Dr. Karl Deisseroth: Understanding & Healing the Mind

00:00:00.000 | - Welcome to the Huberman Lab Podcast,

00:00:02.280 | where we discuss science and science-based tools

00:00:04.920 | for everyday life.

00:00:05.920 | I'm Andrew Huberman,

00:00:10.240 | and I'm a professor of neurobiology and ophthalmology

00:00:12.760 | at Stanford School of Medicine.

00:00:14.920 | Today, I have the pleasure of introducing the first guest

00:00:17.540 | of the Huberman Lab Podcast.

00:00:19.400 | My guest is Dr. Karl Deisseroth.

00:00:22.020 | Dr. Karl Deisseroth is a medical doctor.

00:00:24.320 | He's a psychiatrist and a research scientist

00:00:26.880 | at Stanford School of Medicine.

00:00:28.900 | In his clinical practice,

00:00:30.440 | he sees patients dealing with a range

00:00:32.280 | of nervous system disorders,

00:00:33.520 | including obsessive compulsive disorder, autism,

00:00:37.280 | attention deficit disorders, schizophrenia, mania,

00:00:41.440 | anxiety disorders, and eating disorders.

00:00:44.320 | His laboratory develops and explores tools

00:00:47.680 | with which to understand how the nervous system works

00:00:50.280 | in the healthy situation,

00:00:51.920 | as well as in disorders of the mind.

00:00:54.120 | Dr. Deisseroth's laboratory has pioneered the development

00:00:57.320 | and use of what are called channelopsins,

00:00:59.440 | proteins that come from algae,

00:01:01.620 | which can now be introduced to the nervous systems

00:01:04.300 | of animals and humans in order to precisely control

00:01:07.480 | the activity of neurons in the brain and body

00:01:09.780 | with the use of light.

00:01:11.520 | This is a absolutely transformative technology

00:01:15.000 | because whereas certain drug treatments

00:01:17.060 | can often relieve certain symptoms of disorders,

00:01:19.520 | they often carry various side effects.

00:01:21.960 | And in some individuals, often many individuals,

00:01:24.560 | these drug treatments simply do not work.

00:01:26.880 | The channelopsins and their related technologies

00:01:29.280 | stand to transform the way that we treat

00:01:31.360 | psychiatric illness and various disorders

00:01:34.160 | of movement and perception.

00:01:36.320 | In fact, just recently, the channelopsins were applied

00:01:39.440 | in a human patient to allow an adult,

00:01:42.040 | fully blind human being to see light

00:01:44.580 | for the very first time.

00:01:46.040 | We also discuss Dr. Deisseroth's newly released book,

00:01:49.160 | which is entitled "Projections, A Story of Human Emotions."

00:01:52.960 | This is an absolutely remarkable book

00:01:55.600 | that uses stories about his interactions with his patients

00:01:59.440 | to teach you how the brain works

00:02:01.440 | in the healthy and diseased state,

00:02:03.280 | and also reveals the motivation for and discovery

00:02:06.680 | of these channelopsins and other technologies

00:02:09.240 | by Carl's Laboratory that are being used now

00:02:12.240 | to treat various disorders of the nervous system,

00:02:14.520 | and that in the future are certain to transform

00:02:17.320 | the fields of psychiatry, mental health,

00:02:19.500 | and health in general.

00:02:20.960 | I found our conversation to be an absolutely fascinating one

00:02:24.000 | about how the brain functions in the healthy state

00:02:27.200 | and why and how it breaks down in disorders of the mind.

00:02:30.900 | We also discuss the current status and future

00:02:33.680 | of psychedelic treatments for psychiatric illness,

00:02:36.680 | as well as for understanding

00:02:37.760 | how the brain works more generally.

00:02:39.760 | We also discuss issues of consciousness,

00:02:42.040 | and we even delve into how somebody like Carl

00:02:45.040 | who's managing a full-time clinical practice

00:02:47.840 | and a 40-plus person laboratory

00:02:50.280 | and a family of five children and is happily married,

00:02:53.340 | how he organizes his internal landscape, his own thinking,

00:02:56.720 | in order to manage that immense workload

00:02:59.560 | and to progress forward for the sake of medicine

00:03:02.360 | and his pursuits in science.

00:03:04.360 | I found this to be an incredible conversation.

00:03:06.320 | I learned so much.

00:03:07.740 | I also learned through the course

00:03:09.320 | of reading Carl's book, "Projections,"

00:03:11.600 | that not only is he an accomplished psychiatrist

00:03:14.180 | and obviously an accomplished research scientist

00:03:16.940 | and a family man, but he's also a phenomenal writer.

00:03:19.700 | "Projections" is absolutely masterfully written.

00:03:22.300 | It's just beautiful, and it's accessible to anybody,

00:03:25.080 | even if you don't have a science background.

00:03:27.400 | So I hope that you'll enjoy my conversation

00:03:29.860 | with Carl Deisseroth as much as I did,

00:03:32.000 | and thank you for tuning in.

00:03:33.400 | Before we begin, I want to point out that this podcast

00:03:36.080 | is separate from my teaching and research roles at Stanford.

00:03:39.080 | In my desire and effort to bring zero cost

00:03:41.120 | to consumer information about science

00:03:42.720 | and science-related tools to the general public,

00:03:45.040 | I'd like to acknowledge the sponsors of today's podcast.

00:03:47.960 | Our first sponsor is Roca.

00:03:49.960 | Roca makes eyeglasses and sunglasses

00:03:52.040 | that in my opinion are the very highest quality out there.

00:03:55.340 | The company was founded by two all-American swimmers

00:03:57.600 | from Stanford, and everything about the eyeglasses

00:04:00.160 | and sunglasses was developed with performance in mind.

00:04:03.800 | One of the things I really love about Roca sunglasses

00:04:06.660 | is that unlike other sunglasses,

00:04:08.800 | they make it hard to see when there's a lot of cloud cover

00:04:11.680 | or when the shadows change

00:04:12.960 | or environmental conditions change.

00:04:14.740 | With Roca sunglasses, they clearly understand

00:04:17.360 | the science of the visual system,

00:04:18.960 | because when I put them on for the first time,

00:04:20.820 | I noticed that as I moved into shadows

00:04:23.200 | or the cloud cover changed or the day got brighter

00:04:25.600 | or dimmer, everything was still crystal clear.

00:04:28.500 | And that's also because the lenses

00:04:29.980 | are tremendously high optical clarity

00:04:32.520 | and the glasses are really lightweight.

00:04:34.600 | You don't even notice that they're on.

00:04:36.600 | The other thing is that the eyeglasses,

00:04:38.140 | I wear readers at night, they're incredibly lightweight.

00:04:40.760 | And for both the sunglasses and eyeglasses,

00:04:42.640 | the aesthetic is terrific.

00:04:44.400 | Unlike a lot of performance eyewear,

00:04:46.600 | which frankly can look kind of cyborg-like

00:04:48.800 | and kind of ridiculous,

00:04:49.640 | the aesthetic of the glasses is such

00:04:51.260 | that you could really wear them anywhere,

00:04:53.180 | indoors or outdoors.

00:04:54.960 | If you'd like to try Roca eyeglasses,

00:04:56.640 | you can go to Roca, that's R-O-K-A dot com,

00:04:59.760 | and enter the code Huberman to save 20% on your first order.

00:05:03.620 | That's Roca, R-O-K-A dot com,

00:05:05.960 | and enter the code Huberman at checkout.

00:05:08.160 | Today's podcast is also brought to us by Inside Tracker.

00:05:11.760 | Inside Tracker is a personalized nutrition platform

00:05:14.160 | that analyzes data from your blood and DNA

00:05:16.880 | to help you better understand your body

00:05:18.480 | and reach your health goals.

00:05:20.280 | I am a big believer in getting regular blood work done.

00:05:23.200 | And now with the advent of good genetic DNA tests,

00:05:26.240 | I'm also a believer in analyzing your DNA.

00:05:29.120 | The simple reason for this is that many of the factors

00:05:31.620 | that impact our immediate and long-term health

00:05:33.880 | can only be measured and evaluated

00:05:36.000 | with a quality blood test.

00:05:37.520 | And now the DNA tests further inform

00:05:39.760 | our immediate and long-term health.

00:05:41.780 | One of the problems with a lot of DNA tests

00:05:43.960 | and blood tests out there, however,

00:05:45.640 | is that you get the information back

00:05:47.120 | and you don't know what to do with that information.

00:05:49.140 | With Inside Tracker, you get the numbers back

00:05:51.360 | of different metabolic factors, hormones, et cetera,

00:05:54.000 | but it also provides simple directives

00:05:56.160 | as to how perhaps you might want to change

00:05:58.080 | your nutritional intake or your exercise regimen

00:06:00.980 | or other lifestyle factors to bring those numbers

00:06:03.840 | into alignment with where you'd like them to be.

00:06:06.480 | Inside Tracker also makes this really easy.

00:06:08.640 | They have a dashboard that makes organizing

00:06:10.320 | that all very simple,

00:06:11.680 | and they can even have someone come to your house

00:06:13.960 | to take the blood and DNA test.

00:06:15.840 | If you'd like to try Inside Tracker,

00:06:17.320 | you can visit insidetracker.com/huberman

00:06:20.340 | to get 25% off any of Inside Tracker's plans.

00:06:23.320 | Just use the code Huberman at checkout.

00:06:25.520 | Today's episode is also brought to us by Athletic Greens.

00:06:28.600 | Athletic Greens is an all-in-one

00:06:30.140 | vitamin mineral probiotic drink.

00:06:32.520 | I started taking Athletic Greens way back in 2012,

00:06:35.480 | and I've taken it ever since,

00:06:36.480 | so I'm delighted that they're sponsoring the podcast.

00:06:39.020 | The reason I started taking Athletic Greens

00:06:40.800 | and that I continue to take Athletic Greens

00:06:42.840 | is that it covers all my vitamin and mineral bases

00:06:45.720 | and it covers my probiotic needs.

00:06:48.240 | There's now a wealth of data showing

00:06:50.080 | that probiotics support a healthy gut microbiome

00:06:53.000 | and that a healthy gut microbiome

00:06:54.720 | supports the gut brain axis for healthy mood.

00:06:57.040 | It also supports metabolism, immune function,

00:06:59.880 | endocrine, that means hormone function,

00:07:01.640 | and a host of other important biological functions.

00:07:04.860 | I drink it once or twice a day.

00:07:06.700 | I mix it with water and a little bit of lemon juice

00:07:08.600 | or some lime juice, and it's absolutely delicious.

00:07:11.080 | If you'd like to try Athletic Greens,

00:07:12.640 | you can go to athleticgreens.com/huberman,

00:07:15.740 | and if you do that, you can claim a special offer

00:07:18.400 | where they will give you a year's supply of vitamin D3.

00:07:21.680 | In addition, they'll give you five free travel packs.

00:07:24.200 | Vitamin D3, as we all know, is very important

00:07:26.760 | for a huge range of biological functions and health.

00:07:29.960 | Again, that's athleticgreens.com/huberman

00:07:32.760 | for your Athletic Greens, the five free travel packs,

00:07:35.000 | and the year's supply of vitamin D3.

00:07:37.380 | And now my conversation with Dr. Carl Deisseroth.

00:07:41.720 | - Well, thanks for being here.

00:07:43.040 | - Thanks for having me.

00:07:44.440 | - It's been a long time coming for me

00:07:46.920 | because you may not know this,

00:07:49.200 | but one of the reasons I started this podcast

00:07:51.840 | was actually so I could have this conversation.

00:07:54.400 | It's but one, there are other reasons,

00:07:57.440 | but one of the goals is to be able to hold conversations

00:08:02.360 | with colleagues of mine that are doing incredible work

00:08:05.560 | in the realm of science.

00:08:06.680 | And then here, we also have this really special opportunity

00:08:09.560 | because you're also a clinician, you see patients

00:08:12.040 | in and out for a long time.

00:08:13.640 | So for people that might not be so familiar

00:08:16.040 | with the fields of neuroscience, et cetera,

00:08:18.600 | what is the difference between neurology and psychiatry?

00:08:22.880 | - Well, I'm married to a neurologist and I am a psychiatrist

00:08:26.680 | and we make fun of each other all the time.

00:08:28.280 | So this is a lot of neuroscientists

00:08:32.000 | and a lot of brain clinicians actually think these two

00:08:34.920 | should be the same field at some point in the future.

00:08:38.200 | They were in the past, they started together.

00:08:40.860 | Psychiatry though, focuses on disorders

00:08:44.320 | where we can't see something that's physically wrong,

00:08:47.640 | where we don't have a measurable,

00:08:49.000 | where there's no blood test that makes the diagnosis.

00:08:52.460 | There's no brain scan that tells us this is schizophrenia,

00:08:55.200 | this is depression for an individual patient.

00:08:57.480 | And so psychiatry is much more mysterious

00:09:02.120 | and the only tools we have are words.

00:09:05.600 | Neurologists are fantastic physicians,

00:09:08.780 | they see the stroke on brain scans,

00:09:12.160 | they see the seizure and the pre-seizure activity

00:09:15.580 | with an EEG and they can measure and treat

00:09:20.580 | based on those measurables.

00:09:22.540 | In psychiatry, we have a harder job, I think.

00:09:24.900 | We use words, we have rating scales for symptoms,

00:09:29.100 | we can measure depression and autism with rating scales,

00:09:31.900 | but those are words still.

00:09:34.320 | And ultimately that's what psychiatry is built around.

00:09:37.160 | It's an odd situation because we've got the most complex,

00:09:42.160 | beautiful, mysterious, incredibly engineered object

00:09:47.640 | in the universe and yet all we have are words

00:09:50.040 | to find our way in.

00:09:52.160 | - So do you find that if a patient is very verbal

00:09:56.360 | or hyperverbal, that you have an easier time diagnosing them

00:10:00.080 | as opposed to somebody who's more quiet and reserved

00:10:03.640 | or I could imagine the opposite might be true as well?

00:10:06.920 | - Well, because we only have words,

00:10:08.560 | you've put your finger on a key point.

00:10:10.760 | If they don't speak that much in principle, it's harder.

00:10:14.040 | The lack of speech can be a symptom.

00:10:15.820 | We can see that in depression,

00:10:17.120 | we can see that in the negative symptoms of schizophrenia,

00:10:19.760 | we can see that in autism.

00:10:21.280 | Sometimes by itself, that is a symptom of reduced speech.

00:10:25.180 | But ultimately you do need something.

00:10:26.540 | You need some words to help guide you.

00:10:29.320 | And that in fact, there's challenges that I can tell you

00:10:32.800 | about where patients with depression

00:10:35.480 | who are so depressed they can't speak,

00:10:38.100 | that makes it a bit of a challenge to distinguish depression

00:10:41.380 | from some of the other reasons they might not be speaking.

00:10:43.640 | And this is sort of the art and the science of psychiatry.

00:10:46.920 | - Do you find that there are patients that have,

00:10:52.160 | well, let's call them comorbidities or conditions

00:10:54.440 | where they would land in both psychiatry and neurology,

00:10:58.040 | meaning there's damage to a particular area of the brain

00:11:01.080 | and therefore they're depressed

00:11:02.440 | and how do you tease that out as a psychiatrist?

00:11:06.040 | - Yeah, this happens all the time.

00:11:08.140 | Parkinson's disease is a great example.

00:11:10.280 | It can be debilitating in so many ways.

00:11:15.500 | People have trouble moving, they have trouble walking,

00:11:18.000 | trouble swallowing, and they can have

00:11:21.480 | truly severe depression.

00:11:25.120 | And this is, you might say, oh, well,

00:11:26.960 | they've got a life-threatening illness,

00:11:30.400 | but there are plenty of neurological disorders

00:11:32.360 | where depression is not a strongly comorbid symptom,

00:11:37.360 | like ALS, Lou Gehrig's disease, for example.

00:11:40.000 | Depression is not as strongly comorbid in that disease,

00:11:43.960 | but in Parkinson's it is extremely common.

00:11:46.840 | And as you know, in Parkinson's disease,

00:11:49.360 | we have loss of the dopamine neurons in the midbrain.

00:11:53.380 | And this is a very specific population of cells that's dying

00:11:58.380 | and probably that leads to both the movement disorder

00:12:02.200 | and the depression.

00:12:04.020 | There are many examples of that

00:12:05.160 | where these two fields come together

00:12:06.800 | and you really need to work as a team.

00:12:09.220 | I've had patients in my clinic

00:12:11.320 | that I treat the depression

00:12:13.080 | associated with their Parkinson's

00:12:14.580 | and a neurologist treats the movement

00:12:16.560 | associated with the Parkinson's and we work together.

00:12:19.740 | - Do you think we will ever have a blood test

00:12:22.200 | for depression or schizophrenia or autism?

00:12:24.700 | And would that be a good or a bad thing?

00:12:29.520 | - I think ultimately there will be quantitative tests.

00:12:33.040 | Already efforts are being made

00:12:34.880 | to look at certain rhythms in the brain using external EEGs

00:12:38.760 | to look at brainwaves effectively,

00:12:40.880 | look at the ratios of certain frequencies

00:12:43.420 | to other frequencies.

00:12:45.060 | And there's some progress being made on that front.

00:12:47.460 | It's not as good as it could be.

00:12:49.260 | It doesn't really give you the confidence

00:12:51.120 | for the individual patient that you would like.

00:12:54.200 | But ultimately what's going on in the brain

00:12:56.400 | in psychiatric disease is physical

00:12:59.720 | and it's due to the circuits and the connections

00:13:02.660 | and the projections in the brain that are not working

00:13:05.440 | as they would in a typical situation.

00:13:07.920 | And I do think we'll have those measurables at some point.

00:13:12.280 | Now, is that good or bad?

00:13:14.480 | I think that will be good.

00:13:15.960 | One of the challenges we have with psychiatry

00:13:19.340 | is it is an art as well as a science

00:13:21.940 | to elicit these symptoms in a precise way.

00:13:26.460 | It does take some time and it would be great

00:13:29.340 | if we could just do a quick measurement.

00:13:31.860 | Could it be abused or misused?

00:13:35.220 | Certainly, but that's, I think, true for all of medicine.

00:13:38.380 | - I want to know, and I'm sure there are several,

00:13:40.320 | but what do you see as the biggest challenge

00:13:42.660 | facing psychiatry and the treatment of mental illness today?

00:13:49.260 | - I think we have, we're making progress

00:13:52.300 | on what the biggest challenge is,

00:13:53.940 | which I think there's still such a strong stigma

00:13:56.260 | for psychiatric disease that patients often don't come to us

00:14:01.260 | and they feel that they should be able

00:14:05.660 | to handle this on their own.

00:14:07.500 | And that can slow treatment.

00:14:10.700 | It can lead to worsening symptoms.

