EMERY BROWN: Well, guys, thank you. Thank you so much for inviting me. So what I thought I would do is I'll tell you a little bit about some of the work that we're doing. And I'll just tell you two sentences about me. So my name is Emery Brown. I'm here on the faculty at BCS and MIT.

And I'm also on the faculty at the Institute for Medical Engineering and Sciences here at MIT. And in addition, I'm on the fac at Harvard Medical School and national hospital. I'm an anesthesiologist and professor of anesthesia at Harvard.

So I divide my time between MIT here research and teaching with my clinical practice at Mass General. And I also have a laboratory at Mass General. So the guys in my group sort of work between both locations. And in addition to looking at signal processing problems in neuroscience, we're working on the problem of what happens under anesthesia, understanding that.

So how many people here have had anesthesia?

AUDIENCE: Like local?

EMERY BROWN: Any kind. Great, thank you. See, it's a topic that is very topical.

[LAUGHTER]

So I'm going to tell you a little bit about what happens to the brain under anesthesia. It turns out to be not only something which is important clinically, but it turns out to be a very useful way to study the brain.

So what I'm going to do-- I'm going to begin by giving you just a bit of a clinical look on what happens with anesthesia. And then we'll talk specifically about propofol. Remember propofol was a drug that was associated with Michael Jackson's demise, and it's our most used anesthetic. And then I'll tell you a little bit about what happens to the brain as we age under anesthesia. And then I'll say something about coming back from anesthesia-- turning the brain back on.

So these are going to be my main points. First of all, I don't know what sort of concept you think about-- what you have of anesthesia right now. But the brain is not turned off, it's actually active.

And it's this active-- this highly-structured activity which actually makes it impossible-- excuse me, makes it difficult for parts of the brain to communicate. And therefore, you get the state of what we would call anesthesia. And I'll explain that as we go along.

And these dynamics show up as oscillations. And these oscillations are easy to see. You can see them in the EEG just by putting an EEG strip on the forehead of a patient. And the drugs create these oscillations. They maintain them as long as the drug is there, and so, again, this impedes communication between the different parts of the brain.

And the oscillations are drug specific. So if you change-- if you have a specific drug class, you create a certain type of oscillation. You change the drug class because you change where it targets in the brain. And how those circuits are connected, you get a different type of oscillation. So that's all knowable.

And then for a final idea, as opposed to turning the brain-- just turning the brain off and letting it come back when the surgery is done or an anesthesia is over, we're looking at turning the brain back on.

And this has implications for improving the way people's brains work after anesthesia and also for some ideas of maybe helping with other problems in clinical neuroscience. And as I've suggested, this may be-- we think this is an underutilized way to study the brain.

So let me just start with a definition. So what is general anesthesia? So it's this drug-induced state. It consists of being unconscious. You're not supposed to remember. It shouldn't hurt. It's nice if you're not moving around while the surgeon is operating.

And you see how I have up there drug-induced reversible state? So if you get rid of the reversible and you take these four conditions, that's like death. So that's not cool. So the reversible is important.

But where we earn our money as anesthesiologists is in the last item, maintaining physiologic stability while the person is having this. Making sure the heart rate is OK, the blood pressure is all right, that the-- for example, that your body temperature is fine.

If you just anesthetized someone and don't do something to retain body heat, the person would become the temperature of the room essentially. Because anesthesia turns off the thermal regulatory mechanism-- the natural thermal regulatory mechanism. So that's what we have to do.

So I put this down here. It's not clear how anesthetics work, and nothing could be further from the truth. And I'm going to show you why that's the case in a second.

But just a modicum of history because it's right across the bridge there. The first public demonstration of anesthesia took place in 1846 on October 16 and was done by William Morton. So Morton was a dentist. He was originally from Connecticut. He moved up here to Boston. And the people at the time took very poor care of their teeth. And he realized that he could give people a nice full set of dentures if he could take out all their teeth.

So you can imagine something like this would be amazingly painful. And dentists, like surgeons at the time, were measured by how fast they could do something. So he supposedly could take out a tooth in a little bit over a minute. And so his idea was, well, if he could find some way that people wouldn't-- this wouldn't hurt, that would be a good thing.

