Understanding & Healing the Mind | Dr. Karl Deisseroth

1. 0:00 – 7:41

   Introduction

   1. AHAndrew Huberman0:00

      (music plays) Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today, I have the pleasure of introducing the first guest of the Huberman Lab Podcast. My guest is Dr. Karl Deisseroth. Dr. Karl Deisseroth is a medical doctor. He's a psychiatrist and a research scientist at Stanford School of Medicine. In his clinical practice, he sees patients dealing with a range of nervous system disorders, including obsessive-compulsive disorder, autism, attention deficit disorders, schizophrenia, mania, anxiety disorders, and eating disorders. His laboratory develops and explores tools with which to understand how the nervous system works in the healthy situation as well as in disorders of the mind. Dr. Deisseroth's laboratory has pioneered the development and use of what are called channelopsins, proteins that come from algae, which can now be introduced to the nervous systems of animals and humans in order to precisely control the activity of neurons in the brain and body with the use of light. This is a absolutely transformative technology, because whereas certain drug treatments can often relieve certain symptoms of disorders, they often carry various side effects. And in some individuals, often many individuals, these drug treatments simply do not work. The channelopsins and their related technologies stand to transform the way that we treat psychiatric illness and various disorders of movement and perception. In fact, just recently, the channelopsins were applied in a human patient to allow an adult fully blind human being to see light for the very first time. We also discuss Dr. Deisseroth's newly released book, which is entitled Projections: A Story of Human Emotions. This is an absolutely remarkable book that uses stories about his interactions with his patients to teach you how the brain works in the healthy and diseased state and also reveals the motivation for and discovery of these channelopsins and other technologies by Karl's laboratory that are being used now to treat various disorders of the nervous system and that in the future are certain to transform the fields of psychiatry, mental health, and health in general. I found our conversation to be an absolutely fascinating one about how the brain functions in the healthy state and why and how it breaks down in disorders of the mind. We also discuss the current status and future of psychedelic treatments for psychiatric illness as well as for understanding how the brain works more generally. We also discuss issues of consciousness and we even delve into how somebody like Karl, who's managing a full-time clinical practice and a 40-plus person laboratory and a family of five children and is happily married, how he organizes his internal landscape, his own thinking in order to manage that immense workload and to progress forward for the sake of medicine and his pursuits in science. I found this to be an incredible conversation. I learned so much. I also learned, through the course of reading Karl's book, Projections, that not only is he an accomplished psychiatrist and obviously an accomplished research scientist and a family man, but he's also a phenomenal writer. Projections is absolutely masterfully written. It's just beautiful and it's accessible to anybody, even if you don't have a science background. So I hope that you'll enjoy my conversation with Karl Deisseroth as much as I did, and thank you for tuning in. Before we begin, I want to point out that this podcast is separate from my teaching and research roles at Stanford. In my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public, I'd like to acknowledge the sponsors of today's podcast. Our first sponsor is ROKA. ROKA makes eyeglasses and sunglasses that, in my opinion, are the very highest quality out there. The company was founded by two all-American swimmers from Stanford, and everything about the eyeglasses and sunglasses was developed with performance in mind. One of the things I really love about ROKA sunglasses is that unlike other sunglasses that make it hard to see when there's a lot of cloud cover or when the shadows change or environmental conditions change, with ROKA sunglasses, they clearly understand the science of the visual system. Because when I put them on for the first time, I noticed that as I moved into shadows or the cloud cover changed or the day got brighter or dimmer, everything was still crystal clear. And that's also because the lenses are tremendously high optical clarity and the glasses are really lightweight. You don't even notice that they're on. The other thing is that the eyeglasses, I wear readers at night, they're incredibly lightweight, and for both the sunglasses and eyeglasses, the aesthetic is terrific. Unlike a lot of performance eyewear, which frankly can look kind of cyborg-like and kind of ridiculous, the aesthetic of the glasses is such that you could really wear them anywheres, indoors or outdoors. If you'd like to try ROKA eyeglasses, you can go to ROKA, that's R-O-K-A.com and enter the code Huberman to save 20% on your first order. That's ROKA, R-O-K-A.com and enter the code Huberman at checkout. Today's podcast is also brought to us by InsideTracker. InsideTracker is a personalized nutrition platform that analyzes data from your blood and DNA to help you better understand your body and reach your health goals. I am a big believer in getting regular blood work done, and now with the advent of good genetic DNA tests, I'm also a believer in analyzing your DNA. The simple reason for this is that many of the factors that impact our immediate and long-term health can only be measured and evaluated with a quality blood test. And now, the DNA tests further inform our immediate and long-term health. One of the problems with a lot of DNA tests and blood tests out there, however, is that you get the information back and you don't know what to do with that information. With InsideTracker, you get the numbers back of different metabolic factors, hormones, et cetera, but it also provides simple directives as to how perhaps you might want to change your nutritional intake or your exercise regimen or other lifestyle factors to bring those numbers into alignment with where you'd like them to be. InsideTracker also makes this really easy. They have a dashboard that makes organizing that all very simple, and they can even have someone come to your house to take the blood and DNA test. If you'd like to try InsideTracker, you can visit insidetracker.com/huberman to get 25% off any of InsideTracker's plans. Just use the code Huberman at checkout. Today's episode is also brought to us by Athletic Greens. Athletic Greens is an all-in-one vitamin mineral probiotic drink.I started taking Athletic Greens way back in 2012, and I've taken it ever since, so I'm delighted that they're sponsoring the podcast. The reason I started taking Athletic Greens and that I continue to take Athletic Greens is that it covers all my vitamin and mineral bases, and it covers my probiotic needs. There's now a wealth of data showing that probiotics support a healthy gut microbiome, and that a healthy gut microbiome supports the gut-brain axis for healthy mood. It also supports metabolism, immune function, endocrine, that means hormone function, and a host of other important biological functions. I drink it once or twice a day. I mix it with water and a little bit of lemon juice or some lime juice, and it's absolutely delicious. If you'd like to try Athletic Greens, you can go to athleticgreens.com/huberman, and if you do that, you can claim a special offer where they will give you a year's supply of vitamin D3. In addition, they'll give you five free travel packs. Vitamin D3, as we all know, is very important for a huge range of biological functions and health. Again, that's athleticgreens.com/huberman for your Athletic Greens, the five free travel packs, and the year's supply of vitamin D3. And now, my conversation with Dr. Karl Deisseroth.

2. 7:41 – 12:19

   Using Language to Understand the Mind

   1. AHAndrew Huberman7:41

      Well, thanks for being here.

   2. KDKarl Deisseroth7:43

      Thanks for having me.

   3. AHAndrew Huberman7:44

      It's been a long time coming for me, uh, because, uh, you may not know this, but one of the reasons I started this podcast was actually so I could have this conversation.

   4. KDKarl Deisseroth7:53

      (laughs)

   5. AHAndrew Huberman7:54

      It's- it's but one. There are other reasons.

   6. KDKarl Deisseroth7:57

      Sure.

   7. AHAndrew Huberman7:57

      But one of the goals is to be able to hold conversations with colleagues of mine that are doing incredible work in the realm of science, and then here we also have this really special opportunity, because you're also a clinician.

   8. KDKarl Deisseroth8:11

      Yes.

   9. AHAndrew Huberman8:11

      You see patients and have for a long time.

   10. KDKarl Deisseroth8:13

       Yep.

   11. AHAndrew Huberman8:13

       So for people that might not be so familiar with the fields of neuroscience, etc., what is the difference between neurology and psychiatry?

   12. KDKarl Deisseroth8:22

       Well, it- you know, I'm- I'm, uh, married to a neurologist and I am a psychiatrist, and we make fun of each other all the time. So, um, this is, uh, a lot of neuroscientists and a lot of brain clinicians actually think these two should be the same field at- at some point in the future. They were in the past. They started together. Psychiatry, though, uh, focuses on disorders where we can't see something that's physically wrong, where we don't have a measurable, where there's no blood test that makes the diagnosis, there's no brain scan that tells us this is schizophrenia, this is depression for an individual patient. And so psychiatry is- is much more mysterious, and the only tools we have are words. Neurologists are, uh, fantastic physicians. They see the stroke on brain scans, they see the seizure and the pre-seizure activity with an EEG, uh, and they can measure and treat based on those measurables. In psychiatry, we have a harder job, I think. We use words. We have rating scales for symptoms. We can measure depression and autism with rating scales, but those are words still. And ultimately, that's what psychiatry is built around. It's- it's an odd situation, because we've got the most complex, beautiful, mysterious, incredibly engineered, uh, object in the universe, and yet all we have are words to- to find our way in.

   13. AHAndrew Huberman9:52

       So do you find that if a patient is very verbal or hyper-verbal that you have an easier time diagnosing them, as opposed to somebody who's, um, more quiet and reserved? Or it's- I can imagine the opposite might be true as well.

   14. KDKarl Deisseroth10:06

       Well, because we only have words, you've put your finger on a key point. If they don't speak that much, in principle, it's harder. The lack of speech can be a symptom. We can see that in depression, we can see that in the negative symptoms of schizophrenia, we can see that in autism. Sometimes by itself, that is a symptom, uh, uh, reduced speech, but ultimately you do need something. You need, uh, some- some words to help guide you. And that, in fact, there's- there's challenges that I- I can tell you about where patients with depression, who are so depressed they can't speak, that makes it a bit of a challenge to distinguish depression from some of the other reasons they might not be speaking. And this is, uh, sort of the art and the science of psychiatry.

   15. AHAndrew Huberman10:47

       Um, do you find that there are, uh, patients that have, uh, let's call them comorbidities or conditions where they would land in both psychiatry and neurology, meaning, uh, there's damage to a particular area of the brain and therefore they're depressed, and w- how do you tease that out as a psychiatrist?

