Sunday, January 16, 2011

The Neurobiology of Sleep

There is quite a bit going on, and I'm not always capable of doing it all with one hand behind my back, especially when sleep-deprived. One of my colleagues had a baby recently, and she asked us when our kids began sleeping through the night. Another colleague, mother of three, said "never." And to some extent it is true - sure, the newborn every 3-4 hour torture phase passes, but then you get teething, and then nightmares/fear of the dark, and beyond that I wouldn't know from personal experience, but let's just say I've got one teething and one afraid of the dark, and I am thoroughly sleep-deprived.

Which wouldn't bother me too much, except that I put on a couple of pounds (darn cortisol) and vanity is a failing of mine. From medical training I'm an old hand at sleep deprivation. Now there are actually laws against the amount of work I did back in the day. Not that I disagree with those laws as a rule - I happened to do my psych consultation service on some of the same floors where the medicine interns wore EEG leads post-call (meaning after being up all day and all night, and rounding on patients in the morning) as part of a study on resident work hours. Turns out they spent a good deal of those post-morning rounds in phase I sleep. Since I'm sure most of you don't care for sleepwalking doctors in charge of communicating vital information about your admission and hospital course, I imagine you are probably in favor of laws controlling medical residents' work hours. You might be surprised by the response within the medical community. They want residents to suffer - they think it makes better doctors. And working crazy hours does build confidence and experience faster than anything. However, I hope it is not terribly controversial to suggest that we not make new doctors at the expense of safety (too much).

Well, sleep! Which I am sorely missing. I'm not young anymore, after all. I have at hand a basic reference for the neurobiology of the circadian rhythms. It is from the supplements from the Journal of Clinical Psychiatry (which I normally throw away, as they are generally thinly-gilded advertisements for the pharmaceutical industry. And this supplement is no different- it came out in 2005, which was right about when Ambien CR and Rozerem were being marketed, and if you read the entire supplement you get statements about how cheap, long-used sleeping pills aren't FDA approved (of course they are not - they were generic long before the current FDA approval process, and who would bother to spend the several gazillion dollars needed for the current FDA approval process for generic medicines?) But, pharmaceutical advertising notwithstanding, the paper I'm referencing is rather too basic to be dangerous, and it is free (with free registration) for everyone, so let's call it egalitarian.


The Human Circadian System and Normal and Disordered Sleep

The neurobiology of sleep is nearly as simple as light and dark. We have, in our brains, right in the middle a bit above our eyes, a little area called the superchiasmatic nucleus. It is an area of about 10,000 neurons that runs our circadian rhythms. Without light stimulus, it tends to fire in a rhythmic pattern in a cycle of a bit more than 24 hours. Light stimulus will reign it in and keep it correlated with our natural light/dark cycles.

Light hits the retina of our eyeballs, which then sends a signal up through our optic nerve directly to the superchiasmatic nucleus. There a dimer of two proteins is made in response to the light - CLOCK+BMAL1 (let me suggest that the scientist who named the CLOCK protein was a tad more poetic than the namer of BMAL1). BMAL1/CLOCK starts the day running by binding the per/cry promoter regions in the nucleus, leading to the creation of the PER/CRY protein complex (there are in fact 2 pers and 3 crys, but let's just call it per/cry for simplicity's sake.)

From here, PERs and CRYs have to bond with other PERs and CRYs to form dimers, or else they are broken down very readily. The dimer of PER/CRY is then translocated from the nucleus to the cytoplasm for daytime cellular activity. All right! Throughout the night, when no new PERs or CRYs are made, the dimers already in the cytoplasm slowly degrade, until light comes again and more new ones are made. Thus the cycle of life and light and dark. That, in a nutshell, is the circadian rhythm.

Under conditions of sleep deprivation, our circadian clock will keep us from getting too far out of whack from light/dark cycles. We will readily sleep in the wee hours of the morning (and in fact major industrial accidents such as the Exxon Valdez crash and the Three Mile Island radiation leak happened at 3-4 am - at least according to my book on chaos and sleep), and yet even if sleep deprived and given ample opportunity, we have a hard time sleeping during the "forbidden zones" of 9am and 9pm.

And what of that famous pineal gland hormone, melatonin? It is secreted in response to dark, and light stimulus (such as checking the twitter feed on the ipad at 3am, or turning the hall light on to quell the 3 y/o's fear of the dark) will diminish melatonin secretion immediately. The human superchiasmatic nucleus (SCN) has a bunch of melatonin receptors (there are very few in the human brain outside this region). Melatonin signals the SCN to cool it and settle down for the night. Melatonin seems to sharpen the natural SCN response to light and dark. Without proper melatonin signaling, light and dark signals to sleep or wake up are attenuated, leading to night wakefulness and daytime sleepiness.

