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Ep #35 Transcript | Karl Deisseroth: Psychiatry, Autism, Depression, Anxiety, Dissociation & Emotion

Full episode transcript (beware of typos!) below:

Nick Jikomes

Dr. Karl Deisseroth, can you give everyone a just a brief intro into who you are and what you do?

Karl Deisseroth 3:50

Yeah, hi. I'm Karl Deisseroth. It's really nice to be here. Thanks for inviting me on your your podcast. I'm a professor of Bioengineering and Psychiatry at Stanford, and I'm in the Howard Hughes Medical Institute as well. And we, in the lab develop ways of studying the brain. And we use light in really interesting ways, including a method called optogenetics, which lets us control things that happen in particular cells in the brain, while animals do interesting things.

Nick Jikomes 4:23

So one of the things that's interesting about you is you're a neuroscientist. So you have a lab where people are studying basic research questions and applied research questions in neuroscience, but you're also a physician, you're a psychiatrist, and you see patients. And then the other thing that we'll talk about is this new book that you've written called projections. So can you almost Why don't you walk everyone through what I'm sure every week is different, but what does a week look like for you in terms of the balance of the research, the writing and the seeing of patients?

Karl Deisseroth 4:57

Yeah, those are two other sides of my life you bring up I'm right here in my psychiatry office. Right now, this is where I see patients in my clinic. I focus on treatment resistant depression, and also patients who are on the autism spectrum. And then I do some inpatient work as well, one week a year, I do some acute emergency, inpatient, attending work. And I've been doing this for many years. It's a big part of my life, conceptually, but in reality is I spend most of my time in the lab doing neuroscience and developing technologies. So on a on a weekly basis, I'm really in the lab. I'm a neuroscientist, we're doing experiments trying to understand as much as we can, how the brain works, and then the psychiatry side, the clinical work is always there. It's a it's something I keep returning to. It's a big part of my identity. But it's not as big a fraction of my life as the as the neurosciences. And then the writing that the writing the book projections, this is in many ways this has been going on. For just about 20 years, I've been working on this in various ways. I wrote the first chapter 20 years ago, right after 911. And I've been accumulating thoughts, stories, experiences, ideas along the way, and then it really, but not at a full burn not not in the intense way of generating the book, until just in the last couple years. And then I've turned up the intensity of that quite a bit. And that was an unusual couple years. It was a fun, it was exciting. It was thrilling to be a writer and something I've always wanted to be something I'd always enjoyed. And that was sort of late night, early morning. intense bursts of writing. I loved it. I was sort of addicted to it. I still. Now I want to write more now that I've rediscovered how enjoyable it is to write that way. So you know it's a week of my life is it's hard to describe these days. And I think that's a good thing.

Nick Jikomes 7:15

But it's mostly it's mostly on the research side, mostly research. Yeah. So the book is titled projections, a story of human emotions. So briefly, what is it about how is it structured, and what's the significance of the title for you?

Karl Deisseroth 7:31

So each, each chapter in the book is centered around one or two human stories, stories of people who have gone beyond the bounds, the realm of normal or healthy, let's say, a human experience into realms that are, are causing immense suffering to the patient and in the psychiatry space. And there are stories that are told from in some cases, from the perspective of a patient, there's a fair bit of imagination to get inside the thoughts and the feelings of patients. There are historical and pre historical flights of imagination, you could say, trying to connect the experiences of human beings today with human beings over the course of human history, and connections to my own experiences as well. And importantly, connections to the science to the excitement that's happening in neuroscience these days, driven by our ability to carry out explorations that we had wanted to for so long and not been able to. And so it's, it's, it's meant for the general public, it's meant for everybody. It's written in a way that anybody, I think, can read it or understand it, and it's centered around human beings who are in altered states that relate to psychiatry, there's their stories that relate to eating disorders to schizophrenia, to borderline personality disorder, to grief that comes with loss, bereavement, dementia, and several others. And each of these are, are, I think, rich in in human emotion, but also in new insights that have only been available to us very recently. So that's, that's a picture of the book and I'll talk about the title in a moment. That any other questions on that or I could dive right into the title? No, no, go for it. Yeah. So the title is interesting. The title projections it has meaning for people from all walks of life. There are there's a psychiatry meeting. There's a neuroscience meeting. And then there's a lay public general public meeting of projections and We think about just as, as people in the world, we think about projections, you might think about a projector that's sending an image out, there's something within the projector, there's some light, and there's a, there's something within the projector that changes how the light is, is past, out and propagated and projected out into the world. And so a projection is something that reveals using light, it reveals what's within it reveals something that's within and makes it clear for everybody on the outside. That's how we think about projections normally, but in neuroscience, projection has a meaning, which is a long range connection from one part of the brain to another. And this is something that is a physical material, structural component of the brain, it's part of how the brain is built. It's how different parts of the brain exchange information, how they work together. And how they give rise to the complex states that we have, like anxiety is built from projections. Anxiety is a state that we all know we have physiological changes like heart rate, and respiratory rate changes. That's one thing that anxiety is, anxiety also has behavioral changes, it makes us not do things that we would otherwise do. And also feels bad. That's another thing about anxiety. And it turns out, all these parts of anxiety are built by projections, connections, starting from one part of the brain and going to another that go out and get these different features and bring them back. And so that's the neuroscience meeting. And then finally, projection has a meaning in psychiatry as well, psychiatry, talks about projection as a way of describing how people will sometimes impute their own internal state onto other people, it's a way of sometimes it can be helpful, sometimes it can be harmful, but it's a way of understanding other people,

by thinking about yourself, and what's inside yourself, and sometimes we do it correctly, sometimes we project ourselves on other people correctly and sometimes incorrectly. And so this, this turned out to be a very felicitous word that that helps unify the different themes of the book together. And that's that's where the word came from. What's funny is that in other languages, projections doesn't always translate. And so the Dutch version of projections just came out. But it didn't have all those rich connotations and Dutch and so that title, which is in Sixten, instead, which means insights, which is, I think, a nice way of achieving the same goal. But even the the UK version, it turns out projections in in, in the United Kingdom has more of a negative connotation. And so the title there is connections instead of projections. So we even had to translate it into British English.

Nick Jikomes 13:00

Interesting. Yeah, language, language can be funny like that. And you talk about in the book, how on the psychiatry side when you're seeing patients, language is, in many ways, the most advanced tool that you have you talk about how, you know, compared to, you know, the best drugs, the best microscopes, the best physical inventions that we've that we've innovated. Psychiatry still very much relies on the use of language, listening to the patient, and talking to the patient in order to, to do that part of what you do. Can you expand a little bit about the importance of language in your psychiatry practice?

Karl Deisseroth 13:38

It's a great question. Language is still really the heart and soul of psychiatry, we don't have objective lab tests in psychiatry that like a blood test, or an imaging study that definitively in a single person will tell you. This is the psychiatric disorder that this person has. And instead, we have words that's even when we do quantitative measures, like rating scales, when we measure and quantify depression or autism. It's all essentially done with words and nothing has to be done artfully. You can't just blunder into a psychiatric interview, psychiatric interview and ask a series of questions or, or, or just checkboxes. There has to be a intuitive and and careful and, and, and practice, do use of words much like a surgeon's tools in many ways. And the art and the science of that is something that always intrigued me about psychiatry. And language was also a passion of mine from a very early age. I was always enthralled by how words have power have emotional power in ways that can be surprising and and thrilling and shocking. And so for once I realized that psychiatry was was so intensely verbal in ways that mattered. And in that that was the whole thing. That was all of it. That was one thing about psychiatry that really intrigued me and still does to this day.

