You wake up….luxuriate in that feeling of early morning bliss, yawn, stretch your arms and extend your toes and with a satisfied sigh fall back into the pillows …hmmm…now that was a good nights sleep.
Sleep studies have been pretty unrevealing in ME/CFS…until recently
Those were the days, huh? Now waking up is probably more along the lines of groaning as you try to lift your remarkably heavy feeling limbs. Something definitely went wrong in your big rest and rejuvenate time…
Unrefreshing sleep has been recognized as a major problem in chronic fatigue syndrome for decades; it is for, instance, one of the eight symptoms in the International Definition, but documenting its cause has been difficult to say the least. Some delta wave problems have been found but traditional sleep studies have generally found minor or inconsistent problems in chronic fatigue patients’ sleep and little that could account for the sleep issues found. Several recent reviews of sleep findings highlighted how paltry the findings have been.
A 2012 review concluded that “polysomnographic and other objective measures of sleep have observed few differences in sleep parameters between CFS/ME patients and healthy controls”. A 2011 sleep study reported “While classical sleep studies…. have shown varied, nonspecific changes in sleep structure and efficiency in a subgroup of patients with CFS, these studies have not revealed any substantive evidence indicative of a primary sleep disorder….”
Finally, a 2011 review concluded that “Whilst complaints of non-restorative sleep persist.., there is no demonstrable neurophysiological correlate to substantiate a basic deficit in sleep function in CFS. Polysomnographic findings have not shown to be significantly different between subjects with CFS and normal controls.”
In the absence of significant laboratory findings these reviewers suggested that ‘pyschosocial factors’ caused the poor ‘perception’, but not the reality of poor sleep in ME/CFS. Sleep studies have been so unrevealing that it’s gotten to the point where one of the most enduring and common complaints in ME/CFS was being considered something of a mirage…simply a matter of ‘perception’….
Recently, though, some light began to appear at the end of the tunnel. A 2011 study found no differences in ‘classical’ sleep tests (sleep duration, sleep pattern, sleep activity) or cortisol levels but did find a significant difference in a decidedly non-classical sleep test – a measure of autonomic functioning called heart rate variability. Wyller’s 2011 pediatric study measuring other indices of ANS functioning (heart rates, blood pressure) suggested sympathetic nervous system (fight or flight) activation in chronic fatigue syndrome was occurring precisely when the body should be relaxing and recovering – during sleep.
These studies suggested a) sleep researchers may have been digging down the wrong hole for the 20 years and b) a measurable physiological problem was occurring and c) problems with ‘perception’ could not account for the sleep issues reported by ME/CFS.
The Study
In this small study researchers analyzed a variety of heart rate variability (HRV) measures during sleep to see if ME/CFS patients were different from controls. They looked at HRV measures during different stages of sleep and broke out sleepier patients from non-sleepier patients to see if they were different.
Results
This study found no significant changes in sleep architecture (time spent in various stages of sleep) between ME/CFS patients and controls but found significant changes in all heart rate variability measures between the two groups during sleep.
They also found reduced sleep efficiency and reduced total sleep time in the chronic fatigue syndrome patients. When they looked deeper, they found that patients who felt sleepier had a ‘higher fractal scaling index’,, which is believed to indicate increased sympathetic nervous system activity, in Stages 1, 2 and 3 sleep compared to controls.
Discussion
Heart rate variability tests are believed to provide a ‘mirror’ of the ‘cardiorespiratory control system’. Since the heart rate is a function of parasympathetic and sympathetic nervous system inputs, researchers can use HRV to see if the two are in balance. Increased sympathetic nervous system functioning or decreased parasympathetic nervous system functioning can cause increased heart rates and reduced heart rate variability. Reduced HRV has been associated with increased cardiac risk.
Micro-arousals Getting You Down? The researchers believe the higher fractal scaling indices they found in the sleepier ME/CFS patients suggest ‘micro-arousals’ undetected in traditional sleep studies may be hampering sleep in non-REM periods. With regards to treatment they mentioned Clonidine, an SNS inhibitor and PNS booster (and glutamate inhibitor) as a possibility. Other options are available and we’ll be covering those in an upcoming post.
One study suggested stress or pain wasn’t keeping ME/CFS patients from getting a good nights sleep; it wassimply sympathetic nervous system activation
In one of the earlier HRV sleep studies,Vollmer-Conna et al. stated they believed the heart rate profile found in ME/CFS was indicative of a ‘hyper-vigilant, inflexible physiological state’ probably caused by poor vagal nerve functioning. (The vagus nerve controls parasympathetic nervous system (‘rest and digest’ functioning.) Interestingly, neither stress nor pain – two commonly ascribed reasons for poor sleep – appeared to have any effect on sleep quality in their study. Instead, heart rate variability values indicating increased activation of the sympathetic nervous system had occurred did.
This suggests something that’s been a long time coming in ME/CFS; it’s not ‘stress’ but the ability of the system to tolerate stress. The SNS is activated by stress (and exercise and other events) but if you’re really sick you don’t need to be under a particular stressor to throw your HRV measures off; you simply need for your sympathetic nervous system to have become (and stay) activated.
