Published Research - General Sleep and RLS (WED)

[Polar Bear]

I agree, your experiences would be so interesting, and very enlightening.

[badnights]

This paper is old, but I love it. It contains sensitive and perceptive descriptions of aspects of our disease that are often missed. I have only re-typed a bit of it here, which I shared in another post somewhere already. I don't have a digital copy, but if anyone is interested, PM me and I'll see if I can scan a copy for you.

Dr. Richard Allen's "Diagnosis of Restless Legs Syndrome", Chapter 15 in the book Restless Legs Syndrome by W.A. Hening, R.P. Allen, S. Chokroverty and C.J. Earley , (editors) (published 2009 by Saunders /Elsevier, p. 99). I've added bold, changed "RLS" to "WED" or "WED/RLS", and I've put .... where I left parts out:

Criterion 2: Rest engenders WED/RLS symptoms. Rest here involves two features: decreased movement occurring when sitting or lying down and also decreased mental activity. These provide the conditions that engender WED/RLS symptoms. ... Rest acts as a stimulus producing the symptoms that increase in strength with the degree and duration of rest. It is important to realize that it is any rest situation that produces the WED symptoms and not a particular body resting position. ... Any rest that lasts long enough should engender the symptoms. Because lying down represents a more restful position than sitting, some subjects may report symptoms only when lying down and may not observe them when sitting.
...
It is generally reported that increased confinement and decreasing general movement enhances the effects of rest. Thus, symptoms are commonly reported to occur when sitting in airplanes, cars, or theaters, even in patients who rarely have the symptoms at other times.
...
Criterion 3: Leg movements relieve RLS/WED symptoms. ... Two features of the relief from movement are often missed. First, the relief should at least be partly felt almost immediately or very soon after the movement is started. The relief occurs because of the movement and not as a result of exercise or intensity of activity. ...Second, the relief occurs while moving and should persist for as long as the movement continues. .....
It deserves note that movement is only one method to relieve WED symptoms. Subjects report that any intense conversation or argument, intense mental involvement such as in a computer game, eating, hard rubbing of the legs, and very hot baths also reduce symptoms. ... The activities shown to reduce WED symptoms are identical to those producing alertness. Conversely, situations decreasing alertness engender the WED symptoms. In this sense, WED/RLS can be seen as a disorder of the quiet resting state with decreased alertness producing symptoms and increased alertness reducing symptoms. Movement provides the most consistent method for increasing alertness, and thus it has been recognized as critical for the diagnosis; it is not simply the movement, but rather the motor activation and mental alertness that also occur with the movement that reduce the symptoms.

[badnights]

It seems they found that WED/RLS patients rely heavily on visual cues to control the balance and position of the head with respect to the rest of the body, whereas non-WED people can do this better with the eyes closed than we can.

If I understand correctly, the vestibulospinal tract is a part of the central nervous system that senses and corrects the alignment of the head and limbs in relation to the rest of the body. From wikipedia: "The vestibular nuclei receive information through the vestibulocochlear nerve about changes in the orientation of the head. The nuclei relay motor commands through the vestibulospinal tract. The function of these motors commands are to alter muscle tone, extend, and change the position of the limbs and head with the goal of supporting posture and maintaining balance of the body and head."

This might explain why I have such trouble with balancing poses in yoga when I close my eyes. But it's hard to tell, because I think everyone has trouble with that

The abstract:
Postural control in restless legs syndrome with medication intervention using pramipexole.
Central dopamine regulation is involved in postural control and in the pathophysiology of restless legs syndrome (RLS) and Parkinson's disease (PD). Postural control abnormalities have been detected in PD, but there are no earlier studies with regard to RLS and postural control. Computerized force platform posturography was applied to measure the shift and the velocity (CPFV) of center point of forces (CPF) with eyes open (EO) and eyes closed (EC) in controls (n = 12) and prior and after a single day intervention with pramipexole in RLS subjects (n = 12). CPFV (EO) was significantly lower in the RLS group (p < 0.05) than in controls. After pramipexole intake, the difference disappeared and the subjective symptom severity diminished. Pramipexole did not significantly influence CPFV (EC) or CPF shift direction. Subjects with RLS used extensively visual mechanisms to control vestibule-spinal reflexes to improve or compensate the postural stability. Further research is needed to clarify altered feedback in the central nervous system and involvement of dopamine and vision in the postural control in RLS.