Nick Jikomes 15:18

You, you use language in some interesting ways in the book in the prologue, you tell the reader that you're going to sometimes write from the patient's perspective, and you even state that you're going to talk about altered states, using altered language so that the state of the patient's actually reflected in the language that you're using. In the book, can you give an example of this from the book and and why you chose this stylistic decision?

Karl Deisseroth 15:44

Yeah, this is something I really wanted to make sure that happened, that the feel of the disorder could be felt in some way by the reader. And I adapt that in each chapter to the nature of the illness. So in the chapter, there are a couple chapters where the nature of the illness is exhumed exuberance over the top, you know, rich and, and dynamic mania, being one of them. So there's a chapter on bipolar disorder, where one of the poles of bipolar is mania. And mania people have extremely high volumes of, of words that that come out with and with pressure, and with, honestly, a great richness and charisma and complexity and humor. It's a extremely intense stream of, of over the top, but but still emotionally compelling words. And so in that chapter, you see the same kind of writing style used, what I'm trying to do is to convey that, that feel of of mania with with the words, other chapters, the chapter on on psychosis, or what turned out to be schizophrenia, and there in that chapter, there's a fragmentation or a breaking apart of the of the, the words in a way that relates to some of the physiology of schizophrenia, and perhaps some of the patient's internal experiences. And there's a chapter on grief, which honestly, in tears and crying, and a loss with bereavement, that is, is harder to get through even having written it, I still can't get through it without tearing up and that even though I wrote it, and I've read it, and it still affects me, and and I've heard from many other people from them as well as similar way. And so that's the goal of the language and each chapter. It's it can be it's extreme in different ways, but it's, it's adapted to the disorder and the human story. That's, that's at the core of that chapter. That story.

Nick Jikomes 18:19

I think before we go further, it would actually be good if you could describe and define for people the difference between a psychiatry, neurology and neuroscience,

Karl Deisseroth 18:30

okay, yeah, well, I'm a psychiatrist, and my wife is a neurologist. So we have, that that tension is in our own house as well. You know, they psychiatry neurology used to be unified. And this, hopefully, perhaps someday they will be again, but psychiatry and psychiatric disorders, they fall into this category where right now we we can't point to a material. Reason for the disorder. There are a lot of genes that are linked to psychiatric disorders. There are imaging studies that, on average, if you ever look over 1000s of patients, you can see there are, you know, some consistent differences that can be picked up. But in general, a useful summary is that in psychiatry, we can point to a particular part of the brain or measurable that gives us confidence that here's the reason this is the nature of the illness. This is the physical material form of the disorder in the way that with congestive heart failure, you know that it's due to a weekly pumping heart and you can point to the pump and you can measure how the pump is is weaker. That we don't have in psychiatry, you do have that in neurology. So in neurology, if you have a stroke or you have a seizure, you can point to exactly the part of the brain that's that's causing it and you can discuss Prime why that's happening. And, and the material physical nature is clear. That's probably the simplest way to describe the difference between Psychiatry and Neurology. Those are clinical disciplines that focus on the brain, but the nature of the illnesses are different, in part because of our limitations of what we can do. And then neuroscience is, is the basic study, the fundamental study of nervous systems and neurons and the brain cells that make everything happen, how do they work, out of the properties of the system, arise from the properties of these components?

Nick Jikomes 20:37

I see some neurology is really when there's something physically wrong with the brain that you can point to there's a lesion in a particular area. In psychiatry, it's just more mysterious, it has to do with the function which is invisible.

Karl Deisseroth 20:49

Yeah, it's physical in both ways. But but we can point to it in neurology, I think that's the simplest summary.

Nick Jikomes 20:57

So Turning now to the neuroscience side of this, the the understanding of what's going on in the brain. At one point, in the early part of the book, you write that the intersection of electricity and chemistry somehow gives rise to everything that the human mind can do. Remember, think and feel. And it is all done with cells, which can be studied and understood and changed. So you really take this view of, you know, going down to the cellular level, and talking about understanding cells in the brain and actually changing what they do in order to gain an understanding. So I thought this would be a good spot for you to talk about optogenetics what this tool is, and how it connects with our ability to to get that level of understanding of the brain.

Karl Deisseroth 21:41

Yeah, so this is this is a, this is a great spot to get into that key question, as you say, and that in that excerpt, you just read, highlights the the key aspect, which is changing and changing at the level of cells. So historically, in neuroscience, you know, it's, it's, you know, we've always wondered what makes things happen. And in the brain, the brain does amazing, wonderful things. What's actually going on that makes it happen, sensation, cognition, action, how does it work? And we know the brain is made up of cells, and we know it does these amazing things. Now, how do you begin to study this? Well, you can, first of all you can observe, okay, you can, you can listen, you can look. And there are different ways of doing this, people can put in electrodes that listen, you can pick up on the electrical chattering of cells, as animals do things. And this has been a wonderfully productive part of neuroscience, just listening, just observing, seeing what's happening during sensation, cognition, and action. And we can see the different cells fire away differently in different moments. And this can be studied to great effect, and when great insights, but you don't actually know what's causing things to happen. You don't really know if those cells are making something happen, if they're important for what you think they're important for. And you don't know, how causally how these interesting processes emerge from the properties of the components from the activity of the cells. And you could stimulate electrically, you could send in current, you could send in electricity, but every neuron in the brain works with electricity. And so there's no specificity. If you do that. If you send an electricity through an electrode, you stimulate every cell, and every connection, every wire, effectively, that happens to be passing near that spot. And you can get a regional understanding, you can say, Okay, this part of the brain, maybe does something more like this, because I can see the animal's behavior changes when I stimulate this region. But that's a, a fairly limited level of understanding because you're not getting down to these elements or components, the cells. And that's been such a productive step in essentially every other field of biology and medicine to get down to the cellular level. Because we know we found many times from field, the field from disease to disease. The cellular level is where important things happen. That's a very useful level of inspection and intervention for treatment and understanding. And with optogenetics, what we do is we provide that cellular specificity of control we allow

action to be caused in specific kinds of cells and even specific individual cells and we do that using light. Now, almost, no neurons respond to light. It's pretty dark inside the brain. There's no reason for them to respond to light, which is great. Because if we could confer some lights sensitivity onto some cells versus other cells. That gives us some specificity. That means we can say, okay, when we shine light now, only some cells will be active and others won't. Very different from the electricity case, because all neurons respond electrically. And so that's what we do with optogenetics. The question is, how are you going to do that in a way that actually works in a way that's versatile and powerful and generalizable and works across animals and works in different behaviors. And so the way we figured out how to do this was to take a gene from microbes, single celled organisms, and we can do this from algae, we can do this from ancient forms of bacteria, archaea, bacteria. And we take genes that respond that encode proteins that respond to light by moving ions moving charged particles across the membrane of cells. So proteins that turn light into electricity. And these are beautiful natural proteins evolved by nature, or millions of years. And these are called microbial options, microbial because they come from microbes and options. These are a class of protein that is really good at absorbing photons, and they use a little vitamin A like molecule called retina, now that's embedded within them to receive the photon absorb it, and cause a change to happen in the protein in the full protein that allows it to move ions across the membrane of the cell create electricity. And so that's that's how it works. There was it took a number of years to get all that working to get it to this level where it is powerful, robust, generalizable, were works across systems. But we were able to get this to happen. We use genes, for example, that are called channel route options that come from single celled algae, we can put them into specific kinds of cells, like the dopamine cells in your midbrain, or your serotonin cells are the cells in one layer of your cortex but not another layer. And we can ask questions, what happens when you then shine in light, and you can turn some of these options will send in one kind of ion, others will send in another kind of ion, we can turn cells on or off. Some respond to different colors than others. And so we can use different colors of light as well. We can even guide little light spots and turn on neurons asynchronously or synchronously, we can pick out groups, ensembles of neurons, all this while animals are behaving carrying out complex tasks of sensation, or cognition or action. And we can see how causality happens, how cells make things happen, how signals propagate, and how they lead to the beautiful and mysterious things that the brain is capable of.