Heart Rate Variability Explained (Don’t worry about the remark about ‘sudden cardiac death’; this refers to patients who’ve already had heart attacks, etc. Low HRV increases the risk of that in those patients )
Back to the Autonomic Nervous System
So we’re back to the autonomic nervous system again. This big homeostatic regulator pumps up our systems when we need to exert ourselves and then puts them into rest mode to rejuvenate us. One of two major axes of the stress response, the ANS controls our heart beat, blood pressure, blood flows and it regulates immune functioning. Keep the stress response on long enough and you’ll have pro-inflammatory cytokines flooding the body. Dr Klimas recently tagged the ANS as the system that initiates the pro-inflammatory cascade during exercise she believes causes post-exertional malaise.
Highlights
- Classical sleep studies have failed to find the cause for the sleep problems in ME/CFS
- Several recent studies suggest low heart rate variability (HRV) could play a role
- Low HRV suggests the ‘fight or flight’ system is turned on even during sleep in ME/CFS
- This enhanced ‘fight or flight’ activity may produce microarousals that interrupt sleep
- Sympathetic nervous system inhibitors such as Clonidine may be helpful
Now it appears that that darned system may be keep you and I from getting a good nights sleep. For all the talk on the ANS, though, what it’s doing in ME/CFS is something of a mystery. HRV tests suggest the fight or flight side of the sympathetic nervous system is turned on but other ANS tests are often normal.
That means there’s alot left of learn about the role the autonomic nervous system plays in ME/CFS and surprises are surely in store. For now heart rate variability testing consistently suggests a system that’s too wired for its own good is in play in this disorder.
Coming up we take look at HRV in another fatiguing disorder and see what it tells us about that disorder and ours and we take a look at different options for reducing ‘fight or flight’ activation and increasing the ‘rest and digest’ mode.
Very interesting Cort. I think ME is primarily a disease of the ANS. But what causes this? A problem in the immune system? Damage in the system itself? A foreign substance? An infection? I think high fever has been damaged this system. Almost everybody with ME has had high fever and infection. The disease may start immediately or after a long period of stress because the system is broken and no longer tolerate this. You become sicker and sicker. The ANS symptoms has an overlap with burnout. In this group, the ANS is not broken but upset. Therefore CBT can help in this group, but not in ME. The system is broken. It explains everything. That’s my hypothesis
Great question Gijs…..You may be onto something with the fever; the Dubbo studies indicated the sickest patients were most likely to come down with ME/CFS. What starts the ANS problemm – darn that would be a good question to answer…
I like the distinction between burnout and system upset with ME and system broken. I’m probably more in the burnout category; my systems not broken – I’m not too weak to work obviously – I’m not any prescription meds – but my system does feel pretty burnout out and little things can burn it out even more.
Hi Cort, There is 1 question left: an active ANS can also serve to compensate for lack of energy by increasing the level of noradreanline. This remains to be scientifically excluded.
Mol Cell Endocrinol. 2013 Mar 26. pii: S0303-7207(13)00108-1. doi: 10.1016/j.mce.2013.03.012. Continuous stress promotes expression of VGF in melanotroph via suppression of dopamine. Tokizane K, Konishi H, Yasui M, Ogawa T, Sasaki K, Minamino N, Kiyama H.
Source
This system can also turn on the ANS. A problem with dopamine.
my me/cfs started straight after my last vaccines at school. my body crashed from that
On my.. that is me… I have cfs/me. I also have Narcolepsy with insomnia..I never relax….nothing works.. haven’t slept well since childhood. The only time u sleep Is when I am anesthized because of surgery.. lol.
Anesthesia…that’s a good one :). Actually anesthesia at the dentist usually both mellows me out and increases my energy levels…How often does anesthesis give you MORE energy. We are a strange bunch…
I can’t have anesthesia with adrenaline which is the normal one, i have to have adrenaline free otherwise i’d be in bed for a week, which has happened a lot before i found out what it was.
As for night sleep, well i don’t sleep well. I spend 8-10 hours a night in bed but wake up approximately every 2 hours. I do take 2 drugs amitriptaline & mirtazipine at night. The list of supplements i take is longer than both my arms stretched out & they all help. I also practice transcendental meditation which also really helps calm down the SNS. I also find cranial osteopathy which also helps. But nothing is a cure so far.
I’ve had ME/CFS since being poisoned in utero, Got FM at aged 10, vaccinated with everything, had tons of viruses & i’m still trying to get well, everyday!
Your info is great, keep up your good work. x
Hi Noreen,
i have suffered from ME/CFS since 1999. I have only recently started getting a good sleep due to my Doctor describing a drug call Naltrexone. You actually get it prescribed as LDN (Low Dose Naltrexone). My sleep and quality of life has improved tremendously. You should look into it. 🙂
Thank you Cort. Great information as always. I recently completed a book on fibromyalgia and found two other factors, in addition to the ANS, that would be involved in sleep disturbance. The first would be the lack of the essential amino acid tryptophan. Tryptophan is needed to produce serotonin and melatonin. Melatonin is essential for a good night’s rest. As the following studies confirm, fibromyalgia patients lack tyrptophan, serotonin, and melatonin. In the following study the researchers found that fibromyalgia patients had a 31% lower melatonin secretion.
Fibromyalgia—a syndrome associated with
decreased nocturnal melatonin secretion.
Wikner, J., U. Hirsch, L. Wetterberg, S. Röjdmark. 1998. Clin Endocrinol (Oxf) 49(2):179-83.
“The FMS patients had a 31% lower MT secretion than healthy subjects during the hours of darkness.”
Melatonin is derived from serotonin. The following study confirms that fibromyalgia (FM) patients have significantly lower levels of serotonin.