   16. KDKarl Deisseroth11:06

       Yeah. This happens all the time. Uh, Parkinson's disease is a great example. Um, it's, uh- it's, uh, it can be debilitating in so many ways. Uh, people have trouble moving, they have trouble walking, they have trouble swallowing, and they can have, uh, truly severe depression. Um, and this is, you might say, "Oh, well, they've got a life-threatening, uh, illness," but there are plenty of neurological disorders where depression is not a strong- a strongly comorbid, uh, symptom. Uh, like ALS, Lou Gehrig's disease, for example. Depression is not as strong- uh, strongly comorbid in that disease. But in Parkinson's, it is extremely common, and, uh, as you know, in- in Parkinson's disease, we have loss of the dopamine neurons in the- in the- in the midbrain. And this is a very, uh- uh, you know, specific population of cells that's dying, and probably that leads to both the movement disorder and the depression. There are many examples of that where these two fields come together and you really need to work as a team. I've had patients in my clinic that I- I treat the depression associated with their Parkinson's and a neurologist treats the movement associated with the Parkinson's, and we work together.

3. 12:19 – 13:38

   Blood Tests For Mental Disease

   1. KDKarl Deisseroth12:19

   2. AHAndrew Huberman12:19

      Do you think we will ever have a blood test for depression or schizophrenia or autism, and would that be a good or a bad thing?

   3. KDKarl Deisseroth12:29

      I think, uh, ultimately there will be quantitative tests. Uh, already efforts are being made to look at certain rhythms in the brain using external EEGs, uh, to look at brain waves effectively, look at the ratios of certain frequencies to other frequencies.And there's some progress being made on that front. Uh, it's not as good as it could be. It doesn't really give you the confidence for the individual patient that you would- you would like. But ultimately, what's going on in the brain in psychiatric diseases, physical, uh, and it's due to the circuits and the connections and the projections in the brain that are, uh, not working as they would in a typical situation. And I- I do think we'll have those measureables at some point. Now, is that good or bad? Uh, you know, I- I think that will be good. One of the challenges we have with, uh, psychiatry is, it is an art as well as a science to elicit these, uh, symptoms, uh, in a precise way. It does take some time, and it would be great if we could just do a quick measurement. Um, could it be abused or- or- or misused? Uh, certainly, but that's, I think, true for all of medicine.

   4. AHAndrew Huberman13:37

      Mm-hmm.

4. 13:38 – 20:21

   The Largest Challenges Facing Treatment of Mental Health

   1. AHAndrew Huberman13:38

      I want to know, and I'm sure there are several, but what do you see as the biggest challenge facing psychiatry and the treatment of mental illness today?

   2. KDKarl Deisseroth13:49

      I think we have, uh ... We're making progress on what the biggest challenge is, which I think there's still such a strong stigma for psychiatric disease that, uh, patients often don't come to us. Um, and, uh, they feel that they should be able to handle this on their own. And that- that can slow treatment. It can lead to, you know, worsening symptoms. We know, for example, patients who have, uh, untreated anxiety issues, if you go for a year or more with a- a serious untreated anxiety issue, that can convert to depression. You can add another, uh, problem on top of the anxiety. And so it would be, you know, why do people not come for treatment? They- they- they feel like this is something they should be able to master on their own, uh, which- which can be true, but, uh, usually, uh- uh, some help is- is- is a good thing.

   3. AHAndrew Huberman14:43

      That raises a- a question related to something I heard you say many years ago at a lecture, which was that, um ... This was a scientific lecture, and you said, you know, "We don't know how other people feel. Most of the time, we don't even really know how we feel."

   4. KDKarl Deisseroth14:57

      Yeah. (laughs)

   5. AHAndrew Huberman14:58

      Maybe you could elaborate on that a little bit, and the- the, um, dearth of- of ways that we- we have to talk about feelings. I mean, there's so many words. I don't know how many, but I'm guessing there are more than a dozen words to describe the state that I call sadness, but as far as I understand, we don't have any way of comparing that in a- in a real objective sense. So how, as a psychiatrist, when your job is to use words to diagnose, words of the patient to diagnose, do you maneuver around that and- and what is this landscape that we call feelings or emotions?

   6. KDKarl Deisseroth15:32

      Yeah. This is, uh, really interesting. Uh, people ... Here we have a, there's a tension between the words that we've built up in the clinic that mean something to the- to the physicians, and then there's the col- colloquial use of words that may not be the same, and so that's the first level we have to sort out. When someone says, you know, "I'm- I'm depressed," uh, what exactly do they mean by that? Uh, that may be different from- from what we're talking about in terms of depression. So part of psychiatry is to get beyond that word and to get into how they're actually feeling, get- get rid of the- the jargon and get to real world examples of- of how they're feeling. So, you know, how do you ... What ... How much do you look forward into the future? How much, uh, hope do you have? How much planning are you doing for the future? So these, here now you're getting into actual things you can talk about that are unambiguous. If someone says, "Yeah, I- I can't even- I can't even think about tomorrow. I- I'm not," (laughs) "I don't see how I'm going to get to tomorrow," that- that's a nice, precise thing that, you know, it's- it's sad, it's tragic, but- but it's also, that means something, and we know what that means. That's the hopelessness symptom of depression. And- and that is what I try to do when I do a psychiatric interview. I try to get past the jargon and get to what's actually happening in the patient's life and- and in their mind. But as you say, ultimately, (laughs) you know, this shows up across ... I- I- I address this issue every day in my life, whether it's in the lab where we're- we're looking at animals, whether fish or mice or rats, and studying their behavior, or when I'm in a conversation with just a- a friend or a colleague, or when I'm talking to a patient. I never really know what's going on inside the mind of the other person. I get- I get some feedback, I get words, I get behaviors, I get actions, but I never really know. And as you said at the very beginning of the question, you know, often we don't even have the words and the insight to even understand what's going on in our own mind. I think a lot of psychiatrists are pretty introspective. Uh, that's part of the reason they end up in that specialty. And so, uh, maybe we spend, uh, a little more time than the average person thinking about what's going on within, but it doesn't mean we have answers.

   7. AHAndrew Huberman17:48

      Mm-hmm. So in, um, this, uh, area of trying to figure out what's going on under the hood through words, it sounds like certain words, uh, would relate to this, uh, this idea of anticipation and hope.

   8. KDKarl Deisseroth18:02

      Sure. (laughs)

   9. AHAndrew Huberman18:02

      Um, is it fair to say that that somehow relates to the dopamine system in the sense that dopamine is involved in motivated behaviors? I mean, is that in ... If I say, for instance, and I- I won't ask you to run a session with me here for-

   10. KDKarl Deisseroth18:16

       (laughs)

   11. AHAndrew Huberman18:16

       (laughs) ... uh, for free.

   12. KDKarl Deisseroth18:17

       We'll do that off camera. (laughs)

   13. AHAndrew Huberman18:18

       Okay, right. Um, if I were to say, "You know, I- I just can't imagine the tomorrow. I just, it's, I- I just can't do it." So that's- that's not action based. That's purely based on my- my internal narrative. Um, but I could imagine things like, you know, "I- I have a terrible time sleeping. I'm not hungry. I'm not eating." So statements about physical actions, I'm guessing, also have...... um, validity.

   14. KDKarl Deisseroth18:46

       Absolutely.

   15. AHAndrew Huberman18:47

       And there are now ways to measure the accuracy of those statements. Like, for instance, if I gave you permission, you could know if I slept last night, or whether or not I was just saying I had a poor night's sleep.

   16. KDKarl Deisseroth18:58

       Yes. That's right.

   17. AHAndrew Huberman18:59

       Um, so in moving f- forward through 2021 and into the next 10 and 100 years of psychiatry, do you think that the body reporting some of the actions of a human, um, are going to become useful and, and me- mesh with the words in a way that's going to make your job easier?

   18. KDKarl Deisseroth19:19

       I do think that's true, and these, the two things you've mentioned, eating and sleeping, those are additional, uh, uh, criteria that we use to diagnose depression. These are the vegetative signs, we call them, of depression, poor sleep and poor eating. And if you have a baseline for somebody, that's the real challenge though. What's different in that person? Some people who are depressed, they sleep more. Some people with, who are depressed, they sleep less. Some people who are depressed, they're more physically agitated and they move around more. Some people who are depressed, they, they move less even while they're awake. And so you need... Here's the challenge is you, you can't just look at how they are now. You have to get a, a baseline, um, and then see how it's changed, and that can be a challenge that raises, you know, ethical issues. Um, how do you, how do you collect that baseline information from someone healthy? I don't, I don't think that's something we have solved. Of course, you know, with phones and accelerometers in phones, uh, you could, in principle, collect a lot of baseline information from people. But that would have to be, uh, treated very, uh, carefully, uh, for privacy reasons.

5. 20:21 – 22:47

   Predicting Depression & Suicide

   1. KDKarl Deisseroth20:21

   2. AHAndrew Huberman20:21

      And in terms of measuring one's own behavior, you know, I- I've heard of work that's going on, um, Sam Golden up at the University of Washington, um, works on aggression in animal models, was telling me that there's some effort that he's making, and perhaps y- you're involved in this work as well, I don't know, of, um, devices that would allow people to detect, for instance, when they're veering towards a depressive episode for themselves, that they may choose or not choose to report that to their clinician. Maybe they don't even have a clinician. Maybe this person that, that you referred to at the beginning, uh, this person who doesn't feel comfortable coming to talk to you, they, um, maybe something is measuring changes in the inflection of their voice.

   3. KDKarl Deisseroth21:00

      Mm-hmm.

   4. AHAndrew Huberman21:01

      Or their... the speed at which they get up from a chair. Do you think that those kind of metrics will eventually inform somebody, "Hey, you know, you're in trouble." This is getting to this question of, uh, the... back to the statement that I heard you make and rung in my mind now f- I think for more than a decade, which is oftentimes, we don't even know how we feel.

   5. KDKarl Deisseroth21:17

      Yeah. You know, that, that I do like because that gives the patient the agency to, to detect what's going on, and even separate from modern technology, this has been part of the, the art of psychiatry is to help patients realize that sometimes other people observing them can give them the earliest warning signs of depression. We see this very often in, in, in family. They'll, they'll notice when the patient is changing before the patient does. And then there are things the patient may notice but not correctly ascribe to the onset of depression, and a classic example of that is what we call early morning awakening. And this is something that can happen very early as people start to slide into depression. They start to wake up earlier and earlier, you know, just inexplicably they're awake at-

   6. AHAndrew Huberman21:59

      So, this is like 2:00 AM, 3:00 AM type waking?

   7. KDKarl Deisseroth22:02

      Yeah. It could start, yeah, it could start at 5:00 AM. It could go to 4:00. It could go to 3:00.

