The following is a rough transcript which has not been revised by The Jim Rutt Show or by Emery Brown. Please check with us before using any quotations from this transcript. Thank you.
Jim: Today’s episode is the first in a series of episodes on the scientific study of consciousness. Over the next few months, we’ll be doing at least one episode a month on the topic. The researchers that we’ve booked so far include Christof Koch, Antonio Damasio, Bernard Baars, and today’s guest, Emery Brown.
Jim: Emery Brown is a professor of anesthesia at the Harvard Medical School and Massachusetts General Hospital, and Professor of Medical Engineering and of Computational Neuroscience at MIT. He’s a Principal Investigator at the Neuroscience Statistical Research Lab and is a practicing anesthesiologist. Welcome, Emory.
Emery: Great. How are you doing, Jim? Thanks for having me.
Jim: Yeah, great to have you here. It’s interesting. I connected with Emory by chance. I was at an event at the Brain and Cognitive Science Department at MIT. We happened to be sitting at the same lunch table. I got into a conversation about his work. Holy shit. Why haven’t I heard about this guy, right? People who listen to my show know that I’m very interested in the science of consciousness as opposed to the blather about consciousness that we hear so much about. This is why I invited Emory to be on first, because Emory’s work, it struck me, because why I haven’t heard about this? Why aren’t other people doing this?
Jim: His insight was that anesthesia, bringing people in and out of consciousness on a regular basis, ought to be a really excellent probe on the nature of consciousness at the deepest level or nearly the deepest level. So, hence, somewhere later guests on this series, we’ll get into other aspects of memory management, things about that too, but we’re really going to focus on his work around the study of consciousness in the context of anesthesiology. Surprisingly, it’s a relatively new field of inquiry. Why don’t you talk just maybe a little bit how you happened to come up with the idea?
Emery: Well, as you mentioned, I’m a practicing anesthesiologist. To be honest with you, I didn’t really think that much about the science of what was happening. I was practicing anesthesiology for a number of years. I’ve been doing it for maybe 15 or so years. What was happening was is that I’m also a statistician. So, my research was centering around developing statistical methods to better analyze neuroscience data. As a consequence, I had a lot of interactions with neuroscientists. I realized that the ideas that they were using to study other questions, such as memory formation, vision, cognitive perception, they could be used to study anesthesia. Nobody was really doing it.
Emery: So, I’d say I began about in earnest probably about 15 years ago trying to adapt the ideas from systems neuroscience to think about anesthesia. I think part of the reason that this hasn’t happened before or wasn’t viewed that way is that anesthesiology, because we give a lot of drugs to patients, is viewed as a subfield of pharmacology. It’s not viewed as a subfield of neuroscience, even though the drugs are acting in the brain and central nervous system.
Jim: Makes sense. That’s unfortunately the downfall of academia sometimes is too much in the column, right? Instead of going across. Some of the newer ways of thinking about science has really opened up these fields that go across disciplinary columns, essentially to allow this thinking. So, I definitely commend you for having been one of the people who broke through and said, “This and this go together, and we can learn something new.”
Jim: Before we jump into the details of your research, let’s lay out some basic concept for our listeners. I mean, let’s start with just the simplest bits of brain architecture there, cerebral cortex, thalamus, cerebellum, et cetera.
Emery: So, before I do that, let me just say practically, what is anesthesia? What is general anesthesia? Because once you just hear the definition, you can see why it’s possible to think about it without necessarily thinking about the brain. So, it’s a state which is reversible. It’s drug induced. You’re not supposed to be aware of what’s going on. You’re supposed to be unconscious. You’re supposed to not have pain. It’s nice if you’re not moving around. You should not be able to form memories of what’s going on. Your physiology, heart rate, blood pressure, stress levels, should all be totally controlled. Again, all that’s reversible. So, those are descriptions that we give.
Emery: So, there are no neuroscience details there at all. In other words, it’s almost like you know it when you see it and you know it when it’s not working. You need to do something different. So, you can see why you can work empirically with the concept and not really engaged in a formula and thinking about the brain at all, the central nervous system.
Jim: Interesting, you guys did some experiments on a continuum on loss of consciousness and return of consciousness, having people do some activities as you slowly increase the amount of anesthesia they gave them. Can you talk about that a little bit?
Emery: Right, exactly. So, what we did was we had volunteers agreed to let us anesthetize them. We did exactly what you said. We gave them increasing doses of propofol, which is one of the most widely used anesthetic. It’s the anesthetic, which is unfortunately associated with Michael Jackson’s demise. We gave them increasing doses of it and then decreasing doses. The whole process taking about an hour to reach the maximum dose and about another hour or so to come down.
Emery: Every four seconds, they were answering a question, a simple yes/no question. And then what we’re able to do is actually see empirically when they stop responding. We termed that the point of loss of consciousness. By the same token as the drug dose decreased, we could see when they started responding again. So, we had a very behaviorally defined way of defining loss and recovery of consciousness.
Emery: And then the main thing that we were doing at the same time was measuring EEG across the entire head. So, we could also then see how were the brain oscillations across the head changing as the person was losing consciousness with anesthesia when they reach the deepest level and also, when they recovered. All of that on a continuum, both coming in as well as going out.
Jim: Interesting. That’s a good place to jump to another one of my questions here. So, let’s remind the audience of the various technologies we have for looking at the brain. We have things like EEG, fMRI and single neuron recordings, et cetera. They have different attributes in time and space. Maybe you can talk about that a little bit.
Emery: Right, exactly. So, for example, probably the easiest one to think about is the EEG. So, you can put electrodes on the entire head. You can measure potentials, potential differences across the head. The reason this yields information is you can think of the brain as just a large mass of electric chemical circuits. So, there are always currents flowing. The current flows represent brain activity. So, you can imagine if you give drugs but you’re somehow altering brain function, brain physiology, brain dynamics, that there would be changes in those currents. You could actually then measure that or observe that by looking at the EEG. That’s indeed the case. We’ll get into detail later about how strong those changes are under anesthesia.
Emery: Another very widely used technique for looking at the brain… Again, speaking for the moment, first about humans. Actually, just to mention, so the EEG has been around since 1929. So, it’s basically 90 plus years old, but it still is a very widely used technique in research as well as for clinical purposes. And then as you might be aware, there are a number of imaging techniques like functional magnetic resonance imaging, where you use the differences in the oxygenation state of the brain with changes in blood flow to make images of parts of the brain.
Emery: The difference between this and let’s say, EEG is EEG has very, very precise up to millisecond time resolution, but perhaps very poor spatial resolution. Whereas with the functional imaging, you can have very, very precise down to fractions of a millimeters cubed resolution with the imaging. Whereas the time resolution is on the order of seconds. So, you can see that there are obvious trade-offs there.
Emery: And then just behavioral studies, for example, just watching behavior and relating that to some of the EEG or MRI findings is something which is widely done as well. So, I think that if we’re talking now about humans, those are the primary techniques. We can do other sorts of imaging, but let’s say those are the primary techniques that are used to look at what’s going on in humans.