So there are a series of events. He realized that a possible candidate was ether. And to put this into context-- so ether was something that you kept on maybe your dining room table or you had in your study. Like after dinner, you might take a little sniff to kind of-- in the evening-- Leave on a good not sort of thing.

So he saw someone do this. And there was this thing called ether follies. I mean people used to get-- they used get high with ether. You go [sniffs] Just like they used to get high with nitrous oxide. They would get high and then-- he saw a guy fall out, cut himself, and it didn't bother him. And he realized, hmm, maybe I could use ether for this purpose.

Oh, just parenthetically at Mass General Hospital we celebrate Ether Day every year. [LAUGHTER] We all sit around and sniffle ether. No, no, no. No, what happens is it's our anniversary. Your anniversary of being at Mass General is celebrated as sort of Ether Day.

And so, in 1846 October 16th, this guy Gilbert Abbott had a tumor on his neck. John Collins Warren, who was the surgeon, wanted to operate on him. So they put ether in a glass flask.

You can actually see these flasks. It's worth it since you're here in Boston-- just to take a trip over to the MGH Museum. It's right after you get off the-- after the T-- you cross over the bridge. It's right there. And then just take a trip to the Ether Dome, the place where they did the first public demonstration.

It's worth seeing. It's pretty impressive. It's a historical site. It's right here in Boston. It's literally just about a mile away.

And he gave him the ether through this flask that Abbott breathed. And he went unconscious. They did the surgery. And you see where I put there, "This is no humbug." So that's like 1846 speak for this is no bullshit. It really worked.

Because the year before someone had tried to do this with nitrous oxide, and it didn't work in a public demonstration. And the medical student supposedly went, humbug, humbug, humbug. So that's what he was referring to.

And then as far as the name, about six or seven days-- about a week or so after he did this, he wrote to this guy, Oliver Wendell Holmes, Sr. You've probably heard of Oliver Wendell Holmes who's a Supreme Court Justice. Well, this is his father.

His father was a medical guru at the time. He was considered to be one of the leading medical intellectuals. He had spent time studying in France, so he was considered a very learned man. So they asked him-- or I should say Morton asked him what he should name it. And he's the one who coined the term anesthesia from the Greek anes meaning no sensation.

And he just didn't sort of say it really flippantly. There's a letter you can read where he wrote back and he explains his reasoning. And he said whatever word we pick is going to be with us sort of now and forever more. So that's a little bit of history. And again, like I said, if you have a chance, go check out the Ether Dome across the way.

So here's the way we actually do it. We use combinations of drugs to generate the state. So you have drugs which can produce amnesia. You've probably heard of benzodiazepines-- analgesia, like the opioids for example. The barbiturates, like propofol, can make you unconscious.

We give drugs like the anticholinergics-- sometimes you might think of them as paralytics. They work the neuromuscular junction, and they basically block transmission so the person becomes flaccid or weak. So if you lose muscle tone, it makes it easier for the surgeons to operate.

And if you look at all of this-- you see where I have inhalational drugs? So the inhalational drugs, meaning the ethers-- we still use ether today. All we've done is just florinate them to make them a bit less flammable, and also more stable, and a bit more potent. But we still use it in the operating room. Sevoflurane, isoflurane, and desflurane are all modern day ethers.

They can do all of these. And you might say, well, why don't you just use ether all the time. Because one thing-- you can basically kill multiple birds with one stone. Well, the problem is you get all these very potent side effects. The blood pressure goes down, the heart rate goes up, the thermoregulatory controls even worse.

But if you use combinations of drugs from the different categories, you get most the good effects and few of the side effects. So that's why we call this balance general anesthesia.

So let me show you what to-- get right to your question. What do the oscillations mean? So this is a little video that I'm going to show you. This is a lady who's about-- this is the EEG of a lady who's about to have surgery. And we have-- in our OR, you can put EEG electrodes on the front of the head. So there are two leads here, two leads here, and the reference and the ground are in the middle.

And I'm going to give her a dose of propofol, 150 milligrams-- very standard dose. And we're going to watch the changes in her EEG in real time. And I'll just talk you through it. So let me just play this.

[BEEPS OF EEG]

So those are eye blinks if you've never seen them on the EEG before. And now watch what happens here in a second. You're going to see a lot of noise. It's going to get very, very noisy. Because when you inject propofol into a small vein, like the one in the back of my hand, it burns like crazy. So she's tensing up like this.