   8. AHAndrew Huberman22:05

      And unable to fall back asleep.

   9. KDKarl Deisseroth22:06

      Unable to fall back asleep. Exactly. Uh, so that's... and that they may not know what to do with that. It could just be (laughs) from their perspective, it's just something that's happening, but if you put enough of that information together, that, that could be a useful warning sign for the patient and it could help them seek treatment, and I think that is, uh, something that could be really valuable.

   10. AHAndrew Huberman22:24

       Interesting. So, in this framework of, you know, needing words to self-report or machines to detect how we feel or/and maybe inform a ph- a psychiatrist, uh, how a patient feels, I want to, um, touch on some of the technologies that you've been involved in building. But as a way to march into that,

6. 22:47 – 27:01

   Drugs That Work for Brain Illness

   1. AHAndrew Huberman22:47

      y- are there any very good treatments for psychiatric disease? Meaning are there currently any pills, potions, forms of communication that reliably work every time-

   2. KDKarl Deisseroth23:00

      Yes.

   3. AHAndrew Huberman23:00

      ... or work in most patients, and could you give a couple examples of great successes of psychiatry if they exist?

   4. KDKarl Deisseroth23:05

      Yes. Yeah. We are fortunate and this coming back to my, uh, you know, the, the joking, uh, between my wife and myself in terms of neurology and psychiatry, we actually, in psychiatry, despite the depths of our... the mystery we struggle with, w- many of our treatments are actually... you know, we're, we're, we may be doing better than some other specialties in terms of actually causing, you know, therapeutic benefit for patients. We do help patients. You know, the patients who suffer from... By the way, both medications and talk therapy have been shown to be extremely effective in many cases. Uh, for example, people with panic disorder, cognitive behavioral therapy, just working with words, helping people identify the early signs of when they're starting to move toward a panic attack, what are the cognitions that are happening, you can train people to derail that and, and you can very potently treat panic disorder that way.

   5. AHAndrew Huberman23:57

      How long does something like that take for, uh, on average?

   6. KDKarl Deisseroth24:00

      For a motivated, insightful patient, you can have a, a, a very, uh, you know, cookbooky series of sessions, you know, uh, 6 to 12 sessions, or, or even less for someone who's very, uh, insightful and motivated, and it can have a very powerful effect that quickly. Um, and that's just with words. There are many psychiatric medications that are very effective for, uh, the conditions that they're treating. Uh, antipsychotic medications, they have side effects, but, uh, boy, do they work. They really can clear up particularly the positive symptoms of, of schizophrenia, for example, the auditory hallucinations, the paranoia.... people's lives can be turned around by these, um-

   7. AHAndrew Huberman24:39

      We should clarify positive symptoms. You mean-

   8. KDKarl Deisseroth24:41

      (laughs)

   9. AHAndrew Huberman24:41

      ... not positive in the, in the qualitative sense. You mean positive-

   10. KDKarl Deisseroth24:44

       Yes.

   11. AHAndrew Huberman24:44

       ... meaning the, the appearance of, of something abnormal.

   12. KDKarl Deisseroth24:46

       Exactly. Yeah. Thank you for that clarification. When we say positive symptoms, we do mean the addition of something that wasn't there before, like a hallucination or a paranoia. And that stands in contrast to the negative symptoms, where something is taken away, and these are patients who are... who are withdrawn. They, they have, uh, what we call thought blocking. They can't even progress forward in a sequence of, of thoughts. Uh, both of those can be part of schizophrenia. The, the hallucinations and the paranoia are more effectively treated right now, but they are effectively treated. And then, you know, this is a, a frustrating and yet heartening aspect of psychiatry, there are treatments like electroconvulse- electroconvulsive therapy, which is, uh, where, you know, it's extremely effective for depression. We have patients who nothing else works for them, or they can't tolerate medications, and, uh, you can administer under a very safe, controlled, uh, condition, where the patient's body is not moving, they're put into a very safe, uh, uh, situation where the body doesn't move or seize. It's just an internal, uh, process that's triggered in the brain. This is an extraordinarily effective treatment for treatment-resistant depression. At the same time, I find it (laughs) , as, as, as heartening as it is to see patients respond to this with, with, uh, uh, who have severe depression, I'm also frustrated by it. Why, why can't we do something more precise than, than this for these very severe cases? And people have sought for decades to understand how is it that a, a seizure is leading to the relief of, of depression, and we don't know the answer yet.

   13. AHAndrew Huberman26:20

       Mm-hmm.

   14. KDKarl Deisseroth26:20

       We would love to do that. People are working hard on that. But that is a treatment that does work too. Uh, all... in all of these cases though, in psychiatry, the, the, the frustrating thing is that we don't have the level of understanding that a cardiologist has in thinking about the heart. You know, the heart is, we now know, it's a pump. It's pumping blood-

   15. AHAndrew Huberman26:39

       Mm-hmm.

   16. KDKarl Deisseroth26:39

       ... and so you can look at everything about how it's working or not working in terms of that frame. It's clearly a pump. We don't really have that level of what, what is the circuit really there for in psychiatry. Um, and that's, that's what is missing. That's what we need to find, so we can design truly effective and specific-

7. 27:01 – 32:23

   What Would A Cure For the Broken Mind Look Like?

   1. KDKarl Deisseroth27:01

   2. AHAndrew Huberman27:01

      Mm-hmm.

   3. KDKarl Deisseroth27:01

      ... treatments.

   4. AHAndrew Huberman27:02

      So, what do you... what are the pieces that are going to be required to cure autism, cure Parkinson's, cure schizophrenia? I, I would imagine there are several elements and bins here. Um, understanding the, the natural biology, understanding what the activity patterns are, how to modify those. Maybe, um, you could just tell us what you think, uh, what is the, the bento box of the perfect cure?

   5. KDKarl Deisseroth27:29

      Yeah. I think the first thing we need is understanding. We need, we need, uh, is... a- almost every psychiatric treatment has been serendipitously identified, just noting by chance that something that was done for some person also had a side effect of-

   6. AHAndrew Huberman27:44

      Like lithium or something.

   7. KDKarl Deisseroth27:45

      ... like lithium is, is a good example. Yeah.

   8. AHAndrew Huberman27:46

      Is it true that it was the, the urine of guinea pigs given-

   9. KDKarl Deisseroth27:49

      (laughs)

   10. AHAndrew Huberman27:49

       ... lithium that was given to manic patients that made them not manic? Is that true?

   11. KDKarl Deisseroth27:53

       I don't have firsthand knowledge of that, but, uh-

   12. AHAndrew Huberman27:55

       Okay.

   13. KDKarl Deisseroth27:55

       ... I would, I would defer that, uh, but it's, it's true for essentially every treatment. You know, the, the antidepressants originally, uh, you know, uh, arose as a- anti-tuberculosis drugs, for example, and-

   14. AHAndrew Huberman28:05

       I did not know that.

   15. KDKarl Deisseroth28:06

       ... yeah, and so this is a, it's a classic example for, uh, uh, and this, this is across all of, of psychiatry. Um, and of course, there's the seizures as well. That was noticed that patients who had epilepsy they, or, or had a seizure there, and also had depression, that they became much, uh, at least for a while, they were improved after the seizure.

   16. AHAndrew Huberman28:23

       That's amazing.

   17. KDKarl Deisseroth28:24

       Yeah.

   18. AHAndrew Huberman28:24

       I don't want to take you off-course of the question that... uh, answering the question I asked, but, um, I've heard before that if autistic children get a fever, that their symptoms improve. Is that true?

   19. KDKarl Deisseroth28:33

       I've, uh, I've done a fair bit of, of work with autism. Uh, um, in my clinical practice, I work with adult autism and I have heard, uh, statements like that and, and descriptions like that from, from patients and their, their families. Um, it's, uh, it's... that is very hard to study quantitatively, because often with the children you have this, uh, um, not as quantitative as you'd like collection of symptom information, uh, from, from, uh, from home. But I have heard that enough that I think there, there may well be something to that. And, you know, what is... a- anytime you have a fever, what's going on? Well, we know all the p- cells in the brain, and I know this as an electrophysiologist, if you just change the temperature by a few degrees, everything changes about how neurons work, and that's even just a single neuron. It's even more likely to be complex and different with a circuit of neurons that are all affecting each other. Just elevate the temperature a little bit, everything's different. And so, it's, it's plausible for sure that things like that could happen and do happen. Now, uh, but, and yet, when you think about autism, to take your example, yes, we see changes, but what is the element in the brain that's analogous to the pumping heart? When we think about the symptoms of depression, that's maybe, you know, we think about motivation and dopamine neurons. When we think about autism, it's a little more challenging. Um, you have... there's a, a deficit in, uh, social interaction and, and communication. And so where is that? Where is this (laughs) , where is that situated? What is the key principle, uh, governing the social interaction? Um, this is w- where we need the basic science to bring us a step forward, so we can say, "Okay, this is the process that's going on. This is what's needed for the incredibly complex task of social interaction, where you've got incredibly rich data streams of sound and meaning, eye contact, body movement," uh, and that's just for one person. What if there's a group of people? This is overwhelming for people with, with autism. What's the, what's the unifying theme there? It's a lot of information and, and that-... maybe is unmatched in any realm of biology, the amount of information coming in through a social interaction, particularly with words and, and language. And so then, that turns our attention as neuroscientists. We think, "Okay. Let's think about the parts of the brain that are involved in dealing with merging complex data streams that are very high in bit rate, but that need to be fused together into a unitary concept," and that starts to guide us, and maybe we can... and we know an- other animals are social in their own way and we can study those animals. And so that, there's, that's how I think about it. There's hope for the future, thinking about the symptoms as an engineer might, and trying to identify the circuits that are likely working, uh, to make this typical behavior happen, and that will help us understand how it becomes atypical.

   20. AHAndrew Huberman31:35

       So that seems like the first, to me, the first bin of this, what I call the bento box, uh, for lack of a b- a, of a better analogy, that we need to know the circuits. We need to know the cells-

   21. KDKarl Deisseroth31:46

       Yeah.

   22. AHAndrew Huberman31:46

       ... in the various brain regions and, and portions of the body, and, uh, and how they connect to one another, and what the patterns of activity are under a normal, quote-unquote, healthy interaction.

