Published Research - General Sleep and RLS (WED)

[badnights]

Readers have to understand that the authors are detecting associations, or statistical correlations. The authors are not speculating about cause and effect.

Yes, only 70-80 subjects and 70-80 controls. It's hard to get participants for these studies - a lot of people expect to be paid. 150 is not too shabby for something like this. Certainly better than 20. Definitely not as good as 2000.

And yes, they used questionnaires. It certainly helps that they used standardized questionnaires that have been validated for their purposes, but yes, they used questionnaires.

I wouldn't say these are red flags so much as: readers have to understand what they're reading. I tried to provide enough information in my summary of the full paper, so that a savvy reader such as yourself could understand what could be inferred from the results, and what should not be inferred from the results. I'm glad I was successful.

[badnights]

I will admit I haven't tried to figure out what this abstract means because it would take me a lot of effort and might not be successful but the one take-home that seems evident to me is that there might be a clinical test for WED/RLS that could be developed out of this, assuming F waves are not invasive to measure ...

F wave in restless legs syndrome, as an electrophysiological response of clinical relief
by
Safiye Gul Kenar,Ebru Bilge Dirik,Gorkem Tutal Gursoy,Nuriye Kayali &Sule Bilen

published in Neurological Research, DOI: 10.1080/01616412.2022.2042123
https://www.tandfonline.com/doi/abs/10. ... ode=yner20

ABSTRACT
Objective
The study aimed to evaluate the impact of postural changes on the F wave-related parameters and whether those changes were associated with clinical relaxation, which was achieved in restless legs syndrome patients with standing up.

Methods
F wave duration (FWD), compound muscle action potential duration (CMAPD), and FWD/CMAPD ratio were evaluated in supine and upward positions in 18 restless legs syndrome patients and compared with 18 age and gender-matched healthy volunteers.

Results
FWD/CMAPD was significantly higher for the tibial nerve at supine position (p = 0.043) but not at upright position (p = 0.206) and for ulnar nerve, both at supine (p = 0.007) and upright positions (p = 0.023) in RLS patients compared to controls. Ulnar FWD decreased significantly at the upright position in both control and RLS patients (p = 0.035, p = 0.028, respectively). CMAPD decreased only in the control group with standing up for both ulnar and tibial nerves (p = 0.048, p = 0.017, respectively).

Discussion
Ulnar and tibial FWD/CMAPD ratios increased in RLS patients compared to controls. However, FWD/CMAPD was not affected by the posture within the groups. Postural change seems to be a factor that decreased ulnar FWD both in RLS patients and the control group. Ulnar and tibial CMAPD reduced only in healthy controls with an upright position. Tibial and ulnar FWD/CMAPD ratios are favorable electrophysiological parameters diagnosing RLS. The tibial FWD/CMAPD ratio loses its significance only when the patient stands up, reflecting the clinical relief achieved with the postural change.

[Oozz]

Looks like there they are some disputes to the current research.

Reassessment of candidate gene studies for idiopathic restless legs syndrome in a large GWAS dataset of European ancestry

https://scholar.google.com/scholar?hl= ... xIwDp3k0J

Conclusion

In summary, none of the significant single variant associations from candidate gene studies were confirmed in our GWAS dataset. Therefore, these associations were likely false-positive. Our observations emphasize the need for large sample sizes and stringent significance thresholds in future association studies for RLS.


Revisiting Brain Iron Deficiency in Restless Legs Syndrome Using Magnetic Resonance Imaging

https://www.sciencedirect.com/science/ ... 8222000894

•Increased iron in RLS was found in the caudate, putamen and red nucleus.

•A meta-analysis revealed no significant evidence of reduced iron in RLS as assessed by MRI.

•Evidence suggestive of publication bias for results on the substantia nigra was found.

•Our results support the view that brain iron mobilization or homeostasis is impaired in RLS.

[ViewsAskew]

Looks like there they are some disputes to the current research.

Reassessment of candidate gene studies for idiopathic restless legs syndrome in a large GWAS dataset of European ancestry

https://scholar.google.com/scholar?hl= ... xIwDp3k0J

Conclusion

In summary, none of the significant single variant associations from candidate gene studies were confirmed in our GWAS dataset. Therefore, these associations were likely false-positive. Our observations emphasize the need for large sample sizes and stringent significance thresholds in future association studies for RLS.


Revisiting Brain Iron Deficiency in Restless Legs Syndrome Using Magnetic Resonance Imaging

https://www.sciencedirect.com/science/ ... 8222000894

•Increased iron in RLS was found in the caudate, putamen and red nucleus.

•A meta-analysis revealed no significant evidence of reduced iron in RLS as assessed by MRI.