Nick Jikomes 28:01

So you can take something like a mouse, and you can use molecular and genetic tricks to literally put these light sensitive proteins into specific cells and specific parts of the brain. And then you can effectively control the cells and thereby the behavior of the mouse. By shining light on to these cells, how do you actually get the light into the brain?

Karl Deisseroth 28:26

Yeah, we use a couple of methods, the first method we used was with fiber optics, and lasers. And that we described in 2007, we use a laser diode and a fiber optic and nearly hair thin, we put that into one side of a mouse brain. And that turned out, that's still now almost 15 years later, that's still the workhorse of optogenetics people still use this fiber optic interface that gives incredible versatility, you can stick that in any part of the brain, you can put multiple of these in, and you can carry out delivery of light and also collect light back, you can actually get information back out as well. That was that's been supplemented now by another method that we and our colleagues developed beginning about 2012 where we guide spots of light with holograms basically make 3d projections of many little spots of light, basically using a liquid crystal based hologram. And we can make those single cell sized spots of light so we can play in into the cortex, for example, the surface covering of the brain, we can play in many spots of light and control cells that way, but still, the fiber optic interfaces is the dominant method.

Nick Jikomes 29:46

I want to give people that aren't familiar with this a very concrete picture of of what this actually is. So I'm going to do a screen share and show a video clip. And for people listening on the audio version, we'll we'll try to do a good job of describing Bing, what's going on? But this will be on YouTube as well. So can you see my screen, Carl? Yep. So I've got a video of Carl from a lecture he gave some years ago, which is on YouTube, I'm going to hit play Carl. And if you could just describe what's going on and unpack this for people who've never seen something like this before.

Karl Deisseroth 30:23

Yeah, so this is a mouse, you're gonna see a little blue dot appear right there, and the mouse starts circling left immediately. And when the blue dot turns off, you're gonna see the mouse stop circling one more circle around, then the blue dot will turn off right here, animal stops. Okay. So what's going on there? Why did this mouse suddenly start circling left, like it really wanted to turn left and then immediately stopped, and then just look up at us like it's doing right now? Well, what's going on here is there's a fiber optic in the mouse's brain and the right part of its brain. And as you all might know, the right part of the brain controls movement toward attention toward the left side of the world, and this is in an area called anterior motor cortex m two, that is responsible for some of the motor planning or movement planning that mammals do. And what you can see there is that we've been able to take an animal that was just sitting there not doing anything, and we made it act as if it was really wanting to turn left and turning left, and it didn't appear in pain or distressed, when it simply started doing that. And when the light was turned off, it stopped. And so this is the essence, this is a very vivid demonstration of, of causality in neuroscience, we now know, it's not a correlation anymore, we know that these cells in this part of the brain, and this, and this happened to be layer five of the six layers in cortex, and we now know that these, this particular way, or these cells can cause directly cause initiation of this complex motor plan. And this is a simple action, you know, circling left. But what's happened since that moment, which was in 2007, is this same method, same fiber optic, we entered, and channel rhodopsin based user interface has been adapted to virtually you know, every kind of behavior, you might think of, we now know using this method, the cells and the connections that are causally involved in, in aggression, and parenting and hunger and thirst, you know, motivation, memory, social interaction in general defensiveness and any number of other things you might be interested in would consider. And we now know that aspects of how activity in a few cells propagates out, and spreads to other cells and recruits and begins to recruit these complex brain states and behavioral states.

Nick Jikomes 33:21

So I could imagine, it's very easy for me to imagine two different types of responses that people might have to sing something like that for the first time. One type of response might have a positive valence people might be very excited, or, or curious about how that works. They're very happy to see something like that. It's it's very interesting. I could also imagine someone responding with an A negative valence reaction and being almost fearful or anxious at what the implications of something like this might be. Can you actually use this as an opportunity to explain the concept of Valence to people? And what those two types of reactions tend to be in people? Yeah.

Karl Deisseroth 34:01

Well, Valence is a word we use all the time. I think it's it's kind of I mentioned anxiety earlier. And I mentioned the fact that anxiety feels bad. And released, anxiety feels good. That's an example of Valence. Just the sign of something, if you will, Si, gn, just as positive or negative, how does it what's the subjective net experience. And I never know if another person what their true inner experience is like, but I know if they report something as positive or negative, and I know how it feels and myself as positive or negative, that's that's valence. And different people could respond to the same thing with positive versus negative valence, depending on who they are. So you look at that video. And, you know, it kind of depends on your perspective, or the same person might have have a mix of positive and negative when you look at that. Some people and we certainly were when we first did those experiments in 2007. We had a very positive reaction because this was The moment when we really knew optogenetics was gonna work. So everything, you know, nothing to that point had been, you know, a freely moving mammal, which was, you know, that sort of for us. And for great many people, the Holy Grail, you know, how do you how do you get to that moment, we didn't know until we saw that circling that optogenetics was really going to work in that sense. And it brought together all these things, the fiber optic interface, and the microbial proteins and the delivery strategy. So it was a culmination of years of work for many people in the lab, and it made us you know, we were incredibly excited, okay. At the same time, I fully realize that that's also a little disturbing, when you look at that video, or even a lot disturbing, if you if you look at that. And you think, you know, here's an animal that was doing nothing. Now, it's suddenly doing something very specific, announce stopping. And then you put that in context of what's been done, since you can instantaneously induce an animal's, you know, violent aggression, instantaneous, violent aggression by very specific optogenetic intervention, you can turn it on and off instantaneously, just delivering a few spikes of activity to a few cells, you can make an animal seemingly want to actually act to carry out, you know, violence against another member of its own species, turn them on or off instantaneously. You know, a work done, you know, very remarkable work done by Katherine Dymocks. Lab at Harvard, looking at parenting, we can you can turn on or off parenting behaviors very specifically optogenetically. You look at all these things. And it's, it's a it frames a very interesting question. First of all, if anybody had any doubt that the actions of complex mammals can be and are dictated by a few blips of activity in a few cells? Well, I have no doubt anymore, that that's certainly known. And of course, those cells act through other cells, and they recruit cells, they need to give rise to the actions but but at some level, at a causal, fundamental and specific level, complex actions and decisions are dictated by a few spikes in a few cells. And when you look at that, that has, you have to deal with it, you have to put that in context of questions that relate to freewill, and the ways we think about combating violence and aggression in society. And it doesn't answer, I would say any very, very deep, eternal philosophical questions, but it frames those questions very well, in ways that are objective and concrete and quantifiable. And so even I would say, even if you have a, as I certainly understand a negative valence reaction to that video, I think, in the end, it also can be turned positive, because it, it helps you. It provides a launchpad for us to begin to understand ourselves more deeply.

Nick Jikomes 38:24

So is it possible to use this technology in humans? Is it being used in humans today? And how might this technology be used in humans in the future for good or for ill?

