Pathophysiology of sleep disturbances/unrefreshing sleep in pwME?

I don't follow your logic here to be honest, sorry. Hope you can help me understand you!

(1) What makes you believe that different sleep architectures between pwME and healthy controls are not "universal"? All the data I have seen these past days point towards a consistent difference. Moreover, the studies I quoted were able to differentiate clearly between the architecture in different diseases such as sleep apnea, the architecture in ME and healthy controls (three different patterns/groups here). Think "sleep fingerprint". It's not like there's one fingerprint that's healthy and only one other fingerprint that's unhealthy. Even within the group of ME, I'm sure different studies found different fingerprints (different measuring methods, patient stratification etc), but there's always a different fingerprint between ME and healthy from what I have read so far.

(2) Yes, we agree, it's likely one of many anomalies, I am not expecting this to be the main cause of ME symptoms at all. Personally, I (so far) see unrefreshing sleep (likely due to altered sleep architecture) as a symptom that's caused by something upstream.

(3) Which is why normalizing sleep architecture could in my view potentially improve quality of life but not be a solution to ME. It might still make people feel better.

 

If there was such a fingerprint, or fingerprints, that uniquely identifies ME/CFS, it would serve as a biomarker. As is, sleep disturbance is not even a requirement for the diagnosis. Will the studies that you quoted change that? Maybe. Sleep disturbance is a common feature of psychiatric conditions, btw. So, I don't think that line of inquiry will be too productive.

As to how universal it is, I guess one way is s4me survey. Maybe someone can point to it if there is one already. If you not, perhaps you can start one?

No argument there.

Strangely, I functioned fine with 2-5 hour sleep with occasional nap for 2 weeks when I returned home from abroad 3 weeks ago. Then I overdid with carwash and biking on the same day a few days ago and I've struggling despite 7 hours good sleep according to my fitbit.

 

On point 3 I’m very worried by all of this because I was tortured by sleep hygiene/those obsessed with if you are forced to wake up at set time every day eventually you’ll sleep at the right time. my health made worse and sleep worsened by these presumptions.

I know for sure that I get to choose (but it’s not really a choice as I quickly decline in health far faster than get if I don’t follow my body in sleep and start depriving it so then end up over tired which makes sleep worse) to either have good sleep but be stuck at the behest of my body with only being aware of my energy threshold being the main thing that can help or PEM or over threshold screws it. Or try and do silly things obsessing over ‘being normal’ and make myself much iller much faster.

I have strong views due to strong experience and have been very scientifically-minded from school age so when I say experiment and observation I mean it.

I’ve met enough others who once releasing themselves from the tyranny of what seems to come from values and assumption also realised that napping as needed and following body was eventually the only way for health and therefore ergo sleep. I think this sleep stuff is back to front.

If you try and prioritise sleep wake times you just also end up with not refreshing sleep at all but some I assume prefer that to be half not with it but on the right time zone rather than I lived in a world where I had to be on it too often. So had to if I needed to get x done then wait til I hit good sleep whenever to then function and complete whatever work needed my brain to be on.

there is something very much more than due to routine going on with the sleep thing.

and I know how light weight the research is on sleep because I was shocked at how it summed up to being sleep hygiene and the 4stages 30yrs ago when I did my degree and even more shocked none really moved past that low level still now. And I can’t help but wonder what blind spots get in the way of the area moving to look into it properly


Clearly we know that sleep is where certain key for health and particularly long term health processes take place like the cleansing of certain things out. And other processes must be happening that allow other parts of the brain to then have renewed function after good sleep. But it seems these measures never take place.

so it’s circular (like other have commented FND claims are) in as far as being sure good sleep = about timings and maybe some subjective surveys or tests of certain sleepiness impacted functions , but people just look at these sand things as both the outcomes as the causes rather than thinking other things are impacting both which if you don’t fix those you are just papering over instead of measuring.

but neurology seems to have an issue with wanting to understand other aspects of the body’s systems. Or really understanding how to design experiments to understand causes vs just assume based on association or approx patterns you don’t know if they are cart before horse or both impacted by something else.

 

I admit that I glanced at them, saw a bunch of unexplained acronyms (SWS, US power, etc), and didn't bother to look them up or continue reading. I just now looked at some papers on microarousals, but didn't notice any clear evidence linking abnormal microarousal patterns and lack of refreshment from sleep. If there's a clear connection, it should be reasonably simple to test whether PWME's "unrefreshing sleep" severity correlates with sleep brainwave patterns. For that matter, they could try to find some people without ME who suffer from "unrefreshing sleep" and see whether brain scans during sleep can reliably diagnose it.

What I read gave me the impression that sleep is really complicated, with a lot of interacting biochemical and electrical systems, and they're nowhere near being able to describe a healthy normal microarousal pattern or an abnormal one. How do you "normalize sleep architecture" when no one knows what normal is? More research needed.

