How much sleep do you actually need for peak performance? What is going on in our brain while we're under anesthesia, and is it possible that anesthesia research could lead to the potential to live forever? We touch on all of this and more on Data Nation. I'm Liberty Vittert. Today, my co-host Munther, the head of MIT's Institute for Data, Systems, and Society and I are speaking with Emery Brown. Emery is a professor of anesthesia at Harvard Medical School and Massachusetts General
Hospital. We start with what it means to be asleep versus under anesthesia.
You know, often when someone is going to a surgery. the anesthesiologist will say ‘oh you’re going to go to sleep for a little bit and we're going to wake you up,’ but I know from talking to you so many times, sleep and anesthesia have similarities, but they're different. So maybe just kind of a quick overview - how is sleep different from anesthesia and how much do we know about both?
First of all, we as anesthesiologists shouldn't say to patients we're going to have them go to sleep, because they're not going to be asleep, they're going to be under general anesthesia. So let me just give you a definition of general anesthesia first. So it's a drug-induced reversible state that consists of roughly four components. So you're unconscious,
you won't be able to perceive or process pain, you won't form memories and you won't move around. It makes it easy for the surgeons to operate, but you do that with physiologic stability and it's reversible, so that is basically a drug-induced reversible coma, and if you think about it you need to be in a coma so that someone could do a surgery on you, whether it’s open up your chest or open up your abdomen, so you can tolerate it. But it has to be reversible because you put someone
in the state and you bring them out of it. So that's general anesthesia. When you compare that to sleep, sleep is entirely different. Sleep is a physiologic process that we go through every night in order to help, sort of, restore ourselves, and if you think about it sleep has roughly two components. The non-REM sleep and then REM sleep. So, we alternate between those two states roughly about every ninety minutes, we do that about four to six times a night and we do different things
during two states. During the REM sleep state - rapid eye movement state - our brains are working, probably enhancing connections, pruning some others, reinforcing certain memories or concepts that we want to remember, and during the slow wave part or the non-REM sleep, we're mostly resting. So they're entirely two different processes, and the confusion comes about because we as anesthesiologist get sloppy and say sleep when we talk to our patients, and that we just shouldn't
do. When I talk to my patients, and I say you're going to need anesthesia for your surgery, what I'll say to the patient is ‘you're going to be unconscious, you won't feel any pain, you won't remember anything that's going on. I'll make sure that you're comfortable, watch your heart rate and blood pressure. You won't be moving around while the surgeons are operating, and then as soon as we're done, we'll wake you up.’ So what do I do, I give them a definition of general
anesthesia that a lay person can understand. I don't get anywhere near mentioning the term sleep.
I read some of your work, and you know given the fact that this anesthesia is basically a regulated, or I guess you'd say monitored coma, from my understanding even the deepest levels of sleep - and correct me if this is too much of a lay person's understanding - but that the deepest levels of sleep aren't even similar to the lightest levels of anesthesia. So does that mean that the brain could actually go to many other states under anesthesia that we haven't even
really tested? That there's these depths that you could go to under anesthesia that we don't know?
Well, let me say it this way. So the brain is very complex, a very complex quantity, and let me just make another general statement. There are many ways you can turn off a complex quantity, and so sleep and anesthesia are under two different – they’re two different types
of dynamics that are created within the brain. So, for example, when you're under anesthesia, the drugs create oscillations which are persistent oscillations, low frequency oscillations that are at high amplitudes that are maintained for the whole time that we keep the anesthetic drugs running or infusing. In contrast with sleep, you have oscillations which change
their characteristics throughout the course of the night. What I would think about it is, they both represent dynamic states of the brain and the brain can have a million different dynamic states because it's so complex, and this one that we use with anesthesia is a drug control induction of dynamic states that make it possible for you to tolerate a traumatic procedure,
essentially put you in a coma. It's extremely different from sleep. Remember, one of the key things with sleep is even when you're in your deepest state of sleep, if I shake you I can wake you up, but that won't happen with anesthesia.
So this is very interesting, and I know that interacting with you for so many years, now measuring has become so critical, so important, and we can do it so easily in the operation room and so forth, and so maybe we'll segue to that a little bit in terms of what one can do with it. But one question I always had - have we witnessed evidence, say, by looking at EEG data or different types of data that there are benefits to anesthesia
or harm to anesthesia? So as we think of, we contrasted that from sleep only because we're somewhat unconscious but it's a different process. Sleep seems to have incredible effect on our memory and so forth. Does anesthesia have anything that we measure that has a certain benefit that one can - like an induced coma of some sort you know those things… Of course, I'm mixing a lot of terminology, but somehow one could potentially see some relationships.