00:14:13.660 | We know, for example, patients who have

00:14:16.380 | untreated anxiety issues, if you go for a year or more

00:14:20.400 | with a serious untreated anxiety issue,

00:14:22.640 | that can convert to depression.

00:14:24.380 | You can add another problem on top of the anxiety.

00:14:28.740 | And so it would be, why do people not come for treatment?

00:14:32.700 | They feel like this is something they should be able

00:14:35.180 | to master on their own, which can be true,

00:14:38.260 | but usually some help is a good thing.

00:14:43.180 | - That raises a question related to something

00:14:45.660 | I heard you say many years ago at a lecture,

00:14:48.360 | which was that, this was a scientific lecture,

00:14:51.320 | and you said, you know, we don't know how other people feel.

00:14:54.780 | Most of the time, we don't even really know how we feel.

00:14:57.940 | Maybe you could elaborate on that a little bit

00:14:59.680 | and the dearth of ways that we have to talk about feelings.

00:15:04.680 | I mean, there's so many words, I don't know how many,

00:15:10.060 | but I'm guessing there are more than a dozen words

00:15:11.800 | to describe the state that I call sadness.

00:15:14.980 | But as far as I understand,

00:15:16.300 | we don't have any way of comparing that

00:15:17.700 | in a real objective sense.

00:15:20.160 | So how, as a psychiatrist,

00:15:21.760 | when your job is to use words to diagnose,

00:15:24.940 | words of the patient to diagnose,

00:15:26.820 | do you maneuver around that?

00:15:28.620 | And what is this landscape that we call feelings or emotions?

00:15:33.060 | - This is really interesting.

00:15:35.820 | People, here we have, there's a tension

00:15:38.260 | between the words that we've built up in the clinic

00:15:41.220 | that mean something to the physicians.

00:15:43.980 | And then there's the colloquial use of words

00:15:46.140 | that may not be the same.

00:15:47.240 | And so that's the first level we have to sort out.

00:15:49.560 | When someone says, you know, I'm depressed,

00:15:53.620 | what exactly do they mean by that?

00:15:56.260 | That may be different from what we're talking about

00:15:58.460 | in terms of depression.

00:15:59.460 | So part of psychiatry is to get beyond that word

00:16:02.860 | and to get into how they're actually feeling,

00:16:05.340 | get rid of the jargon and get to real world examples

00:16:09.580 | of how they're feeling.

00:16:10.700 | So, you know, how much do you look forward into the future?

00:16:15.700 | How much hope do you have?

00:16:18.960 | How much planning are you doing for the future?

00:16:21.020 | So these, here now you're getting into actual things

00:16:24.220 | you can talk about that are unambiguous.

00:16:26.420 | Someone says, yeah, I can't even think about tomorrow.

00:16:30.140 | I'm not, I don't see how I'm gonna get to tomorrow.

00:16:33.860 | That's a nice, precise thing that, you know,

00:16:36.900 | it's sad, it's tragic, but it's also,

00:16:39.460 | that means something and we know what that means.

00:16:42.200 | That's the hopelessness symptom of depression.

00:16:45.020 | And that is what I try to do

00:16:46.860 | when I do a psychiatric interview.

00:16:48.080 | I try to get past the jargon

00:16:49.780 | and get to what's actually happening in a patient's life

00:16:51.980 | and in their mind.

00:16:53.380 | But as you say, ultimately, you know,

00:16:55.500 | and this shows up across,

00:16:57.780 | I address this issue every day in my life,

00:17:00.940 | whether it's in the lab where we're looking at animals,

00:17:04.940 | whether fish or mice or rats and studying their behavior

00:17:08.660 | or when I'm in a conversation with just a friend

00:17:12.200 | or a colleague or when I'm talking to a patient,

00:17:15.780 | I never really know what's going on inside the mind

00:17:18.580 | of the other person.

00:17:19.580 | I get some feedback, I get words, I get behaviors,

00:17:24.860 | I get actions, but I never really know.

00:17:27.220 | And as you said at the very beginning of the question,

00:17:29.460 | you know, often we don't even have the words

00:17:31.480 | and the insight to even understand

00:17:33.260 | what's going on in our own mind.

00:17:34.940 | I think a lot of psychiatrists are pretty introspective.

00:17:37.880 | That's part of the reason they end up in that specialty.

00:17:40.060 | And so maybe we spend a little more time

00:17:44.160 | than the average person thinking

00:17:45.300 | about what's going on within,

00:17:46.620 | but it doesn't mean we have answers.

00:17:49.440 | - So in this area of trying to figure out

00:17:53.600 | what's going on under the hood through words,

00:17:55.940 | it sounds like certain words would relate

00:17:58.880 | to this idea of anticipation and hope.

00:18:03.020 | Is it fair to say that that somehow relates

00:18:05.140 | to the dopamine system in the sense

00:18:06.900 | that dopamine is involved in motivated behaviors?

00:18:10.440 | I mean, is that an, if I say, for instance,

00:18:13.140 | and I won't ask you to run a session with me here for free.

00:18:17.920 | - We'll do that off camera.

00:18:18.840 | - Okay, right.

00:18:19.680 | If I were to say, you know,

00:18:22.280 | I just can't imagine the tomorrow.

00:18:26.920 | I just can't do it.

00:18:28.880 | So that's not action-based.

00:18:31.100 | That's purely based on my internal narrative.

00:18:34.680 | But I could imagine things like, you know,

00:18:37.240 | I have a terrible time sleeping.

00:18:39.700 | I'm not hungry. I'm not eating.

00:18:41.160 | So statements about physical actions, I'm guessing,

00:18:43.980 | also have validity.

00:18:46.380 | - Absolutely.

00:18:47.220 | - And there are now ways to measure

00:18:50.240 | the accuracy of those statements.

00:18:51.780 | Like for instance, if I gave you permission,

00:18:53.700 | you could know if I slept last night

00:18:55.840 | or whether or not I was just saying

00:18:57.060 | I had a poor night's sleep.

00:18:58.320 | - Yes, that's right.

00:18:59.440 | - So in moving forward through 2021

00:19:02.720 | and into the next 10 and 100 years of psychiatry,

00:19:05.680 | do you think that the body reporting

00:19:08.800 | some of the actions of a human

00:19:12.400 | are going to become useful and mesh with the words

00:19:16.560 | in a way that's going to make your job easier?

00:19:18.980 | - I do think that's true.

00:19:19.920 | And these, the two things you've mentioned,

00:19:21.680 | eating and sleeping,

00:19:22.560 | those are additional criteria

00:19:25.320 | that we use to diagnose depression.

00:19:26.860 | These are the vegetative signs, we call them,

00:19:28.640 | of depression, poor sleep, and poor eating.

00:19:30.560 | And if you have a baseline for somebody,

00:19:32.420 | that's the real challenge though.

00:19:34.020 | What's different in that person?

00:19:35.700 | Some people with depressed, they sleep more.

00:19:37.720 | Some people who are depressed, they sleep less.

00:19:40.520 | Some people who are depressed,

00:19:41.620 | they're more physically agitated

00:19:43.640 | and they move around more.

00:19:44.920 | Some people who are depressed,

00:19:46.020 | they move less even while they're awake.

00:19:48.340 | And so you need, here's the challenge

00:19:50.100 | is you can't just look at how they are now.

00:19:53.180 | You have to get a baseline and then see how it's changed.

00:19:57.280 | And that can be a challenge that raises ethical issues.

00:20:02.200 | How do you collect that baseline information

00:20:04.700 | from someone healthy?

00:20:05.720 | I don't think that's something we have solved.

00:20:08.560 | Of course, with phones and accelerometers and phones,

00:20:11.860 | you could in principle collect a lot of baseline information

00:20:14.780 | from people, but that would have to be treated

00:20:18.100 | very carefully for privacy reasons.

00:20:21.540 | - And in terms of measuring one's own behavior,

00:20:24.220 | I've heard of work that's going on.

00:20:27.880 | Sam Golden up at the University of Washington

00:20:30.420 | who works on aggression and animal models

00:20:32.080 | was telling me that there's some efforts that he's making

00:20:34.600 | and perhaps you're involved in this work as well.

00:20:36.560 | I don't know of devices that would allow people to detect,

00:20:41.560 | for instance, when they're veering

00:20:43.500 | towards a depressive episode for themselves,

00:20:45.740 | that they may choose or not choose to report that

00:20:47.900 | to their clinician.

00:20:48.820 | Maybe they don't even have a clinician.

00:20:50.180 | Maybe this person that you referred to at the beginning,

00:20:53.380 | this person who doesn't feel comfortable

00:20:54.800 | coming to talk to you,

00:20:55.900 | maybe something is measuring changes

00:20:59.460 | in the inflection of their voice

00:21:01.060 | or the speed at which they get up from a chair.

00:21:03.540 | Do you think that those kinds of metrics

00:21:04.940 | will eventually inform somebody,

00:21:06.180 | "Hey, you're in trouble."

00:21:07.980 | This is getting to this question of,

00:21:10.060 | back to the statement that I heard you make

00:21:11.820 | and it rung in my mind now, I think for more than a decade,

00:21:14.360 | which is oftentimes we don't even know how we feel.

00:21:16.940 | - Yeah, that I do like because that gives the patient,

00:21:20.500 | the agency to detect what's going on.

00:21:23.040 | And even separate from modern technology,

00:21:25.140 | this has been part of the art of psychiatry

00:21:27.380 | is to help patients realize that sometimes other people

00:21:30.660 | observing them can give them the earliest warning signs

00:21:34.380 | of depression.

00:21:35.220 | We see this very often in family.

00:21:37.900 | They'll notice when the patient is changing

00:21:40.480 | before the patient does.

00:21:42.060 | And then there are things the patient may notice,

00:21:43.860 | but not correctly ascribe to the onset of depression.

00:21:47.500 | And a classic example of that is what we call

00:21:49.460 | early morning awakening.

00:21:51.220 | And this is something that can happen very early

00:21:53.460 | as people start to slide into depression.

00:21:55.260 | They start to wake up earlier and earlier,

00:21:57.780 | just inexplicably they're awake at.

00:21:59.860 | - So this is like 2 a.m., 3 a.m. type waking?

00:22:02.140 | - It could start, yeah, it could start at 5 a.m.,

00:22:04.260 | could go to four.

00:22:05.460 | - And unable to fall back asleep.

00:22:06.980 | - Unable to fall back asleep, exactly.

00:22:08.860 | So that's, and that, they may not know what to do with that.

00:22:12.400 | It could just be, from their perspective,

00:22:14.140 | it's just something that's happening.

00:22:15.860 | But if you put enough of that information together,

00:22:18.580 | that could be a useful warning sign for the patient

00:22:20.780 | and it could help them seek treatment.

00:22:22.020 | And I think that is something that could be really valuable.

00:22:24.900 | - Interesting.

00:22:25.900 | So in this framework of, you know,

00:22:29.820 | needing words to self-report or machines to detect

00:22:33.300 | how we feel or, and maybe inform a psychiatrist

00:22:37.220 | how a patient feels,

00:22:38.860 | want to touch on some of the technologies

00:22:42.140 | that you've been involved in building.

00:22:44.080 | But as a way to march into that,

00:22:46.980 | are there any very good treatments for psychiatric disease?

00:22:52.180 | Meaning, are there currently any pills, potions,

00:22:55.660 | forms of communication that reliably work every time

00:23:00.080 | or work in most patients?

00:23:01.520 | And could you give a couple examples

00:23:02.740 | of great successes of psychiatry if they exist?

00:23:05.380 | - Yes.

00:23:06.220 | Yeah, we are fortunate, and this coming back to my,

00:23:09.020 | you know, the joking between my wife and myself

00:23:12.820 | in terms of neurology and psychiatry.

00:23:15.300 | We actually, in psychiatry,

00:23:17.740 | despite the depths of our, the mystery we struggle with,

00:23:21.660 | many of our treatments are actually, you know,

00:23:24.020 | we may be doing better than some other specialties

00:23:26.140 | in terms of actually causing, you know,

00:23:28.020 | the therapeutic benefit for patients.

00:23:29.980 | We do help patients, you know,

00:23:32.020 | the patients who suffer from, by the way,

00:23:35.060 | both medications and talk therapy

00:23:36.660 | have been shown to be extremely effective in many cases.

00:23:39.380 | For example, people with panic disorder,

00:23:42.620 | cognitive behavioral therapy, just working with words,

00:23:45.180 | helping people identify the early signs

00:23:47.260 | of when they're starting to move toward a panic attack.

00:23:49.560 | What are the cognitions that are happening?

00:23:52.060 | You can train people to derail that,

00:23:54.160 | and you can very potently treat panic disorder that way.

00:23:57.480 | - How long does something like that take on average?

00:24:00.400 | - For a motivated, insightful patient,

00:24:02.380 | you can have a very cookbook-y series of sessions,

00:24:06.940 | you know, six to 12 sessions,

00:24:08.740 | or even less for someone who's very insightful and motivated,

00:24:12.020 | and it can have a very powerful effect that quickly.

00:24:14.520 | And that's just with words.

00:24:17.500 | There are many psychiatric medications

00:24:19.540 | that are very effective for the conditions

00:24:22.400 | that they're treating, anti-psychotic medications.

00:24:25.500 | They have side effects, but boy, do they work.

00:24:27.920 | They really can clear up,

00:24:29.800 | particularly the positive symptoms of schizophrenia,

00:24:33.120 | for example, the auditory hallucinations, the paranoia.

00:24:36.720 | People's lives can be turned around by these.

00:24:39.140 | - We should clarify positive symptoms.

00:24:40.780 | You mean not positive in the qualitative sense.

00:24:43.780 | You mean positive meaning that the appearance

00:24:45.400 | of something abnormal.

00:24:46.600 | - Exactly, yeah, and thank you for that clarification.

00:24:48.760 | When we say positive symptoms,

00:24:50.420 | we do mean the addition of something

00:24:52.060 | that wasn't there before,

00:24:53.100 | like a hallucination or a paranoia,

00:24:55.000 | and that stands in contrast to the negative symptoms

00:24:57.720 | where something is taken away,

00:24:59.400 | and these are patients who are withdrawn.

00:25:02.600 | They have what we call thought blocking.

00:25:05.200 | They can't even progress forward in a sequence of thoughts.

00:25:08.420 | Both of those can be part of schizophrenia.

00:25:11.040 | The hallucinations and the paranoia

00:25:14.480 | are more effectively treated right now,

00:25:15.900 | but they are effectively treated.

00:25:18.180 | And then, you know, this is a frustrating

00:25:21.380 | and yet heartening aspect of psychiatry.

00:25:23.920 | There are treatments like electroconvulsive therapy,

00:25:27.260 | which is where, you know,

00:25:29.220 | it's extremely effective for depression.

00:25:31.120 | We have patients who nothing else works for them,

00:25:35.460 | where they can't tolerate medications,

00:25:37.360 | and you can administer under a very safe,

00:25:40.760 | controlled condition where the patient's body is not moving.

00:25:44.560 | They're put into a very safe situation

00:25:46.960 | where the body doesn't move or seize.

00:25:48.580 | It's just an internal process that's triggered in the brain.

00:25:52.780 | This is an extraordinarily effective treatment

00:25:54.820 | for treatment-resistant depression.

00:25:56.880 | At the same time, I find it as heartening

00:25:59.640 | as it is to see patients respond to this

00:26:02.240 | who have severe depression.

00:26:04.980 | I'm also frustrated by it.

00:26:06.180 | Why can't we do something more precise than this

00:26:09.680 | for these very severe cases?

00:26:11.600 | And people have sought for decades to understand

00:26:14.960 | how is it that a seizure is leading to the relief

00:26:18.120 | of depression, and we don't know the answer yet.

00:26:20.420 | We would love to do that.

00:26:21.540 | People are working hard on that,

00:26:23.420 | but that is a treatment that does work too.

00:26:26.060 | In all of these cases, though, in psychiatry,

00:26:28.660 | the frustrating thing is that we don't have

00:26:30.860 | the level of understanding that a cardiologist has

00:26:34.780 | in thinking about the heart.

00:26:35.900 | You know, the heart is, we now know, it's a pump.

00:26:38.180 | It's pumping blood, and so you can look at everything

00:26:40.940 | about how it's working or not working

00:26:43.380 | in terms of that frame.

00:26:45.460 | It's clearly a pump.

00:26:47.120 | We don't really have that level of what is the circuit

00:26:51.700 | really there for in psychiatry?

00:26:54.080 | And that's what is missing.

00:26:56.900 | That's what we need to find so we can design

00:26:59.500 | truly effective and specific treatments.

00:27:02.140 | - So what are the pieces that are going to be required

00:27:05.940 | to cure autism, cure Parkinson's, cure schizophrenia?

00:27:10.940 | I would imagine there are several elements and bins here,

00:27:16.240 | understanding that the natural biology,

00:27:18.820 | understanding what the activity patterns are,

00:27:21.420 | how to modify those.

00:27:22.260 | Maybe you could just tell us what you think.

00:27:25.220 | What is the bento box of the perfect cure?

00:27:29.060 | - Yeah, I think the first thing we need is understanding.

00:27:31.860 | We need, almost every psychiatric treatment has been

00:27:36.140 | serendipitously identified, just noting by chance

00:27:38.900 | that something that was done for some person

00:27:42.760 | also had a side effect.

00:27:44.140 | - Like lithium or something.

00:27:44.980 | - Like lithium is a good example.

00:27:46.760 | - Is it true that it was the urine of guinea pigs

00:27:49.280 | given lithium that was given to manic patients

00:27:51.700 | that made them not manic?

00:27:52.840 | Is that true?

00:27:53.700 | - I don't have firsthand knowledge of that,

00:27:55.420 | but I would defer that.

00:27:57.240 | But it's true for essentially every treatment.

00:27:59.460 | You know, the antidepressants originally, you know,

00:28:02.660 | arose as anti-tuberculosis drugs, for example.

00:28:05.380 | - I did not know that.

00:28:06.220 | - Yeah, and so this is a classic example for,

00:28:08.700 | and this is across all of psychiatry.

00:28:12.760 | And of course, there's the seizures as well.

00:28:14.340 | That was noticed that patients who had epilepsy,

00:28:16.380 | they had a seizure and also had depression

00:28:19.260 | that they became much, at least for a while,

00:28:21.380 | they were improved after the seizure.

00:28:23.580 | - That's amazing.

00:28:24.420 | I don't want to take you off course of the question that,

00:28:26.220 | answering the question I asked,

00:28:27.200 | but I've heard before that if autistic children get a fever,

00:28:31.280 | that their symptoms improve.

00:28:32.840 | Is that true?

00:28:34.160 | - I've done a fair bit of work with autism.