Emery: There’s a very special set of humans that we’ve used and a lot of other investigators who have looked at human neurophysiology abuse. That’s patients who have electrodes implanted in their brain, because they have epilepsy. They need surgery to remove the epileptic focus. That’s because it can’t be controlled with medications. So, the way this works is these patients have the electrodes implanted in their brain. They stay in the hospital for five to seven days off of medication. So, they seize. As they seize, the care team, neurologists, neuroradiologists, neurosurgeons figure out where the seizure focus is. They then come back and remove the electrodes. And then they go on to have the area, which is believed to be pathologic resected.
Emery: What this means is when these patients come back to the operating room and they have electrodes in their brain, you have the rare opportunity to record the active individual neurons from parts of the human brain, which is extremely very rich, rare situation, because normally we do those types of experiments in animals. So, that has been a very rich source of information not only for us, but for other people who’ve been studying various questions in neurophysiology.
Jim: Yeah, interesting. It almost seems like Mother Nature is torturing us. She’ll give us either time or space, but not both, right? With fMRI giving us where and EEG giving us when. And then the single neuron recordings are a limited way to get both. You say, it’s difficult to do in humans. Not too many random volunteers are going to let you drive nails into their head. But with non-human primates, there’s a fair amount of that work goes on.
Emery: Right, exactly. Going back to humans for a second, I mean, what you have there is an experiment of nature. I mean, these patients have the electrodes implanted for therapeutic purposes. And then they’re kind enough quite often to just perform some additional activities, maybe again, executed behavioral task or allow themselves to be part of a special protocol. In our case, for the induction of anesthesia. So, that we can learn something from the fact that they’ve come into the hospital for therapeutic purposes. We’ve been very grateful to those patients, because they’ve enabled us to study the brain from a perspective that, like you just suggested, wouldn’t be possible in humans.
Jim: Yeah, that’s really great. We should always appreciate these people who allow science to use their unfortunate medical condition to advance learning. That’s a real gift to humanity.
Emery: No question. There’s no question about that.
Jim: All right, last glimmery topic before we jump in, which is this is really focusing on EEG brainwaves. Three things that we’ll talk about a fair bit as we get into it are power, frequency, and phase. Maybe if you could define those three terms for our audience. That would be great.
Emery: All right. So, power is probably the easiest to understand. So, if you have like a sine wave, which is going up and down, we can think of the power as being related to the amplitude of the sine wave. So, the larger the amplitude, the greater the power. The smaller amplitude, the less power the oscillation has. It’s either very often plotted as the square of the amplitude, so A squared or sometimes in decibel. So, maybe the log to the base 10 of the amplitude squared or 10 times the log to the base 10 of the amplitude squared would be another way to represent it. But essentially, we can think of power as being related to the amplitude of the oscillation.
Emery: And then the frequency is, “How many cycles of the oscillation do we see in a second?” What we’re going to be talking about are going to be relatively low frequency oscillations, things which go from about one cycle per second up to, let’s say, at most, not too much beyond 20 or 30 cycles per second. The normal brain rhythms where we’re normally processing information is in the range of, let’s say, 25 to about 40 or 50 cycles per second. So, relatively higher frequency compared to the frequencies that we’re going to be talking about for anesthesia.
Emery: Phase refers to so when you have an oscillation, you complete a cycle, you come around essentially 360 degrees. So, phase can be thought of a particular point in that cycle that you keep coming back to. So, we can think of the minimum as one phase. The maximum is another phase. The place where you cross the mean might be a third phase. Those are useful markers to help us track phenomena in the oscillations across time. One- or two-sentence summary of what happens in anesthesia. When the drugs take over the brain, we go from high frequency, low amplitude oscillations to roughly speaking, large amplitude, low frequency oscillations.
Jim: Very good introduction. Next, we’re going to talk a little bit more about the specifics of the mechanisms and the impact on the brain networks of propofol. I read 15 papers of your team’s before this podcast. You talked about some of the others, which we’ll mention, we’ll talk about their differences, which are interesting, some of the other drugs, but that’s the one that you and your people seem to have spent the most time thinking about. Let’s talk a little bit about the nature of the networks that exist in the brain and then how those change as propofol impacts the brain.
Emery: Right. So, I guess the way to think about it is we can divide the brain… Let’s divide the brain regions up into two areas. Let’s say that the cortex, so the outer layers of the brain, the ones that we typically think about. The frontal part being associated with maybe perception and cognition and the more posterior parts being associated with vision. And then we have areas in the middle, which are associated with a whole range of functions, but particularly around the area just probably in front of the ears and the medial temporal lobe being associated with memory formation and also, playing an important role in cognition.
Emery: And then right in the middle, almost in the exact center of the brain is an area called the thalamus, which is a waystation. It’s like a relay. It relays all sorts of information, cognitive information, visual information, auditory information, sensory pain information. So, it’s like a very, very important stopping point or modulating point for a lot of information. That’s going to play an important role. It plays an important role we think in the creation of anesthesia.
Emery: If you take the lower part of the brain, the part we call the brainstem, the part down below, it’s the more primitive part of the brain. The cortex as we often refer to as the neocortex, the newer part of the brain, developmentally thinking about our evolution from reptiles to where we are now, the brainstem controls a lot of the very basic functions, heart rate, breathing, and arousal. Arousal, meaning the signals which emanate from the top part of the brainstem being the midbrain and the pons.
Emery: So, the brainstem has three principal parts, the top pons, the middle, and then the amygdala down at the bottom. There are various areas, what we call nuclei or centers there that send projections up to the thalamus and send projections up to the cortex. For this back of the envelope statement at the moment, they generate what we call arousal. They keep us awake. So, it’s not enough to just be awake to be conscious. You have to be able to be awake and also process information. So, these signals that come from those parts of the brain are there to keep us awake. And then the cortex and thalamus and other parts can then process information.
Jim: What would be a great distinction between being awake and processing information? Is it possible to be awake and not processing information?
Emery: Yes. So, you can imagine just as an illustration, someone who’s awake and delirious or someone who is drunk or that thing. They’re certainly awake. They’re saying things. They may be moving, what have you. But when you ask them a question, you don’t get a coherent response.
Jim: Got it. So, their information processing is certainly addled if not entirely gone.
Emery: Exactly. Right, right.
Jim: Interesting, interesting. Propofol in particular impacts certain sets of networks in distinction from some different mechanisms from others, I believe, this gamma-oriented drug mostly. Can you talk a little bit about that?
Emery: Right. So, the brain has a number of neurotransmitter systems. Again, just to make a simple dichotomy, let’s say, there are ones that are primarily excitatory and ones that are primarily inhibitory. So, an important inhibitory neuromodulator in the brain are the GABAergic circuits. So, they use GABA. The fundamental building block of the brain are neurons.
Emery: We have collections of neurons that transmit information throughout the brain by transmitting very small electrical impulses that are generated by these electrical chemical reactions that take place along the extent of the neuron’s surface membrane. This occurs, because various channels in the membrane open and close. So, you can make the system more excited by putting an excitatory input. You can make the system quieter or turned off or reduce its activity by putting in inhibitory inputs.