Serotonin levels, pain threshold, and fibromyalgia symptoms in the general
population.
Wolfe, F., I.J. Russell, G. Vipraio, K. Ross, J. Anderson. 1997.
J Rheumatol 24(3):555-9.
“Serum serotonin levels are significantly lower in persons with FM compared to those without FM…”
Serotonin is derived from tryptophan. In the following study the researchers concluded that patients with fibromyalgia had significantly lower levels of tryptophan.
Plasma tryptophan and other amino acids in
primary fibromyalgia: a controlled study.
Yunus M.B., J.W. Dailey, J.C. Aldag, A.T. Masi, P.C. Jobe. 1992. J Rheumatol Jan;19(1):90-4.
“Transport ratio of tryptophan was found to be significantly…decreased in PF compared with the control group…Plasma tryptophan level was lower in PF… than in healthy controls… Additionally, plasma histidine… levels were found to be significantly…lower in patients with PF than in controls.”
The second factor would be a dysregulation in the Hypocretin system. The Hypocretin system regulates the sleep/wake cycle. The Hypocretin system is regulated by tumor necrosis factor. Studies show that both CFS and fibromyalgia patients have dysregulated tumor necrosis factor. Following is the title to one such study.
Dysregulated Expression of Tumor Necrosis
Factor in Chronic Fatigue Syndrome:
Interrelations with Cellular Sources and Patterns
of Soluble Immune Mediator Expression
Patarca, R., N.G. Kilmas, S. Lugtendorf, M. Antoni, M.A. Fletcher. 1994. Clin Infect
Dis. 18(Suppl.1):S147-53.
Here is a study that confirms tumor necrosis factor regulates the hypocretin system.
Tumor necrosis factor-alpha regulates the Hypocretin system via mRNA degradation and ubiquitination.
Zhan, S., G.Q. Cai, A. Zheng, Y. Wang, J. Jia, H. Fang, Y. Yang, M. Hu, Q. Ding. 2011. Biochim Biophys Acta. 1812(4):565-71.
“Recent studies recognize that Hypocretin system (also known as Orexin) plays a critical role in sleep/wake disorders and feeding behaviors. However, little is known about the regulation of the Hypocretin system. It is also known that tumor necrosis factor alpha (TNF-α) is involved in the regulation of sleep/wake cycle… These studies demonstrate that TNF-α can impair the function of the Hypocretin system…”
Following is some additional information from my book.
Research has shown that fibromyalgia patients have disturbance of sleep that is similar to narcolepsy (Spitzer, 2010). Excessive daytime sleepiness, which is the main symptom of narcolepsy, is often experienced by patients with fibromyalgia (Himmerich, 2006).
In the following study the researchers found that narcoleptic patients had increased plasma levels of TNF which was suggestive of a “functional alteration” of the TNF cytokine system.
Plasma levels of tumor necrosis factor α and soluble tumor necrosis factor receptors in
patients with narcolepsy.
Himmerich, H., P.A. Beitinger, F. Stephany Fulda, R. Wehrle, J. Linseisen, G. Wolfram, S. Himmerich, K. Gedrich, T.C. Wetter, T. Pollmächer. 2006. Arch Intern Med. 166(16):1739-1743.
“Narcolepsy is a disabling sleep disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis. Recent studies suggest that the immune system might play a pathogenic role pointing to a possible involvement of inflammatory cytokines…Narcoleptic patients show increased plasma levels of sTNF-R p75, suggesting a functional alteration of the TNF-α cytokine system, further corroborating a possible pathogenic role of the immune system in this sleep disorder.”
Some Facebook comments
Rita Gacon -READ. VERY TEMPTED TO SEND IT TO YOU KNOW WHO ???
31 minutes ago · Like
Christine Hill – Thanks so much for this link. I am just in the middle of undergoing tests at hospital so this will be very useful x
Cort Johnson – Good luck Christine..These tests are not that difficult, I don’t believe to administer. They’re simply analyses, I believe, of EEG readings..Darn I forgot to put the video in there….Check back and you’ll see a video explaining HRV tests…
29 minutes ago · Like · 1
Christine Hill– I’ve already had an overnight test with a wrist band and a clip on my finger. The specialist said I had some symptoms of sleep apnoea but not all of them and was inclined to think I was having anxiety attacks in my sleep. He’s still open to further investigations though and I think he will be interested in this. Thanks again x
13 minutes ago · Like
Cort Johnson – Anxiety attacks…maybe that’s his term for microarousals…I’m no expert but I wonder if a small dose of Clonidine prior to bedtime might help with that.
Another great article Cort being so familiar with sleep problems myself. Somehow I think they are beginning to understand it now. From what appeared to be narcolepsy once into troubled sleep with vivid dreams next. Must say I’d always thought of it as losing the deep sleep cycle entirely, but more to it than that. I did find after one restless night retiring to rest/sleep pm for a short time waking with the usual sense of well-being as if flooded by endorphins for once. Any so to speak “chemistry” involved too I wonder.
I’ve had a few experiences where I woke into that kind of blissfully relaxed feeling….what an unusual feeling that is and it does feel like ones chemistry has shifted..and then poof its gone..why it appeared and then why it disappeared I don’t have a clue. Oddly enough it happened several times when I was sleeping in my car…who would have thought?
Here’s to a really good nights sleep at some point. A post on possible treatments, some rather unusual :), is coming up.