00:28:37.820 | In my clinical practice, I work with adult autism,

00:28:40.200 | and I have heard statements like that

00:28:42.420 | and descriptions like that from patients

00:28:44.600 | and their families.

00:28:45.740 | That is very hard to study quantitatively

00:28:50.240 | because often with the children,

00:28:51.400 | you have this not as quantitative as you'd like

00:28:55.800 | a collection of symptom information from home.

00:28:59.720 | But I have heard that enough

00:29:01.260 | that I think there may well be something to that.

00:29:04.140 | And what is, anytime you have a fever, what's going on?

00:29:08.940 | Well, we know all the cells in the brain,

00:29:11.620 | and I know this as an electrophysiologist,

00:29:13.540 | if you just change the temperature by a few degrees,

00:29:15.580 | everything changes about how neurons work.

00:29:17.540 | And that's even just a single neuron.

00:29:19.460 | It's even more likely to be complex and different

00:29:22.360 | with a circuit of neurons that are all affecting each other.

00:29:25.080 | Just elevate the temperature a little bit,

00:29:26.740 | everything's different.

00:29:27.640 | And so it's plausible for sure that things like that

00:29:31.400 | could happen and do happen.

00:29:32.760 | And yet, when you think about autism, to take your example,

00:29:37.680 | yes, we see changes,

00:29:40.760 | but what is the element in the brain

00:29:44.480 | that's analogous to the pumping heart?

00:29:46.600 | When we think about the symptoms of depression,

00:29:49.640 | that's maybe, we think about motivation and dopamine neurons.

00:29:53.940 | When we think about autism, it's a little more challenging.

00:29:57.220 | There's a deficit in social interaction

00:30:03.220 | and in communication.

00:30:04.940 | And so where is that?

00:30:07.260 | Where is that situated?

00:30:09.840 | What is the key principle governing the social interaction?

00:30:14.840 | This is where we need the basic science

00:30:17.740 | to bring us a step forward.

00:30:19.340 | So we can say, okay, this is the process that's going on.

00:30:21.800 | This is what's needed for the incredibly complex task

00:30:25.140 | of social interaction,

00:30:26.960 | where you've got incredibly rich data streams of sound

00:30:30.520 | and meaning, eye contact, body movement.

00:30:33.100 | And that's just for one person.

00:30:34.200 | What if there's a group of people?

00:30:36.080 | This is overwhelming for people with autism.

00:30:39.520 | What's the unifying theme there?

00:30:41.900 | It's a lot of information.

00:30:43.440 | And that maybe is unmatched in any realm of biology,

00:30:48.440 | the amount of information coming in

00:30:49.840 | through a social interaction, particularly with words

00:30:51.900 | and language.

00:30:52.840 | And so then that turns our attention as neuroscientists.

00:30:57.000 | We think, okay, let's think about the parts of the brain

00:31:00.080 | that are involved in dealing with merging complex data

00:31:05.080 | streams that are very high in bit rate

00:31:08.320 | that need to be fused together into a unitary concept.

00:31:11.820 | And that starts to guide us and maybe we can,

00:31:15.160 | and we know other animals are social in their own way

00:31:17.780 | and we can study those animals.

00:31:19.040 | And so that's how I think about it.

00:31:21.120 | There's hope for the future,

00:31:22.360 | thinking about the symptoms as an engineer might,

00:31:25.640 | and trying to identify the circuits that are likely working

00:31:30.140 | to make this typical behavior happen.

00:31:32.360 | And that will help us understand how it becomes atypical.

00:31:35.080 | - So that seems like the first, to me,

00:31:37.480 | the first bin of this, what I call the bento box,

00:31:40.960 | for lack of a better analogy,

00:31:42.980 | that we need to know the circuits.

00:31:44.660 | We need to know the cells in the various brain regions

00:31:47.960 | and portions of the body

00:31:49.320 | and how they connect to one another

00:31:52.240 | and what the patterns of activity are under a normal,

00:31:55.980 | quote unquote, healthy interaction.

00:31:57.800 | If we understand that, then it seems that the next step,

00:32:04.060 | which of course could be carried out in parallel, right?

00:32:06.260 | That work can be done alongside work

00:32:09.100 | where various elements within those circuits

00:32:12.440 | are tweaked just right.

00:32:14.080 | Like the tuning of a piano in the subtle way,

00:32:16.160 | or maybe even like the replacement of a whole set of keys

00:32:18.280 | if the piano is lacking keys, so to speak,

00:32:20.620 | you've been very involved in trying to generate those tools.

00:32:25.120 | So tell us about channelopsins,

00:32:29.620 | why you created them and where they're at now

00:32:34.400 | in the laboratory and perhaps also in the clinic.

00:32:38.520 | - Well, this is a, first of all,

00:32:39.920 | I give nature the credit for creating channelopsins.

00:32:43.960 | These are beautiful little proteins that are made by algae,

00:32:48.120 | single-celled green algae.

00:32:50.280 | And it's a great story in basic science

00:32:53.140 | that our understanding of animal behavior,

00:32:57.480 | sensation, cognition, and action in our brains

00:33:00.680 | all the way back to a botanist in the 1850s and 1860s

00:33:05.680 | in Russia is where the story begins.

00:33:08.520 | So this was a botanist named Andrei Fominzin

00:33:12.320 | who worked at St. Petersburg.

00:33:14.860 | And he had noticed in the river near his laboratory

00:33:19.860 | that there were algae that he could look at

00:33:23.660 | in a dish, in a saucer.

00:33:25.120 | He could put them there.

00:33:26.520 | And when he had light shining from the side,

00:33:29.320 | the green tinge in the saucer of water would move

00:33:34.320 | to a particular distance from the light

00:33:38.760 | that he was shining from the side,

00:33:40.380 | which was an amazing thing.

00:33:42.440 | If he made the light brighter,

00:33:44.840 | the green tinge would back off a little bit

00:33:47.060 | to a more optimal location.

00:33:48.560 | So just the right light level.

00:33:50.400 | So this was plant behavior.

00:33:52.980 | It was light-driven plant behavior.

00:33:54.640 | And he delved into this a little bit.

00:33:56.160 | He identified that with microscopy,

00:33:58.680 | he could see that there were little single-celled algae

00:34:01.020 | with flagella that were swimming to the right light level.

00:34:05.340 | So behaving plants, and this has been the secret

00:34:07.880 | that's helped us unlock so many principles

00:34:10.880 | of animal behavior.

00:34:12.800 | So it turns out these algae achieve this amazing result

00:34:17.800 | with a single gene that encodes a single protein.

00:34:25.400 | What's a protein?

00:34:26.760 | It's just a little biomolecule that does a job in a cell.

00:34:30.280 | And these are proteins that sit in the surface of cells

00:34:34.240 | in their surface membrane.

00:34:36.240 | And when a photon, a light particle hits them,

00:34:39.440 | they open a little pore, a little hole in the membrane,

00:34:42.200 | and charged particles, ions like sodium,

00:34:45.480 | rush across the pore.

00:34:47.320 | Now, why do they do that?

00:34:49.640 | They do that to guide their flagella.

00:34:51.920 | That signal coming in, those ions coming in

00:34:54.380 | through the pore in response to light,

00:34:56.640 | guide their flagellar motor that guides them

00:34:59.780 | to a particular spot in the saucer, okay?

00:35:02.760 | Now that's plant behavior, but it turns out, as you know,

00:35:07.800 | this movement of ions across the membrane,

00:35:09.860 | this happens to also be neural code in our brains

00:35:13.180 | for on or off.

00:35:15.080 | Sodium ions rushing into cells turns them on,

00:35:18.400 | makes them fire away, fire action potentials

00:35:20.880 | communicate to the next cell down the chain.

00:35:24.460 | And this is an amazing opportunity

00:35:26.980 | because we can borrow these proteins.

00:35:31.280 | In fact, we can take the gene

00:35:32.800 | that directs the creation of the protein

00:35:35.320 | and we can use genetic tricks, modern genetic tricks,

00:35:37.540 | to put that gene into neurons in the brains of mammals,

00:35:42.240 | and then use light to turn those cells,

00:35:46.540 | the specific cells that we've put this gene into,

00:35:49.240 | turn them on.

00:35:50.200 | There are other opsins, we call them,

00:35:52.960 | that you can use to turn cells off.

00:35:55.260 | It's all fast, real time.

00:35:57.880 | You can play in patterns of activity in real time

00:36:00.640 | into cells or kinds of cells, just as a conductor,

00:36:03.960 | elicits the music from the orchestra,

00:36:05.720 | and the strings, and the woodwinds.

00:36:07.680 | And you can see what matters.

00:36:09.760 | What matters for sensation, what matters for cognition,

00:36:12.240 | what matters for action, and we call this optogenetics.

00:36:15.200 | - Beautiful, and I must say it was quite an honor

00:36:18.520 | and a privilege to watch optogenetics move

00:36:22.000 | from idea to discovery to the laboratory.

00:36:26.780 | I think we were postdocs at the same time,

00:36:29.140 | which is living proof that people move at different rates.

00:36:32.460 | [laughing]

00:36:33.820 | That's a joke at my expense, by the way.

00:36:36.340 | But it's- - We end up in the same spot.

00:36:39.260 | [laughing]

00:36:41.740 | - Physically, if not professionally,

00:36:44.180 | but nonetheless, it's been a marvelous story thus far.

00:36:48.420 | And I'd like to, maybe you could give us,

00:36:50.720 | I'd like to just touch on a couple examples

00:36:53.220 | of where the technology resides in laboratories now.

00:36:56.820 | So maybe the range of animals that it's being used in

00:36:59.220 | and some of the phenomenon that channelrhodopsins

00:37:03.380 | and their related genes and proteins

00:37:06.160 | are starting to elicit what you've seen.

00:37:09.800 | And then I'd like to talk about their applicability

00:37:13.420 | to the clinic, which is, I think,

00:37:15.860 | the bigger mission, if you will.

00:37:18.000 | - Yeah, so this is, you know, this whole thing,

00:37:22.500 | you know, it's been about now going on 17 years

00:37:25.780 | that we've been putting channelrhodopsins into neurons.

00:37:28.420 | It started just like Andrzej Famincin's work in a dish

00:37:32.540 | by 2000, that was in 2004.

00:37:34.720 | In 2007, we were putting these into behaving mice

00:37:38.180 | and we were able to, with a switch,

00:37:41.960 | cause them to move one direction or another.

00:37:44.660 | By 2009-

00:37:45.900 | - So basically, you're controlling the mouse's behavior.

00:37:48.340 | - Yeah, exactly, in real time.

00:37:49.620 | So we could make a mouse that was just sitting there

00:37:51.260 | doing nothing to then turn left very consistently,

00:37:54.620 | in fact, go around in a circle,

00:37:55.940 | and as soon as we turn off the light, it would stop.

00:37:58.060 | That was an eye-opening moment.

00:38:01.540 | It took really a few years to make optogenetics work.

00:38:04.980 | There was a lot of putting all the,

00:38:08.100 | there were a lot of problems that had to be solved.

00:38:09.620 | These channelrhodopsins actually don't move many ions.

00:38:14.140 | They have a small current, small conductance, as we say.

00:38:17.060 | And so we had to figure out ways to pack a lot of them

00:38:20.100 | into cells without damaging cells

00:38:23.420 | and still make them targetable.

00:38:25.140 | So we don't want them to just be in all the cells,

00:38:27.100 | cause then it becomes just like an electrode.

00:38:29.500 | You're just stimulating all the cells that are nearby.

00:38:31.220 | We had to keep that specificity,

00:38:33.620 | make them targetable to just one kind of cell or another

00:38:37.500 | while still packing in large numbers of them

00:38:39.420 | into those cells.

00:38:40.820 | And we had to get in the light in safe and specific ways.

00:38:43.460 | And so it took probably about four or five years

00:38:46.380 | to really create optogenetics between 2004 and 2009.

00:38:50.580 | By the end of that time, though,

00:38:51.780 | we had all the basic light delivery,

00:38:55.900 | gene delivery principles worked out,

00:38:58.500 | and people started to apply the technology to fish,

00:39:03.500 | to rats, to mice, to non-human primates like monkeys.

00:39:08.620 | And just a couple months ago,

00:39:14.260 | my colleague, Botond Roska in Switzerland,

00:39:17.020 | succeeded in putting channelrhodopsins

00:39:19.860 | into the eyes of human beings

00:39:21.660 | and making a blind person see.

00:39:23.820 | And so that's pretty cool.

00:39:26.900 | This was a patient with retinal degeneration,

00:39:30.660 | and he provided a channelrhodopsin

00:39:32.920 | into the eye of this patient

00:39:34.860 | and was able to confer some light sensitivity

00:39:36.860 | onto this patient that wasn't there before.

00:39:38.780 | - An amazing paper and discovery.

00:39:40.620 | I realize it was one patient,

00:39:42.100 | but it's such an important milestone.

00:39:44.060 | - Well, as you say, it's a very important milestone,

00:39:46.840 | and the history of that is very deep.

00:39:50.660 | Almost 10 years earlier,

00:39:52.260 | Botond, Roska, and I had published a paper in Science

00:39:55.460 | in human retina, but explanted, taken from cadavers

00:39:59.460 | from someone who had died, living retina,

00:40:01.940 | taken out, opsins put into this retinal tissue,

00:40:06.940 | and showing that it worked, recording from the cells,

00:40:09.600 | showing that in these human neurons, retinal neurons,

00:40:12.160 | that you could get light responses.

00:40:14.620 | But then, from that moment,

00:40:16.740 | almost 10 years of how clinical development goes,

00:40:20.060 | and this is a gene therapy,

00:40:21.580 | so you've got all the regulations and concerns and all that.

00:40:25.220 | It took almost 10 years to get to this point now

00:40:27.780 | where a living human being has a new functionality

00:40:30.860 | that wasn't there before.

00:40:32.800 | Now, that's incredibly inspiring,

00:40:34.780 | and it's a beautiful thing.

00:40:38.300 | I would say, though, that the broader significance

00:40:42.900 | of optogenetics is really still understanding,

00:40:45.140 | because once you understand how the circuitry works

00:40:48.660 | and which cells actually matter,

00:40:50.460 | then any kind of treatment becomes more grounded

00:40:53.680 | and logical and specific and principled.

00:40:57.180 | And whether it's a medication or a talk therapy

00:40:59.360 | or brain stimulation treatment

00:41:00.780 | with electrical or magnetic means,

00:41:03.480 | if you actually know what matters,

00:41:05.560 | that is incredibly powerful.

00:41:06.760 | And I think, no, not intended to disparage

00:41:11.760 | the beautiful retinal work and conferring vision

00:41:16.280 | on someone who couldn't see, of course, that's wonderful.

00:41:19.440 | But, and that's direct, what you might call

00:41:22.540 | direct optogenetics in patients.

00:41:24.140 | Indirect is everything that comes from understanding.

00:41:27.420 | Okay, we know these cells matter now for this symptom.

00:41:30.340 | Well, how can we target those cells

00:41:33.040 | and help them work better in patients by any means?

00:41:35.580 | And I think that's the broader significance

00:41:37.640 | of optogenetics clinically.

00:41:39.220 | - You and I know Boton well,

00:41:40.720 | and you and Boton share this incredible big vision

00:41:45.720 | that I think only a clinician can really understand,

00:41:50.340 | being in close contact with and the suffering of patients

00:41:54.580 | as a ultimate motivator of developing technologies,

00:41:57.640 | which makes me have to ask,

00:42:00.340 | did you decide to become a scientist

00:42:02.880 | to find cures for mental disease?

00:42:06.300 | - No, I didn't.

00:42:09.660 | It's a really important question to actually look back

00:42:12.480 | and see the steps that brought you to a particular place.

00:42:16.480 | And that was not what brought me initially to science.

00:42:20.620 | And it's okay to, I think, to embrace the twists and turns

00:42:24.360 | that life brings to you.

00:42:27.360 | But I was always interested in the brain.

00:42:29.060 | And so that was something that for me started

00:42:32.600 | from a very early age.

00:42:34.420 | I was, you know, we talked about being introspective.

00:42:36.860 | I noticed very early on,

00:42:38.800 | I had a deep love of poetry and stories,

00:42:43.440 | and I was a voracious reader.

00:42:46.540 | And I was amazed by how words could make me feel

00:42:51.540 | in particular ways, even separate from their, you know,

00:42:57.020 | of course, dictionary meanings, the rhythm,

00:42:59.320 | and how they work together, even separate from meaning.

00:43:03.180 | And I was stunned by poets that could use words

00:43:06.540 | in new ways that were even divorced

00:43:09.380 | from their meaning at all,

00:43:10.400 | and yet could still trigger specific emotions.

00:43:12.420 | And I was, this was always fascinating to me.

00:43:15.780 | So, you know, I wanted to understand that.

00:43:19.780 | And so I was interested,

00:43:21.140 | and I became interested in the brain.

00:43:23.260 | And I thought, well, I'm gonna have to study the human brain

00:43:26.720 | because only human beings can describe

00:43:31.180 | what's going on inside enough.

00:43:33.200 | So in college, I began to steer myself toward medicine

00:43:38.480 | and with the idea of becoming a neurosurgeon.

00:43:41.900 | And so I came here to medical school

00:43:46.900 | and did an MD/PhD program,

00:43:48.880 | planning neurosurgery all the way through.

00:43:52.080 | The first rotation I did at the end of medical school,

00:43:55.780 | as you know, you do rotations,

00:43:57.500 | you go through different specialties,

00:43:59.060 | and some of these are required rotations

00:44:01.060 | that everybody has to do.

00:44:01.900 | Some are elective, where you can pick what you wanna do.

00:44:04.820 | I elected to do neurosurgery first,

00:44:08.180 | even before regular surgery,

00:44:09.780 | I was not sure I wanted to do it, and I loved it.

00:44:11.980 | I had a fantastic time.

00:44:13.380 | There was an amazing patient who had a thalamic damage,

00:44:17.580 | and there was a neglect syndrome

00:44:19.020 | where the patient was not able to be aware of something

00:44:22.600 | that was right in front of him.

00:44:24.820 | - Even though their vision was perfectly fine.

00:44:25.980 | - Even though their vision was perfectly fine, exactly.

00:44:28.860 | And so I was, and I loved the operating room.

00:44:31.460 | I loved the rhythm of suturing and the precision of it.

00:44:36.260 | And I loved being able to help patients immediately.

00:44:40.000 | But then a required rotation was in psychiatry,

00:44:44.220 | which I was not looking forward to at all.

00:44:48.400 | And that completely reset my whole life,

00:44:51.520 | that experience in psychiatry.

00:44:53.920 | And it was at that moment that I saw this is,

00:44:58.000 | first of all, the greatest need, the depth of suffering

00:45:01.840 | and the depth of the mystery together.

