Karl Deisseroth: Depression, Schizophrenia, and Psychiatry

00:00:00.000 | Where are the darkest places you've ever gone in your life?

00:00:04.200 | The following is a conversation with Carl Deisseroth,

00:00:10.520 | professor of bioengineering, psychiatry,

00:00:12.540 | and behavioral sciences at Stanford University.

00:00:15.580 | He's one of the greatest living psychiatrists

00:00:18.140 | and neuroscientists in the world.

00:00:20.460 | He's also just a fascinating human being.

00:00:23.540 | We discuss both the darkest and the most beautiful places

00:00:26.340 | that the human mind can take us.

00:00:28.620 | He explores this in his book called "Projections,

00:00:31.900 | a Story of Human Emotions."

00:00:33.900 | I highly recommend it.

00:00:35.780 | It's written masterfully.

00:00:38.340 | This is the Lex Friedman Podcast.

00:00:40.260 | To support it, please check out our sponsors

00:00:42.200 | in the description.

00:00:43.380 | And now, dear friends, here's Carl Deisseroth.

00:00:47.220 | You open your book called "Projections,

00:00:50.660 | a Story of Human Emotions" with a few beautiful words

00:00:53.500 | to summarize all of humanity.

00:00:56.140 | The book draws insights about the human mind

00:00:58.180 | from modern psychiatry and neuroscience.

00:01:01.240 | So if it's okay, let me read a few sentences

00:01:03.500 | from the opening.

00:01:05.060 | You gotta give props to beautiful writing when I see it.

00:01:08.820 | Quote, "In the art of weaving,

00:01:12.460 | "warp threads are structural and strong

00:01:14.580 | "and anchored at the origin,

00:01:16.920 | "creating a frame for crossing fibers

00:01:19.180 | "as the fabric is woven.

00:01:21.100 | "Projecting across the advancing edge into free space,

00:01:25.160 | "warp threads bridge the formed past

00:01:27.820 | "to the ragged present, to the yet featureless future."

00:01:32.060 | Yet featureless future, well done, well done, sir.

00:01:35.700 | "The tapestry of the human story has its own warp threads,

00:01:38.840 | "rooted deep in the gorges of East Africa,

00:01:41.520 | "connecting the shifting textures of human life

00:01:44.240 | "over millions of years.

00:01:46.340 | "Spanning pictographs backdrop by crevice ice,

00:01:50.160 | "by angulated forestry, by stone and steel,

00:01:54.000 | "and by glowing rare earths.

00:01:56.040 | "The inner workings of the mind give form to these threads,

00:01:59.400 | "creating a framework within us,

00:02:01.920 | "upon which the story of each individual

00:02:03.680 | "can come into being.

00:02:05.760 | "Personal grain and color arise from the cross threads

00:02:08.880 | "of our moments and experiences,

00:02:11.240 | "the fine weft of life,

00:02:13.420 | "embedding and obscuring the underlying scaffold

00:02:16.580 | "with intricate and sometimes lovely detail.

00:02:19.660 | "Here are stories of this fabric fraying

00:02:22.340 | "in those who are ill.

00:02:24.720 | "In the minds of people for whom the warp is exposed

00:02:28.160 | "and raw and revealing.

00:02:31.100 | "What have you learned about human beings,

00:02:32.920 | "human nature and the human mind

00:02:34.480 | "from those who suffer from psychiatric maladies,

00:02:38.160 | "for those for whom this fabric is warped?"

00:02:41.240 | - One thing we learn as biologists

00:02:43.400 | is that when something breaks,

00:02:45.560 | you see what the original unbroken part was for.

00:02:50.560 | And we see this in genetics, we see this in biochemistry.

00:02:54.040 | It's known that when you have a mutated gene,

00:02:57.440 | sometimes the gene is turned up in strength

00:02:59.880 | or turned down in strength.

00:03:01.280 | And that lets you see what it was originally for.

00:03:03.280 | You can infer true function from dysfunction.

00:03:06.960 | And this is a theme that I thought needed to be shared

00:03:11.160 | and needed to be made communicable

00:03:13.320 | to the lay public, to everybody.

00:03:15.080 | People who, which is I think almost all of us,

00:03:19.440 | who think and care about the inner workings of our mind,

00:03:21.800 | but who also care for those who have been suffering,

00:03:26.360 | who have mental health disorders, who face challenges.

00:03:31.360 | But then more broadly,

00:03:33.760 | it's a very much larger story than the present.

00:03:36.720 | There's a story to be told

00:03:39.960 | where the protagonist really is the human mind.

00:03:42.160 | And that was one thing I wanted to share as well

00:03:44.400 | in "Projections" is that broader story,

00:03:47.360 | but still anchored in the moment of patients,

00:03:50.480 | of people, of experiences of the moment.

00:03:53.960 | - Is there a clear line between dysfunction and function,

00:03:57.320 | disorder and order?

00:03:58.580 | - This is always debated in psychiatry,

00:04:02.440 | probably more so than any other medical specialty.

00:04:05.540 | I'm a psychiatrist.

00:04:07.760 | I treat patients still.

00:04:09.680 | I see acutely ill people who come to the emergency room

00:04:14.320 | where there's no doubt that this is not something

00:04:16.520 | that's working well,

00:04:17.760 | where the manifestation of disease is so powerful,

00:04:21.300 | where the person is suffering so greatly,

00:04:22.980 | where they cannot continue as they are.

00:04:26.680 | But of course it's a spectrum,

00:04:28.000 | and there are people who are closer to the realm

00:04:31.400 | of being able to work okay in their jobs,

00:04:34.560 | but suffer from some small dysfunction.

00:04:36.280 | And everywhere in between.

00:04:37.880 | In psychiatry, we're careful to say

00:04:39.400 | we don't call it a disease or a disorder

00:04:41.160 | unless there's a disruption

00:04:43.200 | in social or occupational functioning.

00:04:46.360 | But of course, psychiatry has a long way to go

00:04:49.320 | in terms of developing quantitative tests.

00:04:51.800 | We don't have blood draws.

00:04:54.700 | We don't have imaging studies that we can use to diagnose.

00:04:57.760 | And so that line ultimately that you're asking about

00:05:00.920 | between order and disorder, function and dysfunction,

00:05:04.420 | it's operational at the moment.

00:05:05.800 | How are things working?

00:05:06.960 | - Can we just like linger on the terms for a second?

00:05:10.760 | So this disease, dysfunction,

00:05:15.440 | how careful should we be using those words?

00:05:17.960 | Can we just, even in this conversation,

00:05:20.220 | from a sort of technical perspective,

00:05:24.400 | but also a human perspective,

00:05:26.560 | how quick should we be in saying that schizophrenia,

00:05:31.560 | depression, autism,

00:05:37.820 | as we kind of go down across the spectrum

00:05:42.860 | of different maladies,

00:05:45.660 | to use the word dysfunction and disease?

00:05:48.700 | - I would say to give ourselves license

00:05:50.760 | to capture the whole spectrum, let's say disorder,

00:05:52.980 | because that captures, truly, I think, the essence of it,

00:05:57.140 | which is we need to talk about it when it's not working,

00:05:59.660 | when there's disorder.

00:06:00.660 | And that's the fairest and most inclusive term to use.

00:06:05.660 | - So is it fair to assume that basically

00:06:11.060 | every member of the human species

00:06:13.660 | suffers from a large number of disorders then?

00:06:17.380 | - Well--

00:06:18.220 | - And we just have to pick which ones

00:06:19.540 | are debilitating for each person?

00:06:23.100 | - You know, if you look at the numbers,

00:06:25.180 | there are, if you look at how our mental health disorders

00:06:29.860 | are currently defined,

00:06:30.820 | you can look at population prevalence values

00:06:34.540 | for all these disorders.

00:06:35.560 | And you can come up with estimates

00:06:37.900 | that somebody will have a lifetime prevalence

00:06:42.180 | of having a psychiatric disorder

00:06:44.660 | that approaches 25% or so.

00:06:46.940 | And so that's, and in some studies it could be more,

00:06:50.180 | some studies it could be less.

00:06:51.480 | Now, what do we do with that number?

00:06:53.300 | What does that mean?

00:06:54.140 | And in some ways, that's the essence

00:06:55.540 | of what I was hoping to approach with the book,

00:06:58.900 | is to reflect on this spectrum

00:07:00.640 | that exists for all the disorders.

00:07:02.020 | There is, and taking nothing away from the severity

00:07:05.460 | and the suffering that comes at the extreme end

00:07:07.700 | of these illnesses, but nearly every one of them

00:07:10.100 | exists on a spectrum of severity,

00:07:12.180 | from nearly functional to completely dysfunctional,

00:07:16.460 | life-threatening, and even fatal.

00:07:19.260 | And so that number, 25%, more or less,

00:07:22.500 | it doesn't capture that spectrum of severity.

00:07:27.500 | - To linger on that number,

00:07:28.980 | where do those numbers come from?

00:07:30.460 | Is it self-report?

00:07:31.340 | Is it people who show up and say, "I need help"?

00:07:35.080 | Is it somebody else that points out,

00:07:36.900 | "That person needs help"?

00:07:38.740 | Or is it like estimates that even go beyond that

00:07:41.220 | for people who don't ask for help

00:07:42.900 | but are suffering quietly alone?

00:07:45.660 | - When you look at self-report numbers,

00:07:47.260 | then those numbers get even higher, beyond 25% or more.

00:07:50.800 | Those, the most rigorous studies are done

00:07:55.820 | with structured psychiatric interviews,

00:07:57.640 | where people who are trained in eliciting symptoms

00:08:01.620 | carefully do complete psychiatric inventories

00:08:04.500 | of individuals.

00:08:05.740 | And these are time-consuming, laborious studies

00:08:09.540 | that are not often repeated.

00:08:10.860 | When they're done, they're done well.

00:08:13.180 | But very often, you'll see a report

00:08:15.900 | or something in the news of a very high number

00:08:19.020 | for some disorder or symptom.

00:08:22.100 | And very often, if it's shockingly high,

00:08:24.500 | that's coming from a self-report of a person.

00:08:27.900 | And so that's another issue that we have.

00:08:30.380 | Again, take nothing away from the severity and reality

00:08:33.300 | and biological nature of these disorders,

00:08:35.860 | which are very genetic, very, you know,

00:08:37.500 | we understand that these are very biological.

00:08:40.940 | And yet, we lack right now the lab tests

00:08:43.500 | and the blood draws to make the diagnoses.

00:08:45.420 | - Well, we'll talk about it, just how biological they are,

00:08:48.240 | 'cause that too is a mystery.

00:08:50.540 | In terms of from a perspective of how to probe

00:08:54.580 | into the disease, how to understand it, how to help it.

00:08:57.660 | So some of it could be neurobiological.

00:09:00.020 | Some of it could be just the dance of human emotion

00:09:04.900 | and interaction.

00:09:05.860 | Is love when it works and is love when it breaks down

00:09:13.540 | biological or is it something else?

00:09:15.540 | So we're gonna talk about it.

00:09:17.340 | But let me just like to linger in terms of disorder.

00:09:20.460 | What about genius?

00:09:23.540 | You know, that sort of cliche saying,

00:09:25.740 | like the madness and genius,

00:09:28.100 | that they kind of dance together.

00:09:29.860 | What about if the thing we see as disorder

00:09:33.380 | is actually genius, unheard, or misunderstood?

00:09:37.540 | - Well, here again, the numbers help us.

00:09:40.300 | And here's where being rigorous and quantitative

00:09:42.340 | actually really helps.

00:09:43.280 | If you look at disorders like autism and bipolar disorder

00:09:47.500 | and eating disorders, anorexia nervosa, for example,

00:09:52.060 | these, you know, particularly bipolar and anorexia,

00:09:56.940 | these can be fatal.

00:09:58.380 | They can cause immense suffering,

00:10:00.760 | but they are heavily genetic, all three of these.

00:10:04.500 | And what's very interesting is each one of these three

00:10:07.760 | is actually correlated positively, positively,

00:10:11.660 | with measures of intelligence, of educational attainment,

00:10:15.580 | and even of income.

00:10:18.220 | And so you look at this, severe disorders in many cases,

00:10:22.700 | causing quite immense morbidity and mortality.

00:10:26.540 | And yet they are positively correlated

00:10:28.900 | at the population level with positive things.

00:10:31.220 | - Can you say the three again?

00:10:32.820 | Autism. - Yeah.

00:10:33.660 | Autism, anorexia, and bipolar disorder.

00:10:37.300 | - Bipolar, right.

00:10:38.380 | What's that book, forgot the book name,

00:10:40.340 | but is intelligence a burden?

00:10:42.520 | - Well, you know, people can get into trouble

00:10:48.100 | when they think they're smarter than they are,

00:10:49.580 | I will say that.

00:10:50.500 | - I don't know.

00:10:52.420 | - Sometimes, like, in the deepest meaning of that statement,

00:10:56.860 | I think ignorance is bliss.

00:10:58.220 | I'm a big fan of Prince Mishkin from "The Idiot"

00:11:00.940 | and Alyosha from "Brother Karamazov."

00:11:04.420 | Optimism can be seen as naivety and dumbness,

00:11:08.100 | but I think it's a kind of deep intelligence.

00:11:12.100 | Maybe inability to reason

00:11:16.660 | sort of about the mechanics of the world,

00:11:18.460 | but instead kind of feel the world.

00:11:20.660 | It seems like that's one of the paths to happiness.

00:11:24.280 | - There is.

00:11:25.120 | How much you think versus how much you feel,

00:11:26.860 | this comes up all the time.

00:11:28.140 | In medicine, we encounter this all the time.

00:11:30.720 | When you, day after day, you encounter this,

00:11:33.900 | you know, the abyss of suffering from patients.

00:11:36.620 | How much do you let yourself feel?

00:11:38.420 | Or how much do you make it abstract and objective

00:11:44.500 | and try to make it clinical?

00:11:46.580 | In that range, how you're able to move yourself

00:11:49.100 | on that spectrum is very important

00:11:52.220 | for survival as a physician.

00:11:54.000 | And the way you protect yourself and your feelings

00:11:58.460 | turns out to be very important.

00:12:00.180 | - You quote "Finnegan's Wake,"

00:12:02.700 | mad props for that James Joyce book.

00:12:05.220 | I took a class on James Joyce in college.

00:12:07.740 | I think I read parts of "Finnegan's Wake."

00:12:10.620 | I might have been on drugs of some kind.

00:12:12.620 | I somehow got an A in that class,

00:12:15.700 | which probably refers to some kind of curve

00:12:18.000 | where nobody understood anything.

00:12:19.800 | The only thing I understood and really enjoyed

00:12:21.420 | is his short stories, "The Dead."

00:12:23.340 | And then Ulysses, I kind of, I think,

00:12:26.380 | read a few Cliff Notes that kind of got to the point.

00:12:28.900 | And then "Finnegan's Wake" was just a hopeless pursuit.

00:12:31.660 | It's a, for people who haven't looked at it,

00:12:35.660 | maybe you can elucidate to me better,

00:12:38.180 | but I felt like I was reading things, words,

00:12:43.180 | and the words made sense, like standing next to each other.

00:12:47.740 | But when you kind of read for a while,

00:12:51.500 | you realize you didn't actually understand

00:12:52.980 | anything that was said.

00:12:54.060 | - Right, but did you have a feeling though?

00:12:55.860 | That's one thing I found interesting about "Finnegan's Wake."

00:12:58.860 | I never fully understood it,

00:13:00.580 | but the words caused feelings in me,

00:13:02.220 | which I found fascinating.

00:13:03.880 | And sometimes I couldn't predict it

00:13:06.820 | from the semantic black and white context

00:13:09.660 | of what I was seeing in front of me on the page.

00:13:11.940 | But the rhythm or the melody

00:13:13.220 | would make me feel certain ways.

00:13:14.520 | And that was what I always was intrigued by with Joyce.

00:13:17.580 | Of course, that was his, he existed on a spectrum too.

00:13:20.860 | And he wrote, as you say, more accessible works.

00:13:24.900 | I learned a lot about Irish history

00:13:26.420 | from "Portrait of the Artist as a Young Man."

00:13:28.740 | And there was just, he could be as objective

00:13:31.140 | as he wanted to be.

00:13:32.300 | But then when he let himself loose,

00:13:35.260 | he was in this realm where the words had their own purpose

00:13:39.820 | separate from semantic meaning,

00:13:42.700 | from their dry dictionary definition.

00:13:46.100 | You know, there's a funny story that was told.

00:13:48.380 | Doesn't matter if it's true or not,

00:13:49.700 | but they said that James Joyce, when he was young,

00:13:53.020 | when he was in his teen years,

00:13:54.340 | would go around sort of Ireland drinking and so on

00:13:57.780 | and telling everybody that he's going to be one of,

00:14:00.020 | if not the greatest writers of the 20th century.

00:14:03.060 | And he turned out to be that.

00:14:06.180 | So I always think about that little story

00:14:09.740 | that somebody told me,

00:14:11.680 | because I have a lot of people come up to me,

00:14:14.140 | including myself, I'm a bit of a dreamer.

00:14:16.260 | You get into certain moods where you say,

00:14:19.500 | I'm going to be the greatest anything ever.

00:14:22.780 | You get like people tell you this,

00:14:25.420 | especially young people.

00:14:27.220 | And it kind of, it makes me feel all kinds of ways,

00:14:32.180 | but that story reminds me that you just might be

00:14:36.260 | one of the greatest writers of the 21st century,

00:14:39.420 | for example, if somebody were to tell me that.

00:14:41.460 | And don't immediately disregard that,

00:14:44.940 | 'cause one of the people that say that,

00:14:47.320 | that's almost like a precondition,

00:14:49.300 | that's like a requirement just to believe in yourself.

00:14:51.600 | Maybe it's not a full requirement,

00:14:53.060 | but it's an interesting story.

00:14:55.240 | - I think when someone tells you that,

00:14:58.300 | then it creates, one sees an opportunity,

00:15:02.880 | and then it would be a tragedy

00:15:03.940 | if the opportunity weren't captured, right?

00:15:05.540 | And so then that creates some impetus,

00:15:09.100 | some motivation to do something good.

00:15:12.020 | - I think the mind, it's like,

00:15:13.860 | I guess that's what books or whatever,

00:15:17.940 | I don't even know if it's a book,

00:15:18.820 | The Secret plugs into,

00:15:20.700 | they kind of make a whole industry out of it.

00:15:23.460 | But there is something about the mind

00:15:26.220 | believing something, making it a reality.

00:15:28.380 | It is just time and time again with Steve Jobs,

00:15:32.060 | your belief in yourself, your belief in an idea,

00:15:35.860 | sort of embracing the me versus the world,

00:15:39.080 | embracing the madness of this idea

00:15:41.980 | and making it a life pursuit,

00:15:44.420 | somehow morse reality for some tiny fraction

00:15:47.900 | of the population, for everybody else,

00:15:49.740 | you descend into all the beautiful ways

00:15:54.740 | that failure materializes in our lifetime.

00:15:58.700 | (laughing)

00:15:59.540 | - You know, you mentioned love earlier,

00:16:00.900 | I mean, that's a great example

00:16:02.340 | of how belief in something makes it real, right?

00:16:05.340 | It's not reasonable on the face of it,

00:16:08.180 | but because you believe it's reasonable,

00:16:09.540 | then it actually does become reasonable

00:16:10.900 | and then it is real.

00:16:11.740 | And so that's a good example.

00:16:13.100 | That doesn't happen.

00:16:13.940 | I'm also in a bioengineering department.

00:16:15.940 | We don't imagine that a bridge is soundly built

00:16:18.460 | and then it is soundly built.

00:16:19.500 | That's something that,

00:16:21.100 | it doesn't come up in too many realms of human existence,

00:16:23.260 | but love is one of them.

00:16:24.500 | And the ability to have a fixed idea

00:16:29.500 | and to say it's true and then it is true.

00:16:32.380 | - A bridge is a kind of manifestation of love.

00:16:34.580 | So maybe it does work a little bit,

00:16:35.980 | but it can break down like Chernobyl did.

00:16:38.340 | You can't just say it's safe.

00:16:39.980 | You have to also prove it's safe.

00:16:42.300 | But on Finnegan's Wake,

00:16:45.380 | I think, maybe correct me if I'm wrong,

00:16:47.100 | you're using kind of Finnegan's Wake

00:16:48.700 | to give one perspective on what madness is,

00:16:52.260 | of what's going on in the mind.

00:16:53.740 | How much of that is that we're simply unable

00:16:58.740 | to communicate with the person

00:17:00.980 | on the other side of their mind?

00:17:03.780 | Like there's almost like a little person inside the brain

00:17:07.580 | and they have some circuitry

00:17:09.620 | that's used to communicate emotion,

00:17:11.740 | communicate ideas to the outside world.

00:17:14.060 | And there's something about that circuitry

00:17:15.620 | that makes it difficult to communicate

00:17:17.180 | with the little person on the other side.

00:17:18.900 | - So if you look at what shows up in schizophrenia,

00:17:21.220 | with many cases, what we call thought disorders,

00:17:25.140 | what we call the individual speech symptoms

00:17:30.020 | of schizophrenia, Finnegan's Wake is loaded with them.

00:17:33.700 | And it's just full of them.

00:17:35.260 | We talk about clang associations in schizophrenia,

00:17:39.860 | where the word that is said echoes in some way

00:17:43.980 | the previous word.

00:17:44.820 | And we call that a clang association

00:17:46.900 | 'cause there's no other reason

00:17:47.900 | than the similarity of the sound,

00:17:49.300 | like a clang of a garage door being hit.

00:17:53.180 | And it has a, and sometimes it's not even a word.

00:17:56.580 | And we call that a neologism, a new word being created.

00:17:59.940 | And of course, Finnegan's Wake is full of that.

00:18:02.220 | And then we also, in schizophrenia,

00:18:05.180 | where there's what we call loose associations

00:18:06.980 | or tangential thought processes,

00:18:10.020 | of course, full of that,

00:18:10.900 | where things just go off in directions

00:18:12.420 | that are not linear or logical.

00:18:15.260 | And you can't read Finnegan's Wake, I think,

00:18:18.620 | without, certainly as a psychiatrist,

00:18:21.500 | you can't read it without thinking about schizophrenia.

00:18:24.100 | And then when we look at the families of people

00:18:27.420 | with schizophrenia, and Joyce was no exception,

00:18:30.540 | there very often are people within the family

00:18:32.540 | who are on the spectrum.

00:18:33.860 | Some have it, some are able to see it from a distance,

00:18:38.860 | from a safe distance.

00:18:40.820 | There's an association between schizophrenia

00:18:43.020 | and what we call schizotypal personality disorder,

00:18:46.580 | where people are not quite in this severe state

00:18:49.900 | of schizophrenia, but have some magical thinking,

00:18:51.900 | have some unusual thought patterns.

00:18:54.540 | Very often, those are family members

00:18:56.020 | of people with schizophrenia.

00:18:57.620 | So this points to this, again, to this idea

00:19:00.140 | that there is a range, even along this very severe,

00:19:05.140 | very genetic biological illness,

00:19:07.500 | that human beings dwell on different spots

00:19:10.260 | along that spectrum.

00:19:11.460 | - I should mention that we have my friend Sergei

00:19:14.340 | pulling up stuff, young Sergei or old Sergei,

00:19:16.860 | I don't know what to call you,

00:19:17.740 | but there's drafts of Finnegan's Wake.

00:19:21.740 | Yeah, I actually saw pictures of this from,

00:19:24.100 | I think it was on Instagram or something.

00:19:27.060 | These are early drafts of Finnegan's Wake.

00:19:29.220 | And it's so beautiful to see,

00:19:30.380 | for people who are just listening,

00:19:31.940 | there's just random paragraphs and writing

00:19:34.740 | all over the page with stuff crossed out.

00:19:37.060 | And it's great to see that Joyce himself

00:19:40.260 | was thinking in this kind of way

00:19:41.900 | as you're putting it together.

00:19:44.740 | How much do you think he was thinking

00:19:45.940 | about the schizophrenic mind?

00:19:48.300 | - I think a lot.

00:19:49.140 | I think it's known that his daughter

00:19:51.140 | suffered from schizophrenia.

00:19:52.860 | And this is, what's depicted here on the page

00:19:56.820 | is something that I'm sure he either felt himself

00:20:00.580 | and some level was able to access

00:20:03.420 | this non-linearity of processing

00:20:06.260 | or had seen enough in family that he knew what it was

00:20:10.580 | and was able to reflect it down in black and white

00:20:13.940 | on the paper.

00:20:14.780 | So what he was able to do was quite authentic in that sense.

00:20:19.220 | Of course, I don't wanna pigeonhole him.

00:20:21.900 | He was doing much more than that.

00:20:23.740 | It was much more than talking about altered human

00:20:27.420 | thought processes and thought disorders.

00:20:31.300 | But that was an aspect that he was so good at representing

00:20:34.740 | that it had to be intentional to some extent.

00:20:37.500 | - And a tiny tangent,

00:20:38.700 | what does your own writing look like for this book?

00:20:41.980 | 'Cause it's extremely well-written.

00:20:44.180 | How many edits?

00:20:45.980 | Did you just drink some whiskey

00:20:48.060 | and like imagine Hemingway style?

00:20:51.420 | What's a very different, the writing is very different.

00:20:53.420 | I mean, it's really, really well-written,

00:20:55.660 | which was like, I was reading it.

00:21:00.180 | It makes you realize,

00:21:01.180 | 'cause I was expecting sort of a science kind of,

00:21:03.580 | which it is like elucidating something

00:21:08.580 | about the human mind kind of thing.

00:21:09.860 | But you could also probably write really strong novels.

00:21:14.860 | So maybe that's in the future.

00:21:16.940 | But anyway, what is your, how many edits?

00:21:19.140 | How many, what's your style?

00:21:20.260 | Does it look like that?

00:21:21.300 | Is it more structured, organized?

00:21:22.860 | - Unfortunately, I used a laptop,

00:21:24.460 | so I didn't have this sort of a beautiful record.

00:21:26.500 | - No typewriter, cigarette and whiskey.

00:21:29.500 | - I did explore, I was, you know,

00:21:31.380 | which was there a particular altered state

00:21:33.140 | that would help me to be most creative.

00:21:34.860 | And I found actually, I actually did the best while,

00:21:38.900 | you know, sober, but slightly disinhibited

00:21:42.620 | in the late hours of the night or early morning.

00:21:46.300 | Yeah, particularly late hours of the night there.

00:21:48.700 | I have a friend who would tell me

00:21:52.380 | that she thought that very early in the morning,

00:21:54.660 | her inner critic was still asleep

00:21:57.140 | and she could write more effectively

00:21:59.260 | before her inner critic woke up.

00:22:01.300 | And I actually found that outstanding advice for me

00:22:03.820 | that I often found that there was,

00:22:05.820 | I was looser and could write more in the morning.

00:22:09.340 | But the other interesting thing is each chapter,

00:22:12.100 | each story, it's about a different human being

00:22:15.500 | with a different class of psychiatric disorder.

00:22:18.460 | That's what each story, each chapter is anchored in.

00:22:22.900 | But I'm trying to use words that in style of writing

00:22:27.900 | and, you know, diction that captures the feeling

00:22:31.980 | of the disorder.

00:22:32.940 | And so it's different in each story.

00:22:34.860 | In the story about mania, which is a very expansive,

00:22:39.500 | exuberant, at least briefly uplifting state

00:22:43.260 | where the words come out in a torrent

00:22:45.180 | and they're complex and pressured and elaborate.

00:22:48.580 | I try to capture that feeling

00:22:50.260 | with the words used in that chapter.

00:22:52.460 | And then in the schizophrenia or psychosis chapter

00:22:56.540 | where things slowly fragment over time

00:22:58.420 | and become looser and separated,

00:23:01.820 | I tried to capture that in the writing too.

00:23:03.820 | So for each, it wasn't as if there was a single mode

00:23:06.720 | I could be in for the whole book.

00:23:08.300 | For each chapter, I had to put myself into a different mode

00:23:11.220 | to capture that inner feeling of the disorder.

00:23:14.380 | - When you put yourself in that mode, does that change you?

00:23:17.460 | - Yeah, I couldn't turn it on and off right away.

00:23:19.860 | I had to, first I would start by thinking about the person

00:23:23.820 | or the people, one or two people based on real patients

00:23:26.180 | and the stories that are put forth.

00:23:29.920 | The symptom descriptions are real,

00:23:31.320 | they're from the patients.

00:23:32.200 | Of course, all details change to protect privacy,

00:23:35.360 | but the actual symptom descriptions are real.

00:23:38.020 | And I would sit with them and really try to inhabit

00:23:41.200 | the space of the mind of that person that I knew.

00:23:45.620 | And that's not instantaneous, it would take some time.

00:23:48.800 | I needed quiet, I needed to be still.

00:23:51.180 | That's another reason late at night is good.

00:23:53.660 | - Sergey posted that drowsiness gives creativity boosts

00:23:56.780 | according to Andrew Huberman.

00:23:58.820 | Thank you, Andrew.

