Circadian rhythm disruption in [ME/CFS]: Implications for the post-acute sequelae of COVID-19, 2022, McCarthy

Highlights

• Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is characterized by disrupted sleep and activity implicating circadian clocks.
• The incidence of ME/CFS is expected to increase as a result of the post-acute sequelae of COVID-19.
• Biomarker studies in ME/CFS patients implicate Transforming Growth Factor B (TGFB).
• TGFB has roles in synchronizing circadian rhythms in peripheral cells.
• Identification of biomarkers and new methodologies may facilitate progress in the chronobiological basis of ME/CFS.
Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a common and disabling disorder primarily characterized by persistent fatigue and exercise intolerance, with associated sleep disturbances, autonomic dysfunction, and cognitive problems. The causes of ME/CFS are not well understood but may coincide with immune and inflammatory responses following viral infections. During the current SARS-CoV2 coronavirus pandemic, ME/CFS has been increasingly reported to overlap with persistent “long COVID” symptoms, also called the post-acute sequelae of COVID-19 (PASC). Given the prominence of activity and sleep problems in ME/CFS, circadian rhythm disruption has been examined as a contributing factor in ME/CFS. While these studies of circadian rhythms have been pursued for decades, evidence linking circadian rhythms to ME/CFS remains inconclusive.

A major limitation of older chronobiology studies of ME/CFS was the unavailability of modern molecular methods to study circadian rhythms and incomplete understanding of circadian rhythms outside the brain in peripheral organ systems. Major methodological and conceptual advancements in chronobiology have since been made. Over the same time, biomarker research in ME/CFS has progressed. Together, these new developments may justify renewed interest in circadian rhythm research in ME/CFS.

Presently, we review ME/CFS from the perspective of circadian rhythms, covering both older and newer studies that make use of modern molecular methods. We focus on transforming growth factor beta (TGFB), a cytokine that has been previously associated with ME/CFS and has an important role in circadian rhythms, especially in peripheral cells. We propose that disrupted TGFB signaling in ME/CFS may play a role in disrupting physiological rhythms in sleep, activity, and cognition, leading to the insomnia, energy disturbances, cognition problems, depression, and autonomic dysfunction associated with ME/CFS. Since SARS-like coronavirus infections cause persistent changes in TGFB and previous coronavirus outbreaks have caused ME/CFS-like syndromes, chronobiological considerations may have immediate implications for understanding ME/CFS in the context of the COVID-19 pandemic and possibly suggest new avenues for therapeutic interventions.

Open access, https://www.sciencedirect.com/science/article/pii/S2666354622000023

 

My ME seems to be insensitive to changes in my sleep patterns. I do tend to feel worse at a certain time of day, but that could be fairly downstream of the circadian system. I'm guessing that after their research is complete, this statement will still be true: "evidence linking circadian rhythms to ME/CFS remains inconclusive."

 

life long for me. strongly related to health status for me as both cause and consequence.

around y2k i went to what is probably a top medical bookstore in the world. in the whole bookstore, i found one sentence, in a thick book [on sleep i think], that mentioned the existence of reversed phase sleep. looking forward to research. cannot visit link however.

 

Agreed it took me decades (due to my non-supported situation) to work out it is a PEM and over-baseline (ie before PEM gets a chance to hit and you might be made to be over baseline continually, or just trigger adrenaline by going over it enough you've 'pushed through) thing.

Yet I cannot tell you how disturbed I am how much I'm hearing of people with ME/CFS getting sent to sleep clinics. I'm assuming they'll talk of sleep hygeine. Great. That will finish them off if you ignore the cause and don't realise it is a body-recovery mechanism that people have to cycle through or they get really worse. Trigger more PEM on top of the PEM?

 

This is a relief to see. I remember once many years ago and mentioning my various test results to someone in biochem they said that Lightman in Bristol was the person to see. I doubt it would have gone well give all the nonsense surrounding things, but this makes me think of it again and wonder why labs like his aren't driving things forward or at least involved now

 

My personal history and the history of others I have talked to suggest circadian disorders are rare in ME in the first three years, and common after year 10 of ME. This is just anecdotal and needs some kind of formal study I think.

I used to have just insomnia. Then non-24, which many doctors think is only in blind people, or at least they used to. Since then I have experienced two further stages which I lapse into from time to time.

The first is a very aggressive non-24 where the sleep hours advance not by an hour a day, but up to twelve hours a day, more commonly about six hours.

