The engineer in me has to wonder: is this something we can synthesize?
If it were possible to induce this "dishwasher-like" surge of cerebrospinal fluid in the brain during waking hours, would we be able to live off of significantly less (or no) sleep?
I'm not saying that it's necessarily a good idea, but it would have a plethora of practical applications -- pilots, truckers, etc. would be able to stay awake in a healthful way, rather than by ingesting stimulants.
I've been interested in the science of sleep for a while -- I wrote a side project, http://sleepyti.me, that actually gets quite a bit of traffic -- but neuroscience is mostly lost on me.
It seems rather likely that other neurological functions occur during that time as well. Unless we have the ability to simulate all of them, we shouldn't assume that the ones we ignore aren't important.
It would be especially harmful if we ended up suppressing the processes that make you feel sleepy when you need sleep, while the harmful effects of sleeplessness remained.
(Former neuroscientist here.) This is true of caffeine, for example, which is an adenosine analog (e.g. it has a similar shape and fits into the same receptors). Adenosine is a signal to a cell that it's running low in energy. Caffeine competitively binds to the spots on receptors where adenosine goes, effectively preventing the cell from communicating its low energy state.
Now here's the kicker. When your body builds 'tolerance' for caffeine, what this usually means* is the post-synaptic cell adjusts how much adenosine it's pumping out so that the "I'm tired" signal can cut through the caffeine. And when you go through caffeine withdrawal, it takes a while for those levels to re-adjust to normal.
* in the brain. Caffeine also has effects on your digestive tract, blood pressure, and some other non-brain parts. :)
Edit: corrected cAMP -> adenosine (simple recall error from a lecture that was 9 years ago). The gist of the reply remains the same.
This is incorrect information. (... Like so many biology/chemistry comments I see on HN.)
Caffeine is more like an adenine analog, not a cAMP (3'-5' cyclic adenosine monophosphate) analog. It binds adenosine receptors, not primarily cAMP receptors. It has indirect effects on cAMP, but I am not aware of direct ones. Also, your description of cAMP signaling sounds confused, since cAMP is an intracellular second messenger. I am not aware of an extracellular retrograde signaling process for this molecule.
Sorry, and your implication that cAMP is a byproduct of ATP consumption is totally wrong. cAMP is synthesized directly from ATP, a reaction catalyzed by the regulated enzyme adenylate cyclase.
Thank you for the correction. I mis-remembered a minor detail from a lecture that was 9 years ago, and have find/replaced cAMP -> adenosine in the above post. The gist of the post, though, remains the same. That is, caffeine competitively inhibits receptors that gate ion channels, and the mechanism of tolerance is an increase in the concentration of the thing that it competitively binds.
(My thesis was on auditory cognition and I haven't touched ion channel biophysics in that long. I have a long-ago memory that adenosine (now corrected) operated as a retrograde transmitter, though since I'm probably not going to spend my afternoon looking for the citations, I'll delete as well for now. Not because I believe it's wrong, just that I can't immediately back it up.)
Are you still doing research yourself or have you left for startup land like most of HN?
Thanks for making your corrections as well. Yes, I am in research, and I mostly come here for what's new in Python, learning algorithms, and data analysis. As an aside, it's tough to wade through the "startup land" and personal health advice and keep a straight face in all honesty, but there are few other places that aggregate the things I'm interested in on the computing side of things. An "HN" with users that specialize in bioscience would be very interesting, but I don't know of one with any level of seriousness/activity.
datatau [0] might be worth checking out, if you're not familiar.
since bioscience isn't on my radar i'm not sure if you'd find anything useful there, however, it feels like a more concentrated version of HN which specializes in some of the other stuff that interests you (e.g. learning algos, data analysis, etc.).
"Caffeine competitively inhibits phosphodiesterase, the enzyme that degrades cyclic AMP...By blocking the degradation process of cyclic AMP, caffeine indirectly affects regulation of cAMP-dependent protein kinases". TIL.
I think it's useful to think of it not as a "bad thing" but as a very high-interest loan from your future self.
