You know you’re in for a different type of study when the lead author hails from the Department of Mathematics and Statistics at his University. This isn’t your usual kind of biology. No human subjects immediately needed – just studies and studies and computations and computational. It’s called computational biology and if, Gordon Brokerick and Travis Craddock at Dr. Klimas’s Institute of Neuroimmune Medicine are correct, it’s going to revolutionize our understanding of the human body. Thalamic Mechanisms Underlying Alpha-Delta Sleep with Implications for Fibromyalgia Sujith Vijayan, Elizabeth B. Klerman, Gail K. Adler, Nancy J. Kopell. J Neurophysiol (August 5, 2015). doi:10.1152/jn.00280.2015
This is the first time, that I am aware of, that these techniques have been used in fibromyalgia. They picked a good symptom to try them out in – sleep. Numerous studies have shown that depriving a person of good, deep sleep doesn’t just make them tired – it ramps up their sensitivity to pain as well.
Restoring restorative sleep in fibromyalgia was the object of this computational biology study
This group focused on alpha-delta sleep wave problems. These sleep wave problems were identified in FM over forty years ago. Alpha waves are higher frequency waves that are associated, interestingly enough, with states of relaxation during wakefulness. When they occur during sleep they’re believed to produce mini arousals that pop people experiencing them out of deeper sleep stages. Alpha waves are not unusual; they are present during sleep in healthy people, but the extent of alpha wave “intrusions” found in fibromyalgia appears to be unusual.
These waves originate in the thalamus, a section of the midbrain that is a relay center for sensory signals making their way into the upper brain. Among other things, the thalamus regulates sleep and wakefulness. Several nonsleep studies suggested this is involved in fibromyalgia. A 2014 study, for instance, finding decreased connectivity between the thalamus and premotor areas, could help explain the fatigue present in FM. Increased connectivity between the thalamus and insula, on the other hand, could help explain the pain problems.
Because delta waves are responsible for “down-scaling” the activity of pain pathways during sleep, alpha wave intrusions are believed to create two problems; they’re preventing the brain from turning off the activity of pain pathways and they’re putting the brain more into wake mode – thus preventing people with FM to experience restorative sleep. It’s no wonder people with FM (and people with ME/CFS with similar sleep problems) tend to wake up exhausted.
Since the early study little research has been done on alpha wave intrusions in FM. A 2010 study by Moldovsky, however, found that Xyrem blocked alpha wave intrusions, improved sleep physiology and improved fatigue and pain in FM.
(Alpha wave problems are also found in ME/CFS. Alpha intrusions were associated with increased anxiety in a 2007 chronic fatigue syndrome (ME/CFS) study and excessive daytime sleepiness in major depressive disorder in 2011. In 2014 at the Stanford Symposium Michael Zinn reported finding large areas of the brain with reduced alpha waves during wakefulness. The reduced alpha waves were highly correlated with fatigue in ME/CFS.)
In this study these researchers, each from a different University in Boston, took what they know about how Xyrem affects the brain, how alpha waves are produced, and how the brain in FM is functioning during sleep, and piled all that data into a mathematical model.
Results
The model suggested that the alpha intrusions could arise in two ways: through depolarization of thalamocortical cells or through the cortex depolarizing the entire somatosensory thalamus. Depolarization occurs when the electrical charge of a cell rapidly shifts from negative to positive – allowing an electrical impulse to flow through the cell. When this happens they send a burst of alpha waves into the brain. A similar situation called thalamocortex dysrhythmia is believed to disrupt brain functions such as sensory perception, cognition and movement control in disorders such as tinnitus, neuropathic pain and Parkinson’s disease.
Alpha intrusions during sleep may be leading to increased pain in fibromyalgia
Xyrem was able to reduce the alpha wave intrusions in fibromyalgia and improve sleep. It’s able to affect three electrical currents – in the thalamus GABA currents, potassium leak currents and hyperpolarization-activated thalamic currents. It wasn’t clear, though, which one or one’s were the key to Xyrem’s success.
GABA was a likely candidate. It is the ying to glutamate’s yang in the brain. This feel good neurotransmitter turns the brains state of arousal down. The model, in fact, suggested that increasing the rate of a “GABA current” in the thalamus – in conjunction with other changes – would help stop the alpha wave intrusions.
More surprising, though was the finding that simply reducing the activity of a calcium channel (Ih) or increasing the activity of a potassium channel (Ikl) in these thalamocortical cells was enough to stop them from producing alpha waves.
