[special post] correlating sleep depth and inflammation

this paper talks about the relation between proinflammatory cytokines (IL-6 and TNF-a in particular) and sleep. this paper does not suggest any causal relationship between the two, only highlighting that they are related to each other. this was also the first paper on sleep and inflammation that i read and i found it so intriguing. but we now know that sleep does affect cytokine levels, and cytokines levels also affect sleep, but there is one main question that i can’t answer: if inflammation makes a person get more NREM sleep, shouldn’t he or she be more energetic after it? but why do my friends complain about lethargy?


Sleep depth and fatigue: role of cellular inflammatory activation
KaMala S. Thomas, PhD, MPH, S. Motivala, R. Olmstead, and M.R. Irwin


In summary:
This paper examines the association between cellular expression of proinflammatory cytokines, alterations of sleep depth and daytime fatigue, and looks at interleukin-6 (IL-6) and tumor necrosis factor a (TNF-a) more specifically. 31 men and women were studied for 3 days in the sleep lap to get data on their sleep patterns. Blood sampling was conducted to measure the levels of inflammatory markers and they tried to correlate the two. It was found that an increase in IL-6 production was positively associated with rapid-eye movement sleep.


Point 1_________________________________________________

Proinflammatory cytokines are associated with a cluster of behavioural symptoms known as sickness behaviours. These symptoms, which include fatigue, sleep disturbance, depression, loss of appetite, and inability to concentrate, are common in individuals with medical conditions involving underlying inflammation.

The first time I saw “sickness behaviour”, I thought a lot of the symptoms paralleled those I experienced (it’s elaborated a lot more in this entry about depression). I can’t really recall fatigue, since I was so low spirited back in those days. Sometimes I feel like it’s the depression that sucked away all of my energy. My sleep was definitely disturbed, and the inability to concentrate? I’m not sure if that’s arising from my constantly itchy skin or not. My appetite got much larger though. It’s a bottomless pit as I recalled. I’m just saying that I share the same symptoms, but whether or not it’s due to the surge of proinflammatory cytokines in my body, I do not know. And I probably never will. HOWEVER, I think it’s useful to use these deviations from the normal as a gauge to see where we stand, and where your friends and families who are NOT going through TSW stand in terms of their health. Afterall, a lot of underlying inflammation that leads to serious problems do not show itself early on in their developmental stages. We can only observe our state of the health from subtle things like these to make a guess about our health.


Point 2_________________________________________________

Prior studies have found that increases in circulating levels of IL-6 correlate with decreases of slow wave sleep (SWS), as well as increase in the amount and percentage of rapid eye movement (REM) sleep and REM sleep density. In addition, stimulated production of IL-6 mixed cell cultures is associated with increases in REM sleep amounts and percentage.

IL-6 is a proinflammatory cytokine, and it’s increase has been associated with a decrease in slow wave sleep. Slow wave sleep is the deepest sleep stages, it’s also the stage that allows the brain to recover from its daily mental activities. Being deprived of SWS would mean your brain doesn’t get enough rest! In addition to the lesser SWS, IL-6 increases REM sleep amounts! So.. more dreams, less quality rest.


Point 3_________________________________________________

1. Evening stimulated monocyte production of IL-6 was associated with less SWS and a longer REM duration. Production of IL-6 was unrelated to stages 1 or 2 sleep, total sleep time, sleep efficiency, time to sleep onset, REM sleep, REM latency or REM density.

2. … participants in the lowest quartile of IL-6 production spent 11.3% of total sleep time in SWS, compared to 2.5% of total sleep time among those in the highest quartile of IL-6 production.

3. … REM duration was 10.6 minutes amongst participants in the lowest quartile of IL-6 production, compared to 22.5 minutes among those in the highest quartile of IL-6 production.

4. … increased evening production of IL-6 was associated with fatigue, and this relationship was mediated by shorter SWS. … REM duration was unrelated to fatigue.

1. Evening stimulated IL-6 production only affected slow wave sleep, which is stage 3 of the NREM, as well as REM duration. All the other parameters were unaffected.

2. Comparing the amount of time spent in SWS between the upper and lower quartile, the upper quartile only spent a quarter of the time that the lower quartile spent. => IL-6 reduces SWS.

3. Comparing between the upper and lower quartile of IL-6 production, the time spent in REM sleep by the the upper quartile is almost twice that of the lower quartile. => IL-6 increases REM sleep.

4. One possible mechanism for the increased production of IL-6 being associated to fatigue is through the decreased SWS duration. REM duration does not affect fatigue.

So I can spend the entire night dreaming and that would not make me feel tired the next day as long as I get sufficient SWS.