Karl Deisseroth 38:36

Well, it is. It is used in in human beings now. So my colleague, Bhutan, Raska in Switzerland, just a few months ago, described the optogenetic restoration of light sensitivity into the eyes of a blind person. And this was something he had been working on for a very long time, more than 10 years. He and I published a paper together. Yeah, about 10 years ago in science, showing that you could do optogenetic control of light responses in a human retina, taken from someone who had passed away a categoric human retina, and we show that optogenetics worked in that setting. But he kept working on that over the last 10 years with a goal of vision restoration in people who are blind. And so he worked hard on all the intricacies of clinical trials, which can be complex, to say the least, as you well know. And he succeeded in the end just in this past year, demonstrating conferral of light sensitivity onto somebody in ways that that they didn't have before due to blindness. And so that's a very interesting example. I would say that the real impact of optogenetics is is a basic science discovery tool, though. This is by far the biggest impact. This allows us to understand, to build up a causal understanding of the brain in a way that that matters. And that could make any kind of treatment more effective, more potent, more specific. If you really know what matters, you know what's causal in a symptom of a disorder, then you can bring anything to bear on it, you can bring a much better targeted electrical stimulation, much more precisely targeted medication, or combination thereof, armed with grounded in this, this causal and specific understanding. So that's the real value of optogenetics. It's for understanding, it's for insight, it's for discovery, and it can make any kind of treatment more more potent and effective.

Nick Jikomes 40:49

So some of the treatments we have today, for for certain debilitating brain problems are fairly invasive and fairly crude. So one that I'm thinking of as deep brain stimulation. Could you imagine a point in the near future where we are using optogenetics and a human being in place of something like deep brain stimulation?

Karl Deisseroth 41:10

I think that's plausible. You know, an interesting thing about deep brain stimulation is it's pretty good, particularly for Parkinson's. And for some related disorders. How does it work, what we do is we put an electrode into a deep structure, sometimes it's a bilateral electrodes you put into one on each side, and you go down to a structure like the subthalamic nucleus, and you stimulate very hard electrically. And so it's not specific, in the sense, you're not hitting one cell type. But you're having a regional effect. And that biases, a Parkinsonian brain away from this state of slow movement and rigid limbs, and high likelihood of falling, and tremor, and it restores a brain state that's more fluid, not so slow, not so much of a tremor. And that's how it works. And it works for about, you know, because it's brain surgery, because it's invasive, it's not, it's not the first line, or second line therapy, it's reserved for people who, for whom medications like dopamine replacement medications have stopped working. And for those people, it works for about half of them quite well. And, and it only gets some symptoms, but not others. But it gets those pretty well. It doesn't help so much with the depression and the dementia and the gait problems that come with Parkinson's, but it helps other things. And but the problem is it stops working after a few years. Also it works, it helps with the function for a while and then it stops, much like the other medications as the disease progresses. So that's deep brain stimulation, now you think well, so could can optogenetics or something like it help in a way that deep brain stimulation doesn't. One problem is we still don't really understand fully if we were to use the specificity of optogenetics, we don't yet know. And certainly for psychiatry, we don't yet know exactly how to use that power. And this is why this work with animal subjects. experimental work in the laboratory over the coming decades is going to be so important, we have to use this power to to figure out which are the cell types, the connection types that we need to target. Brains, very complex places, we don't know that you're never going to be able to, to help human beings. The specificity is almost going to be a handicap at this point. Because if you come in with a very specific intervention, there's a pretty good chance you're going to be wrong, you're going to be targeting the cells or their projections that are actually not causal. So really, what we have is a situation where we now have the power to ask the questions and get the answers that we want. And but there's going to be a long discovery process, particularly for psychiatry.

Nick Jikomes 44:09

So one of the things you mentioned earlier, was to do with anxiety. And that anxiety is very multifaceted. It's not just one thing, it's actually several different components, each of which is controlled to some extent by different projections, different circuits within the brain. Can you unpack for people a little bit how optogenetics and other techniques used in neuroscience have helped give us that more detailed level of understanding and then what achieving that has done for us so far on the psychiatry side?

Karl Deisseroth 44:37

Yeah. Yeah. And this is something that that I talked about and projections in the book in a number of different ways about anxiety and also about this parenting work that came from Katherine DBox lab at Harvard. And the way optogenetics was used in both these studies, for anxiety and for parenting was as follows. So what We can do is ask. If we define a cell type as a cell type that has its origin, its cell body, where the cell itself lives in one part of the brain. And but it sends a connection that sends an outgoing axon and outgoing wire a projection from one part of the brain to another. That's one kind of cell. It's a cell that may have other connections, but it certainly has that one. And here's therefore to be designed to be sending information from point A to point B. Okay, now, so how can you begin to deconstruct a brain state and a complex behavior using this framework? Well, what we can do is we can inject a effectively the gene that encodes a channel rhodopsin, a light activated protein, we can put that into a point a, into into one spot of the brain, maybe here, we put it in here. And if we put that in, if this part of the brain is an anxiety control region, a region that we know is linked to anxiety, and we could make all the cells in that area, produce this channel rhodopsin protein and make them light responses. But the neat trick is, we don't send the light into point A. Instead, we send the light into point B. And what's light sensitive, in point B, are there any channels and options in point B there are. But they're only in the wires that started here, because this is where the cells got the channel rhodopsin gene, and they produce a lot of the channel rhodopsin, the channel wraps and went down the axons went down the outgoing wires. And so the only light sensitive things here and point B are the axons that started here, and then in here, and define that cell type. And so that we call projection targeting. And so of course, it comes up in projections quite a bit. And in this anxiety control region, there are some axons that go to regions of the brain that control breathing, there are some that control go to regions of the brain that control behavioral choices. And there are those that control valence that control positivity or negativity of a state or an experience. And what we found was that different connections coming from point A from the anxiety region, there was one connection that effectively went out and got the respiratory rate changes breathing fast, when you're anxious, another connection went out and got the negative valence, or the positive valence of relief from anxiety. And another one went out and got the behavioral change. And so the complex state of anxiety was assembled from its component parts, by these projections that went out to different parts of the brain. And optogenetics gave us this ability to specifically recruit one or another or another of these sub features of anxiety and see how it's assembled. That's the case of anxiety. What Catherine do ox lab did is they were looking at parenting. And you might not think that that could be studied sort of quantitatively and tracked attractively in the lab, but she's done such a great job of this kind of work. And she was able to set up experiments that separated different parts of parenting.

Anybody who has been a parent or even has been around little kids, which is everybody, you know, you know that there are different aspects of caring for for kids, a big part of that is just keeping them contained, okay, you got to keep them in one spot. And if some of them get away, you got to go get them and bring them back, I think that's completely separate from anything else you might do for the kids, okay, he might, you might want to give them a bath, you might want to teach them something. But all that is separate from just going again, and bringing them back, okay, and that, you know, we've got a bunch of little kids, a big part of my life is just going to get them and bring them back. And that turns out in a parenting part of the brain, there's a whole projection in mice that is, effectively that part of parenting, it's like, go out and get them and bring them back. And so that's, you know, talk about feeling connected across the tree of life. You know, when you see a mouse that, you know, a big part of its parenting experience is just going to get the wayward kids and bringing back you really feel connected with them. Okay, so that's but then once you have them back, then how do you get you know, what do you do then? Well, there's, if you're a mouse, there's a lot of grooming and and that kind of care. And it turns out there's another projection. So there's the go out and get them projection, which is from point A to one part of the brain, but that doesn't control groups. There's another one that starts from pointing and goes another part of the brain. And that controls the grooming. And what the Duloc lab was able to do was turn up or down each of these projections and make things happen, specifically going out and retrieving the young or grooming them. And so in both these cases, we see that the these complex mammalian behavioral states are assembled are put together by the projections by the connections that go out and get particular sub parts of the state. And that's the unifying theme.