In moments of weakness and pushing a deadline, I have sometimes rationalize the trade-off of future time/health to present time, and sometimes, that sticks me with tolerance that it takes time to wean off. I have made a conscious effort to quit caffeine dozens of times in my life, and the most recent time it has stuck, and I plan to stick with it. The thing is, when I gain "time" with caffeine, it's not necessarily time with high-quality cognition or productivity compared to my well-rested self, and it's easy to forget to take that into account when you're making trade-off decisions when tired. You still perform like a tired person, you're just not subjectively feeling the tiredness.
FWIW, drinking decaf gives you the health benefits of coffee with 5% (kinda negligible) amounts of caffeine.
I gave up caffeine a few years ago, for the very reasons you speak of. I feel completely different now - my thinking is broad and calm, rather than narrow and frantic.
Personally, I enjoy the flavor of Swiss water decaf more than others (and by reasoning of the "Dorito effect," that flavor may have something nontrivial to do with the nutrients left in it; it also happens to not use additional solvents).
That said, a lot of the risky solvents used in the usual methods of making decaf are no longer commercially used these days, so I don't think there's a serious health risk in drinking any ol' decaf you want.
I had heard that alcoholics who drink coffee have a markedly decreased chance of developing cirrhosis, something like a 60% reduction. But only for regular caffeinated coffee- not tea, not decaf coffee. Do you have any insight into why or is this not true?
When discussing possible mechanisms for their findings:
"We postulate that the observation of the benefit of coffee on the progression of liver disease may be due to its effects on the oxidative stress/lipotoxicity pathway, which underlie the pathogenesis of cirrhosis related to alcohol, NAFLD and possibly, in part, CHC. However, since oxidative stress is not the predominant mechanism of injury seen in CHB, coffee has no beneficial effect. Polyphenols and melanoidins, which are major components of coffee, have been shown to mediate multiple protective mechanisms in a rat model of steatohepatitis, ranging from increased fatty acid β oxidation, mitigating oxidative stress and curtailing liver inflammation (47). The other components of coffee, cafestol and kahwoel, can induce phase II detoxifying enzymes, including sulfotransferase, UDP-glucuronosyl transferase, glutathione transferase and peroxidase, and thus contribute to the anti-oxidant properties of coffee (14, 48). In addition, chemicals in coffee such as polyphenols and the diterpenes have been shown to down-regulate proinflammatory, fibrogenic cytokines such as transforming growth factor beta (TGF-β) and its downstream modulator, connective tissue growth factor (CTGF), collagen and stellate cell activation (13–16).
Epidemiologic studies on caffeine have been inconsistent in demonstrating a protective effect in liver disease since other caffeine-containing beverages such as tea have not shown to be protective (19–21). Similarly, in our study, the inverse association with caffeine became null after adjustment for coffee, suggesting that ingredients of coffee other than caffeine appear to be responsible for this beverage’s effect on risk reduction. Furthermore, other caffeine-containing beverages like green tea and black tea had no significant effects with cirrhosis mortality in this study."
Modafinil is designed for narcoleptics, people who are theoretically getting too much sleep. It is not actually intended for people to use to stay up beyond the recommended range. If you stay up for multiple days you are increasing the build up of these plaques, because the brain is not able to clear them out while you are awake.
"Is designed for" implies a lot more than what it means here. If I remember correctly, the mechanism behind Modafinil is unclear. The usage is approved for narcoleptics, but also for people who want to shift their circadian rhythm (because it [allegedly] doesn't carry the sleep debt that other stimulants do).
Is there any information (affirmative or negative) about Modafinil's effects on this plaque? Considering how recent this whole discovery seems to be, I doubt there's much conclusive info on this specific interaction.
Yeah, the "doesn't carry the sleep debt" bit is dubious at best. Maybe not at much. But it doesn't fit my experience at all. Anecdotes not being data, and all that, but for me at least I still wear down over time with a couple of uses of modafinil a week unless I actually make sure to catch up on sleep, to the point where I am careful to limit how often I use it, even though it is far easier to avoid totally crashing with than caffeine and generally feels less stressful on the body (whether that feeling reflects reality, I don't know).
Well I think you're talking about something different. From what I've heard (and in my experience), I can skip a full night of sleep with Modafinil and then fall back into my normal sleep schedule the day after.