•Evidence suggestive of publication bias for results on the substantia nigra was found.

•Our results support the view that brain iron mobilization or homeostasis is impaired in RLS.

That's why I love science! You hypothesize, test, and do it all over again always questioning.

[Frunobulax]

Looks like there they are some disputes to the current research.

Reassessment of candidate gene studies for idiopathic restless legs syndrome in a large GWAS dataset of European ancestry

From what I understand, it's a common pattern that some gene candidates are identified for some diseases -- and the followup studies almost always fails to reproduce that. Not specific to RLS at all, just a consequence of the mathematical methods used to analyze the available data. This is very well explained in the book by Stuart Ritchie ("Science Fictions") that I can't recommend enough.

The other paper is very interesting, thanks for sharing! Will have to read this in detail. I wasn't aware that transferrin is increased in RLS patients, a possible connection to oxalates that block iron release from transferrin (see viewtopic.php?f=20&t=11030)?

[XenMan]

F wave in restless legs syndrome, as an electrophysiological response of clinical relief
by
Safiye Gul Kenar,Ebru Bilge Dirik,Gorkem Tutal Gursoy,Nuriye Kayali &Sule Bilen

While the 'iron cult' wastes everybody's time and any progress on RLS, this is significant and supports other papers on nerve irregularities from RLS affected limbs.

No one seems interested in the motor and sensory aspect of RLS anymore, which is shared with many conditions that are now clumped under RLS as the diagnosis criteria is just being 'restless'.

"F wave is a late response that follows the motor response (M) and is elicited by supramaximal electrical stimulation of a mixed or a motor nerve", this is what I like to hear and fits with those who have a physical element. Or maybe everyone has a physical element but it isn't obvious.

As the S in RLS is syndrome, this could be important for diagnosis and treatment and stop the 'RLS is this' generalizations, with progress made when it is seen as a symptom of a variety of conditions.

A very nice find.

[badnights]

Not research but a bit of history & commentary. Not sure if one needs an account to access the link, so I copied the article below. https://www.medscape.com/viewarticle/98 ... 51730#vp_1

<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<BEGIN QUOTE
The Truth About the 'Happy Hormone': Why We Shouldn't Mess With Dopamine
Marta Zaraska
October 10, 2022

Google the word "dopamine" and you will learn that its nicknames are the "happy hormone" and the "pleasure molecule" and that it is among the most important chemicals in our brains. With The Guardian branding it "the Kim Kardashian of neurotransmitters," dopamine has become a true pop-science darling — people across the globe have attempted to boost their mood with dopamine fasts and dopamine dressing.

A century ago, however, newly discovered dopamine was seen as an uninspiring chemical, nothing more than a precursor of noradrenaline. It took several stubborn and hardworking scientists to change that view.

Levodopa: An Indifferent Precursor

When Casimir Funk, a Polish biochemist and the discoverer of vitamins, first synthesized the dopamine precursor levodopa in 1911, he had no idea how important the molecule would prove to be in pharmacology and neurobiology. Nor did Markus Guggenheim, a Swiss biochemist, who isolated levodopa in 1913 from the seeds of a broad bean, Vicia faba. Guggenheim administered 1 g of levodopa to a rabbit, with no apparent negative consequences. He then prepared a larger dose (2.5 g) and tested it on himself. "Ten minutes after taking it, I felt very nauseous, I had to vomit twice," he wrote in his paper. In the body, levodopa is converted into dopamine, which may act as an emetic — an effect Guggenheim didn't understand. He simply abandoned his human study, erroneously concluding, on the basis of his animal research, that levodopa is "pharmacologically fairly indifferent."

Around the same time, several scientists across Europe successfully synthesized dopamine, but those discoveries were shelved without much fanfare. For the next three decades, dopamine and levodopa were pushed into academic obscurity. Just before World War II, a group of German scientists showed that levodopa is metabolized to dopamine in the body, while another German researcher, Hermann Blaschko, discovered that dopamine is an intermediary in the synthesis of noradrenaline. Even these findings, however, were not immediately accepted.

The dopamine story picked up pace in the post-war years with the observation that the hormone was present in various tissues and body fluids, although nowhere as abundantly as in the central nervous system. Intrigued, Blaschko, who (after escaping Nazi Germany, changing his name to Hugh, and starting work at Oxford University) hypothesized that dopamine couldn't be an unremarkable precursor of noradrenaline — it had to have some physiologic functions of its own. He asked his postdoctoral fellow, Oheh Hornykiewicz, to test a few ideas. Hornykiewicz soon confirmed that dopamine lowered blood pressure in guinea pigs, proving that dopamine indeed had physiologic activity that was independent of other catecholamines.

