Full auto-generated transcript below. Beware of typos & mistranslations!
Alex Proekt 5:12
Well, my life is a little bit schizophrenic. I spend about a couple of days a week taking care of patients in the hospital, I'm an anesthesiologist. So I'm there to get them through the surgeons. And when I go to the lab Well, I work on aesthetics. And I started working on aesthetics when I started my own lab, but really I am your physiologist says my background, I did my PhD studying nervous systems of invertebrates. And specifically, I was very interested in how nervous systems generate patterns of activity. So in invertebrates and slugs, specifically, there are very many fewer neurons in the brain, a mouse. So there was still a glimmer of hope that you can understand how these inputs work. In fact, we know a fair bit about them. But it's so far from the story. But when I started my own lab, I figured well, there should be some kind of a connection between what I do in the lab and what are the clinical. So I worked a fair bit on neurophysiology meaning studying electrical signals in the brains of things like mice, I worked on data from primates, I don't really do primate experiments myself. And now as of late, humans, try to understand how these more complicated brains produce different activity patterns and how visibilities change when you change the state of consciousness. For instance, wherever you can consciousness we are now as opposed to, for instance, how we are unregenerate brainless, sensual, always active, and it's the character of this activity that really sort of distinguishes between being awake, normal state in the last two days, we'll be in this weird capitalist state, not sure exactly what to call that is called an insight. But it's quite quite different.
Nick Jikomes 7:20
So that's interesting. So you're an MD, you're an anesthesiologist, you're putting people under part of the week. And then your lab, you're studying brain dynamics and brain states, broadly speaking, I guess.
Alex Proekt 7:33
That's right. So that's kind of that's right. That's, that's very fair. So my, I did a fair amount of work on on aesthetics. But my interests in brain ailments are broader than that. So for instance, one of the things that we're sort of just getting into is learning and memory and things of that nature. So what generally, you know, when we record from the brain, we see some signals that fluctuate in time, and they are different in different parts of the brain. So I'm interested in how that how those patterns emerge, and what those patterns can tell us about how our brains process information, respond to stimuli in the outside world.
Nick Jikomes 8:19
And when we talk about brain states, you know, obviously, when you're awake, versus sleeping versus under the influence of an anesthetic, the brain is doing very different things. And that's why you know, your behavior and your experience is different. But you know, what, exactly, let's define what a brain state is to neuroscientists, for people. And can you talk a little bit about, you know, the extent to which brain states, you know, are they? Do they display smooth variation, or they're just sort of subtle, gradual changes from one state to to another? Or, you know, to what extent is it true that there are sort of discrete fast switches that happened?
Alex Proekt 8:56
Right, so first of all, it's an excellent question. And I'm going to before I say what I know about this, I'm going to say, I don't know. And I don't think anybody really knows what constitutes an adequate description of a stapler when I'm going to take a step back first and say, Well, what is the state or anything? Right? How do you define that? Well, we'll say for instance, you're interested in a relatively simple system like a pendulum. A state of a pendulum would be really the collection of all variables that you need to describe the pendulum. So per pendulum, that would be something like its position and its velocity. But if I know these two things, and I know Utonium mechanics, I can tell you what's going to happen to the pendulum next, I can also infer what has happened to the pendulum, right. So for the brain, ultimately, we'd like to know what are the salient variables that are sufficient to describe the brain. So for instance, we can do that That reasonably well for a single neuron. So a single neuron, as, you know, ion channels and things of that nature that allow current to flow across cell membranes. And we know how these currents work. And we know how to combine these different currency to a reasonable model, or misteriosa. That was pioneered by you know, Munchkin, Huxley in the 50s. And that kind of stuff. So, in principle, in principle, while if I knew everything about every neuron, I can put it together into one giant picture of what a brain says, But, you know, until some people that kind of monochrome is doing that with the Blue Brain and similar kinds of approaches, and well, maybe that's fine. But the problem is that this description is so huge, it's completely new. So you can't, you can't look at a million variables and say anything about it's just just too much. So when we colloquially speak of brain states, maybe we say, while somebody is awake, or somebody's asleep, and what we really mean, when we say that we say, well, behavior, what is the state is a state of a brain in which, you know, if I asked you to do a thing for me to be able to understand me, and, you know, they agree to do the thing I'm asking you to do, as opposed to say, a state of sleep, where, if I give you a relatively mild stimulus, you will probably not respond to it. Now, you've asked me about transitions within the constraints. So that's, that's also an interesting thing. So transitions between these big, big states that awake versus asleep, those tend to be fairly abrupt. And why do I say that? You know, of course, this we record, from the brainwaves in GE or something like that. And I will see that the character of EEG signals changes very quickly. So for instance, it will slow wave sleep oscillations will be slow. And then very quickly, they transition to sort of more awake, like a rig, like, EEG signatures. And we all know this, you know, every morning, you know, when the alarm clock goes off, you know, right before it went off, and we're asleep, we didn't dream, and then alarm goes off, and maybe you're a little bit drowsy, and you're not really fully awake, alert. And you know, I myself need a cup of coffee to do that. But you're definitely something quite abrupt happened. With anesthesia with her singing, it's also seems to be abrupt. So, for instance, it's not very uncommon for somebody to be at the end of surgery, right? The surgery itself was over. And maybe there's so breathing, some relatively low concentration of anesthetic vapor, or something like that. And if you leave them undisturbed, there appear to be asleep, their eyes are closed, they're not really interacting with the world. And then you can tap them on the shoulder and see the Alex wake up under you read. So there's an abrupt transition behaviorally. And there's also abrupt transitions in brain activity as well. So I don't know if that's true for all anesthetics, but it has been shown to be true for a number of different so yes, what appear to be abrupt transitions.
Nick Jikomes 13:41
And, you know, what are the ways that a scientist would typically measure and quantify the brain state that an animal's in what what are the tools there?
Alex Proekt 13:51
Right, so, right, so another very, very important question. And I think depending on who you would ask, they would answer slightly differently. Right? And what I mean by that, because the brain is this vastly complicated thing, and we can't measure all the things about this. So we necessarily have to, you know, kind of remove ourselves a little bit from the nitty gritty of water molecules, how they're moving in every single cell, but it could be just impossible. So different levels of abstraction. So for instance, if you talk to somebody who measures say, firing of individual neurons, well, maybe they would say, Well, you know, for instance, if every moment in time, I have a every neuron that I've recorded, that will see the firing or not. So you can think about it as sort of a binary kind of a code. You say, well, a vector or a collection of all of these zeros and ones constitutes the state of the brain at this one moment in time. Now, that is if you're looking at individual neurons, but what is For instance, you're looking at the level of EEG, you don't really see firing with individual neurons, you see fluctuations in the local field potential. So a reasonable way to define the state of the brain is to say, well, at what frequency are these oscillations occurring? So imagine that, you know, brain activity sort of like, like a musical chord, where all different nodes have played sort of more or less, at the same time, you can say, well, what notes are being played, and how relatively loud is one into the other? Now you have some some definition, you know, just want to make it clear that, you know, these are not entirely ad hoc, but they're definitely incomplete. You know, and, you know, maybe if you ask for a functional MRI person, they would say, Well, you know, I see activity in this part of the brain, but not on that one disturbance of that may be defined as a state. So that's, yeah, there isn't a single agreed upon definition, because we don't all study the brain the same.
