Pathophysiology of sleep disturbances/unrefreshing sleep in pwME?

Thanks for sharing your experience. I experience the same. Do you take gabapentin regularly? Have you tried any other medication - if so, how were the results?

 

No need to be a Dr. or PhD!

I honestly have not been able to fully go through it, but yes - sleep is very complex and amongst others is important for protein homeostasis.

 

I got some insights from the PI of a couple of these studies:

 

I've been thinking more about this, and while waste removal and cellular repair might be an important function of sleep, that doesn't mean that's the cause of why or how we perceive the feeling of being rested or not rested. I expect there's a lot of common knowledge of sleep that arose a long time ago (ancient Greece?) that simply hasn't been challenged, and will turn out to be wrong. So, we can't rule out microarousal architecture as the cause of ME's "unrestful sleep" symptom.

I'm not going to jump on it as a likely cause though. It doesn't match what I'd expect to see from different lengths of sleep or changes in sleep conditions, etc.

 

Could you elaborate on what you'd expect to see (and with whom)?

 

I'd expect the severity of the "unrestfullness" to vary a lot more with different factors. If the symptom severity was due to lack of the restorative functions of sleep, it should consistently get worse the longer since the last sleep. I've had several nights of insomnia, yet I didn't feel significantly less rested even after several nights.

My actual productivity doesn't seem to correlate with the "unrestfullness" symptom. I can awaken feeling unrested, yet manage to get a lot done that day, so the feeling doesn't seem to correlate with actual physical reduction.

Foods can significantly affect my sleep length and number of awakenings, yet doesn't correlate with the unrestfullness symptom.


When we learn something new about how our bodies function, it's sensible to ask "can this explain this disorder?". I can imagine that microarousals could affect the feeling of rested vs unrested, but I'm just not seeing evidence supporting that. My personal experience points to "unrestful sleep" being caused by some factor unrelated to sleep.

 

I am not hypothesizing that "symptom severity" was due to this. I am questioning the pathophysiology of unrestful sleep and questioning whether this symptom can't be tackled adequately by specifically addressing the differences seen in PSG.

Again, if infraslow power and microarousals play a role, we're talking about things you would not perceive. We are not talking about anything you perceive during the night.

I think we're running in circles, let's keep it here

 

Can those differences be addressed? Are there methods for intentionally altering microarousal rates, or power of certain signals in the brain? If there was simple method to do that, then the hypothesis of these factors affecting restfullness could be tested. If there isn't a method available, it's not worth arguing about whether it would be useful. The R&D required might be lengthy and expensive, without any evidence that the result would be helpful.

Unless there already exists a way to intentionally modulate those brain signals (Scalp electrodes? Sounds?), an alternative approach would be to test these brain signals in a wider range of people, such as ones who awaken exceptionally well-rested, and others who feel unrefreshed yet don't have other ME symptoms.

 

I came across this on SciDaily: https://www.sciencedaily.com/releases/2025/05/250508112739.htm It's about a study on protein levels in the blood from sleep-deprived subjects vs controls. It was only a small study (16 young men), so nothing to get too excited about. However, that's the type of study that could be expanded to study the effects of various brain activities during sleep, such as microarousals, on body functions (protein levels, etc). That could then be checked for correlation with reported restfulness. Maybe there could even be blood markers for restfullness.

I had another thought on the subject: perhaps there are animals that have much stronger microarousals or patterns that would make good test subjects for the effects of those. Animals that sleep in secure locations might have less need for microarousals than animals that sleep out in the open (deer for example). I thought of that on noticing a deer bed. How often during sleep do they need to process their sensory information for signs that a predator might be sneaking around? Maybe the effects of microarousal disruption might be easier to detect on them. Alternatively, they might have mechanisms to counter the effects of disrupted sleep, which could potentially be turned into something to help humans with sleep problems.

 

Do we know why we get reverse sleeping?
My pattern is sleep 4/5am through to 12/1pm it does change about at times (such as if I get a migraine and sleep all day, or am woken up a lot and go to bed early rather than nap).

So my sleep has reversed, fine, I can cope with that, I made myself so ill trying to change it, it’s not too inconvenient (to me, it’s outrageous to GP/hospital etc if you ask for afternoon appointment, god forbid!)
but why am I stuck in this pattern?
Why this pattern and not another?
What keeps bringing me back to it?

 

I just came across a news item about a way to measure tinnitus severity: ( https://newatlas.com/aging/tinnitus-test/ ).

"As the condition becomes more severe, the body becomes increasingly hyper-vigilant in assessing perceived auditory threats – which triggers alertness (pupil dilation) and other detectable involuntary movements."

Seems logical that that would affect microarousal architecture. So, another possible test for the hypothesis would be to look for a correlation between tinnitus severity and refreshment from sleep. I'm not sure that a poll about tinnitus and "unrefreshing sleep" would be helpful, since both are personal judgements (unless tinnitus is measured with this new technique).