Emery: One of the principal mechanisms for inhibitory inputs are those which are mediated by gamma in what we call inhibitory usually interneurons as opposed to pyramidal neurons, which are more often than not excitatory. So, when you give propofol, it binds to a very specific site on this receptor for GABA. And then it opens a channel in the membrane. The channel lets in chloride. So, chloride is a negative ion. So, as it enters from the outside of the cell, the inside of the cell becomes more and more negative. The more negative the cell is, the less excited it is, the more difficult it’s going to have to actually propagate information that might be coming along from other neurons. So, that’s what we think is the molecular mechanism through which the drug is acting on these membranes and inhibiting what’s happening in the brain.
Jim: It’s interesting that at a simplistic level, because they’re all inhibition that should slow the brain, but actually, it turns out to be quite a bit more complicated than that. Parts of the brain become more active or at least particular frequencies become higher and amplitude. Other parts become quieter. Could you talk about that a little bit?
Emery: Right, so that’s exactly what happens. So, if things were just laid out on a straight sheet and weren’t interconnected, then as soon as you gave the propofol, everything would probably just turn off. The degree of turn off would be in relation to how much propofol you gave almost in a linear fashion. But the parts of the brain are interconnected and you have very intricate networks of inhibitory and excitatory neurons. So, that when you inhibit one part, that might shut off the inputs going to another part. But those inputs, if they were controlling this other part and now that’s gone, maybe that area becomes more active. What we see is that as opposed to just the system shutting down, the system begins to oscillate.
Emery: One way to think about this is the brain is this very, very complex integrated dynamical system. By that, it means it has a lot of interconnections. So, because of all these interconnections, it probably has natural resonance frequencies the same way like when you thump the side of a glass or something you can hear, like a humming or vibration. So, you have these intrinsic frequencies. So, when you apply these drugs or you apply propofol in this inhibitory way, you push the system to these kinds of natural resonances. These resonances depend upon what receptor you bound, what was inhibited and what was excited, and then how that’s connected to other parts of the brain. It’s the same thing like you’ve probably seen this video on YouTube, where there’s this bridge. I think it’s in Tacoma, Washington.
Jim: Oh, yeah, the famous resonance of destroying the bridge. It’s in every monster movie from the early ’60s, right?
Emery: Exactly, exactly. So, what happens is all of a sudden, the wind comes along and the wind finds the resonant frequency of the bridge. What was a bridge, which was nice and flat, suddenly becomes a sine wave, right? So, that’s exactly what happens with the electric chemical circuits. These circuits are driven to oscillate. If you think of being able to go across the bridge, cars transiting across the bridge from one side to the other, now just make the analogy, you have these oscillations. So, the electrical impulses have much more difficulty transmitting across the brain. So, you can see why you’re going to start inhibiting information flow. It’s like a back of the envelope way of thinking of it.
Emery: As you create these oscillations, you have long periods where the membranes of the cells are quite low. So, they have to be raised in order for the action potentials, which are these electrical impulses, to be transmitted. If they’re not, if they’re lowered, then you’re going to be less likely to transmit information. And then if you do that in enough brain regions, let’s say you do it in the thalamus and the cortex, you’re doing it in parts of the brainstem, then it’s easy to understand why the brain is going to be shut off under anesthesia.
Jim: I understand the mechanism from reading the papers. In propofol for sure, the big mechanism seems to be big, tall, high powered, low frequency waves.
Emery: Right. That’s what we’ve seen both in our human studies… So, not only both, but in our human studies, in our non-human primate studies, as well as in our rodent studies, you see these very large oscillations somewhere between 0.1 to 4 cycles per second. And then in humans, you also see another oscillation which is very, very strong, which is around 10 hertz, between 8 to 12 cycles per second. These two sets of oscillations come on.
Emery: In the study that we talked about earlier with propofol, where we looked at the relationship between when people stop responding or as we termed it for that study, lost consciousness, and the onset of these oscillations, it was strongly associated the onset of the state of unconsciousness was strongly correlated with the appearance of these low frequency. So, to slow 0.1 to 4 hertz oscillations and these alpha oscillations, these 10 hertz oscillations.
Jim: The other thing I picked up, I think I understand it, but I want you to clarify if I was right or wrong, tell me so, it also struck me as interesting from an information processing perspective that these slow waves, they differ in phase, in different brain regions, which in some sense would make it more difficult for the brain regions to communicate with each other while this is going on. Can you talk about that a little bit?
Emery: Right. And then we should just qualify this, so we can just give you a real sense of how far we can interpret this. But what we noticed in the human studies, in these patients that had epilepsy, when we recorded from their brains and they receive propofol for induction of anesthesia. We looked at how the oscillations were related to one another across the different brain regions. These are areas primarily in the medial temporal lobe. So, the area of the brain, as I said earlier, which primarily, one of its primary functions is memory formation. The oscillations there seem to be out of phase.
Emery: So, when one was going up, the other was coming down or vice versa. That seemed to be happening pretty much across that whole local area. Again, thinking back of the envelope, if there has to be some coordination of activity across regions in order to transmit information, if the oscillations are out of phase, one is up and the other is down, one’s in the midpoint and the other is in the high point, that situation alone is going to make it very, very difficult for the neurons to line up and send information reliably across brain regions.
Emery: So, this breaking up of the oscillations, in this case, across the medial temporal lobe, was one of the phenomena we felt was associated with the state of unconsciousness. In some of our more recent work, where we’ve been able to record more extensively from non-human primates, what may be happening in other parts of the brain might be something on the other extreme. Some of the areas might even be hyper. They might even be hypersynchronous. In other words, everybody’s totally in sync. They’re totally in sync for a period. But in other words, you’re locked, you don’t have the flexibility to communicate as you need to.
Emery: So, being hypersynchronous also could be another cause of unconsciousness. That’s analogous to what we can envision happening with a seizure, for example. I’m not saying that people on anesthesia are seizing. I’m just saying it’s analogous to seizure. You see these very regular rhythms, which then themselves make it difficult for normal information or normal oscillations to propagate through the system or neural spiking activity that propagate through the system. So, therefore, you can understand why either a loss of synchrony as you’re saying things being out of phase or things being too much in phase could both be associated with someone being unconscious.
Jim: Yeah, I remember reading about the fact that some of the higher frequency, frequencies can be highly synchronized, which as you say, is another way to lose the ability to transmit information. So, let’s pop up a little bit and talk about at least something we think we know about human consciousness, which are the networks that support it. Two that you guys referenced in your work is the default mode network and the frontal parietal networks. Can you talk about those just a little bit what they do in humans and at least what it appears that happens to break down those networks under anesthesia, propofol leaks, for sure?