Nick Jikomes 16:08
I see. So. So when you measure brain states, you can sort of measure and study these things at different levels. Some people stick electrodes into the brain and listen to individual neurons one at a time, some people use something like E. G, where it's more like, you know, you're listening to the orchestra play and hearing the whole ensemble of music at once. But the point is, in different states, there's different patterns of activity going on. And you mentioned already, that the states often abruptly change. And, you know, we've all had experience with this, you know, we've all, I think, had the experience of sitting on the couch, and you're kind of tired, but then, you know, you sort of suddenly fall asleep. And you know, your head goes down. And, you know, it just takes a second or two for that transition to really happen. And, you know, if you're lying down in a comfortable position, then you'll be asleep and stay asleep for some period of time. So the transitions are quick. And then the states persist for some some length of time. What do we understand so far, about how and why that happens at the level of neurons and circuits? Because I would imagine that a very different kind of circuit, a very different kind of dynamics would be responsible for an abrupt shift that leads to these stable changes versus something that was much more gradual and continuous.
Alex Proekt 17:24
That's right. That's right. That's right, exactly. So maybe I can say a few words about why should there be abrupt changes? Anyways, you know, and sort of the technical term for this would be multi stability. And what do I mean by that? Well, how do I explain this? Well, for instance, let's just say we have two people on a seesaw, right, and you see some swing, right, and let's say the two people weigh about the same amount, and you start with a seesaw and totally horizontal position, right. But that's not a very stable configuration of the seesaw, because maybe a gust of wind or something like that pushes on one side of the seesaw, another, the other as soon as one person is just a little bit lower than the other person while they're gonna go on, and we're gonna go all the way down, and the other person's gonna go all the way up, and that configuration is stable, that is, be fine. Now perturb the system, it will return back to its original state, right? You can imagine, well, now it's a kind of a strange, she saw me do that, you know, it's being shaken all the time that sometimes one person would be down, and sometimes the other person would be down. But once one person goes over, down, they can attend to stay there because the system is stabilizing. So similar kinds of phenomena, neurons, right, for instance, you know, we all know, you see, many people listen to this motor neurons fire what's called an action potential. So usually, if you put an electrode into a neuron, you will see that there's more negative than the outside world. And you can inject some currents into this neuron or mega neuron will receive input from some other neuron that will maybe make a focus over the surface of a new cross a certain threshold, you get this giant sponge, just giant voltage exposure, right? So if you play with the parameters, the currents a little bit, we have found these kinds of cells in different kinds of brains ability to just fire a brief voltage impulse. People just stay at a different voltage level, right? And that just happens to be the consequence of how different currents so some currents wants the open sea open for a long time, some currents from the open, the only seal can briefly read so it determines how stable now, when we're talking came about networks of neurons, which is really kind of irrelevant for say, looking up from sleep or waking up from anesthesia, we don't really have a very sort of detailed mechanistic understanding. But you can imagine that, say I have a bunch of neurons that all excited chatter, right, so one of them starts firing, it excites his neighbor, and the neighbor excites him back, and we're going to find more and more and more more. And then there's another group of neurons that also excite each other. But the two groups in the future, this ends up being in a situation that is very similar to a seesaw. Once one population sort of wins a little bit, it starts winning more and more and more and more, and so the system sort of stabilizes. And then with noise or with input or with something else, you can switch with the situation where the two groups of neurons are exactly balanced, this is kind of unlikely. So, right, and it turns out that these ideas of multistability were generic. So long as you have nonlinear interactions between components, you're almost guaranteed to have multiple stable solutions. And that is probably what we're seeing when we see abrupt transitions between states to go from one stable equilibrium to another. Now the duration of how long we stay, there is a very interesting question, for instance, you know, since we're talking about sleep, you know, human sleep cycles consists of slow wave and REM sleep and most opinion occurs and happens on a scale of one hour and a half. Of course, it's variable between people and depends on age and of course, all sorts of other things. But in a mouse, it's a couple of minutes. Right? So there's a huge difference in how stable these circumstances are. And why should this be more stable than human being in a mouse? Well, nobody really has a good idea. Although the status up is similar. If you look at mouse EEG and human EEG doing so if you would say, well, they're not identical, but the consumption.
Nick Jikomes 22:08
And so when we think about something like sleep, so it's not, it's not simply that we fall asleep, and then we're awake, and we fall asleep when we're awake. When we're in the sleep state, broadly speaking, we're cycling through different states, there's slow wave sleep and different phases of non REM sleep. There's REM sleep. So what's the significance of cycling through those different states? And to what extent doesn't matter what order they go in?
Alex Proekt 22:32
So right, so Okay, so that's another very good question. Well, significance is sort of a loaded term. I mean, it turns out that I believe we're wrong about this, but I am pretty sure that's true. All mammals have something that resembles slow wave sleep, and something that resembles. Now, slow wave sleep, appears to be controlled by two kinds of forces, one of them's circadian rhythm, right. So some animals like people will tend to sleep during the night, some animals will turn out a temperature during the day. But most animals have some preference for one procedure. But another component of this is homeostasis. So the longer you stay awake, the longer the stronger the pressure to go to sleep, people experience this. And these two forces can interact in complicated ways, if you don't have an all nighter, you were dead tired at four in the morning. But now the sun is rising. And all of a sudden, although you haven't slept, you kind of feel a little bit more weaker, as if you've been putting in sort of responses. Now, wrestling is a fascinating thing. I don't know if anybody really knows that much about it, except for the fact that it seems that dreaming is really common in sleep. In fact, it was originally called paradoxical sleep. And that is because if you look at G or some other brain measures of activity during REM sleep, they're remarkably like wakefulness. Right? So brain is quite quite active, but doesn't exhibit the saw solutions. Right. So that's already an interesting thing. Because if you didn't know the person was asleep, you would conclude that this is an awake brain. We're also paralyzed essentially, during REM sleep, except for eye movements, sometimes feet moving and things like that. So you know, what is the significance of REM sleep? The only kinds of things that I know about it's sort of legal that this word if I prevent you from sleeping well Lots of things go back. If I prevent you from sleeping, you know, you're learning you're doing some tension will be much worse. There are all sorts of ideas how sleep may be important for learning or consolidating memories of the form during the day. You know, I'm sure that that's that's the case, but not some people say it has to do with energy balance and that kind of business, synaptic homeostasis that's truly at the moon, these sort of ideas around why sleep happens? I'm not sure if I've answered your question.
Nick Jikomes 25:39
Yeah, no, I think that's interesting. I'm wondering if so for example, you know, and we don't know the answers to all of these things, obviously, but you know, would the outcome of sleep, the physiological effects, it's having be different if you could somehow change the order of REM and non REM sleep, if you could get rid of the REM sleep, or just the non REM sleep? Or switch them around? Does that have any physiological importance?
Alex Proekt 26:05
I didn't answer your question. I think that's right. Remember, there was something missing. So there are disorders, and I'm not like a real sleep expert. But I know this one, nonetheless. Right. So typically, during normal sleep, you know, usually start out in slow wave sleep, you perceive the different sub stages of sleep, sleep on the down and up and around narcoleptics can go straight to or would probably REM sleep well, especially when it's accompanied by cataplexy. I mean, you can be walking around, and then suddenly drop into REM sleep. And as I mentioned, you're paralyzed, that when that happens to the block to the ground, that's, that's, that's what unpleasant. There are people who like sleep walk and things of that nature, but I don't there have been experiments where you can deprive an animal, maybe put some humans to REM sleep specifically, right? Because if you prevent somebody from sleeping, you're going to prevent both non rem and REM sleep. So you can you can disrupt REM sleep specifically, I think you'll also get cognitive effects afterwards, some difficulties with learning.
Nick Jikomes 27:21
And one of the one of the things that I know is important, one of the variables that seems to be very important for defining distinguishing these different brain states are the activity patterns of specific, relatively small populations of neurons that release the major neuromodulators. So can you talk a little bit about what neuromodulators are and why they seem to be particularly important for defining brain states?