You'll probably fall asleep earlier in the day, but you'll only sleep for 8 hours. This is why it's useful for offsetting your rhythm.
Ritalin/Adderall is very different. If you use it to stay up for 8 hours, you'll sleep for 16 hours the next time you pass out.
>Ritalin/Adderall is very different. If you use it to stay up for 8 hours, you'll sleep for 16 hours the next time you pass out.
From my subjective experience, this isn't necessarily true. All-nighters with modafinil vs. all-nighters with adderall require the same amount of catch-up sleep for me. Modafinil just gives me a less jittery wakefulness.
If you fall asleep earlier in the day, you're paying offf your sleep "debt" right away. When I use it I go to bed at roughly normal bedtime the following night. At that point 8h sleep is certainly not enough. Though I'll usually not "catch up" more than 1-2 hours extra that night. If I want to I can push through and continue as normal, and even do multiple more cycles, but over time I do end up tired enough that I need to catch up with more sleep.
I tend to prefer to use it to offset sleep for relatively short periods - e.g. get an extra night of work, and then sleep a bit longer for the next couple of nights - as I feel it's more productive to get a longer block of time where I'm fully alert, and give up late evenings when I'd feel tired anyway to recover.
Modafinil also, in my experience, does not make you likely to sleep less over time. What it does let you, similar to caffeine - but totally different feeling - let you portion out your sleep differently. Whether I delay sleeping with caffeine or modafinil, I end up wearing down until I catch up.
In my opinion, efficiently using our current methods for deferring sleep boils down to understanding that you're merely deferring it, and using it to "schedule" your most awake/concentrated periods when you need it most, rather than try to force yourself to work well all the time.
Maybe one day we have something that can let us cut sleep entirely, but we're still far away from that.
EDIT: As I've clarified in another comment below, my sleep amounts without anything are already fairly low, and that may certainly affect my ability to push it further down with modafinil over the long term.
I take armodafinil for a chronic fatigue condition that has been ruled out as any of the diagnosable sleep disorders. It absolutely causes me to sleep less, but that probably has to do with it making me want to go to sleep just a little bit later and not having room to add more sleep in the morning.
It also builds tolerance in a kind of annoying way; it prevents me from napping or sleeping even when it no longer makes me not tired.
> It also builds tolerance in a kind of annoying way; it prevents me from napping or sleeping even when it no longer makes me not tired.
Interesting. I can sleep just fine on modafinil, but I still have greatly increased focus if I just choose to stay awake. Also, I've never noticed any increase in tolerance (which I get very quickly with caffeine and alcohol), even taking it every day for two weeks, although maybe that's not very long.
I've been taking it for about two years, often skipping it on days I don't have to work, and it's definitely not as effective. Once, though, I did lose about three weeks' worth when it got accidentally tossed during a move. Insurance doesn't tend to cover that sort of thing, and the stuff is $500+/month, so I just struggled without. When I refilled it and started taking it again, I was bouncing off the walls a little bit.
Aside from the above hiccup, I come out ahead on cost if I go through my insurance rather than try to buy from India. There would also likely be some lag time involved that wouldn't have helped in that instance.
You read reviews of suppliers. Lots of reviews. And you look up images of the genuine packaging from reputable manufacturers like Sun Pharma, and compare.
You might very well be in a different situation to me if your fatigue previously made you sleep more than you necessarily need. For my part I sleep less than average already without taking anything at all, so I might very well be pushing the lower end of the viable long term sleep amounts.
Original source: asked doctor for modafinil to enable working harder for more hours. Doctor said, No, you might think it's a good idea now, but if you're back here a couple months later with depression, you'll realize it's not worth the risk.
This shows the importance of sleep, but also adds to the question of what we can do to facilitate this process while awake. It seems the best we can do when we are awake, is to use neuroprotective substances to prevent the build-up of the plaques or to sequester them for easier breakdown while sleeping.
For example, Noopept, the di-peptide form of the nootropic piracetam, has been shown to lower levels of amyloid plaques via "hydrophobic interactions with toxic amyloid oligomers, [which] prompts their rapid sequestration into larger fibrillar amyloid aggregates." In the linked study, researchers concluded that the "mitigating effect of noopept against amyloid oligomeric cytotoxicity may offer additional benefits to the already well-established therapeutic functions of this new pharmaceutical."[1]
The abilities of substances like this to protect the brain as we age, are examples of why we need to move major parts of the medical field to focus on preventative and rejuvenating medicine, instead of just treatment for the final symptoms of a disease that has been in progress for decades...