Really Cort, no clue? Are you sure that’s what you want to go with?
Funny, because I had the same experience as you describe, but I DO have a clue. Of course, you know that.
http://www.cfsuntied.com/videosvictims.html
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Elegant Exotics Marti Z here: Dealing with this exact same thing with my son who has not been diagnosed with ME/CFIDS – rather sleep apnea, POTS and wrong (I think) diagnosis of narcolepsy. I have more energy that he does! Our POTS doc does know about HRV and feels that this is his issue so some docs are aware. He put him on 30mg of Inderol (a beta blocker) which didn’t work so now he is on Tenex 1 mg plus 12mg Melatonin. That’s not working either. Sleep doc discounts this so I am not sure whether to let him to go yet ANOTHER sleep study without this data. Where can I find info on the test so that it can be run during the sleep study?
Elegant Exotics As you stated in the comments on that article – microarousals are his issue – 25 an hour sometimes (in addition to arousals from an apnea event). Thanks for posting – so timely for us! P.S. Turns our my HRV is abnormal as well and I have been responding well to 10mg of Inderal. Better sleep, faster recovery but it’s still early days.
Great article, hope they or someone can follow up with finding the underlying cause of the ANS dysfunction. After 35+ years we have a lot of symptoms, yet no underlying cause of CFS/ME.
Thanks to Annesse for very interesting findings – so brain “chemical” inbalances are involved.
THANK YOU, AGAIN AND AGAIN, CORT !! You are terrific and help us all so much in giving us info that at least lets us know that things are happening in the search for answers to this most frustrating and completely life-altering disease. Ah.. to sleep all the way through the night, to sleep until even six oclock, to wake to an alarm clock.. now , that would indeed be heaven. One of these days I just know all of us will have real, bonafide help for all the problems we suffer with and have endured for so very long.
I’ve been using pituitary glandular for sleep approx 1.5 years. I switched to this when I could no longer tolerate low dose Klonopin. This has worked better than any of the other sleeping aids I’ve tried. I’m also using glandular adrenal, hypothalamus, and thymus, all providing good support.
Do all of these Glandular support have to have an rx? Willing to try something different. Anything. However my mask is not sealing and that is a real issue.
I also breath through my mouth-even with chin strap. I have humidifier on 86 -that does seem to help but still think pressure is too high. As soon as it start to go up my mask comes unsealed and my throat is very dry. Am on Quatro EX.
Thank you ahead of time. Great Posts. Been on this since late June. Tried new seal-same brand. Not working either all the time. Planning to go to new sleep Dr.
Haven’t had the energy to go yet.When it works it does help.
Carole
Forgot to say- My breathing was stopping 30 times a night in the beginning and I would wake up in terror -choking with Heart Palps and Heart racing. Not as much of that now when mask is working.
Also had breathing problems.
Am on Quatro EX with chin strap.
Still not working enough. or well with seal.As I have said before-I want to change to a different Dr. as this one seems to think unless you stop breathing 100 times a night -it is not serious.
Carole
Caused by epigenetic notepinephrine transporter gene suppression which causes blunted sympathetic vasoconstriction upright but increased supine sympathetic activity. Further, chronic sympathetic activation was recently found to increase the elaboration of interleukin 6 – which is also released after exercise.
Cort, I am not clear as to which article you are referring?
Mercy! My head is spinning with all that information above and in these comments! I would say this is a most valuable study, and hopefully, will lead to further studies that may confirm this hypothesis.
It’s quite interesting to me because, when I first became acutely ill with ME/CFS in March of 1997, falling asleep was a nightmare – literally and figuratively. As soon as I would drift off, my body immediately went into a “fight or flight” response. My heart would begin pounding and racing, my stomach would burn like fire, and I would awaken in terror. It got so that I would dread falling asleep. One late night, the symptoms were so terrible, that I asked my teenage daughter to drive me to the emergency room. Thankfully, these severe autonomic system symptoms subsided after a few weeks, but the inability to sleep remained. I’ve taken clonazepam and neurontin (for restless legs) for years now, which really help. It would indeed be great if Clonidine truly worked to provide a more natural sleep by acting directly upon the underlying causes of our sleeplessness.
Thank you so much, Cort, for these insightful, informative articles and your own brilliant (and often witty!) commentary to help us better understand the “whole enchilada!” And thank you to the folks who’ve commented here, and on other posts, which adds so much to the discussion. 🙂
Judith, did you ever beat the night terrors? Mine makes my heart rate and blood pressure skyrocket a few minutes then slowly comes back down, sometimes it happens right when I’d fall asleep, other times usually between 1-3 AM or 2-3 hours into sleep, then the next day my body would be so weak from not sleeping that just getting out of bed would send me gasping for air with a accelerated pulse. Did you ever defeat this spirit if fear? I’ve had plenty if EKGs 4 months ago, but did that night terror ever cause any heart problems? I think my biggest fear is it’s damaging my heart, but if I could confirm that it’s ok, then those night terrors I would just ignore and go back to sleep. Any response would be greatly appretiated. Thanks 🙂
My doctor in Finland (who’s a well-known sleep researcher) has been running some innovative sleep studies, e.g. measuring vasodilation during sleep, but sadly he hasn’t published anything.
