Karl Deisseroth: Depression, Schizophrenia, and Psychiatry #274

Transcript

00:00:01 Where are the darkest places you’ve ever gone in your life?

00:00:07 The following is a conversation with Karl Deisseroth,

00:00:10 professor of bioengineering, psychiatry,

00:00:12 and behavioral sciences at Stanford University.

00:00:15 He’s one of the greatest living psychiatrists

00:00:18 and neuroscientists in the world.

00:00:20 He’s also just a fascinating human being.

00:00:23 We discuss both the darkest and the most beautiful places

00:00:26 that the human mind can take us.

00:00:28 He explores this in his book called

00:00:31 Projections, A Story of Human Emotions.

00:00:33 I highly recommend it.

00:00:35 It’s written masterfully.

00:00:38 This is the Lex Friedman podcast.

00:00:40 To support it, please check out our sponsors

00:00:42 in the description.

00:00:43 And now, dear friends, here’s Karl Deisseroth.

00:00:48 You open your book called Projections,

00:00:50 A Story of Human Emotions with a few beautiful words

00:00:53 to summarize all of humanity.

00:00:56 The book draws insights about the human mind

00:00:58 from modern psychiatry and neuroscience.

00:01:01 So if it’s okay, let me read a few sentences

00:01:03 from the opening.

00:01:05 You gotta give props to beautiful writing when I see it.

00:01:08 Quote, in the art of weaving, warp threads are structural

00:01:13 and strong and anchored at the origin,

00:01:16 creating a frame for crossing fibers

00:01:19 as the fabric is woven.

00:01:22 Projecting across the advancing edge into free space,

00:01:25 warp threads bridge the formed past

00:01:27 to the ragged present to the yet featureless future.

00:01:32 Yet featureless future, well done, well done, sir.

00:01:35 The tapestry of the human story has its own warp threads,

00:01:38 rooted deep in the gorges of East Africa,

00:01:41 connecting the shifting textures of human life

00:01:44 over millions of years, spanning pictographs

00:01:47 backdroped by crevice ice, by angulated forestry,

00:01:52 by stone and steel, and by glowing rare earths.

00:01:56 The inner workings of the mind give form to these threads,

00:01:59 creating a framework within us,

00:02:01 upon which the story of each individual can come into being.

00:02:05 Personal grain and color arise from the crossed threads

00:02:08 of our moments and experiences, the fine weft of life,

00:02:13 embedding and obscuring the underlying scaffold

00:02:16 with intricate and sometimes lovely detail.

00:02:19 Here are stories of this fabric fraying in those who are ill.

00:02:24 In the minds of people for whom the warp

00:02:26 is exposed and raw and revealing.

00:02:31 What have you learned about human beings,

00:02:33 human nature and the human mind,

00:02:34 from those who suffer from psychiatric maladies,

00:02:38 for those for whom this fabric is warped?

00:02:41 And one thing we learn as biologists

00:02:43 is that when something breaks,

00:02:45 you see what the original unbroken part was for.

00:02:50 And we see this in genetics, we see this in biochemistry.

00:02:54 It’s known that when you have a mutated gene,

00:02:57 sometimes the gene is turned up in strength

00:02:59 or turned down in strength,

00:03:01 and that lets you see what it was originally for.

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

00:03:06 And this is a theme that I thought needed to be shared

00:03:11 and needed to be made communicable

00:03:13 to the lay public, to everybody.

00:03:15 People who, which is, I think, almost all of us,

00:03:19 who think and care about the inner workings of our mind,

00:03:21 but who also care for those who have been suffering,

00:03:26 who have mental health disorders, who face challenges.

00:03:31 But then more broadly,

00:03:33 it’s a very much larger story than the present.

00:03:36 There’s a story to be told

00:03:39 where the protagonist really is the human mind.

00:03:42 And that was one thing I wanted to share as well

00:03:44 in projections, is that broader story,

00:03:47 but still anchored in the moment of patients,

00:03:50 of people, of experiences of the moment.

00:03:53 Is there a clear line between dysfunction and function,

00:03:57 disorder and order?

00:03:59 This is always debated in psychiatry,

00:04:02 probably more so than any other medical specialty.