Nick Jikomes 50:33

And so is it common that you have this kind of configuration where you've got a group of cells with their cell bodies in one part of the brain? And then some of them go to one place? Some of them go to another place? Is that kind of configuration where those different projections are controlling different aspects of something? But they're all originating from the same spot? And coordinated in that sense? Is that a good motif? Or a good configuration? If you want to make a complex behavior, like anxiety or like parenting?

Karl Deisseroth 51:04

Yeah, it's certainly seems to work? Well, it seems to be, first of all, a, a, a generalizable theme that works across multiple different brain states and behavioral states. And it does seem to work well. And if you think about it, it makes a lot of sense. It's logical. It helps compartmentalize different features of a state, there might be something that needs to be shared across multiple states. And there are other things that should not be shared or should be shared among a different set of states. And so having this modular organization of features of states is actually if you think about it, a very reasonable way of setting things up. And but we didn't really know, until we had this this causal way of addressing projections. With oxygenics, we didn't really know that this sort of organization mattered or that it was generalizable. Now, it makes a lot of sense. And it does seem to be a general principle.

Nick Jikomes 52:10

So another emotion or rather, another behavior that I thought was interesting that I learned something about from the book is crying, crying in humans, something that we've all done, we've all experienced, crying, sort of interesting, because you can cry for multiple reasons, you can cry, because you're sad, you can cry because you're angry, or even if you're in a state of joy. I can also think of examples from earlier in my own life, where I cried for one of those reasons. But I didn't necessarily want to display that emotion to other people, but I just couldn't help it. And you talk about crying and tears in the book. And so can you talk about the part where well, I didn't know this before, but crying is, I believe, has some specificity to humans. And I wouldn't necessarily have guessed that. But why do we produce tears? And what is crying actually doing for humans?

Karl Deisseroth 53:04

Now, this is a really interesting insight here. And this champion, as I mentioned, how then different chapters the language is adapted to the nature of the human condition that's involved. And so in mania, we have this sort of flowery language and but that's not seen in this in this chapter on on tears and crying there. It's it's really, the language is much more attuned to this to this loss and grief, part of the story. Now, crying is, indeed, the shedding of emotional tears. Is humans specific, even other great apes. They don't shed emotional tears from their eyes. And, of course, they certainly have expressions of what looked like grief and loss and bereavement, for sure. But but the shedding of emotional tears does seem human specific, which is pretty interesting. And you also highlight that it's it's involuntary, largely, people have to work really hard. Even trained actors have a really hard time many can do it but but only with a lot of training in general. People have trouble controlling and causing tears to happen when when you're not in one of these states is hard suppressing the shedding of tears is extremely hard, if not impossible in the States. And as you point out, that doesn't seem an advantage to the individual right? Why should an involuntary expression of this emotion be something we have any complex sign that we have, we should have it for a reason. We know things that aren't useful in evolution are lost quickly. It's is a nearly universal human trait. What's, what's its value? And what is the value of the involuntary nature of crying? Well, we don't know. But we can look at the circumstances that cause or suppress, crying. And we can think about the value of, not for the individual, but for the species of involuntary communication, of emotion. And here, there's a value of truth of true social communication about true deep feelings, we know when we have feelings of loss, a sudden shock of betrayal, or need to recreate our world or model of the world. We cry at those moments. And we're conveying something that is very powerful to other people, it's been documented in very nice studies that just by adding digitally adding tears, or taking them away from images of the people has a much more profound effect on the desire to help, specifically that the desire to help in any other feature that you can, you could digitally alter. And so here's what we now know from the science is that this is an involuntary, human specific trait that powerfully and specifically, recruits a desire to help and others and, and it matters for the species that have be true, which is really interesting, right? If it were to easily gamed, it would not be perhaps so good for the species as a whole, as this channel of true communication. There's also an interesting, I think, part of the tears of joy, which might be best to read the story might be too long to get into here. But the tears of joy are also quite interesting as well. So there's this concept of the truth channel, and why we have this shedding of emotional tears from the lacrimal gland in our eye. It's controlled from a deep brainstem structure, the pons, which there's a particular cluster of neurons there. And in particular nucleus of the of this deep structure that sends connections to the tear ducts and the tear glands and triggers the release of tears. How did that get? How did that feature get looped into this state of grief and loss? Well, it's, it's, you know, because this is a human specific trade, of course, we don't have all the detailed knowledge that we now have for analogous things in mice. But clearly, these cells that control the tear glands and the releases of tears, they must now be this feature of, of crying has now been added into the grief state by a projection that comes from the emotional parts of the brain, and that finds its way directly or indirectly to this deep brainstem structure and triggers the release of tears. And so it's a beautiful case, study that that nature has given us of how a feature of a state in this case, the shedding of a fluid from from a duct, can be specifically added to an emotional state. And so this, it becomes a paradigm when you think about how our, our complex inner worlds are constructed and created with a simple expedient of adding a connection or projection, you can begin to define the material nature of our mysterious interstates.

Nick Jikomes 58:49

Another thing that I found fascinating the book was how you talked about the value of basic research, undirected, basic research with with no apparent purpose to it, no applied purpose, because on the one hand, you're a psychiatrist. So you have this sort of very applied side to your professional life, you're helping people in need. And you've got that. And then on the other side, you've got the basic research, we're using things like optogenetics and other tools to ask basic questions that inform that but but you actually go further than that, and say something like, the more we try to direct research, by concentrating public funding into large projects with targeted possible treatments in mind, the more likely we are to instead slow progress. So you seem to be advocating not just for basic research, but basic research that doesn't even try to apply itself to towards some practical and why is that what you're saying?

Karl Deisseroth 59:46

Yeah, I mean, here again, it's the it's what optogenetics has taught us is something that we have learned, and we'll learn again, which is you can't predict it. Were these big insights being, you know, changes in the landscape of science understanding where where revolutions will come from, you can't dictate that I will understand emotion and psychiatry better. By studying single celled algae, nobody could have said that at the beginning, right. And that's the point at is that we were only able to make the advances that we made because of more than 150 years of pure exploratory curiosity, human curiosity about the world. In 1866, a Russian named Andre from Minsan, a botanist, was studying these single celled green algae, and he noticed that some of them move toward light, they have little flagella, and they swim toward the light. If you just have them in a dish, you collect these algae from a dish and you put them near light, they'll swim to just the right light level for their photosynthesis. Why was he studying that he certainly wasn't thinking about, you know, emotion or or parenting, I think there was no plausible research plan that would have said, we will study this to deepen our understanding of neurology or psychiatry. But that's, that's what he studied and other curiosity driven work led to discovery of other microbial options, wonderful work from my friends and colleagues, David roaster held and Peter Hagerman and others. And, you know, we delve deep into how these proteins work, we discovered more of them, when we got the high resolution structures of all the main types of channels and options and looked to understand how the slight activated ion flow works, we were able to re design them for new kinds of function that let us do new kinds of experiments, including these single cell holographic experiments, and, and all of this, if you look at this in aggregate, none of that would have been possible without 150 years ago, just just pure exploration of the natural world. And so that's kind of the point is that, you know, we, we definitely do need, you know, directed translational research, but we also need an extremely large component of what we do to be pure exploration because no human being can predict where the big leverage will come from.

Nick Jikomes 1:02:45

Are we doing enough curiosity driven research today? And how does that relate to the the general structure of how science is funded? In the present day?