Background info:
This is a process of what is now called the glymphatic system. The scientest quoted in the article (M. Nedergaard), previously coined the term "glymphatic" in her paper[2] "The Garbage Truck." She was a follow-on author on the paper referenced in the NPR story, "Sleep Drives Metabolite Clearance from the Adult Brain." It is a pretty interesting paper and I have a full-text copy available in my private research vault [3].
"The team discovered that this increased flow was possible in part because when mice went to sleep, their brain cells actually shrank, making it easier for fluid to circulate. When an animal woke up, the brain cells enlarged again and the flow between cells slowed to a trickle." So no, probably not.
From what I've read, the brain partially 'compartmentalizes' it's communications at regular intervals, and dreaming is what happens when this process finishes: the different compartments start communicating, synthesizing multiple independent thought processes into a cohesive whole. (Which would explain why they can be seemingly random and also relevant of recent events.)
It feels like since we evolved under conditions of sleeping for a third of our lives, there are probably lots of other biological mechanisms that depend on sleep happening to work.
Your comment made me think that maybe: excess sleep is a wonderful survival strategy for an individual (stay out of danger, and conserve energy), but a disastrous strategy for long term development of a species (everyone sleeps in a cave for half the day, learns nothing, make no progress, fail to evolve faster than competing species that spend more time awake)
The brain only conserves 15–25% [1] of energy during sleep and does not appear to be a reason sleep evolved. It seems that the pressure between the cerebral spinal fluid and the interstitial fluid cannot build up to the required level while the brain is awake and fully active.
He's not talking about the brain conserving energy (the brain doesn't use that much energy anyway) but rather the organism as a whole by not performing other physical activity (e.g. an early human looking for food during the night when the African predators are active.)
Well, IIRC the brain receives 25% of the body's blood flow. I think that means it's using a lot of energy (but I'm not a doctor, or a physiologist, or a biologist...)
I think that's true. Here's more support for the idea that the brain actually uses quite a lot of energy:
"Although the average adult human brain weighs about 1.4 kilograms, only 2 percent of total body weight, it demands 20 percent of our resting metabolic rate (RMR)—the total amount of energy our bodies expend in one very lazy day of no activity."
The figure I've seen is 20%. If you burn about 2000 calories a day that works out at about 97 watts on average. 20% of that is about 19 watts. Bit more detail here:
Despite all of the progress in integrated circuits, the best we have is still nowhere near theoretical limits for computation per unit energy or unit space.
1. What makes you so sure you learn nothing during sleep? All the articles I've read about sleep's role in learning have indicated that it helps us process what we pick up during the day.
2. Why is 'progress' so important? Progress towards what? What are we chasing after?
Whilst I realise you were only questioning sleep from the point of view of its utility, for me utility alone kind of misses the point. For me the rituals around sleep are some of the best parts of daily life. I love drifting off to sleep, I love dreaming (when I'm lucky enough to remember it at least), I love waking up without any great urgency, slowly coming to my senses, wrapped in the warmth of a comfortable bed. Whilst I appreciate it wasn't your intention, I dislike the notion that our time must be spent on making ourselves better people, if we aren't causing great harm isn't enjoying what we do reason enough to do it?
RE 2. I agree with your sentiment, but I think GP didn't intend to imply we're supposed to want progress, only that when you have two competing species, the one that progresses faster will outcompete the other one. Life forms aren't fitness maximizers, they're adaptation executors - they do stuff because they like doing stuff, not because they recognize evolutionary fitness as important.
I'm not arguing against any points you made, but I would like to give a reminder that in human history it's a relatively recent luxury to be able to enjoy sleep like you are describing. It took a lot of 'progress' to get to do that! And still many people are not able to.
Do you mean to say "fail to die faster"? You can't hasten evolution by doing stuff, unless that stuff affects you passing on your genes to your children. You pass the exact same genetic materiel regardless of how many pushups you do or skills you learn.
