Thursday, February 10, 2011

The Neurobiology of Insomnia - How I Learned to *Start* Worrying and Love Orexin

The sleep and insomnia literature is vast enough to make one... well, overwhelmed.  New textbooks, then, can be a nice resource.  But textbooks are a bit of a gamble - some are fantastic, and others are disorganized and hideously boring.  Like the one I'm reading now.  But I spent some $$ and I'm powering through. (Today we're in chapter 7, pages 68-82) 

Insomnia.  There are various types.  Chronic, acute, secondary, primary.  And then there are the sub-varieties- difficulty getting to sleep, difficulty maintaining sleep, early awakening, and non-restorative sleep.  10-20% of the population has chronic insomnia, and the societal costs are huge (poor productivity, car accidents, mood disturbance, irritability, poor academic performance, tension, headaches, and GI problems, to name a few.)

A quarter of those with chronic insomnia have primary insomnia.  That is, these folks just don't sleep well for no particularly good reason.  EEG and neuroimaging findings seem to suggest a general case of hyperarousal.  Like being on cocaine without the cocaine (cocaine intoxication would be a cause of secondary insomnia).  High cortisol levels, high CRH response to stress.  Elevated alpha and beta wave "power" and diminished delta wave power.  Primary insomniacs are alert, and there's no two ways about it.

Serotonin, norepinephrine, dopamine, and histamine are all now thought to be wakefulness-promoting neurotransmitters.  These neurotransmitter concentrations will be highest while awake, low during slow wave sleep, and lowest during REM sleep. 

Sleep promoting neurotransmitters include GABA and adenosine.

Acetylcholine is seen in wakefulness, but also thought to promote REM sleep.  Activation of cholinergic neurons by GABA seems to initiate REM sleep in rats.

But now let's break up the activities of our new friend, orexin.  Orexin if you recall is a neurochemical responsible for promoting appetite and wakefulness made and released in areas in and around the hypothalamus.  Fibers from the orexin neurons reach out to innervate most brain regions, including the brainstem, cortex, and spinal cord.  Orexin neurons discharge regularly during wakefulness, and sputter to a stop when our EEGs start to slow and synchronize during sleep.  They begin to fire again in short bursts prior to waking up.  Orexin excites almost all the wakefulness-promoting neurons (acetylcholine, dopamine, norepinephrine, and serotonin neurons).  Narcoleptic dogs in research seem to lack some orexin receptors.   

There is quite a bit of evidence that various types of stress affect orexin.  However, the effects can differ depending upon the type of stress (cold vs. immobilization, for example), or age (old vs. young rats - presumably shivering and/or tied up in these experiments).  CRH, corticosterone and the gluococortocoids seem to increase orexin.  This will increase wakefulness and increase appetite.

Whew.  I'm exhausted already.  A bit of different music today (Pixies, Where Is My Mind).

Classical depression is often linked with insomnia.  Seems that stress steroid hormones induce orexin, which induces wakefulness.  Orexin will jack up serotonin (and the other wakeful neurotransmitters), which will then (if all is going well) induce negative feedback on orexin.  But say your serotonin machinery isn't running efficiently in the first place.  So you burn it out with too much wakefulness, then you don't have the negative feedback.  So you end up awake and grumpy.  This is one theory of depression.  I'm not sure it holds water, entirely, especially as depression promotes sleepiness OR insomnia and weight gain OR weight loss.  But between the different neurotransmitters and the different negative feedback, issues with any one of those systems could cause issues with sleep, mood, and appetite.

By the time you are depressed enough to be suicidal, your orexin levels in the CSF will drop.  Maybe at this point your hypothalamus has just plumb given out.  Who knows.

Tying it all together:

Primary chronic insomnia is thought to be mediated by hyperarousal.  Stress seems to activate CRH, which activates orexin, which will leave you watching the Home Shopping Network in the wee sma's.  Over time, your entire neural network will get exhausted, and your serotonin and dopamine depleted, leaving you without negative feedback to shut down the orexin, and thus exhausted, hungry, and depressed.  Good night!


  1. Thank you so much for this post. It has helped clarify why my depression seems linked to sleep and food. If I restrict food I am bolstering orexin which then bolsters neurotransmitters, resulting in alertness (insomnia), motivation (obsession), and protection from depression (mania). Bracketed words describe an unfavorable outcome, or when things are too far gone.

    I think in depression, melancholic kind, what's going on is an overactive stress response, triggered by a physical or psychological event. This results in abnormalities in how the brain uses energy and hyperarrousal. Glucocorticoid driven hypometabolism in some parts of the brain, with hypermetabolism in other parts, results in a depressed mood. Simultaneously, the excessive stress response causes alertness, lack of appetite and insomnia. If this hyperactive stress response persists, you get death of brain tissue, loss of brain matter, and psychosis (psychotic depression, features brain changes and loss of brain volume as in schizophrenia). There must be a genetic predisposition to respond to stress with this syndrome, most people will not have this happen to them even under prolonged stress.