Karl Deisseroth 1:02:57

Yeah, this is a big question. Um, I think we're, we're doing pretty well, I think we could do better. I've noticed a shift. In the last, you know, 25 years, more toward application and translation being more dominant. When I was a neuroscience graduate student, you know, anybody who had a translational or medical inspiration to their work, it was kind of it was a little weird. It was sort of, are you? Are you a real scientist? Or what's what's going on here?

Nick Jikomes 1:03:39


Karl Deisseroth 1:03:40

It was definitely on cool. Definitely on cool. And that's changed. Big time. So now, the neuroscience students, you know, I was at Stanford, same institution, same program. Now, students love talking about translation and application. They're there. They're great on the basic science side, too. But they're fully excited and happy to talk about translation and medical applications. So that's pretty cool on the one side, as long as they don't lose that, that basic sign and don't. But of course, it's you know, there's only so many hours in the day, and there's only so many, you know, grant dollars out there. And if you take from something, if you give something you take from something else, to some extent, I think it's, I think we just have to make sure that that we continue this very healthy respect for for the purely undirected research at the same time as we increasingly respect and appreciate translation.

Nick Jikomes 1:04:47

So you also write in the book, one of the sentences I highlight highlighted was the experiences of suffering human beings, and the thoughts and thoughts about mouse and fish brains are informing each other. So talking about the The influence that the basic and the applied side are having on one another. We've already talked about this with some examples, but are there other salient examples you can give from your own career about how this kind of direct bi directional influence between the psychiatry practice and the basic research has, has played out?

Karl Deisseroth 1:05:18

Now. I mean, I, you know, I mentioned my clinical focus is, is on depression, and also autism. And it's been really good. I think, for everybody that, that I can walk from this world, in this office here, and I can, where I see patients, right, I treat them and go back to the lab, and if my graduate students in the lab who are studying, you know, anxiety in, in, in, in mice, or social interaction in mice, or, you know, decisions of fish to, to flee from something aversive or to stay put. Instead of the students just opening up, you know, textbook and saying, okay, here are the five of nine symptoms required to diagnose depression, if they can talk to me, as they do as we then we talked about this, and they can ask, what's the what's the patient really like? What really matters to them? What's the, one of the important parts of it, what are the ones that it strike most of the heart of, of the disorder itself. And, and I've been able to do that, for depression, for autism, for dissociation, we just, you know, we just had a paper last year on this very interesting brain state of dissociation that where people feel separated from their body, their sense of self, becomes separated from their sense of their physical body. That sounds probably very fuzzy and weird and non precise, but actually, turns out, it's first of all, it's, it's very tractable, and as we found can be rigorously studied, and quantitatively and causally. And secondly, a lot of people don't realize, but it's epidemiologically quite common. It's, you know, up to 70% of people who have trauma will experience dissociation that's caused by drugs, that's caused by personality disorders, and ECT and PTSD. And so, the nature of my, you know, work with patients has helped us has helped give us a firm foundation to explore things in ways that are really grounded in the human experience of people. And in ways that matter. And so that, that has been really powerful, and, in surprising ways, always ongoing eat with each year, each new project, I see that happen again, and again, it's so good to have this grounding in the human experience on the clinical side. So that's what I meant with that passage is, is to see that the the insights and motivation that come from the mouse and fish work, of course, they inform, you know, how we think about ourselves and our suffering. But it's a it's a, it's a cycle, I, I do that work, in part because of my inspiration from psychiatry, and then it comes back and helps us understand the psychiatry as well.

Nick Jikomes 1:08:45

Yeah, dissociation is very interesting phenomenon. On the one hand, as you say, it's common, lots of people experienced this, they can arise in many different contexts. On the other hand, if you haven't experienced that, or you haven't seen it firsthand, it's right. It's interesting, it's very hard to wrap your mind around how something like this could even be possible. What do we know about the neural basis of dissociation?

Karl Deisseroth 1:09:08

Well, we knew essentially nothing. Because, first of all, there was not a clear path to studying it in animals. And although it happens in human beings, we didn't have the tools to get in with the right resolution into the brain to see what was actually happening. So we were sort of paralyzed on both fronts, the animal subject and the clinical side for different reasons. And so, in this in this paper that we published last year and 2020 in nature, the the exploration was both in mice and in human beings and the basic approach started was was with, first of all, a new way of looking at the brain, it was a, what we call a wide field optics. So we were able to take a very broad view across all of our called dorsal cortex. So the whole surface part of the brain of the mouse all at once, true simultaneity not like looking at one part, and then another part, but looking at the whole thing all at once. And by doing that, and giving drugs that are dissociative agents, ketamine or PCP, you just looked, we didn't know what we would see, it was a pure exploration curiosity driven exploration, we asked, okay, what if we give dissociative drugs or versus non dissociative drugs? Do we see anything happening in the brain. So we were imaging the brain looking at activity using light, there are ways of collecting activity information, using light also fluorescence changes that come with neural activity. And so we used our Wide Field optics and these light driven reporters readouts of neural activity. And we saw something amazing that within one little patch of the mammalian brain called retrosplenial cortex, there was a pulsation and oscillation that was going about three times a second. And it was only in this one spot, retrosplenial cortex. And in fact, it started in layer five, this deep layer of retrosplenial cortex wasn't happening anywhere else in this this dorsal cortex part of the brain. And we were very curious about that it was a very localized rhythm, it was only in the dissociative drugs, not the others, it happened, Just at the dose were behaviors that looked like dissociation happened in the mice were. So you might ask how you're going to make that happen? Well, if you give a very mildly aversive stimulus to a mouse, like a plate that's too warm, it'll withdraw reflexively withdraw its paw, and that's fine. And that's a reflexive thing, it just means it's detecting the stimulus. But then a normal mouse will also then lick the paw to cool it.

And what we found is that animals that were given a dissociative drug to ketamine or PCD, they would still detect the stimulus and withdraw the paw. But they wouldn't do anything else. They wouldn't carry out the self care, the licking and so on, that you would carry out. So they just didn't care that it happened. And, and I know from patients and people know, and this is, there's no question about this, this is very similar to what happens to people who are dissociating, they're aware of what's happening, they're not numb, they're not unconscious, they're not anesthetized, they perfectly register what's happening to the body. They just don't care because it's not their self anymore. So this is extremely interesting is that there's a separation of stimulus detection from, from caring about it, because it's attributed to the self or not. Well, that's exactly what the mice did, at exactly those that were this oscillation appeared in retrosplenial cortex, they stopped caring about the stimulus that they were detecting. And we did other experiments, we caused the oscillation using optogenetics. So we played in, we delivered this oscillation into this, you know, layer five retrosplenial cortex, and we were able to cause behavioral dissociation. And then we delve deeper into the mechanism, we found a ion channel a native, naturally present channel that we had pacemaker properties, it's also expressed in the heart, which has its own pace that it sets and so it creates its own rhythm. And we, we saw that this was a gene that was very highly expressed in this particular layer of retrosplenial cortex. And so we knocked it out just in that spot, and the rhythm disappeared. And, and the behavior also disappeared. And so all the seem consistent, then you might ask, how are you going to bring this to human because you can't do all this stuff in humans, you can't knock out this, this gene and the human brain, for example. But we had there was an amazing and unpredictable you know, convergence of, of events. So I host a, a get together basically, of neuroscience clinicians at Stanford, the pre pandemic days, it was basically sandwiches, I would just put a order a bunch of sandwiches, put them in a big pile and invite neurosurgeons and neurologists, anesthesiologist, psychiatrists just come and talk and we would talk about our experiments, they would talk about their cases. And one day, the students were talking about this work. And one of the neurosurgeons, Jamie Henderson said, hey, you know, we've got a patient on our epilepsy service who's coming in, so we can map where the seizure is starting. So we can go in and take it out, because this patient had intractable epilepsy medications weren't working. So they have to go in and find where the seizures starting. And he said, this patient has a dissociative aura. An aura is this thing right before a seizure before it starts where the patient starts to feel different people with migraine also have an aura. And so that's what happens just before the event. This was a patient whose aura was dissociating. So okay, that's interesting. But even more interesting, what happens in our Stanford Comprehensive Epilepsy treatment center is when you go in and take out part of the brain, you want to be pretty sure you're taking out the right part, right? So before the neurosurgeon goes in and takes out what he thinks is the seizure, focus what Jamie Henderson thinks the seizure focus is, what he's going to do is first say, hey, you've got to put in electrodes across the brain. And the neurologist do this to the Yosef Parvizi, the neurologist was, you know, they work together to plot the course of the electrodes, and they want to put them in and record from everywhere, so they can see, okay, where's the seizure really starting? And then they can also stimulate with those electrodes too, and see, can we cause a seizure at this spot? So there's this whole week long process of mapping a seizure origin. And as part of that normal clinical care, there's electrodes all in the brain, which is not a normal thing that you typically have with people. So we were, we were like, Oh, my gosh, this is a patient who's dissociating. And as part of their normal care, there's electrodes all over the brain,