   23. KDKarl Deisseroth31:57

       Yeah.

   24. AHAndrew Huberman31:59

       If we understand that, then it seems that the next step, which of course could be carried out in parallel, right? That though, that work can be done alongside work where various elements within those circuits are tweaked just right, like the tuning of a piano in the subtle way, or maybe even like the replacement of a whole set of keys if the piano is lacking keys, so to speak.

   25. KDKarl Deisseroth32:20

       Right. Right.

   26. AHAndrew Huberman32:21

       You've been very involved in

8. 32:23 – 39:10

   Channelopsins: Tools For Understanding & Treating the Mind

   1. AHAndrew Huberman32:23

      trying to generate those tools. So, um, tell us about channelrhodopsins, why you created them, and where they're at now in the laboratory and perhaps also in the clinic.

   2. KDKarl Deisseroth32:38

      Well, this is a ... first of all, I give nature, uh, the credit for, for creating channelrhodopsins. These are beautiful, uh, little proteins that are made by algae, single-celled green algae, and it's a great story in basic science that our understanding of animal behavior, sensation, cognition, and action in our brains, all the way back to a botanist in the 1850s and 1860s in Russia is where the story begins. So this was a, a botanist named Andrei Famintsyn, who, uh, worked at St. Petersburg, and he, uh, had noticed in the river, uh, near his laboratory that there were algae that he could look at in a dish, in a saucer. He could put them there and when he had light shining from the side, the green, uh, tinge in the saucer of water, uh, would, uh, move to a particular distance from the light that he was shining from the side, which was an amazing thing. If he made the light brighter, uh, the green tinge would back off a little bit, to a more optimal location, so just the right light level. So this was plant behavior. It was light-driven plant behavior, and he delved into this a little bit and he identified that h- with mi- microscopy, he could see that there were little single-celled algae with flagella that were swimming, uh, to the, to the right light level, so behaving plants. And this has been the secret that's, that's helped us unlock, uh, so many principles of animal behavior. So, uh, turns out, uh, you know, these algae achieve this amazing, uh, result with a single gene that encodes a single protein. What's a protein? It's just a little biomolecule that does a job in a cell. And these are proteins that sit in the surface of cells, in their surface membrane, and when a photon, a light particle hits them, uh, they open a little pore, a little hole in the membrane, and charged particles, ions, like sodium, uh, rush across the pore. Now, why do they do that? They do that to guide their flagella. That signal coming in, those ions coming in through the pore in response to light, guide their flagellar motor that guides them to a particular spot, uh, in the saucer, okay? Now, that's plant behavior, but it turns out, as you know, uh, this movement of ions across the membrane, this happens to also be neural code in our brains for on or off. P- sodium ions rushing into cells turns them on, makes them fire away, fire action potentials communicate to the next cell down the, the, the chain, and this is an amazing opportunity because we can borrow these proteins. In fact, we can take the gene that directs the creation of the protein, and we can use genetic tricks, modern genetic tricks to put that gene into neurons in the brains of, of mammals, uh, uh, and then use light to turn those cells, the specific cells that we've put this gene into, turn them on. There are other w- uh, opsins we call them, that you can use to turn cells off. It's all fast, real time. You can play in patterns of activity in real time into cells or kinds of cells, just as a conductor elicits the music from the orchestra, the strings and the woodwinds and ... and, and you can see what matters, what matters for sensation, what matters for cognition, what matters for action, and we call this optogenetics.

   3. AHAndrew Huberman36:15

      Beautiful, and I must say it was quite a, an honor and a privilege to watch optogenetics move from idea to discovery to the laboratory. I think we were post-docs at the same time.

   4. KDKarl Deisseroth36:28

      Mm-hmm. Yeah. We were. Yeah.

   5. AHAndrew Huberman36:29

      Which is living proof that, uh, people move at different rates becau- (laughs) that's a, it's a joke a- at my expense by the way.

   6. KDKarl Deisseroth36:36

      (laughs)

   7. AHAndrew Huberman36:36

      Um, but it's real-

   8. KDKarl Deisseroth36:38

      So we end up in the same spot though. (laughs)

   9. AHAndrew Huberman36:39

      (laughs) Uh, yeah. More or less, uh, physically if not, um, professionally, but no- nonetheless, um, it's been a m- marvelous story thus far, and I'd like to, um, maybe you could give us ... I'd like to just touch on couple examples of where... the technology resides in laboratories now, so maybe the range of animals that it's being used in, and some of the phenomenon that, uh, channel op- channelrhodopsins and, um, and their related, uh, genes and proteins are, uh, starting to elicit, what you've seen.

   10. KDKarl Deisseroth37:09

       Mm-hmm.

   11. AHAndrew Huberman37:10

       Um, and then I'd like to talk about their applicability to the clinic, which is, I think the, the bigger mission, if you will.

   12. KDKarl Deisseroth37:18

       Yeah. So this is, uh, you know, this, this, uh, whole thing, uh, you know, it's been about now going on, uh, 17 years that we've been putting channelrhodopsins into neurons. It started just like Andre Flaminson's work in a, in a dish, uh, by 2000. That was in 2004. In 2007, we were putting these into behaving mice, and we were able to, to, with a f- give a, a switch cause them to move one direction or another. By 2009-

   13. AHAndrew Huberman37:45

       So basically con- you're controlling the mouse's behavior.

   14. KDKarl Deisseroth37:48

       Yeah. Exactly, in real time. So we could make a mouse that was just sitting there doing nothing to then turn left very consistently, in fact, go around in a circle, and as soon as we'd turn off the light, it would stop. That was an eye-opening moment. Uh, it took really a few years to make optogenetics work. Uh, there was a lot of putting all the... there were a lot of problems that had to be solved. These, these channelrhodopsins actually don't move many ions. They're, they have a, a small current, small conductance, as we say. And so we had to figure out ways to pack a lot of them into cells without damaging cells, and still make them targetable, so we don't want 'em to just be in all the cells, 'cause then it becomes just like an electrode. You're just stimulating all the cells that are nearby. We had to keep that specificity, make them targetable to just one kind of cell or another, while still packing in large numbers of them into those cells, and we had to get in the light in safe and specific ways. And so it took probably about four or five years to really create optogenetics between 2004 and 2009. By the end of that time though, we had, uh, all the basic light delivery, gene delivery, uh, principles worked out, and people started to apply the technology to, uh, to fish, to rats, to mice, uh, to, uh, non-human primates, uh, like monkeys.

9. 39:10 – 41:58

   Curing Blindness with Channelopsins

   1. KDKarl Deisseroth39:10

      And just, uh, a couple, uh, months ago, uh, my colleague, uh, Botond Rasca in Switzerland, uh, succeeded in putting, uh, channelrhodopsins into the eyes of human beings and making a blind person see. And so that's pretty, uh, cool. Uh, this was a patient, a patient with retinal degeneration, and he was provided a channelrhodopsin into the eye of, of this patient, and was able to confer some light sensitivity onto this patient that wasn't there before.

   2. AHAndrew Huberman39:38

      An amazing paper and discovery. I didn't realize it was one patient, but it's such an important milestone, and yeah.

   3. KDKarl Deisseroth39:44

      Well, it's a, as you say, it's a very important milestone, and, and the, the history of that is, is very deep. Uh, almost 10 years earlier, uh, Botond Rasca and I had published a paper in science in human retina, but explanted, taken from cadavers, from someone who had died, the living retina taken out, uh, um, opsins put into this, uh, uh, retinal tissue, and showing that it, that it worked, recording from the cells, showing that in these human neurons, retinal neurons, that you could get light responses. But then from that moment, you know, almost 10 years of, you know how clinical d- development goes, and this is a, a gene therapy, so you've got to, all, all the regulations, and concerns, and all that. It took almost 10 years to get to, to this point now where a living, uh, human being, uh, has a new functionality that, that wasn't there before. Now, that's incredibly inspiring, you know, uh, and, uh, it's a, it's a, it's a beautiful thing. I would say though that, the, the broader significance of optogenetics is really still understanding, because once you understand how the circuitry works and which cells actually matter, then any kind of treatment becomes more grounded, and logical, and specific, and principled. And whether it's medication, or talk therapy, or brain stimulation treatment with electrical or magnetic means, if you actually know what matters, that is incredibly powerful. And I think, no, no, uh, you know, not intended to disparage this, the beautiful, you know, retinal work and, and conferring, you know, vision on, on someone who, who couldn't see. Of course, that's wonderful. But, and that's direct, what you might call direct optogenetics in patients. Indirect is everything that comes from understanding. You know, okay, we know these cells matter now for this symptom. Well, how can we target those, those cells and help them work better in patients by any means? And I think that's the, the broader significance of optogenetics clinically.

   4. AHAndrew Huberman41:39

      You and I know Botond well, and, um, you and Botond share, uh, this incredible, uh, big vision that, uh, I think only a clinician can really understand, you know, being in close contact with, and, uh, the suffering of patients as a ultimate motivator of developing technologies, which

10. 41:58 – 47:10

    Why Karl Became a Scientist

    1. AHAndrew Huberman41:58

       makes me have to ask, did you decide to become a scientist to cure, find cures for mental disease?

    2. KDKarl Deisseroth42:06

       (laughs) Uh, uh, no, I didn't. Uh, it's a, it's a really important question to actually look back and, and see the steps that brought you to a particular place, and that was not, uh, what brought me, uh, initially to science. And, and it's okay to, I think, to embrace (laughs) the twists and turns that life, uh, brings, uh, to you. But I was always interested in the brain. And so, uh, that was something that, for me, started from a, a very early age. I was, you know, we talked about being introspective. I, I noticed very early on, I had a, a deep love of, of poetry, and, and stories, and I, I was a voracious reader. Um, and I was-... amazed by how words could, could make me feel in particular ways, just the ... even, even separate from their, you know, d- of course dictionary meanings, the, the rhythm and how they work together, even separate from meaning. Um, and I was stunned by poets that could use words in new ways, that were even divorced from their meaning at all, and yet could still trigger specific emotions, and I was ... uh, that was ... this was always fascinating to me. So, uh, you know, I, I wanted to understand that, and so I was interested in, in, in ... I became interested in the brain and I thought, "Well, I'm going to have to study the human brain, uh, because only human beings can, uh, describe what's going on inside, uh, enough." So in, in college I began to steer myself toward, uh, medicine, and with the idea of becoming a neurosurgeon, and so I, I, uh, I came here, uh, to, uh, medical school, uh, and did an MD PhD program, uh, planning neurosurgery all the way through. The first rotation I did at the end of medical school, as you know, you do rotations, you go through different specialties and some of these are required rotations that everybody has to do, some are elective where you can, you can pick what you want to do. Uh, I elected to do neurosurgery first, (laughs) even before regular surgery, I was that sure I wanted to do it, and I loved it. I had a fantastic time. There was an amazing patient who had a, a thalamic damage and there was a neglect syndrome where the patient, you know, was not able to be aware of something that was, you know, right in front of him.

