Anesthetics transformed surgical medicine, but even a century and a half after their introduction, much of the science behind them is still not well understood, especially by the public. In this episode, the noted physician-scientist Emery Brown of the Massachusetts Institute of Technology talks with host Steven Strogatz about how anesthesia differs from sleep, what anesthesiologists should tell patients before surgery, and why recordings of brain waves should be collected from patients much more routinely.
News announcer 1: We’re hearing the news now from multiple outlets citing many sources that Michael Jackson has died.
News announcer 2: Late today, unsealed court records confirm the L.A. coroner has concluded the pop singer died of a lethal amount of that powerful anesthetic, propofol.
Steve Strogatz (narration): When I heard that Michael Jackson had died, like everybody else, I was shocked. And as we all started to learn more about the circumstances surrounding his death, everything just got more and more confusing. Our guest today was called on as an expert by Michael Jackson’s family because of his rigorous data-driven research to help make sense of what happened to the King of Pop. And I think what he has to say is very illuminating, not just for the Jackson case.
Emery Brown: It would have been impossible for him to really be having natural sleep. The drug is hijacking his brain circuits.
Strogatz: From Quanta Magazine, this is The Joy of x. I’m Steve Strogatz. In this episode, Emery Brown.
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Strogatz: We’ll get back to Michael Jackson’s tragic death, because the medical issues surrounding it — anesthesia, sleep, consciousness — are at the heart of Emery’s work as a scientist and as an anesthesiologist.
Brown: If I went to a patient, and I said, “Excuse me, Mr. Jones, but I’m going to put you in a drug-induced reversible coma,” I mean, you know, he would get up and run out of the room. But it’s not fair to say, “I’m going to put you to sleep,” because you’re not asleep. You’re in a much deeper state of unconsciousness than sleep.
Steve Strogatz: Uh-huh.
Brown: So, what we should really do is, we shouldn’t say “sleep.” We shouldn’t. I don’t go to my patients, saying I’m going to put them in a drug-induced reversible coma.
But what I would say them, I’d say, “Mr. Jones, look, I’m going to take care of you today. I’m your anesthesiologist. I’m going to be with you the whole time, or one of our anesthesia team members is going to be with you the whole time. You’re going to be unconscious. You’re not going to be aware of anything that’s going on. You’re not going to perceive any pain, and won’t remember anything that transpires. But I’m going to be watching all your physiological signs — your heart rate, your blood pressure. As soon as soon as everything’s done, you know, we’ll wake you right up here in the operating room and take you to the recovery room.”
What I did there was, as opposed to using a metaphor like sleep, I actually just explained, I just gave a lay definition of general anesthesia, which was —
Strogatz: Right. It was very reassuring.
Brown: That’s what we should be doing.
Strogatz: If you gave that to me, I would feel like, “Bring it on.”
Brown: That’s exactly what we should do, because it is not sleep. And we have a tendency to be, quite frankly, sloppy in our language, and that hurts us, because we’re not being frank with our patients about what we’re doing. And it also hurts our thinking about what the process actually is.
Strogatz: Emery Brown is not easy to classify. He’s an anesthesiologist. He’s a statistician. He’s a neuroscientist. And I’m very proud to say something about him that I can say about very few other people on the planet, which is that he’s now a member of three national academies: He’s in the National Academy of Science, of Medicine, and Engineering. And it’s just astonishing and shows you the breadth of his intellectual interest.
He’s particularly interested these days in the basic science of anesthesia. How does anesthesia work? What’s happening in the brain when someone is under general anesthesia, and what does that tell us about not just how we can make anesthesia better, but also, like, to use anesthesia as a window into the basic functioning of the human brain.
Brown: So, if you’re going to have surgery, you’re going to have some sort of invasive procedure which is going to hurt, we need to put you in a state so you can tolerate that. And that is what we call “general anesthesia.” And general anesthesia has about four components. So, the first one is, you’re insensate to pain. That’s really the key one. You’re also —
Strogatz: Mm-hmm. Definitely.
Brown: You’re unconscious. You won’t remember anything. If you’re unconscious, you won’t remember anything, if you’re truly unconscious. And the final one is, you’re not moving around, so that it makes it easier for the surgeons to operate.