For me personally the biggest sleep problems have to do with my severe hypopituitarism/adrenal insufficiency (I don’t know anyone with CFS/ME who has those as bad as I do, even though my CFS/ME is almost asymptomatic thanks to LDN). I used to sleep just fine with melatonin, baclofen, ashwagandha and hydrocortisone (which I have to take both at bedtime and during the night or I simply won’t sleep at all), but nowadays I can’t sleep long enough.
For me immunostimulants tend to improve sleep, e.g. isoprinosine and some supplements, but even they don’t get me enough sleep. Tamsulosin, which is an alpha blocker like clonidine, only made my sleep more superficial, as do some other things which are supposed to deepen your sleep.
I have a feeling many people who feel too “wired” to sleep would benefit from a tiny dose of hydrocortisone.
This is a great discussion Cort – thanks to all.
I think a logical explanation for the ANS dysfunction would be the inability to produce either of the neurotransmitters that regulate the ANS. I have a section on this in my fibro book. Here is an excerpt:
“The lack of the essential amino acid phenylalanine and vitamin B12 found in fibromyalgia would explain the dysfunction of the autonomic nervous system.
The action of the two branches of the autonomic nervous system is mediated by two neurotransmitters. They are adrenaline and acetylcholine. Adrenaline is the predominant sympathetic neurotransmitter, whereas acetylcholine acts in the parasympathetic periphery.
Adrenaline is derived from dopamine, and as we have shown, dopamine is derived from the essential amino acid phenylalanine.
The parasympathetic neurotransmitter is acetylcholine. Acetylcholine is derived from choline. Vitamin B12 and folate are required for the synthesis of choline before becoming acetylcholine.”
Here is some information from Rich on the lack of acetylcholine in CFS. Just scroll down to post #10.
http://forums.phoenixrising.me/index.php?threads/gastroparesis-delayed-stomach-emptying-and-colonic-inertia.2491/
Although I focused on fibromyalgia studies in my book, I have a graph showing the lack of essential amino acids found in CFS. Here is an excerpt from the book. “In an open trial published in the Journal of Applied Nutrition, it was found that CFS patients were deficient in amino acids (Lord, 1994). The
highest deficiencies were found in tryptophan and phenylalanine. A full
80% of CFS patients were found to be deficient in tryptophan and 72%
had low levels of phenylalanine…The following study also found that patients with chronic fatigue
syndrome (CFS) had significant decreases in phenylalanine and the
branched-chain amino acids (Niblett, 2007). There are three branched chain
amino acids; leucine, isoleucine, and valine…These are not isolated findings. The researchers stated that, “The majority of studies, including the present investigation, have noted reductions in
urine and plasma amino acid levels in patients with CFS compared with
healthy controls.”
The inability to produce adrenaline and acetylcholine (the neurotransmitters that regulate the ANS) would explain the ANS dysfunction found in fibro and CFS.
1. The sympathetic nervous system’s main neurotransmitter is norepinephrine not adrenalin.
2. There is actually NO research-based or peer reviewed evidence of any kind that acetylcholine is specifically decreased in chronic fatigue syndrome or ME.
3. There is a theory that at least in POTS there is reduced expression of the norepinephrine transporter – the protein the recycles norepinephrine back into the synaptic cleft. Where the transporter is not present, the post synaptic alpha receptors may actually stimulate so much release of norepinephrine that pre-synaptic vesicles are depleted. This would mean that on standing or physical exercise, norepinephrine is released continually until the vessicle is bled dry and then there would be no NE left to stimulate sympathetically mediated vasoconstriction – while plasma levels of NE would increase because it leaks out of the synaptic cleft into the plasma. This would basically explain all the characteristcs of POTS.
4. NET deficiency may also stimulate brain stem alpha 2 adrenoreceptors which would suppress norepinephrine release.
5. In some orthostatic intolerance patients there can be a specific ‘neuropathy’ – either through damage to post ganglionic alpha 1 receptors, autoantibodies which were recently identified in a cohort of patients that block alpha 1 receptors and or through other factors which decrease either regional or whole-of-body alpha 1 receptors resulting in the body increasing norepinephrine levels and sympathetic activation to try and get these faulty alpha 1 receptors to vasoconstrict – but the end result is the increased NE levels stimulate beta 1 receptors and are sensed full in areas of the body where alpha 1 receptors are not compromised.
6. Rich’s theories – while being interesting – were never tested in double blind studies and have fairly limited medical research backing.
Hi Cort
That’s a really great article on sleep, thanks!
As is my way I will mention that those two sleep HRV studies were very small (n<20,). The Natelson 2013 study (http://www.ncbi.nlm.nih.gov/pubmed/23499514) finds differences between patients sleepier in the morning vs sleepier in the afternoon, but given only 18 patients I wonder how solid that finding is. Hopefully someone will replicate on a decent sample size.
Aplogies if I missed your mention of Beneva 2007 population study (n=30), which also found elevated HR and reduced HRV in CFS patients awake and asleep: http://www.sciencedirect.com/science/article/pii/S1566070207004468. But given the data and the fact it's from the CDC, it may use Empricial Criteria for diagnosis.
Anyway, fine article, thanks – I've never had the patience to look properly at the sleep literature.
I wanted to mention another connection to low acetylcholine and another sleep issue commonly found in CFS and fibro–sleep apnea. Here is some more information on my fibro book on this.
“Low acetylcholine could also lead to sleep apnea. Sleep apnea is defined as the cessation of breathing during sleep. As the following study confirms, sleep apnea is commonly found in patients with fibromyalgia.