  2. The longer rambling version...
    It's funny, I was JUST thinking about the neurobiology of insomnia when I went to go check my blog subscriptions, and viola a discussion all waiting for me. I'm a bit psychic like that (I get visions & flashes of things which later happen, weird but whatever).

    I used to have really bad primary insomnia. This was caused by me undereating and being underweight plus psychosocial stresses. If I eat too little calories for too long, I start getting insomnia. I also get very obsessive/compulsive. If I merely restrict carbs but eat a lot of calories, I feel normal and motivated and content. On the other hand, if I go too far and start restricting extensively, getting underweight, then I become overly wired and mentally wracked and can't sleep.
    5 or 4 years ago when I was in school I had some horrible insomnia, triggered by intense psychological and physical stress. When I DID have primary insomnia, sedating medication did not help... what did help however were things that suppressed the stress response. If I hysterically cried to release stress, I could fall asleep. I assume the emotional expression would reduce the stress response enough that I was able to finally rest. If I took opoidergic medication like percocet or codeine, I would fall asleep... and taking these medications felt like they were "fixing" what was wrong intuitively speaking. Opioids also suppress the stress response. Trazodone Histamine blockers and meds that affected GABA did not seem to work, they did not "feel" like they helped because I still was sorta lit up from stress, I was just sedated.
    At least in my case, the issue wasn't alertness, the issue is a specific kind of alertness from an overactive stress response. If it was alertness in general, the sedatives would work (trazadone, ambien, histamine blockers like low dose seroquel or benadryl). I would become sedated when I took these things but I still felt wired. What did work, and worked well, were things that specifically suppressed stress in the brain - opiates, emotional expression. Then I could drop my alertness and relax.
    Later on I observed that opiates no longer worked as sedatives and actually seemed to trigger hypomanic symptoms. I think this is the result of my condition worsening (when I graduated, my mood disorder seemed to have become worse in regard to tendency to mania). Recently I had to take percocet and dilaudid for surgery and it made me hyper and disinhibited. It was pretty awful being so lit up while physically miserable, lying in bed with my mind going and going. I remember that first night I was talking to myself and my mind was totally freaked out. Couldn't sleep at all. In the hospital I acted freakishly, I do remember just rambling and crying and doing things I normally wouldn't.
    This was different from my experience with opiates several years ago, where in which if I took them I felt very relaxed and sleepy and not at all high or hyper. The only thing that changed was my vulnerability to mania (which in turn I relate to those years and months under extreme stress not sleeping).
    I think for most people who are not vulnerable to mania, opiates will just make you relaxed and sleepy and feel really good, suppressing stress response. People with any degree of mania might experience increased alertness and excitement., endorphins disinhibit and worsen high dopamine states.

  3. Emily, I like your writings, but why don't you ever mention the word "orthomolecular," for example, as in orthomolecular psychiatry?

    Any comments?

  4. Hi D - "Orthomolecular" is not a word I'm particuarly familiar with - I've normally associated it with naturopathy or alternative medicine, neither of which I am trained in. Looking it up on wikipedia, it seems to be associated with the use of megadoses of vitamins - something I'm not in favor of in general (unless you count vitamin D, which I believe I am fairly conservative comparitively to much of the paleo crowd, recommending testing and supplementation to reach a level of around 50, though preferring sunlight exposure to reach that level). Plain old "nutritional psychiatry" also doesn't quite fit the bill, as I am also interested in changes in environment that could impact mental health.

  5. Hi Emily,

    Would you have any recommendations for a cognitive behavioural therapy for sleep onset?

  6. I've had some patients use the program at (I have no affiliation with that program)

  7. Emily, I too am an MD, and think your blog is wonderful on several levels. As a neurosurgeon steeped in neurology and neuronal wiring and function I am sure you are aware of Russle Blaylock's work on excitory transmitters. Here is my question for you. Aspartame effects on depression seem to be vast and underreported by our collegues. Moreover I am seeing a ton of ALS and MS like symptoms caused by this chemical. Are you seeing the same in psychiatry? This does not seem to just a theory, as many people who have eaten large amounts of aspartame over a long period of time and do not have PKU have been shown to have excessive levels of phenylalanine in the blood. Excessive levels of phenylalanine in the brain can cause the levels of seratonin in the brain to decrease, leading to emotional disorders such as depression. It was shown in human testing that phenylalanine levels of the blood were increased significantly in human subjects who chronically used aspartame. With the omega six excess and low omega three in the diet and the spike of fructose and emergence of statin onslaught to our cholesterol machinery in our brain I cant imagine what aspartame is doing to mental illness prevalence and incidence. It seems like the perfect storm no?