Emery: Yeah, default mode network is a network which has been defined by executing a very basic fMRI experiment, where you basically have someone line a scanner and you say, “Can you just think about nothing for a while? Let me just see who’s talking to whom.” You can image that and see what the dynamics are, which parts of the brains is correlated with whom. And then imagine if you did an experiment, where you then either had someone execute a behavioral task or they’re given a drug, in this case, the anesthetic, what have you, you can look at how the activity in those regions changed.
Emery: The parietal area is an area which, like I said, the frontal area, let’s say we think of cognition maybe. The medial temporal lobe is associated with memory. Some of the areas just off the midline of the cortex are associated with let’s say, language or speech production. The parietal area, which is just moving back from the center of their head, just about halfway between the main point in the back your head, the occiput. This parietal area is used for integrating information across the brain. So, again, it’s another place where if you were to disrupt this, what that part of the brain does, it’s a prime candidate for creating a state of unconsciousness. So, that’s why and to some extent, the problem I worked on is much easier.
Emery: I mean, there are all these places which are seemingly play critical roles for producing consciousness. We know they’re critical, because we’ve learned empirically from neurologic examination of neurological patients over the years that when there are damage to these areas, there are alterations in level of consciousness. But then the more challenging question which a number of my colleagues are working on is, “How do these areas integrate and come together to reduce the state of consciousness?”
Emery: You see, my question is simpler. It’s just like saying, “How is anesthesia breaking these areas?” If we see that it’s having a substantial effect in the parietal cortex, for example, or it’s having substantial effect in thalamus or key areas in the brainstem, then our inference, I underscore inference is that that is one of the mechanisms through which the drug is producing unconsciousness. But then how that area then plays a role in consciousness is still an open question.
Jim: Yeah, it is easier to break something than it is to make something, right?
Emery: I mean, what I like to suggest is I say, “Imagine my cell phone here and it’s very complex device, but I can tell you, if I pull out the battery, it’s going to turn off. If I put the battery back in, it’s going to come back on.” I know that that’s a very effective mechanism for rendering my cell phone in operative, but it doesn’t tell you how the cell phone works.
Jim: Though I imagine if one were doing, especially with sufficient time resolution, studying the re-formation of default mode network and frontal parietal networks, et cetera, task mode networks, as people are coming out of anesthesia, there might be some insights into how those systems stitch together themselves into a system of systems that results in our familiar form of consciousness.
Emery: I think you’re right. I think it is a very productive area of inquiry. I think the challenge is that there’s a lot of redundancy in the brain. And then trying to say, “This is the fundamental unit that’s necessary to turn the brain on and induce consciousness,” is a challenging, I think, statement to make, because there’s a lot of redundancy and a lot of interconnections. But you’re right, watching how someone maybe comes out of anesthesia.
Emery: The other thing too is because of maybe the state of the patient, the nature of the surgery, the particular combination of drugs that were used, how you may come out in one situation might be different from how you come out in another. So, you can imagine one pathway activating primarily when you came out one way, let’s say, using sevoflurane, one of the inhaled ethers. You come out a whole different way just on that given day because of the state you’re in with propofol. But they effectively connected up enough areas in order for you to recover consciousness, if you see what I mean.
Jim: Exactly. Now, it seems to me that variants would actually be a very interesting probe on essentially the network’s self-assembly that appears to be going on in the brain.
Emery: It is. It’s made more difficult by the fact that there is this very, very intricate redundancy across a lot of these networks. I think there are two things as far as anesthesia. I think, anesthesia clearly produces a profound state of unconsciousness. That’s for sure. But one of the things that’s occurring is if you just take a drug like propofol, which acts on GABAergic circuits or drug like sevoflurane, one of the inhaled ethers, which also works primarily on those same circuits, those circuits are everywhere in the central nervous system in the brain.
Emery: So, they’re in the brainstem. They’re in the thalamus. They’re in the cortex. They’re down on the spinal cord. All of them contribute to some extent to rendering you unconscious. So, you never have a clean experiment where it just goes to the thalamus or it just goes to isolated area of cortex or it just goes to isolated area of the brainstem. So, that also makes it more challenging, because you have redundant networks and you have a drug that goes everywhere.
Jim: That’s interesting. In one of your papers, I read somewhere you’re at least proposing potentially trying to put an anesthesia chemical in a specific location in the thalamus as a possible probe.
Emery: Yeah, for sure. So, we did some studies. A few years ago, Laura Lewis, who’s one of my PhD students, as part of her PhD thesis work, did some optogenetic studies, where she activated… So, the thalamus, again, this important waystation sits in the center of the brain, has around it a net, which is called the reticular nucleus of the thalamus. This net is an inhibitory net. So, when information comes out of the thalamus going to, let’s say, cortex, it gets modified. So, it controls the outflow of information coming out of the thalamus by down regulating it or applying some degree of inhibition to it. Different parts of this network, this net around the thalamus control the outputs of different parts of the cortex.
Emery: So, what she did was she stimulated optogenetically parts of the reticular nucleus of the thalamus. She was able to show that she generated these slow wave oscillations in the corresponding parts of the cortex. Now, you’d have to get the whole network or large parts of the whole network to probably make the animal unconsciousness, but it did suggest that you could probably control a network like that and induce a state of decreased arousal.
Jim: Now, interestingly, something I had never heard of, I also dug out of all the papers, was that the opposite appears to be true as well. That a stimulus to a certain thalamic region, which is the intralaminar nucleus, seems to actually revive animals from anesthesia.
Emery: Yeah. Actually, so going back to the human work before that, so my colleague, Nicholas Schiff in New York at Cornell University showed back in 2007 in what was, I think, a very seminal paper, where he had a gentleman who had been in a minimally conscious state for a number of years. They did a very detailed set of experiments on him. They implanted electrodes in his central thalamus. They showed that when they stimulated his central thalamus, they could induce a state of arousal where he had a higher level of functioning. He was able to do more activities than he could when the stimulation wasn’t there.
Emery: Suggesting that if we can learn more about these arousal systems, we can maybe help people recover from coma. So, conceptually barring on that idea, my colleague, Ken Solt at Mass General Hospital has done a number of studies. This is a very active area of research for him. He’s trying to understand, “Can you either chemically or in the case of animals, stimulate parts of the brain and bring an animal out of anesthesia?”
Emery: He’s shown that successfully that you can stimulate various arousal centers, again, these areas which come up primarily from the brainstem going up in the thalamus and cortex. If you drive excitation to an extent, which is can override the inhibition of the anesthetic state, you can wake an animal up. He’s shown that reliably by stimulating a number of areas like the ventral tegmental area, which is in the midbrain part of the brainstem.
Emery: Also, in another set of experiments, Christophe Benoist, who’s one of my colleagues as well has stimulated areas like the parabrachial. It was again, a nucleus down in the brainstem and has shown very similar ideas. So, again, this has two immediate benefits for us. It suggests that maybe it’s a way to help turn the brain back on and get people functioning again after anesthesia, but it’s also translated now into a protocol that’s being carried out by our colleague, Brian Edlow at Mass General Hospital, who is using these ideas to try to help people recover more rapidly from coma, patients with brain injury recover more rapidly from coma.
