Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep

https://www.cell.com/cell/abstract/S0092-8674(24)01343-6

by Jimmc414 • 2 years ago

127 90 2 years ago

Jimmc4143• 2 years ago

key findings:

they discovered the brain's waste removal during NREM sleep (the glymphatic system) is driven by rhythmic norepinephrine pulses controlling coordinated blood vessel movements.

*Zolpidem (Ambien) suppresses this cleaning process by interfering with norepinephrine pulses*

This has implications for Alzheimer's and dementia.

echelon• 2 years ago

Went to look up Ambien's company's stock. Google Gemini is hallucinating like crazy:

Cosette Pharmaceuticals is permanently closed, so there is no stock for the company.
Cosette Pharmaceuticals was a pharmaceutical company that manufactured topical creams, ointments, oral liquids, and suppositories. They had facilities in New Jersey and North Carolina.

No, Google. They're just a private company.

Thanks, Google.

Beyond this, I can't imagine this drug will be something people will want to continue taking. It was already posited to not be good for Alzheimer's, and now they have a smoking gun for a plausible mechanism.

Aurornis5• 2 years ago

Went to look up Ambien's company's stock.

Ambien has been generic for a very long time. It's not an expensive drug.

It's also not even indicated for long-term nightly use. You can find stories online of people who get continuous prescriptions from their doctor, but doing so is a rare practice. Most doctors are nervous to prescribe any drug of this class right now. When they do, it's only for short-term or occasional use.

I don't think this is really a pitchforks-out moment against drug companies.

habitue• 2 years ago

It's one study, on mice. This is the beginning of a long chain where more studies are done -> a consensus is formed -> doctors start to hear about the consensus and take it into account prescribing it

It could plausibly be 20 years before that plays out

AbstractH248• 2 years ago

The other day, I asked Gemini for suggestions on "sunny places in Latin America to visit in January," it recommended Miami.

I'm done with it for another 6 months again.

grahamj• 2 years ago

musk takes Ambien; explains a few things

boringg2• 2 years ago

hey, not everything has to do with musk - he's already enough places without your post.

boringg2• 2 years ago

Question -- will pharma companies try and slander downplay this article?

Jimmc4143• 2 years ago

(edit)

ajmurmann• 2 years ago

Seems like this is an issue for the company that makes Ambien but an opportunity for everyone else in that industry (and for patients)

jayd16• 2 years ago

Why do that when they can sell you even more drugs. Need the glymphowhatever to happily walk down a beach? Try Ambien-G.

TheRealPomax2• 2 years ago

still needs a plain word version of what "norepinephrine pulses" are supposed to be.

varunneal• 2 years ago

norepinephrine = primary neurotransmitter for the sympathetic nervous system (fight or flight). Mostly produced in brain stem/adrenal glands.

vaylian• 2 years ago

Norepinephrine is a hormone which triggers motions of the blood vessels to support the transport of cellular waste products out of the brain.

pjerem• 2 years ago

Zolpidem (Ambien) suppresses this cleaning process by interfering with norepinephrine pulses

Forever or only when taken ? (I can only read the abstract)

Aurornis5• 2 years ago

This has implications for Alzheimer's and dementia.

Long term use of drugs that interact with the GABA-A receptor have been known to be associated with dementia risk for a very long time.

Zolpidem (Ambien) isn't indicated for long-term use, but there are some doctors who ignore this and prescribe long-term. It's rare, though.

I think some people are drawing narrow conclusions from the use of Zolpidem in this study. They're not saying Zolpidem uniquely causes this problem, they're just showing that Zolpidem was one way to trigger this. It's like a property of many sedative hypnotics and quite possibly other types of sleep aids, too. Demonizing Zolpidem isn't the point of this study.

jvanderbot2• 2 years ago

Including Alcohol?

seydor• 2 years ago

implications for Alzheimer's

every other neuroscience paper has that coda

lukeplato• 2 years ago

Michael Edward Johnson has an interesting theory called vasocomputation with the core hypothesis:

vasomuscular tension stabilizes local neural patterns. A sustained thought is a pattern of vascular clenching that reduces dynamic range in nearby neurons. The thought (congealed pattern) persists until the muscle relaxes.

https://opentheory.net/2023/07/principles-of-vasocomputation...

https://x.com/johnsonmxe/status/1863603206649208983

jvanderbot2• 2 years ago

What. This is personally mind-blowing if true.