Alex Proekt 27:46
Sure, sure. Okay, so that's obviously the big field. So well, how do I start? Well, so people have observed this, since the 20s, or 30s. Different kinds of brain states like awake asleep, are associated with different patterns of oscillations in the EEG, that's only in the 70s, and 80s 90s, even to begin to understand how these are solutions come about. And they really come about from the interplay between the powerless and the cortex. So the thalamus, what most people know of the thalamus is that it transmits sensory information to the cortex. And that's definitely a component of what the Congress does. Other parts of the parliament are supposed to be more in control of is your sort of a amorphous things like vigilance, attention, sleepiness, wakefulness, consciousness, things of that nature. But So Thomas Cohen talks to cortex cortex, oxygen abounds. Now, so part of it is the interaction between the different brain regions and part of it is just about physical properties on the neurons that are involved. So for instance, when we are in slow wave sleep or under anesthesia, it's so physiologically somewhat similar states, it's related to the seesaw analogy, thalamic neurons, silence for a little bit, and then they fire for a little bit sounds a little bit quiet for a little bit. And that kind of process repeats, let's say about once a second. And that is really related very closely to the slow waves of observing the EEG. And where this going up and down the discrete levels of voltage and firing rates has to do with the kinds of currents that are expressed in humans and this brings us to neuromodulators. So the throttle cortical system has this very interesting and rich dynamics, but it also receives inputs from these more ancient brainstem and hypothalamic strat. Phase both direct and indirect. What these ancient structures do is that they project a unitary body, you know, a single neuron and go to very large swaths of the brain and they release these chemicals, you know that the actual receptors themselves only unlike sort of canonical neurotransmitters that produce a little blip in the voltage, these things have longer lasting effects, but they modulate the neural activity through different kinds of mechanisms. And what this modulation does, and when the meaning of the word modulation is sort of changes been put out the properties of neurons, right. So now the same circuit is communicating between the thalamus support exploitative, anonymous, but the properties of the constituent neurons change. And as a result of this, the circuit as a whole exhibits different dynamics. So what are these modulation, for instance, norepinephrine is very important. In this process, acetylcholine is sort of a classic culprit that we know probably the most about in terms of this ability to modulate different brain rhythms. It's mostly produced by a small group of cells in the ponds. And here are these documents to change the various kinds of variety ones and viruses something which is slow oscillations or hypertensive social circles. Now, REM sleep is a whole different business, because the solutions in REM sleep are quite like the waking state. So they're not so many neuromodulators that distinguish between RAM Wilkinson, on various things. I don't want to be wrong after that, which was the head?
Nick Jikomes 31:58
And so you've already hinted at at the answer, I think, but you know, when we look at these different brain states, Ram versus non REM, waking versus either of those, to what extent is sort of every neuron in the brain doing something different in each state versus this population is active and becomes quiet, and then a separate population does the opposite thing. What does that how do we think about that?
Alex Proekt 32:20
So well, we don't know very much about that. I think there's, you know, the real sort of by physically detailed work that was done by, you know, Contreras accessorizing, a bunch of other folks who's one neuron, it's very, very challenging to put a federal electrode inside of you on, it has to be in the right place, and the neuron can't move. The brain, circulation, breathing Museum and other vertices. Very, very challenging to do was one year out of town. And that's how we know most of the neural basis of these different rhythms that the brain produces. Okay? Now, now, there are different methods that people use in closing to that microscopy to image and this is a little bit interactive, accurately measuring electrical activity of the brain, but maybe, may be close enough. So but there is very little understanding towards the growing retransmissions between different brain states or sequence. So across different us whether they're all have to be in the same state. In fact, it seems like they don't have to be so there was really compelling work by blood, guys of Stu and a number of other folks who say, Well, certainly if you look at the EEG of a person, you can say, well, this person is asleep or their way. But if you start recording from inside the brain, you will see that some locations in the brain exhibit more sleep like patterns, while other ones at the same time exhibit more awake. The reality is a movie between last few years, there is no such thing as a global state and the brain nobody in the brain knows about the brain is just a huge collection of neurons that interact with one another, the only thing that one neuron knows is who is excited and inhibiting modulating it. And who is it sending neurotransmitters to you know, the the global state have a very real sense of sort of an emergent process, which has to do with interactions between many different parts. And what can happen is, you can have two different parts that are only weakly correlated with one another. But if you have many, many, many such weak correlations, growth states are appealing global recording, right? So that's at least my thinking about the roles of different opinions. shins to transition.
Nick Jikomes 35:05
And so you know, you spend a lot of time putting people and animals under the influence of anesthetics. When, you know superficially, when you see someone who's been anesthetized, the, you know, behaviorally, it's like they're sleeping, right? They're not moving, they're not responding to sensation from the outside world. When you actually look at what's going on in the brain, does the anesthetized brain look like the sleeping brain? Or is it distinct somehow?
Alex Proekt 35:31
So it's this? Well, it's complicated, right? Because well, first of all, it depends on which anaesthetic we're talking about, right. So aesthetics of the kind of propofol, which is, again commonly used intravenous anesthetic bitrates, they can, at certain concentrations produce brain activity that resembles that install race, and probably shares a lot of mechanistic sort of similarities with what's happening in sleep. But if you add a little bit more onset, you would get patterns that are never observed. Simple, something that you would observe in a coma, in general anesthesia, in a surgical, so the arm is much more similar to a coma than it is to sleep. You know, if it was like sleep, I wouldn't have a day job, you know, you could just take a nap. And somebody can, you know, give me a new kitten or something. Right. So obviously, it's behaviorally some differences. But yes, there are some similarities. And if you read some of the older literature, they use it interchangeably. So I don't think it's, you know, I don't think they're completely different, but they're not exactly the same. Now, other anesthetics, for instance, like, Kevin, don't look anything like sleep at all. Right? If you give somebody, Kevin, you don't see suppression, metabolically, don't see suppression, don't see slow waves, you know, it's very much looks like a waiting G. And maybe if I'm allowed some sort of political license you there is some kind of a parallel between what's happening and what I'm seeing, and what is happening and determine activity, the brain vivid experiences, learning how to infringe when, you know, but unresponsive is the outside world. So there are red so. So really, at this level, there is a similarity between Kevin and REM sleep, but mechanistically we don't know.
Nick Jikomes 37:46
So let's say you know, someone has to go to the hospital and get surgery, they've got to get put under so that you have to give them an anesthetic. How does a physician decide which anesthetic to give someone? What's what are the variables that that informed that decision?
Alex Proekt 38:02
Right, so Well, you know, there are not so many anesthetics actually. So the choice is surprisingly simpler than one thing I like, you know, maybe there are 100 different that is medications. Now, also not 100, but quite a few. As far as anesthetics are concerned, well, there haven't really been more anesthetics on the market, since you've been using services, or to anesthetics. There are a lot of them are these about a while ago. Now, anesthetics are one sort of fantastic drugs and look like you know, maybe if you have high blood pressure, and you try a certain blood pressure medication may not work for you. But we can anesthetize everybody, where there is no person who cannot be anesthetized. So that's a really good success story. prosthetics are on the other hand, they, you know, they're kind of dangerous drugs, and that, you know, over pretty small concentration, and you can begin to see cardiovascular problems, respiratory problems, etc. And that's why, frankly, you know, anesthesiologist exists right now we have to have pretty special training in order to give these drugs in a way that is sacred CG in general is very safe, but not the names of people who are not specifically trained. And a lot of the safety is really due to technology that allows us to monitor patients closely, and dose drugs and pretty precisely so it's not. You know, there's several choices that we think about when we think about Winchester, well, first of all, you have to determine if a person needs to go with. For instance, say you have a broken leg or something like that. Well, we don't need to go to sleep to fix that we can do as far as therapy nerve block are something that some less invasive procedures can be done with sedation. If you have to go to sleep. Some of the concerns about choosing anesthetics have more to do with the effects on the heart and the circulatory system than they do on our ability to serve anesthetize a person. Right. So for instance, ketamine, in this case is an interesting example, because ketamine doesn't suppress respiration. So most acids depressed, translated, right. That's why, you know, usually when you're under general anesthesia, they assist your breathing or control your breathing, or your easy intensity. But ketamine doesn't seem to do that. So for instance, if you have to take a wounded soldier out of a battlefield, or maybe you're doing surgery, in a place where you don't have a vessel, and a lot of third world countries, frankly, don't have enough medical equipment. So don't get me becomes a really favorable choice, when the first world you know, when you have these sort of techniques would seem.