Point 4_________________________________________________

Given that the first sleep cycle is generally dominated by SWS in normal sleepers, our findings may reflect a shift away from SWS toward more REM sleep in participants who have high proinflammatory cytokine expression.

I think it’s quite cool that we can now draw some idea about our inflammation levels within our body by observing our sleep. Any deviation from the norm may suggest that there’s underlying inflammation that we’re not addressing.


Point 5_________________________________________________

Psychological stress may be a key factor predicting increases in IL-6 production and alterations in sleep architecture. It has been well documented that chronic stress is associated with increased sympathetic nervous system (SNS) activity as well as a greater production of proinflammatory cytokines. … increased nocturnal SNS activity is associated with a reduction in SWS and an increase in REM sleep. Taken together, these findings suggest that heightened nocturnal SNS activity, possibly due to stress, may lead to increased production of proinflammatory cytokines, which may alter sleep stages.

I had to google what on earth is SNS. Well, it’s the fight or flight response in the body in response to stress. Acute stress increases our cortisol and plasmas cytokine levels. Chronic stress blunts our cortisol levels in the long run as our body adapts to the new state of affairs. As a result, the anti inflammatory cortisol levels are not high enough to bring down the counteract the cytokines. What we get is then a proinflammatory profile. It was found that the body’s response to stress at night is associated with a reduction in SWS and increase in REM sleep.

So long term stress may lead to a proinflammatory profile, which leads to lesser quality sleep, and eventually fatigue (and you feel worst from the bad sleep). Such a bad cycle!!! Gotta take care of stress at its root! And if not, tackle it with other methods like meditating and exercising, otherwise it’s a downward spiral to never ending stress.


Point 6_________________________________________________

Our findings extend research on proinflammatory cytokines and sleep architecture beyond circulating cytokine levels to examine relationships between sleep architecture and cellular cytokine expression. Given that circulating cytokine levels can come from sources other than immune cells and may not necessarily be indicative of immune dysregulation, our findings provide further evidence that increased proinflammatory cytokine activity resulting from immune dysregulation plays an important role in regulated sleep stages.

Initially I only highlighted the second sentence which says circulating cytokines may original from other sources other than immune cells. In my mind, I was thinking “perhaps, just maybe, if it’s even possible, that our skin cells release so much proinflammatory cytokines into our blood stream that led to so much weird symptoms”.

But that’s all in my head. I have no way to prove it. It would be interesting if we can investigate the cytokine levels in our blood during TSW, because as far as I know, the cortisol level is pretty normal. Previously I was so hung up on the effects of cortisol on our state of the skin, but now I’m starting to divert my attention elsewhere.


Point 7_________________________________________________

… circulating markers of inflammation (C-reactive protein) was linked to greater fatigue among healthy individuals who participated in the CARDIA population based study. Additional, the current findings suggest that a reduction in SWS may be one pathway through which inflammation leads to a reduction in general health and fatigue in healthy individuals. … Given that inflammation was associated with fatigue in both studies, these findings highlight the deleterious effects of immune dysregulation on general health and well being otherwise healthy individuals.

I really like this paper because it showed me how sleep architecture can be used as a way to gauge how inflamed I am. It’s not just about the inflammation on the skin, but rather, inflammation INSIDE the body. I’m not sure about you all, but I believe that all chronic sickness are all due to chronic inflammation. Cancer, heart problems, diabetes, EVERYTHING. It has to be noted that inflammation presents itself in many different forms. It’s not all about itching, swelling, and turning red. At the very heart of inflammation is cellular destruction. In the short term, it’s good because inflammation helps our body recover from any damage it received. But chronic inflammation is undesirable because it sets up the breeding ground for a lot of those diseases I just mentioned. You can read how cancer and inflammation is related here.


Point 8_________________________________________________

This is the first published study to examine associations between stimulated IL-6 and sleep architecture. Additionally, given the correlational nature of this study, we cannot infer that a causal relationship exist between proinflammatory cytokines, sleep architecture, and fatigue.

While this study only studies the correlation between IL-6 and sleep architecture, correlation is NOT causal. It doesn’t mean that IL-6 causes the change in sleep architecture. For all we know, it could be the other way, which was discussed earlier on as well whereby deprivation of sleep will lead to an increase in proinflammatory cytokine production. I know it’s kind of pointless to mention this point right now because it feels like I’ve just wasted time reading this paper when it doesn’t tell me whether or not the inflammation causes the change in sleep architecture. However, I still find this paper to be interesting and useful because we now know that sleep and our state of inflammation is related. With a simple relation, I will then be able to link the state of sleep to the state of inflammation, regardless of the causal nature between the two factors.