Sleep-disordered breathing among women with fibromyalgia syndrome.
Shah, M.A., S. Feinberg, E. Krishnan. 2006. J Clin Rheumatol. 2006 12(6):277-81.
“A large proportion of women with fibromyalgia in a general rheumatology practice had sleep-disordered breathing… Studies are needed to examine if treatment of the commonly detected sleep apnea will have a beneficial effect on symptoms of fibromyalgia.”
Acetylcholine-producing neurons are connected to the part of the brain that controls muscles of the upper airway and tongue, which are involved in sleep apnea. A study published in the journal Neurology found that patients with the lowest acetylcholine levels had the most interruptions in their breathing during sleep (Gilman, 2003).”
We seem to be back to hormones (is pituatary a govenor). I’ve no doubts about hormonals dysregulatoin. Think we are onto something here.
I also think we are onto something. The lack of essential amino acids found in CFS and fibromyalgia which are needed to produce dopamine, adrenaline, serotonin etc. are a very large piece of the puzzle and also point us in the right direction to solve the entire puzzle. For instance, the recent findings of low brain glutathione that were discussed here can be explained by the lack of the essential amino acid methionine which is found in fibro and CFS. Methionine is a precursor for cysteine, and cysteine is a precursor for glutathione.
Here is a study that shows fibromyalgia patients lack the essential amino acid methionine.
Altered Amino Acid Homeostasis in
Subjects Affected by Fibromyalgia
Bazzichi, L., L. Palego, G. Giannaccini, A. Rossi, F. De Feo,
C. Giacomelli, L. Betti, L. Giusti, G. Mascia, S. Bombardieri, A. Lucacchini. 2009.
Clin Bioche, 42(10-11):1064-70.
Significant lower plasma taurine, alanine, tyrosine (Tyr), valine, methionine,
phenylalanine and threonine concentrations, and the sum of essential AAs were
observed in FM patients vs. healthy controls (P<0.05). Tyr CAA’ ratio and the sum
of AAs competing with tryptophan for brain uptake were significantly reduced in
FM (P<0.05). A significant correlation was found between FM clinical parameters
and certain AAs.
The following study shows that the lack of methionine will depress brain glutathione.
Nutr Neurosci. 2001;4(3):213-22.
Sulfur amino acid deficiency depresses brain glutathione concentration.
Paterson PG, Lyon AW, Kamencic H, Andersen LB, Juurlink BH.
SourceCollege of Pharmacy and Nutrition, Cameco Multiple Sclerosis and Neuroscience Research Center, University of Saskatchewan, Saskatoon, Canada. phyllis.paterson@usask.ca
Abstract
Dietary sulfur amino acid content is a major determinant of glutathione concentration in some tissues. We examined whether brain glutathione (GSH), a key component of antioxidant defense important for minimizing ischemic injury, was also responsive to short-term sulfur amino acid deficiency. Female Long-Evans adult rats were fed a sulfur-deficient L-amino acid defined diet for five days; the control diet was supplemented with L-cystine and L-methionine (n = 6). Sulfur amino acid deficiency was confirmed by a reduction in liver cysteine and GSH concentrations, marked decreases in food intake, and weight loss. GSH concentration analyzed by reverse-phase high performance liquid chromatography was significantly depressed in the neocortex and thalamus of deficient rats. Brain cysteine was not decreased in a parallel manner. Classical glutathione peroxidase activity was increased in the liver and brain of sulfur amino acid deficient rats. This suggests an upregulation of antioxidant defense but these findings may be complicated by alterations in tissue composition. The depletion of brain GSH by a reduced supply of dietary precursors may be important during brain ischemia when the rate of GSH utilization and the need for synthesis are increased.
Low glutathione levels are also a common finding in people suffering from
autoimmune diseases. In the study “Correlation of lipid peroxidation and
glutathione levels with severity of systemic lupus erythematosus: a pilot
study from single center” the researchers concluded that, “A significant
correlation between plasma GSH (glutathione) and SLE severity exists that
may aid evaluation of the disease severity and usefulness of the treatment of
SLE” (Tewthanom, 2008).
Lupus patients also lack methionine. The following study found that "all" ketogenic and glucogenic amino acids were severely dampened.
Metabolic Disturbances Associated with Systemic Lupus Erythematosus
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0037210
“… all ketogenic and glucogenic amino acids (with the exception of arginine) were also significantly dampened in SLE.”
I have had ME since 1961 in a pattern that came from a love of activity and no explanation. For me, opiates and opioids don’t work. My doctor in the hospital gave me 3 percosets to see if that would help. Only 4th stage sleep meds do.
I believe that unremitting insomnia may be a progression of Nuerally Mediated Hypotension since both involve the brain’s control of heart and blood pressure anomalies. It was first described by doctors at The University of Bologna in Spain, called Insomnia Fatale. People do die from it 6-8 weeks after the onset of delirium. I have found that onset to come sooner with age. Now I get very ill after 3 days. One night is pretty bad. This was printed in The Scientific American in the mid 90’s. Benzodiazaprines– Alprazolem, not Tamazipan (Dr. Nye) trigger 4th stage sleep. The Sci American Article was rather jumbled, mentioning Chronic Wasting Disease (a disease of hooved wild animals, and Mad Cow. The picture was of Cow Cremation.
Probably this means that the responsible party at the NIH couldn’t get anyone to write the article for them. You can decline and lived.