Jim: Very interesting. Okay, next question. People who listen to the show know that I’m always interested in nonlinear dynamics, systems that have phase transitions, et cetera. So, when we think about dose dependency of, let’s say, propofol, does the response… Is it more or less linear or incremental, or do you see phase transitions that occur as dose increases?
Emery: Well, actually, it’s very interesting. You do see these what start to be very nonlinear dynamics as you increase the dose. So, if we take propofol, we can probably identify maybe six, perhaps even seven states that the brain circuits go through. Again, this is looking at the EEG or local field potentials, which might be recorded directly from rodents or non-human primates. So, just to take you through them, if you give a low dose and some low doses on a good number of patients, the brain will first become excited, right? And then what happens is you start to see the formation of very, very regular beta oscillations on the order of about 12 to 16 cycles per second. And then depending upon how the drug is given, if it’s given as a large bolus, just a big dose all at once, I mean, you next start to see very large, slow oscillations.
Emery: And then if the drug dose is increased further, you’ll have a very obvious, again, what you’re talking about, like a phase transition, where you’ll see there’d be bursting and then flat, bursting and flat. If you increase the dose even further, you can have an entire flattening of the EEG. Now, if the drug had been given more slowly and been given more slowly on the induction phase when you went from those beta oscillations, it would then go not to just pure slow oscillations. You would go to slow oscillations with alpha oscillations riding on top, so slow oscillations. Again, it’s slow delta, about 0.1 to 4 hertz with alpha oscillation, something in the order of about 8 to 12 hertz.
Emery: And then if you were to give more drug, you would then go into burst suppression and then you got basically a flat EEG. But the point being is, is that when you look at the nature of these oscillations, you’re moving across different frequency bands, and I said, roughly going from high frequency, small amplitudes down to low frequency, large amplitude. When you look at the nature, the shapes of those oscillation, there’s nonlinear dynamics involved. These are no way linear systems.
Jim: That would have been my guest, glad to hear that confirmed. Another area that I saw some reference to not a lot in your work is age differences in response to anesthesia. That’s an interesting probe if we think about it.
Emery: Yeah, no, it’s very important, because one of the things that we’ve been trying to do is to encourage anesthesiologist to use the EEG when they take care of patients in the operating room. So, just to complete first, the thought of how we think the drugs are working, so the drugs are creating these oscillations. The oscillations impair how the different parts of the brain communicate. By that, they’re modulating how the neurons can spike. So, creating long periods where there’s inhibition and neurons can spike, and then either hyper coupling or making certain regions more synchronous than other regions that’s less synchronous.
Emery: Now, what’s interesting about that is you can see that very easily on the EEG, when you’re in the OR, for example if you have an EEG setup. This is very standard monitors, which are readily available commercially. There are about three or four things that we’ve learned over the years. One is as I was just describing a second ago, the EEG patterns change very systematically with drug dose. That’s the first thing. The second thing is drugs in the same class have very similar EEG patterns, because it makes sense, they’re mechanistically working the same way. So, you can distinguish drugs by the patterns they generate on the EEG.
Emery: And then the third major point is that, as you just said, the patterns change in a very systematic way with age. They go through a situation with very young kids being zero to three months, having just slow oscillations. Then thinking about propofol for the moment, having just slow oscillations. The slow and alpha oscillations appear somewhere around four months. And then the amplitude of all these oscillations and the width of these bands increase. They reach over at maximum, somewhere between six to eight years of age. And then there’s a very, very slow decline in the amplitudes of the oscillations as we get older. We start to lose our ability to produce the alpha oscillation as we get older, pretty much across most adults.
Emery: One of the things that’s occurring there going back to your original question about changing with age, initially, what I was describing is probably neurodevelopment. It takes time for connections to form. There’s more connections to form. You have the likelihood of these drugs acting on the surface and generating the oscillations. And then as you get older, the brain is aging, there’s the degeneration. And then with that degeneration, the ability of those same neurons to transmit information or to be part of oscillatory dynamics becomes much more difficult, so the oscillations become weaker.
Emery: The practical implication of this particularly for older patients is we can follow these oscillations when someone’s under anesthesia and use them in a very reliable way to guide drug dosing. What I can say for myself and I think this is the case for other anesthesiologists who regularly use EEG, you’re able to administer a much more precise dose of anesthetic and you will be less likely to overdose patients and meet their anesthetic needs is if you do it blindly, you’re not using EEG.
Jim: Interesting. That was going to be my next question, which is the clinical implications. Over the last six years, I got anesthetized and whatever the…
Emery: Anesthetize.
Jim: Anesthetize twice, once general for long and complicated thing. The other one, whatever is just shy in general for a hip replacement. Fairly grisly to imagine that I wasn’t fully anesthetized for that but such it goes, but neither time that the anesthesiologist uses the EEG. Where does your technique of using EEGs to carefully modulate dosage stand in terms of clinical acceptance and diffusion?
Emery: I mean, the idea hasn’t diffused as far as we would like it to. I mean, we weren’t the first to suggest this. I mean, other people had suggested using EEG and EEG-based indices have been around since the early ’90s. I mean, the part of it that we’ve tried to do is understand the dynamics and give a very detailed characterization by drug and also relate to the mechanism, because the oscillations relate directly to the mechanism as we see as how the drugs are acting in the brain. So, it’s not just looking at a pattern and just remembering a pattern. The fact that you see these dynamics is actually quite informative of how the drug is acting in the brain.
Emery: So, for example, if I tell you when you see slow oscillations in the EEG, so oscillation between 0.1 to 1 cycle per second and when we looked at our non-human primates, when we looked in our epilepsy patients or subjects in our anesthesia studies, we saw that neural activity was grossly altered such that it would be very difficult, next to impossible to be unconscious. Then you can rest assured that when you see those oscillations in someone under anesthesia with just a monitoring in the OR, that you can make the same inference. So, you can use that as a way to relate the neurophysiology of what we’ve learned in our studies to taking care of the patient in the operating room.
Emery: It’s hard to change clinical practice, because many anesthesiologists have given anesthesia for years without using the EEG. They make inferences of how much anesthesia is needed, looking at things like changes in heart rate and blood pressure, maybe when the patient is moving or this thing. But that doesn’t really give you the same information that would come out of the EEG. We estimate that somewhere between 20, 25% of anesthesiologists might in some way use the EEG.
Emery: We’d like to see that be higher ideally, everybody, whenever it was possible, because we think that it gives information, which is very useful to understanding the state of the patient and also being able to diagnose those drugs in a much more principled fashion. So, it hasn’t penetrated as widely as we would like, but I think part of that just is expanding the educational efforts. Also, practice habits die hard, because people have had success with them. But we think that there’s a better level of success that can be had by using the EEG consistently or reliably in patients who are having anesthesia for surgery or invasive diagnostic procedures.
Jim: Yeah, it makes sense. Fortunately, I lived both times, but probably would have been better if I’d been hooked up to an EEG.