00:23:59.660 | (laughing)

00:24:01.580 | - He's not wrong, he's not wrong.

00:24:03.100 | - Why projections?

00:24:04.780 | Is it, I mean, there's, instead of putting words

00:24:08.220 | into your mouth, 'cause I can imagine a lot,

00:24:11.340 | I mean, to me, I will start putting words in your mouth

00:24:15.720 | despite what I just said.

00:24:16.980 | So, I mean, to me, projections,

00:24:20.520 | working on neural networks, for example,

00:24:22.040 | from artificial neural networks,

00:24:23.400 | from a machine learning perspective,

00:24:25.280 | it's often, that's exactly what you're doing.

00:24:27.560 | You have an incredibly complex thing

00:24:29.320 | and you're trying to find simple representations

00:24:33.000 | in order for you to make sense of it.

00:24:34.680 | So I was kind of thinking about it in that way,

00:24:36.800 | which is like this incredibly complex neuronal network

00:24:41.800 | that is kind of projecting itself onto the world

00:24:46.960 | through this low bandwidth expression of emotion

00:24:50.520 | and speech and all that kind of stuff.

00:24:52.320 | And the way it's, we only have that window into your soul,

00:24:57.040 | the eyes and the speech and so on.

00:24:58.480 | So that, in that way, where when there's any kind

00:25:03.040 | of disorder, we get to only see that disorder

00:25:06.320 | through that narrow window,

00:25:08.160 | as opposed to the full complexity of its origins.

00:25:11.120 | - The word projections definitely serves that purpose here,

00:25:13.880 | but it's got a few other really appropriate

00:25:17.640 | other connotations as well.

00:25:19.360 | So the first thing is a projection

00:25:20.920 | in terms of neuroscience is this long range connection

00:25:24.800 | that goes from one part of the brain to another.

00:25:26.880 | And so it's what binds two parts of our brain together.

00:25:30.560 | There are projections, long range connections of axons.

00:25:33.920 | These are the outgoing threads that connect

00:25:37.320 | one part of the brain to another part.

00:25:39.720 | There's a projection that links, for example,

00:25:41.880 | auditory cortex, where we hear things,

00:25:44.120 | to reward centers where we can feel,

00:25:46.920 | where feelings of pleasure and reward are initiated.

00:25:50.040 | And it's been shown that if you have reduced connectivity

00:25:53.440 | along that dimension, you are less able to enjoy music.

00:25:56.520 | And so these connections, these projections matter.

00:25:58.720 | They define how effectively two parts of the brain

00:26:01.840 | can engage with each other and join together

00:26:04.480 | to form a joint representation of something.

00:26:07.700 | So that's one meaning.

00:26:08.540 | It's pure neuroscience.

00:26:09.360 | The word projection is used all the time.

00:26:11.400 | And it happens to be something that optogenetics,

00:26:13.760 | a technique that maybe we'll talk about a little later,

00:26:16.000 | it works particularly well with.

00:26:17.160 | We can use light to turn on or off the activity

00:26:19.920 | along these projections from one spot

00:26:21.800 | of the brain to another.

00:26:22.840 | - And this is particularly referring

00:26:24.040 | to the long range connections.

00:26:25.800 | - It's particularly straightforward

00:26:27.320 | along these long range projections

00:26:28.680 | that connect different parts of the brain.

00:26:29.800 | But it works over a shorter range too.

00:26:32.040 | But then there's this other meaning of projections

00:26:34.120 | which you were bringing up, which is very relevant,

00:26:35.760 | which is at some point you can reduce something

00:26:39.040 | from one level of dimensionality to another,

00:26:41.120 | and you can project down into a lower dimensional space,

00:26:43.280 | for example.

00:26:44.840 | And then finally there's a psychiatric term,

00:26:48.640 | projections, which comes up all the time,

00:26:50.200 | which is we very often will look at our internal states

00:26:55.200 | and to understand somebody else,

00:26:57.720 | we'll project them onto somebody else,

00:27:00.520 | we'll try to understand someone else's behavior

00:27:02.800 | and make sense of it by projecting our own inner feelings,

00:27:06.400 | our own sort of narrative onto them,

00:27:10.880 | and use that as a way to help us understand them better.

00:27:15.000 | And we'll do the reverse too.

00:27:16.120 | We'll take things we see in the outside world

00:27:18.400 | and we'll bring them into ourselves

00:27:19.640 | and see how well they map, how well they align.

00:27:21.480 | That's called introjection.

00:27:23.200 | So projections turns out to be a really rich word.

00:27:25.840 | And then finally, of course, there's the very common sense

00:27:28.680 | of it as a projector that illuminates

00:27:31.960 | by conveying information across space with light.

00:27:35.920 | So for English, for English language,

00:27:38.280 | perfect word to use for this book.

00:27:40.200 | But what's funny is not every,

00:27:42.340 | there are a lot of international translations now

00:27:45.000 | and all those rich connotations

00:27:46.760 | aren't captured in other languages.

00:27:48.680 | And so for some translations,

00:27:51.920 | connections is used instead of projections.

00:27:54.400 | In fact, even in England,

00:27:56.120 | the British version is connections instead of projections

00:27:58.320 | because apparently projections

00:28:00.040 | doesn't have the full connotation I was told.

00:28:02.600 | - So you have to sacrifice some of the rich ambiguity

00:28:06.560 | of meaning with connections.

00:28:08.880 | That's interesting.

00:28:09.920 | I mean, and words are so interesting.

00:28:12.680 | They have so many meanings.

00:28:14.000 | I love language and how much is lost in translation.

00:28:16.960 | I'm very fortunate enough to be able to speak.

00:28:19.760 | I'm not good at languages.

00:28:20.760 | I was just, I guess, forced to by life's circumstance

00:28:24.560 | to learn two languages, Russian and English.

00:28:27.720 | And it's just so interesting to watch how much of culture,

00:28:30.640 | how much of people, how much of history

00:28:32.680 | is lost in translation.

00:28:34.280 | The poetry, the music, the history, the pain,

00:28:39.960 | the way the scientists actually express themselves,

00:28:41.880 | which is funny.

00:28:43.000 | I mean, just, it's so sad

00:28:48.320 | to see how much brilliant work that was written in Russian.

00:28:53.320 | There's a whole culture of science in the Soviet Union

00:28:56.840 | that is now lost.

00:28:57.920 | It makes me wonder in the modern day

00:29:01.000 | how much incredible science is going on in China

00:29:04.120 | that is lost in translation.

00:29:06.920 | And I'll never, I mean, that makes me very sad

00:29:08.920 | because I'll never learn Chinese in the same way

00:29:13.360 | that I've learned English and Russian.

00:29:15.800 | Maybe, whenever I say stuff like that,

00:29:17.920 | people are like, "Well, there's still time."

00:29:20.120 | Yeah, that's actually fair.

00:29:23.840 | That I think the 21st century,

00:29:26.800 | both China and US will have very important roles

00:29:30.960 | in the scientific development.

00:29:33.640 | And we should actually bridge the gap through language.

00:29:36.880 | And that doesn't just mean convincing Chinese

00:29:39.440 | to speak English.

00:29:40.680 | That means also learning Chinese.

00:29:43.240 | - Well, we need these bridge people who can do both.

00:29:47.760 | Nabokov, for example, writing in English beautifully.

00:29:50.920 | One of my favorite poets, Borges, who I mentioned earlier,

00:29:55.360 | he wrote both in English and in Spanish.

00:29:57.840 | I think beautifully in both.

00:30:00.760 | We need those people who can serve

00:30:02.720 | as bridges across cultures who really can do both.

00:30:05.560 | - You mentioned Borges.

00:30:08.400 | So you open your book with a few lines

00:30:11.240 | from a poem by Jorge Luis Borges, a love poem.

00:30:15.880 | I'm gonna read parts of it

00:30:17.000 | 'cause it's a damn good poem.

00:30:18.640 | It's called "Two English Poems."

00:30:20.360 | I mean, I'd like to understand why you used it

00:30:24.080 | and the specific parts you used, which is interesting.

00:30:27.480 | But then when I read the full thing,

00:30:30.440 | so I think you used it as a sort of beautiful description

00:30:35.440 | of what it means to delve deep into understanding,

00:30:39.040 | offering yourself to the task of understanding

00:30:42.440 | another human being.

00:30:43.960 | But if you look at the full context of the poem,

00:30:46.000 | it's also a damn good description of being hit by love

00:30:49.040 | and overtaken by it and sort of,

00:30:52.120 | trying to figure out how to make sense of the world

00:30:56.520 | now that you've been stricken by it.

00:30:59.280 | It says a bunch of things about chatting insignificantly

00:31:04.280 | with friends and all those kinds of things.

00:31:06.000 | And then the poem reads, "The big wave brought you."

00:31:10.600 | I get this is the moment, I guess, of the universe

00:31:14.160 | where the two people, you fall in love.

00:31:16.720 | Maybe I'm totally misreading this poem, by the way.

00:31:18.800 | Doesn't matter, you can't misread a poem.

00:31:20.840 | So it goes on, "Words, any words, your laughter,

00:31:25.840 | "and you so lazily and incessantly beautiful.

00:31:28.840 | "We talked and you have forgotten the words.

00:31:31.800 | "The shattering dawn finds me

00:31:33.480 | "in a deserted street of my city.

00:31:35.660 | "Your profile turned away.

00:31:37.660 | "The sounds that go to make your name.

00:31:40.220 | "The lilt of your laughter.

00:31:42.040 | "These are the illustrious toys you have left me."

00:31:45.280 | So these little memories of these peculiar little details,

00:31:48.320 | he remembers, those are the illustrious toys.

00:31:51.080 | I apologize to mix my own words with the poem,

00:31:53.200 | but you should definitely read it.

00:31:55.560 | "I turn them over in the dawn.

00:31:57.720 | "I lose them, I find them.

00:31:59.740 | "I tell them to the few stray dogs

00:32:01.660 | "and to the few stray stars of the dawn.

00:32:03.980 | "Your dark, rich life.

00:32:09.000 | "I must get at you somehow.

00:32:11.540 | "I put away those illustrious toys you have left me.

00:32:14.420 | "I want your hidden look, your real smile.

00:32:17.920 | "That lonely, mocking smile your cool mirror knows.

00:32:22.020 | "I want your hidden look, your real smile."

00:32:25.000 | So this is the first part of the poem,

00:32:28.060 | and then it goes on,

00:32:29.420 | which is some of the parts that you referenced.

00:32:31.960 | Second part is, "What can I hold you with?

00:32:35.900 | "I offer you lean streets, desperate sunsets,

00:32:38.420 | "the moon of the jagged suburbs.

00:32:40.240 | "I offer you the bitterness of a man

00:32:42.000 | "who has looked long and long in a lonely moon.

00:32:45.140 | "I offer you my ancestors, my dead men,

00:32:48.360 | "the ghosts that living men have honored in bronze.

00:32:51.260 | "My father's father killed in the frontier of Buenos Aires,

00:32:55.120 | "two bullets through his lungs," and so on, so on.

00:32:57.680 | "I offer you whatever insights my books may hold,

00:33:00.380 | "whatever manliness, a humor my life.

00:33:02.500 | "I offer you the loyalty of a man who has never been loyal.

00:33:05.720 | "I offer you that kernel of myself

00:33:07.960 | "that I have saved somehow,

00:33:09.160 | "the central heart that deals not in words,

00:33:11.560 | "traffics, not with dreams,

00:33:14.000 | "and is untouched by time, my joy, and adversities."

00:33:18.560 | And I think this is the part that you include in the book.

00:33:21.980 | "I offer you the memory of a yellow rose seen at sunset,

00:33:25.520 | "years before you were born."

00:33:27.300 | Damn, that's a good line.

00:33:30.660 | Okay. (laughs)

00:33:32.980 | "I offer you explanations of yourself,

00:33:35.180 | "theories about yourself,

00:33:36.440 | "authentic and surprising news of yourself.

00:33:39.000 | "I can give you my loneliness, my darkness,

00:33:41.920 | "the hunger of my heart.

00:33:43.480 | "I'm trying to bribe you with uncertainty,

00:33:45.560 | "with danger, with defeat.

00:33:47.620 | "That is a man who's in love and longing."

00:33:50.000 | If taken, but I just wanna go back to,

00:33:52.960 | maybe you could say why you wanted to include that poem,

00:33:55.120 | but also, "Your dark rich life, I must get at you somehow.

00:33:59.960 | "I put away those illustrious toys you have left me out.

00:34:03.320 | "I want your hidden look, your real smile,

00:34:05.960 | "that lonely mocking smile, your cool mirror nose.

00:34:08.740 | "Sometimes I meet a stranger, and I just,

00:34:12.060 | "it's like a double take.

00:34:15.800 | "It's like, who are you?

00:34:17.700 | "Have we met before somewhere?

00:34:19.360 | "Who's that person behind there?

00:34:22.200 | "And I wanna get at that, whatever that is."

00:34:24.960 | And of course, maybe that's what love is,

00:34:26.960 | because maybe that's the whole pursuit,

00:34:30.160 | like a lifelong pursuit of getting at that person.

00:34:32.320 | Maybe that's what that is,

00:34:33.600 | and that insatiable sort of curiosity to keep getting,

00:34:37.920 | like, well, who's that person in your own private life?

00:34:40.380 | - Yeah, so that, absolutely, I think that,

00:34:42.660 | it was a beautiful description of what you just said,

00:34:44.860 | when there's that first moment,

00:34:46.800 | and then you wanna dive deeper,

00:34:48.840 | you want to know what the hidden mysteries are.

00:34:52.120 | In a way, it's a love poem.

00:34:55.240 | As a scientist, though, it also,

00:34:57.500 | it's a bit of how a scientist can love science,

00:35:01.080 | and that wanting to dive deeper is,

00:35:07.520 | it's almost like, again, where the,

00:35:09.720 | it could be a love affair with investigating

00:35:11.720 | the human mind, for example,

00:35:13.280 | and that was one reason it spoke to me also.

00:35:16.560 | Again, thinking about the broader sweep

00:35:19.120 | of where the human mind came from,

00:35:20.840 | the steps it took to get where it is today,

00:35:25.000 | what was given up along the way,

00:35:26.920 | what compromises were made,

00:35:28.160 | and here's where the darkness of the poem

00:35:29.760 | starts to come in a little bit, too.

00:35:31.480 | It doesn't shy away from the negativity,

00:35:35.080 | from the confusion, from the danger,

00:35:39.120 | and then at the very end,

00:35:40.360 | the, Borges is offering up scenes from his life,

00:35:46.540 | parts of himself, and this is how we connect with people.

00:35:49.560 | We offer up parts of ourselves, just, here it is,

00:35:51.920 | and then we see, how well does that map onto what you have?

00:35:54.640 | And it's that offering up that I liked,

00:35:57.800 | and not the good stuff, or not only the good stuff.

00:36:00.400 | The yellow rose is nice,

00:36:01.400 | but he's offering up the bad stuff, too,

00:36:03.640 | and that, to me, was important for the book,

00:36:06.240 | because I'm offering up hard stuff, too,

00:36:10.000 | in fact, a lot of it,

00:36:11.200 | and also hard stuff from within me,

00:36:13.420 | from my own personal side, too,

00:36:15.080 | and that was, there's a lot of vulnerability

00:36:17.480 | that comes with that, but that's,

00:36:19.240 | that comes with love, that comes with writing.

00:36:21.280 | You have to be open, you have to be vulnerable,

00:36:23.560 | and so I thought that reflected what I was trying to do,

00:36:28.160 | and I thought it was, as an epigraph,

00:36:29.720 | it kind of made it clear how vulnerable I was

00:36:33.760 | in taking this step, but also what could come out of it.

00:36:38.280 | - And also, in a meta way,

00:36:39.600 | because I was not familiar with this poem,

00:36:41.720 | it made me curious of the poem itself,

00:36:47.640 | to pull at that thread of finding out more.

00:36:50.960 | See, you picked a very particular part

00:36:53.320 | that kind of made you want to pull at that thread

00:36:57.680 | and see where did this,

00:37:00.480 | where did these few lines come from?

00:37:02.920 | 'Cause I read it as a curiosity of a scientist,

00:37:05.800 | those lines alone, and also as a desperate human being,

00:37:10.800 | searching, like offering himself for an understanding

00:37:17.320 | or connection with another human being,

00:37:19.600 | and then, 'cause I wasn't sure if it's a love poem or not,

00:37:21.960 | or if it's desperation or if it's curiosity,

00:37:23.680 | whatever it is, and then you see the love poem.

00:37:26.200 | I mean, I don't know, that's gonna stick with me for a while,

00:37:29.200 | your dark, rich life, and then a few lines in here are just,

00:37:35.240 | I mean, those are, I'm gonna just use them

00:37:38.000 | as pickup lines at a bar.

00:37:40.200 | I offer you the memory of a yellow rose

00:37:42.400 | seen at sunset years before you were born.

00:37:44.880 | (laughing)

00:37:47.360 | Now, that's a pickup line I've never,

00:37:48.840 | if I've ever heard one, anyway, sorry.

00:37:51.440 | - But this is universal, you know,

00:37:52.440 | you see it in so many forms of art,

00:37:54.960 | you know, like, you know, we're in Texas now,

00:37:57.320 | you see this in country and Western songs,

00:38:00.040 | it's often a list of things,

00:38:02.120 | like, here's how I describe myself,

00:38:03.600 | there's this and there's that,

00:38:04.440 | and there's the other thing, and here you are,

00:38:06.320 | these things matter to me,

00:38:07.920 | and I hope they matter to you too.

00:38:09.280 | It's a pretty universal form,

00:38:11.080 | but he did it in this very artful and very vulnerable way,

00:38:16.080 | it was both beautiful and you could feel the hurt

00:38:20.600 | coming from him too, and that was important.

00:38:22.960 | The dark stuff too, I offer you my ancestors,

00:38:25.600 | my dead men, the ghosts that living men

00:38:28.200 | have honored in bronze,

00:38:29.440 | and talking about two bullets through his lungs,

00:38:32.260 | bearded and dead,

00:38:33.800 | wrapped by his soldiers in the hide of a cow,

00:38:37.960 | my mother's grandfather just 24

00:38:40.320 | heading a charge of 300 men in Peru,

00:38:43.600 | now ghosts on vanished horses.

00:38:46.960 | So all of it, the whole history of it.

00:38:49.080 | Since it is a love poem,

00:38:52.640 | what do you think about love, Carl?

00:38:55.920 | What's the role of love in the human condition?

00:38:58.600 | We'll talk about the dark stuff,

00:39:00.640 | but maybe love is the dark stuff too.

00:39:02.920 | - I mean, it's the most powerful connection we can form,

00:39:06.960 | and that's what makes it so important to us.

00:39:11.260 | It's the strongest and most stable connection

00:39:16.260 | that we can form with another person,

00:39:17.680 | and that matters immensely.

00:39:19.880 | It matters for the human family to have evolved

00:39:24.400 | to be something that could survive against the odds

00:39:27.200 | that we've faced over the years,

00:39:29.680 | of that unreasonable bond that becomes reasonable

00:39:34.680 | by virtue of its own existence,

00:39:37.740 | and of course, that joy, the wild, raw joy of love

00:39:43.580 | is not a bad thing either.

00:39:46.680 | So you put these together,

00:39:48.560 | the strongest bridge we can form,

00:39:50.640 | and the reward and the joy that it brings,

00:39:54.360 | that's what love is to me.

00:39:56.800 | And from my perspective, this is something that,

00:40:01.360 | it can be hard to capture fairly

00:40:05.040 | because you wanna talk about the positive

00:40:07.240 | and the negative sides at once.

00:40:09.080 | They need to be wrapped up together

00:40:10.360 | for a full, honest description of what it is,

00:40:13.680 | and that's hard to do in a compact form.

00:40:16.640 | And so you have to take time to talk about love.

00:40:19.360 | You have to take time to do it justice.

00:40:23.600 | It takes a book or at least a poem.

00:40:25.480 | - Or several thousands of them.

00:40:28.440 | I don't know, Sergei, could you pull up,

00:40:30.640 | there's a video I saw, yeah, like right here.

00:40:33.980 | So can you pause for a second?

00:40:35.520 | So this is March of the Penguins.

00:40:39.200 | So you always see penguins huddling together against,

00:40:44.120 | I mean, sorry if I see just metaphors and everything,

00:40:46.320 | but them huddling together against the harshness

00:40:49.920 | of the conditions around them.

00:40:52.160 | That's very kind of, that's like a metaphor for life,

00:40:55.680 | like finding this connection.

00:40:57.520 | That's kind of what love is.

00:40:59.240 | It's like it allows you to forget whatever the absurdity,

00:41:02.120 | whatever the suffering of life is,

00:41:03.760 | together you get to like huddle for warmth.

00:41:06.720 | And that's why I love the sort of just the honesty

00:41:11.520 | and the intensity of the way penguins

00:41:13.120 | just in the middle of like the cold do this.

00:41:15.200 | And then this video I saw, a lonely,

00:41:18.920 | this is misinformation.

00:41:20.920 | So the name of the video is Lonely Deranged Penguin.

00:41:23.880 | I don't know if he's deranged.

00:41:26.040 | So if you play it, so he left his pack

00:41:29.280 | and there's a nice like voiceover,

00:41:34.800 | you don't need to play it, but he, for some reason,

00:41:37.640 | left the pack and journeyed out into the mountains.

00:41:41.800 | And so the narrator says that he's deranged,

00:41:44.720 | he's lost his mind.

00:41:46.480 | Now I'd like to project the idea that he's actually,

00:41:50.680 | there's so many stories you could think of.

00:41:52.920 | He's returning to his homeland.

00:41:55.160 | He's an outsider thinking, journeying out into the unknown,

00:41:58.320 | thinking he may be able to discover

00:42:00.160 | something greater than the tribe.

00:42:02.080 | He might be looking for a lost love.

00:42:04.640 | Why is he deranged immediately?

00:42:06.680 | Why has he lost his mind?

00:42:08.000 | Anyway, but this, people should look up this video

00:42:10.960 | 'cause to me, I might be the only one

00:42:12.920 | who romanticizes this, but it's such a nice kind of,

00:42:17.920 | it's both a picture of perhaps a mental disorder,

00:42:21.800 | which is what the video kind of describes,

00:42:23.880 | and it may be some deeper explanation

00:42:25.920 | that has to do with the motivation of a mind.

00:42:30.920 | Yeah, I don't know if you have a deeper analysis

00:42:35.480 | on this penguin.

00:42:36.320 | - Well, I, like you-- - As a psychiatrist.

00:42:39.120 | - I would wanna sit down with a penguin

00:42:42.040 | and go through, I wanna see the notes

00:42:45.440 | from his prior therapist, but this actually is relevant.

00:42:50.440 | Not knowing what was that penguin's motivation,

00:42:54.640 | we have very clear situations where there are,

00:42:58.280 | both within an individual, we go through periods of time

00:43:00.840 | when we stay in one place and we reap the benefits

00:43:05.720 | from what we've built, and then we go through periods

00:43:08.120 | of foraging, of wandering.

00:43:11.280 | Even if there may be resources where we are,

00:43:15.160 | we have periods of time in our lives where we wander,

00:43:18.240 | where we go in an exploratory mode,

00:43:22.680 | and different people express that trait in different ways.

00:43:26.520 | This is not a human-specific trait.

00:43:27.840 | If you go down to the tiny little nematode worm,

00:43:31.560 | C. elegans, with 302 nervous system cells,

00:43:34.740 | they go through these phases of foraging and rest,

00:43:37.200 | and different individuals have different propensity

00:43:39.560 | to forage or to rest and stay in one place.

00:43:42.920 | At the level of the species, that's really good,

00:43:45.560 | that there's that diversity in their willingness to forage.

00:43:50.560 | Some stay where they are, the species is somewhat

00:43:54.920 | on a firm footing then, but some carry a burden,

00:43:58.960 | a risk for themselves, but it's good for the species

00:44:02.160 | that they're explorers and they will venture out.

00:44:05.480 | The migration patterns that different species blunder into

00:44:09.200 | and that turn out to be really good,

00:44:10.760 | they weren't logically derived.

00:44:13.280 | They most certainly started from something like this,

00:44:17.240 | an exploration.

00:44:18.240 | - And humans do this too, you think?

00:44:19.360 | - And we do it too.

00:44:20.440 | In fact, it's something we do extremely well.

00:44:23.880 | - Let's talk about psychiatry a little bit.

00:44:26.040 | So in my book, you're a rock star.

00:44:30.920 | First of all, for people who don't know,

00:44:33.080 | aside from sort of the neurological view of the brain

00:44:38.080 | and neuroscience view of the brain,

00:44:40.200 | you're also one of the great psychiatrists of our time.

00:44:43.200 | I've always, not always, but when I was younger,

00:44:45.760 | I dreamed about being a psychiatrist.

00:44:47.680 | So it's like getting to meet your heroes

00:44:53.360 | and also getting to meet the people who,

00:44:57.480 | the best at the top of the world

00:45:01.480 | at the thing you've failed to pursue.

00:45:03.560 | So there's, I'm getting a free therapy session

00:45:06.240 | on top of that.

00:45:07.240 | Okay, so what, big picture, what is the practice,

00:45:11.480 | the goal, the hope of modern psychiatry?

00:45:13.880 | If you could try to describe the discipline as you see it,

00:45:18.800 | maybe historically throughout the 20th century

00:45:23.080 | in contrasting to what it is today,

00:45:25.520 | or maybe if you want to describe

00:45:27.480 | to what you hope psychiatry becomes

00:45:29.600 | or longs to become in the 21st century.

00:45:32.720 | - Yeah, it's been an interesting journey.

00:45:36.360 | Psychiatry started out pretty firmly grounded

00:45:39.360 | in neurology and pathology.

00:45:40.960 | Some of the initial founders effectively of the field

00:45:44.260 | were very well grounded in microscopy, looking at cells,

00:45:48.220 | working with patients, particularly on the neurological side

00:45:52.520 | and this certainly included Freud

00:45:54.280 | and some of his contemporaries.

00:45:56.840 | And, but they rapidly discovered that

00:46:00.760 | what they could work with at the level of cells

00:46:05.000 | and microscopy was so far from the realm

00:46:08.400 | of what they could get from a human being.

00:46:11.560 | And what they were getting from the human being

00:46:13.120 | was so much more interesting and had,

00:46:15.480 | was so mysterious and so unknown that many of them

00:46:18.520 | just said, we're gonna inhabit this domain

00:46:20.200 | and we're gonna work with the people with their words

00:46:23.200 | and understand what we can based on verbal communication

00:46:27.040 | because that was the only tool that people really had.

00:46:30.520 | And that was a very important step for the field.

00:46:35.520 | I would say one of the interesting things

00:46:39.180 | that came from the early decades of psychiatry

00:46:42.600 | really was this distinction between the conscious

00:46:45.520 | and the unconscious mind and paying particular attention

00:46:50.120 | to the unconscious mind as something

00:46:51.840 | that was worthy of consideration,

00:46:54.040 | that might be important in explaining people's actions

00:46:58.640 | and that perhaps even insight into that

00:47:00.420 | was valuable in its own right.

00:47:02.640 | And out of that psychoanalysis became a practice

00:47:07.600 | that was not always focused on cures or treatment,

00:47:12.600 | but was more focused on insight.

00:47:14.240 | What does it mean?

00:47:15.400 | How can we help people understand

00:47:17.360 | why they're feeling something or thinking something

00:47:19.920 | or dreaming something?

00:47:21.960 | And that insight, separate even from treatment,

00:47:24.720 | was an interesting thing as long as one was honest

00:47:28.480 | about that and said, we're going for understanding,

00:47:31.160 | we're going for insight.

00:47:32.400 | - Maybe it's useful to just pause on that.

00:47:34.840 | If we look at the father of psychoanalysis,

00:47:37.760 | Sigmund Freud, what do you make of the ideas that he had?

00:47:42.760 | So you mentioned taking the unconscious,

00:47:46.880 | the subconscious seriously.

00:47:49.360 | That's like step one.

00:47:50.900 | Like that there could be worlds

00:47:52.220 | we do not have direct access for

00:47:53.880 | and we probe at them through conversation.

00:47:57.920 | Is that too simplistic to call psychoanalysis conversation?

00:48:03.080 | - That's not too simplistic, but that's right.

00:48:05.200 | And I think that was valuable.

00:48:06.640 | Where Freud ended up breaking

00:48:09.020 | from some of his contemporaries,

00:48:10.320 | he was very focused on this unconscious

00:48:13.280 | as being so tightly linked to libido.

00:48:15.720 | And really, from his perspective,

00:48:18.880 | you couldn't really separate the operation

00:48:20.840 | of the unconscious mind from these aspects,

00:48:23.000 | the libidinous aspects.

00:48:24.160 | And that was one reason.

00:48:25.000 | - What's the libidinous aspect?

00:48:25.840 | - You know, sexually related drives.

00:48:29.140 | Carl Jung, who was his contemporary,

00:48:33.080 | that's one factor that led to them separating

00:48:36.200 | was Carl Jung felt there was a lot more to the unconscious

00:48:40.440 | than this libidinous aspect of it.

