Pathophysiology of sleep disturbances/unrefreshing sleep in pwME?

[rapidboson]

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.

Interesting angle! As an analogy, would you in that case contribute e.g. impaired working memory with running out of RAM to process/save new information? Though the brain surely is more complex than this analogy would make it sound.

Do you know in which sleep stage this complement-mediated forgetting happens?

 

[Jonathan Edwards]

As an analogy, would you in that case compare e.g. impaired working memory with running out of RAM to process/save new information?

Yes.

Do you know in which sleep stage this complement-mediated forgetting happens?

No idea.

 

[rapidboson]

There was just a presentation of the "Sleep-Neuro-Path" study in Germany. More info here. Will share some screenshots of disturbances they found in (if I understood correctly) studies done before this new study. Seem to have found a difference in sleep spindles in NREM2 and will now look deeper into it and additionally check brainstem signals (arousals).
Very interesting stuff.

 

[rapidboson]

Here are the screenshots - I hope it's OK to share them here. Papers in preparation it says.

So they seem to have seen decreased sleep spindles in long COVID patients. Some potential correlations to ACE2-AAbs and serum MDA.
Will be interesting to see the bigger cohort where they will in addition to the thalamo-cortical network also monitor brainstem (HRV, arousals etc).

 

[Nightsong]

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.

Is there any broader evidence for the role of complement in sleep-dependent memory pruning in humans? - in mice there is e.g. the Wang et al demonstration of the engulfment of synaptic components by microglia & that boosting CD55 prevented C1q/C3 tagging & protected memories from microglial pruning.

There's some evidence that certain signalling molecules (complement, ephrin) are affected by sleep deprivation (e.g. in Lucey et al (found C1q/C4-pathway proteins upregulated in CSF after one night without sleep) & Reis et al (showed blunted nocturnal C3a after 24 h wakefulness), & some additional evidence from studies of mild TBI. It's an interesting idea - also reminds me a little of the famous REM-dreaming Crick-Mitchison hypothesis (or, if you go well back into medical history, to William James).

 

[Jonathan Edwards]

Is there any broader evidence for the role of complement in sleep-dependent memory pruning in humans?

I don't think so. I think the data are from mice, as you say.

 

[Jonathan Edwards]

Zhang et al. pulled out three genes related to adenosine metabolism and apparently adenosine is important in sleep pattern. Alleles cover risk for insomnia for instance.

 

[rapidboson]

Has anybody made some pragmatic observations in the meantime?

I've got hold of baclofen, clonidine, and agomelatine and have been trying them out for a little while. No blinding yet.

To me, all of them subjectively improve sleep onset.

Sleep maintenance is drastically increased by baclofen 25 mg and also somewhat by clonidine 75 mcg. Both increased my deep sleep significantly (measured with a polar verity sense and sleep as Android). I wake up significantly more refreshed, and on some days, I dare even say I feel somewhat rested when waking up. This, in my experience, improves the first hours of the day, and as expected, it does not fix all symptoms of my ME.

Agomelatine 25-50 mg has both caused weird nightmares and sleep paralysis, but I'm still waiting and seeing whether these are side effects that subside after a couple of weeks. I have also felt constipated.

None of these has caused drowsiness or anything alike in the mornings.

I will, down the line, decide which of these medications to test for a longer run (~ 3 months) to see if and how the effects change over time.

I am not sure about the combination of these medications; in theory, they all have different modes of action, but who knows?

Wondering if clonidine might negate possible positive effects of agomelatine on fatigue (see other post) due to the reduction of noradrenergic signalling, while agomelatine could maybe enhance it through 5-HT2C antagonism? Interested in hypotheses.

Any other experiences?

 

[wastwater]

 

[Jonathan Edwards]

Interesting that Younger should be talking about orexin.

I am more and more thinking that there may be a close analogy between narcolepsy/cataplexy and ME/CFS as immunological processes.

I actually think the cataplexy is almost more interesting - it can make someone completely paralysed in a matter of seconds and then get back to normal in minutes, all as a result of being pleasantly surprised! I think it emphasises just how little we understand about the way the brain controls muscle activity.

 

[V.R.T.]

Interesting that Younger should be talking about orexin.

I am more and more thinking that there may be a close analogy between narcolepsy/cataplexy and ME/CFS as immunological processes.