Brown: And then just some important addendums. It’s a reversible state. We put you in. We bring you out. In some sense, that’s where we earn our money as, you know, anesthesiologists, by putting you in this drug-induced reversible state. It’s technically a drug-induced reversible coma.
Strogatz: I guess I’m freaked out about the word “coma.”
Brown: We have to really distinguish between the pathological coma that occurs to someone, you know, usually unfortunately, because they had a head injury or brain injury, that sort of thing. But, again, if we go back to why we need general anesthesia to begin with, it’s because someone wants to do an invasive surgical or diagnostic procedure, which you would not be able tolerate otherwise.
Strogatz: Sure. Sure.
Brown: And if you look at the characteristics of someone in coma, and what happens under anesthesia, anesthesia is the same thing, except that what happens is, we can bring you out of the state. We put you in it, and we bring you out. And that happens, you know, roughly 60,000 times a day in the United States.
Strogatz: But, I mean, now that you put it this way, it’s kind of astonishing that someone could open your chest, pull your ribs apart, start doing whatever they’re doing on your heart, and yet the patient under your care is not stressed.
Brown: Oh, exactly. I mean, I think that was, you know, that’s what anesthesiology has evolved into. And it’s no big secret that the first public demonstration of what we now call general anesthesia took place in 1846, here in Mass General Hospital in Boston by William Morton, who was a dentist at the time. And he had realized that he could give people a full set of dentures if he could take out all the teeth. So, you could imagine that would be very, very painful.
Strogatz: Oh, boy. [LAUGHTER] Oh, man. Yeah.
Brown: Yeah. So, he was looking for a way to painlessly extract teeth from a patient. And so, through a number of connections, primarily with a chemist, Charles Jackson, he became aware of ether. And he had the first public-demonstration use of ether for surgery on October 16, 1846 at Mass General Hospital, where the surgeon John Collins Warren removed a tumor from the neck of this gentleman, Gilbert Abbott. I mean, this was truly a transformative event. And if you think about it, this patient was placed in a state where effectively, they could open up his neck, remove a tumor, and then, you know, close it back up.
And what’s so interesting is, we’re still using ethers today. The drugs, like sevoflurane and isoflurane and desflurane, are basically modern day, you know, modern-day ethers. So, we’ve come a long way, and in some respects, we’re still using some — a very original class of drugs that deliver anesthesia.
Strogatz: You’re also more broadly interested in the brain and all kinds of different states of consciousness. So, I mean, we’re used to thinking of consciousness as being conscious, being awake, but you know, we go through life with different states of consciousness.
Brown: As you’re suggesting, it can have this kind of continuum of things, from someone being profoundly unconscious, having no perception whatsoever. Someone being, let’s say, unconscious, perceiving things, but you not realizing it. Right? You not being able to communicate with them. You know, all the way up to dreaming and sleep, and you know, then sort of being wide awake. So, there’s this very, very rich continuum.
And, you know, one of the major fears about anesthesia is, could someone be awake, but an anesthesiologist not perceive it? You know, awareness under anesthesia. This is something that is probably, you know, one of the biggest concerns. It’s the thing which is most — I mean, anesthesia, general anesthesia, the practice of anesthesiology is not something that is written about a lot, but when it is written about, it’s not uncommonly written about in the context of patients having awareness. That is, someone having been apparently under anesthesia, but they were awakening after the surgery is over. When they come to, they tell the anesthesiologist, or the surgeon, you know, “I was perceiving what was going on.” And to be frank, that’s not a public health menace. That’s not something that happens, like, multiple times a day.
Brown: We currently realize that happens one to two in 10-20,000 cases of anesthesia. It’s not a common occurrence. And to my thinking, it’s something which should no longer ever occur if patients are properly monitored during surgery.
Strogatz: You mean, so, like, by looking at their EEG, you would be able to tell that they could perceive? Or how would you know that they might be doing it, if they can’t say it?
Brown: Yes. I think that we should be using EEG in all of our cases, to understand the level of — the state of unconsciousness in the patients. And this is one of the things we’ve spent a lot of time working on in the last few years, which is using the EEG to infer the level of unconsciousness that the person is in for a given drug or a combination of drugs for given patient age, and so forth. So, all of those things can be easily discerned from EEG.
Strogatz: By mentioning the EEG, so, we should remind people that’s the electroencephalogram that can measure your brain waves.