00:48:42.680 | And he saw it as a much more complete

00:48:47.480 | alternate representation of the conscious self,

00:48:50.880 | one that maybe reflected a whole range

00:48:53.480 | of different motivations and desires.

00:48:58.340 | And to properly treat it, one had to consider all of them

00:49:04.760 | rather than the ones that Freud was focused on.

00:49:06.520 | - Carl Jung, your point.

00:49:08.360 | - Thank you.

00:49:09.800 | - Thank you for the high level of images

00:49:13.320 | that Sergei is pulling out.

00:49:14.360 | For people who are just listening,

00:49:15.480 | he pulled up a, as a quote from Sigmund Freud's meme,

00:49:19.920 | your mom, quote Freud.

00:49:23.400 | So the shadow, the Carl Jung shadow,

00:49:26.720 | encompasses everything, not just the desire

00:49:29.680 | to have sex with your mother or sex, period.

00:49:32.600 | - That's right, that's right.

00:49:34.320 | - If you look at those two folks en masse,

00:49:38.120 | I mean, there's a kind of, it's almost like a technique

00:49:41.680 | for philosophical exploration of human mind,

00:49:45.560 | human motivations.

00:49:47.320 | So it's not even like necessarily,

00:49:49.960 | it also doubles as a methodology for helping people.

00:49:53.720 | But it's almost like a,

00:49:54.960 | it's a kind of philosophical method.

00:49:59.920 | - Right.

00:50:01.080 | This is the fascinating thing about psychoanalysis.

00:50:03.720 | And even though it's, I would say,

00:50:06.840 | mostly not considered a treatment today,

00:50:10.360 | it persists for a couple of reasons.

00:50:11.760 | One is it's thought that it gives people some insight.

00:50:15.840 | But second, there's been a huge influence on literature,

00:50:19.960 | on philosophy, on art, and the opening up of discussion

00:50:24.500 | about what was below our conscious mind

00:50:27.560 | was so fertile in the implications

00:50:31.720 | that it sort of reverberated and still does

00:50:34.680 | throughout all these different realms of human endeavor,

00:50:37.120 | from different artistic experiences that people have

00:50:42.120 | can be colored by this concept of the unconscious.

00:50:49.960 | Now, the other thing that was interesting

00:50:51.720 | is this distinction,

00:50:54.060 | what are the parts of the unconscious?

00:50:57.720 | And so there were these id and ego and superego subdivisions

00:51:03.520 | that Freud, for example, would talk about them.

00:51:08.520 | And the id was the primary, the primal drives

00:51:13.080 | that an infant would have, or that a very young child,

00:51:16.480 | just warmth and feeding, and then later,

00:51:19.840 | the sexual or libidinous aspects.

00:51:22.520 | - And for Freud, the later happened very quickly.

00:51:25.180 | (Luke laughs)

00:51:26.880 | That's the controversial thing about him.

00:51:28.660 | I think, I guess he thought like even children

00:51:31.440 | had sexual desires that they're like dealing with,

00:51:33.840 | contending with, so it's the full thing.

00:51:36.360 | Hungry, wanting to eat, wanting to poop,

00:51:38.640 | wanting to have sex.

00:51:39.920 | - Yeah, and he was extremely focused on that aspect.

00:51:43.660 | But then there was the superego,

00:51:46.280 | which brought on these later sort of moralistic

00:51:49.080 | sort of codes of conduct, and that, of course,

00:51:54.280 | was very often in tension.

00:51:56.200 | But all this could play out subconsciously.

00:51:58.560 | And then the ego, this third aspect, was mediating,

00:52:01.800 | and Freud's conception mediated this tension

00:52:04.680 | between the different parts.

00:52:06.320 | Now, I think that's interesting.

00:52:09.480 | I will say that in some ways, it's maybe unnecessary

00:52:14.480 | from the perspective of modern neuroscience

00:52:17.080 | to divide things up that way from the moralistic drives

00:52:22.080 | and the primal gratification drives.

00:52:28.120 | In some ways, they're all drives,

00:52:29.960 | and maybe they're even all primal drives.

00:52:32.280 | You know, the moralistic drives, they're taught,

00:52:35.280 | and they're taught in ways that ultimately relate

00:52:37.880 | back to survival, and you could even say selfish aspects

00:52:42.880 | of health and life for the self and family.

00:52:47.520 | And so this is, I think it's maybe

00:52:51.600 | an artificial distinction.

00:52:53.440 | The concept of the unconscious is very valuable

00:52:56.240 | and very interesting, but these categorizations

00:52:59.800 | of id and superego may not map onto neurobiology

00:53:05.880 | in any particular way.

00:53:07.320 | If there's a town hall of competing drives and desires,

00:53:10.520 | and they interrelate to each other,

00:53:13.720 | they involve different aspects of the brain

00:53:16.040 | and the history of the person, and actions and choices

00:53:20.240 | come out of the result of that overall shouting

00:53:24.440 | in the town hall.

00:53:25.440 | - So in some sense, Carl Jung was a step

00:53:27.200 | into the direction of liberating yourself

00:53:29.000 | from such harsh categorizations.

00:53:32.280 | Do you think, I mean, you have Daniel Kahneman

00:53:35.240 | with system one and system two.

00:53:37.400 | There's just these very compelling categorizations

00:53:40.480 | of the human mind that seem to be sticky

00:53:44.200 | in the superego, no, in how we talk

00:53:50.520 | about these ideas and so on.

00:53:52.680 | Do you think those are helpful or do they get in the way?

00:53:55.480 | Is it some kind of balance in terms of deeper understanding

00:53:57.880 | of how the mind actually works?

00:53:59.360 | - You know, it's from modern neuroscience,

00:54:01.680 | whenever we seem to get closer to addressing a question

00:54:07.880 | like this at the level of cells,

00:54:09.980 | it seems to get farther away, and I'll give you an example

00:54:13.160 | of what I mean by that.

00:54:14.740 | So one thing I'm doing in my laboratory

00:54:16.760 | and many people are doing is we are listening in

00:54:20.720 | on the activity of cells, neurons, in the brain of mice

00:54:25.600 | or rats or fish or monkeys.

00:54:27.680 | - Individual cells.

00:54:28.520 | - Individual cells, exactly, of which there are,

00:54:31.200 | you know, in our brain, many billions.

00:54:33.240 | And when we do and we try to predict

00:54:37.280 | what action will be taken by an animal,

00:54:39.380 | to address this question, where does the choice arise?

00:54:43.640 | Where does the impetus to make a particular selection

00:54:47.080 | of one action versus another action,

00:54:48.780 | where does that start in the brain?

00:54:50.060 | If you're recording, listening in on the activity of cells

00:54:52.960 | all across the brain, where's the earliest spot

00:54:56.680 | you can pick up a choice being made?

00:55:00.640 | Well-- - That's so awesome.

00:55:02.120 | - Yeah, at one level, you might think how excited

00:55:05.640 | would Jung have been to see this or Freud

00:55:08.160 | or the early psychoanalysts to see where this starts,

00:55:11.640 | but it's not so simple because an emerging theme

00:55:15.840 | in very recent neuroscience,

00:55:17.160 | literally over the last few years,

00:55:19.640 | is that things sort of all start together,

00:55:23.220 | all across the brain.

00:55:24.400 | And so you can be recording from the cortex,

00:55:27.080 | this rim of cells at the surface of the brain,

00:55:29.880 | or you can be recording deeper in a structure

00:55:32.360 | called the striatum, which is a little older,

00:55:34.920 | it's more tightly linked to action,

00:55:38.380 | and then structures called the thalamus,

00:55:40.300 | other parts of the brain.

00:55:41.660 | And if you record from these,

00:55:43.040 | these all sort of represent the action and the choice

00:55:48.840 | more or less all at about the same time, very close.

00:55:51.320 | And so you can't point to a particular spot

00:55:54.200 | and say, here's where the choice or the action originates.

00:55:59.160 | It's a group-- - Is this a

00:56:00.640 | finding the free will neuron?

00:56:02.620 | - It's relevant to that question.

00:56:05.120 | Nobody is close to being able to point to such a thing.

00:56:08.120 | - Well, close is a relative term.

00:56:11.840 | And nobody, what I tweet today,

00:56:16.160 | all generalizations are wrong.

00:56:17.920 | (both laughing)

00:56:19.840 | So including this one.

00:56:21.200 | Let's actually talk about that.

00:56:22.280 | So the study of individual cells,

00:56:25.360 | if you could linger on your sense

00:56:27.920 | that as you get closer to that understanding,

00:56:30.480 | it feels like you're getting farther away.

00:56:33.080 | Why is that?

00:56:34.040 | 'Cause that often is the feeling

00:56:36.040 | until you're actually there.

00:56:37.600 | So like, you know,

00:56:40.680 | see that's when I'm running

00:56:42.880 | and I know there's only a mile left,

00:56:44.960 | it just feels like that mile

00:56:46.920 | is just getting longer and longer,

00:56:49.040 | but eventually you finish.

00:56:50.160 | So maybe we're getting close

00:56:51.800 | to cracking open these beginnings of a sense,

00:56:54.520 | like we'll talk about consciousness

00:56:56.160 | or these very difficult, big questions about the human mind.

00:57:00.880 | Where do they start?

00:57:02.360 | - You're right to say we shouldn't generalize

00:57:04.680 | or make absolutist statements.

00:57:06.400 | But I would say right now,

00:57:09.160 | the reason things are looking even harder to crack

00:57:12.860 | than we had initially thought,

00:57:14.720 | we now have the data streams

00:57:16.400 | that we've wanted for so long

00:57:18.160 | in terms of activity patterns all across the brain

00:57:22.240 | at the level of cells.

00:57:23.240 | We can literally see what cells are doing.

00:57:26.640 | Immense data sets, you know,

00:57:28.240 | we get, these are time series of one individual cell

00:57:32.080 | with sub-second resolution

00:57:34.080 | and you can collect this from enormous numbers

00:57:36.360 | of cells across the brain.

00:57:38.080 | So very rich data sets that we've wanted for a long time

00:57:40.880 | and yet having these has not led

00:57:44.560 | to an understanding of truly where actions initiate

00:57:49.520 | in terms of regions or locations.

00:57:51.960 | - Can I ask you a few questions on that?

00:57:54.160 | Is the answer, high level question by your intuition,

00:57:59.160 | is the answer within the data

00:58:01.640 | or do we need different kind of data?

00:58:04.600 | So we should also say that when you collect data

00:58:07.920 | about the brain,

00:58:09.680 | there's like the richness of information you're collecting

00:58:12.600 | but there's also a human doing stuff.

00:58:14.760 | Like, and the information,

00:58:19.320 | so static information about the human

00:58:20.960 | and dynamic information about the human

00:58:23.480 | and you can get them to do different stuff

00:58:25.320 | and you can select different humans

00:58:27.440 | and that's part of the collection of data aspects.

00:58:30.680 | So like when you're collecting data about the brain,

00:58:33.440 | there's some truths that you can,

00:58:36.360 | you know, in machine learning,

00:58:37.200 | it's like annotations, like supervised learning,

00:58:39.680 | there's some true things you can hold onto

00:58:42.080 | before you look at the full rich mess complexity

00:58:46.040 | of the human mind.

00:58:47.600 | So given the data you've looked at,

00:58:50.080 | do you think the answer for the origin of free will

00:58:54.040 | in the human mind can be found?

00:58:56.640 | - Well, one amazing thing is that nobody's found it

00:59:03.120 | but we have these rich data sets

00:59:05.880 | and then there's a conundrum which is,

00:59:09.800 | is it in the data and we just don't know how to look at it?

00:59:12.080 | Maybe we don't know the right scale,

00:59:13.720 | the right projection to make of the data,

00:59:15.760 | the right way to interpret it.

00:59:17.720 | And here's where causal testing becomes very valuable

00:59:21.240 | 'cause then instead of just passively observing,

00:59:23.780 | well, here are the activity patterns

00:59:28.360 | and then here's the choice made by the animal

00:59:30.560 | as we've gotten more powerful at reaching in

00:59:36.000 | and causing things to happen in the brain,

00:59:37.960 | turning up or down the activity of certain types of cells

00:59:42.120 | or defined populations of cells

00:59:44.400 | and seeing how that affects actions.

00:59:46.360 | These causal perturbations have turned out

00:59:48.880 | to be very valuable.

00:59:50.440 | We're just now getting to the point

00:59:52.200 | where we can apply these in very wide swaths of the brain

00:59:57.200 | at cellular resolution and so we're gonna be able,

01:00:01.440 | hopefully to make some headway on this question

01:00:03.240 | with causality and those,

01:00:05.880 | that's the one thing that optogenetics provides us,

01:00:08.720 | this way of using light that we develop to control cells.

01:00:12.160 | This is relatively untapped at this broad brain-wide scale

01:00:17.160 | and hopefully we can get there in the near future.

01:00:18.880 | But I would say that the answer may be in the data

01:00:22.640 | but we don't know how to find it.

01:00:24.360 | - Well, there's this interactive element

01:00:26.000 | like where you can cause stuff that's really powerful

01:00:28.680 | because you get to, I mean,

01:00:30.560 | as opposed to collecting data passively,

01:00:33.800 | you're collecting data actively.

01:00:35.240 | So can you maybe describe one of the many things

01:00:38.400 | you're known for, one of the big things

01:00:40.960 | is called optogenetics, what is it?

01:00:43.560 | - Optogenetics is a way of causing things to happen.

01:00:46.160 | It's a way of determining what actually matters

01:00:50.240 | in terms of the activity of the brain

01:00:52.200 | for the amazing things it does,

01:00:55.040 | sensation, cognition, action.

01:00:57.440 | And what it does is it provides activity.

01:01:01.720 | It's a way of playing in, if you will,

01:01:04.320 | activity patterns into precisely defined cells.

01:01:07.520 | And the way we do it is pretty cool, I think.

01:01:09.720 | Right away there's a problem if you think about

01:01:12.800 | how do we do this?

01:01:13.620 | How could we play in well-defined activity patterns

01:01:16.360 | and provide a stream of activity into this cell

01:01:20.100 | and that cell and that cell but not these other cells?

01:01:22.680 | - But just for context, we're talking about the brains

01:01:25.920 | of mice, monkeys, humans,

01:01:32.120 | and then the goal is to try to control accurately

01:01:35.880 | the behavior of a single neuron

01:01:38.280 | and then to be able to monitor

01:01:40.640 | single collection of single neurons

01:01:44.040 | to then say, well, to draw some deeper insight

01:01:48.080 | about the origins, first of all,

01:01:50.960 | the function of different parts of the brain,

01:01:53.280 | different neurons, different kinds of neurons,

01:01:54.960 | but also the origins of the big things,

01:01:57.400 | the flap of the butterfly wing that leads

01:02:00.080 | to an actual behavioral thing.

01:02:03.480 | - Yeah, so if you could, exactly.

01:02:04.960 | So if you could turn on or off the brain

01:02:08.280 | or parts of the brain or cell types or individual cells

01:02:11.800 | at the natural rate and rhythm and timing

01:02:16.400 | of normal brain activity, that would be immensely valuable

01:02:19.800 | because you could determine what actually mattered,

01:02:21.480 | what could cause complex things to happen

01:02:23.880 | and what could prevent complex things from happening

01:02:25.960 | in a specific way.

01:02:27.700 | But right away you've got a problem if you wanna do this.

01:02:29.860 | And neuroscientists have wanted to do this for a long time.

01:02:34.240 | Francis Crick of double helix of DNA fame,

01:02:37.280 | he wrote a famous paper in 1999.

01:02:40.520 | He got interested in neuroscience later in life

01:02:43.080 | and he said, what we need in neuroscience

01:02:46.720 | is a way that we could turn on or off

01:02:49.760 | the activity of individual types of neurons

01:02:52.600 | in a behaving animal.

01:02:56.640 | And he even said the ideal signal would be light

01:03:00.200 | because it would be fast, it could penetrate

01:03:04.580 | through the brain to some extent.

01:03:06.720 | And he had no idea how to do it.

01:03:10.800 | He said this would probably be very far-fetched

01:03:13.620 | but it would be a good thing.

01:03:15.480 | - And so that's what you're actually saying.

01:03:17.260 | If you wanna do this kind of thing,

01:03:19.280 | and then you imagine, how do I get inside the brain?

01:03:22.780 | It's pretty difficult.

01:03:24.560 | - It's pretty difficult.

01:03:25.400 | And then even once you get in, it's hard

01:03:27.080 | because all brain cells are electrical.

01:03:29.160 | All neurons are electrically activated.

01:03:31.440 | And so if you wanted to use electricity

01:03:33.880 | as what you were putting in,

01:03:37.300 | you won't have any specificity at all.

01:03:39.480 | If you have an electrode, a wire,

01:03:41.340 | and you put it in the brain and you send current through it,

01:03:44.340 | all the cells near the electrode will be stimulated.

01:03:48.260 | - That's like trying to control fish

01:03:50.140 | by spraying them with water.

01:03:51.660 | - Yeah, right.

01:03:54.000 | Because there's already a lot of electricity

01:03:56.280 | going around anyway.

01:03:57.440 | And you're adding more.

01:03:58.280 | But there's no specificity,

01:04:00.800 | even among the different kinds of cells either.

01:04:02.540 | Because all around the wire that you've put in,

01:04:05.020 | there are gonna be so many different cells

01:04:06.800 | doing totally different things.

01:04:08.520 | Many of them in opposition to each other.

01:04:10.520 | We know that's one way the brain is set up.

01:04:12.240 | There are parts of the brain where neurons side by side

01:04:16.000 | are doing completely different things

01:04:17.360 | and maybe even antagonistic to each other.

01:04:20.240 | So what do you do?

01:04:21.080 | How do you play in activity with any kind of specificity?

01:04:23.680 | Well, what you do is use,

01:04:26.440 | what we found is what you can do

01:04:28.040 | is make some cells responsive to light.

01:04:33.040 | Now, normally no cells deep in the brain

01:04:36.720 | really respond to light.

01:04:37.640 | They're not built for that.

01:04:39.120 | There's no reason for them to respond to light in there.

01:04:42.360 | Which is a great situation to start with

01:04:45.240 | because any light sensitivity you can provide to some cells

01:04:48.960 | will be a huge signal above the noise.

01:04:51.560 | And so that's what we do with optogenetics.

01:04:53.520 | We take genes, bits of DNA from microbes,

01:04:58.520 | single-celled organisms.

01:05:00.800 | And these single-celled organisms like algae,

01:05:05.080 | they make little proteins

01:05:09.360 | that sit in the surface of their cells

01:05:11.960 | that receive light, capture a photon of light,

01:05:15.240 | and open up a little hole in the membrane of the cell

01:05:18.400 | and let charged particles, ions like sodium and potassium,

01:05:21.840 | flow across the membrane of the cell.

01:05:24.440 | And that, these algae and bacteria,

01:05:27.440 | they do this for their own reasons

01:05:28.760 | because that helps them move,

01:05:30.280 | it helps them make and use energy.

01:05:32.880 | But that's a beautiful thing for neuroscience

01:05:36.560 | because movement of ions,

01:05:38.400 | charged particles across the membrane of the cell

01:05:40.680 | is exactly the kind of electricity that neurons work with.

01:05:43.960 | So if we can take this bit of DNA

01:05:47.260 | that encodes this beautiful protein

01:05:48.780 | that turns light into electricity from algae,

01:05:51.440 | and if we can put it into some neurons,

01:05:54.600 | but not other neurons,

01:05:55.880 | which we can do using genetic tricks,

01:05:58.200 | then you've got a situation,

01:05:59.440 | then you can shine on the light,

01:06:01.240 | and only the cells that have the gene

01:06:03.900 | and that are expressing the gene

01:06:05.760 | will be the initial direct cells

01:06:08.160 | that are activated by the light.

01:06:09.200 | And so that's the essence of optogenetics

01:06:10.880 | is the ability to do that.

01:06:12.580 | We get that initial specificity

01:06:14.080 | that you could never get with an electrode.

01:06:15.840 | - First of all, let me say that this is,

01:06:18.280 | we recently got the Lasker Prize for this.

01:06:22.560 | It's a brilliant idea.

01:06:24.260 | So I talked to Andrew Huberman,

01:06:28.880 | who's a friend of yours, friend of mine,

01:06:31.080 | not to jinx things,

01:06:33.520 | but he believes that he deserves a Nobel Prize for this.

01:06:36.720 | So, (laughs)

01:06:39.800 | I do too, but what my votes.

01:06:42.560 | Anyway, the thing is, it doesn't matter.

01:06:44.680 | Prizes will be all forgotten.

01:06:46.280 | All of us will be forgotten.

01:06:47.480 | When the cool idea is, cool idea is a cool idea.

01:06:49.920 | It's a really powerful idea.

01:06:51.640 | - It's actually, the origins of it

01:06:53.800 | you might be interested in are even, are very deep.

01:06:57.640 | There was a botanist in St. Petersburg

01:06:59.880 | named Andrei Fomentsen.

01:07:01.600 | In 1866, he published a paper

01:07:05.640 | on the single-celled green algae.

01:07:07.880 | And he was the botanist who first noticed

01:07:10.000 | that they moved in response to light.

01:07:12.120 | These are tiny single-celled algae that have flagella,

01:07:14.560 | so they swim through the water.

01:07:16.500 | And he noticed this, he was a botanist,

01:07:20.120 | and he published this.

01:07:21.560 | It was a paper, he wrote in German,

01:07:26.160 | but he published it in a French journal,

01:07:27.760 | and he was doing it from St. Petersburg,

01:07:29.680 | so it was a very international effort.

01:07:32.440 | But you have to go back to 1866,

01:07:34.160 | and that, I like to highlight how far back

01:07:37.120 | that discovery goes, is back to Andrei Fomentsen.

01:07:40.880 | And this is a, it highlights the value

01:07:43.960 | of just pure basic science discovery.

01:07:45.760 | That always originates somewhere

01:07:48.400 | in the Eastern European bloc.

01:07:50.560 | But I don't think he expected the splicing

01:07:53.640 | of genetic material from the algae into the human brain.

01:07:57.960 | - And one of the cool things we've been able to do now

01:07:59.480 | with modern methods is to really study these proteins.

01:08:02.080 | And so we've discovered some of these proteins,

01:08:04.320 | other groups have as well.

01:08:05.520 | We've dived deep into their structure,

01:08:07.680 | just like the double helix structure of DNA

01:08:09.960 | was uncovered with X-ray crystallography.

01:08:12.580 | We used the same method, X-ray crystallography,

01:08:14.880 | to see how these beautiful little proteins work.

01:08:18.080 | We've re-engineered them for all kinds of function.

01:08:20.080 | We can make them, instead of responding to blue light,

01:08:22.360 | we can make them respond to red light.

01:08:24.520 | We can speed them up, slow them down.

01:08:26.400 | We can make them, with genetic engineering,

01:08:28.920 | we can make them have different ions flow through them.

01:08:32.320 | And so it's this convergence, as you said,

01:08:34.720 | like the botanist in 1866 couldn't have predicted

01:08:36.920 | what we could do with this.

01:08:38.440 | And the fact that we've been able to discover

01:08:40.680 | how these beautiful proteins work,

01:08:42.240 | and then apply them to neuroscience

01:08:45.080 | is really a thrilling story.

01:08:46.320 | - Is it possible to achieve scale, do you think, with this?

01:08:49.480 | Meaning, what is the progress of the next 50 years,

01:08:53.800 | 100 years looks like, in terms of the precision

01:08:56.880 | and the scale of control of using light?

01:08:59.160 | - It's going so fast, it's hard to predict.

01:09:02.360 | I'll give you a sense of it, though.

01:09:04.160 | First paper we published in 2005,

01:09:11.120 | that was just in cultured neurons, by 2007,

01:09:13.600 | so that was in a dish.

01:09:14.520 | By 2007, we had it working in behaving mice.

01:09:17.520 | By 2009, we had it pretty general,

01:09:20.800 | so we had methods to really make it a versatile method,

01:09:23.360 | it could be applied to essentially any cell.

01:09:26.280 | By 2012, we could get to single-cell resolution,

01:09:29.240 | we used light guidance strategies

01:09:31.120 | to target individual cells in the brain of a living mouse.

01:09:36.540 | By 2019, we were able to control up to 20 to 50

01:09:41.540 | individually specified single cells in the brain of a mouse,

01:09:46.100 | and in ways that specifically changed its behavior,

01:09:49.220 | that could bias its decisions one way or the other.

01:09:51.620 | In fact, we could take a mouse,

01:09:55.420 | and without any visual stimulus at all,

01:09:58.980 | we could make it act as if it had seen

01:10:01.740 | a particular visual stimulus by playing in,

01:10:04.900 | using the single-cell resolution optogenetics,

01:10:07.580 | a specific pattern of activity into 20 or 25

01:10:11.020 | individually specified cells.

01:10:12.900 | That's 2019.

01:10:14.500 | To your question of scale, now in 2022,

01:10:16.660 | we're controlling hundreds of

01:10:18.340 | individually specified single cells

01:10:20.820 | over all the visual cortex of a mouse,

01:10:23.840 | all the part of the brain that is the initial

01:10:28.120 | direct target of the incoming information from the retina.

01:10:31.140 | - Are you constrained to specific types of cells currently?

01:10:34.300 | Like you mentioned, long range is easier.

01:10:36.780 | Is there constraints on which cells?

01:10:39.700 | - Now, there really isn't.

01:10:41.020 | Now that we have this individual cell guidance,

01:10:43.580 | we can target any individual kind of cell very reliably.

01:10:47.420 | And so now, to your question of scale,

01:10:52.080 | how far can we go?

01:10:55.500 | Well, things are moving quickly.

01:10:58.660 | It's hard to say.

01:11:00.060 | We can access individual cells across the entire brain now.

01:11:04.540 | If you look 10, 20 years in the future,

01:11:06.780 | I think we'll surprise ourselves.

01:11:11.900 | But the fact that we're already able to cause

01:11:14.580 | specific perceptions to happen and specific actions

01:11:17.580 | means we're essentially where we wanna be.

01:11:19.480 | And now it's a matter of just

01:11:21.300 | more experiments, more discoveries.

01:11:26.820 | But the basic principles are clear now.

01:11:29.960 | The basic capability is there.

01:11:32.180 | - Is there a pathway to doing the same for humans?

01:11:36.300 | - Optogenetics is primarily, it's a discovery tool

01:11:38.380 | that really is well suited for use in mice and rats

01:11:41.780 | and monkeys because it's,

01:11:43.720 | it involves putting in a gene and also delivering light.

01:11:49.700 | And those are two things that you can do in human beings,

01:11:52.620 | but you'd wanna do in a very careful way.

01:11:55.740 | Now, that said, there is actually just less than a year ago,

01:11:59.220 | my friend, Botan Raska in Switzerland,

01:12:02.420 | he did the first human optogenetics therapy.

01:12:06.820 | And he published this in the journal Nature Medicine.

01:12:10.000 | So about 10, 12 years ago,

01:12:14.420 | he and I published a paper together where

01:12:16.780 | we gave him one of our optogenetic tools,

01:12:20.900 | one of these light-activated regulators of ion flow.

01:12:25.060 | These are called microbial opsins, by the way, opsins.

01:12:29.860 | And he put one of those into an extracted retina

01:12:33.140 | from a human being who had died.

01:12:35.740 | So it was a cadaveric retina.

01:12:37.820 | And he was able to show that optical control in this paper

01:12:41.620 | was able to turn on or off individual cells

01:12:45.380 | in the human retina.

01:12:46.420 | So that was a while back.

01:12:48.460 | He spent about 10 years of going through

01:12:50.780 | all the regulatory hoops and hurdles

01:12:54.500 | and going through primate studies.

01:12:56.460 | And finally, he was able to take a human being

01:13:00.540 | with a retinal degeneration syndrome,

01:13:02.940 | so someone who was blind in both eyes.

01:13:05.220 | And he gave one of these opsins

01:13:09.880 | into one eye of this human being who was blind

01:13:14.020 | and with the goal of conferring light sensitivity

01:13:18.500 | onto this retina that was not able to see light.

01:13:23.440 | And he was able to make this person see through that eye.

01:13:26.460 | So he took a blind person, and the blind person could see,

01:13:28.960 | now could reach for objects selectively on a table.

01:13:32.500 | And he published this in Nature Medicine.

01:13:36.400 | And it was, you know, that's an amazing thing.

01:13:39.640 | - Do you know the title of the paper?

01:13:40.520 | What's his name again?

01:13:41.520 | - Roska, R-O-S-K-A.

01:13:43.880 | - And you look up the Nature paper.

01:13:45.440 | - Yeah, Nature Medicine.

01:13:46.800 | - Nature Medicine.

01:13:47.720 | - So that's sort of proof of principle.

01:13:49.400 | Now, the retina is very accessible.

01:13:51.200 | It's near the surface.

01:13:52.680 | You can use natural light,

01:13:54.120 | or you can use brighter natural light.

01:13:56.080 | I'm, myself, I see optogenetics as a discovery tool.