Nick Jikomes 1:17:06

you now have the ability to locate the origin of this dissociation. Yeah,

Karl Deisseroth 1:17:11

exactly. So we said, this is incredible. So it was like a beautiful blind experiment, because all that had been collected all the planning of electrode trajectories, and all that had already been done. So it was not searching under the streetlight of where we expected something to happen. It was a purely unbiased exploration. And we went and looked. And we know, by the way, exactly when the patient's dissociating, and they're describing it. And we saw an oscillation, it was about three hurts. And it was only in these areas of the brain that are homologous to the mouse retrosplenial cortex, it's the human retrosplenial and deep posterior medial cortices, same rhythm, same spot. And it happened only when the patient was dissociating telling us that dissociation is happening. And it was causal to, because when stimulation happened, that these spots but not at the non oscillating spots, the patient dissociated as well. And he had these classic descriptions of healing separated from his, his a cell feeling separated from his body, he described feeling pulled out of the cockpit of the plane, seeing all the gauges, seeing all the information, knowing it's there and knowing exactly what's happening, but not feeling that it was was him. You're not the pilot, but you're in the cockpit. Exactly. Definitely not on the pilots chair, but seeing gauges. And so that was amazing. And then we did, there's a bunch more work in that paper. And now we're following up in various ways where we think we understand aspects of how this now happens. We think the this, this retrosplenial cortex is potently connected to one part of the deep brain called the thalamus and this rhythm sets up a loop. And that excludes other parts of thalamus that are not connected to this part of the brain, and they end up on their own. So you've got half the brain and one rhythm half the brain out of sync on this other rhythm. And different parts of the brain are not active together. And so they can't engage with the same information at this at the same time. Neither party is shut down. Neither part is unconscious, but they're just never active together. And so they can form a shared unified experience of, of the situation or the event. So we're even getting now down to these very deep questions of what to talk about something like the self, and why do we consider our body part of our self anyway? Well, now, that might seem like a impossible question to address although interesting for now, with this combination of optogenetics and working with patients, and this this undirected imaging, we're now we now have a very interesting Whoa, hold on that very deep question.

Nick Jikomes 1:20:01

So this is making me think about something like treatment resistant depression, which you've got a lot of experience and, and, you know, at a very fuzzy, non mechanistic level or someone with severe depression, I would think must, you know, in some sense have an altered model of themselves. People tend to, you know, have very negative thoughts, and your, the way that you're modeling yourself seems seems like it's different in some way. And so connecting everything that you just said about dissociation to something like ketamine, for example, which is a dissociative drug. I've had a couple people on the podcast, talking about recent results showing that ketamine can have these rapid antidepressant effects. And you know, one might, might think, Okay, well, if there's a problem with how you're modeling yourself, or viewing yourself in something like depression, say, and you've got a dissociative drug causing dissociative effects, you know, maybe it's conceivable that dissociated dissociation can be helpful, because it can help you maybe dissociate from this maladaptive model of yourself and maybe, maybe reassociate, some other other more more adaptive model. But the thing that would then confuse me there is, people are seeing these antidepressant effects with ketamine at low doses where you don't get dissociation. So do you have any thoughts about how something like ketamine might be working to cause antidepressant effects?

Karl Deisseroth 1:21:23

Yeah, this is a really great question. We thought about a lot. I don't have the answers. I have some thoughts, though. And I've talked to various people in the field, there are a lot of theories on how ketamine and you're correct, the dosing is different. And so the antidepressant dosing and the dissociative dosing are not quite the same. So that's one one suggestion that, you know, it may, it may not be that the antidepressant actions are because of dissociation, I think, probably most people now think that although it's not not proven so. And, you know, it's it could have been right, it could have been that, that maybe there's a separation from negative things, and that's part of how the antidepressant works, and dissociating of negative things from the self. But that is probably not the case the dosing is different. Some people think the ketamine, an antidepressant action is acting on different brain structures more directly, not on the retrosplenial cortex per se. Some people, including her at Stanford, find evidence that it may be acting through opioid receptors, other people are or are finding evidence for other parts of the brain. So they may well be different actions for for ketamine, per se. Nevertheless, it doesn't really matter to some extent, it's we can study both separately and independently. And the wonderful thing about these advanced molecular tools is, we can start from these initial observations as we did, we gave the dissociative drug saw this oscillation. And then we can dive deep into these mechanisms and processes and get, you know, precise causal understanding and not so much depend on the initial experiments, the initial drug application that was just our way in. That's what got us into these deep questions in the first place.

Nick Jikomes 1:23:30

So what do you make of some of the findings related to say ketamine and psychedelics, on treatment resistant depression we've had, you know, you'll know better than me, and you'll be able to tell us about the history of depression. And you know, how successful classic treatments have been, what fraction of people they've worked for, but there's, I think, a fairly large proportion of people that are treatment resistant, and the classic treatments don't work for. And it seems like some of these drugs that you wouldn't necessarily have thought would have have worked for something like depression even just a few years ago, are having effects that seem to be beneficial for some people with things like treatment resistant depression, so what do you make of that general field?