That’s an encouraging finding since it suggests that a drug need only target these cells to be effective. Since the more portions of the brain a drug targets, the greater chances it will cause side effects, the smaller the target the better.
Another way to get at depolarization problems is to determine what’s causing it in the first place. The researchers believe this depolarization is being driven by over active pain pathways that are overstimulating these thalamocortical cells. Animal studies indicate that pro-inflammatory cytokines Il-8 and IL-1b can cause these thalamic cells to depolarize. The vasoactive intestinal peptide (VIP) – a subject of interest in ME/CFS – can also induce these cells to depolarize as well.
These findings suggest that reducing neuroinflammation, if present, in the brains of FM and/or ME/CFS patients could return the thalamus to normal functioning and give FM and ME/CFS patients bodies the rest they need to heal.
We should know more about neuroinflammation in FM and ME/CFS patients over the next year or two as studies using new techniques to measure it roll out.
I would like to see more studies on xyrem and other sleep meds on cfsme. Im guessing xyrem wont be for everyone so it would be good to have other good alternatives to help improve sleep.
Also xyrem is so overpriced and too regulated that we need other alternatives.
I tried Xyrem when it first came out, perhaps 2007 or so?? My physician who was working on becoming certified in sleep medicine really thought it would be the drug, but I couldn’t sleep on it until manufacturer told me to double the dose, then horrific headaches started, so I stopped it. Been on Ambien since, but I am finding Belsomra really great. You might want to check it out!
Belsomra is something I would like to try but being in australia im guessing it will take time before its allowed here. Glad its working for you. Seems its and miss for a few i have read about who have used it but these are people who have been on benzos long term prior. This might make a difference .
Marilee,
It’s really interesting to me that you find Belsomra to be “really great.” My doc prescribed it for me thinking that I needed something to tell me when to go to sleep–he thinks I need orexins during the day to get me going and an orexin antagonist to settle down at night–but when I read some of the articles online (specifically Consumer Reports) I got cold feet–figured I should try other things first. Very scared of the side effects like hallucinations and suicidal thought.
Another interesting thing related to this article is that since I’ve been wearing a Fitbit HR to make sure I don’t ramp up my heartrate too much, I’ve been seeing what my sleep cycles look like. I’m sure Fitbit’s technology leaves a lot to be desired compared to a scientific sleep study, but the results are amazing. My sleep efficiency scores are between 60 and 70 percent; it’s taking me between 8 and 10 hours to eke out a max of 6.5 hours of sleep. No wonder I wake up exhausted. Much of the time I’m getting well under 5 hours a night.
Thanks for this info!
I read a book early on in my disease (FM) written by a doctor who developed Fibromyalgia. She is a huge proponent of Xyrem. It helped her tremendously, but she did note that it would be extremely difficult to get for most people.
I hate the way FM flips sleeping time. I was very much an “early to bed, early to rise” person. Now I can’t get up in the morning but it’s almost 3:45 am and I’m not tired at all. It’s a vicious cycle really.
Thanks Cort. Very interesting. Many studies have shown that sleeping tablets do not help in the long run with CFS/ME/SEID. It will be interesting if they can develop something that actually targets the real problem, rather than trying to impose sleep onto a damaged system.
Something -whether it’s inflammation or too much signaling – is causing those cells to erupt…If they can just quiet them down….
Diane, if you are still around, I’d be interested in those studies. That was my experience. Klonopin, and ativan (and sometimes trazodone) taken on and off at different periods helped me sleep better (for nine years) but the last time i went off them I never slept right again, and even when they tried having me go back to it, and tried me doing all kinds of other medications. Nothing worked to get restful sleep again. I’m years off of sleep meds now and still trying to heal. I see similar stories in benzo withdrawal groups online of this type of “protracted withdrawal syndrome”
Yes, Gordon Broderick has a really good youtube video at Kilmas’ clinic that speaks about mathematics in biology.
https://www.youtube.com/watch?v=I9NhS_rDfTU
It is difficult stuff but he does a good job putting it in layman terms.
Thanks – I had no idea 🙂
I’d love some restorative sleep for once!!
I use a CPAP so anyone thinking that they might need one, it doesn’t help for our issues. It just provides air for me when I stop breathing due to sleep apnea.