  8. I think you may have written on this before, but primary insomnia isn't helped by assorted tech related stuff like: sitting with a laptop surfing while watching the TV (one gets far sleepier just watching a boring old rerun or a tearjerker than doing same while blogging or reading political or scientific news), and perhaps the LED backlit laptop does something to us (melatonin levels???) when we are peering at the screen until we go to bed...Not to mention reading an eBook on an iPad until we nod off?

    Then (and I was just posting on this), there is the whole problem of people not sleeping in the dark any more. Not only is there light pollution outdoors in suburban and urban areas (street lights, etc.) but most of us now have digital clocks, laptop "sleep" indicator lights glowing, charger lights, and half a dozen other glowing lights around the room. When one wakes up , it's as if one had a lot of nightlights on. How often is anyone in a truly dark room any more? Again, I think you wrote about sleep, dark, and weight awhile ago? Perhaps I read it somewhere else?

    When we go to our family place in the country we have no phone and no broadband, minimal gadgets, and everyone in the family goes to bed when it's dark and sleeps 8-10 hours (perhaps staying up if we have a good video or DVD to watch on the downstairs TV. But after that, everyone just reads REAL books and fatigue from hiking and heavy brush cutting and gardening, etc. usually puts everyone to sleep pretty soon.

    As far as mood related insomnia? Even this can be helped a little by schedule manipulation and a certain amount of beneficial sensory deprivation. We were visiting someone we know in hospital recently, who had been very agitated and depressed and unable to sleep before admission. They were on the same meds they had been on when in their home, but simply NOT being allowed to use a computer, iPod, cellphone, or any electronic gadgets or phone, and having a room where the lights were out at a decent hour, and a regular schedule again, had greatly calmed and helped them sleep. Sometimes boredom and not having certain activities one obsessively pursues can be therapeutic.

    However, that isn't much help to most of us who aren't in an agitated depression, particularly working mothers who just have too much to do, and can't often afford the luxury of just sitting quietly doing nothing and relaxing for a couple of hours before bed (which probably helps a person sleep better).

    In addition to stress, lack of exercise and too much coffee, etc. which people with too much work keep themselves going with, don't help promote restful sleep.

    Finally, one major cause of insomnia that people will often avoid telling their MD about is alcohol abuse: many people who have the habit of drinking in the evening fall asleep promptly, then wake up in the middle of the night and have trouble falling back to sleep for a long time. This can wreak havoc with their energy and their mood.

  9. John - thanks! Always a delight when another MD doesn't think I'm completely off the wall. And I agree with respect to aspartame + omega 6 + fructose + (statins?) = perfect storm. The incidence of low-grade mental illness (mild depression, anxiety, etc) seems to have exploded in the population, especially in the last 20-30 years. Even worse, mental illness has increased exponentially in the young. In the past 10 years, admissions of children to psychiatric hospitals has doubled. And even in Massachusetts, a family has to be in dire straights to get a kid admitted inpatient.

    Retriever - I keep my room as dark as possible (though the moon shining off the snow makes it very bright outside!), and if I drink in the vicinity of bedtime, sleep is pretty much ruined, so I avoid that too.

  10. Well, at least you don't have to be the "Lights Out" Monster for a high functioning autistic gaming fiend (sigh...)

    I have to fight the impulse to go out and try to photograph the moon on the snow or I'd be up all night...I think one problem I've always had since having the kids is that, tho exhausted, it's SUCH a temptation to use wakeful time in the middle of the night to write or work. When I was working for a church, I would work on sermons or lesson plans when the family was asleep if I couldn't sleep. Of course then I'd feel like something the cat dragged in all day...So these days, I try to just keep things dark and boring and resist the temptation to read and write in that beautiful silence and solitude I crave the rest of the time...

  11. Thanks for a wonderful blog.
    I have high cortisol at night, low during the day. The MD at the lab that did the testing suggested using Phosphatidyl Serine, a phospholipid that lowers cortisol. It works. I use 100mgs to start, (at 10p) then when and if I awake at 4am, I take another 50mg, with a slug of magnesium, and I'm good until 7am, when I get up,(easily) to let the chickens out.
    The stuff gave me really vivid speedy dreams for a week or so, I'd start low if anyone tries it.

  12. Emily,
    We are searching for answers for my husband. We live in Cleveland, OH. Is there anyone you would recommend in our area for treatment. He is also in the medical field and has sworn his chronic insomnia is neurological. We just don't know who to see. So excited we found your blog!

  13. I have a question. Do you know why dopamine agonists like Requio are prescribed for RLS, and tend to make one drowsy? It seems odd to me, given that most stuff that acts on dopamine promote arousal.

    1. Of course I meant Requip. Sometimes I don't type well on the iPad. I'm guessing it has to do with which D receptor is targeted.

      I was an English major, haven't taken biology since high school intro, but I've been interested in genopsychopharmacology of late, and am trying to get a grasp on this stuff.


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