00:04:06 I’m a psychiatrist, I treat patients still.

00:04:09 I see acutely ill people who come to the emergency room

00:04:14 where there’s no doubt that this is not something

00:04:16 that’s working well, where the manifestation of disease

00:04:19 is so powerful, where the person is suffering so greatly,

00:04:22 where they cannot continue as they are.

00:04:26 But of course, it’s a spectrum,

00:04:28 and there are people who are closer

00:04:30 to the realm of being able to work okay in their jobs,

00:04:34 but suffer from some small dysfunction.

00:04:36 And everywhere in between.

00:04:37 In psychiatry, we’re careful to say

00:04:39 we don’t call it a disease or a disorder

00:04:41 unless there’s a disruption

00:04:43 in social or occupational functioning.

00:04:46 But of course, psychiatry has a long way to go

00:04:49 in terms of developing quantitative tests.

00:04:51 We don’t have blood draws, we don’t have imaging studies

00:04:55 that we can use to diagnose.

00:04:57 And so that line, ultimately, that you’re asking about

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

00:05:04 it’s operational at the moment.

00:05:05 How are things working?

00:05:08 Can we just linger on the terms for a second?

00:05:10 So this disease, dysfunction,

00:05:15 how careful should we be using those words?

00:05:17 Can we just, even in this conversation,

00:05:21 from a sort of technical perspective,

00:05:24 but also a human perspective,

00:05:26 how quick should we be

00:05:31 in saying that schizophrenia, depression, autism,

00:05:38 as we kind of go down across the spectrum

00:05:42 of different maladies,

00:05:44 to use the word dysfunction and disease?

00:05:48 I would say to give ourselves license

00:05:50 to capture the whole spectrum, let’s say disorder,

00:05:53 because that captures truly, I think, the essence of it,

00:05:57 which is we need to talk about it when it’s not working,

00:05:59 when there’s disorder.

00:06:00 And that’s the fairest and most inclusive term to use.

00:06:08 So is it fair to assume that basically every member

00:06:12 of the human species suffers from a large number

00:06:15 of disorders then?

00:06:17 Well, we just have to pick which ones are debilitating

00:06:22 for each person?

00:06:23 You know, if you look at the numbers,

00:06:25 there are, if you look at how our mental health disorders

00:06:29 are currently defined,

00:06:30 you can look at population prevalence values

00:06:34 for all these disorders,

00:06:35 and you can come up with estimates

00:06:37 that somebody will have a lifetime prevalence

00:06:42 of having a psychiatric disorder

00:06:44 that approaches 25% or so.

00:06:46 And so that’s, and in some studies it could be more,

00:06:50 some studies it could be less.

00:06:51 Now, what do we do with that number?

00:06:53 What does that mean?

00:06:54 And in some ways, that’s the essence

00:06:55 of what I was hoping to approach with the book,

00:06:58 is to reflect on this spectrum that exists

00:07:01 for all the disorders.

00:07:02 There is, and taking nothing away from the severity

00:07:05 and the suffering that comes at the extreme end

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

00:07:10 on a spectrum of severity, from nearly functional

00:07:14 to completely dysfunctional, life threatening,

00:07:17 and even fatal.

00:07:19 And so that number, 25%, more or less,

00:07:22 it doesn’t capture that spectrum of severity.

00:07:27 To look at that number, where do those numbers come from?

00:07:30 Is it self report?

00:07:31 Is it people who show up and say, I need help?

00:07:35 Is it somebody else that points out that person needs help?

00:07:38 Or is it like estimates that even go beyond that

00:07:41 for people who don’t ask for help

00:07:42 or are suffering quietly alone?

00:07:45 When you look at self report numbers,

00:07:47 then those numbers get even higher, beyond 25% or more.

00:07:52 Those, the most rigorous studies are done

00:07:55 with structured psychiatric interviews

00:07:57 where people who are trained in eliciting symptoms carefully

00:08:02 do complete psychiatric inventories of individuals.

00:08:05 And these are time consuming laborious studies

00:08:09 that are not often repeated.

00:08:10 When they’re done, they’re done well.