Reserpine and Rabbit Ears

While Blaschko and Hornykiewicz were puzzling over dopamine's physiologic role in the body, across the ocean at the National Heart Institute in Maryland, pharmacologist Bernard Brodie and colleagues were laying the groundwork for the discovery of dopamine's starring role in the brain.

Spoiler alert: Brodie's work showed that a new psychiatric drug known as reserpine was capable of fully depleting the brain's stores of serotonin and ― of greatest significance, as it turned out — mimicking the neuromuscular symptoms typical of Parkinson's disease. The connection to dopamine would be made by new lab colleague Arvid Carlsson, who would go on to win a Nobel Prize.

Derived from Rauwolfia serpentina (a plant that for centuries has been used in India for the treatment of mental illness, insomnia, and snake bites), reserpine was introduced in the West as a treatment for schizophrenia.

It worked marvels. In 1954, the press lauded the "dramatic" and seemingly "incredible" results in treating "hopelessly insane patients." Reserpine had a downside, however. Reports soon changed in tone regarding the drug's severe side effects, including headaches, dizziness, vomiting, and, far more disturbingly, symptoms mimicking Parkinson's disease, from muscular rigidity to tremors.

Brodie observed that when reserpine was injected, animals became completely immobile. Serotonin nearly vanished from their brains, but bizarrely, drugs that spur serotonin production did not reverse the rabbits' immobility.

Carlsson realized that other catecholamines must be involved in reserpine's side effects, and he began to search for the culprits. He moved back to his native Sweden and ordered a spectrophotofluorimeter. In one of his experiments, Carlsson injected a pair of rabbits with reserpine, which caused the animals to become catatonic with flattened ears. After the researchers injected the animals with levodopa, within 15 minutes, the rabbits were hopping around, ears proudly vertical. "We were just as excited as the rabbits," Carlsson later recalled in a 2016 interview. Carlsson realized that, because there was no noradrenaline in the rabbits' brains, dopamine depletion must have been directly responsible for producing reserpine's motor inhibitory effects.

Skeptics Are Silenced

In 1960, however, the medical community was not yet ready to accept that dopamine was anything but a boring intermediate between levodopa and noradrenaline. At a prestigious London symposium, Carlsson and his two colleagues presented their hypothesis that dopamine may be a neurotransmitter, thus implicating it in Parkinson's disease. They were met with harsh criticism. Some of the experts said levodopa was nothing more than a poison. Carlsson later recalled facing "a profound and nearly unanimous skepticism regarding our points of view."

That would soon change. Hornykiewicz, the biochemist who had earlier discovered dopamine's blood pressure–lowering effects, tested Carlsson's ideas using the postmortem brains of Parkinson's disease patients. It appeared Carlsson was right: unlike in healthy brains, the striatum of patients with Parkinson's disease contained almost no dopamine whatsoever. Beginning in 1961, in collaboration with neurologist Walther Birkmayer, Hornykiewicz injected levodopa into 20 patients with Parkinson's disease and observed a "miraculous" (albeit temporary) amelioration of rigidity, motionlessness, and speechlessness.

By the late 1960s, levodopa and dopamine were making headlines. A 1969 New York Times article described similar stunning improvements in patients with Parkinson's disease who were treated with levodopa. A patient who had arrived at a hospital unable to speak, with hands clenched and rigid expression, was suddenly able to stride into his doctor's office and even jog around. "I might say I'm a human being," he told reporters. Although the treatment was expensive — equivalent to $210 in 2022 — physicians were deluged with requests for "dopa." To this day, levodopa remains a gold standard in the treatment of Parkinson's disease.

The history of dopamine, however, is not only about Parkinson's disease but extends to the treatment of schizophrenia and addiction. When in the1940s a French military surgeon started giving a new antihistamine drug, promethazine, to prevent shock in soldiers undergoing surgery, he noticed a bizarre side effect: the soldiers would become euphoric yet oddly calm at the same time.

After the drug was modified by adding a chlorine atom and renamed chlorpromazine, it fast became a go-to treatment for psychosis. At the time, no one made the connection to dopamine. Contemporary doctors believed that it calmed people by lowering body temperature (common treatments for mental illness back in the day included swaddling patients in cold, wet sheets). Yet just like reserpine, chlorpromazine produced range of nasty side effects that closely mimicked Parkinson's disease. This led a Dutch pharmacologist, Jacques van Rossum, to hypothesize that dopamine receptor blockade could explain chlorpromazine's antipsychotic effects — an idea that remains widely accepted today.