Brown: Right. Exactly. That’s what it is. And it’s a very, you know, it’s a very simple device. It’s been around since, you know, I guess a little over 90 years now, since it was first used. And it’s just a matter of putting electrodes, usually on the forehead in the case of anesthesia, because it’s easily, an easily assessable, you know, part of the head for most surgeries. And all it’s doing is measuring, you know, you have — let’s just say you had two electrodes on the skin. Let’s say on the forehead there, you’re just measuring a potential difference, which is between those two sites. And that happens because the brain is, basically, it’s a mass of electrochemical circuits. So, that means there’s current flowing, and you pick up those current flows by putting electrodes on the brain, measuring, essentially, the potentials.
Strogatz: It’s crazy to think of it like that. I mean, we are so attached to our brain. I mean, like, you think my brain is me. I am my brain. Right? I live in there, and yet, it’s really this big piece of meat or tissue with electricity swirling around in it, and chemistry sloshing.
Brown: Right. And I think the practical implication of what I just said is that if we appreciate that these electrical currents, electrical phenomena are how the parts of the brain communicate. And just to make a little bit more specific, you have your brain waves.
So that’s what we’re looking at in the EEG. Essentially, what the anesthetic drugs do is, they hijack your brain waves. And as long as you’re given the anesthetic drugs, they control them in very organized and systematic ways. And controlling those oscillations makes it difficult for the various parts of the brain to communicate, and we generate states like unconsciousness, for example.
Strogatz: Okay. Wow. So, you’ve really hit me with the punchline there. I think we’ve got to unpack that. What is going on in the brain when a person is being put into a state of general anesthesia? And you’re now telling us, it’s something to do with these waves that the EEG can pick up, the electrical oscillations in the brain?
Brown: Yeah. So, for example … like, we’re talking now… If we were to put electrodes on our scalps and measure these electrical potentials, we would see oscillations that are fairly small: high frequency, desynchronized, kind of disorganized, about five microvolts or so. Not that big. Right?
Strogatz: So, I can’t run a light bulb off — by attaching these to my scalp.
Brown: Yeah. I wouldn’t count on that. Yeah, exactly. Right.
Strogatz: Okay. [LAUGHTER]
Brown: But then what happens is — and it’s one of these things, and I can tell you about this, but once you see it, you really understand why the phenomenon is so, quite frankly, so amazing. So, you watch these oscillations. Now, you inject your anesthetic drugs, and it takes a few seconds for it to get out of the intravenous line and into the person. But within about 10 to 15 seconds, you see these oscillations begin to change dramatically. And they now become larger, lower frequency, and very, very regular. All right?
Strogatz: Hmm. So let me say that — let’s see if I got you. You’re saying your brain is sort of slowing down in its rhythm…
Strogatz: …but getting stronger in its rhythm. It’s like louder but slower, if we’re music.
Brown: Right. So, technically, it’s like the following: It’s like me talking to you right now. Okay. And we’re using a lot of frequencies to communicate this information. In fact, we’re technically using a spectrum of frequencies. Right?
Strogatz: Hmm. Sure.
Brown: And we’re communicating information by changing the size of the of the signals at those different frequencies. So, some are like high frequencies. Some are low frequencies. But, together, they’re creating this conversation, these sound pressure waves that are being conveyed between you and me. Right?
Brown: All right. So, now imagine we do the following. I give you something, or I just — or you say to me, “Look, Emery, all right, so this is really interesting. But what I want you to do is, I want you to tell me everything you’re telling me now, but you get one frequency, or maybe a limited band of frequencies, and you have to continue — you have to speak to me.” So, then everything I’m saying now becomes like [MAKES DRONING SOUND], like that. Right?
Strogatz: Yeah. [LAUGHTER]
Brown: So that, that is like your brain on anesthesia.
Strogatz: So that makes it sound like the information is much more constrained, that it’s…
Strogatz: Because you don’t have this rich spectrum of frequencies.
Brown: You don’t have it.
Strogatz: You’re just droning along at this one note kind of.
Brown: Basically, that’s what’s happening. And then the other part is, if you now look at… Remember, we transmit information through the brain by our neurons sending electrical potentials, like these little, small, little spike wave activities. All right?
Brown: So, if you look at what the neurons are doing when these large oscillations come on, they start spiking much less across the entire brain.