    3. AHAndrew Huberman44:24

       Even though their vision was perfectly fine.

    4. KDKarl Deisseroth44:26

       Even though their vision was perfectly fine-

    5. AHAndrew Huberman44:27

       Yeah.

    6. KDKarl Deisseroth44:27

       ... exactly. Um, and so I was ... and, and I loved the operating room, I loved, uh, the, the, the rhythm of, of suturing and the precision of it, and, uh, and I loved being able to help patients immediately. But then a, a required, uh, rotation was in psychiatry, which I was not looking forward to, uh, at all. And that, uh, completely reset my, my whole life, that, that experience in psychiatry, and, and it was, it was the ... at that moment that I saw this is, first of all, the greatest need, the, the depth of suffering and the, and the depth of the mystery together, and also it was ... and I almost feel a little guilty about this, it's so interesting too. You know, it ... yes, yes, there's ... yes, we can help. Yes, there's need, but as a scientist, this is, uh, amazing that someone's reality can be different from my own. You know, with, with everything physically, as far as we can tell, the same, uh, with, you know, the measures we have, and yet we've got a different reality. That is an amazing thing, and if we can understand that and help these people, that would be, uh, just, uh, you know, more than anybody could ask for. And so that's, that's how I ended up, uh, taking this path, just a, uh, uh, a required rotation in psychiatry.

    7. AHAndrew Huberman45:46

       It all started with poetry.

    8. KDKarl Deisseroth45:48

       And it started with poetry.

    9. AHAndrew Huberman45:49

       Yeah. Out of, out of, um, respect for poetry, are, are there any favorites that you spend time with, uh, on a regular basis?

    10. KDKarl Deisseroth45:57

        I mean, the, the ones who, who got me down this path, uh, early on, I remember in, in childhood, in high school, uh, uh, Borges had an i- immense influence on me. Um, I, I, I studied Spanish all the way through and, and, and, uh, reading his work. He was a, uh, a great writer. He wrote both in, in English and in Spanish, and, and being able to appreciate his poetry both in English and in Spanish was, was a pretty amazing thing. Not many, uh, poets can, can do that.

    11. AHAndrew Huberman46:25

        You're bilingual.

    12. KDKarl Deisseroth46:26

        I s- I've ... I'm not ... I've ... I wouldn't say now, I, I became ... uh, at one point I was effectively fluent in Spanish, um, and I have ... I'm pretty good with medical Spanish still because, uh, you know, we use, uh, Spanish all the time in the ... in the, in the clinic here. Uh, I, I wouldn't claim full fluency but it's something I can ... I definitely use all the time, um, and it's been very helpful in the clinic.

    13. AHAndrew Huberman46:45

        Yeah. Borges is wonderful. As the son of an Argentine, I grew up hearing about it and, uh, I learned that Borges' fav- favorite city was Geneva.

    14. KDKarl Deisseroth46:53

        Oh.

    15. AHAndrew Huberman46:53

        So I spent time in Geneva only for that reason.

    16. KDKarl Deisseroth46:56

        (laughs)

    17. AHAndrew Huberman46:56

        It also turns out to be an interesting city.

    18. KDKarl Deisseroth46:58

        Yes.

    19. AHAndrew Huberman46:58

        Um, so you developed methods to control neurons with these algae proteins using light.

    20. KDKarl Deisseroth47:09

        Yep.

11. 47:10 – 54:12

    Vagus Nerve In Depression

    1. KDKarl Deisseroth47:10

    2. AHAndrew Huberman47:10

       In 2015, there was, uh, this, uh, what I thought was a very nice article published in The New Yorker, um, describing your work and the current state of, um, your work in, in the laboratory, in the clinic, and an interaction with a patient, so this as I recall, a woman who was severely depressed, and you reported in that article some of the discussion with this patient, and then in real time, increase the activation of the so-called vagus nerve, this 10th cranial nerve that extends out of the skull and innervates many of the, the viscera and, and body. What is the potential for channelrhodopsins or related types of algae engineering to be used to manipulate the vagus, because I believe in that instance, it wasn't channelopsin stimulation-

    3. KDKarl Deisseroth47:59

       Right.

    4. AHAndrew Huberman47:59

       ... it was electrical stimulation, right?

    5. KDKarl Deisseroth48:00

       Right.

    6. AHAndrew Huberman48:00

       Or to manipulate, for instance, a very small localized region of the brain. Let me fr- re- frame it a little bit differently, in light of what we were talking about a couple minutes ago. My understanding is that if somebody has severe depression and they take any number of the available pharmaceutical agents that are out there, SSRIs, serotonergic a- agents, increased dopamine, increased whatever, that sometimes they experience relief, but there are often serious side effects. Sometimes they don't experience relief. But as I understand it, channelopsins and their related technology, in principle, would allow you to turn on or off the specific regions of the brain that lead to the depressive symptoms, or maybe you turn up a happiness circuit or an ... or a, uh, a positive anticipation circuit. Where are we at now in terms of bringing this technology to the nervous system? And let's start with body, and then move into the skull.

    7. KDKarl Deisseroth48:58

       Yeah. So starting with the body is a good example because it- it, uh, highlights the opportunity and- and how far we have to go. So let's take this example of vagus nerve stimulation. So the vagus nerve, it's the 10th cranial nerve. It comes from the brain, it goes down, it innervates the heart, innervates the gut. And by innervate I mean it sends little connections down to help, uh, guide what happens in these- these organs in the- in the- in the abdomen and- and chest. Uh, it also collects information back, and- and there's information coming back from all those organs that go, also go through this vagus nerve, the 10th cranial nerve back to the brain. And so this is somewhat of a- of a- of a superhighway to the brain then, was the idea. And maybe the idea is, maybe we could put a little cuff, a little electrical, uh, uh, device around the vagus nerve itself and maybe have just like a pacemaker battery, have a little power source here under the clavicle, everything under the skin, and have a little, uh, cuff and- and drive signals, and maybe they'll get back to the brain. So a way of getting into the brain without putting something physical into the brain.

    8. AHAndrew Huberman50:03

       And why the vagus? I mean, it's there but... and it's accessible.

    9. KDKarl Deisseroth50:06

       That's the reason. (laughs)

    10. AHAndrew Huberman50:07

        Uh, that's the reason?

    11. KDKarl Deisseroth50:08

        That's the reason, yes.

    12. AHAndrew Huberman50:09

        Really?

    13. KDKarl Deisseroth50:09

        Yeah.

    14. AHAndrew Huberman50:10

        You're not kidding?

    15. KDKarl Deisseroth50:10

        I'm not kidding.

    16. AHAndrew Huberman50:11

        So stimulating the vagus to treat depression simply because it's accessible.

    17. KDKarl Deisseroth50:15

        It started as, actually as- as an epilepsy, uh, treatment, and- and it can help with epilepsy, but, uh, yes, simply because

    18. NANarrator50:22

        ... it's accessible.

    19. AHAndrew Huberman50:22

        You got- you got to love medicine. As a scientist, I got... this is where I get to chuckle and just say, I'm in the field of medicine from that perspective. From- from the perspective of a scientist, an outsider, the field of medicine as a field that goes in and tickles pathways because they're there, it's, um, I don't know what to s- say. It's, um, sh- a little shocking.

    20. KDKarl Deisseroth50:44

        Yeah.

    21. AHAndrew Huberman50:45

        Um, and we o- at least in my laboratory, I always say, "You never do an experiment because you can, you- you do an experiment to test a specific hypothesis."

    22. KDKarl Deisseroth50:56

        Yeah. Yeah. I mean, we... there are- there are stories people tell. So the- the soli- the- the vagus nerve lands on a particular spot on the brain called the solitary tract nucleus, which is just one synapse away from the serotonin and dopamine and norepinephrine.

    23. AHAndrew Huberman51:10

        So there's a link to chemical systems in the brain-

    24. KDKarl Deisseroth51:13

        Yeah. Yeah.

    25. AHAndrew Huberman51:13

        ... that make it a rational choice?

    26. KDKarl Deisseroth51:14

        It... yes. It's not, it's not irrational. But I can tell you that even if that were not true, the same thing would have been tried. (laughs)

    27. AHAndrew Huberman51:21

        (laughs) You guys would have done it anyway.

    28. KDKarl Deisseroth51:22

        Because it's accessible. Yeah.

    29. AHAndrew Huberman51:24

        I see. Okay.

    30. KDKarl Deisseroth51:25

        And- and- but- and- and why? Well, it's- it's... and not to, again, not to disparage, uh, what- what's been happening in this branch of medicine. There is immense suffering, treatments, many treatments don't work, and- and w- we try things. And- and this is how s- so many advances in medicine happen. You think about, uh, kidney dialysis which has kept many people alive. That- that was just started by someone saying, "Hey, let's- let's try this. Maybe there's something building up in the blood. Maybe we can dialyze something and help them." Yeah, it worked, and- and it was just sort of a test pilot mentality. We can- we can access the blood. Let's run it across a dialysis membrane, put it back in the body. Oh my god, that actually works. And sometimes you do need that- that test pilot mentality, of course, to do it in a- in a rigorous, safe, controlled way-
12. 54:12 – 58:34

    Challenges To Overcome for Treating Mental Illness with Channelopsins

    1. AHAndrew Huberman54:12

       I see two other, uh, steps that are required. One is to get the channelopsin gene into the cell. In the case of Boton-Roska and colleagues, uh, rescuing vision in this patient, um, they did that by an injection of a virus that doesn't damage the neurons, the virus itself is fairly innocuous, um, but carries a cargo, and it's a one-time injection. The cells express and then they used light to stimulate. So, um, let's say, uh, I'm depressed, um, which I don't think I am, although now sitting in front of-

    2. KDKarl Deisseroth54:42

       (laughs)

    3. AHAndrew Huberman54:42

       ... a psychiatrist, uh, you probably can see signs that maybe I am or maybe I'm not, but, uh, let's say we put channelopsin into my, uh, a specific branch of the vagus that we understand is responsible for mood, um, how are we gonna get it in there, and then how are we gonna deliver the light? 'Cause we're not talking about sunlight or standing in front of a light bulb necessarily-

    4. KDKarl Deisseroth55:04

       Okay.

