Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep, 2025, Natalie L Hauglund et al

[Mij]

Highlights
•
Norepinephrine release from the locus coeruleus drives slow vasomotion in NREM sleep
•
Infraslow norepinephrine oscillations control opposing changes in blood and CSF volumes
•
Norepinephrine oscillation frequency during NREM sleep predicts glymphatic clearance
•
The sleep aid zolpidem suppresses norepinephrine oscillations and glymphatic flow

Summary
As the brain transitions from wakefulness to sleep, processing of external information diminishes while restorative processes, such as glymphatic removal of waste products, are activated. Yet, it is not known what drives brain clearance during sleep.

We here employed an array of technologies and identified tightly synchronized oscillations in norepinephrine, cerebral blood volume, and cerebrospinal fluid (CSF) as the strongest predictors of glymphatic clearance during NREM sleep. Optogenetic stimulation of the locus coeruleus induced anti-correlated changes in vasomotion and CSF signal. Furthermore, stimulation of arterial oscillations enhanced CSF inflow, demonstrating that vasomotion acts as a pump driving CSF into the brain.

On the contrary, the sleep aid zolpidem suppressed norepinephrine oscillations and glymphatic flow, highlighting the critical role of norepinephrine-driven vascular dynamics in brain clearance. Thus, the micro-architectural organization of NREM sleep, driven by norepinephrine fluctuations and vascular dynamics, is a key determinant for glymphatic clearance.
LINK

 

[Ravn]

in mice

Danish article about this study with brief mention of CFS (which doesn't appear to figure in the study itself, assuming my word search didn't miss it)

But just as importantly, the new knowledge about noradrenaline also provides a potentially new understanding of chronic fatigue syndrome, where you feel tired even though you are asleep [auto-translate may have been the one asleep here].
The condition cannot be diagnosed by standard sleep studies because nothing abnormal shows up on the EEG, which measures the brain's electrical activity.
“This may indicate that the pumps are not working in chronic fatigue syndrome and that sleep does not cleanse the brain sufficiently,” says Maiken Nedergaard.

 

[SNT Gatchaman]

Also an article in Science —

https://www.science.org/content/article/scientists-uncover-how-brain-washes-itself-during-sleep

 

[Murph]

POssible linkages here from adrenergic theories of me/cfs / cerebral blood flow theories of mecfs to why sleep is non-restorative in me/cfs, but you'd need a lot more work to establish them as any sort of fact.
Still, could be worth someone applying for funding to look at cerebral blood flow during sleep and adrenergic markers in pwme and controls.

 

[EndME]

POssible linkages here from adrenergic theories of me/cfs / cerebral blood flow theories of mecfs to why sleep is non-restorative in me/cfs, but you'd need a lot more work to establish them as any sort of fact.
Still, could be worth someone applying for funding to look at cerebral blood flow during sleep and adrenergic markers in pwme and controls.

Or perhaps the different levels of Norepinephrine between ME/CFS and HC's recorded in the intramural study?

 

[hotblack]

And a write up on Arstechnica
https://arstechnica.com/science/202...-with-the-brains-internal-cleaning-mechanism/

I was also pondering potential ME/CFS relationships too. Either something disrupting norepinephrine and this process which triggers some symptoms or perhaps something else causing a build up of junk and the brain/body responds with increases in norepinephrine to try to clean up with this process.

Given this how this process is theorised to work I’m not sure if just checking norepinephrine levels in blood would tell us much? And I don’t think anyone would want the same sort of investigations that the mice had…

 

[Sean]

POssible linkages here from adrenergic theories of me/cfs / cerebral blood flow theories of mecfs to why sleep is non-restorative in me/cfs, but you'd need a lot more work to establish them as any sort of fact.
Still, could be worth someone applying for funding to look at cerebral blood flow during sleep and adrenergic markers in pwme and controls.

Definitely worth looking into.

 

[Amw66]

Moved post

From X, interesting thread



1/
New Cell paper from the team that discovered glymphatic clearance (how your brain removes waste during sleep).

Sleep hours DIDN'T predict brain cleaning. Neither did REM or deep sleep.

They found what actually matters - and why some sleeping pills might undermine it


2/
We've known for years that sleep clears toxic waste from the brain (amyloid, tau - proteins linked to Alzheimer's).

But nobody knew what actually drives this cleaning process. Most studies used anaesthesia, which isn't real sleep.

3/
This team instead built a method to watch brain fluid dynamics in NATURALLY sleeping mice.

They found during deep sleep, norepinephrine pulses every ~50 seconds. Each pulse squeezes blood vessels, pushing cleaning fluid through the brain.

4/
Finding #1: Quality of sleep > quantity.
The frequency of norepinephrine pulses predicted brain clearance better than total sleep time, REM sleep, or deep sleep duration.

5/
Finding #2: Those brief awakenings during sleep? Not necessarily bad.

Micro-arousals correlated with better brain cleaning. They're part of the natural norepinephrine rhythm.

6/
Finding #3: They proved causation.
When they artificially made blood vessels oscillate faster, brain cleaning increased in those regions.

More pumping = more clearance.

7/
Finding #4: Zolpidem (Ambien) is a problem.
It helped mice fall asleep faster but suppressed the norepinephrine oscillations.

Result: Significantly reduced brain cleaning compared to natural sleep.

8/
Bottom line: We may have been measuring the wrong things about sleep.