So you see that? That's her tensing up. Michael Jackson actually knew this, and he would say, can you give me the numbing medicine before you give me my milk? Propofol is called milk sometimes. It's really a stupid joke-- milk of amnesia because it knocks you out. And it's white. It's white in color.

But watch what happens here now. See that? See it change? Those are beta oscillations. And you see the large, slow oscillations? That's the drug hitting the brain stem-- just like slow wave sleep.

Now watch what happens here. It's going to go flat and now burst, flat and then burst. That's burst oppression. She's totally out now-- just basically that quickly. And in fact, she's not only out, she's not breathing.

So right now, if I don't breathe for her, the jig is up. So I have to take over her physiology and control her blood pressure, control her respiration. We'll intubate and everything. So this is to sort of get her out-- to induce her-- induce unconsciousness. And then we take over control.

So this is her awake. You see that? That's a very low amplitude oscillation, maybe about five microvolts or so. And then, this was that sedative state I just showed you-- when I said the beta oscillations are there. The reason to appreciate what this means is that when you take a sleeping medication, like Ambien or Lunesta or something like that, this is the state that you produce. You don't produce sleep.

No single drug can produce sleep. Sleep is this, right? REM, non-REM, REM, non-REM. So how can a single drug make you do that? That's not what happens. And this is what the drug companies don't tell you-- that what they're hoping is that drug will sedate you enough so that your natural sleeping mechanisms can take over. But it itself can't help you sleep.

And in fact, this is why people often wake up from sleep after taking a sleeping medication not feeling rested. Because what they've been in is a state of sedation. And so, it's not necessarily like real sleep.

If you think of it-- and just to push it a bit further-- if you think of the sleeping medications as very weak anesthetics, you'd actually make a better-- you'd actually make a more accurate statement. It's much more precise as to what they're doing. They're just sedating your.

Then you saw her go into this state here, these large, slow oscillations. And I'll talk a bit more about that. But slow-wave sleep, when you see the deepest stage of sleep, that's when the brain stem-- the lower part of the brain is most inactivated. That's what's happening here. That's the drug having a very profound effect on the brain stem-- the brain stem inputs going up to the thalamus and cortex.

And you saw these states down, burst suppression, flat EEG. So these are all states that you see in people who would show up with coma, maybe from brain injuries or what have you, or due to trauma or anoxic injury. So this is a state I'm going to talk most about, this state that has a slow oscillation and alpha oscillation. So I'll hold off on going further on that.

And there's one other state up here, which is paradoxical excitation. So I won't talk much about it, but it's called paradoxical because you give a drug which is supposed to sedate you, and it gets you excited. You go, wow, that's paradoxical.

So it's probably not that paradoxical. Because why do people go to cocktail parties? Why do they have a little-- so they tell me. Why do they drink alcohol? Because a little, you get a buzz, right? You drink too much, you end up down here, right?

Alcohol is a very potent anesthetic. Have you ever watched someone who is like totally drunk and fall out or something like that? I'm sure none of the people who ever hang out do that, but you've probably seen on television.

But it makes sense that a drug which could-- that a drug which you would use to maybe inactivate the brain could also have a state where you'd be excited. And that's indeed the case.

I want to make one very important point right here. You see the size of those oscillations? They're very large. They start off at five microvolts. In an adult, these would be 20 to 50 microvolts. I'll show you in a kid. They can be as large as 1,000 microvolts.

This is the strongest EEG signal there is. Of all the things that the EEG is used for, whether it's to define sleep, follow cognition, check meditation, track the stages of people who are in a coma, this is the strongest.

The irony of that is, even though this is the strongest signal, we use it the least even though it's readily available to us in the operating room. We can use this to actually know the state of someone's anesthesia and dose it accordingly, but it's not something which is routinely done.

I'm going to talk about these oscillations in this form here looking at them in what's called the spectrogram. So I'm going to take the signal, and I going to break it down into its frequency components, and I'm going to show it over time. So this was an operation.

This is the EEG measurements which went on-- of an operation that went on for about 40 minutes or so in a young woman when we gave propofol as a bolus up here-- just an injection at the beginning. And then we kept her on an infusion running here for a period of about oh, let's say about 20 minutes-- maybe a little more than 20 minutes.