Brown: And so now, just imagine when we had these high… Like, again, going back to the analogy with, you know, speaking right now, as we’re speaking, we see the neurons across all parts of our brain, you know, spiking like crazy.
And now, with the low frequency oscillations, they’re, like, spiking: now, and now, and now. So, it’s all spread out across the entire brain. So it’s going to be very, very difficult for someone to maintain a state like consciousness if the neurons are constrained as to when they spike, because the different parts of the brain are not going to be able to communicate with each other.
Strogatz: Hmm. So, the subjective feeling of being insensate and being, you know, not remembering anything, and all that stuff that you told us earlier, is coming about because it’s as if, what? The brain is sort of functionally disaggregated into —
Strogatz: Separate modules or something? It’s like different parts aren’t —
Brown: Aren’t able to communicate. And I don’t want to give the impression, like, we have this entirely worked out. But there is this very highly structured way in which the drugs affect the brain. And so, drugs in the same class, which sort of act at the same brain targets, have extremely similar oscillations. No surprise, because they’re hitting the same targets. That’s one thing.
The second thing, there’s a very systematic change in the oscillations as I increase the dose. So, roughly speaking, if we take one of the drugs like propofol or one of ethers that I was talking about earlier, the oscillations make this transition from this high frequency down to the lower frequencies when someone becomes more unconscious. Very systematic. The same way. So, there’s a change with dose, is the point that I was making.
Strogatz: Okay. Yeah.
Brown: And then the third thing, which is really, really, really critical, is to appreciate that the oscillations change systematically with age.
Strogatz: Oh. Uh-huh. How so?
Brown: So, the way a young child… Let’s say, to be very concrete, how a six-year-old looks, you know, the oscillations of a six-year-old would look different from a 60-year-old when they’re both in this inequivalent anesthetic state.
Strogatz: I figured anesthesiologists must’ve known about the subtle differences in brain wave patterns for years, but, actually, it was the work of Emery and his colleagues that helped illuminate all this. In 2013, they published the results of a big experiment. They had volunteers agree to be put under anesthesia in an unusual way, where instead of being put out in a matter of seconds, they would very gradually give them more and more drug, so that they would go deeper and deeper over the course of an hour. And then over the rest of another hour, they would bring them back out.
During this whole time, they were challenging the people to do behavioral things, like “tap this button if you hear your name,” or “press this button if you hear a click.” And also, at the same time, Emery and his team were recording their brain waves all across the different parts of their scalp at 64 different locations.
And so, by collecting all this data, Emery and company were able to get incredibly precise brain signatures that showed exactly what it looks like when somebody loses consciousness. And that information turns out to be a gamechanger for anesthesiology.
Brown: Anesthesiologists don’t use the EEG most of the time. There are EEG monitors that are used. But what a lot of these monitors do is, they process the EEG for the anesthesiologist, convert the EEG into a number between 0 and 100, and the anesthesiologist is told that if you keep the number between a certain range, then the person is sufficiently — and they don’t say “unconsciousness.” They say they have “sufficient depth of anesthesia.” And I quibble with the lack of precision, because what you’re looking at there is unconsciousness. You’re not looking at anesthesia, which has many components. Right?
Brown: So, what does depth of anesthesia mean if you have something that has four components, essentially?
Strogatz: Right. Right. Right. I see, because it’s not just a single number —
Brown: It’s not just a single number.
Strogatz: It’s this four-dimensional thing.
Brown: Right. At least. At least. So, what they’re really talking about is unconsciousness. But what has happened is, the statement is, if the number is between whatever the limits are for the particular monitor that the anesthesiologist is using, the statement up until now has been, no matter which drugs you gave to get you there, if the number is between those particular values, the person’s unconscious.
And that’s not true. We know — I can show you that that’s not true. I can give you a drug, for example, that would sedate you, that would produce, let’s say, a low value on one of these indices, but I could shake you and you would, you know, respond to me. Whereas if I did it with another drug, the same value, you wouldn’t respond.
Strogatz: I see.
Brown: So, that’s how the EEG, when it is used, is most commonly used by anesthesiologists. And because a lot of anesthesiologists have realized that there are these kind-of caveats or obvious caveats where it doesn’t work, it’s made anesthesiologists maybe cynical, if you would —
Strogatz: Oh, I see.
Brown: About EEG. So, it’s had to have, like, a negative effect.