Aurornis5• 2 years ago

The first words of this article are (EDIT: The article in the parent comment, not the HN link)

A unification of Buddhist phenomenology,

The citations include Buddhist writings and an entry that just says "Collected Twitter threads"

This is not serious science. This is Twitter-era new age mysticism with a dash of scientific words.

Jimmc4143• 2 years ago

edit: my mistake

patcon• 2 years ago

This person is part of a group that seemingly posts to twitter and cites twitter as statement against academic institution and traditional scholarship. Some members of the group are academics themselves. Maybe some things can only be posted there, and so your intuition is correct. But I think you misunderstand why specifically you are seeing twitter links so prominently used. My sense is it's attacking the politics of citation.

The politics of citation, to be clear, are actually quite fucked up and elitist. E.g., Feminist Approaches to Citation https://cmagazine.com/articles/feminist-approaches-to-citati...

Bjartr• 2 years ago

If that's true, that might also be part of why dreams exist. If the glymphatic cleanout during sleep is a rhythmic constriction wave across the brain, then whatever the brain is doing at the time the wave crosses it becomes a sustained thought as a side effect.

Maybe that's why sleep, in the sense of becoming immobile, is a thing. The brain disconnects a lot of the motor control so that the hallucination caused by sustained randomness from cleanout waves don't make us flail all over the place and hurt ourselves.

byproxy• 2 years ago

Although, not without fail: https://en.wikipedia.org/wiki/Hypnic_jerk

meindnoch• 2 years ago

Holy shit, what a load of new age crackpottery.

no-dr-onboard• 2 years ago

Does anyone else read the title and only identify ~6/9 of the words in the title here? I've got no clue what this is about before clicking on it.

lokimedes2• 2 years ago

Disk defragmentation for wet sponges was my intuitive take.

binary132• 2 years ago

It’s less like defrag and more like uhhhh literally washing out the gunk and metabolic byproducts

Separo• 2 years ago

Only because I heard about it recently. Alternative title: we figured out how the brain gets rid of junk while you sleep.

kylebenzle2• 2 years ago

Yes, most people can understand the title even if every word isn't familiar. But that's HN these days, dumb jokes about the title and no substance:(

nickpsecurity• 2 years ago

You’re not the only one.

lokimedes2• 2 years ago

Based on the names of the authors, it seems to be in danish.

AdmiralAsshat• 2 years ago

https://www.youtube.com/watch?v=Ac7G7xOG2Ag

kylebenzle2• 2 years ago

Normal human here, when that happens to me I use Google rather than post my question to a forum.

But it's ok if you don't know some words, just no need to tell everyone.

knicholes• 2 years ago

I was exposed to a lot of biology in college, so I understood.

stronglikedan• 2 years ago

We're obviously not the target audience here.

wnmurphy• 2 years ago

I recognized the word "glymphatic" from recent articles about the discovery of the brain's self-cleaning system, and then understood from the headline that these authors identified that the mechanism by which this occurs is driven by norepinephrine.

amelius• 2 years ago

anti-clickbait title

dekhn3• 2 years ago

yes, but after about 30 years of this, your brain will start to create a data structure to represent the claim, and then you can sort of backfill with dictionary lookups. I can trace my entire career to reading a single paper by doing this very tediously (it gets easier; eventually, you build an embedding and every paper is really just another point in hypothesis space).

Bio papers (of this type) follow a fairly straightforward pattern:

in this case norepinephrine is the entity- it's a small molecule the brain uses to transmit information around. It literally floats from one cell to another, and the recipient acts upon it.

The effect in this case would be "slow vasomotion"- I ahdn't actually heard of this before, but apparently blood vessels oscillate, independently of normal heartbeat.

The important system- again, something I wasn't particularly aware of- is the glymphatic system. Apparently, it's used for garbage cleanup?

And the conditions are "during sleep"

So basically the garbage gets taken out at night by a little guy.

PittleyDunkin3• 2 years ago

I can trace my entire career to reading a single paper by doing this very tediously (it gets easier; eventually, you build an embedding and every paper is really just another point in hypothesis space).

Tangential, but it really annoys me how people use computational jargon to represent internal mental processes. These are absolutely terrible metaphors outside of computing and I have no clue what you're referring to. What the hell does "building an embedding" even mean with respect to humans? Yea, I'm sure I encode some embedding inside my brain. I'm also certain this is just a tiny part of the mental processes I rely on.