01:14:02.000 | It's a way to figure out the principles

01:14:03.420 | by which the brain works and how it operates.

01:14:05.800 | - Partial recovery of visual function

01:14:07.600 | in a blind patient after optogenetic therapy.

01:14:10.200 | So he went through the full process of doing primates,

01:14:14.440 | and then going, well, that's dedication,

01:14:17.240 | and that's really exciting to see.

01:14:19.120 | - As beautiful as that is,

01:14:21.640 | and I'm glad he did all that work,

01:14:23.960 | there are so many other ways

01:14:26.320 | that optogenetics could help with therapies.

01:14:28.560 | Once you know the principles,

01:14:30.400 | then any kind of therapy can become more powerful.

01:14:32.880 | Once you know the causal cells in a symptom,

01:14:36.720 | like in lack of motivation, or inability to enjoy things,

01:14:41.240 | or altered sleep, or altered energy,

01:14:43.980 | once you know the cells that are causal,

01:14:46.080 | then you can make medications that address those cells.

01:14:49.640 | You could address brain stimulation treatments

01:14:52.240 | that might address those cells.

01:14:53.440 | - Also diagnosis.

01:14:54.640 | - Diagnosis.

01:14:55.880 | - Very effective, systematic way of diagnosing,

01:14:58.680 | or at least providing you rich data

01:15:01.380 | to some of these deep questions about schizophrenia,

01:15:04.720 | about bipolar, all of those kinds of things that are,

01:15:08.760 | the tools are low resolution currently

01:15:11.680 | for determining the degree to which you have a thing,

01:15:15.280 | and whether you have a thing at all.

01:15:17.080 | - Yeah, exactly.

01:15:18.800 | And so the hope is,

01:15:20.360 | this is a great example of how you can cure,

01:15:25.560 | or you can provide some relief for a symptom of a person

01:15:29.800 | who has a serious degenerative disease.

01:15:32.320 | But the principles are what we're after,

01:15:36.200 | and that's why I spend, even though I'm a psychiatrist,

01:15:39.480 | even though I still see patients,

01:15:41.100 | I'm not myself trying to drive

01:15:43.040 | any clinical trials in the lab.

01:15:45.420 | I'm trying to discover,

01:15:47.280 | and then any kind of therapy could result from that.

01:15:50.860 | - What do you think about my friend Elon Musk

01:15:55.860 | and his efforts with Neuralink?

01:15:58.320 | So this is another,

01:15:59.620 | there's a lot of things to say here,

01:16:02.820 | because there's a lot of ideas

01:16:04.420 | under the umbrella of Neuralink.

01:16:06.280 | But one of them is to use electrical signals to stimulate,

01:16:10.640 | and then you also record,

01:16:13.240 | you collect electrical signals from the brain

01:16:15.820 | at a higher and higher resolution,

01:16:17.880 | and you go implant surgically

01:16:22.240 | the methods by which you do the stimulation

01:16:24.360 | and the data collection.

01:16:26.400 | So it's possible for the ideas of optogenetics

01:16:30.480 | to play well with this.

01:16:32.000 | And we can even zoom out outside of just Neuralink

01:16:35.640 | and just the whole idea of brain-computer interfaces.

01:16:39.520 | What are your thoughts?

01:16:41.760 | - Well, I think the engineering that they've done

01:16:43.600 | is actually pretty cool.

01:16:44.480 | So I like the-- - Robots.

01:16:46.980 | - Yeah, from the design perspective,

01:16:49.500 | and it was a design approach

01:16:52.220 | that wasn't being taken in academia.

01:16:54.560 | And it's great that they did it,

01:16:55.760 | and I think it's pretty cool.

01:16:57.420 | So I'll say that.

01:16:58.980 | Also, there are many ways that you can record

01:17:01.540 | from many thousands of neurons.

01:17:03.840 | That's not the only way.

01:17:05.980 | It's a very interesting way.

01:17:08.000 | We and others are using brain-penetrating electrodes

01:17:12.420 | that actually get quite deep.

01:17:13.820 | The whole structure of the brain is very interesting.

01:17:16.160 | There's the surface cortex,

01:17:17.840 | where it's the most recently emergent part of the brain

01:17:21.920 | in evolution.

01:17:23.640 | Mammals have it.

01:17:24.680 | Reptiles have something a little bit like it,

01:17:26.980 | but it's not really the full thing.

01:17:28.940 | This is a very recent thing.

01:17:31.040 | That's what we can access with some of these,

01:17:33.600 | like the Neuralink approach

01:17:35.080 | and with some of these short electrodes.

01:17:38.280 | This part of the brain, the cortex,

01:17:39.480 | is only a few millimeters thick.

01:17:40.680 | There's so much that's deep, though, that's so important.

01:17:42.880 | There's the striatum, there's the thalamus.

01:17:44.680 | They're the parts of the brain that drive motivation,

01:17:49.140 | that drive hunger and thirst and social interaction

01:17:52.960 | and parenting and flight and fear and anxiety.

01:17:57.960 | All these things are, there's so much that's deep

01:18:00.440 | that these surface approaches are not getting to.

01:18:02.800 | And so we and others are using these very long electrodes

01:18:06.620 | that help us get deep.

01:18:07.920 | And we can still record from many cells,

01:18:09.440 | many thousands of cells.

01:18:11.580 | We can have multiple of these at once in the same animal.

01:18:15.340 | And so there's a diversity of methods to get to this goal.

01:18:18.440 | I think it's great that people coming from

01:18:21.240 | outside academia will bring ideas

01:18:26.740 | that weren't being worked on, at least approaches.

01:18:29.040 | They may turn out to be synergistic.

01:18:31.160 | These things do work very well with optogenetics

01:18:33.600 | because all these electrical recording methods,

01:18:37.400 | that's one channel of information flow.

01:18:39.640 | Light delivery is a separate, more or less independent.

01:18:43.220 | There can be some artifacts that happen,

01:18:45.380 | but if you're careful,

01:18:46.200 | that's another independent pathway of information flow.

01:18:49.820 | And we've done really fun experiments in mice

01:18:53.160 | where we play in patterns of activity with light

01:18:56.260 | and we record activity from all across the brain

01:18:58.720 | of a mouse electrically.

01:19:00.140 | And so using optical and electrical together

01:19:02.320 | is extremely powerful.

01:19:03.980 | - So like optoelectric brain computer interfaces.

01:19:09.260 | Which, by the way, there's efforts on the computing side

01:19:13.080 | to build optoelectric servers.

01:19:16.200 | So like where you have both electricity.

01:19:17.920 | So because optics is really interesting.

01:19:20.160 | Light is a very interesting method of communication

01:19:22.880 | that's, like you said, orthogonal in many ways.

01:19:26.240 | It doesn't have some of the constraints of bandwidth

01:19:28.940 | that electricity does, going through wires,

01:19:32.400 | but you're able to,

01:19:34.320 | but less ability to control precisely at scale.

01:19:38.660 | So there's challenges and there's benefits

01:19:40.700 | and having those two interplays really, really,

01:19:42.860 | really fascinating.

01:19:44.060 | Especially when obviously on the other side

01:19:46.660 | of your signal is a biological mesh,

01:19:51.300 | mush, mushy mesh.

01:19:53.700 | - Well, the mushy mesh is kind of interesting

01:19:55.700 | 'cause we have, there are problems with light.

01:19:57.460 | Light scatters in the brain,

01:19:59.060 | so the photons don't just go linearly through.

01:20:02.660 | Whenever they hit an interface between fat and water,

01:20:05.360 | lipid and water, they bounce off in different directions.

01:20:09.080 | And so you can come in with all the resolution you want.

01:20:11.960 | You could play in an incredibly detailed,

01:20:14.680 | high resolution pattern of light,

01:20:16.560 | but the photons start scattering quite quickly

01:20:19.400 | and by the time you've gone a couple of millimeters deep,

01:20:22.160 | you've lost almost all that fine spatial information.

01:20:25.480 | So, but we've developed workarounds.

01:20:27.920 | The longer wavelength light you use,

01:20:30.080 | if you get into the infrared, there's less scattering.

01:20:32.040 | You can use two photon methods or three photon methods

01:20:34.840 | where the photons have to arrive all together

01:20:37.020 | at the same time.

01:20:38.500 | You can put in fiber optics.

01:20:40.100 | We developed these fiber optic methods in 2007

01:20:43.360 | where you can access these deep structures

01:20:45.080 | with fiber optic methods and you can put many

01:20:46.960 | of these fiber optics at the same time in an animal.

01:20:49.680 | We've used holographic methods, 3D holograms

01:20:53.320 | to play in hundreds of individual cell-sized spots of light

01:20:56.920 | and we can change those quickly.

01:20:59.120 | And so there are a lot of tricks,

01:21:00.360 | a lot of interesting optics engineering

01:21:01.840 | that has come together with neuroscience

01:21:03.880 | in a pretty exciting way.

01:21:04.720 | - All of it is engineering too,

01:21:06.080 | which is super, super, super exciting.

01:21:07.680 | I should mention, 'cause I remember I mentioned Elon,

01:21:10.840 | I recently got, for the first time ever, got COVID.

01:21:15.740 | How did I go so long without, finally,

01:21:22.040 | so I'm all vaccinated and everything like that.

01:21:24.320 | And so I got, 'cause I think he mentioned it publicly

01:21:27.880 | so I can mention it, but I won't mention

01:21:29.640 | anybody else involved.

01:21:30.600 | But hanging out, we all got, Elon got COVID.

01:21:33.760 | And the interesting thing about,

01:21:35.200 | maybe you can comment about this.

01:21:36.520 | So I was only sick for like a half a day.

01:21:38.860 | I got a fever of like 104, I just went up

01:21:42.560 | and then crashed and then I was,

01:21:45.480 | now maybe I'm just seeing the silver lining of everything,

01:21:48.720 | but afterwards, I have like a greater clarity

01:21:53.720 | about the world.

01:21:55.560 | - You just think it's greater clarity.

01:21:58.760 | - Maybe, maybe I just, it was so, maybe so intensely,

01:22:03.760 | the mind fog kind of thing for such a short amount of time.

01:22:07.880 | But the people who were involved were also reporting this.

01:22:12.060 | It's kind of interesting, 'cause like,

01:22:14.120 | because I do know, like the immune system

01:22:17.600 | is involved with the brain in very interesting ways.

01:22:21.840 | So like the human mind also incorporates all these other,

01:22:24.760 | it's not just the nervous system.

01:22:28.120 | And I just wonder, 'cause everyone always says,

01:22:30.240 | no, not like, everyone always says like COVID

01:22:32.560 | does all these bad things or whatever the disease is

01:22:34.760 | or whatever the virus.

01:22:36.080 | But I wonder like, I hate to be a Steven Pinker on this,

01:22:39.760 | but like I wonder what the benefits of certain disease are

01:22:42.200 | if you're able to recover.

01:22:43.880 | Like what, is there some like,

01:22:46.120 | again, don't wanna romanticize it,

01:22:47.600 | but if your system goes to some kind of hardship

01:22:50.200 | and you come out on the other end,

01:22:51.920 | I wonder sometimes if there's a greater,

01:22:54.920 | maybe killed off a bunch of neurons

01:22:56.480 | that I didn't need anyway,

01:22:57.480 | and they were actually getting in the way.

01:22:58.880 | They were the hater neurons.

01:23:00.600 | - Well, that was your inner critic

01:23:01.880 | that I was talking about earlier.

01:23:02.720 | - Exactly.

01:23:03.560 | - You killed off your critic.

01:23:05.040 | Well, you know, there are mechanisms for what,

01:23:07.360 | the potential mechanisms for what you're talking about.

01:23:10.440 | There's actually been a fair bit of research

01:23:13.280 | on post-COVID neurological function.

01:23:18.280 | Actually, my wife, Michelle Monge, who's at Stanford,

01:23:20.960 | she's done a lot of this work.

01:23:22.360 | Hiko Iwasaki at Yale has done a lot of this.

01:23:25.520 | But what they found is that there's a loss of myelin.

01:23:30.320 | This is the coating of those long-range projections

01:23:33.360 | that go from one part of the brain to another.

01:23:35.440 | Myelin is this sort of insulator

01:23:37.560 | that coats these long-range projections

01:23:39.240 | and makes the impulses go faster and more reliably.

01:23:42.200 | And there's altered function of the myelin-producing cells

01:23:48.640 | and altered myelin in the case of COVID.

01:23:52.680 | They've looked in both mouse and human brains.

01:23:55.640 | But of course, it could be very idiosyncratic.

01:24:00.000 | Many people have cognitive problems post-COVID.

01:24:03.400 | You're definitely aware of that.

01:24:04.520 | So many people report this persistent brain fog

01:24:07.240 | and inability to function.

01:24:08.960 | But it depends on where the inflammation was.

01:24:11.480 | Maybe the people who have dysfunction post-COVID,

01:24:15.000 | they had a global effect.

01:24:17.080 | Maybe you lost some of these projections

01:24:20.320 | that were restraining you in some way.

01:24:23.720 | And these plausibly exist.

01:24:25.360 | And it's known that there are cell populations

01:24:30.040 | in the prefrontal cortex that actively restrain

01:24:33.220 | deeper structures from expressing what they do.

01:24:36.400 | And it's theoretically possible that you had a lucky--

01:24:40.060 | - Somebody has to get lucky, right?

01:24:42.440 | - Somebody has to get lucky, yeah.

01:24:44.080 | - Why not me?

01:24:45.200 | All right, if we can actually go back

01:24:47.280 | to this idea of trying, through optogenetics,

01:24:51.900 | to find origins of when the wave first starts.

01:24:58.760 | Origins of a decision, origin of idea,

01:25:04.640 | origin of maybe consciousness or the subjective experience,

01:25:12.040 | or origin of things in the mind.

01:25:15.140 | So one thing, Carl Jung, is there a God neuron?

01:25:20.140 | Is there a belief neuron?

01:25:23.720 | So through this methodology of optogenetics,

01:25:27.560 | can you start getting where a belief begins

01:25:32.560 | or an idea begins?

01:25:37.360 | And especially looking at the strongest of our beliefs.

01:25:41.040 | Maybe beliefs of love and hate,

01:25:43.240 | but religious belief into something really grand,

01:25:48.240 | on the grandest of scale.

01:25:52.900 | - Neuroscience and neurology point us a little bit.

01:25:59.340 | We don't have an answer to that.

01:26:01.800 | - But a lot of these questions I'm gonna ask you,

01:26:04.320 | there's no good answer, but you're providing the tools

01:26:07.340 | that give us hope to find the answer one day.

01:26:09.600 | - Yeah, and we have early clues.

01:26:11.000 | So for example, when patients with epilepsy

01:26:14.640 | have experiences of religiosity as part of their seizure

01:26:19.640 | or the aura before their seizure,

01:26:23.520 | very often those are in the temporal lobe,

01:26:27.600 | in these parts of the brain that are at the side.

01:26:31.280 | And so that's an initial clue.

01:26:34.400 | There are also parts of the brain

01:26:36.280 | that are involved in the definition of the self

01:26:41.280 | and defining the borders or boundaries of the self.

01:26:46.680 | And we know this,

01:26:48.520 | this is some experiments that we did in my lab.

01:26:50.460 | There's a part of the brain where if there's a rhythm

01:26:53.120 | of a particular type,

01:26:56.200 | you can cause a separation of the sense of self

01:27:00.680 | from the sense of the body.

01:27:02.780 | What's normally bound up and unitary,

01:27:05.080 | we normally think of ourself and our body

01:27:06.680 | as pretty tightly bound up together.

01:27:08.820 | Those can be separated, it turns out.

01:27:10.400 | We can't take that for granted.

01:27:11.640 | And there are certain conditions,

01:27:12.720 | certain patterns of activity in one part of the brain

01:27:15.580 | called the retrosplenial cortex,

01:27:17.840 | where you can actually separate those two out.

01:27:20.920 | And so if you think about these very big questions,

01:27:24.860 | what is, where are the origins of religiosity?

01:27:29.440 | Where, how do we define the boundaries of who we are

01:27:33.160 | relative to others and to the world?

01:27:35.500 | How do we link our self to our body

01:27:40.480 | and how can that become separated?

01:27:42.120 | These are actually, believe it or not,

01:27:44.080 | now accessible and rigorously and quantitatively so.

01:27:48.960 | We did an experiment with optogenetics

01:27:50.860 | where we provided this abnormal rhythm

01:27:53.680 | to this particular part of the mouse brain.

01:27:57.120 | And we saw this separation of detection of a stimulus

01:28:02.560 | and caring about it.

01:28:04.640 | - So that's like stimulating something

01:28:06.640 | about the mouse brain that affects these neurons

01:28:10.240 | that give the conception of self.

01:28:11.960 | So you're able to dissociate the experience

01:28:15.400 | from the impact of the experience onto you.

01:28:17.960 | - That's right, exactly right.

01:28:19.520 | - So like these are the goals of meditation.

01:28:22.140 | These are the goals whenever I get drunk,

01:28:25.840 | pretty much effective.

01:28:27.320 | I mean, that's not a scientific statement,

01:28:29.000 | just an experiential, anecdotal one.

01:28:32.060 | Also psychedelics seek to attain this kind of state.

01:28:37.060 | That's so interesting.

01:28:39.120 | - Well, you mentioned psychedelics,

01:28:40.520 | DMT and 5-MeO DMT, these create this religious experience,

01:28:45.520 | this connection, people describe them

01:28:47.600 | as a strong connection to God.

01:28:49.520 | In theory, these are accessible with modern methods.

01:28:53.400 | Now that we have these rich recording methods,

01:28:56.240 | we can explore what are the precise millisecond resolution,

01:29:01.440 | cellular resolution, brain-wide manifestations

01:29:05.300 | of these altered states.

01:29:06.660 | - So like you could look at an altered state like on DMT,

01:29:11.040 | record it across many people,

01:29:14.560 | and then from there see where do these experiences

01:29:18.020 | originate in the brain in terms of single neurons,

01:29:21.580 | and then how do they propagate

01:29:25.280 | and interact with everything else,

01:29:26.560 | and if there's some kind of common signal.

01:29:31.000 | Like how do you narrow down the set of neurons

01:29:34.360 | that are responsible for a particular experience

01:29:36.740 | or for a particular behavioral effect?

01:29:38.720 | - Yeah, here's where optogenetics is so useful

01:29:40.480 | because anytime you give an agent like ketamine or PCP,

01:29:45.480 | which we used for our dissociation experiments

01:29:49.520 | that I was mentioning, or you have a psychedelic,

01:29:52.600 | LSD or DMT for this altered perceptual state,

01:29:57.920 | if you give either of those,

01:30:00.600 | these change everything across the brain, okay?

01:30:03.040 | So just the fact that you maybe give them to a mouse,

01:30:06.080 | let's say, or eventually to a human,

01:30:08.100 | you won't know yet which cells to home in on

01:30:13.680 | as the causal players in all this

01:30:17.200 | just by recording the activity.

01:30:19.400 | But then what we found is that optogenetics

01:30:21.920 | providing a causal pattern of activity

01:30:23.800 | guided by what you see can let you test hypotheses.

01:30:28.040 | And we saw this rhythm with ketamine and PCP

01:30:31.200 | for dissociation, and then we said,

01:30:32.920 | okay, let's test what's causal.

01:30:35.880 | We came in and provided that rhythm.

01:30:38.120 | We tried a few different things,

01:30:39.520 | but only one of the causal tests we tried

01:30:41.920 | actually caused the behavioral dissociation.

01:30:45.120 | And so that's how we home in on what actually matters.

01:30:47.320 | - And is it repeatable once you see the,

01:30:49.280 | so that's one definition of causality

01:30:51.280 | is like you try and it repeats across different mice

01:30:55.120 | and all that kind of stuff.

01:30:56.080 | - Exactly.

01:30:56.920 | - And so you could do that for DMT.

01:30:59.960 | You could do that for the really fascinating

01:31:02.160 | mind-expanding, thank you.

01:31:05.440 | (laughs)

01:31:06.280 | Thank you for the, so the meme for people just listening,

01:31:08.360 | this is, again, another disagreement

01:31:10.160 | between Freud and Carl Jung.

01:31:13.440 | Religion and spirituality.

01:31:15.120 | This is the, I guess, the ring scene

01:31:17.000 | from "Lord of the Rings."

01:31:18.880 | Religion and spirituality, Freud says,

01:31:20.800 | cast it into the fire, destroy it.

01:31:23.440 | Carl Jung says, no.

01:31:25.240 | So for people who don't know,

01:31:26.560 | Sergei is the Slavic Lord of the meme.

01:31:31.520 | Thank you, I appreciate that.

01:31:33.760 | So what we're talking about, so there is,

01:31:35.360 | I mean, I think a connection between DMT

01:31:37.400 | and religious experiences are some of these psychedelics.

01:31:40.320 | Do you think it's possible to

01:31:41.840 | sort of stimulate religious experiences?

01:31:47.280 | And so religious experiences are one of the most

01:31:50.040 | deep kind of experiences.

01:31:52.560 | And so here you could first understand

01:31:57.080 | where they originate, how they propagate

01:32:00.040 | through the brain, and then to stimulate them.

01:32:02.880 | - And so this is, and these can happen

01:32:06.720 | in people who had no predisposition.

01:32:09.640 | You know, people who are, you know,

01:32:13.120 | as agnostic or atheistic as you'd like,

01:32:15.880 | they can have these, they can feel connected to God

01:32:18.080 | in these states.

01:32:20.120 | Now, to be clear, I'm not advocating these.

01:32:21.960 | We don't know what's safe in human beings,

01:32:24.720 | but we definitely-- - Yet.

01:32:25.920 | - Not yet.

01:32:26.920 | But we definitely can do these experiments in mice,

01:32:29.520 | and that was already very productive

01:32:32.280 | in understanding dissociation.

01:32:33.680 | So we can already imagine making headway on these methods.

01:32:37.320 | And then, you know, I had a,

01:32:38.440 | and this does map onto the non-psychedelic human experience.

01:32:42.960 | I had a patient who's actually described

01:32:45.680 | in the book, "Projections."

01:32:47.240 | This was the patient that's in the mania chapter,

01:32:49.680 | the bipolar chapter.

01:32:51.560 | Here was a guy who had never had a psychiatric illness

01:32:56.280 | or symptom in his life.

01:32:57.320 | He was a retirement age gentleman,

01:33:00.480 | and nobody in his family either.

01:33:02.840 | So no family history, no personal history

01:33:04.960 | of any psychiatric illness,

01:33:05.960 | and he had never been religious, particularly, before either.

01:33:08.760 | Certainly no passionate, you know, type of religion.

01:33:13.280 | But he, not through any psychedelic or drug,

01:33:15.840 | he had a stressful experience,

01:33:18.040 | actually a post-9/11 change in how he was thinking,

01:33:21.640 | and he was pushed into a mania, a manic state,

01:33:24.880 | revealing that he had bipolar,

01:33:26.760 | never before known in this case, in this person.

01:33:29.600 | And his mania, his elevated state in bipolar,

01:33:33.920 | included this profound religiosity,

01:33:37.040 | which he had never had before.

01:33:38.200 | And he was, you know, preaching in a elevated,

01:33:43.920 | you know, vigorous way to his family.

01:33:46.120 | And so this state can be created in people,

01:33:50.000 | even late in life, who had no predisposition for it,

01:33:52.520 | and no, even without a neurochemical.

01:33:54.960 | So there's, the causality of that

01:33:59.360 | is very interesting to explore.

01:34:00.760 | How did the manic state unleash this religiosity?

01:34:05.760 | But you see that in other realms of psychiatry too.

01:34:08.560 | OCD can manifest as religiosity also.

01:34:11.680 | You can take people who never really had a,

01:34:14.140 | a religion never played a powerful role in their life,

01:34:18.480 | but then when their obsessive compulsive symptoms

01:34:21.120 | become severe, they can manifest in this.

01:34:23.160 | - I think I'm in that group.

01:34:24.320 | So I'm a bit OCD.

01:34:26.320 | We have, there's, I think there's subreddits,

01:34:29.720 | when there's oddly satisfying things.

01:34:32.840 | So there's certain things that are really satisfying

01:34:35.960 | to my OCD, like my mild OCD.

01:34:39.600 | I think it's pretty much a religious experience.

01:34:42.000 | (laughs)

01:34:43.000 | So I understand that there's,

01:34:44.960 | if it's not direct, it's at least rhymes.

01:34:48.360 | So maybe can you speak to the,

01:34:51.840 | as Sergey's probably desperately scrambling

01:34:54.720 | to pull up oddly satisfying, thank you.

01:34:57.020 | People can check it out themselves.

01:34:58.280 | It is, as the subreddit promises, oddly satisfying.

01:35:01.740 | Can we talk about bipolar and maybe depression?

01:35:08.000 | Well, let's talk about, I mean,

01:35:09.160 | I don't know if there's a nice way

01:35:12.160 | to discuss the differences in the full landscape

01:35:14.960 | of suffering that's here, but maybe what is depression?

01:35:19.960 | And what are the types of depression?

01:35:23.240 | What kind of depression have you seen,

01:35:27.320 | experienced, and researched?

01:35:29.480 | And how can people overcome it?

01:35:31.280 | How can humans overcome it and deal with it,

01:35:33.560 | live with it, and overcome it?

01:35:35.060 | - So this is my clinical specialty.

01:35:38.940 | I see patients in my outpatient clinical work

01:35:42.000 | with treatment-resistant depression,

01:35:44.400 | so very hard-to-treat severe illness

01:35:48.480 | where medications haven't been working.

01:35:51.560 | I also see patients with autism spectrum disorders.

01:35:54.600 | These are my two clinical focal areas.

01:35:58.520 | But then I do emergency room work as well.

01:36:02.560 | But the depression, why do I focus on that?

01:36:06.120 | It's so, one feels tantalizingly close

01:36:11.120 | to helping these people who are suffering so deeply.

01:36:16.820 | And that's why I focused on it,

01:36:17.940 | is these are people who,

01:36:20.620 | there may not even be anything situational

01:36:22.960 | that's difficult or challenging in their life.

01:36:25.420 | You can have people who seem to have everything

01:36:28.100 | that you would want.

01:36:28.940 | Every objective measure of their life is fine,

01:36:30.780 | and yet they can be just hit with this

01:36:36.400 | unstoppable hopelessness,

01:36:41.200 | an inability to see into the future,

01:36:43.340 | a discounting of the value of their own action.

01:36:47.520 | Anything they can imagine themselves doing seems worthless,

01:36:51.000 | or they are unable to enjoy things.

01:36:54.880 | We call this anhedonia.

01:36:56.460 | There's no reward, no pleasure,

01:36:58.220 | not in food, social interaction, movies, books,

01:37:02.200 | anything that they would enjoy, positivity gone.

01:37:05.880 | They can have a profound negative internal state,

01:37:09.280 | psychic pain, and these things can seem,

01:37:13.160 | and in the severe cases are inescapable.

01:37:16.940 | So what is going on?

01:37:19.320 | Why is this state part of human existence?

01:37:23.420 | It's got a strong biological genetic link, we know that.

01:37:27.660 | It's been linked to certain genes,

01:37:31.300 | certain regions of the chromosome, and twin studies.

01:37:34.520 | There's a clear genetic link.

01:37:36.160 | Doesn't explain everything, but it's a big part of it.

01:37:39.160 | Genetics are a strong contributor.

01:37:41.320 | And although you can have depression

01:37:45.920 | without anything terrible going on in your life,

01:37:48.240 | the symptoms can be made worse by stressors, by trauma.

01:37:52.060 | But at a very deep level,

01:37:57.180 | there's nothing we can measure in a person objectively,

01:38:00.920 | so we don't have, there's not a known chemical,

01:38:04.440 | not a known structure that's different,

01:38:07.040 | not a known brain activity pattern

01:38:08.960 | that we can pick up with EEG.

01:38:11.040 | A lot of people are exploring this,

01:38:12.520 | but right now we have no objective measures.

01:38:14.280 | All we do is talk to people and we elicit these symptoms.

01:38:18.200 | We explore them,

01:38:19.700 | distinguish them from other possible causes,

01:38:23.700 | and then what do we do?

01:38:25.320 | Well, we have a range of treatments.

01:38:27.400 | We have medications that can help people,

01:38:30.460 | do help people, but not everybody.

01:38:33.280 | And if they don't work,

01:38:34.320 | then we can go to brain stimulation methods.

01:38:36.760 | We can do things even like electroconvulsive therapy,

01:38:39.640 | which is very effective,

01:38:42.400 | but it's sort of the final thing we go to in the end.

01:38:45.900 | And so we have treatments.

01:38:49.320 | They work for some people.

01:38:52.160 | They don't do everything we'd like.

01:38:53.560 | But here's the problem is at a very deep level,

01:38:56.680 | we don't understand really what's going on in the brain.

01:38:59.540 | We don't have a physical interpretation of the problem.

01:39:03.180 | We have all these symptoms,

01:39:04.780 | but we can't yet point to a set of cells

01:39:07.740 | or a set of circuits or an activity pattern

01:39:10.520 | that is causing major depression,

01:39:12.220 | this disease state per se in human beings.