Strogatz: Yeah. Yeah. Yeah. There’s a backlash in a way that that, you know, here you’re computing this one index. It turns out, it’s sort of drug dependent, and so you shouldn’t really trust it.
Strogatz: So, people thought, “I’m not using that. I can’t trust that. I’ve got to use some other ways of…”
Brown: Exactly. So, what happens is… So, we come along, and we say, “Well, look, it’s a little bit more complicated, but actually very easy to understand, very systematic.” You know, think of three things. Think of the drug class you’re using. Think of the dose of the drug you’re giving and think of the age of the patient. And then we’ll show you the dynamics that occur, you know, given, you know, those three constraints. Right? And not only that, we’ll explain to you in terms of neurocircuits why the oscillations are being produced the way they are.
Brown: So, what I want anesthesiologists to do is to take this neurophysiological understanding of how the oscillation is being produced, and which ones of those states correspond to realign consciousness, if you would, so you can appreciate — you’d appreciate the difference between the two drugs that I was, you know, referring to earlier.
Whereas on the index, they may give very similar values, but if you look at them in terms of their actual patterns, their EEG dynamic, you would go, “Oh, that’s dexmedetomidine. Oh, I know that because the way it works, it will not produce a state of profound unconsciousness.” “Oh, well, that’s propofol. Yeah, this is profound unconsciousness.”
Strogatz: When we come back, Emery talks about being an expert witness for Michael Jackson’s family, and what the science of anesthesia could reveal about the mysteries of the human brain.
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Strogatz: So, can you remind us what the basic case is for anyone who doesn’t follow the story of Michael Jackson much?
Brown: So, he was apparently being given infusions of propofol to help him sleep because he had terrible insomnia. And as we said, taking propofol, which is an anesthetic, is not sleep. It produces a state of decreased arousal or unconsciousness. And, in fact, remember, just to make it clear, we were talking about oscillations before. So, if you look at the oscillations that you see under general anesthesia, and specifically under propofol, they look nothing like the oscillations you see when someone is sleeping.
Strogatz: So, what would be different? What’s happening during sleep that’s not happening in coma or this heavy anesthetic?
Brown: So, let’s go back to the anesthetic first. So, I give you an infusion of the anesthetic, let’s say propofol or one of the ethers, and as long as I keep the anesthetic on, your brain is going to continue to oscillate in basically, like, a fixed state.
Strogatz: Yeah. Yeah.
Brown: Now, remember what sleep is. Sleep is this, grossly speaking, it’s this alternation between two EEG patterns: REM, rapid eye movement sleep, and non-REM, non-rapid eye movement sleep. And so, you go between the state of low frequency oscillations to high frequency oscillations, and you do that roughly every 90 minutes. And there are very specific physiologic changes that you see between the two states.
Your brain is much more active. Your body is sort of more paralyzed during the REM state. The heart rate and blood pressure very often are lower during the non-REM state. And, you know, you do this about every 90 minutes, as I said. You do it about four to six times a night, and you typically wake up out of REM sleep. And REM is typically… We think of dreaming, but you also dream during non-REM sleep. So, but just grossly speaking, your brain is naturally changing every 90 minutes between two states.
If you think of this, the slow wave state, the non-REM state is when you’re resting. And then maybe during the REM state, your brain is doing some work, you know, consolidating some memories, or getting rid of information that you really don’t need to retain anymore. So, that, that’s a very, very highly-structured — and what we’ve come to appreciate, a very important physiologic process for just normal functioning.
I mean, if you look at, you know, one of the things that people stress now for improving health, it’s, you know, really getting sleep. Trying to get, you know, seven to eight hours of sleep as, you know, as much as possible each night.
What we learned in, sort of, reviewing his materials for the, for the trial, was that as best we could discern, for maybe as long as two months, he was probably getting an infusion of propofol every night. And, you know, what the rates were like or how much he was getting, we have no knowledge of that. But it was clear, he was getting propofol every night. So, for those periods while he’s getting propofol fusions, it would have been impossible for him to really be having natural sleep, because the drug is hijacking his brain circuits.
Strogatz: I see. So, he’s not having REM the whole time, maybe for months.
Brown: He may not be having non-REM normally, either.
Strogatz: Or non-REM?
Brown: Right. Exactly.