    5. AHAndrew Huberman55:04

       ... but w- what are- what are the mechanisms for the body?

    6. KDKarl Deisseroth55:07

       Yeah. So we had to solve exactly these questions you're saying. How do you get the light in? How do you get the gene in, in a- in a potent and robust and safe way?And it's, that's now solved and that's not, uh, a challenge. So, there are very safe, well-tolerated, um, uh, gene delivery mechanisms that are called adeno-associated viruses, AAVs, and these are, uh, things that are, are associated with the common cold. They themselves don't cause, uh, any symptoms. They've been engineered, and there's been a broad community of, of viral engineering that's been going on for decades, making these, uh, safer, well-tolerated, and, and so on. We can put the channelrhodopsin gene into these, uh, viral vectors, uh, that deliver the, the gene, uh, and we can have little bits of additional DNA that govern expression only in one kind of cell but not another. These are called promoters and enhancers. All genetic tricks built up by a very broad community of, uh, of great scientists over the decades. We can put these different bits of DNA, package them into this AAV, this little virus, and that, uh, can be then injected, uh, into a particular part of the body. Uh, and sticking with this vagus nerve example, we know that there are particular clumps of neurons, there's one called the nodose ganglion, uh, that has a clump of cells related to the vagus nerve, and you could, for example, target a little injection into that ganglion, but-

    7. AHAndrew Huberman56:36

       Would that be an outpatient procedure?

    8. KDKarl Deisseroth56:37

       Yeah. Yeah.

    9. AHAndrew Huberman56:38

       So you come in in the morning, get your injection, maybe walk out a few hours later?

    10. KDKarl Deisseroth56:41

        Yeah. That's right. And so that's the gene. Um, then the light delivery, this is also something that, that, uh, we worked out. We've worked on making very, very light-sensitive opsins. One challenge, and, and Botond, uh, uh, would be the, the first to state this in fact, (laughs) in solving this problem for the patient, he had to build, uh, goggles that, uh, created much bright- much brighter light than normal ambient light, uh, delivery. Because, as I mentioned earlier, you have to pack a lot of these channelrhodopsins in, they don't have much current. You have to really make sure that you've got a, intense enough light to activate enough of them to cause a stimulation in some cell-

    11. AHAndrew Huberman57:21

        And it has to be the right wavelength, correct?

    12. KDKarl Deisseroth57:23

        Has to be the right wavelength.

    13. AHAndrew Huberman57:23

        In going back to your example of the algae moving toward or away-

    14. KDKarl Deisseroth57:27

        Yeah.

    15. AHAndrew Huberman57:27

        ... uh, uh, the light, it, it has to be tuned just right. So could you, uh, could... I'm imagining in my mind, as a non-engineer, I know you're (laughs) also a bioengineer, the, uh, I'm imagining a little tiny, um, blue light emitting, um, thing, object, that's a little bigger than a clump of cells, or maybe about the size of a clump of cells. And for those who don't know, you know, uh, your cr- credit card is about 200 mi- um, microns thick on the side, and a micron is a thousandth of a millimeter, and so we're talking about a little tiny stamp, um, that's basically, uh, half a millimeter in size, um, all around.

    16. KDKarl Deisseroth58:10

        Yeah.

    17. AHAndrew Huberman58:10

        Each edge, half a millimeter in size. C- I could imagine that being put under my skin-

    18. KDKarl Deisseroth58:14

        Yeah.

    19. AHAndrew Huberman58:14

        ... and then I would, what I, uh, hit an app on my phone, and I'd say-

    20. KDKarl Deisseroth58:18

        (laughs)

    21. AHAndrew Huberman58:18

        ... I'd say, "Dr. Deisseroth, I'm not feeling great today. Can I increase the stimulation?" And you say, "Go for it." And then I ramp it up? Is that how it would go?

    22. KDKarl Deisseroth58:26

        I mean, that's effectively what we already do with the vagus nerve stimulation. The, the doctor in this case, and I, I have this in some of my patients in the clinic, I do vagus nerve

13. 58:34 – 1:00:52

    Using the Dialogue with Patients to Guide Treatment

    1. KDKarl Deisseroth58:34

       stimulation. I talk to them, I say, "How are..." I, I go through the symptoms. I, I use the psychiatric interview to elicit their internal states. And then I have a radio frequency controller that I can dial in, kno-

    2. AHAndrew Huberman58:45

       Right there in real time.

    3. KDKarl Deisseroth58:46

       Right there in real time.

    4. AHAndrew Huberman58:47

       You're holding the remote control-

    5. KDKarl Deisseroth58:48

       Yeah.

    6. AHAndrew Huberman58:48

       ... es- essentially to their brain. Although it's remote, remote control.

    7. KDKarl Deisseroth58:51

       Yeah. Yeah. Through a couple steps, but yeah.

    8. AHAndrew Huberman58:52

       Yeah. Yeah. Yeah.

    9. KDKarl Deisseroth58:53

       And I can, I can turn up, I can turn up the frequency, I can turn up the intensity, uh, all with the radio frequency, and, uh, uh, control, and then it's, it's reprogrammed or, uh, redosed, uh, and then the patient can, can then leave at this altered dose. And-

    10. AHAndrew Huberman59:09

        So this is happening now?

    11. KDKarl Deisseroth59:10

        This is happening right now, electrically.

    12. AHAndrew Huberman59:11

        Yeah. You do this routinely?

    13. KDKarl Deisseroth59:12

        I do it routinely in my clinic, electrically. Yeah.

    14. AHAndrew Huberman59:14

        And you're getting the verbal content, which as you described earlier, is the indication of how well something is working in real time.

    15. KDKarl Deisseroth59:23

        Yes.

    16. AHAndrew Huberman59:23

        So this wa- maybe you could just describe a little bit of the interaction with that particular patient, or a, or another patient. What- what's a typical arc of, um, narrative w- as you go from no stimulation to increased stimulation?

    17. KDKarl Deisseroth59:36

        In most, in most patients, uh, the actual therapeutic effects, the benefits actually take, uh, uh, many days to weeks. Um, and so what I'm mostly focusing on in the office in real time is making sure I'm in a safe, low side effect, uh, regime. And so first I talk to the patient, you know, how, who, who has been on a particular dose of the stimulation for weeks or, or, or longer, and I, I, I talk about symptoms. "How were things over the past, uh, month? How was your hope? How was your energy level? Uh, sleep, uh, you know, h- what is your mood?" Um, and, and then we talk with the patient. We decide, oh, this is, this is not yet where we'd like to be. And so then I can turn up the intensity of the stimulation real time in the office. I don't, i- in most patients, I don't expect an immediate mood change. What I do is I increase the, the dose until, uh, uh, to a next level up while asking the patient for side effects. "Can you still breathe okay? Can you still swallow okay?" And I can hear their voice as well, and, and I can get a sense-

    18. AHAndrew Huberman1:00:32

        And you're looking at their face.

    19. KDKarl Deisseroth1:00:33

        ... and I'm looking at their face.

    20. AHAndrew Huberman1:00:34

        Yeah.

    21. KDKarl Deisseroth1:00:35

        And so I can get a sense, is there a, uh, am I in a, still in a safe side effect, uh, regime? And I, and, and, and then, you know, I, I, I stop at a particular point that looks safe, and then patient goes home, comes back a month later, and I get the report on how things were over that month.

14. 1:00:52 – 1:06:04

    How Our Eyes Reveal Our Mental Health

    1. KDKarl Deisseroth1:00:53

    2. AHAndrew Huberman1:00:53

       Uh, I asked, uh, if you're looking at their face, 'cause in your book, um, you describe the incredible complexity of social interactions, and at one point, you described the incredible amount of information that the eyes inform about the brain, and the, and the context of somebody's inner experience, whether depressed or happy or otherwise.

    3. KDKarl Deisseroth1:01:16

       Yeah.

    4. AHAndrew Huberman1:01:17

       I want to make sure that we-... get back to how to maneuver them, the, and manipulate the nervous system for sake of mental health. But what are you looking for? So as a vision scientist, I think, you know, pupils dilating is a sign of arousal, but that could be a positive arousal, positive valence, like excitement, or it could be terror.

    5. KDKarl Deisseroth1:01:38

       Yep.

    6. AHAndrew Huberman1:01:38

       You're going to get the same dilation of the pupils. Um, and, and I'm always reminding people that these two little goodies are two pieces of brain, basically. They're just outside the cranial vault. So they're not unlike the vagus in that sense, but they're more of a report than a control knob, although they, I like to think they could be used as control knobs too. Um, so without putting you on the spot, again, to diagnose me-

    7. KDKarl Deisseroth1:02:01

       (laughs)

    8. AHAndrew Huberman1:02:01

       ... uh, something I would never ask you to do, uh, with the cameras rolling, but, um, what are you looking for that the patient might not be aware of? In other words, can you see depression in somebody's eyes, and if you know a patient or if you don't, can you see it in their body posture when they walk in? Realizing, of course, that a trained psychiatrist, like yourself, develops an intuitive sense that's aggregating lots of different features of a patient.

    9. KDKarl Deisseroth1:02:28

       Mm-hmm. Yeah.

    10. AHAndrew Huberman1:02:29

        But what about the eyes? What's, what's going on there?