The second is a complete failure of sleep architecture, where I sleep a few minutes here and there and have no discernible circadian structure. I can get severe cognitive dysfunction in this phase, and to an inexperienced observer I might appear in some kind of mental breakdown. Days to weeks with almost no sleep can do that. This is on top of my other ME issues.

 

My personal experience has been that hypersomnia or increased sleeping is a feature of the early stages of ME and the early stages of major relapses. Then as you say disrupted sleep patterns and insomnia come later.

 

Its possible to have hypersomnia and a circadian issue. If you cannot get to sleep except at certain times and then sleep a long time it can be a problem. In my early days I could never seem to get enough sleep, and slept in whenever I could for as long as I could. The insomnia did not seem to be an issue until maybe 10 years into my ME.

 

This is my nightmare. I'm in year 6 and I've had hypersomnia since the beginning. I sleep very well all night, then wake up in the morning, have breakfast, drink my coffee, read some news, then often go back to bed to nap more because of the literal "unrefreshing" sleep (this usually means several hours). Then I force myself to wake up again, prepare lunch, eat, then go back on the couch to nap again because digesting makes me even sleepier. Then I wake up after 1 or 2 hours and I can usually resist the urge to sleep better later in the afternoon and in the evening. Then at night I have no problem falling asleep.

To be honest, I think I could probably sleep all day, I just wake myself up because their are certain necessary tasks you must do!

Not all of my days are like this (way too many though) but I know I could easily fall asleep anytime even on the better days. Usually any time I'm awake is because it is a conscious choice, which is sometimes easier, sometimes extremely difficult.

And I keep hearing this from pwME, @Peter Trewhitt and @alex3619 , that this turned into insomnia for them later and the insomnia was much worse. I guess at least I know about it in advance if it happens but I'm not looking forward to it.

 

My experience has been terrible insomnia from the day I came down with EBV. I don't think I slept at all during the first few weeks of my EBV infection. Since then, I've had shocking insomnia (difficulty getting to sleep, constant waking, difficulty getting back to sleep) throughout the next 23 years.

Worse insomnia is one of the first signs of PEM for me. I sleep even less in crashes or periods of severe PEM.

ETA: I've also never been able to sleep during the day and sleep best after 2-3am.

 

This was my experience too, I had hypersomnia in the first 9 years of M.E. I woke up feeling refreshed, but still needed to nap soon after I ate breakfast, after lunch and then fall asleep early in the evening.

When severe insomnia hit 10 years later (lasted 2 years), I longed for the days I had hypersomnia. I'll take hypersomnia over insomnia any day.

PEM doesn't have much effect on my sleep.

 

Insomnia and sleep phase shift are features for my daughter .
Sleep issues worsened after year 3 , but also as overall health got worse.Quality if sleep has gotten worse too.

Sleep shift has been more pronounced for past 28 months - we have had a weird temporary blip of normality for about 10 then 5 days mid March for past 2 years. Despite trying everything to " keep" normality it flips back again slowly. Currently sleep is between 4-5am and 11am - 12 noon ish.
I thought the genetic expression link to African Sleeping sickness was interesting as this illness is a complete sleep reversal .

We also have insomnia the night before start of period and sometimes the night after it.
Lack of sleep induces horrible itchiness.

 

An addendum of concern having read this through. This seems to be a review of the literature (well isn't new research, I'm not sure it includes all the literature/whether it is selective of papers or what that would be based on), and isolated only to circadian rhythms. There are sections that include things like: "Therefore, fatigue and inactivity in the context of ME/CFS may be both a cause and effect of circadian disruption."

This sort of thing is where design and someone actually taking really good input from the person whose body it is are vital. I have a horrible feeling (given this was under the cognition, mood, motivation type section) this veers into cart before the horse simply due to trying to lump it in with literature in other illnesses on the same 'issue'.

*EDITED this sentence out as I don't know what I meant by it.

I have always said that the amount of rest I need is directly linked to the energy I expend - and not in the way normal people's is. You go over and it needs days to recover. This is like an essential over-ride of any circadian system. Many people's issues are due to an illness not acknowledged having to fit into a world that means they are doing 'coping strategies' ie sleeping when they can because they are always 'over' and never able to rest or limit activity ie be body-led. The idea most can and make a living is almost laughable in current world.

So a nod to 'yeah, yeah, there is PEM' is not the same as really understanding the stages and states of the illness at all. Only those who've had some time out to do the hypersomnia, recover from the cumulative over-exertion and not being able to listen to the body ie spent years giving body what it needs can really be in the position where it is 'clean' re: you not really just talking about one of those.