00:45:05.760 | And also it was, I almost feel a little guilty about this.

00:45:09.160 | It's so interesting too.

00:45:10.840 | Yes, yes, yes, we can help.

00:45:13.820 | Yes, there's need.

00:45:14.800 | But as a scientist, this is amazing

00:45:18.280 | that someone's reality can be different from my own.

00:45:22.120 | With everything physically, as far as we can tell,

00:45:25.360 | the same with the measures we have,

00:45:29.020 | and yet we've got a different reality.

00:45:30.440 | That is an amazing thing.

00:45:32.080 | And if we couldn't understand that and help these people,

00:45:35.240 | that would be just more than anybody could ask for it.

00:45:39.320 | And so that's how I ended up taking this path,

00:45:42.460 | just a required rotation in psychiatry.

00:45:46.280 | - It all started with poetry.

00:45:47.920 | - And it started with poetry.

00:45:49.320 | - Yeah, out of respect for poetry,

00:45:52.320 | are there any favorites that you spend time with

00:45:54.880 | on a regular basis?

00:45:57.500 | - I mean, the ones who got me down this path early on,

00:46:02.600 | I remember in childhood in high school,

00:46:05.520 | Borges had an immense influence on me.

00:46:08.400 | I studied Spanish all the way through and reading his work.

00:46:14.080 | He was a great writer.

00:46:15.560 | He wrote both in English and in Spanish,

00:46:17.560 | and being able to appreciate his poetry both in English

00:46:20.680 | and in Spanish was a pretty amazing thing.

00:46:23.120 | Not many poets can do that.

00:46:25.640 | - You're bilingual.

00:46:26.480 | - I'm not, I wouldn't say now.

00:46:28.560 | I became, at one point I was effectively fluent in Spanish,

00:46:32.300 | and I'm pretty good with medical Spanish still,

00:46:34.520 | because we use Spanish all the time in the clinic here.

00:46:38.940 | I wouldn't claim full fluency,

00:46:41.460 | but it's something I definitely use all the time.

00:46:44.240 | And it's been very helpful in the clinic.

00:46:45.900 | - Yeah, Borges is wonderful.

00:46:47.000 | As the son of an Argentine, I grew up hearing about it,

00:46:49.820 | and I learned that Borges' favorite city was Geneva.

00:46:53.560 | So I spent time in Geneva only for that reason.

00:46:56.360 | It also turns out to be an interesting city.

00:47:00.200 | So you developed methods to control neurons

00:47:04.720 | with these algae proteins using light.

00:47:08.740 | In 2015, there was this,

00:47:12.680 | what I thought was a very nice article

00:47:14.340 | published in "The New Yorker" describing your work

00:47:17.200 | and the current state of your work

00:47:19.920 | in the laboratory in the clinic,

00:47:21.600 | and an interaction with a patient.

00:47:24.440 | So this is, as I recall, a woman who was severely depressed.

00:47:28.320 | And you reported in that article

00:47:30.360 | some of the discussion with this patient,

00:47:32.480 | and then in real time,

00:47:34.800 | increased the activation of the so-called vagus nerve,

00:47:38.240 | this 10th cranial nerve that extends out of the skull

00:47:40.360 | and innervates many of the viscera and body.

00:47:43.280 | What is the potential for channelrhodopsins,

00:47:48.840 | or related types of algae engineering,

00:47:52.300 | to be used to manipulate the vagus?

00:47:56.160 | Because I believe in that instance,

00:47:57.360 | it wasn't channelopsin stimulation,

00:47:58.960 | it was electrical stimulation, right?

00:48:00.720 | Or to manipulate, for instance,

00:48:02.240 | a very small localized region of the brain.

00:48:04.840 | Let me frame it a little bit differently

00:48:07.400 | in light of what we were talking about

00:48:08.360 | a couple of minutes ago.

00:48:09.560 | My understanding is that if somebody has severe depression

00:48:14.000 | and they take any number of the available

00:48:17.320 | pharmaceutical agents that are out there,

00:48:19.640 | SSRI, serotoninergic agents,

00:48:22.040 | increased dopamine, increased whatever,

00:48:24.000 | that sometimes they experience relief,

00:48:26.360 | but there are often serious side effects.

00:48:28.200 | Sometimes they don't experience relief,

00:48:29.920 | but as I understand it,

00:48:32.080 | channelopsins and their related technology, in principle,

00:48:35.640 | would allow you to turn on or off

00:48:39.640 | the specific regions of the brain

00:48:41.560 | that lead to the depressive symptoms,

00:48:43.380 | or maybe you turn up a happiness circuit

00:48:45.480 | or a positive anticipation circuit.

00:48:49.780 | Where are we at now in terms of bringing this technology

00:48:53.400 | to the nervous system?

00:48:54.960 | And let's start with the body and then move into the skull.

00:48:58.920 | - Yeah, so starting with the body is a good example

00:49:01.440 | because it highlights the opportunity

00:49:04.680 | and how far we have to go.

00:49:06.700 | So let's take this example of vagus nerve stimulation.

00:49:09.720 | So the vagus nerve, it's the 10th cranial nerve.

00:49:12.080 | It comes from the brain, it goes down,

00:49:14.080 | it innervates the heart, innervates the gut.

00:49:16.400 | And by innervate, I mean it sends little connections down

00:49:18.880 | to help guide what happens in these organs

00:49:22.120 | in the abdomen and chest.

00:49:25.840 | It also collects information back,

00:49:27.800 | and there's information coming back from all those organs

00:49:30.720 | that also go through this vagus nerve,

00:49:32.680 | the 10th cranial nerve, back to the brain.

00:49:35.200 | And so this is somewhat of a super highway to the brain then

00:49:39.520 | was the idea.

00:49:40.340 | And maybe the idea is maybe we could put a little cuff,

00:49:43.160 | a little electrical device around the vagus nerve itself

00:49:48.160 | and maybe have just like a pacemaker battery,

00:49:50.680 | have a little power source here under the clavicle,

00:49:53.360 | everything under the skin,

00:49:55.040 | and have a little cuff and drive signals,

00:49:57.940 | and maybe they'll get back to the brain.

00:49:59.360 | So a way of getting into the brain

00:50:00.920 | without putting something physical into the brain.

00:50:03.700 | - And why the vagus?

00:50:04.760 | I mean, it's there, and it's accessible.

00:50:06.880 | - That's the reason.

00:50:07.800 | - That's the reason?

00:50:08.640 | - That's the reason, yes.

00:50:09.460 | - Really? - Yeah.

00:50:10.300 | - You're not kidding. - I'm not kidding.

00:50:11.360 | - So stimulating the vagus to treat depression

00:50:13.680 | simply because it's accessible.

00:50:15.400 | - It started as actually as an epilepsy treatment,

00:50:19.420 | and it can help with epilepsy, but yes,

00:50:21.920 | it's simply because it's accessible.

00:50:22.760 | - You got to love the medicine.

00:50:23.660 | As a scientist, this is where I get to chuckle and just say,

00:50:26.900 | I mean, the field of medicine, from that perspective,

00:50:30.220 | from the perspective of a scientist and outsider,

00:50:33.160 | the field of medicine as a field that goes in

00:50:35.360 | and tickles pathways because they're there,

00:50:39.820 | it's, I don't know what to say, it's a little shocking.

00:50:44.620 | - Yeah.

00:50:46.460 | - And we all, at least in my laboratory,

00:50:50.020 | I always say you never do an experiment because you can.

00:50:53.000 | You do an experiment to test a specific hypothesis.

00:50:56.040 | - Yeah, yeah.

00:50:57.300 | I mean, there are stories people tell.

00:50:59.600 | So the vagus nerve lands on a particular spot on the brain

00:51:04.320 | called the solitary tract nucleus,

00:51:05.920 | which is just one synapse away from the serotonin

00:51:09.280 | and dopamine and the norepinephrine.

00:51:10.680 | - So there's a link to chemical systems in the brain

00:51:13.280 | that make it a rational choice.

00:51:14.760 | - Yes, it's not irrational,

00:51:16.200 | but I can tell you that even if that were not true,

00:51:19.340 | the same thing would have been tried, you know?

00:51:21.800 | - You actually would have done it anyways.

00:51:22.640 | - Because it's accessible, yeah.

00:51:23.900 | - I see, okay.

00:51:24.980 | - And why?

00:51:26.940 | Well, it's, again, not to disparage what's been happening

00:51:31.940 | in this branch of medicine.

00:51:33.920 | There's immense suffering, treatments,

00:51:36.180 | many treatments don't work, and we try things.

00:51:39.780 | And this is how so many advances in medicine happen.

00:51:42.980 | You think about kidney dialysis,

00:51:44.640 | which has kept many people alive.

00:51:46.680 | That was just started by someone saying,

00:51:48.360 | hey, let's try this.

00:51:49.720 | Maybe there's something building up in the blood.

00:51:51.480 | Maybe we can dialyze something and help them.

00:51:53.400 | Yeah, it worked.

00:51:54.240 | And it was just sort of a test pilot mentality.

00:51:56.640 | We can access the blood.

00:51:59.680 | Let's run it across a dialysis membrane,

00:52:01.720 | put it back in the body.

00:52:02.680 | Oh my God, that actually works.

00:52:03.920 | And sometimes you do need that test pilot mentality,

00:52:06.920 | of course, to do it in a rigorous, safe, controlled way,

00:52:10.120 | which is what we do.

00:52:10.960 | And so, anyway, that's how we ended up with,

00:52:14.520 | but still, with the vagus nerve stimulation,

00:52:16.640 | okay, so what does it, does it work?

00:52:18.720 | It has, it's FDA approved for depression,

00:52:22.780 | this vagus nerve stimulation.

00:52:24.080 | But on a population level,

00:52:25.520 | if you average across all people,

00:52:28.120 | the effect sizes are pretty small.

00:52:30.720 | Some patients it has an amazing effect in,

00:52:33.660 | but some patients it doesn't work at all.

00:52:35.520 | And average across everybody,

00:52:37.200 | the effect size is pretty small.

00:52:38.480 | - How do you think it's working when it does work?

00:52:39.960 | Is it triggering the activation of neurons

00:52:42.420 | that release more serotonin or dopamine?

00:52:44.440 | - It could be, but I would say

00:52:46.080 | we don't have evidence for that.

00:52:47.880 | And so I just don't know.

00:52:50.480 | But what is clear is that it's dose limited

00:52:53.320 | in how high and strongly we can stimulate and why.

00:52:57.280 | It's because it's an electrode

00:52:58.940 | and it's stimulating everything nearby.

00:53:01.460 | And when you turn on the vagus nerve stimulator,

00:53:03.680 | the voice, patient's voice becomes strangulated and hoarse.

00:53:07.200 | They can have trouble swallowing.

00:53:09.040 | They can have trouble speaking for sure.

00:53:11.340 | Even some trouble breathing

00:53:13.000 | because everything in the neck,

00:53:14.320 | every electrically responsive cell and projection

00:53:17.600 | in the neck is being affected by this electrode.

00:53:20.060 | And so you can go up just so far with the intensity

00:53:24.040 | and then you have to stop.

00:53:25.720 | So to your initial question,

00:53:28.000 | could a more precise stimulation method

00:53:31.040 | like optogenetics help in this setting?

00:53:33.420 | In principle, it could,

00:53:34.360 | because if you would target the light sensitivity

00:53:38.120 | to just the right kind of cell,

00:53:39.800 | let's say cell X that goes from point A to point B

00:53:44.060 | that you know causes symptom relief of a particular kind,

00:53:47.400 | then you're in business.

00:53:48.240 | You can have that be the only cell that's light sensitive.

00:53:51.500 | You're not going to affect any of the other cells,

00:53:53.460 | the larynx and the pharynx

00:53:54.920 | and the projections passing through.

00:53:57.460 | So that's the hope.

00:53:58.300 | That's the opportunity.

00:53:59.120 | The problem is that we don't yet have

00:54:01.480 | that level of specific knowledge.

00:54:02.900 | We don't know, okay,

00:54:04.640 | it's the cell starting in point A going to point B

00:54:07.440 | that relieves this particular symptom.

00:54:09.200 | - We want to fix this key on the piano.

00:54:11.040 | - Yeah.

00:54:11.880 | Then I see two other steps that are required.

00:54:14.980 | One is to get the channelopsin gene into the cell.

00:54:17.540 | In the case of Boton,

00:54:18.700 | Rosca and colleagues rescuing vision in this patient,

00:54:21.740 | they did that by an injection of a virus

00:54:25.540 | that doesn't damage the neurons.

00:54:27.620 | The virus itself is fairly innocuous,

00:54:30.300 | but carries a cargo,

00:54:31.780 | and it's a one-time injection.

00:54:33.080 | The cells express,

00:54:34.060 | and then they used light to stimulate.

00:54:36.300 | So let's say I'm depressed,

00:54:40.020 | which I don't think I am,

00:54:41.140 | although now sitting in front of a psychiatrist,

00:54:42.940 | you probably can see signs that maybe I am,

00:54:44.920 | or maybe I'm not.

00:54:46.020 | But let's say we put channelopsin

00:54:48.600 | into a specific branch of the vagus

00:54:51.840 | that we understand is responsible for mood.

00:54:56.580 | How are we going to get it in there?

00:54:58.360 | And then how are we going to deliver the light?

00:55:00.320 | 'Cause we're not talking about sunlight

00:55:01.760 | or standing in front of a light bulb necessarily,

00:55:04.260 | but what are the mechanisms for the body?

00:55:07.020 | - Yeah.

00:55:07.860 | So we had to solve exactly these questions.

00:55:09.580 | You're saying, how do you get the light in?

00:55:10.920 | How do you get the gene in,

00:55:12.520 | in a potent and robust and safe way?

00:55:16.640 | And that's now solved,

00:55:19.000 | and that's not a challenge.

00:55:20.760 | So there are very safe,

00:55:22.480 | well-tolerated gene delivery mechanisms

00:55:27.400 | that are called adeno-associated viruses, AAVs.

00:55:31.160 | And these are things that are associated

00:55:34.220 | with the common cold.

00:55:35.720 | They themselves don't cause any symptoms.

00:55:39.360 | They've been engineered,

00:55:40.380 | and there's been a broad community of viral engineering

00:55:43.400 | that's been going on for decades,

00:55:44.660 | making these safer, well-tolerated, and so on.

00:55:48.300 | We can put the channelrhodopsin gene

00:55:49.920 | into these viral vectors that deliver the gene,

00:55:54.920 | and we can have little bits of additional DNA

00:55:57.560 | that govern expression only in one kind of cell,

00:56:00.000 | but not another.

00:56:00.840 | These are called promoters and enhancers,

00:56:03.160 | all genetic tricks built up by a very broad community

00:56:06.040 | of great scientists over the decades.

00:56:08.840 | We can put these different bits of DNA,

00:56:10.740 | package them into this AAV, this little virus,

00:56:13.800 | and that can be then injected

00:56:16.600 | into a particular part of the body.

00:56:20.400 | And sticking with this vagus nerve example,

00:56:23.220 | we know that there are particular clumps of neurons.

00:56:25.600 | There's one called the nodos ganglion

00:56:27.880 | that has a clump of cells related to the vagus nerve,

00:56:32.040 | and you could, for example,

00:56:33.260 | target a little injection into that ganglion.

00:56:35.960 | - Would that be an outpatient procedure?

00:56:37.600 | - Yeah, yeah.

00:56:38.440 | - Come in in the morning, get your injection,

00:56:40.240 | maybe walk out a few hours later.

00:56:41.680 | - Yeah, that's right.

00:56:42.680 | And so that's the gene.

00:56:44.180 | Then the light delivery.

00:56:46.380 | This is also something that we've worked out.

00:56:48.660 | We've worked on making very, very light-sensitive opsins.

00:56:52.560 | One challenge, and Botand would be the first to state this,

00:56:57.480 | in fact, in solving this problem for the patient,

00:57:00.120 | he had to build goggles that created much brighter light

00:57:05.840 | than the normal ambient light delivery.

00:57:08.740 | Because as I mentioned earlier,

00:57:10.600 | you have to pack a lot of these channelrhodopsins in.

00:57:13.920 | They don't have much current.

00:57:15.640 | You have to really make sure

00:57:17.200 | that you've got a tense enough light

00:57:19.520 | to activate enough of them to cause a stimulation.

00:57:21.720 | - And it has to be the right wavelength, correct?

00:57:23.120 | - It has to be the right wavelength.

00:57:23.960 | - And going back to your example

00:57:24.800 | of the algae moving toward or away the light,

00:57:28.480 | it has to be tuned just right.

00:57:30.160 | So could you, I'm imagining in my mind as a non-engineer,

00:57:34.400 | I know you're also a bioengineer,

00:57:36.840 | I'm imagining a little tiny blue light emitting thing,

00:57:42.560 | object that's a little bigger than a clump of cells

00:57:47.200 | or maybe about the size of a clump of cells.

00:57:49.360 | And for those who don't know,

00:57:50.800 | your credit card is about 200 microns thick on the side

00:57:56.560 | and a micron is a thousandths of a millimeter.

00:57:58.760 | And so we're talking about a little tiny stamp

00:58:03.380 | that's basically half a millimeter in size all around.

00:58:08.380 | Each edge, half a millimeter in size.

00:58:12.400 | I can imagine that being put under my skin

00:58:14.840 | and then I would hit an app on my phone

00:58:17.560 | and I'd say, "Dr. Deisseroth, I'm not feeling great today.

00:58:22.220 | Can I increase the stimulation?"

00:58:23.680 | And you say, "Go for it."

00:58:24.760 | And then I ramp it up.

00:58:25.680 | Is that how it would go?

00:58:26.520 | - I mean, that's effectively what we already do

00:58:28.220 | with the vagus nerve stimulation, the doctor in this case.

00:58:31.040 | And I have this in some of my patients in the clinic.

00:58:33.280 | I do vagus nerve stimulation.

00:58:34.480 | I talk to them.

00:58:35.320 | I say, I go through the symptoms.

00:58:37.380 | I use the psychiatric interview

00:58:39.100 | to elicit their internal states.

00:58:41.200 | And then I have a radio frequency controller

00:58:44.060 | that I can dial in.

00:58:45.620 | - Right there in real time.

00:58:46.460 | - Right there in real time.

00:58:47.280 | - You're holding the remote control

00:58:48.480 | essentially to their brain,

00:58:49.760 | although it's remote, remote control.

00:58:51.420 | - Through a couple of steps, but yeah.

00:58:53.460 | And I can turn up the frequency.

00:58:56.400 | I can turn up the intensity

00:58:58.420 | all with the radio frequency and control.

00:59:02.200 | And then it's reprogrammed or redosed.

00:59:05.520 | And then the patient can then leave at this altered dose.