00:08:13 But very often you’ll see a report or something

00:08:16 in the news of a very high number

00:08:19 for some disorder or symptom.

00:08:22 And very often, if it’s shockingly high,

00:08:24 that’s coming from a self report of a person.

00:08:27 And so that’s another issue that we have, again,

00:08:31 take nothing away from the severity and reality

00:08:33 and biological nature of these disorders,

00:08:35 which are very genetic, very, you know,

00:08:37 we understand that these are very biological.

00:08:40 And yet, we lack right now the lab tests

00:08:43 and the blood draws to make the diagnoses.

00:08:45 We’ll talk about it, just how biological they are,

00:08:48 because that too is a mystery.

00:08:51 You know, in terms of from our perspective

00:08:53 of how to probe into the disease,

00:08:55 how to understand it, how to help it.

00:08:57 So some of it could be neurobiological,

00:09:00 some of it could be just the dance

00:09:03 of human emotion and interaction.

00:09:05 And it’s like, is love when it works

00:09:11 and is love when it breaks down biological

00:09:14 or is it something else?

00:09:15 So we’re gonna talk about it.

00:09:17 But let me just like to linger in terms of disorder.

00:09:21 What about genius?

00:09:23 You know, that sort of cliche saying,

00:09:25 like the madness and genius

00:09:28 that they kind of dance together.

00:09:30 What about if the thing we see as disorder

00:09:33 is actually genius, unheard or misunderstood?

00:09:38 Well, here again, the numbers help us.

00:09:40 And here’s where being rigorous

00:09:41 and quantitative actually really helps.

00:09:43 If you look at disorders like autism

00:09:46 and bipolar disorder and eating disorders,

00:09:50 anorexia nervosa, for example,

00:09:53 these, you know, particularly bipolar and anorexia,

00:09:56 these can be fatal, they can cause immense suffering,

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

00:10:04 And what’s very interesting is each one of these three

00:10:07 is actually correlated positively,

00:10:10 positively with measures of intelligence,

00:10:13 of educational attainment, and even of income.

00:10:18 And so you look at this severe disorders

00:10:20 in many cases causing quite an immense morbidity

00:10:25 and mortality, and yet they are positively correlated

00:10:28 at the population level with positive things.

00:10:31 Can you say the three again, autism?

00:10:33 Autism, anorexia, and bipolar disorder.

00:10:37 Bipolar, right.

00:10:38 What’s that book, forgot the book name,

00:10:40 but is intelligence a burden?

00:10:45 Well, you know, people can get into trouble

00:10:48 when they think they’re smarter than they are,

00:10:49 I will say that.

00:10:51 I don’t know.

00:10:52 Sometimes, like, in the deepest meaning of that statement,

00:10:56 I think ignorance is bliss.

00:10:58 I’m a big fan of Prince Mishkin from The Idiot

00:11:00 and Aliosha from Brother Karamazov.

00:11:04 Optimism can be seen as naivety and dumbness,

00:11:08 but I think it’s a kind of deep intelligence.

00:11:13 Maybe inability to reason sort of about the mechanics

00:11:17 of the world, but instead kind of feel the world.

00:11:20 It seems like that’s one of the paths to happiness.

00:11:24 There is.

00:11:25 How much you think versus how much you feel,

00:11:26 this comes up all the time.

00:11:28 In medicine, we encounter this all the time.

00:11:31 Day after day, you encounter the abyss of suffering

00:11:36 from patients.

00:11:36 How much do you let yourself feel?

00:11:39 Or how much do you make it abstract and objective

00:11:44 and try to make it clinical?

00:11:46 And that range, how you’re able to move yourself

00:11:49 on that spectrum, is very important for survival

00:11:52 as a physician, and the way you protect yourself

00:11:57 and your feelings turns out to be very important.

00:12:00 You quote Finnegan’s Wake, mad props for that,

00:12:04 James Joyce book.

00:12:05 I took a class in James Joyce in college.

00:12:07 I think I read parts of Finnegan’s Wake.

00:12:10 I might have been on drugs of some kind,

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

00:12:15 which probably refers to some kind of curve

00:12:18 where nobody understood anything.