Authors: Ahlgrén-Rimpiläinen A, Lauerma H, Kähkönen S, Aalto H, Tuisku K, Holi M, Pyykkö I, Rimpiläinen I
Journal: Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology [2014, 35(2):199-204]
DOI: 10.1007/s10072-013-1478-6

[Polar Bear]

Regarding the ""postural control"".....
Is it possible - Could this be relative to my balance which in general has not been good for some years and I am now very aware of being careful. No way would I walk down a staircase without holding the handrail. I'm not even really using it, it is more of a comfort issue.

[badnights]

Regarding the ""postural control"".....
Is it possible - Could this be relative to my balance which in general has not been good for some years

The way I read it, yes. (Of course, balance can be affected by many other things too.)

EDIT March 19: I got it backwards. WEDers have poorer control (balance) with eyes OPEN. No different from controls with eyes closed.

[ViewsAskew]

WOW!

http://www.news-medical.net/news/201403 ... brain.aspx

The intro paragraph reads:
'n a study published online in Genome Research, researchers of the Helmholtz Zentrum München und the Technische Universität München have demonstrated that a common genetic variant associated with Restless Legs Syndrome (RLS) alters the expression of a critical gene during fetal development of the brain. This leads to alterations of the developing forebrain indicating an anatomical region involved in RLS."

[badnights]

At first I read it as "doomed from the start" but it's not quite: yes, the susceptibility is there from the fetal stage onward, but environmental factors are required for it to kick in.

Anyway this is a great thing to wave at people who think WED/RLS is not associated with any physical abnormalities. Along with the one about decreased myletinization.

[ViewsAskew]

Interesting research at Emory by Dr Rye and his team:
http://news.emory.edu/stories/2012/11/a ... ampus.html

They found a "sleep" substance in the cerebrospinal fluid in those people who have hypersomnia - sleepy all the time and need extra sleep (like 10 or more hours every night). This substance enhances GABA.

Huh. Wonder if there is something in here for WED and our glutamate issue....like, do we have less of this? How does it affect glutamate?

[Neco]

Regarding the ""postural control"".....
Is it possible - Could this be relative to my balance which in general has not been good for some years and I am now very aware of being careful. No way would I walk down a staircase without holding the handrail. I'm not even really using it, it is more of a comfort issue.

I totally know what you mean. My sense of balance has slowly gotten worse over the years

[badnights]

Interesting research at Emory by Dr Rye and his team:
http://news.emory.edu/stories/2012/11/a ... ampus.html

They found a "sleep" substance in the cerebrospinal fluid in those people who have hypersomnia - sleepy all the time and need extra sleep (like 10 or more hours every night). This substance enhances GABA.

Huh. Wonder if there is something in here for WED and our glutamate issue....like, do we have less of this? How does it affect glutamate?

Fascinating. They have too much of an unknown substance that activates GABA receptors, maybe we have a similar but unrelated problem - too much of an unknown substance that activates glutamate receptors.

Not that this would lead to the excess glutamate noticed by Dr. Allen's team.

[badnights]

A study of mice shows that extended periods of being awake leads to death of neurons in an area of the brain that is essential for optimal cognition. They think this result could very well apply to humans as well, putting the lie to current thinking which is that lost sleep can be made up by sleeping lots at a later time.

I admit I find this a bit scary, because I've been telling people for years that the worst part of this disease is that it makes me stupid. It would be even scarier if we didn't know about neuroplasticity (growth of new brain cells). I am going to firmly believe that any neurons I've lost, I can re-grow. Whether it's true or not. The study is described at:
http://www.sciencedaily.com/releases/20 ... ceDaily%29

I replicate it below (except for the references) in case the page is removed.
How lost sleep leads to lost neurons
Date: March 18, 2014
Source: University of Pennsylvania School of Medicine
____________________________
Summary:
Extended wakefulness is linked to injury to, and loss of, neurons that are essential for alertness and optimal cognition, the locus coeruleus neurons, a mouse model of chronic sleep loss has revealed. According to common wisdom, catch up sleep repays one's "sleep debt," with no lasting effects. But the new study shows disturbing evidence that chronic sleep loss may be more serious than previously thought and may even lead to irreversible physical damage to and loss of brain cells.
____________________________

Most people appreciate that not getting enough sleep impairs cognitive performance. For the chronically sleep-deprived such as shift workers, students, or truckers, a common strategy is simply to catch up on missed slumber on the weekends. According to common wisdom, catch up sleep repays one's "sleep debt," with no lasting effects. But a new Penn Medicine study shows disturbing evidence that chronic sleep loss may be more serious than previously thought and may even lead to irreversible physical damage to and loss of brain cells. The research is published in The Journal of Neuroscience.