Now, that's a good question. So, let's start with the harm. When we place you in a state of general anesthesia, the drugs create these oscillations and these oscillations are not natural, they're not states your brain naturally goes into. So keeping a person in - particularly an older person - in a state like that for an extended period of time is really not a good thing
if you could avoid it, but you need it because the person needs surgery. So, not surprisingly, when a lot of patients, particularly elderly patients, wake up from anesthesia, they have trouble with maybe memory formation, word finding, and they may be delirious and some of these side effects can last for several hours or going on to several days. So that's a part which is not beneficial. Another case, though, where anesthesia is actually helpful, which is rather interesting, is in
treating depression. So the anesthetic ketamine is now used in low dose to treat depression and it turns out to be highly effective. Many hospitals have set up ketamine clinics where patients come in in the afternoon, they get an infusion of ketamine, they do that for a series of weeks,
and these are people who usually failed other medications. So that's actually a helpful benefit of anesthesia, and I think the jury is out because we have really not studied in detail the neuroscience of anesthesia as much as you might have thought we would have now, and this is I think an area for us to continue to pursue actively over the next several years.
In the same sense of these benefits that could come from anesthesia or sedation or these sort of altered states, there was a study that looked at COVID-19 Patients who'd been treated for weeks or months with mechanical ventilations, and they'd been slow to become conscious even after they were taken off sedation, and there was an article - it was in the Proceedings of the National Academy of Sciences (PNAS) that offered this hypothesis that this response could
be the effect of sort of this hibernation-like state invoked by the brain to protect cells from injury when oxygen is scarce. So is there a chance that anesthesia or sedation or regulated coma would be the key to in some way, almost this very futuristic movie-like idea of preserving our bodies or defying aging or, you know, is there any sort of truth to these Matrix-like movie concepts?
Well, so in the spirit of full disclosure, so I was co-author on those two articles.
Ah that's why I have them. (Laughs)
So the first article was the consortium effort between three hospitals: between Columbia, Cornell and also Mass General Hospital, in which we compared our COVID patients who are recovering from COVID after their mechanical ventilation had stopped, and there was a significant proportion of the patients who had some degree of hypoxia for extended periods, and those patients seemingly it took them a long time to finally wake up after all their respiratory issues had
resolved, and when they woke up, they came to, their brains were perfectly intact. And then in the PNAS paper, what my colleague Nico Schiff (Dr. Nicholas D. Schiff) and I did, we started speculating as to what could be going on. It's a perspective paper, it's a hypothesis, and the hypothesis is maybe what happened was those patients stumbled into a brain-protective state, and we looked at some situations in nature where things like this happen,
and one of the things that we looked at in detail was the painted turtle. So the painted turtle goes into a period of a hibernation-like state for a period of several months during the year, and during that time when it becomes hypothermic because the temperatures outside go down, and what it does is it turns up its responsiveness to GABA. So GABA is one of the principal receptors that
anesthetics bind to. It turns up its production of GABA and its sensitivity to GABA, and then the other thing that happens is when you look at its EEG, its EEG looks like a patient who's deeply anesthetized, and they can stay in this state for several months, and then when the winter's
over they bring themselves out of it. And so what we conjectured was maybe these patients had stumbled into a state like this in their recovery from COVID, because one of the key features of this state, in the case of the turtle it’s profound anoxia – a limited to no oxygen
supply. So we put that out there, and if this is the case, and we could find a way to control this, then it means there's a possibility of coming up with a way to maybe better treat patients in the ICU who need to have their brains protected for extended periods of time.
I don't mean to push this, but I can't help it because I've seen too many movies. Is the future of something like anesthesia, and as we understand more and more about it, is it something where we could preserve people's bodies for long periods of time or that we could defy age? Is that - is that a possible future finding given this hypothesis?
Well, with this hypothesis, I think what it suggests is if we could build a way to create this state, it would certainly to first order be a way to maybe treat really sick patients in the ICU. So we could legitimately rest their brains and their bodies while they recovered from whatever illness that had afflicted them and maybe some wild kind of science fiction epic, you know, this is the way we do suspended animation and send people to Mars or something and
we wake them up. But again, it's a hypothesis and it's something we want to start exploring, but it's very interesting that there's this really clean analogy with the painted turtle, so if we're able to create a similar state in humans there could be enormous therapeutic value for patients
So, Emery, tell us a little bit about the research trajectory in anesthesia. Initially, presumably all of this was done experimentally and there's so much data, so much ways in which we can exploit the information that we're gathering. We can also maybe build
simulation systems where can test the impact on sleep or so forth. How's that been working, and do you expect really big steps in terms of the progress, because now our capability of building complex models and understanding how to use the data for that?