Total hours, REM percentage, deep sleep duration - none predicted brain cleaning as well as norepinephrine pulse frequency did.

cell.com/cell/fulltext/…

 

[Jonathan Edwards]

Bottom line: We may have been measuring the wrong things about sleep.

And may still be?
I have yet to be convinced that any of ths stuff makes sense.
Why should this 'pumping' have to occur particularly during sleep. Maybe it doesn't.
Maybe it doesn't do much either.

 

[Hutan]

If zolpidem suppresses the norepinephrine oscillations, and inadequate brain cleaning contributes to ME/CFS, then presumably zolpidem would make ME/CFS worse.

Has anyone here with ME/CFS used zolpidem?

I was also pondering potential ME/CFS relationships too. Either something disrupting norepinephrine and this process which triggers some symptoms or perhaps something else causing a build up of junk and the brain/body responds with increases in norepinephrine to try to clean up with this process.

That's an interesting idea. I wonder if more rapid norepinephrine pulsing in response to a waste product might result in the increased heart rate that we seem to see during sleep in ME/CFS? Although perhaps we actually have to show that the heart rate during sleep really is increased in ME/CFS first.

 

[Utsikt]

If zolpidem suppresses the norepinephrine oscillations, and inadequate brain cleaning contributes to ME/CFS, then presumably zolpidem would make ME/CFS worse.

Has anyone here with ME/CFS used zolpidem?

I’m on 10mg and some milder sleep meds. I slept very very little before starting it. I still only sleep a few hours, but especially my cognitive capacity is way better than before.

 

[hotblack]

Never zolpidem but I was prescribed zopiclone. Some years pre ME/CFS I was prescribed it and used it to great effect intermittently for a short period and slept very well and restfully each time. Post ME/CFS the effects were wildly different, with some help getting to sleep and then massive and unpleasant rebound a few hours later.

 

[Stuart79]

And may still be?
I have yet to be convinced that any of ths stuff makes sense.
Why should this 'pumping' have to occur particularly during sleep. Maybe it doesn't.
Maybe it doesn't do much either.

Assuming the observed pumping is real, is it possible pumping isn’t primarily about waste clearance?

Perhaps the pumping serves some other purposes, like maintaining homeostasis in some way. Something more akin to mixing or using force from the waves to better reach tissue with fluid.

Playing the devil’s advocate, if the waves are real, doesn’t evolution suggest they likely has some sort of purpose?

 

[Hutan]

3/
This team instead built a method to watch brain fluid dynamics in NATURALLY sleeping mice.

They found during deep sleep, norepinephrine pulses every ~50 seconds. Each pulse squeezes blood vessels, pushing cleaning fluid through the brain.

Playing the devil’s advocate, if the waves are real, doesn’t evolution suggest they likely has some sort of purpose?

I suppose, playing devil's advocate back, it could just be as simple as being just a result of deep sleep involving relaxed muscles and reduced muscle activation (which it does). So, perhaps there is a risk of everything becoming sluggish and not enough oxygen getting to the brain during these times. Perhaps the norepinephrine pulses are simply to keep the brain alive, bring nutrients to the cells and do a somewhat normal amount of waste removal at a time when the muscles, including those around blood vessels, otherwise wouldn't work very well to do that job?.

 

[SNT Gatchaman]

I would recommend people read this review article if they want to understand the glymphatic system; what sleep is for and why the brain does poorly without it. It's comprehensive, but well written.

Fluid transport in the brain (2022, Physiological Reviews)

The aim of this review is to provide a detailed description of the current understanding of brain fluid dynamics, which in the past years has undergone a major overhaul. Diffusion was long believed to be the predominate transport mechanism within the brain, even though early work had already shown simple diffusion to be insufficient as a clearance mechanism for brain, one of the most metabolically active tissues in the body.

The discovery of the glymphatic pathway provided not only an explanation to the decades old mystery but also opened up a new biological field of study, which is helping us to understand how brain clearance is maintained in the healthy brain, why we need to sleep, and the root cause of neurodegenerative diseases. The biological constraints of state-dependent higher brain functions have rarely been considered, but emerging evidence points to a deterioration of homeostatic glial function in the genesis of most, if not all, neurological and psychiatric diseases.

 

[Kitty]

Never zolpidem but I was prescribed zopiclone.

Me too. I stopped because it never felt like sleep; I just wasn't awake.

Not only did it offer no benefit over poor sleep, it made me feel worse because I was hung over the next day. It's not supposed to make you hung over, but it did.

I tried three different sorts of sleep meds, and none of them seemed to induce actual sleep. They were just a way of being less bored in the middle of the night, but with unwanted side effects. I ended up wondering why in God's name anyone would take them! I probably didn't think about the possibility they might work better in other people...

 

[Jonathan Edwards]

Assuming the observed pumping is real, is it possible pumping isn’t primarily about waste clearance?

Playing the devil’s advocate, if the waves are real, doesn’t evolution suggest they likely has some sort of purpose?

But the aorta pulsates and as far as know nobody thinks that has a function. It is simply a necessary side-effect of blow flow being maintained by a cyclical pumping device. What matters for the tissues is simply the continuation of flow.

EEG brain waves are 'real' but the persistent idea that somehow they 'do' something is nonsense. They are just a statistical measure of billions of separate events being partly synchronised.

I would recommend people read this review article if they want to understand the glymphatic system; what sleep is for and why the brain does poorly without it.

Maybe, but please do not believe it is authorittive. From the opening sections I strongly suspect it is based on a string of misconceptions. Reviews in immunology usually are and reviews in the area of neuroscience I know best (the study of conscious experience) always are.