01:39:14.620 | - Why do you think you can't yet

01:39:17.860 | from an optogenetics perspective?

01:39:19.320 | Is it because there's so many possible causes?

01:39:22.200 | Is it so many things involved?

01:39:24.920 | - So I think the answer is there are many things involved

01:39:27.540 | and all these different symptoms that I've mentioned,

01:39:30.640 | those we can study and those we can fix,

01:39:32.900 | the individual symptoms.

01:39:34.580 | And we can do this in animals to be clear.

01:39:37.200 | So in a mouse, for example,

01:39:39.060 | we can instantaneously and precisely turn up or down

01:39:44.060 | the motivation of an animal to overcome a challenge.

01:39:48.080 | We can turn up or down its ability to be motivated by,

01:39:52.520 | or we think experience reward from situations or actions.

01:39:59.220 | We can increase its apparent energy level,

01:40:01.560 | its drive to meet challenges.

01:40:06.200 | We can turn up or down social interaction.

01:40:10.120 | All these individual features of depression,

01:40:12.300 | individual symptoms, we now can point to exact projections

01:40:17.180 | and cells that are causal in meeting these.

01:40:20.720 | But what we don't know is why all these different symptoms

01:40:24.760 | show up together in major depression,

01:40:27.480 | in the human disease syndrome.

01:40:29.040 | And that's the mystery.

01:40:30.600 | It's sort of in other fields of medicine,

01:40:33.940 | someone with congestive heart failure

01:40:35.440 | who comes into the clinic,

01:40:36.720 | they have very different symptoms.

01:40:38.040 | They have shortness of breath and they have swollen feet.

01:40:41.080 | Couldn't be two more different across the body

01:40:46.240 | sets of symptoms.

01:40:47.740 | Neither one obviously related to the heart,

01:40:49.760 | but they're both happening

01:40:50.800 | 'cause the heart is not working as a pump.

01:40:53.040 | And now thankfully in cardiology,

01:40:57.100 | we understand these disparate symptoms

01:40:58.980 | that seem totally unrelated can be completely understood

01:41:03.620 | because there's an altered pump action of the heart.

01:41:05.740 | That's what we are hoping for in psychiatry

01:41:10.340 | and in the study of depression or any disease.

01:41:13.620 | These different symptoms, the inability to enjoy things,

01:41:17.740 | the hopelessness.

01:41:18.840 | What's the unifying principle?

01:41:22.380 | - Unifying.

01:41:23.300 | I mean, is there some truth to that, the Tolstoy quote,

01:41:26.780 | that all happy families are alike

01:41:28.820 | and each unhappy family is unhappy in its own way?

01:41:31.740 | So basically, I mean, this is the human condition.

01:41:36.480 | And basically, the physicists long to find

01:41:42.260 | the theory of everything.

01:41:43.620 | Isn't understanding depression essentially

01:41:48.180 | require you to really have the big theory of everything

01:41:52.940 | for the human mind?

01:41:55.380 | - I think it would certainly be nice

01:41:57.820 | to have a theory of everything.

01:41:59.700 | Don't get me wrong.

01:42:00.740 | I don't think we need--

01:42:01.580 | - Understatement of the century.

01:42:03.860 | It would be nice.

01:42:04.700 | It's also a good question if it's possible.

01:42:07.820 | - Yeah, yeah.

01:42:08.780 | Well, that I have some thoughts on too.

01:42:11.940 | But to this specific question,

01:42:14.900 | I don't think we need a theory of everything.

01:42:16.340 | I think there will be unifying principles we can get to.

01:42:20.380 | But even shy of that, we can treat symptoms

01:42:23.540 | and that's a big step.

01:42:24.620 | And as you say, different unhappy families are different.

01:42:27.900 | Different unhappy people are different.

01:42:30.060 | If we have somebody who comes to the clinic

01:42:31.740 | and I see someone with a profound anhedonia

01:42:34.700 | as one of their main symptoms, inability to enjoy things.

01:42:38.060 | And if I know based on optogenetics work and animal work

01:42:41.380 | that a particular medication can treat anhedonia,

01:42:44.700 | even if it doesn't fix major depression in everybody,

01:42:47.340 | if I treat that one symptom in that one person,

01:42:50.420 | that's a good thing.

01:42:51.340 | And so we don't need the theory of everything

01:42:55.300 | and we don't even need the unifying principle

01:42:58.420 | to help people with insights that come from optogenetics.

01:43:01.620 | - How much does talking help for diagnosis

01:43:05.580 | and for treatment, would you say, for depression?

01:43:09.740 | - It's a big part of what we do.

01:43:11.540 | Every good psychiatrist should be pretty adept

01:43:15.260 | in these verbal communications and talk therapy

01:43:18.200 | as part of what they do.

01:43:20.020 | I give medications.

01:43:21.100 | I deliver brain stimulation treatments,

01:43:22.900 | but a big, big part of everything I do with every patient

01:43:26.340 | is talk therapy because it works so well together

01:43:31.000 | with these other modalities.

01:43:33.300 | Even alone, it can help people with moderate

01:43:36.180 | or mild depression by itself.

01:43:40.020 | People with severe depression,

01:43:41.620 | people with other psychiatric illnesses that are severe,

01:43:46.300 | you don't wanna do talk therapy alone.

01:43:47.820 | That's not gonna do it,

01:43:48.880 | but it still is crucial to do together with the others.

01:43:52.240 | And it's critical because it's part of how you reshape

01:43:57.240 | cognitions, complex activity patterns,

01:44:01.360 | and you won't get to that with a medication

01:44:03.600 | or a brain stimulation treatment.

01:44:05.420 | - Do you have advice for people who suffer

01:44:07.820 | from mild forms of depression or feel as they might,

01:44:12.700 | both for those people, and do you have advice for people

01:44:16.560 | who love the people who suffer from depression

01:44:20.840 | and want to help?

01:44:22.120 | - Yeah.

01:44:23.680 | One of the incredibly frustrating things about depression

01:44:27.180 | is the very nature of it makes it hard for the people

01:44:31.160 | who suffer to get treatment because they're hopeless,

01:44:35.800 | so they don't think treatment will help.

01:44:37.520 | They have low energy, so they're not motivated

01:44:40.600 | to participate in treatment in many cases.

01:44:44.000 | Sometimes they're actively suicidal.

01:44:46.520 | That certainly doesn't help.

01:44:48.320 | They have all these things that seem to prevent treatment

01:44:53.320 | from being effective, so the loved ones,

01:44:55.520 | that's where the loved ones are so important

01:44:57.360 | is helping them overcome these barriers to treatment,

01:45:00.360 | the motivation, the safety, and the insight.

01:45:04.080 | That's critical, and particularly for the severe cases.

01:45:09.520 | For the mild cases where people still have some insight

01:45:13.840 | and motivation and energy to get something done,

01:45:16.640 | there are many things you can do.

01:45:19.240 | Exercise is extremely important in mood, maintenance,

01:45:25.540 | regulation of sleep, and getting sufficient

01:45:28.480 | and regular enough sleep is very important.

01:45:31.200 | And talk therapy can be helpful

01:45:33.040 | in those mild or moderate cases,

01:45:34.640 | just looking at cognitions, looking at patterns of thought

01:45:38.720 | that people may have fallen into, where they catastrophize,

01:45:43.560 | where they spiral from small things into big things.

01:45:47.700 | A little bit of talk therapy, 10, 12 sessions,

01:45:52.680 | can help people identify those patterns

01:45:55.120 | they may have in themselves

01:45:57.280 | that are taking occasional negative thoughts,

01:46:01.000 | which everybody has, and magnifying those

01:46:03.840 | into more persistent negative states.

01:46:07.680 | Once you, if you work at this, and it's kind of like homework,

01:46:10.800 | this is what we call cognitive behavioral therapy,

01:46:13.260 | it's very structured, very organized, you work hard,

01:46:16.320 | it requires insight and motivation,

01:46:18.120 | and you have to be motivated.

01:46:20.360 | But if you are, then you can identify these triggers

01:46:23.420 | that send you down particular pathways

01:46:25.320 | and work to intercept them.

01:46:27.100 | And that is amazingly very effective

01:46:30.480 | in mild to moderate cases.

01:46:32.340 | - So you basically have to train yourself

01:46:35.440 | to see the world as a collection of triggers,

01:46:40.280 | and you have to first understand, collect the data,

01:46:44.880 | like basically see every experience

01:46:47.200 | as a thing that creates a follow-on emotion, a feeling.

01:46:53.760 | I've learned this on social media,

01:47:00.520 | where early on, like all of us,

01:47:05.960 | I'll say something, I'll kind of respond to negativity

01:47:10.880 | with negativity, and then you observe the result of that.

01:47:15.880 | - That's more like it.

01:47:17.480 | - Over time, you think, wait a minute,

01:47:21.280 | this thing that I've been doing,

01:47:23.260 | where when somebody says, "You suck,"

01:47:25.680 | and you say, "No, you suck,"

01:47:27.560 | that never produces the result you thought it might.

01:47:32.960 | - Yeah, so might not want to just,

01:47:35.380 | don't say you suck back.

01:47:38.440 | And I do this through a lot of things in life.

01:47:41.640 | I'm very fortunate to not suffer from depression,

01:47:46.480 | but I, first of all, I have had

01:47:50.360 | and have people in my life who do.

01:47:53.100 | And also, all of us have depression,

01:47:57.080 | who don't suffer from depression, have depression out.

01:48:01.440 | It's always knocking on the door.

01:48:03.120 | - Right, yeah.

01:48:03.960 | - And so you have mild,

01:48:06.880 | I mean, if you're very careless

01:48:11.320 | with the triggers all around you,

01:48:14.280 | then you're just, I think all of us have the capacity

01:48:17.960 | to really suffer from that kind of chemical

01:48:22.280 | or psychological or philosophical existential crisis.

01:48:26.220 | - But then it raises the question,

01:48:29.080 | why are we built this way?

01:48:30.400 | It seems like it doesn't make sense, right?

01:48:32.720 | And here's where some of this thinking

01:48:34.440 | about where we came from

01:48:35.760 | as the human family is kind of interesting.

01:48:40.520 | It doesn't make sense that somewhere on that spectrum

01:48:44.400 | that it's good to detect that there's an array

01:48:48.200 | of adverse forces out there in the world right now

01:48:51.900 | at this moment, and to withdraw,

01:48:55.400 | to hunker down, to not fight, not strive,

01:49:00.320 | not try to meet the challenge,

01:49:02.480 | and outweigh these negative forces

01:49:06.560 | that are present out there.

01:49:08.240 | And that makes a lot of sense.

01:49:09.760 | And all animals that have been studied

01:49:13.960 | in one form or another show this.

01:49:15.960 | Even the worm that I mentioned earlier,

01:49:18.240 | C. elegans with 302 neurons,

01:49:20.920 | it can effectively give up in challenging situations.

01:49:24.020 | We've done this with zebrafish,

01:49:25.880 | tiny little transparent fish.

01:49:28.420 | You can give them a challenging situation

01:49:30.360 | and they will give up.

01:49:32.280 | But then if you stimulate a couple

01:49:34.920 | of very specific brain regions in particular ways,

01:49:37.180 | you can motivate them to overcome the challenge.

01:49:40.460 | And if you inhibit those regions,

01:49:41.800 | they give up much more easily than they would otherwise.

01:49:44.680 | You can do this in mice, you can do this in rats.

01:49:47.220 | So this is an ancestral conserved pattern

01:49:49.880 | to detect that things are pretty bad out there.

01:49:54.920 | And to conserve energy, to hunker down,

01:49:58.660 | to wait out the storm.

01:50:00.260 | - So as use, unfortunately,

01:50:03.060 | many of our maladies have useful roots

01:50:06.140 | in our, that contribute to our survival.

01:50:10.240 | So both depression and motivation have uses.

01:50:14.900 | And sometimes it's nice to just shut the hell up

01:50:18.540 | and huddle with the penguins.

01:50:20.420 | - Right.

01:50:21.260 | - Versus for some unknown reason,

01:50:23.700 | venture out on your own into the mountains,

01:50:25.880 | like a David Goggins type character.

01:50:28.060 | So what's the difference to you between,

01:50:31.660 | you see patients, between sort of rigorous

01:50:35.140 | psychoanalysis, I don't know if you consider

01:50:39.820 | where you, like talk therapy and psychoanalysis,

01:50:41.900 | are they neighbors, are they overlapping?

01:50:43.740 | - They're neighbors.

01:50:45.220 | Psychoanalysis is, it's a, they're relatively,

01:50:49.100 | it's not nearly done as much as the talk therapy,

01:50:51.920 | like the cognitive behavioral therapy I mentioned.

01:50:54.420 | The psychoanalysis is a little more niche now,

01:51:00.540 | and partly because it's not,

01:51:03.140 | data isn't, in terms of actual treatment,

01:51:06.900 | of actual therapeutic effects,

01:51:09.100 | data not as supportive as for cognitive behavioral therapy.

01:51:13.060 | But it's still interesting as, for insight,

01:51:16.020 | people, a lot of people still do it

01:51:17.560 | to gain insight into themselves.

01:51:19.740 | And in general, it's a good sort of conversation starter,

01:51:23.200 | those methods, they're good for getting things out.

01:51:27.500 | We don't focus on dreams, typically these days

01:51:30.320 | in psychiatry, but they're great conversation starters,

01:51:32.560 | they're great ways to get things out if people have,

01:51:35.560 | and so we like to use those methods

01:51:39.040 | just to get the ball rolling sometimes,

01:51:41.080 | get people to open up a little bit.

01:51:42.940 | But the actual treatment tends not to involve

01:51:46.000 | these psychoanalytic approaches,

01:51:48.080 | where you are really probing the unconscious mind

01:51:52.580 | and its manifestation through dreams, for example,

01:51:56.480 | as the goal, that's not the goal.

01:51:59.220 | Modern talk therapy, we're really focusing on treatment,

01:52:01.560 | how to get people to feel better.

01:52:03.040 | - See, I use that as a conversation opener,

01:52:05.120 | the Freudian thing, where I try to delve at a bar

01:52:09.840 | of the deep sexual desires in a person's subconscious,

01:52:13.220 | and I find that opens up possibilities very quickly.

01:52:16.040 | - No, I mean, this is a silly sounding question,

01:52:20.360 | but what's the difference between

01:52:22.200 | cognitive behavioral therapy and conversation?

01:52:26.040 | So, 'cause I personally, as a fan of conversations,

01:52:30.320 | as a fan of just, I like listening to podcasts,

01:52:32.840 | versus like audiobook, I like both,

01:52:36.040 | but they're very different, and I like conversation.

01:52:38.600 | I like, it makes me personally very anxious,

01:52:41.240 | so I like to be the listener, like a third wheel,

01:52:45.040 | like overhearing a conversation kind of thing,

01:52:47.680 | but it's a really powerful method for humans

01:52:51.200 | to explore each other's mind, just raw conversation.

01:52:54.360 | So, do you think it can be more productive

01:52:58.280 | to be very systematic about it,

01:53:00.040 | or is conversation itself the art form of helping each other,

01:53:04.720 | understanding each other and helping each other?

01:53:06.760 | - There are forms of talk therapy

01:53:08.640 | that are essentially conversational,

01:53:10.960 | or they much more approach pure conversation.

01:53:14.760 | There's a befriending therapy,

01:53:17.120 | there's interpersonal therapy.

01:53:18.520 | These are approaches that are purely talk therapy,

01:53:23.080 | but they're not as structured as cognitive behavioral therapy.

01:53:26.800 | Cognitive behavioral therapy, there are manuals,

01:53:30.200 | there are guidelines, you can almost go through it

01:53:32.120 | in a very cookbook-y way,

01:53:33.680 | there's homework that you get done.

01:53:35.720 | So, in its fullest form, it's very different

01:53:39.380 | from these more conversational strategies.

01:53:42.160 | But what's interesting is sometimes people compare them,

01:53:44.280 | and so you'll see almost like randomized controlled studies

01:53:47.800 | comparing cognitive behavioral therapy

01:53:51.320 | with interpersonal therapy, for example.

01:53:53.520 | And they both can work, and actually in some studies

01:53:56.120 | they look comparable.

01:53:57.960 | So, to your point, conversation and insights

01:54:03.280 | that come from conversation, if done well,

01:54:05.460 | if done artfully, can be as powerful.

01:54:09.040 | - This reminds me of Robin Williams,

01:54:10.880 | so I have to ask you several questions here on that.

01:54:13.940 | But one of my favorite movies is "Good Will Hunting."

01:54:16.960 | I don't know if you've seen it with Robin Williams.

01:54:19.360 | So, as a psychiatrist yourself,

01:54:21.900 | can you do a deep analysis of this other famous psychiatrist,

01:54:25.600 | which is the movie character,

01:54:27.720 | played by Robin Williams in "Good Will Hunting"?

01:54:30.680 | Is it just the caricature between a psychiatrist

01:54:33.240 | and patient relationship, or is there something to you

01:54:38.240 | that was moving about his ability to connect

01:54:41.200 | to this obviously struggling young kid?

01:54:44.260 | - I think you've hit on the key thing there,

01:54:46.540 | which is the depth of the connection.

01:54:48.960 | If there's a too powerful connection,

01:54:53.960 | that can impair therapy,

01:54:58.340 | because it could impair open communication.

01:55:01.120 | If someone, if a patient sees the role,

01:55:05.540 | sees the relationship in a particular way,

01:55:08.140 | like in a friendly way, maybe,

01:55:09.700 | or like a parental child type way,

01:55:14.400 | that can cause problems,

01:55:16.480 | because then what they choose to share,

01:55:18.620 | what they choose to bring up,

01:55:20.400 | is selected to be appropriate

01:55:22.880 | for that view of the relationship.

01:55:25.640 | And so, I and many other talk therapists

01:55:29.520 | actually prefer not to let things get,

01:55:33.620 | not let the connection get that deep.

01:55:37.520 | You wanna have trust,

01:55:39.200 | you wanna have a therapeutic alliance,

01:55:41.580 | we sometimes call it,

01:55:42.640 | but it's got to be enough of a blank slate

01:55:47.200 | that the patient is not consciously or unconsciously

01:55:52.160 | constrained in what they choose to share.

01:55:54.540 | And so, great movie, great actors, all good,

01:56:00.800 | no complaints, except realistically,

01:56:06.360 | the relationship should be a little more

01:56:08.480 | arm's length than that.

01:56:09.640 | - Let's pretend this is real life.

01:56:13.160 | Sometimes, can't you leave a little bit of yourself

01:56:16.920 | in the interaction with the patient?

01:56:18.520 | - Yeah. - I mean,

01:56:19.360 | it's another human being. - Yes.

01:56:21.040 | So, it's a balance, and actually you do need some of it,

01:56:24.400 | because let's say this person is having challenges,

01:56:28.840 | interpersonal challenges in their life.

01:56:30.800 | The best way to notice what those are

01:56:36.080 | and to identify them and to work with them

01:56:38.880 | is if you can elicit some of those problems

01:56:43.200 | in the office, in the therapeutic interaction.

01:56:47.600 | And this is really powerful.

01:56:49.960 | As long as you're alert to it, aware of it,

01:56:54.400 | and you don't let it go out of hand,

01:56:56.960 | this transference, we call it,

01:56:58.960 | is when you transfer in between the current

01:57:04.800 | therapeutic relationship and external relationships

01:57:08.560 | that the patient may have had with others.

01:57:10.660 | And so, if the therapist starts to feel an inner feeling,

01:57:16.600 | like anger, let's say, so let's say you have a patient

01:57:20.080 | who is stirring frustration in you,

01:57:23.400 | or even in extreme cases, anger,

01:57:25.480 | the best thing for the therapist to do in that case

01:57:27.960 | is to recognize it and to realize

01:57:32.160 | that's probably being stirred by other people

01:57:34.360 | in the patient's life, and that could be the source

01:57:36.800 | of a lot of problems.

01:57:38.160 | And so, instead of trying to wall it off

01:57:41.000 | and say, "Oh, I shouldn't be feeling that,

01:57:42.800 | "I better be a better therapist,"

01:57:44.840 | instead, recognize it and use it

01:57:46.640 | and help the patient that way.

01:57:48.980 | And so, you've gotta be a human being,

01:57:50.360 | you've gotta be a person who feels,

01:57:52.840 | you've gotta be open.

01:57:54.440 | - But be in control of it and be aware of it.

01:57:57.280 | If I may, I just wanna read, 'cause it's one

01:57:59.640 | of my favorite scenes.

01:58:00.760 | Probably one of the greatest scenes,

01:58:03.320 | one of the greatest scenes in movie history

01:58:05.260 | because Robin Williams does a single take.

01:58:08.180 | - Is that right?

01:58:10.120 | - So, this is a very interesting interaction between them.

01:58:12.040 | So, Will, and I'm sure this is a common interaction,

01:58:15.380 | maybe with a therapist and a patient,

01:58:19.080 | maybe with a father and son,

01:58:21.280 | where Will, the young character,

01:58:23.480 | the young, brilliant mathematician,

01:58:25.040 | and Sean is the therapist, the older therapist,

01:58:28.360 | where Will looks at a painting that Sean painted

01:58:31.840 | and then does a deep, critical analysis of the painting

01:58:35.940 | that basically describes,

01:58:38.780 | pretending as if he can understand

01:58:41.880 | another human being completely

01:58:43.400 | by just looking at their painting.

01:58:45.440 | And then Sean gives this whole speech

01:58:48.100 | that contrasts sort of raw intelligence

01:58:52.320 | and the wisdom of experience.

01:58:54.280 | And Sean says, "Single take."

01:58:56.880 | He says, "You've never been out of Boston, right?"

01:58:59.640 | And Will says, "Nope."

01:59:01.280 | All this in a sexy Boston accent, by the way.

01:59:03.680 | And then Sean gives this speech.

01:59:07.360 | "If I asked you about art,

01:59:08.800 | "you'd probably give me this skinny

01:59:10.300 | "and about every art book ever written.

01:59:12.900 | "Michelangelo, you know a lot about him.

01:59:15.660 | "Life's work, political aspirations,

01:59:17.500 | "him and the Pope, sexual orientation,

01:59:19.660 | "the whole works, right?

01:59:21.340 | "But I bet you can't tell me what it smells like

01:59:23.940 | "in the Sistine Chapel.

01:59:26.000 | "You never actually stood there

01:59:27.600 | "and looked up at that beautiful ceiling, seeing that.

01:59:31.400 | "If I asked you about women,

01:59:32.720 | "you'll probably give me a syllabus

01:59:34.780 | "of your personal favorites.

01:59:36.640 | "You may have even been laid a few times.

01:59:40.140 | "The language here is just beautiful.

01:59:42.640 | "But you can't tell me what it feels like

01:59:45.340 | "to wake up next to a woman and feel truly happy.

01:59:49.040 | "You're a tough kid.

01:59:50.520 | "If I asked you about war,

01:59:51.680 | "you'd probably throw Shakespeare at me, right?

01:59:54.400 | "Probably not, but let's say.

01:59:57.320 | "Once more into the breach, dear friends.

01:59:59.800 | "But you've never been near one.

02:00:02.160 | "You've never held your best friend's head on your lap

02:00:05.000 | "and watched him gasp his last breath,

02:00:07.020 | "looking to you for help.

02:00:09.240 | "If I asked you about love,

02:00:11.360 | "you'd probably quote me a sonnet.

02:00:13.320 | "But you've never looked at a woman

02:00:16.100 | "and be truly vulnerable.

02:00:18.500 | "Known someone who can level you with their eyes,

02:00:21.720 | "feeling like God put an angel on earth just for you,

02:00:25.360 | "who could rescue you from the depths of hell

02:00:27.720 | "and you wouldn't know what it's like to be her angel.

02:00:31.400 | "To have that love for her,

02:00:34.260 | "be there forever, through anything, through cancer.

02:00:38.320 | "And you wouldn't know about sleeping,

02:00:40.220 | "sitting up in a hospital room for two months,

02:00:42.580 | "holding her hand because the doctors could see in your eyes

02:00:46.220 | "the terms visiting hours don't apply to you.

02:00:49.160 | "You don't know about real loss

02:00:51.220 | "because that only occurs when you love something

02:00:55.100 | "more than you love yourself.

02:00:56.680 | "I doubt you've ever dared to love anybody that much.

02:01:01.780 | "I look at you, I don't see an intelligent, confident man.

02:01:05.640 | "I see a cocky, scared, shitless kid.

02:01:08.840 | "But you're a genius, Will.

02:01:10.300 | "No one denies that.

02:01:11.980 | "No one can possibly understand the depths of you.

02:01:14.760 | "But you presume to know everything about me

02:01:16.660 | "because you saw a painting of mine.

02:01:18.680 | "You ripped my fucking life apart.

02:01:21.560 | "You're an orphan, right?

02:01:22.900 | "Do you think I know the first thing

02:01:25.220 | "about how hard your life has been,

02:01:27.540 | "how you feel, who you are, because I read Oliver Twist?

02:01:31.660 | "Does that encapsulate you?

02:01:33.900 | "Personally, I don't give a shit about all that

02:01:35.920 | "because you know what?

02:01:37.460 | "I can't learn anything from you

02:01:39.140 | "that I can't read in some fucking book,

02:01:41.660 | "unless you want to talk about you, who you are.

02:01:45.160 | "And I'm fascinated, I'm in.

02:01:47.460 | "But you don't want to do that, do you, sport?

02:01:50.300 | "You're terrified of what you might say.

02:01:53.600 | "Your move, chief."

02:01:55.820 | Well done, sir, I know it's a movie.

02:01:57.520 | It's interesting, right?

02:01:58.820 | So some of that conversation

02:02:00.140 | is at some intellectual level, too.

02:02:03.140 | It's not just emotional, it's something,

02:02:05.420 | the reason I kinda connect with that is,

02:02:10.700 | that's a lot of work for a therapist.

02:02:14.300 | Like, to really understand another, 'cause he's,

02:02:17.020 | I mean, from, okay, I know this is fictional,

02:02:19.500 | but just, there's calculation happening.

02:02:22.860 | He deeply cares to say the words

02:02:26.020 | that the other person needs to hear,

02:02:27.960 | but also a little bit loses himself in the pride,

02:02:32.620 | but then catches himself again,

02:02:35.220 | switches from anger to connection.

02:02:38.620 | - Yeah, a lot is brought up there.

02:02:40.900 | You're right, there has to be some emotion

02:02:42.900 | in the therapist to care enough to keep going,

02:02:46.140 | to keep probing, to open up as he's doing so, right?

02:02:51.140 | He revealed a lot about himself, his own vulnerabilities,

02:02:53.900 | but that gave him authenticity.

02:02:56.740 | He had to open himself up so that the kid

02:02:59.940 | would see the authenticity and open himself up in return.

02:03:03.740 | So how do you do that as a psychiatrist, as a therapist?

02:03:10.020 | You have to be careful.

02:03:10.860 | You don't wanna do too much,

02:03:13.720 | but opening up a little bit does help.

02:03:17.520 | It does create a chance.

02:03:20.080 | You're offering up something,

02:03:21.380 | and that helps the patient come back in return,

02:03:24.700 | and it gives you that believability and authenticity.

02:03:28.700 | - Do you pay the price for that, for opening up?

02:03:31.340 | - You can.

02:03:32.860 | - You have a family, you have an incredibly

02:03:36.500 | difficult research.

02:03:38.180 | You're doing a lot of things in your world.

02:03:40.340 | I mean, it's a price you pay for like,

02:03:43.580 | - Well, this is one of the terrifying things

02:03:45.740 | about writing the book was,

02:03:47.560 | I do open up in a little bit about my own personal life,

02:03:52.580 | my own personal challenges,

02:03:53.800 | and that was a considered decision

02:03:55.500 | because I could have done the patient work

02:04:00.500 | and the science work and the history

02:04:03.840 | of the human family work and tied it all together,

02:04:07.820 | but it wasn't, in an early draft, it was like that,

02:04:12.820 | but it wasn't real yet.

02:04:15.640 | It wasn't something that everybody could connect with,

02:04:19.480 | and I said, then I realized, look, if I'm gonna do this,

02:04:22.280 | I've gotta open up myself,

02:04:26.320 | and then people can connect with me

02:04:28.320 | and see what I'm really saying, and so I did,

02:04:31.720 | and that was, it was not something

02:04:34.200 | that I'd gone in planning to do.

02:04:37.440 | In retrospect, I learned a lot about myself.

02:04:39.320 | It was actually really, I think, a good thing that I did,

02:04:42.260 | but it was scary.

02:04:43.760 | - Where are the darkest places you've ever gone in your life?

02:04:47.880 | - You know, I had, things haven't always been easy,

02:04:55.500 | personally or professionally.

02:04:57.300 | I had moments, you know, I was effectively a single dad

02:05:00.820 | for a while, a number of years,

02:05:03.180 | and these came at probably the hardest, also, professional.

02:05:07.220 | A lifetime's for me, too.