Now if the result of investigating this was clues to what is going on with the illness great, but when it starts linking back to the same old cliches of just addressing circadian rhythm without realising there is an illness underneath I get... twitchy to say the least. Interesting to find these various genes (even if sample small) but don't assume what they are and mean yet - there is a lot of cart before horse in the illness's history.

 

Looks to be a reasonably thorough overview of the research done into circadian issues in ME though it misses at least one small study from Prof Tate's team that also found signals of circadian problems.

Sleep in ME is definitely an area of research that deserves more attention.

Based on a quick search the author appears to be new to the ME field. Unfortunately it looks like he fell for the myth that ME is a fatigue illness of the consistently tired all the time kind. PEM is mentioned (and confounded with both post-exertional fatigue and exercise intolerance) but not further considered. There's no attempt to explain how PEM would fit into the author's hypothesis of there being a disconnect between brain and peripheral circadian clocks. How would exertion make that disconnect worse? The closest he comes to discussing the link between exercise and circadian rhythm disturbance is suggesting a lack of exercise may make it worse - which may be the case, unavoidably, or this rule for healthy people may not apply to pwME - but either way, "carefully timed exercise schedules" to reset the circadian clock is not a helpful suggestion for pwME.

It also doesn't explain the great mystery of why, for many pwME, the more we rest during the day the better we sleep at night and conversely, the more active we are during the day (independently of timing in my experience) the worse we sleep at night. So it looks like it's not a lack of exercise but exercise (exertion) itself that throws our circadian rhythm out of whack.

I had a period of day-night reversal which re-reversed after light therapy, melatonin and eating by the clock. My "exercise schedule" though consisted of further reduced activity and increased rest. I don't know if the day-night reversal would have gone away on its own anyway. A prior period of hypersomnia did just that, started without discernible cause and finished without one. Now I'm in the insomnia camp. Ugh.

 

This paper signals that more research is yet to come from this author.

 

From memory, sleep is initiated by a complex interaction between 3 systems.

There is one involving melatonin which is set by sunlight in the morning. This is connected to the circadian rhythm which works best if there is a routine to life with set times for getting up and meals.

Then adenosine accumulates throughout the day and causes drowsiness which it reaches a certain level. Since this comes from adenosine triphosphate it must be influenced by the cellular respiration breakdown in ME.

Thirdly, there is a part of the brain which switches it to the stages of sleep. This is the part that is damaged in narcolepsy and fatal familial insomnia.

All these processes are vulnerable to ME directly and to the consequences of having ME. We need imaginative research done that understands ME and can connect our symptoms with what is going wrong. There is a vicious cycle in that ME is made worse by the consequences of disordered sleep but we can get no useful help because the glibbest of "sleep hygiene" is all we are offered.

 

When I investigated this twenty odd years ago there were already something like 15 or more different systems involved. This was before we even discovered the second sleep centre in the brain, in the brain stem. Most of them were suspected of involvement with ME. This needs way more research than it is getting, which is the standard ME story.

We know from African Sleeping Sickness and other findings that sleep is a complex orchestration of things, and is actively imposed on the brain in complex sequences. Its not just relaxing and lights out. Its not even like the brain turns from wake to sleep mode. Parts of the brain cycle off and on in complex patterns, and my understanding of it is not even close to adequate, its almost dismal. For example, it requires adequate synthesis and release of prostaglandin D2, which is impacted by general diet, oxidative stress (glutathione status) and dietary salicylates. Its also tied into other cycles including immune circadian patterns.

It is beyond just complex. Its something we have a bare minimal understanding of.

 

Yep it is funny how so many so qualified can miss the penny-drop moment that it is the equivalent of trying to map a diabetic's various cycles without controlling for the insulin issues/ignoring them. There are probably better analogies. But if light absence is so key it sends a blind person non-24, and everything thinks that is obvious, why is this so hard?

I also wonder, though can't 'construct' exactly why but wouldn't comparing those with ME to blind people with non-24 reveal whether it is cart-before horse on this gross assumption that the sleep/circadian being fixed will fix the health/it's all about training?

 

Any idea of whether anything might have triggered the switch other than time? Mine has been, ironically, only when hygiene is enforced (or short times e.g. recovering from travel or over-exertion), but not to the extent you've suffered by the sounds. I basically got sicker due to it (overdoing things and being forced to not sleep when needed) and sleep did so feel it is a worrying idea that people think its a virtuous circle rather than vicious one.