And so at the beginning, you see these large, slow oscillations. And that's this point here. So the way you read this is, this time. This is frequency. And then what you do is you read across here, and that tells you what frequencies are present at that particular time.

Just to explain what's going on here-- so look at this oscillation right here. This oscillation has a part which is a low frequency. It looks like that. Then it has a part which is a higher frequency. It looks like that. So that together, they look like-- looks like that.

So the spectrogram comes along and says, OK, I'm going to extract this out and show you what's sitting in this. So it extracts out a component which is around 10 hertz. That's the high frequency one. And it extracts out another one which is between one to four hertz-- so one to four cycles per second. That's the slow oscillation.

So when you just look at this, you can see this-- it looks like this when you just plot the raw EEG. But if you do the spectrogram, you see, oh, there's a 10 hertz component. There's a slow component. That's the signature of propofol. Every time you give propofol, if you were to measure the EEG, this is what it would look like in a young adult.

And when the drug is turned off-- like somewhere in here these oscillations dissipate, and then she woke up someplace over here. It goes back to sort of a standard--

So these are the guys who did most of this research. Patrick Purdon at MGH. ShiNung Chang who's over at-- he's now at Wash U. Nancy Kopell, who is a mathematician at Boston University. My longstanding colleague, Emad Eskandar, who is a neurosurgeon was at MGH and now is at Einstein. Eric Pierce, anesthesiologist at MGH. Laura Lewis, who was a graduate student here in BCS, was the junior fellow at Harvard, now is joining the faculty at Boston University. And Syd Cash is a neurologist at MGH.

So now this will-- to answer your question about does it look the same over the entire head? So what we did was we've done studies where we've been volunteers. So if you guys have nothing to do sometime, come and volunteer. We'd be happy to anesthetize you and let you see it from the other side as a sense.

[LAUGHTER]

We actually can't do that, but that's what we-- we ask people to volunteer so we can understand what goes on in the brain under anesthesia. But this is an example of that.

So imagine a whole head of EEG leads now, not just the ones in the front-- over the whole head, 64 leads. These are 44 of those leads. So at each site, I can compute a spectrogram just like I was showing you.

So now I just have to tell you a little bit of basic biology. If you close your eyes like this now, and I put electrodes in the back of your head right here, I would see an oscillation that's at 10 cycles per second. Pretty much everybody has it. It will be very, very strong too. It's called the eyes closed alpha oscillation.

And very often, when you're doing EEG recordings, this is one of the things that they'll have a subject do to make sure the EEG is working well. Because this is very-- it's a biological phenomenon.

So what we're going to do is we're going to give this subject increasing doses of propofol in about five steps. And each step-- each dose is going to last for about 14 minutes. And what you're going to see is this is the back of the head over here. Those are those two sites back here in the back. This is the right side. That's left side. The nose is up there.

And this oscillation, which is at 10 hertz-- you can count it out-- zero, 10, 20, zero, 10, 20-- is going to move from the back of the head to the front. It's going to concentrate in the front, as long as we keep the drug running. When we turn the drug off, it's going to move backwards. This is a phenomenon called anteriorization.

And this was first pointed out by John Michenfelder and John Tinker from the Mayo Clinic back in 1977 doing experiments in monkeys. And this happens every time you would give a GABAergic. And I should have said this before, but the way propofol works is it binds to GABA receptors.

And, as you probably know, GABA is one of the primary inhibitory neurotransmitters in the brain. So it enhances inhibition globally at all those sites because receptors for GABA are all throughout the brain and central nervous system. But as a consequence, it doesn't necessarily turn things off, it creates oscillations. It creates highly-structured oscillation. So that's the main idea.

So watch this. You're going to see this oscillation start here, move to the front, and then come back. And then we're going to go over like five levels. So let me just start this year.

So no drug yet. It says baseline. So the drug infusion has started. You see how it's breaking up now? Now you see it appearing in the front? And it gets very intense in the front. We're only at the third level. We're going to go up two more levels.

So there's nothing back here. And now here's the fifth level-- completely disappeared in the back. And now as we turn the drug off right here at level six, see how it disappears from the front and reappears in the back. So there's a different spatial dynamic. It's highly-structured in addition to a temporal dynamic. And this reflects how the drug is acting on different circuits.