00:59:09.000 | - So this is happening now.

00:59:10.100 | - This is happening right now, electrically.

00:59:11.280 | - You do this routinely.

00:59:12.200 | - I do it routinely in my clinic, electrically.

00:59:14.080 | - And you're getting the verbal content,

00:59:17.160 | which as you described earlier,

00:59:19.520 | is the indication of how well

00:59:21.480 | something is working in real time.

00:59:23.400 | So maybe you could just describe a little bit

00:59:25.280 | of the interaction with that particular patient

00:59:27.200 | or another patient.

00:59:28.300 | What's a typical arc of narrative

00:59:32.460 | as you go from no stimulation to increased stimulation?

00:59:36.180 | - In most patients, the actual therapeutic effects,

00:59:39.540 | the benefits actually take many days to weeks.

00:59:42.980 | And so what I'm mostly focusing on in the office

00:59:46.620 | in real time is making sure

00:59:48.420 | I'm in a safe, low side effect regime.

00:59:51.300 | And so first I talked to the patient,

00:59:53.460 | who has been on a particular dose of the stimulation

00:59:56.220 | for weeks or longer.

00:59:58.700 | And I talked about symptoms.

01:00:00.500 | How were things over the past month?

01:00:02.740 | How was your hope?

01:00:03.560 | How was your energy level?

01:00:05.000 | Sleep, what is your mood?

01:00:07.020 | And then we talk with the patient and we decide,

01:00:10.060 | oh, this is not yet where we'd like to be.

01:00:12.260 | And so then I can turn up the intensity of the stimulation

01:00:15.740 | in real time in the office.

01:00:17.460 | In most patients, I don't expect an immediate mood change.

01:00:21.100 | What I do is I increase the dose

01:00:23.180 | until a next level up while asking the patient

01:00:27.340 | for side effects.

01:00:28.180 | Can you still breathe okay?

01:00:29.460 | Can you still swallow okay?

01:00:30.820 | And I can hear their voice as well.

01:00:32.220 | And I can get a sense--

01:00:33.060 | - And you're looking at their face.

01:00:33.900 | - And I'm looking at their face.

01:00:34.980 | And so I can get a sense, is there a,

01:00:37.500 | am I still in a safe side effect regime?

01:00:40.420 | And then I stop at a particular point that looks safe

01:00:45.420 | and then patient goes home, comes back a month later,

01:00:49.460 | and I get the report on how things were over that month.

01:00:53.200 | I asked if you're looking at their face

01:00:54.940 | 'cause in your book,

01:00:56.040 | you described the incredible complexity

01:01:00.040 | of social interactions.

01:01:01.860 | And at one point,

01:01:04.340 | you described the incredible amount of information

01:01:09.100 | that the eyes inform about the brain

01:01:12.260 | and the context of somebody's inner experience,

01:01:14.900 | whether depressed or happy or otherwise.

01:01:17.180 | I want to make sure that we get back

01:01:19.540 | to how to maneuver and manipulate the nervous system

01:01:23.240 | for sake of mental health.

01:01:24.420 | But what are you looking for?

01:01:28.820 | So as a vision scientist,

01:01:30.280 | I think pupils dilating is a sign of arousal,

01:01:33.140 | but that could be a positive arousal,

01:01:34.800 | positive valence like excitement, or it could be terror.

01:01:38.260 | You're going to get the same dilation of the pupils.

01:01:40.860 | And I'm always reminding people

01:01:43.940 | that these two little goodies are two pieces of brain,

01:01:45.900 | basically, they're just outside the cranial vault.

01:01:47.940 | So they're not unlike the vagus in that sense,

01:01:49.780 | but they're more of a report than a control knob,

01:01:52.300 | although I like to think they could be used

01:01:54.720 | as control knobs too.

01:01:55.820 | So without putting you on the spot, again, to diagnose me,

01:02:01.380 | something I would never ask you to do

01:02:03.300 | with the cameras rolling,

01:02:04.540 | but what are you looking for

01:02:06.940 | that the patient might not be aware of?

01:02:09.160 | In other words, can you see depression in somebody's eyes?

01:02:12.560 | And if you know a patient or if you don't,

01:02:15.220 | can you see it in their body posture when they walk in?

01:02:19.140 | Realizing, of course, that a trained psychiatrist

01:02:22.380 | like yourself develops an intuitive sense

01:02:25.260 | that's aggregating lots of different features of a patient.

01:02:29.020 | But what about the eyes?

01:02:30.220 | What's going on there?

01:02:32.060 | - The eyes are incredibly rich in information.

01:02:34.580 | And as you allude to though,

01:02:37.560 | it's not as if any one measurable

01:02:40.900 | conveys all the information you need.

01:02:42.420 | It's what an engineer would say joint statistics.

01:02:46.140 | It's many things all at once,

01:02:49.020 | whether they're in synchrony or out of synchrony

01:02:52.060 | that actually turns out to matter.

01:02:54.700 | And the eye contact question,

01:02:57.980 | we all know eye contact is incredibly important.

01:03:00.120 | You don't feel you've connected with somebody

01:03:02.620 | unless there's eye contact.

01:03:04.420 | But eye contact can go awry too.

01:03:06.260 | It can be too intense or it can be mistimed

01:03:11.900 | or if there's someone with autism,

01:03:15.540 | it can be barely there at all.

01:03:17.300 | And this is one of the most striking symptoms of autism

01:03:21.260 | is the avoidance of eye contact

01:03:23.980 | almost as if it's a harmful quantity.

01:03:31.660 | And so there's an immense amount of information

01:03:35.180 | you get from the eyes,

01:03:36.440 | but it's the pairing of what's going on in the eyes

01:03:40.380 | with everything else going on, the body language,

01:03:43.160 | the verbal content of what's coming out.

01:03:46.900 | All that together is the art of psychiatry

01:03:50.620 | and social interaction.

01:03:53.180 | But sometimes you don't have the eye contact.

01:03:55.180 | And this is an amazing thing.

01:03:56.280 | And I do talk about this in the book as well.

01:03:58.140 | In many cases in psychiatry,

01:04:00.540 | sometimes it's over the phone

01:04:01.620 | that you have to make key decisions.

01:04:04.120 | And I recall vividly being as a resident very often

01:04:10.120 | you have to take these phone calls

01:04:12.720 | from people who are not in the hospital,

01:04:17.080 | people you can't see.

01:04:18.300 | You can't see their eye, you can't see their body,

01:04:20.360 | anything about them, just the sound of their voice.

01:04:23.200 | And you can ask them questions

01:04:24.720 | and you have to make, in some cases, life or death decisions.

01:04:28.480 | Is this person truly suicidal?

01:04:31.720 | Something like that as it comes up all the time.

01:04:34.120 | And so I developed over the course of training

01:04:38.800 | and I think all psychiatrists do this

01:04:41.840 | is you develop a way to whatever data stream you have,

01:04:44.980 | whether it's the eyes or whether it's just the sound

01:04:47.480 | of a voice coming over the phone,

01:04:49.520 | you learn to home in on that data stream you have

01:04:51.720 | and focus on it and identify changes.

01:04:55.340 | And it's quite amazing.

01:04:58.600 | I found that you can actually, if you know a patient,

01:05:03.360 | you can detect very precise changes in mood

01:05:05.720 | just from the sound of the voice.

01:05:07.180 | And you can have a realization

01:05:11.000 | that, oh, this patient's depression has improved

01:05:13.400 | by about half, just by the tone of their voice.

01:05:18.600 | And same with eyes, with enough practice,

01:05:21.400 | you can get enough information from a single data stream

01:05:24.760 | to give you some information.

01:05:26.380 | But when you do have the whole picture,

01:05:27.940 | that of course is best.

01:05:29.860 | - So many theories out there

01:05:32.240 | about excessive blinking and lying,

01:05:36.000 | lack of blinking and sociopathy.

01:05:38.080 | I like to remind people that people have varying degrees

01:05:42.400 | of lubrication of the eyes,

01:05:43.620 | which also influence the frequency of blinking

01:05:45.740 | and presumably have nothing to do with whether or not

01:05:48.880 | what they're saying is true or not.

01:05:50.800 | But incredible nonetheless,

01:05:52.320 | that the eyes are a portal to overall arousal state.

01:05:56.520 | I'm fascinated by the effects of light on circadian biology

01:05:59.020 | and just overall desire to be awake or asleep, et cetera.

01:06:04.160 | - So the eyes are on the outside of the cranial vault.

01:06:06.440 | The vagus is outside the cranial vault, obviously.

01:06:10.820 | What about the goodies in here?

01:06:14.520 | Parkinson's, we know at least one of the major sites

01:06:19.040 | of degeneration and failure that lead to those symptoms.

01:06:22.320 | I can name off any number of other things.

01:06:25.860 | In your book, you talk about the beautiful work

01:06:27.560 | done with optogenetics of active versus passive coping,

01:06:30.520 | that there are areas of the brain,

01:06:31.600 | like the habenula that make, when active, make animals

01:06:34.920 | and presumably people passive and unwilling

01:06:38.660 | or uninterested in fighting back against pressures of life.

01:06:42.160 | Whereas another region, the raphe, you stimulate that

01:06:46.120 | and they actively cope, they get their grit going

01:06:49.520 | and they are able to lean into life.

01:06:51.860 | So how does one get to those structures in a focused way?

01:06:57.540 | And what does the next two to five to 10 years look like?

01:07:02.540 | - Yeah, well, this is the promise on that

01:07:05.420 | and it is on that timescale

01:07:08.220 | that I think things may start to play out.

01:07:10.800 | You know, the specificity of optogenetics

01:07:14.880 | is really only useful if you have some idea

01:07:18.220 | of how to use that specificity.

01:07:20.460 | And it's an actually, it's a frustrating aspect

01:07:23.860 | of psychiatry that in many cases,

01:07:26.300 | the most effective treatments we have

01:07:28.940 | have the least specificity.

01:07:30.940 | Electroconvulsive therapy being a great example

01:07:33.280 | where you're causing a brain-wide-

01:07:34.880 | - Which looks barbaric, but as you mentioned, is effective.

01:07:37.680 | - I mean, it is, these days, it's much more clinically-

01:07:41.700 | - It doesn't look like one flu,

01:07:42.860 | the last seen in one flu over the cuckoo's nest.

01:07:45.260 | - Now it's a very clinically safe and stable procedure,

01:07:47.980 | but where I would say, yeah,

01:07:51.400 | it's got this almost medieval lack of specificity.

01:07:56.260 | Even if the procedure is well-controlled

01:07:58.140 | and clinically safe and stable,

01:07:59.740 | and it has a, it's not very specific.

01:08:02.700 | You're causing a brain-wide seizure.

01:08:04.220 | How could you be less specific than that?

01:08:06.200 | - And we don't know the source of the relief.

01:08:08.980 | We don't, presumably it's a dump of neuromodulators

01:08:11.320 | like dopamine and serotonin, but we don't-

01:08:13.060 | - There certainly is a dump of neuromodulators.

01:08:14.880 | We don't know that that's the cause for the relief.

01:08:18.180 | And likewise with medications,

01:08:20.180 | this is also an interesting thing.

01:08:22.740 | Some of the most effective antidepressants,

01:08:26.140 | some of the most effective anti-psychotics

01:08:28.200 | are the ones that have the most side effects.

01:08:30.700 | And many examples of this, for example,

01:08:32.980 | the most effective anti-psychotic

01:08:35.160 | is something called clozapine,

01:08:36.980 | which has, it's unquestionably has the most side effects.

01:08:39.700 | It had terrible, terrible side effects.

01:08:41.000 | - Is it D4 antagonist?

01:08:42.300 | - It has basically every receptor.

01:08:44.820 | - Does it really?

01:08:45.660 | - Yeah, it acts- - Interesting.

01:08:46.500 | - Yeah, it has prominent serotonin, prominent muscarinic,

01:08:51.000 | certainly acts on dopamine receptors,

01:08:52.840 | but it causes blood cell counts to change.

01:08:57.840 | - How do people feel?

01:08:59.360 | So if I were schizophrenic

01:09:02.040 | and I was getting auditory hallucinations, et cetera,

01:09:05.200 | and I took clozapine, what could I expect to feel?

01:09:10.200 | - Well, so you would notice side effects

01:09:13.520 | and you would notice resolution of symptoms both and-

01:09:16.520 | - So the voices would go away in a good situation.

01:09:20.160 | The voices would go away,

01:09:21.360 | but I would feel not good in my body.

01:09:23.680 | - You would have, you might have dizziness,

01:09:26.240 | you might have drooling,

01:09:28.800 | you might have any number of physical sensations

01:09:33.240 | that would be due to these off-target effects,

01:09:38.160 | the medication acting on these other receptors.

01:09:40.520 | - And I'm certainly not suggesting this,

01:09:41.760 | but what if somebody without schizophrenia took clozapine?

01:09:45.280 | - They had the same side effects, presumably, yeah.

01:09:47.320 | And so it would not be something that I would recommend.

01:09:50.920 | - Do psychiatrists take the drugs that they prescribe?

01:09:53.560 | I just finished, for the third time,

01:09:55.720 | Oliver Sacks' autobiography, which is marvelous

01:09:59.640 | and I highly recommend to people.

01:10:02.080 | He certainly took a lot of drugs,

01:10:03.820 | not as part of his professional role,

01:10:07.120 | but just out of curiosity,

01:10:10.040 | what is the interest or kind of role of drugs

01:10:13.720 | in the field of psychiatry?

01:10:14.960 | Because I would imagine for a group of very curious,

01:10:17.640 | introspective people who are making recommendations

01:10:20.440 | about what to take,

01:10:21.600 | there could actually be some benefit

01:10:23.440 | for understanding what the experience of those drugs

01:10:25.960 | was like for their patients.

01:10:27.320 | - I think that's true.

01:10:28.800 | And I will say that probably many or most psychiatrists

01:10:32.200 | have sampled a number of these

01:10:35.360 | for exactly the reason that you're saying

01:10:37.040 | is to understand better

01:10:38.520 | and to help treat their patients better.

01:10:40.080 | And I've spoken to people who have really been,

01:10:45.080 | have found this very helpful to know,

01:10:47.040 | okay, this sleep disruption caused by this medication

01:10:50.320 | or the libido disruption caused by this other medication,

01:10:53.240 | wow, that is a big effect.

01:10:55.160 | And it really helps with empathy

01:10:57.640 | for the patients to understand.

01:10:59.440 | - I'm not suggesting that physicians

01:11:02.520 | or anybody experiment with drugs,

01:11:05.640 | but I am relieved to hear that

01:11:07.440 | because I think that when you're talking about

01:11:09.640 | accessing somebody's mind and their basic physiology,

01:11:12.540 | as you mentioned, relate to appetite, libido, and sleep,

01:11:15.480 | you really, one is acting as a mechanic

01:11:18.720 | of the person's whole experience.

01:11:20.800 | They walk out of the office

01:11:21.720 | and they have a life experience

01:11:24.320 | that extends beyond the script.

01:11:25.840 | - Yeah. - Yeah.

01:11:27.000 | - And so, yeah, and so at the same time though,

01:11:30.360 | you can't let that completely guide your clinical decisions

01:11:32.740 | because as I mentioned,

01:11:33.900 | some of these medications that have the most side effects,

01:11:36.440 | they are also the most effective.

01:11:38.160 | And clozapine's a great example.

01:11:39.580 | That will work in patients where nothing else works.

01:11:42.460 | And believe me,

01:11:43.300 | we don't take the step of clozapine prescription lightly

01:11:46.680 | because of all these side effects.

01:11:48.260 | You have to come in for a weekly blood cell

01:11:50.640 | or every few weeks of blood cell check

01:11:52.420 | to make sure that the blood counts are not off, for example.

01:11:55.800 | But there are patients where no other medication works

01:11:58.580 | for the schizophrenia and clozapine works amazingly well.

01:12:01.320 | And so we do it even though there are the side effects.

01:12:05.280 | And so then this comes back to your question,

01:12:07.300 | what if we had better and better specificity?

01:12:09.820 | Well, only if we know exactly what we're doing is the point.

01:12:12.940 | And so, because as we become more refined,

01:12:15.880 | we better be right about where we're refining to.

01:12:19.240 | - And you imagine a day where it will be a single,

01:12:22.560 | maybe even outpatient neurosurgery

01:12:24.280 | would go in through the skull or the back of the ear,

01:12:26.380 | deliver a small viral injection

01:12:27.960 | of one of these adenoviruses,

01:12:29.560 | a little sticker of light emitting diode.

01:12:32.520 | Is that deep in the brain?

01:12:34.320 | Is that how you envision this someday?

01:12:36.560 | - That certainly could happen.

01:12:37.680 | What I actually prefer as a vision is still medications

01:12:42.680 | because those are minimally invasive.

01:12:48.720 | If we knew what we were doing,

01:12:49.840 | we could make them more specific, have fewer side effects,

01:12:53.940 | but optogenetics that'll arm us

01:12:56.100 | with true causal understanding.

01:12:58.020 | And so we'll know,

01:12:59.980 | and we're already moving rapidly toward this point,

01:13:02.440 | we'll know, okay, this symptom,

01:13:05.460 | the loss of pleasure in life that we call anhedonia

01:13:08.280 | or the loss of motivation or energy

01:13:12.180 | to overcome challenges, active coping,

01:13:14.360 | these are largely subserved,

01:13:18.540 | largely controlled by this circuit or that circuit

01:13:21.680 | or the cell that inhabits this other circuit.

01:13:24.160 | - And we will know that

01:13:25.040 | because of the work done with channel ops.

01:13:27.380 | - Exactly. - Yeah, I agree.

01:13:28.720 | - In ways that we never could have the confidence otherwise.

01:13:32.260 | And so we'll know that this is the circuit that underlies

01:13:35.680 | the symptom or its resolution.

01:13:38.560 | And then we'll get to understand these cells very deeply.

01:13:42.880 | Okay, these cells that are causal, that do matter,

01:13:46.520 | who are they?

01:13:47.800 | What's their wiring?

01:13:48.820 | What are the proteins that they make?

01:13:51.120 | What are the little things that are on the surface

01:13:54.040 | of the cell that could be receptors for specific medications

01:13:57.560 | or combinations of receptors

01:14:00.280 | that would give us the specificity we need?

01:14:02.820 | And then armed with that causal and precise

01:14:06.440 | and rigorous knowledge,

01:14:07.340 | then you can imagine medication development

01:14:09.980 | becoming totally different, no longer serendipitous,

01:14:13.200 | but truly grounded in causality.