    11. KDKarl Deisseroth1:02:31

        Yeah. The eyes are incredibly rich in information, and, uh, as you, as you alluded to though, it's not as if any one measurable conveys all the information you need. It's what we, you know, what, what an engineer would say, joint statistics. It's- it's-it's many things all at once, whether they're in synchrony or out of synchrony, that- that actually, uh, turns out to matter. And, uh, you know, the eye contact question, we all know eye contact is incredibly important. You don't feel you've connected with- with somebody unless you- unless there's eye contact. But eye contact can go awry too. It- it can be, um, it can be too intense or it can be mistimed, or if there's, uh, someone with autism, it can be barely there at all. And- and this is one of the most striking symptoms of autism is the, uh, avoidance of- of eye contact as if it's, um, as if- as if it, almost as if it's a harmful, uh, uh, quantity. And so there's an im- immense amount of information you con- you get from the eyes, uh, but it's- it's the pairing of what's going on in the eyes with everything else going on, the body language, the what's, the verbal content of what's- what's coming out. All that together is- is- is- is the art of- of psychiatry and- and social interaction. But, you know, sometimes you don't have the eye contact, and this is, uh, an amazing thing, and I do talk about this in the book as well. In- in many cases, you know, in psychiatry, sometimes it's over the phone that you have to, uh, make key decisions. And as a ... and I recall, you know, vividly being as a resident, uh, very often you have to take these phone calls from, uh, uh, people who are not in the hospital, people you can't see, you know, you can't see their eye, you can't see their body, anything about them, just the sound of their voice, and you can ask them questions and you have to make, in some cases, life or death decisions, you know. Is this person truly suicidal? Something like that, uh, as it comes up all the time. And so I developed over the course of training, uh, uh, and I think all- all psychiatrists do this, is you develop a way to- to ... whatever data stream you have, whether it's the eyes or whether it's just the sound of a voice coming over the phone, you learn to home in on that data stream you have and focus on it and identify changes. And it's quite amazing. Uh, I- I found that you- you can actually, uh, if you know a patient, you can detect very precise changes in mood just from the sound of the voice, and- and you can have a- a- a realization that, oh, this patient's depression has improved, you know, by- by about half just by the tone of their- of their voice. And same with eyes, you can ... with enough practice, you can get enou- enough information from a single data stream to give you some information. But when you do have the whole picture, that, of course, is best. Mm-hmm. So, um, so many theories out there about, um, excessive blinking and lying, uh, lack of blinking and sociopathy. Um, I like to remind people that, uh, people have varying degrees of lubrication of the eyes- (laughs)

    12. AHAndrew Huberman1:05:43

        ... which also influence the frequency of blinking and presumably have nothing to do with, uh, whether or not what they're saying is true or not. Uh, but in- incredible nonetheless that it's, that the eyes are a portal to overall arousal state. I'm fascinated by the effects of light on circadian biology and just overall desire to be awake or asleep, et cetera. Um,

15. 1:06:04 – 1:08:23

    Controlling Structures Deep In the Brain

    1. AHAndrew Huberman1:06:04

       so the eyes are on the outside of the cranial vault. The vagus is outside, uh, the, uh, the cranial vault, obviously. Um, what about the goodies in here? Um, Parkinson's, we know the, at least one of the major sites of degeneration and failure that lead to those symptoms. Um, y- I can name off any number of other things. In your book, you talk about the beautiful work done with optogenetics of active versus passive coping, that there are areas of the brain like the habenula that make, uh, when active make animals and presumably people, uh, passive and unwilling or uninterested in fighting back against pressures of life, whereas another region, the raphe, you stimulate that, and- and they actively cope. They- they get their grit going, and they- and they are able to lean into life. So how do, how does one get to those structures in a, in a focused way, and, um, w- what- what does the next two to five to 10 years look like?

    2. KDKarl Deisseroth1:07:02

       Yeah. Well, this is the- this is the promise on that, and it is on that time scale, uh, that I think things may start to play out. You know, the- the specificity of optogenetics, uh, is really only useful if you have some idea of how to use that specificity, um, and-E- it's an actually, it's a frustrating aspect of psychiatry, that in many cases, the most effective treatments we have, have the least specificity, e- electroconvulsive therapy being a great example, where you're causing a brain-wide seizure.

    3. AHAndrew Huberman1:07:34

       Which looks barbaric, but as you mentioned, is effective.

    4. KDKarl Deisseroth1:07:37

       I mean, it is, it, it, these days, it's, it's much more clinically, uh, you know, safe and stable.

    5. AHAndrew Huberman1:07:41

       It doesn't look like One Flu-

    6. KDKarl Deisseroth1:07:42

       No.

    7. AHAndrew Huberman1:07:42

       ... the last scene in la-

    8. KDKarl Deisseroth1:07:43

       No.

    9. AHAndrew Huberman1:07:43

       ... One Flew Over the Cuckoo's Nest.

    10. KDKarl Deisseroth1:07:45

        No, it doesn't. Now, it's a very clinically, uh, safe and stable procedure, but I, I, what, where I, I, I would say yeah, it is, it is g- it's got this almost medieval lack of, of specificity, even if the procedure's well-controlled and, and clinically safe and stable, and it, it has a ... it's not very specific. You're causing a brain-wide seizure. How, how could you be less specific than that?

    11. AHAndrew Huberman1:08:06

        And we don't know the, the, the source of the relief.

    12. KDKarl Deisseroth1:08:09

        We don't, we don't know-

    13. AHAndrew Huberman1:08:09

        Presumably it's a dump of neuromodulators like dopamine and serotonin, but we don't really know.

    14. KDKarl Deisseroth1:08:13

        The, we, there certainly is a dump of neuromodulators.

    15. AHAndrew Huberman1:08:14

        Okay.

    16. KDKarl Deisseroth1:08:14

        We don't know that that's the, the, the cause for the relief. Uh, and likewise with medications, this is an also an interesting thing, some,

16. 1:08:23 – 1:09:50

    The Most Effective Drugs Often Have the Most Side Effects

    1. KDKarl Deisseroth1:08:23

       some of the most effective antidepressants, some of the most effective antipsychotics are the ones that are, have the most side effects, and many examples of this, for example, the most effective antipsychotic is something called clozapine, which has, it unquestionably has the most side effects. It had terrible, terrible side effects.

    2. AHAndrew Huberman1:08:41

       The D4 antagonist?

    3. KDKarl Deisseroth1:08:42

       It has m-

    4. AHAndrew Huberman1:08:42

       Yeah.

    5. KDKarl Deisseroth1:08:43

       ... basically every receptor. (laughs)

    6. AHAndrew Huberman1:08:44

       Does it really?

    7. KDKarl Deisseroth1:08:45

       Yeah. It acts-

    8. AHAndrew Huberman1:08:45

       Interesting.

    9. KDKarl Deisseroth1:08:46

       Yeah, it, uh, it has prominent serotonin, prominent muscarinic, uh, certainly acts on dopamine receptors, but, uh, it ha- it ha- it causes, uh, you know, blood, uh, blood cell, uh, counts to change. (laughs)

    10. AHAndrew Huberman1:08:58

        How do people feel ... so if, if, if, um, if I were schizophrenic, and uh, I was getting auditory hallucinations, et cetera, and I took clozapine, um, w- what could I expect to feel?

    11. KDKarl Deisseroth1:09:10

        Well, uh, so you would notice, uh, side effects, and you would notice resolution of, of symptoms both, and, and-

    12. AHAndrew Huberman1:09:16

        So the voices would go away-

    13. KDKarl Deisseroth1:09:17

        Yeah.

    14. AHAndrew Huberman1:09:18

        ... i- in, in a good situation, the voices would go away.

    15. KDKarl Deisseroth1:09:21

        That's right. That's right.

    16. AHAndrew Huberman1:09:21

        But I would feel not good in my body?

    17. KDKarl Deisseroth1:09:23

        You would have, uh, you might have dizziness. You might have, uh, uh, drooling. You might have, uh, any number of, of, uh, uh, uh, physical sensations that, that would be due to these off-target effects, the, the medication acting on these other receptors that-

    18. AHAndrew Huberman1:09:40

        And I'm certainly not suggesting this, but what if somebody without schizophrenia took clozapine?

    19. KDKarl Deisseroth1:09:44

        Uh, they have the same side effects presumably, yeah, and so it would not be something that, that I would

17. 1:09:50 – 1:14:15

    Do Psychiatrists Take the Drugs They Prescribe?

    1. KDKarl Deisseroth1:09:50

       recommend. Um-

    2. AHAndrew Huberman1:09:50

       Yeah. Do psychiatrists take the drugs that they prescribe?

    3. KDKarl Deisseroth1:09:53

       (laughs) .

    4. AHAndrew Huberman1:09:53

       I just finished up for the third time, uh, Oliver Sacks' um-

    5. KDKarl Deisseroth1:09:57

       Yeah.

    6. AHAndrew Huberman1:09:57

       ... autobiography, which is marvelous, and, and I highly recommend to people. Um, he certainly took a lot of drugs. Um, h- not as part of his professional role.

    7. KDKarl Deisseroth1:10:07

       Yeah.

    8. AHAndrew Huberman1:10:07

       Um, but wh- uh, just out of curiosity, what is the interest or kind of role of, of drugs in the field of psychiatry? Because for, I would imagine for a group of very curious, introspective people who are making recommendations about what to take, there could actually be some benefit for understanding what the experience of those drugs was like for their patients.

    9. KDKarl Deisseroth1:10:27

       I think that's, that's true, and I, I will say that probably many or most psychiatrists have, uh, uh, you know, sampled a number of these for exactly the reason that you're saying is, is to understand better and to help treat their patients better, and I've, I've spoken to people who have, you know, really been, uh, uh, have found this very helpful to know, okay, this, this sleep disruption caused by this medication, or the libido disruption caused by this other medication, wow, that is, that is a big effect, and, and, and it really helps with empathy for the, for the patients to understand, uh ...

    10. AHAndrew Huberman1:10:59

        I'm not s- I'm not suggesting that, uh, physicians or anybody, um, uh, experiment with drugs, but I, but I am relieved to hear that, because I think that when you're talking about ac- accessing somebody's mind and their basic physiology, as you mentioned re- related to appetite, libido, and sleep, you really, you're really, um, one is acting as a mechanic of, of their, the person's whole experience. They walk out of the office and they have a, a life experience, um, that extends beyond the script.

    11. KDKarl Deisseroth1:11:25

        Yeah.

    12. AHAndrew Huberman1:11:26

        Yeah.