Emery: One general comment about the EEG, which I should have mentioned earlier, so the EEG is used for a lot of things. Like I said, it’s been around since 1929, the original work of Hans Berger. So, it’s used for cognitive studies. It’s used to analyze the state of patients who maybe have brain injuries or who are in coma. For sleep studies, in fact, the sleep stages are defined by certain EEG states. We use it now for biofeedback into devices like wearables, but of all those things, of all those various applications of the EEG, the one where the signal to noise ratio is the highest is anesthesia. Because, as we said, the drugs come in, and they take over the brain circuits. They get them to work in concert and produce these large oscillations.
Emery: The other thing is that pretty much in any other circumstance where you use the EEG, you’d have noise, because someone’s moving around when they’re sleeping or maybe someone who’s in coma. Coma doesn’t mean that you have no ability to move. You have muscle tone and all these sorts of things. All that’s gone when someone is under general anesthesia. So, the EEG anesthesia has the highest signal to noise ratio of all the things which the EEG is used. So, we have the strongest signal as anesthesiologists, but we’re the group that use the EEG the least. I just find that rather ironic.
Jim: I suppose that has an implication, because it’s such a high signal noise ratio, the training necessary to use it well ought to be less.
Emery: We can make it very focused. We have training programs online, eegforanesthesia.iars.org, where you can take our training modules and learn a very short period of time how to read the EEG under anesthesia. In fact, we have students who come and work with us for the summer, high school students, college students. They take the training course and then we can go in the operating room. We can ask them, “What anaesthetic is that? So, that’s sevoflurane. How do you know? Oh, alpha oscillations, beta oscillations, and slow delta oscillations? Old or young person?” I mean, it’s totally tractable. So, we’ll have to do more, we’ll have to advertise more, but we think that there are very important benefits to be had there.
Jim: Makes complete sense to me. Again, I’ll be looking for an anesthesiologist that knows this stuff. Let’s go on to our next topic. We’ve talked mostly so far about propofol and the work you guys have done with that, but your teams have also worked with some of the other agents. The next one I want to ask briefly about is dexmedetomidine.
Emery: Yeah, dexmedetomidine. Yeah.
Jim: That’s it. At least, my takeaway from reading your papers on that was that it is more like sleep than propofol in that while it is engaging the corticothalamic network, that seems to have less impact on the cortex to cortex networks? Is that approximately correct?
Emery: Yeah, I mean, so when we look at the EEG dynamics of someone receiving dexmedetomidine at low doses or higher doses, they look very much like the patterns we see when someone’s in one of the stages of non-REM sleep. It was somewhere between non-REM stage II or non-REM stage III. Remember I said that the EEG, one of the principal components is used to define the stages of sleep in addition to maybe physiologic responses, heart rate, and blood pressure, and this thing, but the EEG is one of the principal factors that’s used. When you look at the deepest state of sleep, which is slow wave sleep, you see a predominance of oscillations that are somewhere between again 0.1 to maybe 4 hertz, like I was talking about with anesthesia.
Emery: Now, we have to be careful there, because those slow wave oscillations are created by different mechanism from the ones I was talking about for propofol, right? So just because you see slow oscillations, it doesn’t mean they correspond to the same brain state. Because remember, if you’re in a state where you’re asleep and you had slow waves, I went and shook and woke you up, I could wake you up. But by comparison, if you were in is one of these slow wave states, which was induced by propofol and I shook you, I wouldn’t be able to wake you up, because the way the brain is turned off is different under one than is in the other. The external manifestation is a slow wave. The character slow wave is probably larger in amplitude than the one when you’re under propofol.
Emery: But going back to dexmedetomidine, the dexmedetomidine slow oscillations seemingly come about by working on the primary circuits in the hypothalamus and brainstem that are associated with initiating sleep, probably areas coming out of the preoptic area of the hypothalamus controlling the arousal centers in the brainstem. The targets that the dexmedetomidine would hit these alpha-2 adrenergic receptors are on these areas like the locus coeruleus in the brainstem. It’s believed that this is an important network for turning the brain off during sleep. It’s probably no accident that the actions of dexmedetomidine on those same circuits produces patterns which look very much like sleep.
Emery: So, if you were to look at the EEG of someone under dexmedetomidine sedation, because it doesn’t really produce this profound the state of unconsciousness as propofol unless you get very large doses, you would see patterns, which would look very much like stages two and stages three of sleep. So, stage two was spindles, oscillations that are waxing and waning between about 9 to 15 hertz and then mix them with slow oscillations. And then with non-REM stage III sleep, you would see these large slow oscillations. That’s approximately what you see when someone receives dexmedetomidine for sedation.
Jim: Interesting. An interesting probe on that which was mentioned in one of your papers is the question of subjective awareness of subjects during anesthesia. What do we know about that? What do we remember? Do we dream, or is there some other thing like dreaming? Do different agents have different attributes? Go on a little bit about what we know about subjective awareness in anesthesia unconsciousness.
Emery: Let’s go back to propofol here, because I think this is important too and one of the reasons why we should use the EEG, because having awareness under anesthesia is probably something that we get a lot of bad press about when it occurs, because it means that someone was awake under anesthesia. We didn’t appreciate it. We didn’t realize it. I would submit this is a solved problem. Preventing this, I think, is a solved problem in 2020. Because if you use the EEG, you understand what the dynamics of the oscillations mean, then you can use that to guide drug dosing and avoid the states of awareness.
Emery: So, when someone is in the states that I was describing before with propofol, where you have these slow oscillations and alpha oscillations, pure slow oscillations, again, with propofol or you have burst suppression or just the flat EEG, those people in those states are profoundly unconscious. They’re not going to have any subjective awareness, right? It’s when you move to the lighter states, when you have the beta oscillations or what have you, in the case of propofol or the inhaled ethers or you’re perhaps in any one of the states like with dexmedetomidine, you could certainly have awareness, because the brain is not as profoundly turned off.
Emery: One of the best examples is with the opioids. So, a standard practice in cardiac anesthesia, which began in the latter part of the ’60s, was using high doses of fentanyl or actually morphine initially, but then eventually fentanyl, synthetic opioids for cardiac anesthesia. The big upside was it gave a lot of stability to the cardiovascular system during the surgery. The downside was that it wasn’t sufficient by itself to produce unconsciousness. So, patients would have awareness during the surgery, because the drug is primarily an antinociceptive agent. It turns off pain processing, but it doesn’t sufficiently turn off arousal or the ability to process information consciously.
Emery: So, the fact that you could have these states is certainly the case. If we’re trying to prevent that, then using drugs whose mechanisms of action we’re starting to develop a clear understanding of and what they mean neurophysiologically is basically the way to prevent that. Because nobody wants to be having major surgery and then be aware of what’s going on. I think that’s totally preventable. Again, when we hear these cases of people having these situations of arousal, I’m always curious to know, “Was the anesthesiologist using EEG?” Very often it’s not the case.
Jim: Interesting. Yeah. I would say my two cases are the damn thing. I counted down from 100, made to about 97, boom, next thing you know I woke up. Life is good, right?