Sleep is not created equal. We get our rest mainly from the (stage 3 of the) NREM sleep, and the deprivation of it will lead to fatigue, that’s why some people complain about tiredness even after sleeping for 8 hours or more – if it’s mostly REM instead of NREM, they’re hardly resting at all! Remember it’s quality over quantity!

During my worst TSW moments, I could hardly sleep. And when I do fall asleep, I know I’m in very light sleep because I wake very easily (which is not typical of NREM) and I have so many dreams during those times!!! Waking when I’m having my dreams allow me to remember my dreams easily, and that’s how I come to conclude that my sleep is usually in the lighter stages back then. I’m not sure if it’s the itching that kept me in the light sleep stages, or if it’s just my body’s state of inflammation.

I’ve also had a chance to try out some sleep monitoring apps with 2 other skin friends, I only tried it recently when I’m sleeping normally, but they’re still in the midst of it and their results are vastly different from mine. While I had a normal sleep cycle, they hardly reach the deep sleep stage. Also, they are sleeping much more than I do, but still feeling tired. Something is amiss here.

However, the sleep monitoring app correlates movements to the state of your sleep, so it may be less accurate for our case because I know we will scratch a lot during our sleep, and this doesn’t necessarily mean we’re NOT in the deep sleep stage.

Despite the possible inaccuracy, it gives us a possible view into our body by observing our sleep. Assume the app data to be valid, then this would very much explain for their crazy sleeping (and fatigue)!

If IL-6 decreases slow wave sleep, it doesn’t matter how much longer you spend in NREM due to the increase in IL-1, if you’re not in stage 3 of the NREM, you’re not getting quality rest. And the paper suggested that fatigue is brought about by the decrease in slow wave sleep, which may be why my friends sleep so endlessly because the body is making up for the lack of quality sleep by quantity!

So it’s reasonable to attribute fatigue to our withdrawals, not only are we using a lot of energy to regenerate skin cells and to maintain our body temperature (as we’re giving off so much heat to the surrounding), we’re not getting the rest that we need.

There was one question that popped up when I was reading all these papers. If increase in IL-1 increases NREM sleep time (which should mean you get more stage 3 rest assuming the percentage time spent in each stage doesn’t shift), and the increase in IL-6 decreases slow wave sleep, why is the overall effect of fatigue more prominent? Shouldn’t the shifts cancel each other out?

I think I found my answer when reading the first set of paper.

Image taken from the paper. A) IL-1 beta levels, B) IL-6 levels, D) IL-10 levels. The coloured lines are added by me to indication increments/reduction between the different groups. Pink/red is for normal mice, while blue/green is for psoriatic mice.

Recall this part of the paper, where sleep deprivation will increase the levels of proinflammatory cytokines. The increment of IL-6 is almost twice that of IL-1! I was too fixed on the idea that when they increase, they all increase equally. I was wrong. And the symptoms that I observe are in fact the net effect of the actions of the different cytokines! And who’s to say that each unit of the cytokines will exert the same effect on our system? Perhaps, they all illicit different magnitudes of response, which just makes things more complicated.

I can sleep in peace now. One more question off my mind. Now, I’m going to ponder about the mystery of the universe. (this question puts me to sleep everytime).


11 thoughts on “[special post] correlating sleep depth and inflammation

  1. Hello,
    Sorry I keep asking questions but this is urgent. A few days ago I went to the doctors and he said not to put anything on it cause its damaged from too much steroid. Just now I spoke to a dermatologist and he said its not skin damaged and that its moderate/severe eczema. So he gave me probiotic cream. I’m kind of scared to use it cause he might be wrong and I don’t want to damage my face again.

    Do you happen to know about this cream?
    If so if I put it on tsw face would it damage my face even more? What should I do.. Trust the derma or? Cause I’ve been reading about tsw and I most symptoms apply to me. 😥

    • hello diana!

      hope i replied quick enough, i was busy the entire day and i just saw your comment.

      protopic (not probiotic HHAHAHAHAHHA) is a non steroidal anti-inflammatory drug. they are immuno suppressants when taken orally. i don’t think it’ll damage your skin further because it works a different pathway from steroids. i feel that when you use protopic during TSW, yes, it suppresses the withdrawal symptoms to a certain extent (lesser inflammation), however i feel that it also suppresses true healing. meaning, when you go off protopic in 6 month’s time (it’s not meant for long term usage), your skin will flare and may rebound to an even worse state.

      it’s entirely up to you on whether you wanna use it though. considering you only used steroids for 3 months, the withdrawal period should be much shorter, meaning, by the end of 6 months of protopic use, your TSW recovery should be pretty good already, even if you do go off the drug that time, it shouldn’t flare too badly. and you’ll just continue healing from there.

      if i were you, i’d ask myself – do i have the luxury to let my skin rot and heal? if not, i’ll go for the protopic.