Yeah, I think there's a lot of possibilities there now. One of the first things to understand is sort of the philosophy of anesthesia research, the way it's been up until now. So up until now, it's focused mostly on pharmacology, sort of drug design. How the drugs are metabolized in the body, how the drugs have effects in the body, and very little if any at all on the neuroscience of anesthesia, and in fact we're taught conventions
to deliver, let's say, the inhaled gases. The inhaled gases, let's say like sevoflurane, isoflurane, desflurane, they’re still ethers, the same ethers that were discovered in 1846, they're derivatives of ether. So, we dose those drugs based on projected concentrations in the expired gases, not thinking at all really about what's happening in the brain. So, the one thing that we've tried to emphasize in our research is that - something really simple,
the drugs are acting in the brain. So why don’t we understand how they're having those effects in the brain and then use that understanding to design better approaches to deliver anesthesia? So I think in one sentence, the future of anesthesia lies in incorporating more neuroscience into
the study and practice of anesthesiology. Munther: Do you see that advancing more rapidly today with the advanced methods of learning from data and the ability to measure and so forth, or do you see this sort of linear progression in research? I think the ability to use data more effectively will help us quite a bit. I think it'll help us understand the measurements that we're making both in clinical patients like in
the operating room and the ICU. I think it'll help us analyze these larger data sets much more efficiently, but that won't replace doing good first principled experiments that try to decipher how various parts of the brain work and how we could get to various parts of the brain to
control them and create the states of anesthesia. So, I think, if I had to pick one to choose first, I would choose the principled experiments and then the analysis of volumes of data, because the data without really strong and principled hypotheses will not help us very much.
I can't help but bring it back around to sort of what we originally started with, you know. what's the difference between sleep and anesthesia, and I want to just touch on sleep a little bit more because I know listeners are super interested in how they can better their sleep, how they optimize their sleep and whether it's that, you know, anesthesia and these sort of
regulated comas could maybe help us understand more about someone's sleep. I don't know whether they're connected in that way, or even if there is a way to understand how to get better sleep or what a person's optimal level of sleep is. For all the good benefits that we've talked about that it does. Is there is there a perfect number, is there a magic number when it comes to sleep?
So there is an intersection between studying sleep and also studying anesthesia, and it relates to one of the drugs that we have which is called Dexmedetomidine. So, Dexmedetomidine is a derivative of Clonidine which has been around for a number of years. It's been used as a sedative for a long period of time. Dexmedetomidine is a sedative, it's not an anesthetic. In other words, it itself will not make you profoundly unconscious or not
sufficiently unconscious so you could have surgery, but it's a sedative. So we use it in the ICU to sedate patients or we use in the operating room as an adjunct. So what happens is that if you look at how Dexmedetomidine turns off the brain - that is produces it states of unconsciousness - it very closely mimics the way that sleep initiates itself, and the way you go into slow wave sleep, and that's by turning the brain off from the brain stem,
right. And the reason this is important is that this is one of the ways that you produce non-REM sleep, non-REM stage two sleep and also non-REM stage three sleep. So there have been studies which have shown that this drug when used as a sleeping agent enhances slow wave sleep, and there's work being done now to build a sleeping aid based on this and in terms of having a more principled approach to producing a sleep aid which actually works more closely
the way the brain itself turns off when you have sleep, this would be the candidate. Because if you think of most drugs that are out there on the market as sleep aids, if instead of sleep aids you call them weak anesthetics or sedatives that would be a much more active description of what
they do. They may act as sedate you and some of them actually act very much watch the way anesthetics do in terms of the way they alter brain circuit activity to create sedation, but what happens is they're just not as potent, and so the thought is just by turning down your level of brain activity your natural sleep mechanisms take over and that's how these drugs these sleep
aids help you become sleepy. With Dexmedetomidine it may actually work in such a way that actually initiates sleep more closely the way the brain would initiate sleep, and in principle that would be more desirable. So there's developmental work being done on that idea right now.
Sign me up for the clinical trial. I'm in. You have a patient right here.
Okay, I've got - I wrote you down.
So Emery, just in terms of that kind of progress - what about the duration of anesthesia? And you do hear, I don't know, whether it's myth or kind of hearsay about the fact that some people start waking up in the middle of a surgery and then some other mechanism is employed, and also kind of stories about how ‘I felt, I felt really terrible, even though I didn't feel anything.’ Are these things sort of ad hoc or are they related to what's going on in the operation room?