So what to do if you have insomnia? The first thing is to cut out any late night retina stimulators - like TV or internet. Music or low-light reading is probably okay. Our retinas were never designed for HDTV at midnight streaming so much signal straight into our brains (I'm reminded of when my oldest as a baby was awake at night, and my husband, trying to spare me, dutifully took her downstairs and began watching "Three Kings" with her at 2am - well, that Iraqi sun on the big screen TV at 2am did nothing for our baby's ability to sleep, and she was WIRED for several hours.) Do not turn on the lights for a midnight visit to the refrigerator or the restroom. I'm not entirely convinced that complete, black darkness is necessary given our ancestral propensity to sleep under the moon and stars, but as little light as possible is likely ideal.

Get rid of the clocks, too. I don't use an alarm and haven't for many years. If you need an alarm to wake up, you aren't getting nearly enough sleep in the first place.
There is an online resource called "CBTforInsomnia.com" that has an inexpensive program to help with insomnia (I have no connections to this resource and receive no money from promoting it).

Failing that, if you have a condition such as depression, anxiety, or bipolar disorder, sleep is exceedingly important. I'll focus more on these individual conditions in separate blog posts. In these cases I often feel it is prudent to prescribe sleep medicines (in fact, with an escalating mania, especially a psychotic mania, sleep medicines will nip it in the bud as quickly as anything else), but it is obviously not the ideal and is not a long term solution.

My own preferred sleep remedy is magnesium supplementation. I take magnesium oxide (low bioavailability, but easy to find at any drugstore) 250-500mg (depending on how many nights in a row I forget to take it), a lower dose of magnesium citrate, or a low dose of magnesium gel meant to spread on the skin, and I sleep well, right up until one of the children wakes me up. Maybe I should coat them with magnesium too.

20 comments:

  1. Lovely post, Dr. Deans. Thank you.

    I ran across this method for making magnesium water out of Milk of Magnesia, which is magnesium oxide and seltzer or soda water.

    http://www.afibbers.org/Wallerwater.pdf

    I don't know why the "recipe" recommends refrigerating the water.

    I find it very calming and nice. Much less expensive than buying magnesium oxide tablets or gelcaps.


    On getting a good night's sleep, my additions to your nice list:

    I also keep the bedroom a bit on the cool side.

    No phone calls in the bedroom.
    No business work or unpleasant conversation in the bedroom.
    No shoes in the bedroom.
    No television, videos, internet or similar. (I don't watch television at all.)

    An air purifier and carbon fabric curtains keep the air a little more pleasant, and sometimes a negative ionizer or salt lamp. The carbon fabric curtains also help darken the room, as they are black. They can be used as curtain liners.

    A quiet fan when there is distracting noise outside

    Only natural fiber nightclothes and bedclothes.

    Dimming the indoor lights for a period of time before bed, as though the sun were setting.

    Yoga or stretches, prayer, meditation, something to let go of the cares of the day and calm the thoughts, so that one is at peace before retiring.

    Retiring early and at pretty much the same time each night.

    Thank you very much for your blog. It is delightful to visit here.

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  2. thank you - I've been meaning to check out the MOM selzter remedy - mag oxide is only a few dollars for 120 pills at the local store so I haven't blown through my bottle yet.

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  3. Thank you for exploring this. Would you consider looking at the following studies to see how they might fit with this and perhaps address in a future post?

    Biological rhythms, higher brain function and behavior

    Upper airway resistance syndrome is a distinct syndrome

    Sleep disordered breathing and hypotension

    Association of low blood pressure with anxiety and depression

    Effect of anxiety and depression on blood pressure

    N.B. The symptoms list for UARS describes me almost perfectly except for not being Asian heritage and since I live alone, I don't have confirmation about snoring, restless legs, apnea, etc but don't perceive that I do/have those issues.

    Sorry these are only tangentially related to the topic. I couldn't find an open thread or contact email address to submit for your consideration as a blog post.

    Thanks-

    chronically hypotensive (70's sys)and extremely sleep deprived

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  4. Addendum:

    There is a free software program called f.lux which when installed, changes the light wavelengths of your screen to mimic your local natural daylight/night light cycles. I have it on my laptop, and it doesn't interfere with reading. There is a way to temporarily disable it if you need to work with full screen brightness during the night.

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  5. Perishedcore - very interesting links! I have purchased a textbook on sleep and mental illness, and there are a number of subtopics of sleep... so there will definitely be more posts (the third link is not functioning, by the way). I had not realized that UARS was associated with hypotension, though there are some parasomnias that are (I believe). Interesting connection with depression and anxiety too. I actually check a lot of blood pressures (myself) in my office and I rarely find anyone with raging hypertension, though my population will tend to be younger and perhaps healthier than who shows up in a typical primary care doctor's office. I don't generally check for orthostasis (no table, just a chair) though I suppose I could do sitting to standing.