So incredibly frustrating. It is so obvious that the reason sleep researchers have been looking in the wrong place for 20 years is that they, like nearly every other researcher, never bothered to ask M.E. patients! WHY is it that every single shortcoming of doctors is blamed directly on the people who are sick?? This is just one of those days when it gets to me, I am tired of being blamed, and being reminded of how the medical establishment often thinks they are God and that we, the patients who provide their careers, are stupid nothings. It never seems to occur to them that many of us would BE doctors right now if we were not busy being sick (and generally much better ones than they ever hoped to be).
Anyway, rant aside, I have been finding consistently that I feel incredibly ramped up just as I try to go to sleep, that my heart rate increases, my body feels under stress like a panic attack, but my mind does not feel upset at all. As I sleep, I frequently wake up at the slightest noise, draft, discomfort, etc., again despite not feeling emotionally upset. I used to dream vividly almost the entire night, and would routinely remember hours of dreams, often 3 or even 4 elaborate dreams per night. Since I got sick, I almost never dream at all. It has been said that M.E. patients get considerably less “deep sleep” – the portion of sleep that is restorative – and I would say that seems true, my sleep has changed dramatically so that most of it is in the light phase one would encounter at the beginning or end of sleep, but no middle. I have found that using a small amount of an anti-anxiety such as Ativan, or any other medication that can slow the brain and body down (like an anti-convulsant such as Seroquel), makes a marked difference in my sleep. However, I do not find using these long-term as they build tolerance within a matter of days, and using them does not solve the problem but merely addresses a symptom. My cortisol is also completely backwards, but despite these findings I have been given no help medically to try to reverse it, so I work on my own with a light box first thing in the morning and some movement, and with various supplements, to try to reverse my internal clock on my own… with only mild success. Although using a Bipap machine for the sleep apnea I developed while sick has lessened the times that I wake up feeling like I’m dying, it still has not fixed the hyperactive feeling in my body/brain, so that was not the issue (and indeed, my sleep issues began very soon after becoming sick, while the sleep apnea developed later as my illness got worse and my body started to forget to breathe due to severe ANS dysfunction – this also happens during the day).
The sleep dysfunction is complicated. For many of us, it is a combination of ANS and other issues that, should one deal with symptoms alone and not directly address the problem (because we don’t have that option yet), may require improvement of nutritional deficiencies due to malabsorption (like magnesium, vit. D, etc.); a bipap machine for sleep apnea (cpap is useless because the problem is ANS dysfunction and the regulation needed changes throughout the night); reversal of cortisol, LDN or other methods to diminish pain while sleeping; methods to help reduce disturbance during the night like softer sheets, temp control, and silicone earplugs; medications or supplements to help fall asleep; and then medications that slow the body’s hyper response like anti-anxieties or anti-convulsants to help stay asleep. It is a lot of work, and almost never do I get all of the factors working properly at the same time to actually reach deep sleep more than perhaps 30 min. a night. I hope such findings as this study will encourage the medical community to see their own failings and to create greater dialogue with the patient community. I could have told them a traditional sleep study would show them nothing, but no one ever asked me what I think works! (And still, doctors continue not to ask, but rather to tell me, what SHOULD work, and then why it is my fault that it didn’t because I must not have been completely compliant or something. Please!…) Best wishes to all to get good sleep tonight, and for us to find our voices to advocate for our health during the day.
As a note, it is my belief that every doctor – ESPECIALLY those involved with research – should ask every patient at every single appt. one simple question: “What seems to work?” Over countless hours in consultation, it would become apparent which types of treatment and symptom abatement are helpful for which types of patients, and many methods could quickly become the standard protocol for each symptom. It may be a long time before we cure this thing. The best chance patients have is to minimize the distress the body is under and the severity and number of different symptoms it suffers as quickly as possible, so decline can be arrested, and the body can work to heal itself. If you can have a written record of answers as to what helps with each major group of symptoms, such as given with an appt. survey for each visit (perhaps filled out prior to appt. and submitted online), so much the better. The patients are the best resource to what helps, and also what makes them worse – if researchers do not ask them directly, they have no chance of understanding what is really going wrong in such a complex and confusing disease.
Interesting article.
I have suffered from CFS/M.E since the age of 14/15. It came on gradually at a time of acute stress (G.C.S.E coursework and exams, bullying and other stressors). I did not have a fever/virus of any kind (i.e I do not have PVS: Post Viral Fatigue and I do not have fibromyalgia). But I had and still have debilitating cognitive fatigue (and all the other symptoms of autonomic overload) that unfortunately prevents me from being able to work or lead any kind of normal life.
Has anyone heard of the HSP connection? Psychologist Elain Aron (www.hsperson.com) has identified that 15-20% of all animal populations (including human) are born with a highly attuned/sensitive nervous system. The brains of such individuals are shown to process incoming stimuli more deeply/intensely, which while having a range of unique benefits also makes one subject to over-stimulation, sensory sensitivity and overload.
I fit the profile of an HSP perfectly. For me it has provided so many answers and a deeper understanding as to how my body/brain works and reacts the way it does and why this may have caused chronic fatigue.
I have suffered with insomnia and un-refreshing sleep the entire time while having CFS. In my research on HSPs, I came across this article (http://sensitiveandthriving.com/2009/10/why-so-many-hsps-struggle-with-insomnia-and-what-you-can-do-about-it.html) that pretty much hit the nail on the head of my experience (of insomnia).