No, they're very real. I mean, I think that on the list of things that patients are most paranoid about when they realize they're going to have to have general anesthesia, I would say that's one of the things that's most frightening to them, the likelihood that they may be aware and the anesthesiologist not appreciate it. So, first of all, let me just put this into perspective. I mean, it gets a lot of press when it happens, but it's not a public health
menace. Awareness under anesthesia happens one in every 10,000 or one in every 20,000 cases, and it's perfectly preventable, and one of the ways to prevent it is to use the EEG to monitor the level of unconsciousness of patients under anesthesia, and pretty much in all these cases
where people have had awareness, the EEG wasn't being used. And now having said that, the EEG is not a requirement to administer anesthesia as you might think it would be, and that's a major issue and that's something that we've been campaigning for trying to provide good solid scientific support as to why that should be the case, because it's very clear to us that by tracking the EEG you can have very good understanding of how unconscious someone is, and if that is the case,
then just like we eradicated smallpox, we could eradicate awareness under anesthesia the same way.
So we shouldn't be scared going into our general anesthesia?
You shouldn’t be, you shouldn't be.
But the idea that you may be waking up, is that a real thing?
Let's say it's real but rare.
Okay, right, so awareness is connected to being awake.
Being awake, and so if I made you profoundly unconscious you will not be aware.
Right.
So in the last few years, we've really done detailed studies of this both in human as well as in non-human primates, and in a paper we published two years ago with Earl Miller, my colleague in Brain and Cognitive Sciences at MIT, we did some detailed anesthesia studies in non-human primates where we recorded simultaneously from four brain regions, and we have this really nice picture in
the paper which shows the brain activity when the animal’s awake and executing a task. So you see these very low frequency oscillations, you see the neurons spiking wherever they want and just to make it quantified a little bit, the spike rates of the neurons are about 10 to 12 spikes per second, then we look at with the animal when it's profoundly unconscious, you see very large slow oscillations and then when you look at how the neurons are spiking,
the neurons are spiking at one-half to one spike per second. So how do we use that information clinically? So if I'm anesthetizing someone and I bring them to a state where I see the slow oscillations and also Alpha oscillations the way that we saw in these nonhuman primates, then I can infer that their brains are in a similar state to what we see in the non-human primates, and so I can feel pretty comfortable and let them rest assured that they're not going to have awareness.
Emery, every research community has aspirations, and you can do a lot with anesthesia today, but by understanding the science and understanding the neuroscience and bringing it together with the drug design, what do you hope to accomplish and what is the dream result that the community is looking at?
Yeah, for me I can define it sort of in two stages. So what I'd love to see over the next, let's say, one to three to five years, I'd love to see everybody using the EEG. So let's talk about improvements we could make without changing the current level of technology, but just using the current level of technology better. I'd like to see is everybody use the EEG so they're monitoring
their patients under anesthesia and using that to guide drug dosing. I’d really like to see us develop closed loop control systems that can help us deliver the drugs in a much more efficient way, because we can teach computers to watch the brain more carefully than we can ourselves, particularly for long cases, and actually probably more importantly for patients in
the Intensive Care Unit who end up being sedated for like several days. I would also like to see us use some neuroscience principles to deliver the drugs in a much more neuroscientific fashion, and we've written about this in a paper we call multimodal general anesthesia, and it explains the neuroscience of how the drugs act to actually choose the combinations in a much more principled way. Then finally, I'd like to see us develop drugs so – like, right now when the
surgery's over, we just turn the drugs off. We try to time it so it they come off at the right time relative to when the surgeon finishes the surgery and we hope you wake up. We don't give anything to turn the brain back on. This is an area where my colleague Ken Solt has been working on for a
little over ten years, to come up with drugs that can help us turn the brain back on. So, I'd love to see us do this over the next several years, and with that alone over the next five years, that will dramatically improve anesthesia care, and then beyond that - I mean on my big wish list for the future, I'd like to see us develop more site-specific anesthetics. Right now,
anesthetics work by going everywhere in the brain and central nervous system. What I’d love is to see us develop site-specific drugs that actually just control specific targets, and in controlling those specific targets - generate a state of general anesthesia - we then remove the drugs from the targets and the person comes to. I mean, that would be the aspiration.
Yeah, I can tell you I'm never going under general anesthesia again unless my anesthesiologist has an EEG. I'm on it now. (Laughs.) I'm - that's the first question I'm going to ask.
Just get Emery to be there.
Yes, thank you so much.
Happy to.
This has been MIT's Data Nation. Please rate and review us on Apple podcasts, it really does help listeners find us. I'm Liberty Vittert, thanks for listening.