  2. Hi Juliana

    I have followed your blog since the beginning of my TSW withdrawal 21 months ago. Whenever I felt depressed during TSW (which was often… TSW sucks!!) I would turn to your blog and see how you were doing. Often your skin was really great (as you were many months ahead of me) and I had to remind myself that the passage of time would heal. Anyway, my skin gradually got better from months 18 onwards, thank goodness (I didn’t think I could take any more, honestly!) My main reason for writing is that I just wanted to let you know, I recently got a sleep study done as I’m still very tired in the daytime. Main results: night-time sleep study, 15 mins REM sleep, 5 hrs non-REM sleep. A bit more SWS sleep than normal due to the greatly reduced REM sleep (only 5% of time instead of 20-25% as REM should normally be). Lots of awakenings & leg movements in the night. Daytime sleep study: fell asleep at 8am, 10am, 12pm and 2pm within 7 minutes. I found your discussion re: proinflammatory cytokines and REM/NREM sleep really fascinating. Definitely needs to be more research done in this area, there’s so much we still don’t understand.

    • WOW thank you so much tess!!! your results are absolutely interesting! i’m so glad to know that your skin is getting better finally!

      wow, your sleep architecture is so out of whack! sometimes i feel like TSW opens a little window for us to observe how the different chemicals and hormones affect our body and its functions! your sleep lab must be so intrigued by your results! perhaps sleep engineers and scientist will be super interested in studying people like us! have you also done a blood work to have an idea of how crazy your cytokine levels are?

      • I’d never heard of cytokines till I read this post, so I have no idea how feasible it is to do a blood test to check cytokines. I do get regular blood tests though, (basic ones like iron etc) and throughout TSW all my blood work said I was a fairly healthy normal person (even if I felt like a wreck). I get the results explained to me by the specialist in 1 week so I will fill you in on what he said – will be interesting to know if he ever sees people with very little REM sleep. I pulled off the oxygen clip on my finger in the middle of the night of my sleep study, probably from scratching LOL.

        Yes TSW has been a blessing and a curse in a lot of ways. I feel like a bit of a lab rat sometimes with the number of things I’ve discovered about myself – a MTHFR mutation which probably made TSW worse due to something to do with nitric oxide or something or other. But almost 2 years on, I can say it was all worth it. I felt like giving up so many times but so glad I chucked out all the steroids from my home so I could not cave in!!

      • too interesting! i have never gotten my blood checked during those times, so i’m really really interesting in other’s results. if you don’t mind, perhaps you can ask your specialist about inflammation markers (and not the usual things they check for in blood tests like cholesterol, immunoglobin E and.. some other stuff) and whether they tally with a normal person. surely, something must be off the chart of us to be in prolonged inflammation, right? but that’s just my guess.

        hahaha when i see MTHFR…….. i can’t help it, but the word “mother fucker” just appeared in my mind. had to read it two times and then google it to see what it is exactly. hahahaha! :X

        are you sure you have that mutation!? genetics is way too complicated and i don’t deny that it many play a more profound role in answering the question: why are we addicted but not others?

        that’s the right attitude to have! i also threw out all of my steroids once and for all. you have to stay strong!!!


      • Rofl at mother-f. Yes I definitely do have MTHFR, but only one copy of the A1298C. So it’s not life changing for me. Some other TSWers have it too like Tracy S. http://stoppingtopicalsteroids.blogspot.com.au/

        Anyway for me, MTHFR definitely explains a lot of things for me (won’t bore you but basically can’t really process NO… finally this explains why I had such a severe reaction to the laughing gas (nitrous oxide) when having my bub!!)

        The only interesting blood tests I did were homocysteine and histamine. My histamine was quite high but my husband’s was even higher and he has no skin issue like I do. So who knows what it all means…. and when we’ll ever find out or understand TSW completely…!

      • hahahahahha sorry for that vulgar link.. but.. it just made all the right links in my mind to fish that word out.

        holy cow, you guys brought the scientific stuff of TSW to the next level. getting genetically tested is something so relatively common these days but i just never thought of linking that to TSW!

        ahhhh… hopefully having MTHFR doesn’t mean you have a worse time with TSW!!!

        i think it’s gonna be very difficult to try to pin point specific markers for TSW, because it’s such a systemic thing, and there’re a thousand and one things at play at a certain time. looking through such a small window is so limiting. maybe one fine day, we’ll be able to find out all the data points that could help us have a big picture outlook at the entire ordeal.

        hehehe thanks for that laughter btw, i love this MTHFR thingy. next time i’ll just curse something with that, it sounds much more scientific and elegant.

  3. Pingback: TSW: day 31 where are my allergies? did they go off on vacation??? | Minding the Castle

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