A CPAP is inappropriate for ME patients. Those of us who stop breathing (both in the daytime and at night) do so due to autonomic dysfunction, because the body is not regulating simple things like breathing properly. We need a BiPAP, which is much more sensitive and follows our own natural rhythm rathering than forcing air down our lungs when we don’t need it. I have found my BiPAP to be extremely helpful. The problem is, because I am so hyper-sensitized to pain, to every little breeze or feel of the sheets, because I also cannot regulate my body temperature, I am constantly bothered by the feel of the BiPAP on my face, and so I wake up just as many hundreds of times during the night as I did before it. BUT, my breathing is better and I am less likely to have a heart attack because my body forgets to breathe, and that knowledge helps me relax a little more to get SOME sleep. For those of us with severe autonomic dysfunction, including POTS, temperature regulation, and other problems, the BiPAP is an appropriate way to go. But, it is very difficult to get doctors who are totally ignorant of M.E. to prescribe it, as they are very expensive.
I should point out that all I need is a medication that helps my brain be less on hyper-alert, in conjunction with the BiPAP, and I would do much better. (As I note in another comment, to some extent the combination of a tiny amount of Seroquel and Ativan seem to do that for me decently well, when I can get them prescribed.) Of course, the BiPAP would not be necessary if there were something that could address my brain forgetting to breathe, but I would think that solving autonomic dysfunction would take a lot longer that these quicker partial fixes.
Never heard of Bipap before – thanks for mentioning it.
I had a total of 30 minutes of sleep last night and was in awful pain. I opened my email and there I was being quoted by Cort Johnson. (I’m the sleepless ME person). What a delight! And then to go on and read such hopeful progress in the area of sleep. I need to get me some Xyrem. It feels like I’m coming out of a war zone when the sun rises, like I’m fighting in the trenches all night. Why can’t my body do such a simple thing as sleep?!!!
That was you :). ..That was a very poetic statement.
I know of someone for whom Xyrem has done wonders….and others for whom it has not helped. You just never know.
Xyrem’s big issue is that it is/was used as date rap drug so it’s regulated heavily and is very expensive…
Ha! You’re describing my experience exactly, for 4 nights in the past week….hope is good!!!
I’ve been saved by Xyrem, been using it for almost ten years now. The good, deep, restorative sleep enables me to have a more productive life. The pain is lessened, considerably, and my energy in the morning is healthy. Yes, it is expensive, and very regulated, still, it’s been the only solution to my insomnia.
Thats great its helping. Dont hear enough good reviews. I think the Internet is biased toward bad reviews so makes it hard to work out how effective it is without trying it.
I have been using Xyrem for about ten years. It enables me to have deep, restorative, slow wave (delta?) sleep. I also use a vpap machine, so that apnea doesn’t wake me up, either.
Yes, Xyrem is expensive and regulated, but it’s a life-saver. Wouldn’t want to live without it.
I’m a narcolepsy with cataplexy. I was on xyrem for around 5 year. It did help quite a bit. I stopped over side effects twice. There was a paper that came out recently on non neuropeptide selective orexin-2 agonist. (narcoleptics with cataplexy don’t have that neuropeptide). We don’t have good or restorative sleep. belsomra is an antagonist for hypocretin/orexin. The side effects are largely narcolepsy symptoms. There are also papers out there about baclofen (a muscle relaxant that has been around for around 50 years). baclofen is a GABA-B agonist. I started it last week hoping for some relief with out as many side effects as xyrem. I was able to talk to a patient listed in a case study on Baclofen and Narcolepsy. Just something to think about. I’m just a patient and not a doctor. My wife has fibro so I’d be glad to find out about any thing that helps. Only five days in and at the very least I’ve had better sleep and more physically active during the day. Don’t get me wrong Xyrem was great for me but it was hard on the rest of my family.
How does this help a FM patient? Has your wife tried any of these drugs that you have mentioned?
I would like dr Klimas to have a look at this:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157093/
It really peaked my interest bc/ immunoexcitotoxicity links Cytokines, calcium, Glutamate, etc etc in a way things make sense.
The tests i had, the sleep studies, the only med that helps me sleep is lyrica (gaba agonist), calcium imbalance, Cytokines il1 and 8 (amongst others), alpha intrusions, concussion in early teens, … It’s a long read but so very worth it.
Could You send it over to klimas Cort?
You never know … a few questions may find the answer in this study.