Nick Jikomes 41:13
So I definitely have questions about ketamine in particular, before we go there. You know, let's just pick one of the more commonly used anesthetics. And can you just talk about what one of the common ones is and then how it's actually working at the sort of cellular and pharmacology level?
Alex Proekt 41:32
Sure. That's very simple, nobody knows. Okay, well, the rights to the well, so anesthetics in general fall into two different classes, intravenous anesthetic, so something will be given an anesthetic. So, intravenous asset, only really one that is used in public housing 90% of the cases use it. Now, we do know some things about proposed mechanism of action, we know it potentially some inhibitory neurotransmitter GABA, it can either potentially take up of GABA to the GABA receptor or kind of concentration, so replace GABA. But but that's not it's only target targets other ion channels in the nervous system. It also has effects outside of the brain as well. So so we do know that if you mutate GABA receptor in a specific way, in mice, you can decrease the potency of the drug don't eliminate it don't make somebody knew he propofol, but it takes more probable to get that mouse the anesthesia. So that's as close as we can to a molecular mechanism. And people have studied where exactly when the GABA receptor binds, you know, some details, but that is a no assets are very difficult words to study because because precisely bind to so many different things. lipofilling means they do like mean, in fatty solutions like membranes of cells. So it's very complicated to study describes propofol is probably, you know, a source, it comes to be known GABA receptors, and there's another drug that is very specific. And that's what actually comedy nematology knows it's even better in a set of things. That drug is not nearly upon us that that is, I could not give you enough dexmedetomidine to take you to surgery, but it's definitely a very good sedative. And that drug is quite specific to alpha two adrenergic receptors. And, you know, I sort of alluded to earlier that noradrenaline and adrenaline are neuromodulators, that modulate things like sleep and wake mat, and Opera to receptor decreases the release of norepinephrine. That is our present understanding of the drug, but again, not a competing set, that aesthetic papers, no clue. We know, they bind to literally hundreds of focusing, making hundreds that's for certain. And, you know, I don't know if how much How intuitive is pharmacology for your listeners, but you know, like say I had to use a Singaporean, which happens to be one of our cell papers. So, roughly speaking to anesthetize a young healthy person to take one to 2% co2 Rain, that means out of every 100 molecules of air that you breathe in, you know, one or two will be Singaporean, which is a huge consequence relative to sacred sins or biologic engines that is designed to very specifically go after those specific cancer. So that's millions of times more of co2 molecules. And when you have drugs delivered such representations, they bind to a. And it is very, very difficult to sort out which one of these binding interactions actually are relevant for anesthesia. And also, of course, these target servers and storage systems. So not only which was up there, but where we obviously, there's been a puzzle over
Nick Jikomes 45:28
nicely. So So anesthetics tend to bind multiple receptors of many, many receptors. So that makes it very difficult to disentangle very specifically, which interactions are responsible for the anesthesia. And I guess when you're looking for anesthetics, or they were trying to develop anesthetics, the main criteria is does it knock someone out and not have too many negative side effects? So it's really a behavioral definition for for finding these things?
Alex Proekt 45:53
Exactly. So we've got a couple of people working on the new anesthetic of making new molecules apparently, statics, and I'm not a chemist, so I don't really want to say too much. But it's usually based on existing setting or they say, Well, you want I want an anesthetic that's going to, you know, dissipate quicker smile, so you can derivatized existing instruments and play around with their their chemical structures to make something like this on several drugs in development, or in various stages of testing, try to do this. But it's still based on existing structures, you can try to engineer some side effects of these drugs, for instance, a less commonly used aesthetic is for the candidate, and the problem was imposed a beam of suppression. So I know that more somebody I know at Mass General is derivatized accommodates such doesn't do that and maybe become a more prevalent disease clinically. So but with no no principal new anesthetics in a long time.
Nick Jikomes 47:02
And, you know, you mentioned very briefly earlier, the comatose state. And I imagine that there are many different ways someone can go into a coma, there's probably not just one part of the brain that needs to be damaged. But are there any? Are there any basic sort of learnings or principles there in terms of which parts of the brain get damaged to put someone into a coma? And does that state? You know, to what extent does that state resemble something like slow wave sleep or an aesthetic state?
Alex Proekt 47:30
Right? So it's, so Well, maybe I'll go on a tangent. And if you think I'm going too far, you can stop? Right? So it used to be for the longest time that you sustained some devastating going injury will impair your consciousness, those would just die, again, was the statins quite tragic. Nowadays, of course, we have intensive care, and we have ways of sustaining a patient alive, even in a state where they're completely unresponsive. That ability changed our understanding sort of depressed states of consciousness. So coma, is a transient state, you don't stay in coma forever, coma may ensue after a devastating injury, now what kind of injury so sometimes it is, for instance, say somebody had a cardiac arrest, and there was just no blood flow to the brain. Right. So very diffuse syndrome, there are some specific injuries have been caused, those tend to be more so in the brainstem. lesions of the brainstem can produce profound, decreased consciousness, but usually similarities. But the opposite is true gonna say that. Typically, if a person survives, the other genes, they will snap out, then it becomes a very sort of complex landscape. And it's actually in my mind, I think it's related to some of the challenges women's teenager is that there is this evolving terminology and sort of the consciousness there is something called a vegetative state. vegetative state means you're not uncommon. Like if you look at a person in a coma, look, they will be unresponsive to anything, he would not have sleep wake cycles, GE would have this highly abnormal birth suppression pattern, where all the neurons are quiet for several seconds and then everybody fires and quiet down. So kind of recovering deep anesthesia. Right, but vegetative state person production up parts of the day when it sort of looks more awake and then at night, maybe we'll look sleep right Have some circadian rhythm and things of that nature, but they are not interactive, you can try to examine them. And, you know, try to ask him to do things or respond to anything. Besides primitive inputs, they don't do much more. But then there is another category which is called minimally conscious. People are minimally consciously appear to sometimes on some occasions, exhibit some interaction. So, there is maybe a family member who was at the bedside is of no, no, no, I swear, I hold their name and excuse my something. But it's very difficult to sort of caption act, right, you know, to be sure to distinguish between the vegetative state which by definition, Roxanne's or consciousness. In a minimally conscious state, we're for pieces to equal therapists or moments of consciousness. And the most remarkable thing is that we used to believe that once this depressed state of consciousness is establish, well, that's what the explanation was, well, a certain part of the brain has died. neurons don't really regenerate. So you will be stuck in the state rather. But that turns out to be not the case. There will be several instances where people after years, wake up. And there have been instances where it's very, very bizarre that some people when they're given either benzodiazepines or Ambien, wake up, right, although they've been in a minimally conscious state for a long time, have not really been awoken. But they can be awoken by Sopia. They're also been cases of Deep Brain Stimulation stimulators implanted into talons that cause, you know, I don't want to create an impression that, oh, they wake up and they're just like, you and I totally normal, you know, teaching and outdoor sports in college, no, but huge, the counselors are able to do basic things for themselves that they're able to recognize their family membership, huge improvement, so. So it doesn't seem to be an adequate explanation with just a lesion particular part of the bone, especially to experiment because there are people who have delusions, who can nevertheless be perturbed with the state of wakefulness. So I guess maybe what I'm saying is that maybe that's the situation more similar to my seesaw analogy, that the brain is just stuck in a particular state. It's too stable, right, it's not able to explore others of possible states, and maybe given the right