Emery: Life is good.
Jim: So, the guys did their job. Another question and again, this relates to sleep, particularly REM sleep-
Emery: Actually, Jim, just on one point there. So, doing their job, what they probably had to do is just err on the side of giving you probably more than you needed.
Jim: That’s true. That’s one of the benefits of your EEG approach. You cannot have the risk of awareness without also buying the risk of overdosing or just getting too much.
Emery: Right. One of the things which is well recognized now is that as we get older, the older brain as you were suggesting earlier, older patients are more susceptible to brain dysfunction following anesthesia. So, trying to get the dose right, I think, is important in general, but it’s especially important in older patients.
Jim: Yeah. As an older patient, I will agree with that. I got my AARP cards some time ago.
Emery: So, did I. I’m in double digit number of years ago here as well.
Jim: Yeah, same here, same here. So, we both have concerns about this thing. So, the next topic, which we talked about briefly, is the relationship between consciousness anesthesia and motor centers. Particularly in REM sleep, we know that our motor centers are turned off. So, while you may be dreaming of being chased by bad guys with red fountain pens for some god awful, weird reason, you don’t actually be moving your legs and stuff. How does anesthesia work with respect to our motor centers?
Emery: Well, so this is one of the big differences between the inhaled ethers and propofol. So, just a two second bit of anesthesiology history. So, the first anesthetic that was identified as such was ether. The first public demonstration that took place in 1846, October 16th in National Hospital. It was William Morton who anesthetized a patient of John Collins Warren, who was having a tumor removed from his neck. So, the patient was allowed to breathe in ether. The word ‘anesthesia’ didn’t even exist then. He was given these vapors. He was placed in a state where the surgeon was able to successfully operate. And then we realized we had the first public demonstration of ether. I say that because it’s now well documented.
Emery: Probably the first person to use ether successfully was Crawford Long in Georgia back in 1842. They didn’t publish his results until 1849. So, that’s why I emphasize the first public demonstration of this. So, the drug ether was given and it did everything. I gave the definition of anesthesia at the start. I said, you had to be unconscious, not form many memories, be insensate and not moving. So, one of the things that the ethers do a lot better than… I keep saying the ethers, because we still use ethers today.
Emery: So, sevoflurane, isoflurane, and desflurane are modern day ethers. They’re less flammable, they’re more potent, but they’re still ethers. So, those drugs produce muscle relaxation in addition to making you unconscious. So, they’re the only drugs that we have, which we would consider to some extent, total anesthetics or able to get all the characteristics of anesthesia. Propofol on the other hand is primarily a drug. We call it hypnotic, but that’s just anesthesia speak for meaning the drugs that primarily produces unconsciousness.
Emery: Now, propofol also will produce some muscle relaxation, because it acts at the level of the spinal cord as well. Also, it probably acts like motor relays in the brainstem. So, these drugs have very direct effects on the motor system. So, it makes sense that with the return of function falling anesthesia and you see the effects coming off of the muscles as well as the effects coming off of the circuits that are responsible for cognition or arousal, that you start to see an increase in electromyogram activity as the person returns.
Emery: So, the anesthetics are working on the motor system as well, not just on the circuits involved in producing decreased arousal or producing altered states of arousal. So, in fact, that was why ether was so good, because you had one drug, fortunately… We know, we didn’t have this elaborate definition like I gave at the outset. We had one drug that could basically do everything. So, now we use combinations of drugs to basically achieve the same states.
Emery: But going back to what you were saying about REM sleep, yeah, so REM sleep is one of the states where we dream, but because our motor system is roughly inhibited, you’re dreaming but you’re not moving around acting on those dreams. Whereas we also dream in non-REM sleep as well and probably sleepwalking. Somnambulism is one of the probably stage II sleep, where again, your motor pathways are not inhibited. As a consequence, you’re able to maybe move around or we act out when you’re dreaming. The way which the anesthetics inhibit, that say the motor pathways don’t necessarily have to map on to the way the body inhibits the motor pathways during REM sleep.
Emery: So, I think that this is where maybe they’re probably a less perfect model of this one component of decreased arousal, which is REM sleep, as opposed to maybe a model like you’re talking about, dexmedetomidine being a model for sleep. Propofol and its effects and the ethers, their effects on the components in the motor system are probably not a good model for REM sleep inhibition of motor activity.
Jim: Nice distinction, nice distinction. We talked a lot about research and thinking and experience in the clinical context. Your group also does some more theoretical work. I read one paper, I think it was two, where you guys had built simulations of the thalamocortical networks and their influence on propofol. Could you describe a little bit what your simulator setup was? We do talk about simulations and agent-based modeling here on the show a fair amount. So, just a little bit about that technique and what you learned.
Emery: Right. We have the good fortune to be here in Boston, where there are a number of people who have expertise in a number of different areas and we’re able to collaborate with them. So, the human studies I was describing earlier with the patients in the operating room, as well as the volunteer studies I mentioned with propofol, so those were done by my colleague, Patrick Purdon. And then as we executed those experiments and we started to see very robust dynamics coming out of the EEG, actually, we decided this before we did the studies, because we had some idea that we would see these very rich dynamics coming out of the EEG.
Emery: We figured we should have a program or a parallel research program that looked at trying to model that activity to understand why it was coming about. So, that’s a collaboration which has been ongoing now for at least 15 years with Nancy Kopell, who’s a very well-known mathematician, who specializes in dynamical systems, particularly dynamical systems that describe neural circuits in Boston University. So, what we’ve done is we’ve taken the various stages, propofol’s the one we’ve dissected the most, dissected most carefully as you suggested earlier.
Emery: So, when I was describing the various stages that propofol dynamics go through, so first wake, you have low amplitude oscillations, then maybe larger when you go into this state of paradoxical excitation, then moving from there to beta oscillations, then to slow oscillations and alpha oscillations on down the burst depression. So, we’ve done modeling work to describe pretty much all of those transitions, because they help us understand… The way we’ve posed the question with Nancy is given we see these oscillations… They’re not subtle. Like I said, they’re probably the strongest EEG signal around. They’re not subtle.
Emery: Given that, given we know the architecture of the cortex and given we know something about the neurotransmitters that affect the neurons that are part of that architecture, can we do simulation studies that will allow us to reproduce the oscillations that we see in the EEG when a patient is going through the various stages of anesthesia? It turns out that that we can. So, that’s been very helpful to us as a way to add support, add modeling support to the work that we’ve done experimentally, recording the EEG.
Emery: So, one of the things that came out of that was we saw these alpha oscillations. They have a very specific characteristic. This is why it’s important to emphasize the study that Patrick did in our human volunteers, where we recorded this EEG, giving volunteers increasing and decreasing dose of propofol, the alpha oscillation wasn’t just willy-nilly all across the cortex. It was sitting primarily in the front of the head, in the front of the scalp. Again, something which is robustly found across all the 10 subjects that we looked at indicates that there should be a readily accessible mechanistic description or explanation for that phenomenon.