I at least am going to check it out…..If you’re interested in doing a blog on it = please let me know 🙂
I have found that alternating very small amounts of Seroquel and Ativan (and on a bad day, both together) have helped a great deal, although neither are cures to the underlying problem. It makes the difference between whether I am bedridden, or able to complete one or even two tasts per day, which for me is huge. However, local doctors do not want to prescribe them because they are so off-label, even though they are the only things that WORK for me! IT makes me angry that sleep is so obviously fundamental to health and to the body’s ability to heal itself, and yet it has taken this long for anyone to seriously study how to remedy sleep in either FM or ME/CFS, both diseases which entail profound sleep disorders. This would be a simple, if temporary or only partial, solution to a very complex and hard-to-solve problem. IF they could find only one or two things that work for us, at least we patients would have even ONE approved option for a treatment to try, and over time our bodies might start to heal themselves or at least we could be partially functioning without having to wait another 10 years or more for a treatment that is specific to whatever might be closer to the root cause of ME. It is so obvious, it seems like the very least a study team or M.E. task force could do is to take that on and push for funding in that area, which could have very quick, easy, and significant results for so many people. It’s hard not to have a feeling about a lapse of 40 years in the research of this topic, as a patient who’s life was completely taken from them by this disease.
My doctor said that I could not get the sleep medicine because I am on Medicaid – and I’m sure it’s expensive.
I had a sleep study done at a major hospital in my state and they told me that I did not have a sleep problem. They also told me that I didn’t wake up at night. Last night I woke up at least five times, and went back to sleep at 5 am – since that’s the time that I often wake up (or get up if I didn’t sleep at all)
Are sleep studies not accurate when you have fibromyalgia and POTS? It made me feel like they thought I was lying about not sleeping well and waking up during the night.
I have me/ cfs and fm and sleep apnea. Dr Rey prescribed for me remron (mirtazapine) which has helped me as I wasn’t getting rem. sleep study doctor never addressed this only put me on a cpap. Lucky for me dr Rey saw the oversight of the other doctor. I only take 7.5 mg unless I’m having a viral relapse then I take the whole 15 mg. with my insurance it is very inexpensive .
Interesting. My first abnormal test result back when I got sick was a sleep study showing alpha-wave intrusion. The sleep doctor gave me clonazepam for it, which helps some. I wish I could get a full sleep study now to see how it’s doing, but I’m homebound/bedridden. I did get a home sleep study (no electrodes) recently and found I’ve developed severe sleep apnea as well and an APAP has helped a lot with that.
I don’t know but I had to do this sleep home app and get a week to configure the results.
I always thought I slept though the night most nights,but on two nights I work up repeatedly 296 times (and yes I listened and heard myself mumbling about every 10 minutes?) the second time was 87 times wow I thought 5-10 could be possible for my tiredness apron awakening. Also not much deep sleep mostly light, and Rem only recorded on 2 occasions 37 minutes on one can’t think of the other. My quality of sleep was less than 37 compared to a 100…I always believed it had to do with sleep. After my car accident in 2005. I had whiplash which started my sleep issues, then fibro, then caught Mrsa from hospital and full stress was uncontrollable.falling asleep at work during the day numerous times Security would call to wake me up. I do believe we are predispositioned to these illnesses but if we could of avoided the big stresses near peri menopause I was 43 we would be okay. Now my hiuman growth hormone is nonexsistant, my testosterone free and regular lowest my dr. Has ever seen. Came up negative foe ebv but with pretty high tillers IGG…
Very interesting article. It ties in with some information I learnt about the Alpha-Stim. This microcurrent device (ear-clips) increases Alpha waves during the day time and then this helps the brain produce more Delta waves at night. I certainly noticed a big improvement in my deep sleep after using the ear-clips daily. For more information see: http://www.alpha-stim.com/wp-content/uploads/CES_Research/kirsch-insomnia.pdf
Another concern for me is whether the brain wave studies are accurate if one has taken medication. In my case, I don’t believe they were. My first sleep study, I could not sleep so they had me take trazodone and ativan, and my sleep study showed “normal”…that is – no alpha wave intrustion and normal stages of sleep including delta. But I had a wretched night of sleep in my own experience, nothing close to restful. In a later sleep study, i did not take medication, and that’s when it finally showed the severe alpha wave intrusion and not just into my delta sleep but through all my other sleep stages. With many full awakenings too. I didn’t need a study to tell me what i already knew. But what does this mean for sleep studies done with drugs taken? Do the drugs cover up the alpha wave somehow? I’m not even sure the alpha wave is the problem. The drug may (or may not?) have stopped the alpha wave, but perhaps that’s not the problem. It may be the chemistry or (who knows what?) causing the awful sleep and the alpha wave is only a result of it. If this is true, research may be looking at the wrong thing. I’m hoping for more answers that aren’t medications because medication (klonipin, ativan, trazodone) ultimately made me worse and xyrem did nothing to give me restful sleep