population through a deep brain stimulator, or to some drug or whatever else. But maybe you can take the brain out of that. And so depressed consciousness data, maybe at least in some cases, in consciousness. But the point I'm trying to make is, it's very, very difficult to diagnose this disorder. At least according to publisher, culture, mistakes are very, very common. And in fact, the same kind of problem happens on a seizure, luckily, a lot more infrequently. But it's kind of like a puzzle, right? How do I know that you're unconscious? Right? For instance, usuals on surgery, we give people paralytics agency prevent you from moving. So I can't rely on you moving or indicating to me somehow, hey, I'm awake. You know, so how do we decide, right? Luckily, for normal, regular ascetics, I'm not talking about emergency surgery or something like that. No, the incidence of being awake is quite, quite low. It's maybe one in 10,000 to 1000. Quite well, not. Not perfect, but not not so bad. But it's very difficult to determine when somebody's going with that also, this highly abnormal states where these experiments have been done since the 70s, and recently have been sort of capitulated is your fleet a tourniquet on the arm, say of the patient before you give them a paralytic agent? So they process their hand is not parallel. Right? So you can then ask them say, Hey, Alex, if you can hear me squeezed? And remarkably, a lot of people do that. Right? We're talking the 10% of people who do that. So a couple of orders of magnitude difference. And then you talk to them after surgery, they have no recollection of this whatsoever. Right. As far as they were concerned. They were completely unconscious. But it's really hard to sort of understand what does that say So maybe name injection, maybe, depending on the specific person on the state of anesthesia set, or maybe you can produce these kinds of partial switch purchases, or vegetative or minimally conscious state, but social mistakes. So you know, what would happen to you? Right? It's so hard to tell if somebody is actually having a conscious experience. How do we know?
Nick Jikomes 55:30
Yeah, I mean, that sounds like a very difficult puzzle. And that was something I was curious about, which is, you know, how exactly do we know whether or not someone's having any sort of conscious experience? Because that would seem to me that a key distinction there is, you know, if someone's completely unresponsive in certain ways, and they don't report that they had any experiences when they were under the influence of anesthesia, or new wake them up from deep sleep, for example? How do we distinguish between the absence of conscious experience and simply being in a state where the memories can't be encoded?
Alex Proekt 56:06
Well, I don't think you can. And that's the whole problem. For instance, I personally think that dreams are very interesting. I have them, I want to know why I have them. I want to understand how I have them. But I have no idea how you will study. So some people apparently can be trained to report when they're having a dream. I don't know if anybody can be trained. You know, I don't know what kind of training it is, you know, it's, it's, it's impossible to say the same kind of thing applies to say, animilitia. While How do I know that myself anything resembling conscious experience in the first place? I know they can be awake, and they can run around. And now I give him a seizure. Now, we don't do that. Okay, so that's reasonable. But when you get to say like a drug like ketamine, or nitrous oxide, or psychedelics or something like that, well, how do I know that they have that altered experiences? It's, it's impossible. I think it's one of those, you know, Calandra, but I certainly do.
Nick Jikomes 57:18
So the other thing that you said was interesting is that homos technically speaking, comas are transitory states, they don't last forever. And so I guess when we when you hear about someone in the news, who's been in a coma for years, what that really means, I would suppose is that they're in a coma for some period of time. And then they transition to having this vegetative state where the brain is now cycling through what looks like waking and sleep and things like that.
Alex Proekt 57:43
That's right. That's right. That's right. That's right. Exactly. It can be very confusing and challenging. More obviously, for the patient, but also for the family members. You may have heard or number a number there was this whole Terry shaido story? Yes, yes. And I forget exactly what happened to her. But there was this huge controversy about like, she was there, there there, right. Because people who thought that she was there to run, you know, she opens her eyes. How can she be in a coma? winterizer. All right. But, you know, I'm not going to decide anything about texture. But that alone is not really enough to, to make any inferences about what is happening inside a huge challenge. So I don't know if you know about this experiment. So this was kind of an incredible thing. Because I Adria and Owen where she took some patients who were deemed to be in a vegetative state and in vegetative state means no experience definition. And he put them into the FMRI machine. And he said, Well, imagine you're playing tennis, or Imagine you're walking through your house. And what he has observed is that in a subset of these patients, you will get activation with parts of the brain that are similar to goals. That would happen when you and I if I asked you to imagine, right, and then we started examining the species more carefully, and then they realize that no, no, they actually do have at least a bizarre, conscious experience and can interact and things like that. So, you know, a seizure. And, you know, in practicing in neurology and dealing with these very complicated cases where you can't really rely on behavior, right? You can't rely on report you. It's of great interest to try to develop some kind of measure of brain activity. That would tell me is somebody awake with the app? In are they at least capable of having some sort of experience? So that's a really interesting problem, which I think if you could solve that problem, which we making some headway is different people are just different people. But if you can at least say something intelligent about that question movie, you can begin to hack into well, consciousness and invincible. Yeah.
Nick Jikomes 1:00:29
So, you know, because of this fundamental problem with, you know, the question of, you know, if someone is in deep sleep or under anesthesia, or in a coma or vegetative state, we can't distinguish between the absence of conscious experience, and the absence of the ability to encode the experience in memory, so they can tell us about it later. Or important. Yeah, yeah, exactly. So so we don't know if they can't report it, because they can't remember it, or because they can't report it, because there was nothing there to report. Now, that brings me to the question of, you know, so that means, you know, even for a normal, healthy person, when I go to sleep every night, if you wake me up from deep sleep, it's entirely possible that there is some kind of conscious experience there. I just can't remember it when I wake up. So how do we think about the null hypothesis? Should the null hypothesis be that conscious experience is there or that it's not there? Or it's we can't we can't resolve that. That question.
Alex Proekt 1:01:23
I think, you know, okay. So I think formally, if, you know, like, if you ask the basic scientist in and say, Do I know, you say, I want you to tell me with 100% certainty, that, you know, there is no experience under anesthesia of any kind. It's like nothing to be a person under anesthesia. I can see. I don't, I don't know how I would know that. I don't know what evidence I can provide to say that certainty. Now, I think it, you know, but if I had to make a bet, you know, what I mean? This is a lot, much less stringent requirements. If I say, okay, you know, I'm betting on the possibility that there is no consequence. I think that's barely like, you know, it's not a slam dunk. It's not 100% certainty. But, you know, I have myself been under general anesthesia. I have no, no knowledge of it was like nothing. You know, I've put 1000s of patients in a state of general anesthesia. And it's like, nothing. So you know, but it could be some altered state of consciousness that just doesn't leave a mark. You know, we all know that. We wake up in the morning, you have this really vivid dream, and maybe for the next couple of minutes, you're kind of thinking about the dream, and you have memory of it, that by the time you made your morning cup of coffee, it's going on, right, and some of them you remember, but a lot of them are gone. So our brains are definitely capable of producing very vivid experiences that you know. Yeah, yeah. That's a very powerful state of affairs. But,
Nick Jikomes 1:03:11
yeah, I mean, I think the answer really is unknowable. It seems. What's kind of funny about about what you just said is, you know, if you if you read the literature on meditation, and you listen to what very, very, very highly practice meditators say they, they often say things like, you know, I don't have a direct quote, but they say things like, the deepest states of meditation, leave no mark on consciousness. And, you know, it's akin to saying that there is conscious experience, in the absence of the ability to encode it, and memory.