Though having a highly sensitive nervous system is not in and of itself an illness/disability, I believe it is the pre-requisite for chronic fatigue syndrome. I highly recommend Aron’s book The Highly Sensitive Person to see if this resonates with you. I believe there is a connection to be made between HSPs and CFS.
Thanks Jen,
A review of an study by Baraniuk in GWS suggests something similar I think is going on.Check back in a couple of days and see what you think. I’ve never heard of Aron before.
Hi Jen
A highly sensitive nervous system sounds a lot like me.
By any chance did you come across my series of articles here starting with the first dealing with the issue of sensory gating? :
http://www.cortjohnson.org/blog/2013/01/17/not-fatigue-after-all-new-model-suggests-other-symptoms-explain-chronic-fatigue-syndrome-mecfs-better/
What I’m proposing for at least a sub-set of folks with ME/CFS sounds a lot like what you’re describing.
I remember back as a psychology undergrad that the famous psychologist Hans Eysenk referred to a personality type with a labile (easily disturbed) autonomic nervous system. The original Ramsey ME definition also refers to emotional lability as a key symptom.
Part two of my series refers to a gene called COMT val158met which is associated with increased pain and vulnerability to stress. In broad terms this gene has been proposed as determining those who are ‘warriors’ and those ‘worriers’.
The prevalence of the met/met (worrier) variant is around 28% in the european derived population.
Interesting comment on the Warrior and the Worrier. I am BOTH!!!
I am a RESCUER and darn good at it, animals , children, older sick people
Anyone that needs me if I know I can help-them I do. I am also a worrier
as this causes exhaustion in myself. I love people-but am sometimes
exhausted from it. I want to absorb every bit of knowledge I can about them. They all have value..
I am also HIGHLY SENSITIVE-BUT CAN DEBATE WITH THE BEST if it involves the underdog or underprivleged.
Just pulled up the website on Highly sensitive people. Excellent.
Planning on getting the book.
I was brought up in a home where conflict and disfunction
was everywhere. One therapist years go, said ” You raised yourself”.. This was years ago where a child could do things safely on their own- now not so safe. I do not rec it -but it made me stronger. I always felt like I was the parent and much smarter than my parents on street smarts Since I couldn’t depend on them I did a lot on my own and had many adult teachers, and etc that I idolized. Strange Upbringing.
I don’t understand the kids now that have everything and whine about everything they don’t have.
My problem is my High Sensitivity now causes fatigue with my CFIDS.
Sensitivity can be great- if you are not sick.
Carole.
“Low HRV suggests the ‘fight or flight’ system is turned on even during sleep in ME/CFS
This enhanced ‘fight or flight’ activity may produce microarousals that interrupt sleep”
That might explain why I woke up a hundred times during my sleep analysis session a few years back. Not that I noticed, I awoke after a full night’s sleep feeling as I always do: still sick.
This study resonates with my experience.
For me, the severity of this ME/CFS symptom varies according to my environment. If I am trying to sleep in a place with a lot of the toxins I am susceptible to, I have trouble falling asleep because my heart is pounding. If I finally do fall asleep, I wake up every two hours or so with a pounding heart.
When I am sleeping in an environment that is good for me, I can fall asleep easily, stay asleep, and wake up feeling more rested. This is probably the main reason I am living an extremely difficult lifestyle of searching for good environments. Having a restful night’s sleep makes such a big difference in my health and well-being.
It’s encouraging that someone is starting to figure this out.
Snoring during sleep is the the cause of stress and depression but there is no needs to worry about because it is general health problem and try to stop it soonly. You can get better releafe get the proper treatment to buy resmed cpap machine with discount.
Stupid people! try monitoring the amount if oxygen and the number of breaths in chronic fatigue syndrome sufferers and you will find the cause of this problem. Psychological my ass!
It also depends on WHY YOU CAN’T GO TO SLEEP OR STAY ASLEEP.
THE CPAP HAS DEFINITELY HELPED ME. HAVE TO KEEP WORKING AT IT.
HOWEVER SOMETIMES HARD TO TURN MY BRAIN OFF.
CAROLE
http://www.plosone.org/article/info%3Adoi/10.1371/journal.pone.0051515
I have what I always think is great sleep. I sleep straight through 7-8 hours mostly, with no awareness of having tossed and turned, or been disturbed. It’s like I’m under anesthetic.
But when I wake up and at least for the first few hours of the day I don’t feel good….exacerbation of symptoms slightly, disorientation, weakness, muscle weakness, exhaustion, inability to focus, emotional numbness, loss of appetite, shakiness.
I feel better late at night, can even feel pretty normal then! And often feel better when I have had little sleep which cannot obviously be sustained.
Awful….do need sleep but sleep makes me worse, even “good sleep”!
I have pleasant or neutral dreams, and no bad things happen to me in the night.
But I always wake up feeling much worse than when I went to bed.
I completely relate! I go to bed feeling not too bad and wake up with bone crushing exhaustion, weakness, cramping legs, heavy head – basically, worsening of all symptoms for the first few hours of each day. It’s like I’m a completely different person later in the day. I have more stamina, more strength and less pain. I usually get 7 – 8 hours of uninterrupted sleep. And the less I sleep, the better I feel, except this can’t be sustained unfortunately. I wonder what percentage of other people with this condition are also stuck in this groundhog day routine.