01:14:15.360 | - I see, so using channel ops sense

01:14:17.760 | as a way to probe the circuitry

01:14:19.160 | and figure out the sites that are disrupted,

01:14:22.940 | what patterns of activity are required,

01:14:24.860 | and then by understanding the constituents of those cells,

01:14:28.360 | like what they express and what they make,

01:14:30.000 | then developing drugs that could target those cells,

01:14:32.840 | not necessarily putting light-inducing diodes into the brain

01:14:35.920 | or walking around with wire packs attached to our skull

01:14:39.120 | or something like that.

01:14:40.840 | That's fantastic, and I realize no one has a crystal ball,

01:14:45.840 | but what do you think the arc of that is?

01:14:50.360 | Meaning, are we going to see that in a year,

01:14:53.000 | in two years, three years?

01:14:55.360 | Let me reframe that.

01:14:57.440 | How soon will a pill-based treatment

01:15:00.840 | for a psychiatric disease be available

01:15:03.040 | that targets a specific set of cells

01:15:06.320 | that we know are important

01:15:07.900 | because of the work done with channel ops sense?

01:15:11.920 | - I think that is, in some ways,

01:15:14.440 | it's already happening at the level of individual patients.

01:15:19.080 | - Here at Stanford?

01:15:20.960 | - Yeah, yep, and more broadly in terms of new drugs,

01:15:26.440 | new multicenter clinical trials

01:15:29.880 | that'll play out over the next few years.

01:15:32.180 | And these could be drugs that are already safe

01:15:36.280 | and approved for other purposes,

01:15:39.360 | but we might say, okay, now we know that this medication,

01:15:43.320 | based on what we know from causal optogenetics,

01:15:47.440 | this could be useful for this other purpose,

01:15:50.520 | this psychiatric symptom.

01:15:52.680 | And so the path to helping patients could be relatively swift.

01:15:57.680 | - That's very exciting.

01:16:00.680 | What are your thoughts about brain-machine interface?

01:16:03.880 | And Neuralink always comes up,

01:16:06.720 | although I do want to point out it,

01:16:08.880 | tremendous respect for the folks at Neuralink,

01:16:10.800 | including someone who came up through my lab

01:16:12.480 | is now there as a neurosurgeon,

01:16:13.680 | but the brain-machine interface is something

01:16:16.920 | that's been happening for a long time now.

01:16:19.160 | Some of the best work,

01:16:21.160 | among the best work being done here at Stanford

01:16:23.100 | and elsewhere too, of course.

01:16:25.320 | How is what you just described compatible with

01:16:27.980 | or different than brain-machine interface?

01:16:29.740 | Meaning devices, little probes,

01:16:31.800 | they're going to stimulate different patterns of activity

01:16:33.600 | and ensembles of neurons.

01:16:35.400 | And what are your general thoughts

01:16:36.680 | about brain-machine interface as going forward?

01:16:40.240 | - Yeah, I mean, this is, first of all,

01:16:43.300 | it's an amazing scientific discovery approach.

01:16:47.240 | As you mentioned, we and others here at Stanford

01:16:49.360 | are using electrodes, collecting information

01:16:52.160 | from tens of thousands of neurons.

01:16:54.500 | - In humans, I should add.

01:16:56.340 | - And even, yes, there's quite even separate

01:17:00.320 | from the Neuralink work, as you point out,

01:17:02.120 | many people have been doing this in humans

01:17:05.100 | as well as in non-human primates.

01:17:06.800 | And this is pretty powerful.

01:17:10.280 | It's important.

01:17:11.120 | This will let us understand what's going on in the brain

01:17:13.680 | in psychiatric disease, in neurological disease,

01:17:18.080 | and will give us ideas for treatment.

01:17:20.100 | It is, of course, it's still invasive.

01:17:24.740 | You still are talking about putting a device into the brain

01:17:29.740 | and that has to be treated as a situation

01:17:35.080 | that has some risks

01:17:36.760 | and a step that has to be taken carefully.

01:17:39.360 | I see that as something that will be part of psychiatry

01:17:45.580 | in the long run.

01:17:47.940 | Already with deep brain stimulation approaches,

01:17:51.020 | we can help people with psychiatric disorders

01:17:54.640 | and that's putting just a single electrode,

01:17:56.520 | not even a complex closed loop system

01:18:00.260 | where you're both playing in and getting information back.

01:18:02.780 | Even just a single stimulation electrode in the brain

01:18:05.960 | can help people with OCD, for example, quite powerfully.

01:18:10.060 | And that will become much more powerful

01:18:12.680 | when we get to a true brain machine interface,

01:18:14.980 | collecting information back,

01:18:17.320 | stimulating only when you need to.

01:18:18.880 | If we could identify a pathological activity pattern,

01:18:23.280 | a particular, almost like the prodrome

01:18:25.640 | or the early stage of a seizure,

01:18:27.080 | maybe there are events that happen leading up to,

01:18:30.320 | on some timescale, a psychiatric symptom.

01:18:34.600 | We could intervene in a closed loop way,

01:18:37.280 | detect what's happening, what's starting to go wrong,

01:18:40.240 | feed that back to the brain stimulation electrode,

01:18:43.280 | have it be in that way more efficient and more principled.

01:18:47.280 | This is, I think, it's great.

01:18:50.320 | It's something that of course will be grounded again

01:18:53.400 | in causal understanding.

01:18:54.380 | We'll need to know what is that pathological pattern

01:18:56.720 | that we're detecting and we need to know that it matters.

01:18:59.040 | And so again, that's where optogenetics is helping us

01:19:01.280 | and helping us know, okay, this pattern of activity

01:19:04.160 | in these cells, in these circuits,

01:19:05.620 | this does mean that there's a particular kind of symptom

01:19:10.280 | that's happening.

01:19:12.180 | But armed with that knowledge, absolutely.

01:19:14.260 | Even the simple closed loop device detect and stimulate

01:19:17.560 | is going to be part of psychiatry in the future.

01:19:19.260 | And then of course, as you get to more cells,

01:19:22.600 | more connections, the ability that we have to help people

01:19:25.720 | will become more powerful.

01:19:27.020 | - One of the questions I get asked a lot is about ADHD

01:19:32.120 | and attention deficit of various kinds.

01:19:34.980 | I have the hunch that one reason I get asked so often

01:19:39.160 | is that people are feeling really distracted

01:19:42.280 | and challenged in funneling their attention

01:19:46.020 | and their behavior.

01:19:47.100 | But, and there are a number of reasons for that, of course.

01:19:51.200 | But what is true ADHD?

01:19:54.000 | And what does it look like?

01:19:56.460 | What can be done for it?

01:19:57.960 | And what, if any, role for channel options

01:20:01.360 | or these downstream technologies that you're developing?

01:20:04.720 | What do they offer for people that suffer from ADHD

01:20:08.440 | or have a family member that suffers from ADHD?

01:20:11.440 | - This is a pretty interesting branch of psychiatry.

01:20:16.760 | There's no question that people have been helped

01:20:18.620 | by the treatments.

01:20:20.600 | There's active debate over what fraction of people

01:20:25.440 | who have these symptoms can or should be treated.

01:20:29.800 | - This is typically Adderall or stimulants of some kind.

01:20:32.840 | - For example, the stimulants, that's right.

01:20:34.680 | So ADHD, as its name suggests, it has symptoms of,

01:20:39.360 | it can have either a hyperactive state

01:20:41.860 | or an inattentive state.

01:20:44.360 | And those can be completely separate from each other.

01:20:48.040 | You could have a patient who effectively

01:20:51.460 | is not hyperactive at all,

01:20:53.080 | but can't remain focused on what's going on around them.

01:20:57.040 | - So their body can be still,

01:20:58.440 | but their mind is darting around.

01:21:00.600 | - That's right.

01:21:01.440 | - Or they can be very hyperactive with their body.

01:21:03.320 | - Yeah, it happens both ways.

01:21:04.160 | - Probably rarely is somebody hyperactive with their body,

01:21:06.080 | but their mind is still.

01:21:07.280 | Although I have to say,

01:21:08.120 | and this is a benevolent shout out to Botan Roska,

01:21:11.040 | Botan has an incredibly sharp and focused mind.

01:21:15.380 | And his hand movements are extremely exact also.

01:21:17.960 | So I do sometimes wonder whether or not our body movements

01:21:21.440 | and our head movements are,

01:21:22.920 | whether or not they're coordinated or not is a readout

01:21:25.520 | of how directed our attention is.

01:21:28.480 | - I notice I have to think complex, abstract thoughts.

01:21:31.360 | I notice I have to be very still.

01:21:32.960 | So my body has to be almost completely unmoving

01:21:36.000 | for me to think very abstractly and deeply.

01:21:39.580 | Other people are different.

01:21:40.580 | Some people, when they're running,

01:21:41.760 | they get their best thoughts.

01:21:42.760 | I can't even imagine that.

01:21:44.060 | My brain does not work that way at all.

01:21:45.800 | I have to be totally motionless,

01:21:47.840 | which is kind of interesting.

01:21:48.860 | - How do you go about that?

01:21:50.000 | - I sit much like this.

01:21:52.720 | I try to have time in each day

01:21:56.120 | where I am literally sitting almost in this position,

01:22:01.940 | but without distraction and thinking.

01:22:04.160 | And so it's kind of a,

01:22:05.760 | it's almost meditative in some ways,

01:22:07.400 | except it's not a true meditation,

01:22:10.400 | but I am thinking while not moving.

01:22:12.940 | - You're trying to structure your thoughts in that time.

01:22:15.580 | - Yeah, that's right. - Interesting.

01:22:17.500 | - So, but everybody, as you say, is very different.

01:22:20.720 | And so with ADHD, you have,

01:22:23.160 | the key thing is we want to make sure

01:22:24.560 | that this is present across different domains of life,

01:22:28.960 | school and home,

01:22:30.460 | to show that it really is a pervasive pattern

01:22:32.800 | and not something specific to the teacher

01:22:35.480 | or the home situation or something.

01:22:38.000 | And then you can help patients.

01:22:39.160 | It's interesting that ADHD is one of those disorders

01:22:42.540 | where people are trying to work

01:22:43.880 | on quantitative EEG-based diagnoses.

01:22:46.580 | And so there's some progress toward making up a diagnosis

01:22:50.760 | with looking at particular externally

01:22:53.400 | detectable brainwave rhythms.

01:22:55.320 | - So skull cap with some electrodes

01:22:57.020 | that don't penetrate the skull.

01:22:58.280 | - That's right.

01:22:59.120 | - And this can be done in an hour or two hour session.

01:23:01.720 | - That's right.

01:23:02.560 | - Has to be done in a clinic, right?

01:23:03.940 | - Yeah, in the clinic, right,

01:23:04.940 | you have to have the right recording apparatus and so on,

01:23:07.620 | but that's in principle as increasing confidence

01:23:12.620 | comes in exactly which measurements

01:23:15.440 | one could even imagine moving toward home tests,

01:23:20.500 | but we're not there yet.

01:23:22.420 | - Amazing.

01:23:23.260 | I think one of the reasons I get asked about it so much

01:23:25.260 | is a lot of people wonder if they have ADHD.

01:23:27.980 | Do you think that some of the lifestyle factors

01:23:30.820 | that inhabit us all these days

01:23:34.480 | could induce a subclinical or a clinical-like ADHD,

01:23:39.260 | meaning if I look at people's phone use, including my own,

01:23:42.700 | and I don't think of it like addiction,

01:23:44.460 | it looks to me and feels to me more like OCD.

01:23:47.060 | And I'll come clean here by saying when I was younger,

01:23:48.940 | when I was a kid, I had a grunting tic.

01:23:51.340 | I used to hide it.

01:23:52.180 | I actually used to hide in the closet

01:23:53.500 | 'cause my dad would make me stop.

01:23:55.700 | And I used to, I couldn't feel any relief of my mind

01:23:59.180 | until I would do this.

01:24:00.540 | And actually now, if I get very tired,

01:24:02.940 | if I've been pushing long hours, it'll come back.

01:24:05.540 | I was not treated for it,

01:24:06.960 | but I will confess that I've had the experience of,

01:24:11.740 | I always liked sports where I involved a lot of impact,

01:24:14.440 | fortunately not football, because I went to high school

01:24:16.940 | where the football team was terrible.

01:24:18.420 | Maybe that would have avoided more impact,

01:24:20.280 | but things like skateboarding, boxing, they bring relief.

01:24:24.600 | I feel clarity after a head hit, which I avoid.

01:24:27.980 | But I used to say that's the only time

01:24:30.080 | I feel truly clear for a long,

01:24:31.720 | and then eventually it dissipated.

01:24:33.200 | By about age 16, 17, it just disappeared.

01:24:35.720 | So I have great empathy for those that feel

01:24:40.000 | like there's something contained in them

01:24:41.600 | that won't allow them to focus

01:24:42.840 | on what they want to focus on.

01:24:44.560 | And these days with the phone and all these email, et cetera,

01:24:49.080 | I wonder, and I empathize a bit when I hear people saying

01:24:53.200 | like, "I think I might have ADHD or ADD."

01:24:57.520 | Do you think it's possible that our behaviors

01:25:00.200 | and our interaction with the sensory world,

01:25:02.600 | which is really what phones and email really are,

01:25:04.900 | could induce ADD or reactivate it?

01:25:07.720 | - This is a great question.

01:25:10.440 | I think about it a lot.

01:25:12.640 | And you mentioned this tic-like behavior in yourself.

01:25:16.560 | It's very common that people who have tics

01:25:19.280 | have this building up of something

01:25:20.840 | that can only be relieved by executing the tic,

01:25:23.360 | which can be a motor movement or vocalization

01:25:27.000 | or even a thought.

01:25:28.440 | And people do, I think these days do have this,

01:25:32.560 | if they haven't checked their phone in a while,

01:25:34.240 | they do have a buildup, a buildup, a buildup

01:25:36.140 | until they can check it and relieve it.

01:25:38.560 | And there's some similarities.

01:25:41.040 | There is a little reward that comes with the checking.

01:25:44.800 | But the key question in all of psychiatry,

01:25:48.800 | what we do is we don't diagnose something

01:25:50.980 | unless it's disrupting what we call social

01:25:54.980 | or occupational functioning.

01:25:56.320 | Like you could have any number of symptoms,

01:25:59.200 | but literally every psychiatric diagnosis

01:26:02.440 | requires that it has to be disrupting

01:26:05.680 | someone's social or occupational functioning.

01:26:08.400 | And these days, checking your phone is pretty adaptive.

01:26:11.040 | That pretty much helps your social

01:26:12.840 | and occupational functioning.

01:26:14.000 | And so we can't make it a psychiatric diagnosis

01:26:18.760 | that's interesting, at least in the world of today.

01:26:22.000 | - Yeah, opting out of communication now

01:26:24.360 | makes you in some ways less adaptive,

01:26:27.360 | though I would point to you as an example

01:26:29.800 | of somebody who is quite good at managing his interactions,

01:26:34.480 | at least from the outsider perspective.

01:26:36.760 | I do want to ask you a little bit about you.

01:26:39.500 | And first of all, and I realize this is only a partial list,

01:26:44.500 | but you're a clinician, you see patients,

01:26:48.080 | you run a big laboratory.

01:26:49.220 | How many people are in your laboratory now?

01:26:51.440 | That's a huge laboratory.

01:26:53.840 | From experience, I can say that's an enormous laboratory.

01:26:56.800 | You have a family of five children

01:27:00.940 | and you're happily married

01:27:02.400 | to a wonderful colleague of ours as well

01:27:04.620 | who does incredible work.

01:27:06.380 | How do you organize at a kind of conceptual level

01:27:13.940 | the day and the week?

01:27:16.600 | And I should say what stress mitigation practices, if any,

01:27:20.740 | do you incorporate?

01:27:21.700 | I've received emails from you at three in the morning.

01:27:24.540 | I sometimes send emails at three in the morning,

01:27:26.040 | but that's when I wake up, maybe I'm depressed,

01:27:28.400 | but I go back to sleep.

01:27:30.060 | So maybe you just describe the arc of the blocks of the day,

01:27:34.680 | not hour by hour,

01:27:35.960 | necessarily the details of what are in those blocks,

01:27:38.240 | but how do you conceptualize the day?

01:27:41.120 | How do you conceptualize the week?

01:27:43.540 | And how do you feel about how that's lined up

01:27:47.920 | with your larger goals

01:27:49.380 | of making sure these five young people flourish,

01:27:53.900 | which I hear they are.

01:27:55.100 | But how do you go about this?

01:27:58.300 | What for most people would just be

01:27:59.720 | an overwhelming set of items?

01:28:02.340 | - Well, of course, sometimes it's just to take it day by day

01:28:07.340 | and so I don't claim-

01:28:10.980 | - So you bring the horizon into the unit of the day.

01:28:13.120 | - I do, I do.

01:28:15.200 | The unit is the day, that's right.

01:28:16.760 | And what I try to have in each day,

01:28:21.520 | as I mentioned earlier,

01:28:22.660 | some, at least an hour of time where I can think.

01:28:26.400 | And that can be, it can be when kids are napping,

01:28:29.520 | it can be, you know,

01:28:32.080 | actually, because like while driving, I can do that too,

01:28:35.140 | because I'm sitting still.

01:28:36.440 | But that's the one thing I try to preserve.

01:28:42.320 | When I was writing the book,

01:28:43.420 | I adapted that time to be my writing time,

01:28:46.960 | but it wasn't enough.

01:28:48.400 | It's, you know, so I had to add in a new block of time,

01:28:52.140 | which was sort of midnight to 2 a.m. writing time.

01:28:56.340 | And so that, carving out these even small protected times

01:29:02.700 | are very important.

01:29:04.140 | There's, of course, you know,

01:29:05.880 | obligations will expand to fill the time available

01:29:09.580 | and you have to be disciplined.

01:29:10.780 | In my, at least I found I had to be disciplined

01:29:13.420 | in truly protecting those times where one can think.

01:29:18.200 | - So that means no phone.

01:29:19.620 | - That means no phone, no checking of the phone.

01:29:22.080 | I would, you know, when I was writing the book,

01:29:25.460 | I would have, there's a focus mode on the MacBook,

01:29:30.460 | which kind of removes the border

01:29:35.940 | and you just have your document and it's very pure

01:29:39.520 | and you don't have the temptation of distraction.

01:29:43.760 | - I'm a big believer in,

01:29:45.460 | because the vision and the eyes play such a prominent role

01:29:48.560 | in directing our cognition,

01:29:49.720 | something you talk about in the book really beautifully

01:29:53.040 | and with a lot of depth and rigor,

01:29:54.940 | using visual tools to harness one's complete mental

01:30:00.800 | attention.

01:30:01.820 | When you do this practice of sitting and just thinking,

01:30:04.480 | sitting still and thinking, you said your eyes are open.

01:30:08.560 | Are you hearing your own verbal voice,

01:30:11.680 | although in your head?