Strogatz: Oh, wow. Oh, wow. So, he’s not even having any sleep.
Brown: Probably, he’s depriving himself.
Strogatz: He’s sleep depriving in this weird state.
Strogatz: Oh, wow.
Brown: So, once you realize that, you realize that he was just continually, like, hurting himself, making himself sort of, you know, more and more fragile in a sense, because he had a prolonged period — and again, we don’t know the exact amount of time, and as best we can estimate, it could have been as long as two months or so — where he really wasn’t sleeping.
And so, you can imagine that the same amount of propofol one night, which might have made you just nice and groggy, could make you even more profoundly unconscious or profoundly — have a more profound effect on you at a later time And, you know, the next night, you know, no anesthesiologist would administer propofol to someone to sleep. I mean, it’s just not something we do. The one thing we never do is have someone on an infusion of propofol, and then leave them unattended.
Strogatz: Oh. Yeah, I noticed when you said earlier with the imaginary patient, that you would be taking care of when you were telling me about what you would say, you said, “I’ll be right with you the whole time.”
Strogatz: That’s very important.
Brown: That’s very important. We’re always watching you. We’re always monitoring your physiology. Literally, second-to-second, there is always someone there from the anesthesia team to see what state you’re in. So, this was a set-up, maybe not the first night, the second night, the third night. But at some point, something was not going to go right. And that’s what became, you know, very clear looking in looking at this. And, again, this is one of the reasons why it’s important to appreciate that, you know, making these colloquial references to anesthesia sleep just is — it’s not good, because the anesthetic drugs are quite potent. And so, you wouldn’t want to take them, something like propofol to try to sleep, because it wouldn’t allow your brain to do what it does, what it’s supposed to do when it’s sleeping.
Strogatz: What makes Emery’s work so fascinating is that he has a very original take on how to study anesthesia. He doesn’t see it as part of any one isolated discipline.
Brown: It’s been viewed as a field or subfield of pharmacology.
Strogatz: Oh. Uh-huh.
Strogatz: Really? That’s interesting. I wouldn’t have known that. I see. Uh-huh.
Brown: Right. Because you’re giving drugs, so you think about the kinetics of the drug — you know, how fast it’s cleared, you know, where it’s acting, and all that.
Brown: But what has driven our research is to say: Okay, that’s important, we don’t deny that. But if you really want to understand how the drugs are working and how the state is produced, and if you really want to make progress in the future, you really need to think of it as a field of clinical neuroscience.
And as soon as you say that, and then you start focusing on anesthesiology from the perspective of clinical neuroscience, it opens up the possibilities of… Because then you say, “Okay, well, are the new things that are happening in neuroscience? How can these new insights help us understand what is happening to the brain under anesthesia? And then how do we use those ideas to improve anesthesia?” Or better yet, “How can insights from anesthesia help us understand what’s happening to the brain better?”
Strogatz: Right. Wow. What a cool window on the brain.
Brown: Yeah. It is.
Strogatz: It’s very interesting.
Brown: Because, I mean, think about it: Sixty thousand times a day, people in the United States are being rendered into, you know, a state of unresponsiveness, and brought in and brought out. And if we study that, and really come to appreciate it, we’re going to learn things not only about how to do anesthesia better, how to give anesthesia better, we’re going to learn about how the brain is also working, as well.
Strogatz: Wow. So, you’re saying there’s something like 60,000 very natural, perfectly ethical experiments happening on human brains every day that we could be learning from?
Brown: We can be learning from. And if we just take some small fraction of those, and systematically study them. And that’s it, to a large extent, what we — just to make that more concrete. Beginning back in 2011, every case that I’ve done since then, I’ve used EEG on, and we just offloaded the data and analyzed it.
Strogatz: Hmm. I was going to ask you, where is your statistical side coming into this? And so, this sounds like this is one place where it’s coming in.
Brown: This is one place where it came in, because when we did these… As I recorded the data, and it just so happened that, in that time period, this was like September of 2011, I moved around to different [surgical] services. So, I was doing a lot of different anesthesia for different types of surgeries, so, I was using different combinations of drugs. So, what that meant was, in a six-week period, I got to see pretty much all the common combinations that were being used. And I just paid attention.
And because we had written papers already about the framework of how the drugs acted in the brain, we could put them together with the patterns we’re actually seeing on the EEG, and the modeling work that we were doing, and were doing then and still are doing with Nancy Kopell.