I do wonder whether findings about levels of restfulness of sleep are based on someone judging whether the mice look unrefreshed when they wake up (after sleeping with electrodes stuck to their heads).

 

The studies I quoted are 10 years old, so I don't think they changed anything in terms of diagnostics, unfortunately. I have tried to find hints as to why this research hasn't gone further - as the same group published several papers on sleep from 2003 or so on - but haven't come to a conclusion as of yet. I have reached out to the PI, so let's see if he replies.

Yes, that's for sure. The question though in my mind is "If we can distinguish between different psychiatric conditions during wake time - can we also do so during sleep?" And at least in those studies I checked so far, they were able to distinguish between two (non-psychiatric) conditions. I will have to read more to find my answer.

Are we talking a survey that would inquire about whether somebody has or doesn't have unrestful sleep? As I don't think many people here will have done a sleep study and have access to their raw data? I may be mistaken.

I have made similar observations and have always attributed it to serotonin rebound from sleep deprivation, akin to wake therapy? Unfortunately, it is not sustainable for me and I eventually end up crashing.

 

First off, I am sorry to hear - that sounds awful. I hope you are better now.
Secondly, I am not sure I understand you. What I am saying in point 3 is that I believe if we are able to find the nature of unrestful sleep in pwME and specifically tackle that mechanism, we might see some improvement in quality of life. How does this worry you?

I think think that is very reasonable.

I agree, I don't think this is about routine - but rather about something during sleep not letting us rest entirely. (maybe microarousals, maybe reduced ultra slow delta power, maybe something else entirely)

I have found my thinking along similar lines, especially regarding unrestful sleep in pwME in general. It seems to me like it is widely accepted that sleep is unrestful for pwME, but I haven't yet seen any consistent deep digging.

 

Sorry for that!

Regarding "clear evidence" as in doing a deep dive and scrutinizing data on microarousals in different conditions - I have not done that yet, but from review papers there does seem to be a connection between increase of microarousals - especially during deep sleep (SWS). I found this piece of literature quite the interesting read.

Agreed. Which is what the Le Bon group has done 10 years ago, but it either hasn't gained traction or something else I don't know yet made them stop looking into it. Does not seem obvious to me yet why.

Agreed.

At least the studies I quoted are on humans (healthy vs ME) and use questionnaires to asses restfulness of sleep.

 

Ditto @Trish

 

As in, we might have to distinguish between two concepts in ME/CFS, (1) unrefreshing sleep and (2) poor sleep quality? Do you have a suggestion on how you'd do that? Just for my understanding.

What I currently envision is something like:
1) pwME have unrefreshing sleep (potentially due to imperceptible - but measurable - changes in sleep architecture) as a baseline

2) pwME often also have perceptible sleep disturbances (such as sleep onset and/or sleep maintenance insomnia) on top of the baseline

What I am somehow trying to figure out/look into is part 1 of this - and whether we can't do anything about that baseline?

Same here! Hence me calling this the baseline.

Same again and in my mind this would be part 2, as I subjectively am able to perceive that I slept worse (cause of insomnia, waking up a lot, moving around a lot etc).

 

Ha! Just re read and spotted that first bit is a big error. Apologies - I’ll go back and edit as I’ve missed the bit after the word tortured of ‘by sleep hygiene/those obsessed with if you are forced to wake up at set time every day eventually you’ll sleep at the right time’

it doesn’t just makes the ME and exhaustion worse and things go even more all over the place. So more ill and then more bad sleep and so on in a cycle. Yet people are wedded to it as a concept.

 

I've been thinking about the sleep issue. First, if ME's unrefreshing sleep symptom was due to abnormal microarousal architecture, I would expect much more variation between individuals and for the individual, due to activity, diet, etc.

Second, if that symptom was due to inadequate sleep, shouldn't the severity increase during the day, being longer since actual sleep? Some people report feeling worst upon waking, then getting a reprieve in the afternoon or evening.

As for what the scans mean, the connection to sleep refreshment isn't clear. Questionnaires about such things as personal judgement of a symptom is far from reliable. From what I read, microarousals are a mechanism for creatures to switch between resting and checking whether it's safe to rest (Is that a predator I hear?). The abnormalities could mean that PWME are more stressed due to worrying about triggering PEM, financial woes, etc. Perhaps microarousals are different in unhealthy or less active people in general. That's something the study could have checked. I'm sure there are many other possibilities.

Yes, but the baseline could just as easily be due to chemical ratios in certain cells. There's probably a chemical that would produce a similar feeling, so a person dosed with it daily would fill out the questionnaires the same way without having any actual sleep abnormalities. The perception of lack of sleep isn't caused by lack of sleep; it's caused by an accumulation of chemicals or cellular damage that hadn't been properly cleared by sleep, and that in turn alters other cells' functions, which affects other cells and organs, eventually leading to the perceptions.