In the 1970s, dopamine was linked with addiction through research on rodents, and this novel idea caught people's imagination over the coming decades. A story on dopamine titled, "How We Get Addicted," made the cover of Time in 1997.

Yet as the dopamine/addiction connection became widespread, it also became oversimplified. According to a 2015 article in Nature Reviews Neuroscience, a wave of low-quality research followed — nonreplicated, insufficient — which led the authors to conclude that we are "addicted to the dopamine theory of addiction." Just about every pleasure under the sun was being attributed to dopamine, from eating delicious foods and playing computer games to sex, music, and hot showers. As recent science shows, however, dopamine is not simply about pleasure — it's about reward prediction, response to stress, memory, learning, and even the functioning of the immune system. Since its first synthesis in the early 20th century, dopamine has often been misunderstood and oversimplified — and it seems the story is repeating itself now.

In one of his final interviews, Carlsson, who passed away in 2018 at the age of 95, warned about playing around with dopamine and, in particular, prescribing drugs that have an inhibitory action on this neurotransmitter. "Dopamine is involved in everything that happens in our brains ― all its important functions," he said.
We should be careful how we handle such a delicate and still little-known system.

END QUOTE>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>

[stockton2malone2]

https://academic.oup.com/sleep/article/ ... 12/6356055
Evidence that a lot of neurologists still aren't up to date on how to use dopamine agonists.

https://www.sciencedirect.com/science/a ... 5722012254
More evidence of seasonal variation in RLS. Still far from set in stone, but it seems like for some people it is worse in summer. I cant think of any reason why though. Bodies are ridiculous.

[Yankiwi]

A possible reason for seasonal variation in RLS—at least for me—is that I sleep better in cooler weather and less well in warm or hot weather.
If I'm waking up due to being hot in the night my RLS seems to be worse.
That might not matter where summer air conditioning is popular but most Kiwis don't have air conditioning.

[jul2873]

This is all really interesting. Since I've had the iron infusions, my RLS is "moderate" I'd say. With kratom, I usually wake up two or three times in the night, get up, take a little kratom in orange juice, and then can usually go right back to bed. So I'm guessing that's a moderate disease. I don't have PLMS, and I've never augmented on anything. I'm thinking maybe I don't have any kind linked to genetics, but both of my daughters also have RLS, and I'm very worried about one of my grandsons. But then I'm wondering if the reason mine is manageable is that I've never taken a DA long enough to augment on it. The most that I've taken one is only a week or two, almost as a favor to my doc. Damn! What I really wish is that some brilliant researcher would have RLS, and decide to really figure it out!

[Rustsmith]

What I really wish is that some brilliant researcher would have RLS, and decide to really figure it out!

There has been a "breakthrough" into the mechanism of RLS that was done by a brilliant neuroscientist at the NIH about 3 yrs ago. Here is a link to the first part of the summary of his efforts. viewtopic.php?p=98769#p98769

The important thing was that this was the first time that a theory was proposed that explained the role of brain iron deficiency as well as why this causes a buildup of both the dopamine that causes our movement issues and the glutamate that causes our insomnia.

As a result of his research, two clinical trials were done in Europe looking at the use of dipyriadamole, which were unfortunately delayed by Covid. Dipyriadamole is an old anti-clotting agent that was used only because it is readily available, cheap and has few side effects. The trial results showed that the theory is sound, but that more work needs to be done. The patients in the trials only had mild to moderate RLS and benefited. Several of our members with severe RLS convinced their doctor to let them try it. It helped most of them a little bit, but wasn't as effective as any of the other treatments. But there are loads of possible experimental compounds in that same class, so there is hope that something will eventually be developed that is as effective as the opioids and doesn't have the side effects of any of our current treatments.

[XenMan]

The important thing was that this was the first time that a theory was proposed that explained the role of brain iron deficiency as well as why this causes a buildup of both the dopamine that causes our movement issues and the glutamate that causes our insomnia.

In most of these papers there is the reference to motor and sensory functions, and in this one "deficits of sensorimotor integration" is used, which either isn't understood by people on the forums and doctors, or is ignored as it doesn't fit with their beliefs.

There are numerous conditions or situations where restless legs is described as a symptom, from mental health issues, drugs use and withdrawal, physical and neurological abnormalities. There is this absolute obsession that RLS has to be neurological and from a cascade effect from low iron.

There is no common sense that it is possible that there could be a range of contributing factors to those with RLS, of which no change of brain function is a possibility. There are papers that support this, but the tunnel vision continues.