Strogatz: She was my post-doctoral advisor.
Brown: Right. Right.
Strogatz: Nancy Kopell, a great mathematical biologist and mathematician.
Strogatz: But I think it would be unclear to many listeners. What does math have to do with the brain, what does math have to do with anesthesia? I mean what, what’s the connection there?
Brown: Well, the key thing that we’ve been talking about, we were talking about anesthesia, are the oscillations. So, they have to come about somehow. We could analyze them as a phenomenon statistically, and say — tell you, what frequencies, how they change with time, with dose, or what have you. But then there remains a fundamental question of what did the drugs do at the receptors that cause neurons to change their activity in a way that produce these oscillations? That can be written down and studied as a well-posed mathematical biology question. And that’s what — I mean, this is the type of thing that you were doing, you’ve been doing for years. You certainly did with circadian rhythms.
Strogatz: Sure. But pretend I don’t know. [LAUGHTER]
Brown: Okay. All right.
Strogatz: I mean, what does it look like, this? For anyone who hasn’t done this.
Brown: So here here’s a story. So, take a drug like propofol. We know the types of receptors; we know the types of receptors that it binds to in the brain. Okay?
Brown: So, it binds to these receptors called GABA receptors. And when that happens, it enhances inhibition. So, other words, the neurons that contain the GABA receptors act like routers in a computer network. So, they control the flow of information around the brain the way a router would control flow of information around a computer network. So, if I take control of the router, I’m going to take control the information flow, or in this case, the neural activity.
Brown: All right. So, we give the propofol. And so now, look at where these routers are sitting. They’re sitting all throughout the brain. So, the cortex, you know, the top part of the brain, the thalamus in the middle part of the brain, and the brain stem, the lower part of the brain. The drug hits all of these locations at the same time. And these are — these locations are interconnected.
Brown: The interconnections, they’re nonlinear connections. So, what happens is that when you give the drug, it alters the way the currents are flowing, but it doesn’t shut circuits down. It makes these circuits resonate, or it makes them — you’re finding what are, essentially — finding the modes of the system, if you would.
Strogatz: Uh-huh. The natural ways they would like to ring or oscillate.
Brown: The natural ways in which they would like to ring. And so, when I said the different — the same drug, drugs in the same category will have the same sorts of patterns, it’s basically showing that the way they like to naturally ring are all — are the same. That’s what these oscillations are. So, all of that can be described mathematically by making some assumptions, which — about, you know, the anatomy, the connections, and the types of receptors. You know, where they’re located. What have you.
So, that allows us to generate mathematical models of how could these oscillations be produced. And we started studying, sort of, the basic biophysics of how the oscillation under anesthesia might be produced.
Strogatz: So, here’s where the math comes in. Emery has all this data and information about the brain. He and his mathematical modeler friends take all that information and then write equations, where the variables in the equations represent things like levels of brain activity, concentrations of certain chemicals like potassium, calcium flowing across membranes of nerve cells. They then solve all these equations in a computer, typically, and create models of how the different brain wave patterns are produced. All this is important for anesthesia as part of medicine, but it’s actually important well beyond that. Because the study of anesthesia creates an amazing testing ground for all of neuroscience, for fundamental brain science.
Brown: I think we all have some insight into what brain waves are. You know, we’ve heard them talked about a lot in the EEG. You know, these electrodes you can place on the brain, on the scalp, and measure, you know, the brain’s activity. We use it to help define sleep. We use it to track the states of patients who are in coma or recovering from coma. It’s used, you know, in meditation. It’s used for various cognitive studies. It’s used to, in some cases, to measure stress. So, there a lot of things which the EEG is used for.
Anesthesia is one of them. Of all those things that the EEG is used for, anesthesia has the strongest signal. And it’s for two reasons. First of all — and this is why it’s useful to actually see this occur, you know, to actually see a video of this happening, the EEG of anesthesia of someone going from the awake state to the anesthetized state:
While they’re awake, they’re moving around, so you may see all sorts of artifacts from the movements. But as soon as the person becomes unconscious and the drugs take over, those movement artifacts disappear, because a person is not moving anymore. You’ve removed one of the main sources of noise, which is movements, eye blinks, you know, muscle twitches, and these sorts of things. And now, you have a phenomenon where circuits are working in concert, so you end up with a very high signal-to-noise ratio. And that’s what’s so ironic. We have, as anesthesiologists, we have the signal, the EEG signal that has a high signal-to-noise ratio, but we probably use the EEG least of anyone who sort of has license to use it.