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  6. Thanks for your response. Sorry for the link fail - cut and pasted incorrectly - trying again:

    Sleep disordered breathing and hypotension

    No behavioral interventions or meds have touched this (delayed sleep, frequent awakening and early awakening = <4 hrs sleep x years)

    However, agomelatine is supposed to address both depression and sleep wake cycles, so maybe it would be of use?

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  7. Agomelatine is brand spankin' new - blitz of academic papers though so I imagine some marketing to follow. Interesting mechanism (serotonin antagonist and melotonin receptor agonist). I've never prescribed it. Melotonin in general doesn't seem to work for the toughest insomniacs, though I've seen it work great for brief interventions and phase sleep issues due to shift work or travel.

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  8. Excellent post, Dr. Deans. I've been following your blog for some time, and love the combination of evolution, nutrition, and mental/physical health issues.

    I was wondering if you could briefly elaborate on the possibility of supplemental melatonin down-regulating our own endogenous production? T.S Wiley's book "Lights Out: Sleep, Sugar, and Survival" warns of this very thing, yet I cannot find a reputable study reference to it.

    Personally, I have had very limited success (and rebound insomnia) with melatonin in the past, but had had great sleep success with Mg (citrate and aspartate) and GABA.

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  9. Dr. Dean

    Have you explored the use of vitamin D taken at night in doses of at least 2000iu's to help with sleep. I started supplementing this way about a year and a half ago, and my sleep improved tremendously. Not only quicker to achieve sleep, but deeper and more intense dreams, which as long as no nightmares is wonderful.
    I read somewhere there was a D3 and melatonin connection somewhere, but now I wonder bout the circadian rhythms and d3 peaking at night when the sun goes down somehow stimulating sleep.

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  10. Great post!

    I was very fortunate to have an infant (now age 12) who was an unusually long, deep nighttime and nap sleeper from age 7 wks until about 5 or 6 yo (I won't gloat, because now he won't fall asleep until very late and try to sleep until noon, which is driving me nuts).

    Most of my sleep deprivation in the past decade+ has arisen from what seems like the world's longest perimenopause phase plus hypothyroidism that was undiagnosed for at least several years (I'm now 49 yoa). Compounded progesterone cream applied at night has helped my sleep, as has splitting my natural desiccated thyroid hormone dose to take 1/3 at bedtime (to prevent intense and recurring coughing attacks, which I think is a form of hypothyroid-induced apnea).

    Like you, I also take supplemental magnesium in the evening or before bed (seems to have stopped the occasional lower leg cramps, too), and since last spring I've used the transdermal magnesium oil or gel lotion. I really like the transdermal magnesium for alleviating jet lag. I also installed the f.lux software on my computer to alter the monitor light a couple years ago.

    With tweaking the details you mention in your post, and the progesterone and small nighttime dose of T4/T3, I've been able to improve my sleep immensely over the past 3-5 years, but it requires continual attention to maintain.

    The past two weeks, though, starting about a week after I experienced a distal non-displaced clavicle fracture from a hard fall on ice onto my shoulder, I routinely wake around 4 or 5 am. I don't need to wake until about 6:45 or 7am during the week, so this regular waking pattern is annoying after I worked so hard to achieve restful sleep patterns. Sometimes I'm able to get back to sleep, but too often I'm not. I am sleeping with my arm in the sling (with a strap around my lower ribs), so that does restrict my ability to change sleeping position somewhat. I only needed OTC NSAIDs for a few days after this fracture, but even if I now take an OTC ibuprofen before bed, it doesn't seem to make any difference with the 4 or 5 am waking, so I don't usually bother. I wouldn't say I wake in pain, but I do wake feeling stiff and with an awareness of my shoulder injury (and really wanting to roll over onto my preferred side, which of course, isn't possible). And I'm also probably not sleeping as deeply, because I'm again aware of my husband's snoring, something I'd been sleeping through for most of the year or so prior to my injury :-).

    I've never broken a bone before, but I have no reason to think it isn't heal well. I'm consuming lots of homemade bone broth, GF and mostly grain-less real foods with ample natural fats, complete protein, and produce, plus I'm supplementing with Vit C, magnesium, trace minerals, and I maintain a good 25 (OH)D level.

    Do you have any idea why this fracture, which isn't especially painful if I keep my shoulder fairly immobile (day and night in the sling/torso belt, which isn't too tight) and don't try to overuse/overdue the ROM exercises for the lower arm, would cause me to start regularly awakening too early, and always around the same time? I'm stumped.