Karl Deisseroth 1:24:12

I'm intrigued by it. I think it's it's definitely worthy of exploration. And the results are intriguing. No doubt about it. I have a you know, from from speaking to people who, who, who explored this, this path, it's, it's clear that and this is both a positive aspect and a cautionary note is many times people who have taken psychedelic medication they describe it as sort of an opening up of possibilities. And they never quite go back to how they were ever. Okay, so this is this is an interesting it is. And as I said, it's good and bad, right? You, you know, this could be if you do it right. It's the foundation for a great kind of treatment, right? You open up the brain to a new way of being that never had access to before, a new way of experiencing the world of a self, of creating a unified and consistent picture. We're in one mode for much of our lives. For some people, that's great for other people, they end up in a state of suffering or dysfunction. Opening up a new way of being is potentially Great. This, you know, we have treatments in psychiatry, like electro convulsive therapy, which are very effective, we don't know how they work. That's very nonspecific. It's all over the brain, it's probably just opening up a new set of possibilities, a new way of things happening. And these microdoses may be doing something analogous. Now, what's the downside? Well, things never quite go back to how they were. You know, there are potentially very serious complications and risks that come with that. You know, you know, some people their lives are, quite sadly, the nature of their daily experiences is great suffering, and of course, no problem. And seeking, you know, ways for those people to find a new way of being particularly patients who are treatment resistant, suicidal, you know, no question, we want to help those those patients. But for people who may be more on the mild or moderate spectrum, are not yet quite established as true treatment resistant, people whose current mode of being maybe pretty good in other ways, functional people with with jobs and families, we have to think hard about this, what what what could we be altering in a way that we don't understand and might not be able to reverse with these approaches. So that's, that's the caution. As with everything I think we need to study, we need to understand what we're doing. And here's where, you know, in our dissociation work, I think was helpful in this, you don't have to just throw up your hands and say, well, we can study things like this, and animals or we can go back and forth from from mouse to human and back again. Well, you can, you can, if you have an integrated set of people unified and their willingness to talk to each other to share data to explore together. And I think that's the path forward with the psychedelics and the micro dosing, we need to ground ourselves in a deep understanding of what we're actually doing. And, and and we're, we're exploring that here we have I have a safe with LSD. And, you know, we have, we're doing collaborations on MDMA. And obviously, we're doing a lot with ketamine and PCP, we're, we're doing the basic work. But with a firm grounding in causal, rigorous cellular mechanisms.

Nick Jikomes 1:28:24

I want to ask you about autism as well. This is an area that a lot of people have interest in for personal and academic reasons. Can you speak a little bit about what autism is, and what we've maybe started to learn in the past five to 10 years about how the brain of an autistic person is different from that of a neurotypical person?

Karl Deisseroth 1:28:46

Yeah, so autism always intrigued me. I was. So both dismayed and intrigued by how physically, you know, on damage these people in their brains are, in fact, many people with autism, their brains are larger even than a typical brain. And there's no real structural problem, there's no real EEG thing you can maybe there's a little more power in one band of the spectrum, you know, maybe in some forms of the disorder, you can see as a few more one kind of cell and another. But in general, brains look fine body is fine. And yet, you can have very severe dysfunction in these very specific domains. And autism is defined by deficits in communication and social interaction, and also by in many cases, stereotyped or repetitive repair. If behaviors, and why do these go together? And what's the mechanism? Where does it come from? Now, there are a lot of genes that are associated with autism, it's very genetically associated. But we, those genes don't fall into a simple picture. Some of those genes are related to synapses. Some of those genes are related to projections across the brain. Some are related to chromatin, how DNA is wound up and structured within the nucleus of a cell. Why chromatin? Nobody knows. So it doesn't fall into a neat picture. There are some themes, though, some, some, some sort of little cracks in the, in the door that let us tear into this mystery. One of them is that there's a theme of over excitation of over excitability, and this a number of different things pointing in the same direction. So first of all, people who have autism are more likely to have epilepsy, more likely to have seizures. And so there's association with over excitability, there is more of this high frequency power and one band of the spectrum on average, and people with autism. So there's a, there's a little more power in that, in that spectrum in their brain activity. And then there's a lot of their behavioral properties and symptoms that suggest this preponderance of excitation there. There's a, an ease of being overwhelmed a susceptibility to being overwhelmed by by things. And this shows up and can even be simple sounds, unexpected sounds or touches, but then certainly, social interaction, very rich information, you know, you think of all the streams of information, that, that you're synthesizing to make sense of what I'm saying, you've got, I've got my hands here, I've got the, you know, you, there's the eye contact, there's whatever facial expression I've got. And then there's the complexity of the words coming out in a sentence, as you're, as you're listening, you're fusing all those together into this model of me and what I'm saying. And that that's human social communication, it's extremely information rich, there's a lot of it, patients with autism experience that is very overwhelming, that that information rate itself, there's just too much, and they can't keep up with it. And that the great value and I talked about this and projections as well. And discussing with my my patients, they very much endorse this concept of being overwhelmed by the information by the rate of information, it's not so much they couldn't grasp any one part of it. But it's it's it's the rate of information flow. And so this is this is a very thing interesting and helpful way to look at this and optogenetics. And work in animals has also given us a window into this as well, we've been able to test questions like is, is there a causal significance of over excitation relatives, in addition, in terms of how social interaction happens, and we were able to find quite a bit of evidence for that. And so it's a pretty interesting, you know, process where, again, the animal work and the human clinical work are helping each other and helping us move toward understanding.

Nick Jikomes 1:33:49

Are there any fields of neuroscience that you're particularly excited about that, that are making really nice progress right now that are maybe not not as sexy as some of the other fields that get a lot of attention?

Karl Deisseroth 1:34:04

Well, you know, one thing with optogenetics that's been great as how almost everybody who's been interested in trying it has found that useful and this is across for people studying worms to fish, insects, mice, rats, monkeys, and now human. And, you know, I think these value judgments of you know, what's the hot area? You know, that's, I think there's a real risk in people being too excited by what's the current hot area and not paying enough attention to where truly, you know, surprising or shocking or unusual discoveries might come from? We started my lab a whole fish effort because If we wanted to work with much smaller, transparent brains, where we could count all the cells where there were relatively fewer cells, and where we couldn't see and control almost all the cells individually, and a lot of people were surprised that that, you know, a psychiatrist, like me would, would put so much effort into into fish. But it's been really helpful, we turns out, they have a lot of the same, you know, behaviors, even even very young, you know, barely, barely hatched, larval zebrafish, they, they do something very interesting they, they give up. If a situation scenes in Super Bowl that can't solve a problem, they'll try for a little bit, then they'll just give up the answer into this passive state. And we were able to look at the brain structures and networks that underlie this state transition to this passive coping state. And it's a lot of the same structures that are present in mammals and that have been associated with depression, and, and giving up in the passive coping, the lack of motivation, lack of energy to to meet challenges that comes with depression. So I would just, I would, I think it's, it's great to study small, strange organisms, that you might not expect, to give insight. Nature always instructs us where, you know, preconceived ideas are usually wrong, we have to keep our eyes open our minds open, and explore freely, and I think that means looking at the brains of, of whatever nature has, has to give us.

Nick Jikomes 1:36:54

Well, Carl, before we go, do you have any final thoughts you want to leave people with about the stories of human emotion generally?

Karl Deisseroth 1:37:02

Well, the, you know, for me, it was such a, an important moment to write the book projections. Because it brought these different parts of the excitement of the science and the these universal human experiences of, of, you know, altered states, whether in, in grief or in psychiatric disorders, and bring them all together in ways that, that, I think, help people understand themselves in the course of human history. more deeply. It was a for me, it was an interesting exploration into myself as well, I came to understand myself a lot better after writing the book. And actually, it's kind of funny, as when I wrote was writing the epilogue, I was looking back and I noticed, you know, themes in the book that told me a little bit about myself that I maybe haven't quite fully appreciated. So it was, it was a really a powerful experience to, to put it out there and, and to try to live in the mind and to express in the words and in the style, the the inner experience of these disorders. But I, I have the just the greatest respect and deep empathy for everyone around the world who is experiencing the suffering of these disorders and I, I just want to pass along that there is hope that I think that's the main message of the book and where things are, is that you know, we may not we definitely don't have all the answers now but But there's hope. There's hope now. We're we've come to a point in human history where our, our scientific explorations are converging with these states that have been part of us as as people in humanity for so long.

Nick Jikomes 1:39:13

Karl Deisseroth off thank you for your time. Thank you.

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