 

Same for me.
And for many patients

I know cortisol levels are reversed during the day for many ME.

Something hormonal?

 

Many of us have it, you’d think there would be some biological evidences?

 

I am actually not sure that waste accumulation or damage are established. There is a lot of talk about waste disposal and glymphatics recently but I am doubtful that any of it is very well validated in humans. Waste products are generally cleared via blood vessels within seconds or less I am not sure what damage would mean or that we have any evidence of that.

Sleep seems to be important for forming memories but an important part of that may be forgetting. Sleep may serve the function of erasing useless information from short term store while securing useful memories. In the past I have wondered whether the problem in ME/CFS may be a failure to 'forget' material from yesterday. Hence the interest in complement regulatory proteins since complement is apparently necessary for this forgetting process.

I don't think there is yet a real consensus about the functions of sleep. All we know is that without it we function increasingly badly and in the disease where sleep becomes impossible, death supervenes.

With data on genes relevant to synapse formation coming out from e.g. Zhang et al. I suspect we may begin to understand what the sleep problem is all about in ME/CFS fairly soon.

 

Do you think it's likely that we may then be better able to pick off individual symptoms like this with better targeted drugs even if we don't quickly get the 'one ring to to rule them all' drug that tackles ME/CFS at its root cause?

 

No idea, I tend to think not. But then I have always gone for the jugular.

 

I'm not sure either. For me poor sleep is a symptom of ME/CFS, and it's probably going to be an issue until the whole syndrome is tackled.

 

This is facinating to me because my OCD has gotten so much worse as my ME has progressed, and that often feels like an inability of the brain to sort of 'forget' facts or memories that most people would be able to, and so the brain keeps sort of scanning or interrogating them over and over, hence rumination.

And many people on long covid forums and support groups report worsened or new onset OCD type symptoms.

I wonder if these OCD symptoms could be somehow related to this process of celluar forgetting you describe. In addition, when I get PEM from stressful films and tv, or heavy music, it often sort of feels in the moment like my body is both responding excessively to stimuli but also cannot sort of move past or dismiss said stimuli.

Incidentally, my OCD began to be quite debilitating at the same time I developed insomnia.

My sleep problems started at 19, and I first got noticable PEM at 26 after strep. But I think I either had POTS or a prodromal form of ME during those years as I suffered from dizzyness, depression, dpdr and lost my youthful energy. I was also studying literature, which requires very little in person teaching compared to say biology, and when I worked it was casual bar work so very flexible. So if I had very mild ME it may have done unnoticed.

My point is that my poor sleep, if not linked to ME per say, was definitely linked to some biological process going permanently awry within me.

 

I don't know—I have the same thing with almost the same timings.

But it's interesting, and possibly unusual enough to be useful in a treatment trial. Not everyone has this kind of reversal, but for those who do it might serve as a marker of improvement after treatment.

I'm only making a note of it here because I always forget about it when we're discussing questionnaires. Other people might have better memories!

 

Pharmaceutically, I believe there is reasonable evidence for certain drugs to be able to modulate this. Also within the 'inverted u' for sleep microarousals of the Lüthi paper I linked various times. Selectively through deep brain stimulation or something like that, I have no idea of.

Drugs that, based on my understanding of the literature, could address potential sleep fragmentation seen in some of these studies on pwME could be (non exhaustive): clonidine, baclofen, gabapentinoids.

I'm not a clinician, but I would like to see tests done with these medications purely as sleep adjunctive medications, i.e. taken solely before bedtime. My current understanding is that these medications are normally taken throughout the day and I wonder whether (quicker) tolerance buildup might over time lead to diminished returns in regards to sleep quality improvement in people taking these medications several times a day.

FWIW, I have obtained some baclofen to test one of the possible pharmaceutical solutions on myself. Unblinded and not placebo controlled surely, so take it with a grain of salt. Tried it 3 nights so far at 25 mg and have consistently seen more time spent in deep sleep as measured by the polar verity sense + sleep as Android. I have noticeably also woken up less often at night and more rested in the morning. Due to it being "open-label", I cannot rule out placebo at this point, so I am working out a way to placebo control myself.

Thinking about making two preparations of my night medications in opaque containers and randomly selecting one of the two (taking the meds without checking). The next morning and throughout the day, I will note my feeling of restedness. In the evening I will check my sleep data of the previous night and unblind the previous night (to reduce potential bias of waking up to "YOU'VE SLEPT AMAZING. Check out your sleep score and have a wonderful day"). I will then prepare my night medications again and start over.
This will only show me rather short term effects of the medicine though. Better than nothing, but I would really like to see longer term data of having modulated sleep.

Maybe, if in this short term test baclofen consistently gives me better restfulness, I can opt into a longer term test - potentially seeing diminishing returns due to tolerance and/or accumulative improvement of unrestful sleep.