Aurornis5• 2 years ago

Glymphatic system: Waste clearance system in the brain. More active during sleep.

Slow vasomotion: Squeezing and relaxing motion that pumps fluid through glymphatic system

Norepinephrine-mediated: Norepinephrine is a signaling chemical. They discovered that norepinephrine is key to the signaling chain that drives slow vasomotion in the glymphatic system during sleep.

In short, they found that norepinephrine signaling pulses in a specific system trigger a pumping motion that helps with waste clearance from the brain in sleep. They also found that a sleep medication suppresses that norepinephrine signaling, reducing waste clearance during sleep.

As always, be careful interpreting these studies. The amount of medications used in these studies tends to be very high to elicit the desired effect, so we don't know if doses used medicinally in humans cause the same effect or if that effect is significant.

moffkalast2• 2 years ago

Inject norepinephrine into the brain for good sleep, got it.

hn_throwaway_992• 2 years ago

As a Gen Xer, the relatively recent discoveries around the purpose of sleep are pretty fascinating to me. Throughout most of my life, we basically didn't know why we need sleep. It's very clear we (and essentially all vertebrates) do need sleep, but we really didn't know why.

Now we basically do: sleep is when you clear out waste products in your brain. As someone who definitely doesn't understand all the details, it's when "channels" it your brain get opened up so these waste products can be swept away. This study (based on the title) claims to show the mechanism for doing that:

1. Norepinephrine-mediated: norepinephrine is a neurotransmitter, so this is saying it's responsible for the mechanism of action.

2. slow vasomotion - you can Google what vasomotion means, but it's essentially a rhythmic change it the walls of blood vessels - this is essentially the "sweeping away" part I mentioned above.

3. glymphatic clearance - the glymphatic system in the brain is that network of fluid filled spaces in the brain, and it's what clears away brain waste products, so glymphatic clearance means allowing the glymphatic system to "wash away" those waste products.

So, this study claims to explain the mechanism by which waste products get cleared from the brain during sleep, and the larger context is that it is indeed why we need sleep in the first place.

PittleyDunkin3• 2 years ago

sleep is when you clear out waste products in your brain.

It's unfortunately more complicated than this: we also clear out the same waste products in our brain during wakefulness. Mostly at a higher rate, too. Perhaps there's some unique way in which this happens during sleep but this certainly isn't the "key" (if there is in fact one) to why we need to sleep.

AbstractH248• 2 years ago

Another big learning from this is that "not all sleep is created equal." What happens during NREM isn't the same as what happens during REM.

Which surprises me because I thought we were all taught that REM is the best kind of sleep (and the hardest to induce). But also doesn't Ambien reduce the amount of time in REM and increase NREM.

I'm confused again. Someone better educated than me care to explain?

stuff4ben• 2 years ago

Your questions around why we need sleep make me wonder if we could develop a drug cocktail to do that work for us while we're awake. Similar to Iain M. Banks' "Culture" book series where humans can inject themselves with their "drug glands" to improve their capabilities.

TheRealDunkirk• 2 years ago

I'm also squarely GenX. While studying mechanical engineering, one of my roommates was in psychology. He said "we" didn't need sleep. He said one of his professors told them that. I said, "But we ALL do it." He said it was just a convenience thing.

To his credit, he decided to test his theory. By not sleeping. During FINALS WEEK. He said, by the third day, he saw Tom Sawyer and Huck Finn walk across the pages of the book he was reading, and decided it was time to take a nap.

But, hey, I tried smoking banana peel, ala the Anarchist's Cookbook, so I don't have any room to talk.

noveltyaccount• 2 years ago

I know what "sleep" means!

liveoneggs• 2 years ago

Click it because norepinephrine-impacting drugs include ADHD and depression meds.

TheRealPomax2• 2 years ago

"[...] in lab mice", which is always an incredibly important bit to add to titles.

AbstractH248• 2 years ago

It's interesting because I just started taking Qelbree\Viloxazine (a selective norepinephrine reuptake inhibitor), and even though I feel great I have a ton of trouble staying asleep. It seems to be a common complaint among folks talking it.

Before this, I took Strattera\Atomoxetine (which has the same method of action) for at least five years. And while falling asleep has long been difficult for me, staying asleep hasn't been.