01:30:13.080 | So you're actually in conversation with yourself.

01:30:15.360 | - Yes, and hearing literally, I mean, not quite literally.

01:30:18.320 | I don't actually hear a phonation, but I'm hearing words.

01:30:21.620 | And so it's, I discovered this about myself, other people,

01:30:26.580 | I think, you know, may operate differently,

01:30:29.600 | but I'm extremely verbal in how I think.

01:30:32.280 | That's how all my reasoning is done.

01:30:33.860 | That's with sentences and construction of, you know,

01:30:38.860 | almost equations with words.

01:30:41.060 | - The complete sentences?

01:30:42.300 | - Complete sentences, or completish anyway, mostly complete.

01:30:45.860 | And then, and when writing the book,

01:30:47.740 | everything about the writing, I would always,

01:30:50.540 | every sentence was always played out in my mind,

01:30:54.180 | listening for rhythm and timing.

01:30:56.860 | And I would obsess over exact placement of words

01:31:01.260 | to get the right rhythm of the spoken sentence

01:31:03.480 | in my mind.

01:31:04.960 | - I don't mean to interrupt your flow,

01:31:06.360 | but when you do that,

01:31:08.080 | and having experienced this process a bit,

01:31:10.240 | although differently,

01:31:12.300 | do you experience any kind of welling up of anxiety

01:31:15.200 | when you're hitting the friction points?

01:31:18.000 | And if so, do you have tools

01:31:20.440 | or ways that you quell that anxiety in real time?

01:31:24.040 | 'Cause what we're really talking about here is your mind,

01:31:26.980 | but what we're really talking about is this process

01:31:29.120 | of converting the activity of neurons

01:31:32.920 | into something physically concrete in the world.

01:31:36.240 | And these intermediate steps are so mysterious to everybody.

01:31:39.480 | We hear, you know, just write the book, just do it,

01:31:41.860 | whatever that means.

01:31:43.180 | In fact, the statements like that to me

01:31:44.480 | are kind of empty and meaningless.

01:31:46.180 | But when you hear your voice

01:31:49.400 | and you're trying to find the correct word

01:31:51.600 | and you keep hitting, it doesn't sound quite right.

01:31:55.680 | What is the experience in your body?

01:31:58.160 | - Yeah, when it's not right,

01:32:00.000 | it's definitely, it's aversive, it doesn't feel good,

01:32:05.000 | but it's not, but there's also a hope

01:32:08.580 | because I know I can solve it too.

01:32:10.200 | And so there's this,

01:32:12.380 | it's almost like you're almost there.

01:32:16.600 | There's a path that you know is there.

01:32:19.200 | You don't quite see it, but it's there.

01:32:22.480 | And I keep that in mind.

01:32:24.140 | And so there's this propulsive force forward

01:32:29.600 | because I know that the solution is there.

01:32:31.520 | And that said, there were single words

01:32:36.520 | that I would spend days on

01:32:39.600 | because I was just not happy until I got it right.

01:32:42.360 | And there were some things that I never quite got perfect.

01:32:45.380 | And so I left out of the book entirely

01:32:47.080 | because it was so close, but not quite there.

01:32:50.400 | And so at the end I was like, no, I can't put that in.

01:32:53.640 | - Everything you just said is entirely consistent

01:32:55.440 | with my experience of you and the way you go about everything.

01:33:00.440 | I have to ask, are your kids writers?

01:33:02.980 | Do they like books and words and poetry?

01:33:05.240 | I know one of your children is going on

01:33:07.160 | to a career in medicine and science.

01:33:09.240 | - Yeah, they're each different, which is amazing.

01:33:11.680 | Yet they all, I think do have some appreciation

01:33:14.400 | or a lot of appreciation for reading,

01:33:17.120 | but some are very musical.

01:33:19.000 | Two of the five are extremely musical, very, very talented

01:33:22.520 | with guitar and singing and vocal impressions.

01:33:27.280 | It's just astonishing.

01:33:28.640 | And some of them are great with drawing and artistry

01:33:32.920 | and some are very physical and vigorous

01:33:35.660 | and are never happy except when leaping about.

01:33:39.320 | And so it's just amazing how different they are honestly.

01:33:42.420 | But I think there is a shared appreciation for language.

01:33:46.040 | - Do you think that one can train their mind

01:33:49.900 | in using these practices?

01:33:52.040 | - I really like your description of the sitting,

01:33:55.920 | staying physically still and learning to grapple

01:33:58.720 | with those challenges.

01:34:00.620 | It's something that, especially in laboratory science,

01:34:03.140 | we aren't really trained to do.

01:34:05.520 | Like many professions, we're taught to come in

01:34:07.400 | and just get into motion.

01:34:09.080 | And I found that very relaxing as someone

01:34:11.000 | who probably has an underlying tick or something like that.

01:34:14.000 | It felt great to be in motion.

01:34:15.340 | One of the hardest things

01:34:16.180 | about becoming a university professor and running a lab

01:34:18.880 | was that I was no longer working with my hands.

01:34:21.680 | And it felt like some big important part of my life

01:34:26.640 | had been amputated.

01:34:28.160 | But what sorts of practices do you incorporate there?

01:34:31.100 | And do you think people can learn to get better at focusing

01:34:35.520 | through a dedicated practice of the sort that you describe?

01:34:38.780 | - I think that I also, I remember the rhythms

01:34:44.240 | of physical work in the laboratory very well.

01:34:49.320 | My work these days as a laboratory leader,

01:34:54.200 | my job is returned mostly to words now again.

01:34:57.040 | And so it's kind of coming full circle.

01:34:59.400 | So it's a different mode.

01:35:04.360 | I think you just have to embrace

01:35:06.040 | that different stages of life come with different modes,

01:35:09.240 | but you can definitely train yourself for each mode.

01:35:11.240 | I was not,

01:35:12.080 | I loved, as I mentioned,

01:35:17.560 | the rhythm of sewing and suturing and surgery.

01:35:22.480 | And I worked really hard on that and became good at it.

01:35:27.960 | And now I never do it, but it's what's the next challenge.

01:35:31.440 | You know, there's all the various experimental techniques,

01:35:33.720 | the dissections of the brain, you know,

01:35:36.080 | I can't tell you how many thousands of brain dissections

01:35:39.200 | I've done in my life, and now I don't do them at all.

01:35:41.280 | - And then you developed a method

01:35:42.480 | so that we don't have to dissect brains.

01:35:44.200 | As you mentioned, maybe tell us for a moment about clarity

01:35:46.800 | and for people who will probably never set foot

01:35:50.600 | into a laboratory, what an incredible,

01:35:53.840 | yet another incredible discovery and development clarity is

01:35:58.840 | and why it helps us understand how the brain is structured.

01:36:02.360 | - Yeah, so this is a different technology

01:36:04.840 | also developed in my lab here,

01:36:06.840 | and it's part of a broader approach

01:36:10.000 | that we call hydrogel tissue chemistry.

01:36:12.240 | And what this is is it's building a gel,

01:36:15.240 | like a clear and jello-like substance

01:36:18.400 | from within all the cells of a tissue

01:36:22.000 | or even an animal all at once.

01:36:23.920 | So you're building, effectively building a gel

01:36:26.440 | inside all the cells at once.

01:36:28.800 | Now that's an odd thing to do.

01:36:30.920 | Why do we do it?

01:36:31.760 | Well, we do it to transform the tissue

01:36:36.000 | into a more tractable, accessible object.

01:36:39.840 | And the reason that works is having built this gel,

01:36:43.200 | this new infrastructure inside the tissue.

01:36:47.120 | We can then use chemical tricks

01:36:48.720 | and we can link the molecules we care about,

01:36:51.440 | like proteins or RNAs, which are the things, as you know,

01:36:55.920 | right before they become proteins.

01:36:57.960 | We can link them, physically anchor them to this gel,

01:37:02.960 | which is a scaffold, basically.

01:37:04.480 | It's an interlocking network of polymers.

01:37:07.960 | We can link all these interesting molecules in place,

01:37:10.640 | lock them in where they were initially,

01:37:13.280 | in the tissue, in the cell, in all the cells.

01:37:16.400 | And then we can remove, very vigorously,

01:37:18.520 | everything we don't care about that's blocking our light,

01:37:21.840 | that's blocking our molecules coming in

01:37:23.940 | to exchange information with the tissue.

01:37:26.520 | We can get rid of everything else,

01:37:28.080 | like the lipids, the fats.

01:37:29.420 | We can effectively use detergents to get them all out.

01:37:33.560 | And then we can see in all the things

01:37:35.600 | that were absorbing our scattering light are gone.

01:37:38.080 | You can have a brain that's completely transparent

01:37:40.760 | and yet all the interesting molecules

01:37:42.320 | are still locked into place there

01:37:43.560 | at the cellular and subcellular level.

01:37:45.720 | And so this is hydrogel tissue chemistry.

01:37:47.620 | The first form we described was called clarity.

01:37:50.840 | We use that quite a bit still,

01:37:52.440 | but there are many variants now that we and others

01:37:54.920 | have developed on this basic concept of building this gel

01:37:58.360 | within the tissue and anchoring molecules into place.

01:38:00.560 | - Literally glass clear brains.

01:38:02.120 | I've done this, I've taken a brain clear with this method

01:38:05.320 | and looked at somebody through it.

01:38:06.880 | And although you don't want to get it too close to your eye,

01:38:08.800 | you don't want to touch it to your own eye.

01:38:10.240 | But, and you can see direct all the way through it.

01:38:13.440 | That's incredible for the,

01:38:18.200 | it raises an important question,

01:38:19.700 | which is again about the human brain.

01:38:22.160 | I mean, as somebody who essentially started out

01:38:23.880 | in neuroanatomy and then got into other things,

01:38:26.480 | I always am bothered by the fact

01:38:31.320 | that we actually know very little

01:38:32.880 | about the microstructure of the human brain

01:38:35.760 | compared to the brains of other organisms.

01:38:38.580 | And in thinking about understanding the circuitry

01:38:41.400 | and the piano, so to speak, that,

01:38:43.580 | and how to manipulate it in order to relieve suffering,

01:38:47.660 | one wonders are the structures in these animal brains

01:38:53.480 | and how they behave and active coping,

01:38:56.720 | passive coping, ADD, et cetera, those models,

01:39:00.000 | how well they translate to the human condition.

01:39:03.900 | Do you think it's fair to say

01:39:05.020 | that there are entire regions of the human brain

01:39:08.080 | that aren't just bigger,

01:39:09.460 | but that exist only in the brains of humans,

01:39:12.500 | especially given that we have this speech,

01:39:14.840 | although I do wonder sometimes if, you know,

01:39:17.000 | animals are reporting to each other there,

01:39:18.940 | maybe they have little psychiatric sessions

01:39:20.780 | with one another.

01:39:22.300 | - You know, I'm always careful

01:39:23.900 | to not assume we do things better.

01:39:26.980 | We certainly understand what we're doing better

01:39:29.460 | than we understand what animals are doing,

01:39:31.000 | and they certainly do things better than we do.

01:39:33.980 | That said, we do have amazing, wonderful brains

01:39:36.820 | and many structures that are very highly developed

01:39:39.420 | in our brains that are not nearly so developed

01:39:42.300 | in mice and fish, for example.

01:39:45.420 | Now, that said, when I look at the big picture,

01:39:49.220 | you know, what is the mammalian brain really doing?

01:39:52.880 | There are things that you would never have thought

01:39:57.020 | we could study in animals, in laboratory mammals like mice,

01:40:03.620 | that it turns out you can, actually.

01:40:05.780 | And so I would never draw the line and say,

01:40:08.140 | here's something you can't study in mice,

01:40:10.100 | or here's something that has no parallel in mice.

01:40:12.740 | I would be very careful before making

01:40:14.540 | any statement like that.

01:40:17.160 | A good example of that is we've been able to study

01:40:19.040 | just in the past year,

01:40:19.960 | come to an understanding of dissociation.

01:40:22.500 | And both, we had a paper that came out in late 2020,

01:40:26.180 | both mouse and human work,

01:40:28.660 | in which we got to the sort of the circuit basis

01:40:32.420 | for dissociation.

01:40:34.100 | Now, what is dissociation?

01:40:35.540 | A lot of people might not have experienced it,

01:40:38.760 | but it's actually very common.

01:40:40.500 | More than 70% of people who've been through trauma

01:40:44.260 | experience dissociation.

01:40:45.820 | It shows up in borderline personality.

01:40:47.820 | It shows up in PTSD.

01:40:49.700 | What it is is a separation of the sense of self

01:40:53.580 | from the body.

01:40:54.920 | And so you can have someone who,

01:40:55.980 | it's not as if you're numb, you're not anesthetized.

01:40:58.500 | You can still, you know that something's happening

01:41:00.820 | to the body, but you just don't care

01:41:03.260 | because you don't ascribe it to yourself,

01:41:05.980 | which is very interesting, right?

01:41:07.740 | That is, how interesting is that?

01:41:09.100 | - The self-report narrative.

01:41:10.420 | - Yeah, yeah.

01:41:11.260 | - Almost in your book, you touch on this,

01:41:13.560 | and I will say is the most precise and meaningful

01:41:18.560 | and eloquent description of what might be consciousness,

01:41:21.740 | this narrative toward the self or of the self

01:41:25.300 | and where it might reside.

01:41:26.380 | So in dissociative conditions,

01:41:29.460 | people are feeling as kind of an absence of a merge

01:41:32.760 | between mind and body.

01:41:34.040 | Is that one way to describe it?

01:41:35.420 | And as I recall, this paper involved

01:41:37.520 | an exploration of ketamine.

01:41:39.300 | - Ketamine was a big part of it.

01:41:40.340 | Yeah, that's right.

01:41:41.180 | And so ketamine is another one of those cases

01:41:43.000 | where people can experience dissociation.

01:41:45.660 | Ketamine or PCP, we call these the dissociative drugs.

01:41:48.880 | They cause it just like these other psychiatric conditions

01:41:52.840 | can cause it.

01:41:54.180 | And so we were able to manifest this in mice,

01:41:59.340 | administering these dissociative agents in mice.

01:42:02.100 | We could make them still able to detect stimulus,

01:42:04.580 | but not care that it was happening.

01:42:07.140 | All the while, we were recording the activity

01:42:11.380 | of individual cells in the brain to see what was going on,

01:42:13.740 | what was happening along with this dissociation,

01:42:18.080 | and then use optogenetics to see that it mattered

01:42:20.540 | to actually provide that pattern of activity

01:42:23.380 | and see, oh, that actually causes the dissociation.

01:42:26.580 | So we could do all that in mice,

01:42:28.900 | which was just a, who would have thought

01:42:32.600 | that you could study something like this in mice.

01:42:34.660 | And we were able to go back and forth with human work

01:42:38.340 | because here in our Stanford Comprehensive Epilepsy Center,

01:42:41.940 | there are a lot of what we call stereo EEG recording.

01:42:45.300 | Patients who come in and in the course

01:42:46.760 | of normal clinical care, they have electrodes recording

01:42:50.420 | in their brain to identify where the seizure is

01:42:53.420 | so they can be candidates for removing a little patch

01:42:57.320 | of the brain that's causing the seizure.

01:42:58.700 | This is done for patients who medications

01:43:00.780 | are not helping their seizure disorder.

01:43:03.560 | And there was a patient who had a dissociative state

01:43:08.160 | before every seizure.

01:43:09.340 | So this was a human being who was really dissociating,

01:43:11.460 | who could tell us literally as it was happening.

01:43:13.620 | And we could see this pattern,

01:43:15.980 | the same pattern that was happening in the mice

01:43:18.300 | in the same patch of the brain.

01:43:20.780 | We could see that happening in the human being

01:43:22.700 | at exactly the right time in the same patch of the brain

01:43:25.260 | that's homologous across these immense evolutionary distances.

01:43:29.580 | And we knew that it mattered too, both in mouse and human,

01:43:31.960 | because in the human, we could cause it to happen.

01:43:34.540 | - And I just want to underscore the power of not just that,

01:43:38.420 | I want to underscore the power of optogenetics

01:43:41.140 | and the ability to not just remove a particular experience

01:43:45.500 | or behavior by lesioning or destroying,

01:43:47.380 | but then to go back and actually activate the same structure

01:43:51.820 | or group of structures and see the emergence.

01:43:54.100 | So it's essentially, these days you hear a lot

01:43:56.620 | about gain-of-function research

01:43:57.940 | in the context of viral manipulation,

01:43:59.540 | but gain-of-function is something that we do

01:44:01.140 | in the laboratory and you do in patients

01:44:04.580 | to both take away something and put it back,

01:44:07.740 | which gives you causality.

01:44:09.140 | - That's right, yeah, and so, exactly.

01:44:11.060 | And so with optogenetics, we were able to provide

01:44:14.140 | in animals without being on any ketamine or any drug,

01:44:18.100 | and we could cause the dissociative state

01:44:19.620 | by playing in a precise pattern of activity.

01:44:22.060 | And that, who would have thought you could do that?

01:44:23.680 | There was a combined mouse and human paper.

01:44:26.300 | Likewise, we've been able to play in, you know,

01:44:30.740 | visual sensations into the brains of mice.

01:44:34.860 | And by observing which cells in the visual part

01:44:39.360 | of the brain, visual cortex, are naturally responsive

01:44:42.860 | to, for example, vertical bars instead of horizontal bars

01:44:46.020 | in the visual world, we could see which cells

01:44:48.620 | were normally reporting on vertical bars,

01:44:51.200 | and then we could use optogenetics to come and play in

01:44:54.780 | activity just to those cells.

01:44:56.420 | - So these animals are not viewing anything?

01:44:58.140 | - Not viewing anything at all.

01:44:59.340 | And we could activate just the vertical bar cells,

01:45:02.500 | and not only did the animal act as if it was seeing

01:45:04.980 | a vertical bar behaviorally, it was trained

01:45:06.940 | to do a particular thing if it saw a vertical bar,

01:45:08.860 | and it did that just as if it was seeing something visually.

01:45:12.660 | But everything in the brain that we were recording to,

01:45:14.740 | the internal representation of this external world

01:45:18.560 | was naturalistic, too.

01:45:19.820 | It looked like the brain was seeing something visual.

01:45:23.120 | So that's gain of function, too, you know,

01:45:26.200 | playing in, providing a complex sensation or percept

01:45:30.160 | that wasn't there before.

01:45:31.480 | And we can do that, you know, across species.

01:45:34.480 | So we haven't, you know, and of course, mice are social,

01:45:38.120 | and they do amazing acts of information processing,

01:45:41.780 | and so I try not to disparage our cousins too much.

01:45:46.780 | - They certainly have helped the field of neuroscience

01:45:48.600 | - And medicine, I should mention.

