatically slow.
Utsikt
Senior Member (Voting Rights)
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/
Yes to the above. If you want more to read there have been studies on heat shock proteins (HSPs) and ME/CFS too. HSPs are important to protect celluøar proteins from external stressors and avoid structural degradation (they got the name from heat stress, but are also activated by other types of stress).
The idea is a bit like exercise (which also increase ROS): If the body can deal with it builds back stronger, but the system can be overextended.
Kitty
Senior Member (Voting Rights)
Two of my colleagues could warn me when I'd gone over the line. I don't think there was a big difference in my ability to work; what they were seeing was "wired" setting in.
It was only after my former manager described it to me that I was able to recognise it properly myself. I'd begin to talk more, with more animation, and my focus would tend to jump around. He said the nearest comparison he could make was to someone who'd taken cocaine, though not as extreme as that.