So here's kind of the punch line. So we can draw diagrams like this which allow us to say what the circuits might be. And one of the key elements of this is the interneuron-- the inhibitory interneuron. So roughly speaking, in the cortex, there's one interneuron for about every 10 pyramidal neuron. So one inhibitory neuron for every 10 excitatory neuron.

So you can think of the inhibitory interneurons as kind of like routers. They control the network all across the brain. So we can write that down and talk about where they're located.

And I want to just tell you about this circuit here because it's important for what I saying earlier on sleep. So that circuit there looks like my wrist and my fingers. So this is the hypothalamus. So it's hypothalamus. It's a structure under the thalamus. And it's important for control of visceral and metabolic functions.

And for you to sleep, this preoptic area of the hypothalamus comes on, and it activates these inhibitory projections here, which are like my fingers, and it turns off all of the brain stem circuits. So like right here, that's where they are. They're hitting these brain stem circuits.

So when this is maximal, that's when you see slow-wave sleep. So that's why we're able to infer that when we saw the large, slow oscillations appear on the EEG trace, that that was the drug coming up through this area here hitting the brain stem. There's a little bit more evidence for that, but let's just take that as an order-- kind of a first order approximation.

That you can write down from neuroanatomy and neurophysiology. That's what you see in the operating room. Here's what you see when you do an experiment. And I need to tell you just one other thing about this. This was that frontal concentration of the alpha oscillation.

And if you take the various sites where the alpha oscillation is appearing, they're totally coherent. They're like this. They're totally in phase. The coherence is like about 0.8 or 0.9. It's very, very strong. So it's concentrated in the front of the head.

So if you can write down those circuits, you see this empirically. You study it a bit more, and that's the spatial dynamic. What's a possible cause? So with the help of Nancy Kopell, who's a mathematician at Boston University, we came to postulate that what's going on here is an oscillation going back and forth between the thalamus and the cortex.

So why would something like this make you unconscious? So first of all, if you could just have one brain region that you could tie up-- I'll give you only one. And I said make someone unconscious. I'll give you one brain region to do it with. It would be the thalamus.

The thalamus is a way station. Everything goes through there-- visual information, auditory information, sensory information coming up from the body, pain information. So if you tied up the thalamus, you would take someone offline essentially.

And so what this is doing-- based on these measurements here, and also now experiments we've actually done in rats and also in monkeys sticking electrodes in these sites-- we figured this oscillation was going back and forth between these two areas. So phenomenology why would this make you unconscious? Because that's kind of the $64,000 question.

Well, it's something like this. So the parts of the brain have to exchange information, and rhythms are one of the ways in which they do it. So if all of a sudden-- you could take my voice, for example. And my voice has a spectrogram. You could break it down into its high frequencies, its low frequencies. There are some small amplitudes, some with big amplitudes.

And you could make a spectrum of my voice. It would look like this going through time. And if you said, OK, Emery. That's all cool and what have you. But what I want you to do is give your lecture, but you get one frequency and you get to keep the amplitude constant. So everything I'm saying now would become wah.

If you give me a frequency band, kind of like this, it would wah-wah. I don't know if-- you guys are a little bit too young, but Charlie Brown-- the adults on Charlie Brown, they always sounded like that. That's what was happening. But the thing is if my voice is like this, this is like wah. It's really like that because the amplitude is much larger than the rhythms I showed you when the person was just conscious.

So hand-waving-- I would argue that that's probably what's happening here when this oscillation comes on. And if these guys need to be able to send broadband communications back and forth in order for you to be conscious, that's going to very much disrupt it. Because this is an area which is important for-- very, very important for cognition. Now that's a bit of hand-waving. I think the most important information is we stuck electrodes in both places and shown that that happens.

But let me just tell you two sentences about the slow oscillations. So in addition to these alpha oscillations, see these guys here. That was alpha. That's this. The slow oscillation comes on the same time. It looks just as strong.

But whereas the 10 hertz oscillation-- the alpha oscillation is like this, the slow oscillation is like this. It's totally incoherent. It's not connected across the scalp.

But going back to the slow oscillations-- so this is totally empirical here. So these are patients-- this is the human brain now. These are people who are going-- who have epilepsy. And they come to have surgery to have part of their brain removed. Because they have epilepsy, they can't be controlled by drugs.