I've wondered about that for years. I've always felt the body/mind heals/repairs itself during sleep.
It's too bad our economic society doesn't value sleep? Never understood having to arrive at most jobs before 10 a.m. I've had so many jobs that want employees there the job site at 7 a.m.? I show up, but I'm not truly working until afer 10 a.m., and I'm not the only one?
Then again--I have honestly never been a morning person.
Seems like a different issue. Nothing about the start time says anything about how much sleep you get.
On the other hand people sleep better in the dark so if your start time implies you're going to bed when it's light out it could cause problems. Unless you use a prosthetic night (curtains).
>> On the other hand people sleep better in the dark
I don't understand how people manage this. I fall asleep in less than 5 minutes if I lie down while the Sun is up in the morning, and stay solidly asleep until an appropriate number of hours have passed. Going to bed in the dark, I can toss and turn for anywhere from 30-120 minutes before finally dozing off.
Night owlism is real, and it's seriously debilitating to be required to conform to working a 9-5/10-6 job. It's Friday night, so I get to live my weekend hours. It's 2:30am now, and I'll be up another few hours. Whenever I am on vacation, or between jobs, I instantly swap to a nocturnal schedule. It is extremely painful to have to work during the day, to the point where I burn out after 12-18 months at a job. For the first time in a decade, I've almost made it 2 years at a single employer. That time is running out. I need a reversion back to my normal hours for a while. :(
I wonder how cognitive functions and our personality would be affected? Two halfs make a whole, yin and yang and all that, if half the brain is asleep, would we even be able to think straight?
Hemispherectomy (removal of one half of the brain) is a treatment for Rasmussen's encephalitis when it's sufficiently severe (or the seizures are not responding to drugs). If done very early in life, the plasticity of brain makes it such that those patients grow up to be normally functioning adults. We believe this is because the regions that specialize for different tasks are able to combine their function on the same half.
Think of, for instance, the "language" areas (Broca's area and Wernicke's area). (The following over-simplified explanation assumes typical right-hand dominant individuals for the sake of brevity.) If you inactivate that area in the left hemisphere (using drugs or transcranial magnetic stimulation), you'll lose "language" processing of data that occurs around 1 Hz (in English, this corresponds to individual words, phonemes; in tonal languages, this includes tones of lexical significance). If you inactivate that area in the right hemisphere instead, you'll lose "language" processing of data that occurs an order of magnitude slower than that (in most languages, this corresponds to pitch and volume changes over the level of the sentence, and can convey prosody information such as speaker intent as well as speaker identity).
Due to specializations like this, hemispherectomies are not performed later in life. You would get symptoms similar to stroke patients. But for all areas, not just language.
So the brain can function normally without a whole half? That's very interesting. Now I'm wondering how much can be removed without adverse effects :-)
A non-precise answer: a surprisingly large amount if you're careful about which parts to remove and if you do it really, really early in life. ;)
In adults (or even adolescents) though, not as much luck.
In the case of hemispherectomies on Rasmussen's patients, you can analogize it as: people are dual-core by default. If you remove one of the cores early enough in life (like <5 yrs old), you can re-route the wiring so that processing can done by one of the cores, and still be pretty much normal. But whatever subtle thing is lost when if we don't do parallel processing like we usually do -- that things is pretty subtle to test for as well.
We would be able to think reasonable normally, apparently, assuming the sleeping half doesn't send confusing signals.
There have been quite a bit of research on people with severed brain stems, where the brain halves effectively are cut off from each other and limited to communicating through external senses. In those situations the brain halves are actually exceedingly good at trying to obscure that anything is wrong by making inferences of actions carried out by one brain half that the other one could not possibly have knowledge of.
The bigger problem is that because the brain halves control different parts of the body, we'd likely lose a lot of our physical function.
Probably would not be very useful. You would lose motor control of half of your body. When the left half of the brain sleeps, you would be a total mute as well.
Sleep has been shown to be a factor in learning, so functions that happen during sleep could be related to learning disabilities. So yeah, being able to induce this state might be very useful for treating some conditions.
If we could accelerate the process and/or control duration and/or induce it at will it would have major implications even if we're unable to remove the need to sleep fully.