I actually think the cataplexy is almost more interesting - it can make someone completely paralysed in a matter of seconds and then get back to normal in minutes, all as a result of being pleasantly surprised! I think it emphasises just how little we understand about the way the brain controls muscle activity.

Just anecdotally, I have episodes of temporary paralysis when I crash, and I know others do too. My partner who is also a pwME has episodes where she falls asleep very quickly in the daytime that do not feel to her like the regular feeling of getting sleepy and taking a nap. She has never been evaluated for narcolepsy.

 

[Jonathan Edwards]

Just anecdotally, I have episodes of temporary paralysis when I crash, and I know others do too.

I think this may be quite important. A number of people report 'paralysis' when severe. Such paralysis is not strictly speaking a recognised feature of ME/CFS, unless perhaps you include it in ICC criteria. But perhaps it really is a key feature, even if the tip of the ME/CFS iceberg.

It might also be relevant to dystonic movements that also seem to be a feature of ME/CFS and some chronic pain problems but are not strictly in criteria.

 

[V.R.T.]

I think this may be quite important. A number of people report 'paralysis' when severe. Such paralysis is not strictly speaking a recognised feature of ME/CFS, unless perhaps you include it in ICC criteria. But perhaps it really is a key feature, even if the tip of the ME/CFS iceberg.

It might also be relevant to dystonic movements that also seem to be a feature of ME/CFS and some chronic pain problems but are not strictly in criteria.

Interestingly i began to have paralysis episodes when I was still mild but beginning to deterioate a bit, but only in very bad crashes. Much more frequent now of course.

I get the dystonia too.

What makes you speculate that it is a key feature?

 

[Jonathan Edwards]

What makes you speculate that it is a key feature?

Key in the sense of a key clue to what may be going on - because it is unexpected.
It also has implications for the 'FND' pseudo-diagnosis the focuses on 'inconsistency'.

 

[hotblack]

I get the dystonia too.

I’d never heard of this. But weird muscle ‘tremor’ or ‘shakiness’ that gets worse when moving is something I get when particularly bad. Quite common for me in summer. I was lying there watching my muscles in my legs move in little waves just a couple of days ago. And discussing nuances and interpretations with my Parky mum. So really interesting to come across the term and others experiencing similar.

 

[V.R.T.]

Key in the sense of a key clue to what may be going on - because it is unexpected.

Do you have any idea what it could indicate?

 

[Utsikt]

I think this may be quite important. A number of people report 'paralysis' when severe. Such paralysis is not strictly speaking a recognised feature of ME/CFS, unless perhaps you include it in ICC criteria. But perhaps it really is a key feature, even if the tip of the ME/CFS iceberg.

It might also be relevant to dystonic movements that also seem to be a feature of ME/CFS and some chronic pain problems but are not strictly in criteria.

N=1, but I’ve had several episodes of temporary paralysis that takes hours to gradually subside.

I also have gotten many episodes of feeling like someone just pulled the plug out of the drain in terms of how much energy/pep I have. It usually only happens when I push for many hours, and it caused a couple of almost crashes when driving during the first months of being sick. I think I tries to explain it as being under many Gs at the time.

 

[Jonathan Edwards]

Do you have any idea what it could indicate?

It could indicate that, l ike cataplexy, ME/CFS is mediated by an interaction between T cells and specific brain areas near the hypothalamus. Orexin might even be involved but there must be more than just orexin involved even for narcolepsy/cataplexy. And orexin-based neurons might do various things and be susceptible differentially to different immune errors.

My general rule for spontaneous immunoregulatory diseases is that they all arise from uniquie anomalies related to specific mis-steps.

That means that we may find different diseases involving several shared elements to causation but equally they will have key differences.

 

[V.R.T.]

It could indicate that, l ike cataplexy, ME/CFS is mediated by an interaction between T cells and specific brain areas near the hypothalamus.

How would one test this hypothesis? Is it something that can be measured somehow or would it be a therapeutic experiment?

That means that we may find different diseases involving several shared elements to causation but equally they will have key differences.

Do you mean several different ME/CFSes or different diseases like ME/CFS, narcolepsy and cataplexy all sharing the same mechnism?

 

[Jonathan Edwards]

Do you mean several different ME/CFSes or different diseases like ME/CFS, narcolepsy and cataplexy all sharing the same mechnism?

The latter.

How would one test this hypothesis? Is it something that can be measured somehow or would it be a therapeutic experiment?

It might require therapeutic intervention of the sort Younger hints at.