And what the neurosurgeon does is implant electrodes under anesthesia. They bring them out. They stay in the hospital for five to seven days. They seize off of medications, and once they seized enough, they come back in. They remove the electrodes, and then they come back in and do a resection or remove the area which they think is pathologic.

So when the person comes back the second time for surgery, they actually have electrodes in their brain. And you can ask a question. What happens when you induce anesthesia? So that's what Laura did in her PhD thesis. So that's the person awake. And these traces correspond to these parts-- these three dots here on the brain. The colors correspond.

And now look what happens right here when the slow oscillations come on. So these are the neurons here spiking wherever they want to like this when the person is conscious, and then spiking wherever they want.

But now look. They can only spike here at very limited phase locations. So those are the neurons that are next to the red electrode. The blue or green electrodes are seated over here. They're out of phase.

So if the neurons can only spike in local locations at limited phase windows, it's going to be very difficult for the areas to communicate. So we think the slow oscillation actually represents a fragmentation of the cortex, which again would also help you globally be unconscious under propofol.

So those two things together are the reason we think that when you see a pattern like this-- this is, let's say, thalamus and cortex tied up-- this is the brain in general just being disconnected-- you can feel comfortable if someone's unconscious. The reason this is important is that people want to-- when people write about anesthesia-- folks will call me up and say, oh, Emery. I hear you're doing some cool research on anesthesia. Can we talk about one of those patients where they were awake and you didn't realize?

And I go, no, I don't want to talk about that because that's not good. I don't look good if we were to do that. But that's what people think. It's this blind thing going on where you have no idea like what's happening. And awareness is something that people are paranoid about. But awareness under anesthesia, even when it's done blindly, happens one in 10 or one in 20,000 cases.

The thing is it gets a lot of press, and it's the sort of thing that science journalists love to write about. But in 2018, it's a solved problem. It was solved well before this, but it's certainly solved now.

If someone came to me and said, Emery, the last time I had anesthesia, I awareness, that's not going to happen again. Because I would dial you down with the propofol until we got a pattern like this, and I know that you're unconscious. Even if anything that I've said is even remotely correct, you can see that it's essentially an avoidable phenomenon.

So this is what I've told you, the alpha oscillations and the slow oscillations, how they come about. What we think-- how they're affecting the brain-- thalamus and cortex tied up-- the slow waves essentially being this fragmentation. I showed you this movement forward and back the anteriorization.

And just to put this in to say that general anesthesia is not sleep. So nothing could have been more ridiculous for Michael Jackson to do. So if you look over here-- so that's the awake brain. There's that eyes closed alpha oscillation there from the back. And here's just a regular frontal EEG.

And if you look down here, as you go down through the states of anesthesia, when we anesthetized you, we give you drugs and we hold you in this state here. But over here is sleep. So sleep starts here, non-REM stage one, two, three. Then you cycle back up to REM like this.

So this is a physiologic oscillation going across about four-- or depending upon how you want to count them-- five states during the course of the night. Whereas anesthesia means we give you a drug which holds you right here. So these two states are not the same.

And as I said before, if you think of sleeping medications as being weak anesthetics, you're far more correct than if you think of them as sleeping medications. Because they can't induce this. They can't make your brain go through these sorts of oscillation. I think this is something that all of us just as sort of generally well-informed scientists should appreciate.

And then this generalizes. So if you change the drug class, you get a different signature. And so these are just examples of that. So you'll get different spectral signatures because you're hitting different targets. You have different circuits that are connecting them, so you get different oscillations.

And we can write down the circuit diagrams for each one of those. We took a deep dive into propofol, and we could take a deep dive with any of the other drugs. So I just want to tell you a little bit about the aging brain.

So this is Laura Cornelissen, my colleague from Children's Hospital, along with Chuck Berde, who's also there. Seun Akeju at MGH. Seong-Eun Kim, who was here with us for a couple of years and now is back in Korea as a professor. And my colleague, Patrick Purdon.

So that's someone who is 30 years of age, and that's propofol. That's the signature I showed you before. Here's somebody who's 57. So let's say this guy could be this guy's dad. And so here you can see the alpha oscillations, the slow oscillations. The same thing here. Maybe these are a little fainter, but they're there.