02:05:09.440 | The absolute hardest, days of late medical school,

02:05:13.400 | internship, you know, taking call,

02:05:16.320 | you know, getting up at 3 a.m., you know, surgery,

02:05:19.140 | medicine, rounds, unforgiving environments,

02:05:24.360 | and then all the while, you know, personal life,

02:05:27.740 | you know, stripped down to the bare,

02:05:29.980 | and these were low moments,

02:05:32.520 | and then I was hit particularly hard by

02:05:35.740 | just experiences on the clinical ward,

02:05:39.400 | connecting too deeply with patients,

02:05:42.020 | like a child with a brain tumor,

02:05:44.040 | and feeling it too strongly,

02:05:45.660 | and those things,

02:05:47.440 | when you get down to those lowest of the low moments,

02:05:51.760 | when everything is stripped away,

02:05:53.560 | and there's only this raw core,

02:05:58.160 | well, yeah, that's pretty hard.

02:06:00.240 | That was probably the lowest moment,

02:06:02.080 | and you learn a lot about yourself in those moments,

02:06:04.200 | you know, what's left,

02:06:05.760 | and then what are the roots out from there,

02:06:10.040 | and that can be powerful to see in yourself.

02:06:15.040 | - Have you thought about killing yourself?

02:06:18.840 | - I have not.

02:06:20.280 | I have not.

02:06:21.120 | - Have you seen that thought in the distance?

02:06:23.580 | - I am fortunate that that has not come to my mind,

02:06:28.960 | and I have not seen it even in the distance,

02:06:32.000 | and in some ways, I've wondered if that's made me,

02:06:36.900 | am I a less effective psychiatrist because of that?

02:06:40.720 | I've felt everything stripped away.

02:06:44.080 | I've been at the lowest of the low,

02:06:46.440 | and yet that--

02:06:48.200 | - There's still hope.

02:06:49.040 | There's a light of hope still at the end of the tunnel.

02:06:51.280 | - Right, right.

02:06:52.400 | - So you never lost, even for brief moments, that--

02:06:55.320 | - Never did.

02:06:57.600 | I don't know why.

02:06:59.040 | - You don't know why.

02:06:59.880 | - There was no reason.

02:07:00.840 | - You don't know why.

02:07:01.680 | - There was no reason to feel hope at that moment, honestly.

02:07:03.960 | - So it was just a light without reason.

02:07:07.720 | - Yeah, that's right.

02:07:08.860 | - What wisdom do you draw from that time?

02:07:13.180 | So first of all, you said something funny,

02:07:19.480 | which is I wonder if it,

02:07:22.040 | that it's somehow not having thoughts of suicide

02:07:26.480 | limits your capacity to truly understand

02:07:30.440 | somebody who is having those thoughts.

02:07:34.760 | So how many demons must a psychiatrist have

02:07:39.360 | in order to be a good psychiatrist?

02:07:41.460 | - You know, this is a really interesting question.

02:07:45.440 | I think everybody knows, and I can say this,

02:07:47.580 | that psychiatrists can be a little unusual.

02:07:50.660 | We think about ourselves, right?

02:07:53.680 | We think about our brains.

02:07:54.760 | That may be one reason why we become psychiatrists

02:07:56.920 | is we think, oh, that's interesting going on in there.

02:07:59.320 | What's that about?

02:08:00.600 | So a little introspective, a little introverted maybe,

02:08:03.880 | and that's what can make us good when we're good.

02:08:07.080 | But also that may select for people

02:08:12.680 | who have some unusual aspects,

02:08:14.700 | but you don't have to have all of them.

02:08:17.100 | There's a lot that can go wrong in the psychiatric realm.

02:08:21.080 | I think having some of those,

02:08:24.320 | some of it but not all of it is enough.

02:08:26.080 | You get to see how low things can get.

02:08:29.600 | You can get a,

02:08:30.880 | you get empathy from that,

02:08:35.680 | even if the symptoms are not the same.

02:08:38.440 | - Just empathy for struggle, for suffering.

02:08:41.080 | - That's right, that's right.

02:08:42.840 | - Do you yourself have to practice observing triggers

02:08:46.840 | just as a human operating in this world?

02:08:49.500 | - I've definitely, those skills that have come from therapy,

02:08:53.200 | I've found them useful.

02:08:55.960 | If I notice that,

02:08:57.060 | we've all been through experiences where we wonder,

02:09:00.520 | oh, I got really mad in that interaction.

02:09:03.400 | Why did I get that mad?

02:09:05.320 | Yeah, sure, maybe I could have been irritated,

02:09:06.960 | but man, why did I?

02:09:08.160 | And then thinking about it and realizing,

02:09:12.160 | okay, back up here, think about the broader context.

02:09:16.540 | Think about how that relates to prior events in my life.

02:09:23.160 | Okay, yeah, so this is a thing for me

02:09:25.920 | when something of this class happens, then it triggers me.

02:09:30.160 | So going forward, I'm gonna be aware of that.

02:09:32.420 | And I've definitely used that 'cause it's,

02:09:36.260 | you don't wanna be out of control of those emotions.

02:09:40.400 | You wanna identify them,

02:09:41.440 | you wanna know where they come from,

02:09:42.880 | and you wanna head them off

02:09:44.760 | as a civilized human being living on this earth,

02:09:48.280 | trying to get along with other people.

02:09:50.060 | You wanna understand those moments.

02:09:52.000 | - Let me return to Robin Williams for a second,

02:09:56.880 | and looking at Robin Williams, the actor,

02:10:00.800 | sorry, the human.

02:10:02.640 | And 'cause you mentioned for depression,

02:10:06.320 | you can have everything going well.

02:10:08.240 | And I think there's just famous cases of just public figures

02:10:12.920 | 'cause a lot of people know them,

02:10:15.120 | where they suffer quietly,

02:10:19.720 | and it seems like from the outside perspective

02:10:22.640 | that they have everything going for them,

02:10:24.840 | that they're at the top of their career.

02:10:26.920 | You know, two people that come to mind

02:10:28.600 | are Robin Williams and Anthony Bourdain.

02:10:32.320 | What insight do you have in why either of those taken,

02:10:36.560 | why Robin Williams, a comedian,

02:10:39.880 | one of sort of the most jolly humans.

02:10:42.360 | Obviously, there was always the darkness

02:10:43.840 | that he was channeling in order to present the happiness.

02:10:49.840 | But it feels like that realness is only possible

02:10:53.160 | when you're deeply self-honest and analytical.

02:10:56.320 | And then if you're deeply self-honest,

02:10:59.440 | you're going to realize

02:11:00.280 | that there's a lot of beautiful things about life

02:11:02.200 | that you can discover.

02:11:03.600 | And if you do that,

02:11:05.240 | how can you possibly then take your own life?

02:11:07.800 | And you go through all of these thoughts.

02:11:10.200 | And I think a lot of people really loved Robin Williams,

02:11:15.200 | which is why it was really difficult to see.

02:11:18.000 | How can even him,

02:11:20.040 | how can even Robin Williams take his own life?

02:11:22.200 | So I don't know if there's something to be said

02:11:24.600 | about the nature of depression

02:11:25.920 | from just looking at his case.

02:11:27.760 | - I think the action of suicide is not well understood.

02:11:33.080 | It doesn't always, although often is,

02:11:36.200 | correlated with depression.

02:11:37.640 | There are cases of suicide

02:11:39.280 | where there is not clear depression.

02:11:41.320 | That's in the minority.

02:11:42.880 | - By the way, if I just,

02:11:44.240 | 'cause you said it's so interesting,

02:11:46.080 | action of suicide.

02:11:47.680 | 'Cause there's also thoughts of suicide.

02:11:49.800 | And probably those,

02:11:51.320 | they're probably somewhat understood,

02:11:54.560 | but it's an interesting,

02:11:55.840 | 'cause you can think of suicide,

02:11:59.280 | if you have suicidal ideation,

02:12:00.880 | you can think of that for so many reasons.

02:12:04.000 | - That's right.

02:12:04.840 | - And the,

02:12:07.280 | I mean,

02:12:09.520 | thoughts sometimes,

02:12:14.640 | like painful thoughts,

02:12:16.400 | angry thoughts, or thoughts in general,

02:12:19.240 | can be very different.

02:12:20.240 | Like fantasies, for example.

02:12:21.320 | You can fantasize, like sexual fantasies.

02:12:24.440 | You can fantasize,

02:12:27.120 | I was just for humor's sake,

02:12:28.480 | wanted to mention stuff,

02:12:29.400 | but then people will think I'm serious.

02:12:30.800 | So I'm not gonna mention anything.

02:12:32.360 | But sexual fantasies,

02:12:34.120 | and then there's,

02:12:34.960 | I know there's people that have sexual fantasies

02:12:36.400 | and they don't wanna actually do that in real life.

02:12:38.560 | That that sexual fantasy serves some kind of purpose

02:12:41.400 | in imagination only.

02:12:43.160 | And in that same way,

02:12:44.320 | suicide might serve a purpose in imagination only

02:12:46.920 | is very unlikely to lead to action.

02:12:48.800 | And yet there's other thoughts

02:12:51.160 | that maybe are more amorphous

02:12:52.520 | that do lead to action.

02:12:54.160 | And that leap,

02:12:55.320 | yeah, that, oh boy,

02:12:57.720 | that's a fascinating,

02:12:58.560 | and that's such a philosophically powerful thought

02:13:02.120 | to not exist.

02:13:03.680 | Like that question,

02:13:04.680 | that's this, is it Sartre or Camus,

02:13:07.880 | Camus, or the mythicist, Camus,

02:13:11.000 | who says like basic question of why live?

02:13:14.600 | Good question.

02:13:16.520 | - Yeah, right.

02:13:18.080 | So that's a great question actually.

02:13:20.840 | And there are other related questions.

02:13:22.840 | Some people may have the thought of suicide

02:13:26.320 | because there seems no point,

02:13:31.760 | there's no joy in life.

02:13:33.160 | That's one reason that some people can put forward.

02:13:36.760 | Sometimes there's an,

02:13:37.600 | it's not just the absence of joy,

02:13:39.880 | there's an active pain,

02:13:41.480 | an active psychic pain in some people.

02:13:44.000 | And that, the inescapability of that

02:13:46.560 | is enough to drive the thoughts of suicide.

02:13:50.520 | And then there are interpersonal

02:13:52.400 | and cultural reasons as well that can show up.

02:13:54.680 | But the act,

02:13:57.320 | this act of ending of the self is,

02:14:00.080 | in all these cases,

02:14:01.120 | there's no real way to study this in animals.

02:14:03.440 | No other animal as far as we know that we can study

02:14:07.160 | has this concept of this is myself.

02:14:10.760 | The situation is not tolerable,

02:14:13.160 | therefore I will end the self.

02:14:15.400 | To our knowledge,

02:14:16.240 | this is not something that can be studied in other animals.

02:14:18.760 | So it remains this

02:14:20.720 | very poorly understood action.

02:14:26.240 | And in predicting it,

02:14:28.600 | so what do we do as psychiatrists?

02:14:29.840 | We have this challenge.

02:14:30.680 | People come to the emergency room,

02:14:32.680 | they say they're suicidal,

02:14:33.960 | or their friends say they're suicidal,

02:14:35.360 | or they've taken some action that didn't lead to death.

02:14:39.000 | What do we do?

02:14:41.040 | Well, there's a whole range of options.

02:14:44.000 | Was it a suicidal gesture

02:14:45.640 | in the sense of not intending death?

02:14:48.280 | Or was it,

02:14:49.800 | was the intent death?

02:14:51.920 | And if it was the intent was death,

02:14:53.560 | what were the reasons?

02:14:54.400 | Are the reasons transient?

02:14:55.440 | Are they gone now?

02:14:56.920 | What's the probability that it'll be repeated?

02:15:00.160 | So we do all these things

02:15:01.560 | just to decide what sort of treatment should be carried out.

02:15:04.280 | But nowhere is there a deep understanding of the biology,

02:15:09.040 | of the cells and circuits and activity patterns

02:15:12.480 | that underlie the action to end the self.

02:15:16.840 | It's a very,

02:15:17.880 | it's this frustrating thing.

02:15:21.440 | It's so timely,

02:15:23.680 | it's so common,

02:15:24.960 | it shows up in veterans,

02:15:26.440 | it shows up in kids,

02:15:27.760 | it shows up in people at every stage of life.

02:15:32.360 | And yet we're very bad at understanding it

02:15:35.080 | and we're relatively poor at predicting it

02:15:37.040 | and our tools are not very powerful.

02:15:40.760 | We can put people in a locked unit,

02:15:42.720 | we can give them care therapy for a while.

02:15:44.880 | At some point,

02:15:46.280 | we release them and there's only so much we can do.

02:15:48.680 | It's one of the most frustrating things,

02:15:50.840 | the suffering that is linked to suicidality.

02:15:53.600 | - But it is a decision and it is an action.

02:15:56.680 | And if you look at optogenetics,

02:15:58.400 | you should be able to one day

02:16:00.800 | sort of understand the dynamics of such weighty decisions.

02:16:05.480 | - Individual causes then,

02:16:06.520 | if someone is anhedonic,

02:16:07.600 | if there is no joy in life,

02:16:09.360 | that very likely is addressable by optogenetics.

02:16:12.760 | We know how to turn that dial very robustly in animals.

02:16:16.880 | The motivation to overcome challenges,

02:16:20.680 | that we have some hope of understanding.

02:16:25.680 | Psychic pain, internal negative states,

02:16:28.400 | we have actually a handle on that as well.

02:16:30.360 | There's a structure in the brain called the habenula

02:16:33.000 | and some linked structures around it

02:16:35.440 | that seems to generate this negative internal state.

02:16:38.760 | It's active when a state of acute disappointment,

02:16:42.520 | acute outcomes that go wrong, not as expected.

02:16:47.280 | Moments of unexpected pain.

02:16:52.240 | The habenula is there, it seems,

02:16:54.240 | it's active to report on internal negativity

02:16:59.080 | with its action.

02:17:00.920 | And so you could imagine strategies

02:17:02.680 | to target this brain structure

02:17:03.880 | that might have the effect of reducing psychic pain,

02:17:07.240 | reducing the negativity of internal states.

02:17:09.760 | That is a very concrete hope.

02:17:11.960 | It's precise, it's anatomical.

02:17:14.160 | Optogenetics has given us all the firm foundation we need

02:17:17.400 | to go after that question.

02:17:19.760 | So I think there is hope.

02:17:21.440 | If you look at the individual causes,

02:17:22.960 | the individual symptoms relating to suicide,

02:17:25.960 | and then it's like a puzzle,

02:17:26.960 | you put together the puzzle pieces.

02:17:29.000 | - By the way, I do think my habenula

02:17:33.280 | is functioning very actively.

02:17:37.440 | (Dave laughing)

02:17:38.280 | And I wonder if it's like,

02:17:39.920 | 'cause you can also learn to channel these things, right?

02:17:43.120 | Some of the things we suffer from,

02:17:45.920 | I mean, there's degrees of suffering,

02:17:48.160 | can be a source of progress and personal growth

02:17:53.160 | and development and all those kinds of things.

02:17:57.000 | I mean, what is it, Nietzsche suffered from stomach issues.

02:18:02.000 | I wonder if he's written some of those things,

02:18:09.160 | if his stomach was all great.

02:18:11.600 | I kind of think that a difficult life in some form,

02:18:18.880 | you get to choose in some regard,

02:18:21.760 | in some you don't.

02:18:22.800 | The difficulties you have and the ones you do have,

02:18:25.360 | it's nice to use if possible.

02:18:27.240 | It's sometimes it's nice to treat,

02:18:28.760 | sometimes it's nice to use.

02:18:31.460 | - Well, the way you phrase it, I think you're using it.

02:18:33.560 | I could be wrong, but if you phrase it

02:18:36.560 | in this semi-humorous way about your habenula,

02:18:39.180 | it seems to me that you're using that to good effect.

02:18:43.780 | Now, but one never really knows

02:18:46.280 | what someone else's internal state is.

02:18:48.120 | As I look at you, I don't know the depths

02:18:50.280 | of what's going on.

02:18:51.840 | And it's possible that it's a much harder situation in there.

02:18:56.840 | - Yes, so I actually worry about this a lot.

02:19:00.400 | So I'm extremely self-critical.

02:19:02.120 | Like in the privacy of my own mind,

02:19:04.400 | which is an interesting thing when you get

02:19:06.820 | to meet the internet and the internet will tell you you suck.

02:19:09.940 | But for now, now this is what I worry about

02:19:15.080 | and I'm very paying attention.

02:19:16.840 | For now, it's really, I just have this very negative voice.

02:19:20.760 | But that voice seems to be very useful for productivity.

02:19:25.080 | And so I channel it.

02:19:26.320 | I just put it on the table and let that voice talk to me.

02:19:29.880 | But I'm very, I'm like monitoring that voice

02:19:33.960 | 'cause looking at Robin Williams,

02:19:35.600 | you know, you get older, your brain changes,

02:19:38.160 | or like you're, and then that voice can now

02:19:41.240 | all of a sudden grow, right?

02:19:43.560 | And then where you can't control it as much,

02:19:45.240 | you have to be very careful with these kinds of things.

02:19:47.880 | - You're very right about that.

02:19:50.160 | So my negativity, I have this,

02:19:53.080 | I never think I've done enough

02:19:54.440 | is sort of where my negativity comes from inside.

02:19:57.440 | I never think that I've met the potential of the moment.

02:20:02.440 | I haven't done, I haven't, you know,

02:20:07.400 | made the most of the opportunities that are available.

02:20:12.200 | Still early, I haven't, you know,

02:20:15.080 | progressed as far as I should.

02:20:16.680 | And exactly as you're saying, that works for a while.

02:20:20.960 | But then what happens as you get later in life

02:20:23.640 | and there's less runway to, you know, fix that.

02:20:28.640 | And then maybe then that negative voice is a problem.

02:20:33.040 | - But also at that point, the negative voice

02:20:34.920 | starts having more and more of a point.

02:20:36.680 | It's when you're being very successful,

02:20:39.880 | it's easy to be like, no, okay, well.

02:20:42.180 | Like, but later in life, you're really,

02:20:45.720 | literally just sitting there on a rocking chair

02:20:49.000 | doing nothing and then it's,

02:20:51.480 | or maybe any kind of tragedy happens.

02:20:53.640 | Loss of a loved one, loss of a job,

02:20:57.160 | loss or you get screwed over in some kind of way.

02:21:01.480 | I don't know.

02:21:02.560 | And then all of a sudden, the negative voice

02:21:04.200 | is just you and the negative voice

02:21:05.680 | for days and days and days.

02:21:07.960 | - And so I don't know,

02:21:09.480 | to go back to your example of Robin Williams,

02:21:11.160 | I don't know what was going on inside him.

02:21:13.400 | I don't know the nature of his internal state.

02:21:15.440 | Was it active psychic pain that--

02:21:18.080 | - May I mention, may I interrupt to just say

02:21:20.240 | that Sergei posted an examination of Robin Williams.

02:21:23.560 | His brain tissue suggested that he suffered from,

02:21:26.600 | quote, diffuse LEWY, Lewy body dementia, LBD.

02:21:31.600 | Depression is a symptom of LBD

02:21:36.560 | and it's not about psychology, it's rooted in urology.

02:21:40.480 | This is words from Sergei.

02:21:42.000 | His brain was falling apart.

02:21:43.640 | - Yeah.

02:21:44.480 | - Lewy body dementia,

02:21:45.360 | this is a very interesting neurological disorder

02:21:47.680 | where among other things, there's neuron death indeed.

02:21:51.880 | So you've got frank neuron loss.

02:21:54.560 | It's not just a matter of some longstanding psychic pain,

02:21:58.280 | but you've got a progressive loss.

02:22:00.920 | And so clearly you've got a situation

02:22:03.000 | where he could have finally reached a point

02:22:04.480 | where the balance that he'd worked out

02:22:07.520 | between negativity and positivity was disrupted due to loss.

02:22:12.440 | The wrong cells died.

02:22:13.480 | The wrong projections were cut by the Lewy body dementia.

02:22:16.920 | Certainly dopamine neurons die in Lewy body dementia.

02:22:19.600 | Those are neurons that give rise to much of the feelings

02:22:23.440 | of reward and pleasure that we experience,

02:22:25.760 | among other roles.

02:22:27.360 | So clearly in his case,

02:22:30.200 | there could have been a very concrete

02:22:32.720 | cellular neurological issue that was progressive

02:22:35.280 | and pushed him to that point.

02:22:36.860 | - But were you about to make a point about broader

02:22:41.720 | that if there is a neurological degeneration?

02:22:45.040 | - Yeah, so in his case, not knowing that,

02:22:47.340 | it could have been simply that,

02:22:49.680 | let's say he had an internal psychic pain state

02:22:52.760 | and he was in sort of a compensated mode

02:22:56.680 | for much of his life,

02:22:57.520 | able to generate enough joy from his comedy

02:22:59.800 | and his social interactions.

02:23:01.200 | And then, but eventually later in life,

02:23:04.160 | those things drop away, the balance shifts.

02:23:08.160 | You get tired of fighting the pain for that long.

02:23:10.760 | And then, so you've got this time dependent

02:23:13.280 | non-stationarity that happens.

02:23:14.760 | And then the same symptom

02:23:18.280 | becomes no longer tolerable in the end.

02:23:20.240 | - What is autism?

02:23:22.680 | What do we know about autism?

02:23:24.320 | - Human beings exist on a spectrum of how social we can be.

02:23:30.440 | And this is pretty interesting actually, scientifically,

02:23:34.640 | but also very important clinically.

02:23:38.240 | There are hyper-social states

02:23:39.640 | where people are almost too social.

02:23:42.800 | There are chromosomal deletion states

02:23:44.760 | where people have instant affinity and bonding

02:23:47.760 | and rich, deep seeming connections with people, very verbal.

02:23:52.760 | On the other end, people with autism spectrum disorder

02:23:57.600 | are not able to keep up with social interactions.

02:24:02.600 | And it's a spectrum.

02:24:06.560 | Some have mild to moderate difficulties.

02:24:09.480 | They may have an inability to understand

02:24:13.800 | what the next thing to do in a social situation is,

02:24:16.120 | but may have perfectly good language abilities.

02:24:18.960 | And as you progress further along the spectrum,

02:24:21.880 | that gets more and more severe.

02:24:23.200 | So they can't make eye contact

02:24:26.200 | because it's too overwhelming

02:24:28.080 | to think about what has to be done next

02:24:29.760 | if a person looks in a particular way.

02:24:32.280 | And then as you go farther,

02:24:33.460 | then language and social communication themselves break down

02:24:38.000 | so there's no reciprocity, there's no shared enjoyment.

02:24:41.980 | And this gets very hard then

02:24:43.480 | as you get to this far end of the spectrum

02:24:45.340 | where there's really an absence of social cognition at all

02:24:50.080 | and social bonding.

02:24:52.840 | So why does this exist?

02:24:54.560 | What is it?

02:24:55.620 | It's very genetic.

02:24:56.840 | As I mentioned, it's one of the top three or four

02:25:00.040 | most biological in the sense of most genetically

02:25:03.000 | determined of the psychiatric illnesses.

02:25:05.400 | It does have these interesting positive correlations,

02:25:08.000 | slight positive correlations

02:25:09.240 | with intelligence and education.

02:25:11.420 | And the reason for that is kind of interesting

02:25:17.240 | to think about.

02:25:18.300 | Is there something good about it?

02:25:19.480 | Just like, or at least, with at least part of the spectrum,

02:25:23.040 | is there something good about it?

02:25:23.980 | Just as we were talking about for depression,

02:25:26.200 | as you could say for mania,

02:25:27.480 | as you could say for schizophrenia.

02:25:30.400 | And here it's kind of interesting to think about

02:25:34.680 | the underlying science of what it means

02:25:38.320 | to be good at a social interaction.

02:25:40.200 | Someone who's very good at a social interaction

02:25:44.040 | is incredibly good at dealing with unpredictable information

02:25:48.400 | is able to handle this torrent of information

02:25:51.420 | coming through rapidly changing model of the other person

02:25:57.360 | and of the interaction and their model of you,

02:26:00.720 | your model of them.

02:26:02.520 | With each word that changes,

02:26:03.920 | with each new bit of information

02:26:05.560 | that comes in through the conversation,

02:26:06.940 | each bit of body language, all this is rapidly changing.

02:26:09.720 | And some people are able to keep up

02:26:12.400 | with that fire hose of information perfectly well.

02:26:15.640 | But that's a special brain state to be in.

02:26:17.300 | That's working with unpredictability.

02:26:20.400 | That's, the only way that can be done

02:26:24.480 | is most likely by constantly running models

02:26:29.080 | of what the other person might be about to say.

02:26:32.200 | So you can't stop and think, oh, what did that word mean?

02:26:34.360 | What did that shift in eye contact mean?

02:26:37.280 | You know, what do they mean together?

02:26:38.800 | There has to be some advanced work going on

02:26:41.200 | where you're predicting what's going on

02:26:42.440 | if you're to keep up with a rich

02:26:43.840 | and fast social interaction.

02:26:45.280 | Now, on the flip side,

02:26:49.960 | there are brain states that maybe don't have to work so fast

02:26:53.600 | that are extremely important still.

02:26:54.920 | Dealing with something that's not moving

02:26:57.040 | or that's predictable, still complex,

02:27:00.200 | like mathematical proof

02:27:03.400 | or a very complex arrangement of geometrical shapes,

02:27:07.920 | a large number of individual non-moving things.

02:27:11.080 | There's possibly a way of being

02:27:13.600 | that's particularly good at dealing with these static,

02:27:15.760 | unmoving, or predictable situations,

02:27:19.320 | and less so with these rapidly changing social situations.

02:27:22.880 | And so the way I conceptualize autism

02:27:25.960 | is these are people whose brains are not so good

02:27:31.000 | with the high bit rate, unpredictable information,

02:27:34.440 | but may be quite good at, given enough time,

02:27:38.040 | given the grace to work with the system,

02:27:43.040 | to look at it from different angles,

02:27:46.920 | to take different perspectives

02:27:48.980 | with a confidence that it's not changing

02:27:51.360 | in between perspectives.

02:27:52.840 | That's a brain state that's valuable.

02:27:55.640 | It's something that has probably has contributed

02:27:59.560 | to a lot of the success of the human family,

02:28:01.140 | being able to design something,

02:28:02.340 | being able to consider all the different contributions

02:28:07.340 | to a static, predictable system.

02:28:13.280 | - So autism, in a sense,

02:28:14.760 | is a spectrum that has identifiable characteristics

02:28:20.960 | about the way people deal with dynamic information,

02:28:25.120 | often express itself as social dynamic information.

02:28:29.080 | - But you critically,

02:28:29.920 | your use of the word often there is really, I think, smart,

02:28:32.720 | because it's not just social interaction

02:28:35.920 | that is a challenge in autism.

02:28:37.240 | And so many people conceptualize it purely

02:28:40.000 | as a social dysfunction disorder,

02:28:44.800 | but it's really any unpredictable information

02:28:47.560 | that's a problem, that's a challenge

02:28:49.520 | for people on the spectrum,

02:28:50.880 | they react very negatively to unexpected sounds,

02:28:55.880 | even if not social sounds,

02:28:58.040 | unexpected lights, unexpected touches.

02:29:01.160 | And so it's really unpredictable information

02:29:03.360 | that is, in my view, the core problem

02:29:06.040 | with the processing in autism, not just social.

02:29:09.200 | Social just shows up because it's so unpredictable.

02:29:11.520 | - Yeah, it's so interesting.

02:29:12.960 | I mean, I try to not to think about that stuff.

02:29:19.360 | I'm afraid of thinking about disorders and things like that

02:29:23.280 | because just like I don't like sort of economics

02:29:26.640 | or game theory, I wanna be careful with it

02:29:30.160 | because whenever you have a category or a model,

02:29:34.280 | it's too easy to just, for everything,

02:29:37.640 | I mean, it's the OCD thing.

02:29:39.400 | I like models too much, I like categories too much.

02:29:42.200 | The moment you acknowledge to yourself,

02:29:44.160 | well, I have an eating disorder, for example,

02:29:46.320 | or something like that,

02:29:47.520 | as opposed to just being, well, I'll just leave it at that

02:29:51.320 | for my own critical understanding of myself.

02:29:54.520 | Let's just say I don't know how to moderate eating fruit.

02:29:56.960 | People make fun of me,

02:29:57.800 | they think all fruit is healthy.

02:30:00.760 | I know.

02:30:01.600 | I don't know how to moderate anything,

02:30:05.160 | but even fruit, apples and cherries is a nightmare.

02:30:10.160 | Anyway, that's such a psychiatrist thing to say.

02:30:14.360 | Very interesting.

02:30:16.200 | But there's characteristics,

02:30:19.640 | and it's interesting to think about,

02:30:23.520 | like for example, I have trouble making eye contact,

02:30:26.520 | but actually, as you said it now,

02:30:29.000 | it's not that I'm shy at all in that sense.

02:30:34.000 | It's literally, I'm getting way too much information,

02:30:38.520 | it's distracting me.