Alex Proekt 1:03:40
Let's call this the future very well. But I do know that some like expert meditators, they, when they enter this trance state, the brain activity resembles that of sleep, they're not asleep, but they can kind of evoke that state. So, you know, that's also really hard to study. How do you define an expert meditator? You know, like, are they just special humans that have this superpower that, you know, I, for instance, don't seem to have? Or can anybody I think this power by practicing a lot, you know, so if you if you, you know, it could be very interesting, interested in what happens in states of consultation. But it's been challenging.
Nick Jikomes 1:04:29
And you mentioned briefly earlier, that there is this phenomenon, and, you know, this has been in the news before and, and people have talked about it because it is so fascinating, the phenomenon where you've had to have someone in a vegetative state potentially for a very long time. And then paradoxically, you give them a sleeping pill, like Ambien, and they effectively wake right up. So what is going on there? Do we have any clue what's happening there and how reliable is that phenomenon?
Alex Proekt 1:04:56
So there are, you know, it theory difficult to do such studies. The person who knows the most about this is a new co chef at Cornell, who's a neurologist who specializes in coma, disorders of consciousness. So, you know, because these patients are sort of scattered all over the country all over the world, you know, so it's, everybody's a little bit different, you know, it's not, we can't say I only want to take people with this particular lesion and see if they can be aroused by ambulance. But they did identify a new GE phenotype that predicted that people would respond to it. So I think it's way, way way, mechanistic, we're just kind of groping our way to, you know, throw the dark, you know, towel with trying things, because while you know, if you're that patient, I think it what, people who are just willing to try it, you know, I mean, we've seen people work, but I don't think there was any robust understanding why that is, what you do see is remarkable, if you didn't see us changing our brain metabolism changing brain activity, you know, behaviorally, it's, it's a huge, huge difference, right? But, you know, how do we generalize from very complex heterogeneous population of patients, some of whom response and if you don't, so, that'd be and there have been a number of cases, I believe, within a couple of cases with benzodiazepines as well. These are really drugs, dancing around in battle and things of that nature. But it's also very interesting that, you know, wants to get the drug more consciously. And then when the drug fades, the snap back into a useless thing. And I don't know, if they know that there can be woken up around like, say, I have given this person Ambien are Monday. And you know, maybe they were kind of conscious for a couple of hours, and you can interact with them. And then you come back on Tuesday and say, Hey, remember, with digital Monday? I'm not sure that they do. Right? I don't know. I don't know if an app is known about that. So it could be kind of similar to this phenomenon of having an experience. Because you're interacting with a person, there's no denying that. So, but no, no traces are a little piece.
Nick Jikomes 1:07:36
How does it How does sleeping pills like Ambien actually work? Do we know how that happens?
Alex Proekt 1:07:41
They are also GABA a receptor agonists. You know, they have the deliver Ambien GABA receptor is a hugely complicated, they're made up of five different proteins that have to come together. Each one of these five parties comes in several varieties and sort of like a jigsaw puzzle when you're assemble these receptors, the community's identity, zolpidem is more specific to one of the subtypes of GABA receptor, but it is in many ways, similar features. It was sort of marketed as a replacement for benzodiazepines, which eternal replacements for barbiturates, you know, so, but the, at a global scale, they have a similar mechanism. Yeah, but you know, who suffers everyone? Everyone protects them. So, so just knowing, you know, I think in general, just knowing what receptor a drug works on, doesn't necessarily tell you that much about what it does to the brain. Because the net effect of the drug is, so filter the percolator for these vastly complex networks. Okay, so that's, that's my advice.
Nick Jikomes 1:09:02
I do want to start asking you about ketamine a little more. So ketamine is super famous recently for to use as a potential antidepressant. Obviously, it has a history of use as an anesthetic. It has, you know, very different effects depending on the dose that you use it in. And you mentioned earlier that, you know, on the one hand, it can be used as an anesthetic. But on the other hand, it seems to be very different in terms of the effects it has for many other anesthetics. So what are we starting to learn about? What kind of brain states are induced by ketamine and how they're similar and different to other anesthetics?
Alex Proekt 1:09:35
Yeah, sure. So let me say a couple of words about that. Right. I want to maybe add a little bit more nuance to a different concentration business, you know, it's definitely been sort of talked about in this context, but I'm not so sure that's quite right. There's something to do with I don't know if it's quite as strong as you know. Because savings. So, you know, what am I trying to accomplish when I'm giving an aesthetic to somebody, I'm trying to make sure that the person is comfortable, they don't have any negative experience of the procedure. And they're not moving around so much. They're not responding to what the surgeons can do. And I can most definitely accomplish that. Now, what happens? What's interesting is what if you ask the person afterwards you say, Okay, what was it like? And you ask a person who had a regular job, and I said, I'm gonna say, What are you even talking about, but I remember coming into the operating room, and that's it. I don't remember anything else. As far as I'm concerned, nothing. If you talk to the person who received the asset or subcategory, you will not get that story. You will get just phantasmagorical stories, just, you name it. You know, people have really, really vivid visions, and experiences on Kevin, that are so kind of durable, that they don't know what is happening in our world. And that is why it's called the dissociative asset.
Nick Jikomes 1:11:11
I see. So you're dissociated from your incoming sensory signals into your eyes and ears and everything else. But you're having an experience, which is just sort of uncorrelated and uncoupled from that.
Alex Proekt 1:11:24
That's correct. That's correct. That's exactly right. Right. So all I know, know, if I'm giving you an aesthetic, and giving it to you for surgery, and so long as you don't have a negative reaction to this, okay. We've done our job. But, you know, with this higher doses of ketamine, you can also get somebody who is just, you know, out of their minds, various, you cannot talk them down, they are in the middle of this dissociated state, you know, so it is quite quite uncommon in modern medicine, when we get into first world that I think it's true, and you don't want to get Kevin along, just because it's kind of uncomfortable, you might get somebody completely out of their mind, agitated, confused, they can correct themselves, because, you know, they're not there. You know, so typically, when Kevin was used in surgical concentrations, in medicine, it was given in combination with other drugs. So they commonly the President as it means, sometimes it's given as a component of general anesthesia. And what happens is, when you combine two drugs, you get something completely, you don't get, you don't get as much of this dissociated state, or you get more of an elastic state where you can get more of a sleeping stick, you know, the combination of two drugs when they interact with the brain, which is this complex, nonlinear thing. It's not one plus two, it's something else. Right? So, so I'm not so sure that there is a fundamental difference between, you know, a little bit of caffeine and a lot of things. So, for instance, people who receive antidepressant doses of ketamine, we also have a dissociative experience, it's just blessing that you can talk to them and you can for most people, this present, you know, what you say will feel normal, I said, No, I don't feel normal. If you can, floating, I can see stuff just doesn't look or sound quite the same. So that they will talk to you they are connected, but but their experience of the world is different than it is you know, and then you add more and that becomes more intense, sensitive or interested in you. So doses of things by psychiatrists, and paying physicians do something Addiction Medicine has all of these potential interesting implications, their sub state, but they still receipt to a degree this dissociates. And you probably notice there is a big day, to what degree the state is actually relevant for treatment. But this is the kind of questions that people ask about psychedelics, you know, Sidon, LSD, or these kinds of drugs seem to be beneficial for a number of psychiatric conditions. You know, maybe, you know, maybe the stronger and say this is associated with psychedelic experience, whatever it is, plays a home. Say thanks for say, because a lot of the drugs will people derivatized drugs, psilocybin LSD per second. We all know assisted suicide was LSD or aborting sort of chemically modified to engineer out the psychedelic effects, but the reality is these drugs are only been tested in animals, right? So do know that animals don't exhibit the economical behavior associated with psychedelic drugs. These drugs are still appear to be beneficial for whatever the behavior when the stations of depression, mice, but at least as far as I know, no humans. So we don't actually push for sure now. Yeah, so I think that remains a very interesting question. But yeah, but the point I will make is, people who are getting depression or pain or addiction treatment, determining do experience, a lot of them is experience dissociative effects,
Nick Jikomes 1:15:55
which is, I see. So so when people say, ketamine used as an antidepressant is given at a sub threshold dose? That's maybe not quite right. It's not it's not like some threshold is reached, and then you have a dissociative psychoactive experience. It's just it's a lower dose. And so that experience is much less intense.