Here's someone who's 81. So this is a lady I took care of about seven years ago who had a tumor on her chest the size of an American football. And it took the thoracic surgeon about six and 1/2 hours to basically remove it. And if you look carefully here, you'll see she has the alpha oscillations there. They're very weak, but they're there. In other words, as opposed to oscillating like this, she's oscillating like this.

And one of the advantages of seeing this is that I could dose her drug at 1/3 of what was already an age-adjusted dose and have her be adequately anesthetized and unconscious. Whereas if I'd followed the standard recommendation, she would have been totally overdosed. So that's why this is useful.

But this is what we see. Our oscillations get weaker as we get older. Here's the part that's sobering. These two guys are roughly the same age. His oscillations look like hers. His oscillations look like someone who's maybe 30 years younger. We age different physically on the outside, maybe our brains age differently. Makes sense. What's wild is you can see it under anesthesia.

And when we first realized this, it seemed like, wow, that's kind of amazing. But then if you think of anesthesia not as something you need so you could be unconscious, but it's something that you give so that you could just do an experiment. You put in a stimulus, and you look at the response.

So when your brain is young, you put in a stimulus, and it oscillates like this. As you get older, it oscillates like this. Now why is that?

So we don't have to invoke anything about dementia or Alzheimer's or what have you. Just think of normal brain aging. Take any neuron. You've got 10 of the 10 neurons. Someone who is 81-years-old. They've been there for 81 years.

So take each neuron. You have the myelin sheath, which breaks down. The cell volume decreases. The dendrites don't extend and retract as much. You produce less neurotransmitter. The cell is more susceptible to oxidative stress. So as a consequence, each one of those neurons is getting older. So the ability of that network to transmit signals is going to be weaker.

On the other in age [INAUDIBLE] you can guess what the kids look like. So that's someone who's three-years-old, and that's someone who's 14. So the kids are like-- I mean it actually is beautiful in the operating room to watch. Their brains are gorgeous-- to see them anesthetized.

[LAUGHTER]

It's like art. You can just feel the energy there.

But this is what happens. So it turns out-- so you know I'm older. So you guys are older than you think too. You're past your peak too. See the peak amplitude was back here when you were six or eight. Aha, you too!

[LAUGHTER]

Not just me. So this is where the peak is up in here, and it declines with age. So the 81-year-old lady was somewhere out here. And if you look at the very young-- see how this rises up?

So if you come down here and look at the kids right down here at this really young age group-- so that's someone who's three months of age. Three months of age. No alpha, just slow oscillations. That's all there is.

Something magical happens right here at four months of age. At four months, the alpha oscillations form for the first time. They don't move. There's not the dynamic-- the spatial dynamic like we were talking about before. They're the same across the entire head. They don't start moving until the kids get to be about 11 or 14 months of age.

So when we talk with developmental biologists about this, they said that the first demonstrable signs of changes, let's say, in a human electrophys are probably around the age of maybe a year or so. It turns out under anesthesia, you can see changes as early as three or four months.

And this is extremely robust. We had a kid who was three months and 29 days, and we put him in the three month category because he was three months. But he actually looked like this. He was starting to-- he had already shifted basically. So there's something very robust that's happening there.

So I'll just tell you about one final idea. That's my colleague, Ken Solt. And the New York Times did a piece on our laboratory back in 2011, and this was a letter to the editor. So the person says I had my first corrective surgery for infantile paralysis. That's polio.

And it was in 1949. We got the bill for the anesthesiologist. It was $400. He says my mother was horrified, but my father calmed her when he said it was probably $50 for the procedure. But I'd gladly pay $350 because he knew how to wake her up.

You know we hear this all the time. As an anesthesiologist, people joke about what we do. [CHUCKLES] You sit around. You read your yachting magazine in the OR sort of thing because patient is out most of the time. Or the rude comments like, you pass gas or all this sort of thing. Or you knock people out.

Look, dude, any fool can knock you out. I bring you back.

[LAUGHTER]

That's the key part. But we don't bring you back actively. We just turn the drugs off and let you come back. So Ken is working on turning the brain back on-- saying could you turn the brain back on after anesthesia?

So he has these rats who come over to his lab. His rat volunteers.

[LAUGHTER]

So this is one of them. He's out on his back here. He's like anesthetized. So he has an IV in his tail vein there. So he's anesthetized. And so what Ken is going to do is he's going to inject-- you can see the IV going to his tail vein there. So Ken is going to inject Ritalin, the same Ritalin that's used to treat ADHD.