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  11. Hi Anna,
    Glad to see you reading Emily's blog. Sorry to hear about your injury. Being a learning and memory psychologist, there is one thing that comes to my mind to explain your early waking post-injury. It is possible that you woke up at the earlier time on the first few nights after sustaining the injury to your clavicle. Once this pattern occurs, even after only 2 or 3 early wakings, your system might start to become entrained on this new cycle. That is, a mixture of Pavlovian conditioning (or habit learning, a form of instrumental conditioning) and/or entrainment of your circadian rhythm may have occurred. As for a solution, not sure how to do it but you need to retrain yourself to wake at the preferred time, which in part may involve methods to train yourself to fall back asleep after your early waking. Hopefully Emily will have good suggestions on how you might achieve this. Best of luck!

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  12. Hi everyone,

    Just a heads up: Milk of Magnesia isn't Magnesium Oxide but Magnesium Hydroxide. The difference is significant from a digestive perspective. Oxide won't loosen stools for most whereas Mg Hydroxide will when taken per bottle directions and still sometimes will when taken as the seltzer drink described.

    My need for magnesium appears to be pretty high and for whatever reason, magnesium oxide doesn't do the trick. Magnesium citrate is a powerful stool stoftener for me even at low doses (ie 100-200 mg per day).

    While it's pricey and I hate to spend $$ on it, I finally gave in and purchased Jigsaw Health's time released magneisum dimalate formula. Depending on a variety of factors, I take 250-1000 mg per day in divided doses. It's very helpful in keeping me sleeping well, has reduced muscle tension, eliminated muscle cramps (at night and during the day), eliminated a problematic cardiac arrhythmia and has been, generally speaking, very calming overall. Oh! And if I take the 1000 mg doses (divided) for 3 days before onset of menses, I have literally no cramping--none. Pretty cool stuff!

    Best,
    Katherine

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  13. Phosphatidyl serine can be helpful in restoring the integrity of the hippocampus, which plays a role in regulating circadian rhythms. And of course adrenal adaptogens like eleutherococcus, ashwagandha and panax ginseng will also help modulate cortisol output (which in turn affects melatonin). But more important than anything else in my experience is managing blood sugar. Blood sugar fluctuations throughout the day will torpedo the cortisol/melatonin rhythm faster than anything else.

    Thanks for the great article!

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  14. Katherine, thanks for the correction. I thought it looked "off" when I typed the post.

    I take magnesium citrate from Source Naturals, and have been happy with it.

    Yes, the MoM/seltzer water does have that special effect sometimes.

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  15. Here in France we have 100 mg magnesium oxide tablets that dissolve in water to form a non-carbonated drink that tastes like a sweetened, watered down milk (kinda like Calpis if you know it). Its a delicious way to get magnesium and perfect before bed.

    Does anyone know if this this available in the states?

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  16. Great tips, Dr. Deans. In my experience, darkness is very important, but a cool temperature is equally important (for me, <65F), and waking up in the morning and immediately getting lots of bright light and some exercise is also helpful.

    Chris

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  17. Dr. Horvitz - I find your experience with D3 at night intriguing, mostly because everyone suggests taking it midday is best (to emulate midday sun exposure) and I know I've read that some people may experience insomnia with D3 at night, but I've never seen any data either way. I'll have to look more into that.

    Anna - I don't know for sure, but I do know that musculoskeletal injuries seem to release (my personal theory, anyway) a lot of nasty cytokines into the system, so that I see plenty of people after injuries or bone surgery with recurrences of depression. It seems that inflammation might affect sleep as well (or be part of conditioning).

    Thanks Chris, Chris, and Katherine, as always, for your comments!

    Anomadic - that's interesting to know, as I did read a study as part of my magnesium series that demonstrated that the bioavailability of mg oxide in the effervescent tablets was quite robust in humans - I googled looking for some but couldn't find any available. What is the name of the French tablet, if I may ask? I'm always looking for cheap products that are just as effective.

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  18. Emily,

    That's very interesting. I certainly feel like the effervescent is working better than the capsules.

    It's called Juvamine Fizz Magn├ęsium.

    Here's a link :

    http://www.maboutiquesante.com/magnesium-vitamines-b6-b2.html

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  19. Sorry, mike, I didn't mean to ignore you! I do wonder about melatonin and down regulation. I'm going to look into it as part of this series.

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  20. Emily

    The vitamin D I use and suggest for my patients comes in a dropper form, containing d3 and olive oil. I theorize it gets absorbed quickly peaking vitamin d levels within an hour of supplementation. I am trying to figure out the quicker time to sleep and the vivid dream scenario, which has occurred in a large number of my patients.
    So perhaps the dropper form is responsible for the nighttime dosing as opposed to mid afternoon dosing?

    Steven Horvitz, D.O.

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