Using a mouse model of chronic sleep loss, Sigrid Veasey, MD, associate professor of Medicine and a member of the Center for Sleep and Circadian Neurobiology at the Perelman School of Medicine and collaborators from Peking University, have determined that extended wakefulness is linked to injury to, and loss of, neurons that are essential for alertness and optimal cognition, the locus coeruleus (LC) neurons.

"In general, we've always assumed full recovery of cognition following short- and long-term sleep loss," Veasey says. "But some of the research in humans has shown that attention span and several other aspects of cognition may not normalize even with three days of recovery sleep, raising the question of lasting injury in the brain. We wanted to figure out exactly whether chronic sleep loss injures neurons, whether the injury is reversible, and which neurons are involved."

Mice were examined following periods of normal rest, short wakefulness, or extended wakefulness, modeling a shift worker's typical sleep pattern. The Veasey lab found that in response to short-term sleep loss, LC neurons upregulate the sirtuin type 3 (SirT3) protein, which is important for mitochondrial energy production and redox responses, and protect the neurons from metabolic injury. SirT3 is essential across short-term sleep loss to maintain metabolic homeostasis, but in extended wakefulness, the SirT3 response is missing. After several days of shift worker sleep patterns, LC neurons in the mice began to display reduced SirT3, increased cell death, and the mice lost 25 percent of these neurons.

"This is the first report that sleep loss can actually result in a loss of neurons," Veasey notes. Particularly intriguing is, that the findings suggest that mitochondria in LC neurons respond to sleep loss and can adapt to short-term sleep loss but not to extended wake. This raises the possibility that somehow increasing SirT3 levels in the mitochondria may help rescue neurons or protect them across chronic or extended sleep loss. The study also demonstrates the importance of sleep for restoring metabolic homeostasis in mitochondria in the LC neurons and possibly other important brain areas, to ensure their optimal functioning during waking hours.

Veasey stresses that more work needs to be done to establish whether a similar phenomenon occurs in humans and to determine what durations of wakefulness place individuals at risk of neural injury. "In light of the role for SirT3 in the adaptive response to sleep loss, the extent of neuronal injury may vary across individuals. Specifically, aging, diabetes, high-fat diet and sedentary lifestyle may all reduce SirT3. If cells in individuals, including neurons, have reduced SirT3 prior to sleep loss, these individuals may be set up for greater risk of injury to their nerve cells."

The next step will be putting the SirT3 model to the test. "We can now overexpress SirT3 in LC neurons," explains Veasey. "If we can show that we can protect the cells and wakefulness, then we're launched in the direction of a promising therapeutic target for millions of shift workers."

The team also plans to examine shift workers post-mortem for evidence of increased LC neuron loss and signs of neurodegenerative disorders such as Alzheimer's and Parkinson's, since some previous mouse models have shown that lesions or injury to LC neurons can accelerate the course of those diseases. While not directly causing theses diseases, "injuring LC neurons due to sleep loss could potentially facilitate or accelerate neurodegeneration in individuals who already have these disorders," Veasey says.

While more research will be needed to settle these questions, the present study provides another confirmation of a rapidly growing scientific consensus: sleep is more important than was previously believed. In the past, Veasey observes, "No one really thought that the brain could be irreversibly injured from sleep loss." It's now clear that it can be.

[ViewsAskew]

So, we know about the glutamate issue - that this may be a big part of the insomnia. We also know, anecdotally, that some people are having luck using some amino acid supplements.

I ran across this research yesterday, "Effects of L-theanine or caffeine intake on changes in blood pressure under physical and psychological stresses."
Yoto A1, Motoki M, Murao S, Yokogoshi H.

It was very interesting - the conclusion was, "The findings above denote that L-theanine not only reduces anxiety but also attenuates the blood-pressure increase in high-stress-response adults."

Very cool, right? But what really interested me was this statement in BACKGROUND section of the article:

"L-theanine, an amino acid contained in green tea leaves, is known to block the binding of L-glutamic acid to glutamate receptors in the brain, and has been considered to cause anti-stress effects by inhibiting cortical neuron excitation. Both L-theanine and caffeine, which green tea contains, have been highlighted for their beneficial effects on cognition and mood." (emphasis mine)

I did a quick search and we haven't talked about this amino acid specifically, that I could find. I wonder if this could be the amino acid we need to target? In this study, the participants took 200 mg - not sure how much we'd need to take.