So he's going to inject it. So he injects it. He has to flush it through. So he flushes it through the IV so it gets into the rat. So we didn't turn the-- we're not going to turn the anesthesia off. We're going to leave it on.

So now he's got a turn over for this to count. If he doesn't turn over, it doesn't count. So he's working on that. But he's managed to get his feet kind of trapped in the wires here. He does make it. I've seen the end of the video. Come on guy.

He did. All right.

I want to share with you what I call science from the word on the street before I tell you about the mechanism of this. So this was in the New York Times also. This was in the New York Times back in 2015. And it was on the front page. I think this was the Sunday Times, "Workers Seeking Productivity in a Pill Are Abusing ADHD Drugs."

So it's a story about this woman who has this startup company. And she gets this phone call late at night where her investors say, look, we need a new financial plan on our desk first thing in the morning. We don't like what you're planning. So she goes, oh.

So she calls up her dealer. He comes up to her apartment-- her third floor apartment. She gives him a wad of money. He gives her a bag of pills. She goes back. She sits down. She gulps them down. She ponders taking another one.

And see this right here? She said she felt her brain snap to attention. This idea that these-- there are people who use these all the time, even though they don't have ADHD. They use them just so they can be on their game, sharp as they say.

So people in high-stress jobs, financial traders or what have you. Now let me just be clear about it. This is dumb. Do not do this. This is not good. Avoid this like the plague. Not good.

But there's something she's telling me here. She says my brain snapped to attention. One of the big problems we have after anesthesia, particularly in older patients is their brains don't work. It may just be delirium for a few hours or a few minutes, but it may be post-operative cognitive function that could last for several months.

And depending upon what study you want to look at and the severity, it could be anywhere from 20% to 40%, particularly of people over the age of 60 years of age. So maybe we should turn the brain back on. So that's why Ken was essentially working on this.

And the way this would work is like this. So what Ritalin does is it blocks the reuptake of dopamine, like in this pathway going from the midbrain out to the cortex. It goes through what's called the limbic system here up to the cortex.

And so we think that this neurotransmitter is helping to-- like in kids with ADHD. They have hypofunction of their frontal cortex. This reestablishes the function so that they are sharper. So the idea here is that maybe something like this would work for people who are coming out of anesthesia because their brains have been scrambled.

And this is different from what happens with a narcotic. So let's say this is an opioid receptor, and you have the opioid binding here. And so that generates this decreased level of arousal because you're on opioids. You have an opiate overdose. So when the naloxone is given, naloxone comes in and competes for this site, and you remove the opioid.

This is different. What happens here is that the inhibitory interneurons are inhibiting this neuron here because they have the GABAergic circuits and propofol is helping them. Or the isoflurane is helping them. What happens in this case is by activating this pathway, you're driving stimulation of this neuron. So the stimulation of the neuron actually helps you overcome the inhibitory state.

So Ken is testing this out. We've done this also optogenetically and electrically. So Ken is testing this out now in a clinical trial at Mass General.

So this is what I've told you. So the brain is not turned off under anesthesia. It's actually quite dynamic. We think that the oscillations which I've shown you are one of the ways in which the drugs are working. You can use it to monitor the brain because the oscillations change systematically to drug dose. Drug category and also with age. We should turn the brain back on after anesthesia.

And maybe you've gotten some sense of this might be a way to investigate how the brain works. Or let me put it this way. So here's the world of general anesthesia, and the rest of clinical neuroscience rotates around us because we're really at the center. Anesthesia is really the centerpiece of all this. We just haven't stepped into our ownership of this. We're going to own this now sort of thing.

But you can pick any one of these topics. Like epilepsy, if you use methohexital, which is a barbiturate, at a low dose, it'll actually induce a seizure. You give it at a high dose, you can use it to treat a seizure. In fact, if the surgeon is in the operating room and can't find the seizure focus, we'll give a little bit of methohexital or alfentanil to induce a seizure so they can actually find it.

Or like over here, ketamine used to treat pain. It's a model for schizophrenia. And at low dose now it's actually being used to treat depression. And you've heard a lot about the opioid overdoses and opioid addiction. And if you think of people who are overdosed as just being in a very profound state of general anesthesia, you're not far from wrong in terms of where their brains are.