I've complained multiple times about the label for the symptom. Having "sleep" in the term biases thoughts in terms of it being a sleep problem, despite a lack of supporting evidence. If the term had been something like "toxic grogginess", the approach to the symptom would be "what is causing it?", rather than just assuming it's a sleep disorder.

 

I'm not sure I'm following your points here, sorry. Would you mind elaborating?
Increased microarousals seems to be one measurable differentiator between healthy people and pwME, that does not mean that it is the (or the only) cause for unrefreshing sleep. In fact, as mentioned before, it has also been seen in several trials that pwME apparently have significantly more SWS than healthy controls - but also seem to lack ultra slow delta waves during SWS.
I am not saying microarousals = reason for unrestful sleep. It seems to be a common denominator amongst pwME - but as of now that's it. It would make logical sense that it could influence restfulness.
Non-restful sleep is also not the same as excessive daytime sleepiness.

I definitely have experienced that. I don't see how this would be an argument against sleep architecture disturbances though?

Correct. I am not aware of an objective measurement for feeling rested or not - I have not looked into it either. I do not think questionnaires are useless though.

That is one hypothesis, yes. Other hypotheses include an active role in glymphatic circulation for example, as discussed in the paper I linked you to previously. As of now, I don't think it is fully known.

I don't think you can see microarousals as a singular aspect. From what I read, the consistent findings in studies that measured are increased MAI, (paradoxically) increased SWS and reduced ultra slow delta power.
Stress for example is known to increase MAI but decrease SWS. This is not the same as what they have found in the trials I mentioned.

Do you have any proof for this statement?

 

Besides looking for anecdotal reports, I would really love to discuss literature here and jointly come up with hypotheses based on said literature. Hoping for more people to chime in - ideally people that are more knowledgeable about sleep architecture than me!

 

To add to Sleep complexity, I want to add the anecdote of patient Martin and his temporary semi-remission after extreme sleep deprivation. I have been in contact with him so I know the story is legit. He is (very) severe again.

https://www.healthrising.org/blog/2024/07/31/martin-chronic-fatigue-syndrome-remission/

there is some interesting comments on sleep (specifically from a commenter Cristoph D) you might want to check out @rapidboson
- includes some links to papers on sleep, although not Specifically ME CFS

“either CFS patients alone or BOTH CFS and FIBRO patients, to me, seem to be experiencing glutamate excitoxicity which awakens them somewhat out of Delta Phase sleep into phase 3 or 2 or 1… or completely. It’s not a lack of duration asleep as much as a deficit of that time being in Delta brainwave Sleep. Delta does not include rapid eye movement nor dreaming, nor memory consolidation. It is strictly the autonomic brain resetting receptors to homeostasis and orchestrating healing”

“Furthermore, the worst feature of non-restorative sleep us that all receptors are intended to be reset to baseline to start as “innocent” tomorrow morning, but the sleep is interrupted or kept out of Delta Phase restotative sleep to an extent, and the receptors awake “experienced” if you will. If I understand CFS patients correctly, they feel as though they never rested at all.
No reset.”

“Jonas Berquist is studying sleep (OMF funded study) and is – I believe – hoping to find orexins in participants, which are very low in those with narcolepsy and so thought to be the cause. From my own experience, I’m convinced this is going on with me but I don’t know how much it determines the persistence of my ME.”

 

If restfulness is eroded by time since sleep, then unrestfulness should increase throughout the day. Also, if our sleep is failing to reset our "rested" state fully, then it seems logical that our unrestfulness should increase each day. Instead, I feel that my sleep does reset what it's supposed to, but there's some other mechanism causing the feelings we associate with lack of sleep.

No, I have never studied the biochemistry and biophysics of sleep in depth. My vague understanding of the mechanism of sleep is that being awake causes accumulations of wastes and cellular damage, which is dealt with by sleep.

Sleep is also supposed to be important for forming memories. While many of us do report memory problems, there doesn't seem to be a dramatic loss of memory formation in most of us. You could pose a theory in which the changes in sleep patterns affect the "feeling rested" part without affecting the other functions. That could be a followup study: ME memory problems and brain activity during sleep.

 

Interesting, sounds like something along the lines of what I managed to see in the literature as well. I'm skeptical about "excitotoxicity" being of any significance, but I'll check it! Thanks for sharing!

 

Then please don't make these statements as if they were true, this is a science-focussed forum after all.

 

From what I’ve tried, low-dose gabapentin (around 300 mg) before bed really helped smooth out my sleep, fewer wakes overnight and more deep sleep, so mornings feel way less brutal. I haven’t tried clonidine or baclofen yet, but they might be worth a shot if you can get them.

 

I usually take care to use terms such as "seems like", "might be", etc. Sometimes I miss. There's no "Dr." or "PhD" on my posts, so base your judgement on their value on that.

Was my statement about waste accumulations and cellular damage being fixed by sleep wrong? Incomplete, yes, but I'm unaware of any more important mechanisms of restoration by sleep.