    13. KDKarl Deisseroth1:11:27

        And so, and yeah, and so that's, so w- at, at the same time though, you can't let that completely guide your clinical decisions, because as I mentioned, some of these medications that have the most side effects, they are also the most effective. And clozapine's a great example. That will work in patients where nothing else works, and believe me, we don't take the step of, of clozapine, uh, prescription lightly, because of all these, these side effects. You have to come in for a weekly blood cell, uh, or every few weeks, a blood cell check to make sure that the blood counts are not off, uh, for example, but there are patients where no other medication works for the schizophrenia and clozapine works amazingly well.

    14. AHAndrew Huberman1:12:01

        And it's marvelous.

    15. KDKarl Deisseroth1:12:01

        And, and, and so we do it even though there are the side effects, and so then this comes back to your, your question, what if we had better and better specificity? Well, only if we know exactly what we're doing is the point, and so because as we become more refined, uh, we better be right about where we're refining to.

    16. AHAndrew Huberman1:12:19

        Mm-hmm. And you imagine a day where it will be a single, um, maybe even outpatient neurosurgery would go in through the skull or the back of the ear, deliver a small viral injection of one of these adenoviruses, a little sticker of light-emitting diode, is that, um, deep in the brain? Is that how you envision this someday?

    17. KDKarl Deisseroth1:12:36

        Tha- that certainly could happen. What I, what I actually, uh, prefer as a vision is, is still medications, uh, because, uh, those are, you know, minimally invasive. Uh, if we knew what we were doing, we could make them more specific, uh, have fewer side effects. But optogenetics, that'll arm us with true causal understanding, and so we'll know, uh, and we're already moving rapidly toward this point, we'll know, okay, this symptom, the loss of pleasure in life that we call anhedonia or the loss of, of motivation, or, or, or energy to overcome challenges, active coping. Um, these are largely subserved, largely controlled by this circuit or that circuit or the cell that inhabits this other circuit.

    18. AHAndrew Huberman1:13:24

        And we will know that because of the work done with channelopsins.

    19. KDKarl Deisseroth1:13:27

        Exactly. Yeah, exactly.

    20. AHAndrew Huberman1:13:28

        Yeah, I agree. Yeah.

    21. KDKarl Deisseroth1:13:28

        In ways that we, we never could have the confidence, uh, otherwise, uh, and so we'll know that this is the circuit that, that underlies the symptom or its resolution. And then-... we'll get to understand these cells very deeply. Okay, these cells that are causal, that do matter, who are they? What are they- what's their wiring? What are the proteins that they make? What are the little things that are on the surface of the cell that could be receptors for specific medications, or combinations of receptors that would give us the specificity we need? And then armed with that causal and precise and rigorous knowledge, then you can imagine medication development becoming totally different. No longer serendipitous, but truly grounded in causality.

18. 1:14:15 – 1:16:00

    Moving From Experimental Tools To Novel Treaments

    1. KDKarl Deisseroth1:14:15

    2. AHAndrew Huberman1:14:15

       I see. So, using channelopsins as a way to probe the circuitry and figure out the sites that are disrupted, what patterns of activity are required, and then by understanding the constituents of those cells, like what they express and what they make, then developing drugs that could target those cells-

    3. KDKarl Deisseroth1:14:32

       Yeah.

    4. AHAndrew Huberman1:14:32

       ... not necessarily putting light-inducing diodes into the brain, or-

    5. KDKarl Deisseroth1:14:36

       Right.

    6. AHAndrew Huberman1:14:36

       ... walking around with wire packs attached to our skull-

    7. KDKarl Deisseroth1:14:39

       Right.

    8. AHAndrew Huberman1:14:39

       ... or something like that.

    9. KDKarl Deisseroth1:14:40

       That's exactly ...

    10. AHAndrew Huberman1:14:41

        W- th- th- that's fantastic, and I- and you ... it ... I realize no one has a crystal ball, but, um, w- what do you think the arc of, um, of that is? Meaning, are we going to see that in a year, in two years, three years? And let me reframe that. If ... How soon will a pill-based treatment for a psychiatric disease be available, that targets a specific set of cells that we know are important b- because of the work done with channelopsins?

    11. KDKarl Deisseroth1:15:12

        I think, uh, that is, in some ways it's already, uh, happening at the level of individual patients. Uh, and-

    12. AHAndrew Huberman1:15:20

        Here at Stanford?

    13. KDKarl Deisseroth1:15:21

        Yeah. Yep. Uh, and it- and, and more broadly, in terms of, uh, new, new drugs, new multi-center, you know, uh, clinical trials, that'll play out over the next, uh, few years. Um, and these could be drugs that are already safe and approved for other purposes, uh, but we might say, "Okay, now we know that this medication, uh, based on what we know from causal optogenetics, this could be useful for this other purpose, this psychiatric symptom." And so the path, uh, to, to helping patients is- could be relatively, uh, swift.

    14. AHAndrew Huberman1:15:59

        That's very exciting.

19. 1:16:00 – 1:19:30

    Brain-Machine Interfaces & Neuralink

    1. AHAndrew Huberman1:16:00

    2. KDKarl Deisseroth1:16:00

       Yeah.

    3. AHAndrew Huberman1:16:00

       What are your thoughts about, um, brain-machine interface, and, um, Neuralink always comes up, although I do want to point out, it, um ... uh, tremendous respect for the folks at Neuralink, including someone who came up through my lab, is now there as a neurosurgeon. But, um, the brain-machine interface is something that's been happening for a long time now. Some of the, some of the best work, uh, among the best work being done here at Stanford and elsewhere too, of course. How is the, what you just described compatible with or different than brain-machine interface, meaning devices, little probes that are going to stimulate different patterns of activity and ensembles of neurons, and what are your general thoughts about, um, brain-machine interface as going forward?

    4. KDKarl Deisseroth1:16:40

       Yeah. I mean, this is ... Uh, first of all, it's an a- it's an amazing, uh, scientific discovery approach. Uh, as you mentioned, we and others here at Stanford are using, uh, electrodes, collecting information from tens of thousands of neurons.

    5. AHAndrew Huberman1:16:54

       In humans, I should add. (laughs)

    6. KDKarl Deisseroth1:16:56

       (laughs) And even, yes, there's, there's, uh, it is quite ... Even separate from the Neuralink work, as you point out, many people have been doing this, uh, uh, uh, in humans as well as in non-human primates. Um, and this is pretty, uh, powerful. It's important. This will let us, uh, understand what's going on in the brain, in, uh, s- in psychiatric disease and neurological disease, it'll give us ideas for, for treatment. Um, it is, of course, it's still, uh, invasive. You still are talking about putting a device, um, uh, into the brain, uh, and that has to be, uh, uh, treated as a, as a, as a situation. It has some risks and, and a step that has to be taken carefully. I see that as something that will be part of psychiatry, uh, in, in, in the long run. Already with deep brain stimulation, uh, approaches, we can help, uh, s- people with psychiatric disorders, and that's putting just a single electrode, not even a, a complex, you know, a closed loop system where you're both playing in and getting information back. Even just a single stimulation electrode in the brain can help people with, uh, OCD, for example, uh, quite powerfully. Uh, and that will become much more powerful when we get to a true brain-machine interface, collecting information back, stimulating only when you need to. If we could identify a pathological activity pattern, a particular, almost like the, the prodrome or the early stage of a seizure, maybe there are events that happen leading up to, on some time scale, uh, a psychiatric, uh, symptom, we could intervene in a, a closed loop way, detect what's happening, what's starting to go wrong, feed that back to the brain stimulation electrode, have it be, you know, in that way, more efficient and more principled. This is, is, uh, I think, uh, it's great. It's a, it's, uh, something that, of course will be grounded again in causal understanding. We'll need to know, what is that pathological pattern that we're detecting? And we need to know that it matters. And so again, that's where optogenetics is helping us. It's helping us know, okay, this, this pattern of activity in these cells, in these circuits, this does mean that there's a particular kind of, of, of symptom that's happening. But armed with that knowledge, absolutely. The ... Even the, even the simple closed loop device detect and stimulate is going to be part of psychiatry in the future. And then, and then of course, as you get to more cells, more connections, the ability that we have to help people will become more powerful.

    7. AHAndrew Huberman1:19:28

       One of the questions I get asked a lot is

20. 1:19:30 – 1:26:36

    ADHD & Dr. Deissroth’s Approach To Focusing His Mind

    1. AHAndrew Huberman1:19:30

       about, um, ADHD and, uh, attention deficit of various kinds. I have the, uh, hunch that, uh, one reason I get asked so often is that people are feeling really distracted and, and, uh, challenged in, um, funneling their attention and their behavior. But, uh-... and there are a number of reasons for that, of course. But what is true ADHD, and what does it look like? What can be done for it, and, uh, what, if any, role for channelopsins or these downstream technologies that you're developing? Um, what do they- what do they offer for people that suffer from ADHD, or have a family member that suffers from ADHD?

    2. KDKarl Deisseroth1:20:11

       Yeah. This is, uh, it's a pretty interesting branch of, of psychiatry. There's no question that people have been helped by the, the treatments. Uh, there's, you know, active, you know, debate over, you know, uh, what fraction of people who have these symptoms, uh, can or should be, be, uh, treated.

    3. AHAndrew Huberman1:20:29

       This is typically Adderall, or stimulants of some kind.

    4. KDKarl Deisseroth1:20:32

       Yeah. For example, stimulants. That's right. Um, so ADHD, it's, as, as its name suggests, it has, uh, symptoms of, uh... it can have either a hyperactive, uh, state, or an inattentive, uh, state, and, uh, those can be completely separate from each other. You could have a patient who, who, uh, effectively, uh, is, is not hyperactive at all, but can't, uh, remain focused on the, the, what's going on around them

    5. NANarrator1:20:57

       <<Yeah. >>

    6. KDKarl Deisseroth1:20:57

       ... so they've got kind of massive-

    7. AHAndrew Huberman1:20:57

       So their body can be still, but their, their mind is darting around.

    8. KDKarl Deisseroth1:21:00

       That's right. That's right.

    9. AHAndrew Huberman1:21:01

       Or, they can be very hyperactive-

    10. KDKarl Deisseroth1:21:02

        Yeah.

    11. AHAndrew Huberman1:21:02

        ... with their body.

    12. KDKarl Deisseroth1:21:03

        Yeah. It happens both ways.

Episode duration: 2:02:05