Study link is here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518171/

[Rustsmith]

Interesting stuff about L-theanine. I did some digging and came up with another paper.

The Neuropharmacology of L-Theanine(N-Ethyl-L-Glutamine): A Possible Neuroprotective and Cognitive Enhancing Agent by Pradeep J. Nathan, Kristy Lu, M. Gray and C. Oliver.

In the conclusions they stated

Pre-clinical studies suggest that L-theanine increases a number of neurotransmitters including serotonin, dopamine and GABA levels and has micromolar affinities for AMPA, kainate and NMDAreceptors.

The also found that L-theanine crosses the blood brain barrier about 30 minutes after ingestion. And,

There are no reported side effects in studies investigating L-theanine within animals or humans . L-theanine
has also shown to produce no drowsiness in humans.

I have the complete paper, so if anyone would like to see it, send me a PM.

[ViewsAskew]

C-Reactive Protein is a marker of vascular inflammation.
http://www.plosone.org/article/info%3Ad ... ne.0092607

The following is an excerpt - please take the above link for the whole discussion.

Results
Females were more likely to report poor sleep quality than males (26% vs. 19%, p<0.0001). Each sleep disorder was significantly associated with increased hs_CRP and correlative to other sleep disorders. In fully-adjusted linear regression model, poor sleep quality was significantly associated with elevated hs_CRP (log transformed) among the overall sample and in females only (β = 0.10, se = 0.03, p<0.01 and β = 0.13, se = 0.04, p<0.01, respectively). In fully-adjusted logistics regression model, poor sleep quality was linked with risk of high CRP(OR: 1.42, 95%CI: 1.15–1.76 in overall sample and OR: 1.59, 95%CI: 1.18–2.14 in females, respectively).
Conclusion

We found that poor sleep quality was independently associated with elevated hs_CRP in females but not in males in a U.S. adult population.

[ViewsAskew]

Another study showing heart issues with unresolved leg movements. http://www.plosone.org/article/info%3Ad ... ne.0078359

I posted the Abstract and Conclusions - see the link for the full article

Abstract
Sleep apnea has been recognized as a factor predisposing to atrial fibrillation recurrence and progression. The effect of other sleep-disturbing conditions on atrial fibrillation progression is not known. We sought to determine whether frequent periodic leg movement during sleep is a risk factor for progression of atrial fibrillation. In this retrospective study, patients with atrial fibrillation and a clinical suspicion of restless legs syndrome who were referred for polysomnography were divided into two groups based on severity of periodic leg movement during sleep: frequent (periodic movement index >35/h) and infrequent (≤35/h). Progression of atrial fibrillation to persistent or permanent forms between the two groups was compared using Wilcoxon rank-sum test, chi-square tests and logistic regression analysis. Of 373 patients with atrial fibrillation (77% paroxysmal, 23% persistent), 108 (29%) progressed to persistent or permanent atrial fibrillation during follow-up (median, 33 months; interquartile range, 16-50). Compared to patients with infrequent periodic leg movement during sleep (n=168), patients with frequent periodic leg movement during sleep (n=205) had a higher rate of atrial fibrillation progression (23% vs. 34%; p=0.01). Patients with frequent periodic leg movement during sleep were older and predominantly male; however, there were no significant differences at baseline in clinical factors that promote atrial fibrillation progression between both groups. On multivariate analysis, independent predictors of atrial fibrillation progression were persistent atrial fibrillation at baseline, female gender, hypertension and frequent periodic leg movement during sleep. In patients with frequent periodic leg movement during sleep, dopaminergic therapy for control of leg movements in patients with restless legs syndrome reduced risk of atrial fibrillation progression. Frequent leg movement during sleep in patients with restless legs syndrome is associated with progression of atrial fibrillation to persistent and permanent forms.

Conclusions
We report that frequent periodic leg movement during sleep in patients with clinical suspicion of restless leg syndrome is associated with the progression of atrial fibrillation. Since atrial fibrillation is the most common arrhythmia encountered in clinical practice, particularly in the elderly who also may have restless legs syndrome, another commonly prevalent condition [50], recognition of this association and underlying mechanisms predisposing to atrial fibrillation and its progression becomes important. With the rapid change in population demographics [51] and a projected increase in the prevalence of atrial fibrillation [2,24] and restless legs syndrome [5,6], it is important that mechanisms underlying atrial fibrillation development and progression in the elderly need to be better defined so preventive strategies can be implemented to reduce morbidity, death and cost associated with these conditions.