If it were easy, think of the evolutionary advantage: you're never vulnerable to predators and you get twice as much working time per day.
The fact that sleep still exists seems to suggest that this is hard and involves some nasty tradeoffs between the "dishwasher mode" and more operational neurological states. It's also likely that more than just this occurs, and that sleep is used to take care of a whole laundry list of housekeeping operations.
Except prior to artificial light sources, you would still be forced to stay sheltered or spend your time huddled up with weapons at the ready.
> and you get twice as much working time per day.
Until our work consisted of something other than hunting and gathering this would likely not have been all that much of a benefit.
On evolutionary timescales it would seem most of our evolution has happened in conditions where we were severely constrained with respect to what we could safely do during the night anyway, and so there'd be relatively little benefit to working around whatever the problems of avoiding sleep are.
I don't doubt that cutting sleep will pose all kinds of challenges we're not even aware of yet, though.
The evolutionary argument is nice but maybe we're just stuck in an old 'branch' local minima. Think of axolotl limb regeneration. We only have partial regeneration but somehow nature felt it was more efficient not to regenerate full limbs and try to survive crippled. Long sleep may have been necessary, but maybe that's not the case anymore.
neurologists at UCLA Alzheimers center have developed a formulation of Curcumin called "Longvida" which appears to reduce the accumulation of this brain plaque: http://alzheimer.neurology.ucla.edu/Curcumin.html
Curcumin and Alzheimer’s disease. Our group has tested curcumin in several models and found that it not only reduces oxidative damage and inflammation (as expected), but also reduces amyloid accumulation and synaptic marker loss while promoting both amyloid phagocytosis and clearance. In in vitro studies, we found curcumin worked to prevent synaptic marker and cognitive deficits caused by amyloid peptide infusion and abeta oligomer toxicity. Our work on curcumin and AD is discussed in detail in our publications
its important to note that it is only the Longvida formulation of Curcumin which effect because it crosses the blood-brain barrier, although other types seem beneficial for other conditions.
It seems more that Curcumin that isn't passed into the kidneys can pass the blood-brain barrier[0], and you can help prevent that by taking it with piperine; most formulations, at least on Amazon, have piperine in it, if it doesn't take it with some black peppercorns. It appears the only difference between most formulations and Longvida is that they pair it with coconut oil? That's what I could gather from their formulation, they don't even list piperine.
I'm skeptical of the brand in particular, not in the sense that it's bio-available, but their claim that only their brand crosses the blood-brain barrier[1][2].
In general I agree with the other comments that discuss that lack of sleep might have other issues so "work arounds" designed to help pilots and truckers probably aren't a good idea. However and in particular connection to this article there might be people who are at risk for Alzheimer's where it makes sense to "sweep" the brain more than once a day? So normal sleep + another process around 2pm? Not sure if it would work like that but that was what I wondered when reading this/
Some people have difficulty falling asleep, and other people have trouble staying asleep (often waking up really early in the morning). The latter is much more common amongst older people, even though the amount of sleep they "need" has not decreased -- they just have a hard time staying asleep for long periods of time. In that scenario (when falling asleep is not the hard part), a nap is probably a pretty good idea.
There's reason to believe that there are other processes that would have to co-occur, like an increase in the extracellular space to allow for clearance of these toxins, AB proteins, etc.
It's not so simple as simply increasing the amount of CSF influx into the brain, but also increasing interstitial space via adrenergic receptor inhibition.
The clearance of beta-amyloid, etc. is largely linked to the state of sleeping that would be tough to isolate without inducing sleeping itself.
Was just about to go to bed, when I saw you mentioned that you wrote http://sleepyti.me. Got up to go to my computer to say that I use it all the time!! Thanks for the awesome tool.
If it were possible to induce this "dishwasher-like" surge of cerebrospinal fluid in the brain during waking hours, would we be able to live off of significantly less (or no) sleep?
I'm not saying that it's necessarily a good idea, but it would have a plethora of practical applications -- pilots, truckers, etc. would be able to stay awake in a healthful way, rather than by ingesting stimulants.
I've been interested in the science of sleep for a while -- I wrote a side project, http://sleepyti.me, that actually gets quite a bit of traffic -- but neuroscience is mostly lost on me.