Alex Proekt 1:16:15
Exactly. That's exactly right. I mean, this is in psychiatric literature, if you read the papers by psychiatrists, and obviously, they would freely acknowledge this, and it is a fairly low dose in that, you know, you know, if I was receiving currently a southern circuit, and you and I could continue having a conversation, maybe I wouldn't strike you as somebody who is, you know, completely altered. But if you ask me like, well, you know, we have given capital in southern state versus continue on tourism, just about everybody says, yeah, it was weird. It was strange. Most people don't think negatively or return the same way, their daily ability between people, but definitely, you will be able to do a placebo controlled trial person would know that they're getting tired.
Nick Jikomes 1:17:09
Yeah, yeah. And what are we learning from basic research in terms of what's going on in the brain? When you when you apply ketamine? Well, you know, we can image the brain or record from the brain, people have started to do experiments, animals, where they give ketamine and look and see what's happening. What sorts of things are we starting to see there?
Alex Proekt 1:17:28
So right, so Well, maybe before I say that, I will say, I think that at least to me, because I'm interested in dynamics and things like that. That is, I think your your important is no, say you were trying to treat some psychiatric condition like depression or something like that, right? The traditional model says, Well, we're going to give you a drug that's going to correct some neuromodulator imbalance, and because depression is really some imbalance of chemicals in your brain. That's true. But if you think about what is the most effective treatment for depression, it's initiative. People who are resistant to all drugs, electroconvulsive therapy, nowadays, we use a seizure. Right?
Nick Jikomes 1:18:15
Right. So literally shocking the brain.
Alex Proekt 1:18:17
Yeah, exactly. Like different relating the heart, right? We do it under anesthesia. It's not like when to fly to Vancouver, Brookings, Nas, you know, it's very much civilized, but you know, but that's what inducing seizure. So, and the effects of that seizure lasts a long time. So it's as if we kind of forget perturb the brain from one state to the other.
Nick Jikomes 1:18:42
So to use your, your teeter totter analogy, if the brain is stuck on one side, you're just sort of throwing in a big, big push to try and get it to flip the other way.
Alex Proekt 1:18:52
That's right. For instance, in animal models, and I shouldn't you shouldn't put a lot of faith in animal models of psychiatric disease because we know what the depressed graph looks like. But whatever it's worth behavior or manifestation. Depression can also be alleviated with anesthetics. If you anesthetize a rat, with some anesthetics, not rather specifically, the ones that produce for suppression, you can alleviate some depressive symptoms are possible. So while we take a drug like ketamine, so Kevin, you know, if I gave you a sub anesthetic brochure, ketamine, you would feel a little bit altered a little bit scared of dissociated but feel a little bit abnormal. But then an hour after the fusion is over, we'll be back to normal cell and there's been literally no ketamine or it's actually metabolites in the body. But those depressive effects last week. When with psilocybin again, it seems too good to be true. I don't know. You know, I am not involved in that work. It seems like the most So, the question is, right, so again, there is some sort of a perturbation that the drug produces to go and 70 among the perturbation leaves a lasting imprint. So what do we know about So, this has been studied a fair bit in conventional psychedelics, but also ketamine, which this you shouldn't consider a psychedelic, but let's just put it in the broad categories. After a single dose of these bags, you see that there are more synapses, more litter, we can see now with modern microscopy, for dendritic spines, which is sort of done a clinical consequence of synapses, and we see more of them. And this increased last soil, so provide some kind of correlate, at least in the view of these long lasting effects. But you know, most plasticity in the brain depends on brain activity. So it's the firing of neurons, activity of neurons, good drivers, the driver for changes in synaptic style, right, ultimately, because it has to come from within the ground. So it is of interest to know what sort of activity does get British, right. And we knew some things about that. But for instance, if you look at EEG, or question on ketamine, say subasta, ketamine, well, we see that, you know, it's not like as to his actual EEG, if you look at the total number of neurons firing, so in the cortex, and like an aesthetics, that depressive happening music, more or less unchanged. But what was really less clear, is more which neurons are which neurons. Right? And that is really, really hard to answer without being able to look at electrodes, we can just sort of hear the electrical impulses, and read some tricks to try to say, who is making the action potential, but it's not perfect, because if a neuron was silent, it's not firing, you don't see it, but you're actually. But with microscopy, you can begin serving an unbiased way, look at a field of neurons and force them to express some sort of calcium indicator and say, Well, okay, well, this is your brain awake. And well, that's your breeding company. So what's the difference? So that's actually why we did the work. And by we, I really mostly mean Josie, Shawn, because of just all of this, basically, he's a good friend and collaborator. So what Joe did is simply looked at this firing, and like the original G work, we confirm that, yeah, G is activated in mice. And behaviorally, they're a little bit altered. They don't act normally. But they're not under anesthesia, they can still move. Okay. But when we look at neurons firing, we also see what about the same number of means found. funny, interesting, because it was a totally different set of neurons. So neurons that are firing normally, when the mouse was just sitting the room, you're depressed, Kevin, and a whole new set of neurons at work. So silent normally became active. Remarkably, this kind of business happens, no matter where we looked in the cortex to various degrees, you know, some were much more robust than others. But for good approximation, doesn't heritability number of sensory cortex over looking in some more sort of complex Association, higher order cortex? Yeah, they switch doesn't matter whether we look at superficial cortical layers, or deeper cortical layers. There's the switch. Okay. And that was true for what are called pyramidal neurons in the cortex. It's much more complicated.
Nick Jikomes 1:24:06
So, so basically, using some modern technology, you can give a mouse ketamine, you can literally point a microscope that its brain at its cerebral cortex, and you can watch whether the neurons are becoming more active or less active than what you're saying is when you give them ketamine, where it's it's obviously having effects but it's not having anesthetic effects. The mouse is awake and everything. No, basically no matter where you look in the brain, sensory cortex, association cortex, anywhere you look, what you generally find is that some neurons are active and some neurons are inactive, but it's separate populations compared to when the animals not under the influence of ketamine.
Alex Proekt 1:24:48
So, you know, it's, you know, it was kind of striking it took, took a little bit of really looking at the data to appreciate this, but I imagine you're looking for microscope when you see 10 neurons, okay, and let's say for the sake of argument neurons one through five are active, normally mouse is just sitting there doing whatever my student wanted five or active, six hours of silence. And then you give this mouse ketamine, and we see that one to five or seven, but 60 times that that's that's really was for more. And it's interesting versus, you might say, well, it's random, right? You know, maybe if you come in today, and we see five neurons that were activated by Katherine, and five ones that were suppressed, but if you do tomorrow, it's gonna be different products. But it's the same for exactly the same but it's correlated from day to day. So if caffeine inactivated a particular neuron or Monday, it has a propensity to activate it on Tuesday and inhibited, because it's also not the most perfect in biology, but there was a pretty significant correlation between several basic surface so. So that's the major point here.