Strogatz: Wow. So, you’ve got this beautiful signal that everybody else would be envious of. [LAUGHTER]
Brown: Right. Right.
Strogatz: Why not measure it?
Strogatz: You are measuring it.
Brown: We are. We are. And, again, and just to, sort of, along those lines, remember I said how the oscillations change with age? So, they’re strongest, they have the highest amplitudes for the broadest frequency band when you’re younger. And as you age, the frequency band tends to drop, and the amplitude tends to decrease. So, imagine a nomogram of that.
Suppose there’s some — again, defined relative to anesthesia — some normal way in which that transpires, maybe in some people in certain disease states, maybe it happens faster or slower than quote/unquote “normal.” So, this is a way in which, I’m saying, maybe learning more about the brain’s response to anesthesia might help us understand a little bit more about the brain itself, and how it’s developing.
Strogatz: I see, so possibly diagnostic of some conditions that might be too subtle to pick up otherwise.
Brown: Yeah. You know, I had the good fortune to work with Laura Cornelissen and Chuck Berde who are in anesthesiology research at Boston Children’s Hospital. They had done these very elegant experiments, where they collected data on young kids, kids zero to six months of age, under anesthesia. So, it’s very interesting.
Strogatz: Little babies, then.
Brown: Basically, yeah.
Strogatz: I mean, zero to six months old.
Brown: Yeah. Right. Zero to six months of age. They had no, sort of, brain disorders there, but they had surgeries, which had to be done within the zero-to-six-month age range, surgeries which couldn’t wait. So, what was interesting was the zero-to-four — the four-to-six-months of age children had patterns which looked something like adult patterns. Not completely, but just like — so the sake of this discussion, let’s say they look like adults. They had the same types of oscillations that you see in adults. The zero-to-three-months of age children only had slow oscillations.
Strogatz: Oh, that’s interesting.
Brown: So, there’s something magical that occurred between three months and four months of age. And then you can lay that on the backdrop of what’s happening developmentally. Like, so, you know, their degree of inhibition is changing, and more circuits are being formed. And we think it just reflects the course of, essentially, brain development.
Strogatz: I wonder if we could ever be able to see anything… They talk about teenagers and developing, you know, like better judgment at a certain age, you know, with regard to risk taking and stuff like that. I wonder if anything like that would show up.
Brown: I state this with guarded optimism.
Strogatz: Right. Okay.
Brown: Let me put it that way.
Brown: But there are some things that we could see. And every now and then, we see people who are — whose EEG patterns seemingly are older than their stated age. And it starts us thinking, is there something about that we know for their medical history that would be consistent with that?
Strogatz: To me, one of the most exciting things about Emery’s work is that consciousness, which many people think of as one of the greatest mysteries in all of science, can now start to be studied with biology, and chemistry, and neuroscience, and math, and statistics. We can use all of our tools to look at this really ineffable thing. What does it mean to be aware? What does it mean to be conscious? What are the physical and chemical and biological properties that go along with that weird state?
And also, that there are many weird states of consciousness. There’s sleep. There’s coma. There’s under anesthesia. There’s wide awake. There is what you experienced during meditation. How do you put numbers on that? How do you make science out of something like that? You know, it used to be just the stuff of poetry and music. Can we bring this into the orbit of science? And so, Emery is doing that.
Strogatz: Next time on The Joy of x, pioneering dynamicist Amie Wilkinson brings her feisty spirit to everything mathematical.
Amie Wilkinson: I, all caps, HATE that equation. I think I’ve posted it on Facebook. I hate that equation.
Strogatz: The Joy of x is a podcast project of Quanta Magazine. We’re produced by Story Mechanics. Our producers are Dana Bialek and Camille Peterson. Our music is composed by Yuri Weber and Charles Michelet. Ellen Horne is our executive producer. From Quanta, our editorial advisors are Thomas Lin and John Rennie. Our sound engineers are Charles Michelet and at the Cornell University Broadcast Studio, Glen Palmer and Bertrand Odom-Reed, who I like to call Bert.