01:45:50.040 | And I know that people have various sensitivities

01:45:51.860 | about animal research, but the work that's been carried out

01:45:55.140 | in mice has been absolutely vital and instructional

01:46:00.140 | for treatment of human disease.

01:46:02.700 | Since we talked about dissociation and dissociative states,

01:46:08.920 | rather, and ketamine, I'd love your thoughts

01:46:11.540 | on psychedelic medicine.

01:46:14.900 | You know, I sort of half joke, having grown up,

01:46:18.460 | in this area in Northern California,

01:46:19.760 | when it was much more counterculture than it is now,

01:46:22.360 | that many of the things that we're hearing about now,

01:46:26.100 | at least from my read of the history books,

01:46:30.520 | happened before.

01:46:31.680 | There was a movement aimed at taking

01:46:34.440 | the very same compounds, essentially,

01:46:36.780 | putting them into patients,

01:46:37.860 | or people were obviously using them recreationally,

01:46:41.100 | but putting them into patients

01:46:42.720 | and seeing tremendous positive effects,

01:46:44.900 | but also tremendous examples of induced psychiatric illness.

01:46:49.900 | In other words, many people lost their minds

01:46:52.420 | as a consequence of overuse of psychedelics.

01:46:54.740 | I'll probably lose a few people out there,

01:46:57.740 | but I do want to talk about

01:47:01.780 | what is the state of these compounds?

01:47:04.300 | And I realize it's a huge category of compounds,

01:47:06.420 | but LSD and psilocybin, as I understand,

01:47:08.500 | trigger activation of particular serotonin receptor

01:47:11.420 | mechanisms may or may not lead

01:47:13.340 | to more widespread activation of the brain

01:47:16.340 | that one wouldn't see otherwise.

01:47:18.300 | But when you look at the clinical

01:47:19.620 | and experimental literature,

01:47:21.260 | what is your sort of top contour sense

01:47:23.860 | of how effective these tools are going to be

01:47:26.140 | for treating depression?

01:47:27.700 | And then if we have the time,

01:47:29.100 | we could talk about trauma and MDMA and some of that work.

01:47:32.620 | - Well, you're right to highlight both the opportunity

01:47:36.140 | and the peril that is there.

01:47:38.740 | And of course, we want to help patients,

01:47:41.780 | and of course, we want to explore anything

01:47:45.260 | that might be helpful,

01:47:47.340 | but we want to do it in a safe and rigorous way.

01:47:50.420 | But I do think we should explore these avenues.

01:47:53.540 | These are agents that alter reality

01:47:57.120 | and alter the experience of reality, I should say,

01:48:00.180 | in relatively precise ways.

01:48:02.420 | They do have problems, they can be addictive,

01:48:05.140 | they can cause lasting change that is not desirable.

01:48:10.260 | But we have to see these as opportunities.

01:48:12.340 | We have to, first of all, study in the laboratory,

01:48:15.500 | and I'm doing this here.

01:48:17.940 | We have big, we have safes

01:48:20.980 | with many interesting psychedelics

01:48:23.000 | that are all very carefully regulated.

01:48:24.780 | We get inspections from the DEA and so on.

01:48:27.180 | - If anyone's hoping to find these labs,

01:48:28.540 | they exist in outer space,

01:48:29.780 | so you need to be on board one of the SpaceX missions

01:48:34.220 | in order to access them, so don't try and come find them.

01:48:36.140 | - No, that's exactly true, yes.

01:48:38.480 | And we're doing exactly this.

01:48:42.280 | We're saying this is an incredible opportunity.

01:48:43.780 | If we could understand how the perception of reality

01:48:48.320 | is altered, we could create new kinds of intervention

01:48:52.040 | that don't have the risks and the problems

01:48:56.580 | of causing lasting change or addiction.

01:49:00.180 | Now, that said, even as these medications exist now,

01:49:06.180 | as you know, there's an impulse to use them

01:49:09.220 | in very small doses and to use them as adjunctive treatments

01:49:12.700 | for the therapy of various kinds.

01:49:15.120 | And I'm also supportive of that

01:49:16.800 | if done carefully and rigorously.

01:49:19.940 | Of course, there's risk,

01:49:20.820 | but there is risk with many other kinds of treatment,

01:49:23.900 | and I'm not sure that the risks for these medications

01:49:28.900 | vastly outweigh the risks that we normally tolerate

01:49:31.380 | in other branches of medicine.

01:49:32.820 | - Why would they work?

01:49:34.380 | I mean, let's say that indeed their main effect

01:49:39.380 | is to create more connectivity,

01:49:44.700 | at least in the moment, between brain areas.

01:49:48.220 | So the way I think about a very,

01:49:50.820 | I think about the two extremes of my experience anyways,

01:49:53.820 | a high degree of stress and focus, for whatever reason,

01:49:57.320 | is going to create changes in my visual field

01:49:59.780 | and changes in the way that I perceive time

01:50:02.160 | so that I'm going to micro-slice time,

01:50:03.900 | I'm in a very contracted view of whatever my experience is.

01:50:07.300 | Whereas on the opposite extreme,

01:50:09.440 | in a dream or in sleep, space and time are very fluid,

01:50:13.420 | and I'm essentially relaxed,

01:50:15.180 | although it might be a very interesting dream,

01:50:16.980 | it might not be.

01:50:18.580 | Psychedelics seem to be a trajectory,

01:50:21.680 | I'm not too far off from the dream state

01:50:25.340 | where space and time are essentially not as rigid.

01:50:29.900 | And there is this element of synesthesia,

01:50:32.140 | of blending of the senses, you know,

01:50:34.620 | feeling colors and hearing light and things of that sort.

01:50:39.620 | You hear these reports anyway.

01:50:42.380 | Why would having that dreamlike experience

01:50:46.540 | somehow relieve depression long-term?

01:50:51.580 | Do we have any idea why that might be?

01:50:53.980 | - We have some ideas and no deep understanding.

01:50:59.580 | One way I think about the psychedelics

01:51:02.100 | is they increase the willingness of our brain

01:51:07.100 | to accept unlikely ways of constructing the world,

01:51:13.340 | unlikely hypotheses, as it were, as to what's going on.

01:51:16.420 | The brain, in particular our cortex,

01:51:18.260 | I think is a hypothesis generation and testing machine.

01:51:21.820 | It's coming up with models about everything.

01:51:23.840 | It's got a lot of bits of data coming in

01:51:26.900 | and it's making models and updating the models

01:51:29.420 | and changing them theories, hypotheses for what's going on.

01:51:32.620 | And some of those never reach our conscious mind.

01:51:36.020 | And this is something I talk about in projections

01:51:38.340 | in the book quite a bit is many of these are filtered out

01:51:42.300 | before they get to our conscious mind.

01:51:44.500 | And that's good.

01:51:45.340 | We think how distracted we'd be

01:51:47.420 | if we were constantly having to evaluate all these,

01:51:49.860 | you know, hypotheses about, you know,

01:51:51.540 | what kinds of shapes or objects or processes were out there.

01:51:54.820 | And so a lot of this is handled

01:51:56.420 | before it gets to consciousness.

01:51:59.020 | What the psychedelics seem to do

01:52:00.780 | is they change the threshold for us to become aware

01:52:05.780 | of these incomplete hypotheses or wrong hypotheses

01:52:09.540 | or concepts that might be noise, but are just wrong

01:52:14.140 | and so are never allowed to get into our conscious mind.

01:52:17.060 | Now, you know, that's pretty interesting

01:52:20.900 | and it goes wrong in psychiatric disorders.

01:52:23.260 | I think in schizophrenia,

01:52:25.660 | sometimes the paranoid delusions that people have

01:52:29.380 | are examples of these poor models

01:52:33.260 | that escape into the conscious mind

01:52:35.100 | and become accepted as reality

01:52:37.380 | and they never should have gotten out there.

01:52:40.340 | Now, how could something like this in the right way

01:52:43.180 | help with something like depression?

01:52:45.340 | Patients with depression often are stuck.

01:52:49.940 | They can't look into the fact

01:52:54.940 | to the future world of possibilities as effectively.

01:52:59.740 | Everything seems hopeless.

01:53:04.060 | And what does that really mean?

01:53:05.220 | They discount the value of their own action.

01:53:08.340 | They discount the value of the world

01:53:10.780 | at giving rise to a future that matters.

01:53:13.300 | Everything seems to run out

01:53:14.820 | like a river just running out into a desert and drying up.

01:53:18.300 | And what these agents may do

01:53:22.380 | that increase the flow through circuitry, if you will,

01:53:25.460 | the percolation of activity through circuitry

01:53:27.420 | may end up doing for depression

01:53:29.300 | is increasing the escape of some tendrils of process,

01:53:34.300 | of forward progression through the world.

01:53:37.900 | That's a concept, that's how I think about it.

01:53:41.660 | There are ways we can make that rigorous.

01:53:43.420 | We can indeed identify in the brain by recording.

01:53:47.060 | We can see cells that represent steps along a path

01:53:50.780 | and look into the future.

01:53:54.160 | And we can rigorously define these cells

01:53:56.540 | and we can see if these are altered on psychedelics.

01:53:59.260 | And so that's one of the reasons

01:54:00.500 | that we're working with these agents in the laboratory

01:54:04.020 | to say, is this really the case?

01:54:05.860 | Are these opening up new paths

01:54:08.820 | or representations of paths into the future?

01:54:11.920 | - MDMA, ecstasy, is a unique compound

01:54:17.420 | in that it leads to big increases in brain levels

01:54:21.940 | of dopamine and serotonin simultaneously.

01:54:24.660 | And I realized that the neuromodulators

01:54:26.740 | like dopamine and serotonin often work in concert,

01:54:29.340 | not alone, the way they're commonly described

01:54:31.580 | in the more general popular discussions.

01:54:35.420 | However, it is a unique compound

01:54:38.880 | and it's different than the serotonergic compounds

01:54:41.060 | like LSD and psilocybin.

01:54:43.420 | And there are now data still emerging

01:54:48.100 | that it might be, and in some cases can be useful

01:54:52.600 | for the treatment of trauma, PTSD and similar things.

01:54:56.460 | Why would that work?

01:54:59.260 | And a larger question,

01:55:01.920 | perhaps the more important question is,

01:55:04.060 | psychedelics, MDMA, LSD, all those compounds,

01:55:08.460 | in my mind, there are two components.

01:55:10.100 | There's the experience you have while you're on them.

01:55:12.780 | And then there's the effect they have after.

01:55:15.220 | People are generating variations of these compounds

01:55:18.900 | that are non-hallucinatory variations.

01:55:21.980 | But how crucial do you think it is to have,

01:55:25.940 | let's stay with MDMA, the experience of huge levels

01:55:30.820 | of dopamine, huge levels of serotonin,

01:55:33.460 | atypical levels of dopamine and serotonin released,

01:55:35.780 | having this highly abnormal experience

01:55:38.020 | in order to be normal again.

01:55:39.620 | - Yeah.

01:55:40.840 | I think the brain learns from those experiences.

01:55:43.020 | That's the way I see it.

01:55:44.460 | And so, for example, people who've taken MDMA,

01:55:48.440 | they will, as you say, they'll be the acute phase

01:55:51.680 | of being on the drug and experiencing

01:55:55.820 | this extreme connectedness with other people, for example.

01:55:59.420 | And then the drug wears off,

01:56:02.980 | but the brain learned from that experience.

01:56:06.120 | And so what people will report is,

01:56:09.160 | yeah, I'm not in that state, but I saw what was possible.

01:56:12.660 | I saw, yeah, there don't need to be barriers,

01:56:17.460 | or at least not as many barriers as I thought.

01:56:19.740 | I can connect with more people in a way that is helpful.

01:56:23.980 | And so I think it's the learning

01:56:26.380 | that happens in that state that actually matters.

01:56:29.500 | - And as you described that,

01:56:30.820 | that sounds a lot like what I understand

01:56:32.500 | to be the hallmark feature of really good psychoanalysis,

01:56:35.260 | that the relationship between patient and therapist,

01:56:38.620 | hopefully evolves to the point where these kinds of tests

01:56:43.140 | can be run within the context of that relationship

01:56:45.820 | and then exported to other relationships.

01:56:47.840 | Is that- - Exactly right, yeah.

01:56:49.220 | - And that probably, I'm assuming,

01:56:51.280 | is still the goal of really good psychiatry also.

01:56:53.840 | - It's a part of- - Intimacy, really.

01:56:56.700 | - It should be, when we have time,

01:56:59.820 | I think all good psychiatrists try to achieve

01:57:02.320 | that level of connection and learning,

01:57:05.600 | try to help patients create a new model that is stable,

01:57:10.600 | that is learned,

01:57:12.120 | and that can help instruct future behavior.

01:57:16.160 | - One of the things that I took from reading your book,

01:57:19.600 | in addition to learning so much science

01:57:22.120 | and the future of psychiatry and brain science,

01:57:24.520 | was amidst these, in many cases,

01:57:29.000 | very tragic cases and sadness,

01:57:31.500 | and a lot of the weight that that puts on the clinician,

01:57:35.200 | on you also, that there's a central chord of optimism,

01:57:40.200 | that where we're headed is not just possible,

01:57:45.840 | but very likely and better.

01:57:48.880 | And, you know, are you an optimist?

01:57:53.280 | - I am, and this is, by the way,

01:57:54.880 | this was a really interesting experience

01:57:56.560 | in writing projections because I had a dual goal.

01:58:00.840 | I wanted it to be for everybody,

01:58:02.720 | literally everybody in the world who wants to read it.

01:58:07.720 | And yet at the same time,

01:58:09.900 | I wanted to stay absolutely rigorously close to the science,

01:58:14.900 | what was actually known when I was speaking about science,

01:58:20.720 | when I was speaking about the neurobiology of the brain

01:58:24.240 | or psychiatry,

01:58:25.280 | I wanted to not have any of my scientific colleagues think,

01:58:30.400 | oh, he's going too far, he's saying too much.

01:58:33.040 | And so I had these two goals,

01:58:34.920 | which I kept in my mind the entire time,

01:58:37.060 | and a lot of this trying to find exactly the right word

01:58:39.680 | we talked about was on this path

01:58:42.040 | of staying excruciatingly rigorous in the science,

01:58:45.120 | and yet letting people see the hope,

01:58:48.460 | where things were, have everybody see

01:58:51.040 | that we've come a long way, we have a long way to go,

01:58:54.180 | but the trajectory and the path is beautiful.

01:58:58.360 | And so that was the goal.

01:59:01.120 | I think, of course, that sounds almost impossible

01:59:06.120 | to jointly satisfy those two goals,

01:59:10.600 | but I kept that in my mind the whole way through.

01:59:12.920 | And yes, I am optimistic,

01:59:14.520 | and I hope that came through in the book.

01:59:16.320 | - But it certainly did,

01:59:17.320 | and at least from this colleague,

01:59:18.920 | you did achieve both.

01:59:22.680 | And it's a wonderful, it's a masterful book, really,

01:59:26.480 | and one that as a scientist and somebody

01:59:29.320 | who is a fellow brain explorer hits all the marks of rigor

01:59:34.320 | and is incredibly interesting,

01:59:36.480 | and there's a ton of storytelling.

01:59:37.840 | I don't want to give away too much about it,

01:59:39.280 | but people should definitely check out the book.

01:59:41.600 | Are you active on social media if people want to follow you

01:59:45.760 | and connect with what you're doing now and going forward?

01:59:48.640 | - Yeah, I have a Twitter.

01:59:50.120 | That's where I mainly do exchange,

01:59:54.200 | tell people about things that are happening.

01:59:56.320 | We'll provide a link to it,

01:59:57.200 | but that's Karl Deisseroth, as I recall, with a K.

01:59:59.280 | - That's right. - Yeah.

02:00:00.520 | And so you're on Twitter, and people will hear this.

02:00:04.440 | Definitely check out the book.

02:00:06.600 | There are other people in our community

02:00:09.080 | that of course are going to be reaching out on your behalf,

02:00:13.200 | but it's incredible that you juggle

02:00:15.880 | this enormous number of things.

02:00:17.800 | Perhaps even more important, however,

02:00:22.080 | is that it's all in service to this larger thing

02:00:24.800 | of relieving suffering.

02:00:25.860 | So thank you so much for your time today,

02:00:28.320 | for the book and the work that went into the book.

02:00:30.560 | I can't even imagine.

02:00:31.780 | For the laboratory work and the development channel ops

02:00:33.880 | and clarity and all the related technologies

02:00:35.880 | and for the clinical work you're doing

02:00:37.720 | and for sharing with us.

02:00:39.080 | - Well, thank you for all you're doing and reaching out.

02:00:41.640 | I'm very impressed by it.

02:00:43.720 | It's important, and it's so valuable.

02:00:46.240 | And thank you for taking the time

02:00:47.400 | and for all your gracious words about the book.

02:00:49.760 | Thank you.

02:00:51.320 | - I hope you enjoyed today's discussion

02:00:52.880 | with Dr. Deisseroth as much as I did.

02:00:55.060 | Be sure to check out his new book "Projections,

02:00:57.240 | A Story of Human Emotions."

02:00:58.800 | It's available on Amazon, Audible,

02:01:00.920 | and all the other standard places where books are found.

02:01:03.760 | If you'd like to support this podcast,

02:01:05.560 | please subscribe to us on YouTube.

02:01:07.720 | As well, you can subscribe to us on Apple or Spotify.

02:01:11.180 | At Apple, you also have the opportunity

02:01:12.960 | to leave us a five-star review and to give us feedback.

02:01:16.480 | Please put any questions you have

02:01:17.860 | in the comment section below the YouTube video.

02:01:20.380 | If you'd like us to address certain things

02:01:22.200 | in future episodes or if you have questions

02:01:24.360 | about this particular episode.

02:01:26.380 | In addition, please check out our sponsors.

02:01:28.560 | That's a terrific way to support us.

02:01:30.520 | We also have a Patreon.

02:01:31.940 | It's patreon.com/andrewhuberman.

02:01:35.060 | There, you can support us at any level that you like.

02:01:38.120 | Last but not least, if you're interested

02:01:39.820 | in understanding more about how the brain works

02:01:41.760 | and how it functions and how it breaks down

02:01:43.840 | in various conditions, check out the first episode

02:01:46.560 | of the Huberman Lab Podcast.

02:01:48.340 | The title of that episode

02:01:49.620 | is "How Your Nervous System Works and Changes."

02:01:52.420 | If you're watching this right now on YouTube,

02:01:54.240 | you can simply click on the title card for that episode.

02:01:57.340 | And last but not least,

02:01:59.060 | thank you for your interest in science.

02:02:00.840 | [upbeat music]

02:02:03.420 | [MUSIC PLAYING]

Dr. Karl Deisseroth: Understanding & Healing the Mind

Chapters