02:30:40.160 | Like I need to just close my eyes so I can,

02:30:43.800 | like all the things that people seem to be able to do

02:30:46.560 | in parallel, it's just, you just asked me a question,

02:30:51.000 | for me to think about the answer to that question,

02:30:53.280 | I can't have all this cool, rich,

02:30:55.120 | visual information coming my way.

02:30:57.160 | That's literally, 'cause I often close my eyes to think,

02:31:01.000 | it's not because I'm afraid of something, whatever,

02:31:04.040 | it's just like too much information happening here.

02:31:06.960 | - Well, that's a beautiful description.

02:31:08.960 | It's amazing that that is how you experience

02:31:12.280 | the eye contact aspect.

02:31:15.640 | I think that's, I mean, you've articulated what,

02:31:18.780 | captures it for so many people,

02:31:22.600 | which is that it's overwhelming.

02:31:23.720 | There's just too much information

02:31:25.440 | just coming in through the eyes.

02:31:27.680 | And to keep up with it, to know you're gonna be expected

02:31:32.560 | to keep up with it, first of all, so there's that aspect.

02:31:35.140 | You know, you learned socially

02:31:37.200 | that there's gonna be an expectation.

02:31:38.900 | If you're making eye contact,

02:31:40.740 | people are gonna think you're keeping up with it,

02:31:42.720 | and you don't want to,

02:31:44.720 | 'cause you wanna focus on other things

02:31:46.320 | and make progress in other dimensions.

02:31:50.200 | Yeah, and so then there's a strong desire to look away

02:31:52.800 | or to close the eyes because it's overwhelming,

02:31:56.960 | it's a distraction, and it's gonna cause errors

02:31:59.240 | of understanding.

02:32:00.200 | - And of course, our eyes, that's part,

02:32:02.000 | the way we use our eyes is part of the human communication,

02:32:04.520 | so you have to kind of be aware of that element of it.

02:32:10.560 | So yeah, I mean, but it's fascinating.

02:32:12.140 | You should be aware of your own self

02:32:13.900 | and those little characteristics,

02:32:16.160 | whether it's classified on some aspect

02:32:19.540 | of the autism spectrum or just in general,

02:32:22.820 | whether it's eating, whether it's depression,

02:32:26.180 | whether it's even like schizophrenia,

02:32:29.140 | that I hope we get a chance to talk to a little bit.

02:32:32.940 | Yeah, but those things are all made up

02:32:35.400 | of different symptoms and characteristics,

02:32:40.060 | and use them as a superpower, I suppose,

02:32:43.380 | is the best we can hope for in mild cases, I guess.

02:32:47.900 | - I do think both brain states can't coexist

02:32:50.300 | at the same time.

02:32:51.140 | The way of dealing with something unpredictable

02:32:52.820 | and dealing with something predictable,

02:32:55.140 | those are different ways of being.

02:32:56.500 | Here's a huge opportunity for very creative model building

02:33:01.500 | in theoretical neuroscience and linking that

02:33:05.460 | to these data streams we're getting across the brain

02:33:09.460 | that we talked about earlier,

02:33:11.020 | these immense data sets of activity across the brain.

02:33:13.620 | Here's where I think there could be a real convergence

02:33:18.220 | of theoreticians and experimentalists to say,

02:33:20.140 | okay, given what we know about wiring of the brain,

02:33:23.040 | here is what the brain state is likely to be

02:33:27.860 | that deals well with unpredictable information,

02:33:30.940 | and here's the brain state

02:33:31.820 | that deals with predictable information.

02:33:33.860 | Here's why they're incompatible, at least at the same time.

02:33:36.540 | Here's why you've gotta be able to detect

02:33:39.100 | which state you should be in.

02:33:40.140 | Here's how you could switch between them.

02:33:42.300 | Here's the kind of cells that you would predict,

02:33:44.700 | almost like predicting the Higgs boson.

02:33:46.540 | Here's the kind of circuitry that I would predict

02:33:49.540 | should govern the switching

02:33:51.820 | or might make one state too sticky,

02:33:55.340 | too hard to get out of.

02:33:56.460 | That is a huge opportunity for an interaction

02:34:01.120 | from the theoretical and experimental side together.

02:34:04.300 | - Make one state too sticky.

02:34:07.940 | The sort of measure the stickiness of the state

02:34:12.620 | and how to lessen the stickiness.

02:34:15.020 | Get some oil in the machine.

02:34:16.540 | - Yes, yeah, what would,

02:34:17.940 | predict the kind of oil that would work well.

02:34:20.440 | - What in your practice is treatment or advice

02:34:27.300 | for people on the autism spectrum?

02:34:31.380 | - So right now there's no real medical treatment.

02:34:34.460 | There are behavioral treatments

02:34:36.580 | that are most effective early in life.

02:34:38.860 | They make sure people don't fall too far behind.

02:34:42.140 | If you're not interacting socially,

02:34:43.740 | you create this vicious cycle

02:34:46.900 | where you fall farther and farther behind

02:34:48.580 | because you're not interacting.

02:34:49.700 | And these therapies which are applied early in life,

02:34:52.680 | therapists work with the kids,

02:34:54.380 | train them to deal with these things

02:34:57.860 | that otherwise would be aversive to them,

02:34:59.860 | teach them how to predict things and interact.

02:35:02.660 | And that has a big effect.

02:35:04.820 | But it's behavioral therapy.

02:35:06.820 | There's no medicine that works.

02:35:08.820 | There are ways of reducing individual symptoms though

02:35:12.020 | that sometimes come along with autism

02:35:13.980 | and those do respond to medications.

02:35:15.700 | So you can, you know, one thing,

02:35:17.820 | very often my patients with autism are very anxious

02:35:21.380 | 'cause they live in a world

02:35:23.820 | that they have a really hard time

02:35:25.500 | predicting what's gonna happen.

02:35:26.500 | And so they find, and some of these are high functioning,

02:35:29.180 | you know, Silicon Valley types who, you know,

02:35:31.500 | they may make, you know, great livings

02:35:33.860 | but they're very unhappy because they're on the spectrum.

02:35:37.220 | They don't understand how social interactions really work.

02:35:43.140 | They're very anxiety provoking

02:35:46.220 | 'cause they don't know what to say.

02:35:47.220 | They don't have any clue

02:35:48.380 | how anybody else knows what to say.

02:35:50.940 | They're constantly worried they're gonna say something

02:35:52.740 | that's completely inappropriate.

02:35:54.580 | And so they're very anxious.

02:35:55.600 | And I can treat their anxiety.

02:35:57.460 | It doesn't touch the autism per se

02:35:59.700 | but I can help them with their anxiety.

02:36:02.500 | What I just talked about, eye contact.

02:36:05.220 | I am richly, even with the eyes closed

02:36:08.260 | and all those kinds of things,

02:36:09.340 | I'm richly experiencing the world.

02:36:12.220 | And it's not like you're afraid of the world

02:36:14.420 | or you're not able, I don't know what to do.

02:36:16.060 | No, I know everything.

02:36:17.420 | In fact, I know way too much.

02:36:19.120 | There's so many cool options.

02:36:20.820 | Like at any one moment, there's all this stuff happening

02:36:24.540 | and it's all beautiful.

02:36:26.180 | And at any one moment, you can do anything you want.

02:36:28.660 | You can take off your clothes.

02:36:29.800 | You can punch that guy over there.

02:36:31.740 | You can run away.

02:36:33.820 | You can go in for a hug.

02:36:35.840 | You can say something profound and deep

02:36:38.380 | or you can say something generic

02:36:40.000 | or you could do so many things you can say.

02:36:42.260 | And then it'll go, it'll unravel in all these kinds of ways

02:36:46.380 | and this moment could be completely life-changing

02:36:48.900 | or it can be mundane and meaningless.

02:36:51.300 | And all of those options are before you at any one moment.

02:36:54.520 | (laughing)

02:36:55.820 | And so it's like-- - Isn't that amazing?

02:36:57.780 | - It's amazing and overwhelming

02:36:59.820 | if you allow yourself to think about it.

02:37:02.100 | Which-- - It's like chess.

02:37:03.780 | - Whatever, exactly.

02:37:05.180 | Well, unfortunately, with chess, you have a few set options.

02:37:08.460 | - Two-dimensional. - Two-dimensional constraints.

02:37:11.860 | There is unlimited possibilities

02:37:15.140 | and unlimited beautiful things happening all around you.

02:37:18.420 | So I don't think there's a kind of sense

02:37:20.520 | that somehow you're limited in the places of,

02:37:28.140 | in the way you can see the world

02:37:29.820 | and how you can interact with that world.

02:37:31.840 | I am overwhelmed by the lack of limit

02:37:35.300 | that all of us should be.

02:37:37.540 | Have you looked around?

02:37:38.540 | You can do whatever the hell you want.

02:37:40.180 | Nobody will remember you anyway.

02:37:42.180 | All of us will be dead one day.

02:37:44.100 | You could do anything.

02:37:45.820 | You can, I don't know.

02:37:48.620 | You can get naked and run around the city

02:37:50.900 | as long as you're not hurting anybody

02:37:52.700 | and it doesn't matter.

02:37:54.580 | - So it's Austin anyway. - Austin, yeah.

02:37:57.380 | - Vagabond, exactly.

02:37:59.060 | Seems like a to-do item

02:38:01.780 | for anybody living in Austin for sure.

02:38:04.540 | But the spectrum is an interesting concept

02:38:07.220 | because that is, when I say,

02:38:10.420 | when I refer to the spectrum,

02:38:12.460 | I'm actually referring to, it's a precise clinical term,

02:38:15.320 | but you're right, it's been co-opted more broadly

02:38:17.900 | and it is widely used

02:38:19.100 | and it can be an unfair categorization

02:38:22.140 | of someone who's socially and occupationally very healthy.

02:38:25.860 | And that is critical

02:38:28.140 | because we don't define a disorder

02:38:32.260 | unless there's social or occupational dysfunction.

02:38:34.740 | It doesn't matter what the symptoms are.

02:38:36.800 | I've had patients who are pleasantly hallucinating,

02:38:39.740 | so frankly, psychotic, but doesn't affect their lives.

02:38:43.140 | So I don't give that person a diagnosis

02:38:46.380 | because there's not social or occupational dysfunction.

02:38:49.960 | Same with anything on this,

02:38:53.660 | any of the diverse symptoms of autism spectrum disorder.

02:38:57.320 | If someone has them,

02:38:59.980 | but they're successful socially and occupationally,

02:39:03.140 | we don't say that there's a disorder.

02:39:05.620 | But then you're right,

02:39:06.460 | that the concept of the spectrum does become a useful,

02:39:09.700 | you know, pigeonholing device,

02:39:12.720 | which is maybe not the best thing.

02:39:14.840 | - Yeah, and eye contact is an interesting one.

02:39:20.020 | Is an interesting one.

02:39:21.220 | I'm torn on it.

02:39:23.260 | I'm torn about the usefulness of eye contact

02:39:25.900 | 'cause people kind of make fun of it.

02:39:27.460 | But let me just say one thing about eye contact

02:39:31.660 | and about life in general.

02:39:33.180 | It's okay to be weird.

02:39:34.720 | But like some people,

02:39:38.140 | when you have your eyes closed and there's that weird,

02:39:40.260 | what is happening to this creature?

02:39:41.760 | Like you see a weird creature on the side of the road.

02:39:44.860 | It's interesting.

02:39:46.340 | And you wanna, I mean, the weird stuff,

02:39:49.120 | I'm gonna go back to Robin Williams with the,

02:39:51.560 | that's the good stuff, right?

02:39:53.780 | He has that whole speech about him and his wife

02:39:56.380 | and what he loves all the little peculiarities,

02:39:59.300 | all the weird stuff and that,

02:40:00.780 | like let those flourish.

02:40:04.220 | Let those like celebrate those in yourself

02:40:06.420 | and not in some kind of woke way,

02:40:08.580 | but in some like very human way.

02:40:10.940 | This is what makes us, this is the weirdness.

02:40:13.060 | - Yeah, I'm 100% on board with that.

02:40:17.060 | And I don't think, you know,

02:40:19.780 | people who are happy and who have people in their lives

02:40:24.780 | who are happy with them,

02:40:27.120 | these are, I think, let the weirdness flourish.

02:40:30.440 | Let the, all the different ways

02:40:33.280 | members of the human family can be different.

02:40:35.200 | Let's see them all.

02:40:36.100 | That's one of our,

02:40:37.480 | that's one of the joys of being alive

02:40:38.800 | is seeing all the ways we can be human.

02:40:41.120 | And I think about it all the time.

02:40:43.920 | Why do we have all these ways of being human?

02:40:47.980 | And even within one individual,

02:40:52.980 | you go through phases of life

02:40:54.180 | where you express different sides of your way of being,

02:40:57.140 | which is also a pretty fun opportunity, right?

02:40:59.240 | You can go through phases where you're in one mode

02:41:02.820 | and phases when you're in another mode.

02:41:05.260 | And let that, you know, just let that flourish too.

02:41:09.700 | Let the ways that you can be you vary as well.

02:41:13.340 | I think that's important for people to explore.

02:41:15.740 | - And I should, like, as if you can address the internet,

02:41:19.900 | but I would like to sort of ask the internet

02:41:25.340 | to celebrate the weirdness of people.

02:41:31.420 | Like that's, it's the Robin Williams,

02:41:35.680 | people call these imperfections, but they're not.

02:41:39.780 | That's the good stuff.

02:41:40.820 | For any one individual person,

02:41:43.820 | find the weird stuff and celebrate it

02:41:47.700 | as opposed to what the internet often does,

02:41:50.500 | which is find the weird stuff and criticize it.

02:41:55.020 | Because when you criticize the weird stuff,

02:41:57.580 | you're creating conformity, which is another human thing.

02:42:01.700 | But that conformity creates a boring world.

02:42:05.700 | You want the weird.

02:42:09.660 | You want the crazy.

02:42:10.780 | That's what fun is made of.

02:42:12.500 | That's the foundation of humor

02:42:16.220 | and all the ways in which we deal

02:42:19.020 | with the suffering in the world,

02:42:21.620 | with the injustices in the world,

02:42:23.500 | is like this like huge variety of weird.

02:42:28.300 | Yeah, I don't know.

02:42:32.620 | And that's what at the depth of psychiatry is like,

02:42:35.680 | you wanna acknowledge the weird, celebrate the weird,

02:42:40.360 | like step around it to find the particular aspects

02:42:44.360 | of weird that are debilitating, like you said.

02:42:47.240 | They're somehow negatively affecting your ability

02:42:49.600 | to function in the world,

02:42:51.040 | as opposed to trying to shut it all down.

02:42:54.640 | - That's right.

02:42:55.480 | - Well, on that topic, I mean,

02:42:58.400 | I'd love to talk to you about schizophrenia.

02:43:00.640 | What is schizophrenia?

02:43:04.880 | From your research and from your general understanding,

02:43:07.600 | and what is the full landscape of suffering

02:43:10.680 | and wisdom that schizophrenia explores?

02:43:14.980 | - Schizophrenia is a state

02:43:18.400 | where there is a break from reality.

02:43:22.240 | And so this can show up as we call them

02:43:25.000 | the positive symptoms of schizophrenia.

02:43:27.660 | These include hallucinations,

02:43:29.720 | hearing something or seeing something that's not there,

02:43:32.000 | usually auditory hallucinations.

02:43:34.640 | Paranoia, people can have complex fears,

02:43:38.440 | delusions, which we call fixed false beliefs.

02:43:41.160 | People get an extremely unshakable,

02:43:43.360 | but completely implausible idea about something.

02:43:46.560 | Sometimes it relates to themself, sometimes to the world.

02:43:49.840 | These we call the positive symptoms,

02:43:51.480 | break from reality as we know it.

02:43:53.220 | Then there are the negative symptoms that come with it.

02:43:56.980 | And these are progressive.

02:43:59.800 | These are flattening of emotion as we call it.

02:44:04.460 | So starting to express less and less positive emotion,

02:44:07.520 | ending more in a neutral or flat state.

02:44:12.040 | Thought disorder, inability to work with complex patterns

02:44:16.520 | of planning or thinking.

02:44:18.040 | So you can't make plans, you'd have poor working memory,

02:44:21.200 | you can't keep track of where you were in a conversation,

02:44:25.420 | in a sequence of actions.

02:44:26.900 | So poor and impaired,

02:44:31.960 | working with the thoughts of oneself

02:44:34.620 | and then these positive symptoms of break from reality.

02:44:37.980 | Okay, now why do these come together?

02:44:41.080 | What's the neurobiology of it?

02:44:44.060 | Again, we don't know.

02:44:45.380 | Schizophrenia, extremely genetically determined.

02:44:48.020 | If you look at the numbers,

02:44:48.860 | could be upwards of 80% genetically determined.

02:44:51.920 | 1% of the human population around the world,

02:44:57.220 | it's universal, okay?

02:44:58.820 | It's not confined to any one culture,

02:45:00.860 | not even really biased in one culture or another,

02:45:04.620 | about 1% around the world.

02:45:06.160 | And has this progressive quality to it, untreated.

02:45:12.340 | So it's very interesting.

02:45:13.500 | There's a break that happens, we call it first break.

02:45:17.020 | When someone experiences their first disruption of reality,

02:45:22.020 | they can have a completely typical life up until that point.

02:45:25.100 | So you might have a, and I've seen,

02:45:27.140 | just heartbreaking cases of like this,

02:45:29.100 | like this in the Stanford emergency room

02:45:31.540 | where a kid who's come there,

02:45:33.100 | who's been extremely high functioning

02:45:36.960 | in that sense of academic achievement

02:45:39.140 | and athletic and interpersonal,

02:45:41.700 | and then comes to college.

02:45:43.300 | Usually in men, it's around 18, 19,

02:45:46.860 | when the first break happens.

02:45:48.300 | Some terrifying paranoia hits

02:45:52.500 | or some auditory hallucinations start.

02:45:55.260 | They're getting screamed at by a voice in their head.

02:45:57.760 | So devastating.

02:45:59.520 | With women, comes on also often a little later,

02:46:02.780 | sometimes in the 20s.

02:46:03.960 | And it can be progressive.

02:46:06.120 | If it's not treated, it just progresses and progresses.

02:46:09.620 | The voices become overwhelming.

02:46:12.900 | The delusions and paranoia extend and expand.

02:46:16.740 | The thought, the negative symptoms particularly

02:46:18.360 | become more and more severe.

02:46:20.360 | So one can't even maintain thoughts

02:46:23.120 | in any sort of ordered fashion.

02:46:26.340 | And then eventually, it can be fatal,

02:46:30.040 | it can lead to suicide,

02:46:31.440 | it can lead to erratic behavior that leads to accidents.

02:46:35.480 | Now, it can be treated.

02:46:38.880 | There are medications that help, fortunately.

02:46:42.240 | They have side effects, so they're not perfect.

02:46:44.080 | You can have movement problems

02:46:46.300 | and actually a whole host of different side effects

02:46:50.520 | that come from the medications.

02:46:51.640 | But we can help people now with schizophrenia

02:46:55.200 | very, very significantly.

02:46:56.620 | But the amazing thing,

02:46:59.420 | and this is emblematic of where psychiatry stands,

02:47:02.380 | we don't have the deep understanding,

02:47:04.480 | just like with depression,

02:47:05.780 | we don't have that heart as a pump level of understanding

02:47:09.640 | that we'd like to have with schizophrenia,

02:47:11.480 | despite it being so biological, so genetic in its nature.

02:47:15.380 | - So is there a way once,

02:47:17.740 | a way to return to the other side of the first break?

02:47:22.380 | So when you have a break with reality,

02:47:24.060 | is there a way to kinda stitch it together?

02:47:26.940 | - Yeah, so some people, that works.

02:47:29.500 | But we don't really know how.

02:47:32.380 | So medications, antipsychotic medications, we call them,

02:47:36.100 | they block a particular neurotransmitter receptor

02:47:39.220 | called the serotonin 2A receptor,

02:47:44.220 | and they modulate dopamine as well

02:47:46.460 | and other neurotransmitters.

02:47:48.280 | These can take someone who's actively hallucinating,

02:47:53.700 | actively paranoid,

02:47:55.140 | put them back in a completely normal state,

02:47:57.140 | and some people stay that way indefinitely.

02:48:01.260 | So you can bring people back from that,

02:48:04.220 | back to the other side, have it stitched together.

02:48:07.220 | More typically, you'll end up in some intermediate state

02:48:11.900 | where symptoms are reduced powerfully,

02:48:15.420 | but there might be still something there

02:48:16.940 | and you've got a drop down in functioning

02:48:19.460 | that may be persistent for a while.

02:48:21.980 | But concepts, what physically is going on?

02:48:26.020 | One idea is that it's communication within the brain.

02:48:31.020 | One part of the brain is not able to tell

02:48:34.740 | other parts of the brain what it's doing.

02:48:36.340 | And so the auditory hallucinations

02:48:37.980 | are very interesting in this regard.

02:48:40.200 | They often have this conversational

02:48:42.060 | inner monologue-like quality.

02:48:44.220 | As we're walking along the street,

02:48:45.400 | we may have an inner monologue,

02:48:47.140 | thoughts about what's going on.

02:48:49.160 | If we see somebody we don't like,

02:48:50.640 | we may have a thought of,

02:48:52.020 | wish somebody would punch that guy, something like that,

02:48:54.100 | or maybe I should punch that guy.

02:48:55.260 | But these are so far below where we would ever act

02:48:59.900 | or even think of acting,

02:49:02.340 | but they're just things that come up.

02:49:04.380 | And in people with schizophrenia,

02:49:05.980 | those inner thoughts, that inner monologue

02:49:09.940 | is not recognized as the inner monologue of the self.

02:49:14.940 | And so it's perceived as something coming from the outside.

02:49:20.840 | - Or from inside, but from another entity.

02:49:23.400 | - Another, oh, another entity.

02:49:25.080 | I thought you meant like another room

02:49:27.760 | inside the same building.

02:49:29.200 | - Another room in the--

02:49:30.040 | - Inside there, yeah.

02:49:31.840 | - And so that's, so it could be conceptualized

02:49:35.280 | as a communication within the brain problem,

02:49:38.320 | notifying another part of the brain what's going on.

02:49:40.880 | And there's some evidence consistent with that.

02:49:43.360 | - I don't know if you can help with this,

02:49:45.760 | but I sometimes, 'cause I've been talking

02:49:48.320 | to quite a few homeless folks recently,

02:49:50.260 | just, that's what I do is I hang out at night

02:49:54.100 | and talk to interesting people.

02:49:59.780 | And some of them, and I've known people in the past

02:50:02.540 | who suffer from schizophrenia,

02:50:03.900 | and some of them, like self, will describe

02:50:07.020 | that as something they suffer from.

02:50:11.340 | And they seem to understand something deeply

02:50:14.380 | about this world.

02:50:15.920 | I don't know if it's correlated,

02:50:17.960 | or maybe it's another aspect of depression,

02:50:22.960 | all those things that I've encountered in my own life,

02:50:27.720 | is maybe just the struggle and the suffering

02:50:31.600 | has taken you through a life

02:50:33.200 | where you think deeply about life.

02:50:35.600 | There's self-reflection that society forces on you

02:50:39.720 | because it's a disorder of some kind.

02:50:43.340 | - It's interesting.

02:50:45.080 | I guess my only sort of anecdotal observation

02:50:47.480 | is people who suffer from schizophrenia

02:50:49.720 | seem to be very interesting and very thoughtful

02:50:55.920 | in a nonlinear way about the world.

02:50:58.340 | - I've noticed that it's not always positive,

02:51:02.960 | the unusual ways they view the world.

02:51:06.600 | But it's always interesting.

02:51:10.000 | - That could be conspiratorial thinking, too.

02:51:13.040 | - But the theories they have

02:51:15.020 | about the way the world functions,

02:51:17.080 | often very well read, which is also interesting,

02:51:20.460 | because they're almost like looking for helpful answers

02:51:22.720 | from somewhere. - Yes, they are.

02:51:23.640 | Absolutely, they are.

02:51:24.520 | - And so they might be citing

02:51:26.440 | some very interesting literature,

02:51:27.920 | and then using that to,

02:51:29.480 | there's a stickiness in their mind

02:51:33.440 | to different models of the world

02:51:34.800 | and trying to make sense of that world.

02:51:36.640 | And those models could include conspiracy theories.

02:51:39.120 | - Yeah.

02:51:40.160 | They're very attuned to complexity,

02:51:42.400 | and they come up with unlikely explanations,

02:51:44.940 | which is one of the things that makes them,

02:51:48.440 | it makes it hard for them to function in the world

02:51:50.520 | is how unlikely their explanations are.

02:51:52.720 | But you're right, there's a depth of consideration

02:51:55.800 | of the complexity of the world,

02:51:58.080 | and a concern about it,

02:51:59.600 | and an impulse to work to understand it

02:52:04.640 | that is actually quite refreshing.

02:52:07.080 | But the first case in the medical literature,

02:52:11.140 | there was a classical schizophrenia.

02:52:15.300 | There was a patient named James Tilly Matthews,

02:52:17.900 | who had this, he sketched out for his doctor

02:52:22.380 | the experiences he was sensing.

02:52:26.580 | And he drew himself as a cowering figure on the ground,

02:52:31.580 | controlled by a loom, a weaving device

02:52:35.540 | that was sending threads, long threads, projections,

02:52:39.720 | across space from the loom to him,

02:52:41.980 | to his arms and to his body,

02:52:44.100 | and controlling him from afar.

02:52:46.780 | And he called this the air loom, a loom in the air.

02:52:51.740 | And it was such an evocative thing

02:52:54.200 | because this was the start of the Industrial Revolution,

02:52:56.640 | or mid, and it was where really industrial strength,

02:53:01.300 | looms and weaving devices were really

02:53:04.060 | kind of the emblematic of the most complex,

02:53:08.660 | powerful technological achievements of the time.

02:53:10.860 | And so that was the explanation available to him

02:53:14.100 | to explain how his body was seemingly moved

02:53:18.060 | without his volition.

02:53:19.380 | And these days, of course, people with schizophrenia

02:53:22.900 | will have more technology-appropriate interpretations.

02:53:26.340 | They'll have delusions of satellite or alien control

02:53:30.940 | or beamed information, very, very common

02:53:34.140 | to have this delusion of a government agency

02:53:38.180 | sending electromagnetic or radio frequency information

02:53:41.620 | to control their limbs.

02:53:43.400 | But it's the same thing, whether it's a thread

02:53:45.800 | from an Industrial Revolution loom,

02:53:48.300 | or RF radiation, it's the same thing,

02:53:52.860 | just adapted to the moment, explaining,

02:53:55.380 | trying to explain the world they live in

02:53:57.220 | and their relationship to the world.

02:53:58.540 | - But unconstrained by sort of the thing

02:54:01.180 | that's socially acceptable,

02:54:02.780 | which is both refreshing and dangerous.

02:54:05.300 | - Yes.

02:54:06.980 | (sighs)

02:54:08.660 | I wrote down a question.

02:54:10.900 | Why do we cry?

02:54:12.000 | Are tears a window to some depths

02:54:15.200 | that we ourselves don't know?

02:54:16.660 | I almost wanna make fun of myself for that question,

02:54:19.620 | but you do talk seriously about crying in the book.

02:54:22.620 | - In fact, the whole first chapter really,

02:54:25.060 | really tussles with crying as a,

02:54:27.860 | why do we do it, what does it mean,

02:54:29.260 | why is it involuntary?

02:54:30.980 | It seems like a weakness, right?

02:54:32.300 | It's because it's so involuntary,

02:54:34.220 | and it's reflecting something true and inside.

02:54:36.740 | At the level of the individual,

02:54:39.140 | that seems like a problem, right?

02:54:40.500 | Wouldn't it be better if we could control it,

02:54:42.600 | if we could not show that emotion

02:54:46.980 | when it's not useful, show it when it's useful?

02:54:49.500 | But it's not, it's largely involuntary.

02:54:51.820 | And so there's a value to it, I think,

02:54:55.560 | as an honest reporter of a need,

02:54:58.700 | of hope and frailty at the same time.

02:55:03.540 | I'm a human being, there's a frailty to myself

02:55:08.540 | or my situation where I need social help,

02:55:12.340 | I need help from my community.

02:55:14.740 | I have hope that that is possible,

02:55:16.800 | but I'm not enough for myself, I need the community.

02:55:21.580 | That, I think, is what the social signal of crying is.

02:55:25.460 | Now, people have studied crying.

02:55:27.060 | It's an extreme, you can quantify the extent

02:55:31.860 | to which the presence of tears on a face

02:55:34.860 | triggers reactions in onlookers.

02:55:37.940 | And you can show the same face

02:55:40.460 | in the presence or absence of tears,

02:55:42.460 | and show that to people under quantifiable

02:55:45.540 | and rigorous psychological conditions.

02:55:49.380 | And tears are much more powerful

02:55:52.260 | at stirring the desire to help in viewers

02:55:57.060 | than any other facial feature,

02:56:01.140 | which is pretty interesting that it's the honest one

02:56:04.060 | that's also the most powerful, right?