Emery: With Nancy’s help, we developed this model of these oscillations perhaps being this futile oscillation going back and forth between the thalamus and cortex. That made sense, because our models show that as you increase inhibition, GABAergic inhibition across cortical-thalamic networks, you could move from these higher frequency gamma oscillations down to beta and also in the alpha oscillations. The thalamus would do that. The cortex would do that. They would lock in with each other. They’d lock in in the front, but not in the back, because the neurons in the back had different properties, different channels. That’s why we don’t see it in the back.
Emery: So, what that meant was is that it gave us an idea of what we should be looking for. And then we went on to do a series of additional experiments. So, Francisco Flores, who’s in our group, did experiments in rodents, where he stuck electrodes in the thalamus and electrodes in the cortex and showed that that was indeed the case. We did see this very coherent coupled oscillation between the thalamus and cortex when we anesthetize rats with propofol. So, the modeling was and continues to be very, very useful for helping us organize our information and to think through what some of our next experiments should be.
Jim: Very good. The other theoretical bit that I was taking to being a network complexity dude was your work on state-space global coherence measures. Could you tell us a little bit about that?
Emery: Yeah. So, we talked a bit earlier a little bit about fMRI. With fMRI, one of the things which is done when we’re talking about the default mode network, the default mode network determinations are made by looking at correlations between different brain regions when you’re asking someone to lie into the state, where they’re essentially thinking about nothing, doing nothing. One of the things that makes the brain so interesting and so exciting is that it’s never just really sitting still. It’s always dynamic.
Emery: So, one of the things you realize is if you want to really track how brain networks are moving or what the brain is doing, you have to have statistical techniques or signal processing techniques that allow you to follow dynamics. So, coherence, just essentially measuring the correlation between two brain regions at a given frequency is a very natural way to start thinking about looking at relationships between brain regions, because one, the correlation tells you something about whether or not they’re coupled.
Emery: Because at least for anesthesia, as I’ve been saying, the drugs are inducing and maintaining these very strong and often inflexible oscillations in between different brain regions. So, it makes sense that you would have a technique that would allow you to measure how tightly brain regions are coupled at a given frequency. And then you should be able to track that over time and see how it evolves.
Emery: So, that’s what this state-space global coherence idea is looking at. So, the coherence is really just computing the correlation at a given frequency. So, let’s say it’d be very specific at 10 hertz, how tightly coupled is the frontal region in the brain, let’s say, with the parietal region? So, that’s just a correlation. Now, you can have a window. So, you do that over various time windows. So, the state-space idea is just to have a model of how that might evolve over time and then use that to track those brain dynamics.
Emery: The global coherence comes in where essentially looking at correlation not just among pairs, but you’re looking at correlations among a set of electrodes perhaps either in the same brain region or over a number of different areas all at the same time. It’s generalizing the idea of this simple correlation, because there what you are doing is you have a matrix, which describes the correlation between the various regions.
Emery: And then for a given frequency, you can look at the Eigenstructure of that matrix. The first ratio of the first Eigenvalue to the others gives you a measure at that frequency of how tightly coupled that network is. And then you say, “Okay, now let that evolve in time.” That’s the state-space part. So, you can look at how a network is coupled or coherent over time as, let’s say, a subject executes a task or moves through the different states of anesthesia.
Jim: What have you found? Have you been able to run those numbers on the various states of consciousness tasks and unconsciousness?
Emery: So, we have. I mean, to be fair, I think it’s still a work in progress. We haven’t done as many analyses using these, because some of these ideas we just developed literally in the last year, year and a half or so. So, I think the jury’s out at the moment as to what they’re telling us. We certainly think they’re going to give us a better sense of the dynamic structure within the data. That’s going to then help us refine our modeling descriptions of the data. And then from there, I think it’s going to guide our experiments. So, at the moment, I would say, it’s a very, very promising technique to be fair.
Jim: Very good. Well, we’re coming up on our time check here. So, Emery, our last question will be, “What do you see new coming out of your lab and with your collaborators in this domain you’ve been working on over the next few years?”
Emery: I think starting from the most practical, I think the most practical thing is what we talked about earlier, just really creating the knowledge base. A scientific knowledge base is translated into clinical application. So, that the EEG can be used as a meaningful tool to help guide the care of patients under anesthesia. I see that as very, very feasible. I think we have to make clear to our anesthesiology colleagues why this is the case. I think that part of the issue is that anesthesiology, as I said earlier, has been viewed as a subdiscipline of pharmacology and not neuroscience.
Emery: So, this is a bit of a change in perspective, but making it, I think, is going to be critical for improving care. In other words, so much now is being learned about the brain from studies in human, studies in animal models. The whole BRAIN Initiative was set up to develop techniques that allow neuroscientists to interrogate the brain and extract information in ways that were impossible before. If anesthesiology doesn’t view itself as a subdiscipline of clinical neuroscience, then it’s essentially shutting itself off all those advances and what those advances can mean for patient care.
Emery: So, I think, putting the emphasis on the neuroscience and putting emphasis on the immediate benefits which can be had by using the EEG in particular to guide patient care, I think, is something which we’re going to place a lot of effort on, even more so than we have in the past. I think that developing better ways to monitor the brain to understand more deeply what’s happening in the brain under anesthesia, I think those things will also translate into other areas. I mean, you’ve probably heard about all this work that’s going on now, where ketamine which is one of our core anesthetics is used to treat depression.
Emery: For example, like you were mentioning before, dexmedetomidine closely resembles sleep. So, the way I like to think about it is anesthesia is solving the order zero problem. The brain is turned on, turn it off profoundly. But if what you do is you say, “Okay, turn it off but turn it off in a physiologically sound way, so you can gain rest,” well, that’s an approximation to sleep. Or if you want to turn it back on, you’re turning the brain back on, turn it on in such a way that you’re happy and you feel better, therein lies a way to perhaps treat depression.
Emery: Or the changes that we saw with age, just like we age different physically, it’s clear from some of the data we’ve collected that people’s brains also age differently as well. Could giving someone a dose of anesthesia and seeing what state their brain is in… Could that be a diagnostic test for understanding brain age or brain state? The same way if you really want to know whether or not someone is at risk for having a heart attack, you just don’t have them walk across the floor. You actually put them on a treadmill and stress them and you try to induce the state. So, it could something similar be possible with anesthesia.
Emery: So, I think that going forward, embracing this neuroscience paradigm is central to the future development of anesthesia. It’s going to offer greater benefits for taking care of patients in the operating room, but also perhaps open up new areas of research where concepts from anesthesia maybe feed over into other areas of neurology and psychiatry and perhaps sleep medicine, and move those fields forward as well.
Jim: Well, that’s very hopeful and extremely interesting. I’ll continue to be following your work and see what comes next. Thank you very much for a wonderful talk where we got into some deep things, but you made it very clear.
Emery: I really appreciate it, Jim. So, kind of you to have me on. I really appreciate it. Thank you so much.
Jim: This has been great.
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