Not quite sure how my experience relates, but makes me wonder if either too much norepinephrine also adversely impacts sleep or if I'm sleeping more "efficiently," so to speak, which is why I wake up feeling rested.

I don't remember any sort of similar experience when taking Effexor about a year ago, but I don't believe I ever reached a high enough dosage for the norepinephrine reuptake to take effect.

InDubioProRubio• 2 years ago

Maybe a receptor resistance build up? Seems to be a common pattern that medication needs to be dosed up to work- and blunts the receptors for the "normal" amount the body produces, if it does not cease to produce it at all.

AbstractH248• 2 years ago

I'm not quite sure I'm smart enough to follow.

Don't sNRIs increase the availability of norepinephrine rather than decrease it? Which is effectively the equivalent of producing more, not less?

Llamamoe• 2 years ago

One of the primary roles of norepinephrine is literally mediating alertness, including stress/fight-or-flight responses more specifically.

AbstractH248• 2 years ago

“Mediating alertness”, as in more available norepinephrine increases or deceases how alert you are?

From my experience while awake, I would assume decreases. While it’s yet to have a huge impact on my ADHD, it’s has had a noticeable impact on reducing my self-doubt and hesitance to speak up. But I’m not sure how to unify that with it reducing the quality of my sleep.

Maybe, since I’m taking it in the AM it’s wearing off at night, and thus my level of alertness in the middle of the night is being heightened. That would line up with antidotal reports I’ve read of people saying they had less sleep disruptions when they took it at night. Something I’m planning to try moving to.

It’s also possible it takes take to reach a steady state (I’ve only been taking it two weeks)

monktastic1• 2 years ago

For anyone else not well-versed in the lingo, I thought I'd share this Smithsonian article and attendant Reddit thread. I found them informative:

https://www.smithsonianmag.com/smart-news/in-a-study-on-mice...

https://www.reddit.com/r/science/comments/1hyychf/scientists...

The brain’s waste-removal process is “like turning on the dishwasher,” a neurologist says, but common sleep medications may harm it"
The team then tested the impact of Zolpidem (a common sleep medication also known as Ambien or Zolpimist) on this system, and found that the norepinephrine waves during sleep decreased by 50 percent and fluid transport into the brain decreased by around 30 percent in zolpidem-treated mice. These results suggest that sleeping aids that impact norepinephrine production—which includes most sleeping aids—might harm the brain’s waste-removal system.

1024core3• 2 years ago

but common sleep medications may harm it

Anecdata (size = 1): I was going through a phase of terrible sleep, and one day decided to take some CBD. I woke up feeling terrible in the head. I had slept like a log, but it felt in my brain as if I hadn't slept at all!

trehalose• 2 years ago

You say you were going through a phase of terrible sleep. Would you say that particular night of sleep was worse than your average night of sleep during that phase?

euroderf• 2 years ago

“like turning on the dishwasher"

More like a movie theater ? By the end of the day your shoes stick to the floor and there's a crunch under every step and ideally you'd just hit it all with a firehose.

QuantumGood• 2 years ago

"common sleep medication": not as a percentage of overall usage.

WhitneyLand2• 2 years ago

They found that Ambien interferes with the natural cleaning process or removal of waste products from the brain.

It suggests that artificially induced sleep might not provide all the benefits of natural sleep.

WhitneyLand2• 2 years ago

On a related note, what are the best sleep aides as of 2025?

Are any of the side-effect profiles worth it?

rkagerer• 2 years ago

Does the study cast any concern on melatonin?

rsync• 2 years ago

Exercise.

rickcarlino• 2 years ago

Could this finding have implications for people taking medications like Atomoxetine (an SNRI prescribed for ADHD)?

owkman2• 2 years ago

I was wondering the same thing. I couldn't find any research on what increased baseline norepinephrine does to the pulses. I can see it being detrimental (pulses don't work as well) or neutral (brain adjusts to the new baseline).

fredgrott• 2 years ago

note its not just sleep meds that harm the process....

taking caffeine several hours before sleep does as well as caffeine co-competes with adenosine...adenosine serves to close the hetodimer dopamine receptors...i.e. the dopamine receptors that are tied to locomotion and other things are closed due to the action of adenosine during sleep.

dang2• 2 years ago

Scientists uncover how the brain washes itself during sleep - https://news.ycombinator.com/item?id=42644204 - Jan 2025 (273 comments)

Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep

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