Nick Jikomes 1:26:07
And what are you guys working on anything now? Like, what what are the sort of the the big unknown questions that are being pursued with respect to what ketamine is doing in the brain?
Alex Proekt 1:26:18
So what I would love to know about Katherine is this is like, okay, so it just kind of interesting, maybe this poetic to say that when you're in this kind of a dissociated state and surveyed and different network of neurons, that is actually what I'm much more interested away with what's interesting, but what I'm very interested in seeing what are the long term consequences like, yeah, we know that after Kevin, there are more synapses, but were right, how does this change in activity that the brain produces after ketamine? How does it lead to longer term changes? Because I think if you could understand that, or maybe you can understand why is it that ketamine has this goal that antidepressant with the anti drug addiction, anxiety, whatever properties, right? And it seems like it's not really nitrous oxide, for instance, in other assets, which we did not really talk about, it also seems to have less durable but much more durable than matress up, bring it out in a couple of minutes, because the metabolites, but its effects on psychiatric conditions, and those of us who are established and protected from loss the way our lives, right, psilocybin or LSD, it seems to do a bleak sloths, right? So it seems to be a common motif amongst many drugs that are queued for collusion, elicits long term change. So I'm thinking people understand the connection will also keep affecting their long term wisdom be really so foundation of their own understanding of mental health treatments, will benefit from this treatment. So that's kind of where I would like.
Nick Jikomes 1:28:12
And, you know, some of these dissociatives that you mentioned, like ketamine and nitrous oxide, they are also used recreationally. You know, assuming assuming that you're talking about a pure drug, and that's a pretty big assumption. I think, when you're talking about recreational use, do these things have any overdose potential or any neuro toxicity or anything like that?
Alex Proekt 1:28:36
So well, so yeah, first. And really, this is, this is a huge problem, right? Because you definitely don't want to, you know, we all know about the opioid epidemic, you know, I personally do not want to give a drug to somebody who's gonna get hurt, right off the bat, you know, ruin their life because of drug addiction or overdose. So, that's a real concern. Now, nitrous can be quite dangerous repose. To get an effect of nitrous, you have to breathe the waters. So there's a danger of asphyxiation. Whereas if you're not breathing enough oxygen, essentially, all you're breathing is nitrous while you can become frequency, you know, and pass out the eye. You know, all sorts of things can happen. I think it's fairly rare, luckily, that this happens, but it's sitting. Now, ketamine, I think it is a less of a danger of really getting somebody hurting in that way. Like you're kind of unlikely to die from ketamine itself. They can raise blood pressure and heart rate and all that kind of stuff. But for for a healthy person that's not particularly good. Extreme. But if you have somebody with coronary artery disease or something like that, and we took a lot of it, yeah, they could suffer serious consequences. The problem with checking in is that people don't do to spank or get hurt, because things have been doing that stuff definitely true. So yeah, it's a real issue. And this is, you know, if it turns out to be the case that you cannot disentangle this dissociated state or a psychedelic state from the therapeutic effects of these drugs, and what are we a society going to do? Are we going to say, well, you know, we're gonna give them out to people, we're going to give a give these drugs in very controlled settings. But what is going to be the approach, I don't think it's simple. And it's especially hard on psychedelics, because ketamine is at least a clinical use drug. Right? You know, I don't have to go to the zba to give somebody Kevin's a controlled substance, both as medicinal use with drugs like psilocybin or LSD, it seems that people are working trying to get them approved. But currently, they have no additional potential, right, their schedule and drugs. So even studying them in the lab on animals, you have to do a lot of people. So I don't think it's, I don't think it's settled issue at all, whether these drugs will work, but I think understanding the mechanisms are probably worth needing, in the future, you can make a drug with the Nautilus things, but again, we don't really know if that's possible. We don't know, non hallucinogenic as Deanna, or is enormous novels, in general from people, and be
Nick Jikomes 1:31:59
one of the things I ask scientists sometimes is, you know, what are some really exciting areas of science that you're following, that don't have anything directly to do with your own research?
Alex Proekt 1:32:14
That's a really big one, I tend to kind of very, I'm interested in philosophy. So I've been reading a lot about AI. It's a, I did a little bit of work on a lot actually analyzing AI dynamics in the eye, but that kind of forced me to really think about the deeper issues. You know, we've all seen some of the amazing things that engineers built, you know, Chanteys, from spectacular, and nobody will ever really turn paper again. You know, but you know, and you start wondering, maybe kind of similar questions like, well, definitely try to deceive the passenger. And if you didn't know, you ain't familiar with the Turing test.
Nick Jikomes 1:33:03
Yes, yes. Why don't Why don't you just explain it for people? As well as chat? GPT? For those who have not used it yet?
Alex Proekt 1:33:09
Yeah, sure. So, you know, a Turing test was an idea this proposed by volunteering, and it had to do with well, how do you know, for machine intelligence? What's Turing service as well, if you're interacting with this machine? And you believe that you're interacting with an intelligent being? Well, maybe it's right. And well, what certain turgidity is natural language processing software that has recently been released to the public? That, while as far as I can tell, can answer any question you want. For instance, I've asked you to composing a sonnet that will tell me how to make a chocolate cake. Right? So it doesn't just rehash things that are on the internet. It sounds like a Siri that can turn on and off chaotic locations, you can have an interaction with it. I think you can do that. No, you were talking to some very sophisticated AI network, you would be convinced you're talking to somebody. So you can pass it on to us. But, you know, at some point, you have to begin to wonder like, well, are these things are actually intelligent and begin to wonder that you have to wonder, well, what would it take for them to be truly intelligent? I don't think I don't think we're anywhere near there yet. But, you know, it's an interesting question, you know, maybe if you can understand how you can engineer a thing to be truly intelligent. And what I mean by that is to be able to generalize, you know, it is there's no doubt that you can, it's been demonstrated now, but I think, for any one specific task, you can train an AI system that will be taking, there's no no question about that. But But the bigger question is, can you have learning and understanding and the way that we as humans, think about the child, learning how to speak, for instance, it happens remarkably quickly. And they can generalize from the few ideas that we know and ask questions about things and be inquisitive and curious and interact in real time with the world. So while maybe the weight of understanding how the brain does this is strictly engineered a system that does something, something similar, you know? And yes, of course, brains are not like computer code or anything of that nature. But maybe at a more abstract level, if you could sort of distill down what is necessary for such a truly intelligent system you can begin to make is what are you looking for? So yeah, so that's been my recent foray into you know,
Nick Jikomes 1:36:02
yeah. And for those listening, if you haven't tried chat, GPT, it's free to use. Everyone's using it, it seems. And it's quite remarkable. So if you haven't played with it, go to Open API's website and try it out. Professor Alex product, this has been a fascinating conversation. I think we've covered a lot of interesting ground that people will find really interesting. All right. Any final thoughts you want to leave people with or anything you want to reiterate from, from what we spoke about?
Alex Proekt 1:36:31
How I'm not sure I think neuroscience is kind of a really exciting field. I think people practice people from all sorts of walks of life, people who I think everybody should be curious about the brain is working access in VR. And you know, there are many ways to address this question. Be a biologist, if you want to be a scientist, a physicist or mathematician. We are so glad to hear that people are interested in these issues and I hope the people to know
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