02:56:05.680 | It kind of indicates there's a certain logic to our design

02:56:08.780 | as social beings that we have an honest report.

02:56:14.580 | - That's hard to control.

02:56:17.180 | But is it well understood how that connects

02:56:21.580 | to the internal state of emotion?

02:56:26.380 | - Yeah, there are long-range projections that come.

02:56:30.520 | So where is crying generated?

02:56:31.860 | This is the confusing thing about it.

02:56:33.260 | So we have a little tear duct, the lacrimal gland,

02:56:36.640 | that leads to the release of fluid, it ejects fluid,

02:56:38.860 | and it comes out, and those, of course,

02:56:42.160 | that whole system was designed to keep the eye clean,

02:56:44.660 | to wash out particulate irritants.

02:56:47.060 | So it's a longstanding, as long as we've had eyes

02:56:49.800 | and have been out of the water in our evolution,

02:56:52.860 | we've needed this sort of thing.

02:56:53.980 | So longstanding biological structure,

02:56:56.160 | recently co-opted, it seems, by our evolution

02:57:00.000 | as social primates.

02:57:02.060 | Now, how could that happen?

02:57:03.900 | Well, the lacrimal gland is controlled by structures

02:57:07.580 | in the pons, which is a structure deep in our,

02:57:10.320 | just above our neck, between our neck and our head,

02:57:14.140 | and reflecting its ancient origin, right?

02:57:16.800 | As you go farther down toward the spinal cord,

02:57:18.620 | these are the more basic, early evolved structures.

02:57:21.860 | And in the pons, that's where breathing is controlled,

02:57:25.300 | tear, duct contraction.

02:57:30.300 | And what we found, and with optogenetics,

02:57:34.040 | we helped sort this out, there are long-range projections

02:57:36.800 | from fear and anxiety regions in the forebrain

02:57:41.000 | that project all the way to the pons,

02:57:43.400 | in and around those areas.

02:57:45.400 | The reason those are there, we think,

02:57:47.720 | is to regulate the respiratory rate changes,

02:57:50.760 | the breathing changes of fear and anxiety.

02:57:53.000 | So we know when we're in a state of fear and anxiety,

02:57:55.740 | we need, we cope better if we have elevated heart rate,

02:57:58.860 | elevated respiratory rate, more blood pumping around,

02:58:01.500 | more oxygenated blood, we're ready to meet the threat

02:58:03.700 | if it happens.

02:58:05.060 | All those cells are down there in the pons too,

02:58:07.540 | right next to the lacrimal duct, the tear gland neurons.

02:58:12.540 | And so, almost certainly, this fear-anxiety-induced crying

02:58:19.700 | arose from a very slightly misdirected

02:58:22.520 | long-range projection that was there to regulate breathing.

02:58:27.520 | And a little twist, just a little misdirection,

02:58:29.800 | a little missing of one sign post to stop here,

02:58:33.640 | going on a little farther, getting to the lacrimal gland

02:58:36.800 | neurons gave us crying.

02:58:38.880 | - And that's, and we just have it,

02:58:40.400 | that peculiar sort of structure, neuronal structure

02:58:43.680 | that resulted in that, that's what we're stuck with.

02:58:46.640 | And that ends up being, in terms of social interaction,

02:58:49.980 | one of the more important authentic involuntary displays

02:58:54.980 | of inner state.

02:58:57.020 | - That's right.

02:58:57.860 | - And social communication.

02:58:58.980 | - Yeah.

02:58:59.820 | (laughing)

02:59:00.640 | - Oh, yeah.

02:59:02.420 | Is there other stuff like that?

02:59:03.980 | I mean, do you, yeah, I mean, the human face

02:59:07.380 | is fascinating as a display of emotion,

02:59:09.660 | as a display of truth and lying

02:59:12.300 | and all those kinds of things.

02:59:13.900 | I personally, I mean, we're all, I suppose,

02:59:18.900 | have different sensors that are sensitive

02:59:24.160 | to certain aspects of the human face,

02:59:25.760 | but to me, it seems like the eyes

02:59:28.360 | are really important communication or something.

02:59:31.280 | You know, I've talked to a few sort of girls

02:59:33.160 | about like Botox and stuff like that,

02:59:35.320 | and it always bothers me when,

02:59:37.600 | I guess guys could do this too,

02:59:38.800 | but like when women speak negatively

02:59:43.440 | of, I guess you can call them wrinkles

02:59:46.300 | at the tips of an eye, but like to me,

02:59:50.780 | when you smile, when you, not wink,

02:59:55.180 | but like narrow the eyes, something is communicated,

02:59:59.300 | and that stuff is really useful, the human face.

03:00:03.100 | And when it's gone, something is missing.

03:00:05.500 | And a lot of little stuff, it feels like can really,

03:00:08.540 | it's almost involuntary, I guess,

03:00:10.660 | but it's harder to describe as the presence

03:00:12.860 | or absence of tears.

03:00:13.900 | It's like something about this person,

03:00:16.600 | you can tell they're not bullshitting you.

03:00:18.820 | - Yeah, yeah.

03:00:19.660 | And so that was what made, presumably,

03:00:21.940 | that tear recruitment so powerful,

03:00:24.860 | is it just landed in this very high-value real estate

03:00:28.420 | for social communication.

03:00:29.780 | If it had gone to, you know, there's a lot of neurons

03:00:33.020 | in the pons that control movement of large muscles,

03:00:38.020 | elsewhere, that would have been much less effective

03:00:41.620 | as a social signal than something around the eye.

03:00:43.460 | So it was, however that little misdirection happened,

03:00:46.820 | it landed in a great area for social communication.

03:00:50.420 | And because it was coming from the fear and anxiety circuits

03:00:53.420 | that regulate that necessary involuntary change

03:00:57.020 | in heart rate and respiratory rate,

03:00:59.660 | it also was involuntary, and that became valuable

03:01:02.460 | as a truth signal as social beings.

03:01:05.900 | So very interesting when you think about the origins

03:01:08.940 | of the human family, origins of social structures

03:01:12.500 | and our ability and need to call for help

03:01:14.940 | when there's hope, but need at the same time.

03:01:18.100 | - What is consciousness, Carl?

03:01:23.100 | So you're actually using techniques,

03:01:26.580 | I mean, even putting psychiatry aside,

03:01:28.420 | just looking at optogenetics,

03:01:31.820 | you're trying to understand some of these deep aspects

03:01:34.460 | of the human mind.

03:01:36.100 | And maybe this is a good time to return to a question

03:01:38.420 | you mentioned you might have an opinion on,

03:01:41.220 | if there's such a thing as a theory of everything

03:01:43.300 | for the human mind.

03:01:44.980 | Because surely answering of what is consciousness

03:01:47.820 | is as, well, that's not sure.

03:01:50.980 | But it seems like it's a fundamental part

03:01:53.540 | of the human experience in the human mind

03:01:56.220 | and solving that question will result in solving

03:02:00.740 | the bigger thing about the human mind.

03:02:02.660 | The flip side could be consciousness

03:02:05.020 | is just the few neurons that are generating

03:02:07.700 | some useful thing that make us,

03:02:10.100 | it's like the sense of self that you talked about

03:02:14.220 | in the mice, maybe it's a subset of those cells

03:02:18.660 | that are just creating a richer sense of self,

03:02:21.140 | and that's it.

03:02:21.980 | - So this is a great question.

03:02:26.260 | All neuroscientists think about this

03:02:28.100 | and a lot of non-neuroscientists too.

03:02:29.860 | It's such a, it's the reason a lot of people

03:02:32.900 | came to the study of the brain,

03:02:34.540 | is to think about consciousness.

03:02:36.100 | And not just being awake or alert,

03:02:38.380 | but really what's sometimes called

03:02:40.500 | the hard problem of consciousness,

03:02:42.260 | which is what is that nature of that

03:02:45.260 | inner subjective sense we have?

03:02:47.820 | Not just information processing,

03:02:50.180 | but feeling something about the information.

03:02:54.380 | What is that inner state of subjectivity physically?

03:02:59.140 | What is it?

03:02:59.980 | And that's called the hard problem of consciousness.

03:03:03.380 | And it's not a extremely well-defined question.

03:03:08.380 | Everybody has sort of a sense of what it means,

03:03:11.380 | but it's such a hard problem

03:03:14.260 | because you run into paradoxes quite quickly

03:03:17.180 | the more you think about it.

03:03:18.500 | And that is exciting also,

03:03:21.860 | because it makes us think,

03:03:23.380 | actually there's some fundamental,

03:03:25.140 | there's a big thing that we're missing.

03:03:28.180 | The brain is not just a collection of little tricks.

03:03:30.940 | There is a big, big concept.

03:03:32.820 | - So that's your sense of the big,

03:03:34.020 | 'cause a flip side could be with optogenetics.

03:03:37.780 | There's an engineering question.

03:03:40.340 | Can you turn consciousness on and off,

03:03:43.060 | like a light switch?

03:03:43.940 | - Okay, so here's where exactly consciousness

03:03:47.220 | frames the problem extremely well.

03:03:48.940 | And it frames it the following way.

03:03:50.620 | So I told you earlier that we can

03:03:54.100 | stimulate 20 or 25 cells in the visual cortex of a mouse,

03:03:59.100 | and we can make it behave,

03:04:01.820 | and we can make its brain act

03:04:03.500 | as if it's seeing something that isn't there.

03:04:06.060 | We have that level of control now.

03:04:07.260 | We can pick out 25 neurons, play an activity,

03:04:10.940 | and both behavior and in the brain,

03:04:13.080 | it's as if it's seeing something specific.

03:04:16.140 | Okay, now let's do a thought experiment,

03:04:18.620 | you know, a Gedanken experiment,

03:04:20.600 | and let's play this out.

03:04:21.860 | Let's say we could do the same thing

03:04:24.380 | for every single neuron in the brain of a human being.

03:04:27.860 | Let's say we had total control,

03:04:30.100 | and I could do something like,

03:04:31.540 | I could show you a rich, deep color red,

03:04:34.820 | and you could look at it,

03:04:35.740 | and you would be aware that it's red,

03:04:36.980 | but also you might have some feelings about it.

03:04:39.300 | Something would be stirred in you,

03:04:40.320 | some subjective sense as you looked at that rich color red.

03:04:43.500 | And then I would take away the visual stimulus,

03:04:48.880 | and I would, in this thought experiment,

03:04:50.340 | I would, using some hyperoptogenetics,

03:04:53.300 | I would play in exactly the same pattern of activity

03:04:57.020 | in every cell in your brain for as long as was needed,

03:05:00.360 | whatever, 15 seconds, something like that,

03:05:02.460 | that exactly matched what was going on

03:05:06.900 | when you were feeling that inner subjective sense.

03:05:10.340 | Okay, so in that thought experiment,

03:05:12.180 | a question for you is,

03:05:13.540 | would you be feeling that same inner subjective sense?

03:05:18.100 | Stimulus is gone, every neuron's doing the same thing

03:05:20.540 | 'cause I'm controlling it.

03:05:21.840 | - There's a philosophical question there.

03:05:25.820 | If you ask me specifically, I would say yes.

03:05:29.360 | - Okay, good, most people would say that

03:05:31.420 | because it's hard to say no, right?

03:05:33.740 | - It's very hard to say no.

03:05:34.820 | - If every cell in your brain is doing what it was doing,

03:05:38.260 | what else could be different?

03:05:39.540 | How could--

03:05:40.380 | - Well, most normal people would say yes.

03:05:42.700 | Of course, philosophers would then start saying no.

03:05:46.340 | They're the ones that say,

03:05:48.220 | I'm gonna sort of, to parallel,

03:05:52.620 | and sorry if it's a bit of an interruption,

03:05:54.220 | but if there's a robot that's conscious in front of you,

03:05:58.420 | if it appears conscious, then it's conscious.

03:06:02.900 | Like to me, of course, philosophers again speak up

03:06:07.300 | and say, well, no, how do you know it's conscious?

03:06:10.020 | Well, how do you know anything is conscious?

03:06:12.340 | And sort of as normal humans,

03:06:15.460 | we tend to lean on the experience

03:06:19.140 | versus some kind of philosophical concept.

03:06:22.640 | - So the great thing about what you just said,

03:06:25.300 | the Turing test, is it's very practical.

03:06:28.380 | If it acts conscious, it is conscious.

03:06:30.980 | But I think that's limiting.

03:06:32.860 | I like the thought experiment.

03:06:34.740 | I think it's actually more informative.

03:06:36.220 | And so I'm halfway to the conclusion there.

03:06:39.760 | But let's take it as your answer was yes,

03:06:42.780 | that you would be feeling the same thing.

03:06:44.900 | Okay, now here's where it gets fun.

03:06:47.100 | Now that every cell in your brain

03:06:51.860 | knows what it has to do in the sense that we know it

03:06:56.940 | and we're providing it,

03:06:58.100 | your brain cells don't need to be in your head

03:07:02.660 | anymore at all, right?

03:07:04.740 | The only reason they're next to each other,

03:07:06.500 | the only reason they're wired together

03:07:08.180 | is to affect each other, to stimulate or inhibit each other.

03:07:12.260 | But we don't need that anymore 'cause optogenetically,

03:07:15.320 | we're providing that activity pattern

03:07:17.300 | for as long as needed.

03:07:18.140 | We're providing the effect of the communication.

03:07:20.060 | They don't need to be connected anymore.

03:07:22.620 | They don't even need to be in your head.

03:07:24.520 | I could spread your neurons all over the continent,

03:07:28.100 | all over the galaxy,

03:07:29.220 | and I could still provide the same stimulus pattern

03:07:34.060 | over 10 or 15 seconds to all those neurons.

03:07:36.780 | And somewhere, Lex Friedman would have to be,

03:07:41.600 | even though no longer existing as a physical object anymore,

03:07:45.300 | would be feeling that subjective feeling.

03:07:48.260 | And it's inescapable because it's exactly the same

03:07:50.640 | as the previous situation.

03:07:52.060 | All the neurons have to be spatially,

03:07:54.420 | like the locality constraint,

03:07:56.880 | they have to be spatially close to each other.

03:07:58.940 | And you talk about light, Opto,

03:08:03.700 | which is funny because light is the fastest traveling thing

03:08:08.700 | that we know of.

03:08:10.340 | - Maybe let's not put 'em all over the universe

03:08:13.060 | 'cause we might get relativistic problems then.

03:08:14.660 | Let's just keep them, let's keep all your neurons,

03:08:16.940 | let's spread 'em over North America, okay?

03:08:19.220 | And let's play them out, same pattern of activity.

03:08:22.660 | And it seems absurd, right?

03:08:24.180 | There's no way that could be true.

03:08:25.920 | There's no way that Lex would be feeling

03:08:28.700 | that internal sense if his neurons

03:08:30.300 | were spread all over North America.

03:08:32.760 | And yet, it's exactly the same as the previous situation

03:08:35.140 | where you said, "Sure."

03:08:36.700 | - Wow. - So we got a paradox.

03:08:37.980 | And this is what makes people think--

03:08:39.540 | - Is this a paradox, though?

03:08:40.380 | Sorry, you-- - Well, maybe paradox

03:08:42.180 | is the wrong word.

03:08:43.020 | We got a problem. (laughs)

03:08:43.980 | We got a problem because it reveals

03:08:46.100 | that there's something big about those,

03:08:49.860 | that internal subjective state that we're not explaining.

03:08:53.100 | And we don't really have a hope of explaining

03:08:54.700 | in the near future.

03:08:55.700 | - But don't you think we would still have that?

03:08:58.660 | It's just the word internal loses meaning,

03:09:00.580 | but don't you think we still have

03:09:02.200 | that internal subjective state?

03:09:03.820 | If not, then where the heck is the magic coming from?

03:09:09.540 | Okay, well, I just think,

03:09:13.460 | I think one of the problems

03:09:16.820 | that I think we need to let go of

03:09:19.140 | is we tend to, outside of the experience of consciousness,

03:09:23.460 | the hard problem of consciousness,

03:09:25.700 | we tend to think that we individual humans

03:09:27.940 | are really special.

03:09:29.180 | Not the subjective experience, but the entirety of it,

03:09:33.200 | like the body that contains the thing.

03:09:35.780 | So the local, the constraint of all the stuff

03:09:40.820 | has to be together and it's all mine.

03:09:43.320 | (laughs)

03:09:45.020 | That's a very, I don't know if that has anything to do

03:09:48.660 | with the mechanisms that are creating this.

03:09:51.980 | So, and in fact, one really nice way

03:09:55.460 | to break through that is to either observe

03:10:00.460 | or create consciousness that spans multiple organisms.

03:10:07.380 | Sort of, like, let's say it's not,

03:10:10.780 | it's not an organism-dependent phenomena.

03:10:15.140 | That the phenomena can,

03:10:17.540 | that's just a peculiar way it has evolved on Earth,

03:10:22.140 | but it's a phenomena that doesn't have anything to do

03:10:26.300 | with a specific biological system.

03:10:30.500 | - Yeah, so, and we have different parts of our brain exist,

03:10:35.780 | and sometimes create complex awarenesses of things

03:10:40.780 | that involve different neurons that are distributed widely,

03:10:46.380 | and that need to communicate with each other

03:10:49.020 | to form this joint representation,

03:10:51.240 | this state of consciousness.

03:10:53.140 | But indeed, why do they have to be in the same head?

03:10:57.300 | We don't know why that would be the case that they do.

03:11:02.160 | And so that's a huge unanswered question in the field,

03:11:06.640 | is what is it that binds the activity of neurons together

03:11:11.640 | so they can form a joint representation?

03:11:14.440 | And actually, this comes back to the dissociation experiment

03:11:16.840 | we talked about before, where you can,

03:11:18.560 | your sense of self becomes separated from your body.

03:11:22.440 | Those things that were fused in a joint representation,

03:11:26.600 | the same concept, unitary, are now separate.

03:11:31.400 | And in late 2020, we published a paper in Nature

03:11:35.440 | showing how this could be.

03:11:37.160 | We used optogenetics to drive this rhythm

03:11:41.000 | that ketamine and PCP cause in retrosplenial cortex,

03:11:44.000 | and we got different parts of the brain to be out of sync

03:11:47.480 | and when they were active,

03:11:49.360 | never able to be active at the same time,

03:11:51.680 | never able to form a joint representation at the same time.

03:11:56.120 | And so we've got a toehold into these questions.

03:11:58.080 | We don't have the answers, but--

03:11:59.920 | - And that mimics the dynamics of ketamine effects.

03:12:02.600 | - Exactly, exactly.

03:12:04.280 | - And you're able to find that kind of oscillation,

03:12:06.760 | the wow, wow, wow.

03:12:09.920 | And so if you get even greater and greater control

03:12:13.520 | with more control over individual neurons

03:12:16.000 | and understanding, like if you think of certain neurons

03:12:19.840 | that having some role to play in the sense of self,

03:12:24.520 | you can play like an orchestra.

03:12:27.760 | That to create certain degrees of consciousness,

03:12:31.720 | degrees of subjectivity,

03:12:33.240 | and thereby understand what is consciousness

03:12:36.800 | by having a very complicated light switch, essentially.

03:12:41.960 | - And here's the challenge,

03:12:43.400 | is the nice thing about the thought experiment

03:12:46.360 | is it kind of highlights

03:12:48.240 | that we're gonna hit a point where

03:12:51.760 | we're addressing some very, very fundamental questions.

03:12:57.400 | What allows the activity of two sets of neurons

03:13:02.400 | to become mutually relevant to each other?

03:13:07.080 | This is in some ways,

03:13:09.600 | maybe one of the deepest remaining questions

03:13:12.360 | in neuroscience is what allows activity patterns

03:13:15.520 | to become relevant to each other?

03:13:18.880 | Do they have to be in sync temporally?

03:13:21.200 | Do they need to be,

03:13:22.460 | is there some other quality that we don't know about

03:13:26.880 | that also needs to be present

03:13:28.440 | to allow cells to fuse together into a joint representation?

03:13:32.120 | - Just so I understand,

03:13:34.040 | 'cause it feels close to some very, very deep idea.

03:13:39.040 | So there's a bunch of semi-distributed signals

03:13:43.600 | going on in the brain.

03:13:44.820 | And you're saying there could be

03:13:50.240 | something like a theory of everything, if one to exist,

03:13:53.800 | is to understand why,

03:13:56.160 | how and why signals close to each other

03:13:59.560 | start becoming relevant to each other.

03:14:05.320 | - That's right, that's right.

03:14:07.040 | - As part of some very much bigger signal

03:14:10.880 | that they're producing.

03:14:12.440 | How they coordinate, essentially.

03:14:14.960 | 'Cause it's very distributed.

03:14:18.440 | I mean, that's a kind of,

03:14:20.680 | within a distributed system, how is order achieved?

03:14:24.260 | And this is a very specific kind of distributed system

03:14:28.840 | that is one of the most intelligent

03:14:31.000 | that we're aware of in the known universe.

03:14:33.880 | In that would maybe be something,

03:14:37.000 | also an understanding of the full conscious experience, too.

03:14:42.000 | That this kind of coordination,

03:14:44.440 | how does the coordination between different neurons

03:14:46.640 | that are responsible for sense of self,

03:14:49.060 | how do they begin to form a big picture

03:14:51.760 | that we see as a human experience?

03:14:54.080 | That's really, really interesting.

03:14:55.520 | So uniting the small,

03:14:57.080 | (laughs)

03:14:58.320 | that's actually literally theory of everything.

03:15:00.960 | Uniting the small, the sort of the theory of the neuron,

03:15:03.840 | the function of the neuron with the big,

03:15:07.800 | just the functioning of the entire mind.

03:15:12.040 | - That's right.

03:15:12.880 | And I think keeping a toehold in both

03:15:14.920 | at the cellular level of resolution

03:15:17.800 | and the brain-wide resolution will be critical.

03:15:19.720 | If you lose touch with either,

03:15:21.320 | I think you'll miss the big insight.

03:15:23.580 | So that's what we're trying to do,

03:15:25.380 | keeping grounded in the cellular resolution,

03:15:29.180 | trying to keep the broadest brain-wide perspective

03:15:32.180 | and meet in the middle.

03:15:33.340 | - Do you think you'll see it in your lifetime,

03:15:36.900 | a major breakthrough in that dimension?

03:15:39.540 | - I have hope, I have hope.

03:15:40.940 | It's very hard to predict what will happen

03:15:43.780 | with big things like this.

03:15:45.460 | If we don't get there,

03:15:46.880 | there'll be plenty of other exciting stuff, so it's okay.

03:15:49.780 | - But the other aspect of this whole thing

03:15:52.920 | is that your life is pretty short.

03:15:55.200 | - That's true.

03:15:56.880 | - So first of all, you can die any day.

03:15:59.440 | I tend to try to think about that,

03:16:01.320 | that it ends, you can end at any moment

03:16:03.880 | because it really, really can.

03:16:05.640 | And if not, it'll be soon anyway.

03:16:08.760 | Do you think about that?

03:16:09.960 | Do you think about your mortality?

03:16:12.280 | - I do, yeah.

03:16:13.820 | It comes back to what we talked about earlier.

03:16:16.020 | I never think I've done enough,

03:16:18.500 | and it's relevant to that, for sure.

03:16:20.780 | - There's a deadline.

03:16:23.540 | - Yeah.

03:16:25.060 | - Do you think there's ever going to be a feeling

03:16:27.180 | where you sit back and you're really proud of yourself?

03:16:31.700 | - I hope so.

03:16:35.300 | - Like, I've done enough, I've done everything there is.

03:16:39.560 | Because the thing is, a warrior has some number

03:16:43.160 | of battles in them, and at a certain point,

03:16:45.840 | if you're deeply honest, it's like,

03:16:47.480 | well, that was a pretty good run.

03:16:50.240 | As far as runs goes, that was pretty good.

03:16:53.040 | And you can hang up your helmet,

03:16:55.240 | and then go sort of drink some ale,

03:17:00.240 | listen to some music with the old lady,

03:17:03.600 | and say, I did pretty good.

03:17:04.920 | You think you'll get there?

03:17:08.600 | - You know, with something,

03:17:10.340 | nature always has surprises for us.

03:17:12.980 | The curious mind is always after more.

03:17:17.400 | But biology gives us other rewards.

03:17:22.120 | Children, and family, community.

03:17:25.000 | And one can feel good about those things.

03:17:28.420 | - Biology's full of rewards,

03:17:31.740 | but do you think, about those rewards,

03:17:34.780 | what do you think is the why of those rewards?

03:17:37.040 | What's the meaning of life?

03:17:38.460 | And this existence?

03:17:40.180 | What's the why of biology?

03:17:44.500 | What does it want from us?

03:17:45.460 | Why are all these cells very busy

03:17:47.980 | putting together an organism that seems to want to

03:17:50.500 | just be in a hurry to do stuff?

03:17:53.660 | And survive?

03:17:55.180 | But it also just doesn't, it's not happy being survived.

03:17:57.580 | Like you said, it's curious.

03:17:59.220 | It keeps wanting to get into more trouble.

03:18:01.620 | Why?

03:18:02.980 | - Yeah, that, you know, we're clearly designed for that.

03:18:06.860 | This is, we're clearly designed to ask why and to answer.

03:18:10.700 | And that, I think, is,

03:18:12.900 | I don't know the meaning of all life.

03:18:15.300 | I think a meaning of our lives is that,

03:18:17.900 | and this is the Aristotelian happiness.

03:18:21.540 | This is, an organism is happy, an animal's happy

03:18:24.340 | if it's performing to its design, right?

03:18:26.420 | If it's doing what it was made for.

03:18:29.740 | - Yeah.

03:18:30.580 | Well, you have to understand, what's the design?

03:18:33.680 | And, you know, who is the designer?

03:18:38.680 | And what were they up to?

03:18:41.980 | And how hard is it?

03:18:43.820 | Do you have to build the whole universe?

03:18:45.180 | And does the design even know what the hell they're doing?

03:18:47.640 | Because, you know, maybe the designer built humans

03:18:51.700 | to find out about themselves.

03:18:56.500 | That's what I would do.

03:18:57.500 | Like, if I had the power to build clones,

03:19:00.740 | I would build a lot of clones

03:19:02.500 | and I would get them into different trouble

03:19:04.840 | to understand, like, what's this body designed to do?

03:19:09.840 | - How far can I go that way?

03:19:11.700 | - Exactly.

03:19:12.900 | And then I dissociate myself completely

03:19:15.640 | from having any way to know, like, that I know that person.

03:19:19.100 | - Oh, that's good.

03:19:19.980 | - I mean, I suppose you could do that

03:19:21.300 | in a single person's body by dissociation.

03:19:25.100 | But I do wonder what,

03:19:30.180 | if you look at Earth as a collection of humans,

03:19:33.780 | as a collection of biological organisms,

03:19:35.900 | it seems that we're busy doing something.

03:19:38.980 | And it just seems too beautiful and too special

03:19:45.400 | to be a random,

03:19:47.580 | a random experiment.

03:19:51.660 | It seems like it's an experiment that's cleverly designed

03:19:58.060 | by some forces of nature

03:20:00.660 | that are beyond our current understanding.

03:20:03.700 | And maybe that's part of our design,

03:20:05.540 | is to keep asking why.

03:20:06.540 | You said answer.

03:20:07.380 | I'm not sure that's part of the design, the answer.

03:20:10.380 | I think we're given just the sufficiently limited

03:20:15.060 | cognitive capability that we know how to long

03:20:19.020 | to find the answer and we lack the ability

03:20:22.500 | to find the answer.

03:20:24.100 | That's basically a summary of your career.

03:20:26.460 | No, I'm just kidding.

03:20:27.820 | And then we give each other Nobel prizes

03:20:29.540 | for having even an inkling of a good step

03:20:33.220 | towards the right direction.

03:20:35.140 | Carl, you're an incredible human being.

03:20:37.260 | I'm a huge fan of who you are as a person,

03:20:41.020 | who you are as a scientist, who you are as a writer.

03:20:43.560 | I just thank you so much.

03:20:45.340 | I'm so honored that you would sit down

03:20:46.740 | and talk to me today.

03:20:47.580 | It was amazing.

03:20:48.400 | - It's been incredibly fun.

03:20:49.860 | Let's do it again sometime.

03:20:50.700 | - Let's do it again. - It's been really great.

03:20:51.780 | Your insights and wit and modesty

03:20:55.660 | are really quite rewarding.

03:20:58.260 | - Thanks so much, man.

03:20:59.360 | Thanks for listening to this conversation

03:21:02.060 | with Carl Deisseroth.

03:21:03.700 | To support this podcast, please check out our sponsors

03:21:06.220 | in the description.

03:21:07.500 | And now, let me leave you with some words from Carl Jung.

03:21:11.540 | Knowing your own darkness is the best method

03:21:13.980 | for dealing with the darkness of other people.

03:21:16.380 | Thank you for listening and hope to see you next time.

03:21:20.460 | (upbeat music)

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Karl Deisseroth: Depression, Schizophrenia, and Psychiatry | Lex Fridman Podcast #274

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