The simple version of motor and sensory is that the brain has parts that sense what is happening in the body, and the restlessness or symptoms are a reaction to abnormalities. These can exist with something physical or a 'hyperactivity' in that part of the brain that get false 'wrong' signals. Try to find an explanation in a paper as to why when you move your legs the symptoms stop. It just isn't there because it is assumed that you understand that it is because of the motor and sensory aspect.

The paper linked, "The Adenosine Hypothesis of Restless Legs Syndrome" is interesting as one pathway, but is in no way the answer to all causes and all the symptoms experienced.

There will be no real progress and improvements for sufferers until there is a major overhaul on diagnosis, as the current criteria is too wide and captures too many conditions and causes for a vague diagnosis of 'restless legs'.

[Frunobulax]

There is this absolute obsession that RLS has to be neurological and from a cascade effect from low iron.

[...] Try to find an explanation in a paper as to why when you move your legs the symptoms stop. It just isn't there because it is assumed that you understand that it is because of the motor and sensory aspect.

Well, you know the story of the man who is apparently searching for his car keys in the middle of a night? Somebody comes by and helps him. Both happen to search under a lamp post. After looking for a while, the helper asks "are you sure your keys are here?"? The other answers "actually I lost them over there in the dark, but the lamp light makes it so much easier to search.". (Or something like this.) In medicine, 99% of the research is trying to make sense with the diagnostics we know, typically the stuff that has been around for 50 years or so and can be found every medical textbook. We mostly ignore new technologies.

The adenosine hypothesis is a good one, and one can argue that RLS is likely neurological because we haven't found a biomarker yet and brain chemistry can't be easily researched. While this is a valid argument, it's in no way a proof and it greatly overestimates our understanding of biochemistry and signal processing in the body. But "neurological" is also a label that is applied way too often -- many metabolic diseases manifest first in the brain, because it has a higher demand of energy (by an order of magnitude) compared to any other body organ including the heart. But you may still find abnormalities in the blood, if you look for them.

As for the iron -- if iron deficiency was the key, why is it that iron IVs help only half of us? The iron-driven research went nowhere so far, and it's high time to consider that iron deficiency might be a *symptom* of whatever causes RLS, just a correlation and not the *cause* (if we assume that BID correlates tightly with RLS). Even for those patients that have low iron and an iron IV fixes the symptoms, it's still a good idea to wonder why these patients had low iron in the first place.

This whole discussion reminds me very much of Alzheimers research. We know that these patients have beta amyloid buildup in their brains, so research has focused pretty much exclusively on preventing this buildup -- with disastrous results. Many drugs designed to slow down beta amyloid went into trials that had to be stopped because they actually accelerated the disease, at best they were neutral. So, conclusion? Amyloid buildup is most likely a correlated symptom, a side effect from whatever causes Alzheimers. (Some doctors like Bredesen even argue it's protective, and a body response designed to slow Alzheimers, and have pretty convincing arguments for that.) And still, seems like every new Alzheimer trial is just another drug targeting beta amyloid.

This tunnel vision is typical for medicine, unfortunately. People have tried to explain atherosclerosis with cholesterol since about 1950, because cholesterol was well known and could be measured (cheaply). Newer research is simply ignored, for example the fact that studies in the 60s established that triglycerides (which were known and measureable, but not cheaply at the time) are a much better predictor for atherosclerosis than cholesterol ever was. Forget about anything newer, like that we have known for 20 years that atherosclerosis seems to be linked tightly to inflammatory processes, while higher cholesterol actually correlates with a higher life expectancy. Even today most doctors go ballistic if a patient has slightly elevated cholesterol and refuses to go on a statin.

Sorry for rambling.

[XenMan]

This whole discussion reminds me very much of Alzheimers research.

The latest drug that is proving effective actually targets amyloid. I have been following the 'it is amyloid, the research was flawed on amyloid, now a drugh works' story for a while and I really don't know what to make of it. More data is needed.

"Lecanemab finds and removes amyloid that builds up and forms clumps in the brains of people with Alzheimer's disease. Lecanemab is the first drug to help improve the symptoms of Alzheimer's by slowing the disease."

Aduhelm didn't work and was approved by the FDA in the US and uses the same principle.

You make some good points on iron. There are many papers that support iron, fail to find it, and have found the original studies to be flawed. As you mentioned it is interesting that low iron then iron infusions help many with RLS, so it is a factor for some people. It is most likely linked to hyperactivity in motor and sensory parts of the brain.

But as I have stated previously, until the criteria separates people into specific groups of uncomfortable symptoms, an urge to move due to pain or the general urge to move legs, nothing is going to improve as a large range of conditions are going to be included in research.

Which helps no one.

[Frunobulax]

Moved my answer to a place where it's more on topic: viewtopic.php?p=108405#p108405