00:12:19 The only thing I understood and really enjoyed

00:12:21 is his short stories, The Dead, and then Ulysses.

00:12:24 I kind of, I think, read a few Cliff Notes

00:12:27 that kind of got to the point,

00:12:28 and then Finnegan’s Wake was just a hopeless.

00:12:34 For people who haven’t looked at it,

00:12:35 maybe you can elucidate to me better,

00:12:38 but I felt like I was reading things, words,

00:12:43 and the words made sense, like standing next to each other,

00:12:47 but when you kind of read for a while,

00:12:51 you realize you didn’t actually understand

00:12:53 anything that was said.

00:12:54 Right, but did you have a feeling, though?

00:12:55 That’s one thing I found interesting about Finnegan’s Wake.

00:12:59 I never fully understood it,

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

00:13:02 which I found fascinating,

00:13:03 and sometimes I couldn’t predict it

00:13:06 from the semantic black and white context

00:13:09 of what I was seeing in front of me on the page,

00:13:11 but the rhythm or the melody

00:13:13 would make me feel certain ways,

00:13:14 and that was what I always was intrigued by with Joyce.

00:13:17 Of course, that was his, he existed on a spectrum, too,

00:13:20 and he wrote, as you say, more accessible works.

00:13:24 I learned a lot about Irish history

00:13:26 from Portrait of the Artist as a Young Man,

00:13:28 and there was just, he could be as objective

00:13:31 as he wanted to be, but then when he let himself loose,

00:13:35 he was in this realm where the words

00:13:37 had their own purpose separate from semantic meaning

00:13:42 from their dry dictionary definition.

00:13:46 You know, there’s a funny story that was told,

00:13:48 doesn’t matter if it’s true or not,

00:13:49 but they said that James Joyce, when he was young,

00:13:53 when he was in his teen years,

00:13:54 would go around sort of Ireland drinking and so on

00:13:57 and telling everybody that he’s going to be one of,

00:14:00 if not the greatest writers of the 20th century,

00:14:03 and he turned out to be that.

00:14:06 So I always think about that little story

00:14:09 that somebody told me,

00:14:11 because I have a lot of people come up to me,

00:14:14 including myself, I’m a bit of a dreamer.

00:14:17 You get into certain moods where you say

00:14:19 I’m going to be the greatest anything ever.

00:14:22 You get people tell you this, especially young people,

00:14:27 and it kind of, it makes me feel all kinds of ways,

00:14:32 but that story reminds me that you just might be

00:14:36 one of the greatest writers of the 21st century,

00:14:39 for example, if somebody were to tell me that,

00:14:41 and don’t immediately disregard that,

00:14:44 because one of the people that say that,

00:14:47 that’s almost like a precondition,

00:14:49 that’s a good requirement just to believe in yourself.

00:14:51 Maybe it’s not a full requirement,

00:14:53 but it’s an interesting story.

00:14:57 I think when someone tells you that,

00:14:58 then it creates, one sees an opportunity,

00:15:02 and then it would be a tragedy

00:15:03 if the opportunity weren’t captured, right?

00:15:05 And so then that creates some impetus,

00:15:09 some motivation to do something good.

00:15:12 I think the mind, it’s like, I guess that’s what

00:15:16 books or whatever, I don’t even know if it’s a book,

00:15:18 The Secret plugs into, they kind of make

00:15:21 a whole industry out of it.

00:15:23 But there is something about the mind

00:15:26 believing something, making it a reality.

00:15:28 It is just time and time again with Steve Jobs,

00:15:32 your belief in yourself, your belief in an idea,

00:15:35 sort of embracing the me versus the world,

00:15:39 embracing the madness of this idea

00:15:42 and making it a life pursuit,

00:15:44 somehow morphs reality around you

00:15:46 for some tiny fraction of the population.

00:15:48 For everybody else, you descend into

00:15:54 all the beautiful ways that failure

00:15:56 materializes in our lifetime.

00:15:59 Well, you know, you mentioned love earlier.

00:16:00 I mean, that’s a great example of how

00:16:02 belief in something makes it real, right?

00:16:05 It’s not reasonable on the face of it,

00:16:08 but because you believe it’s reasonable,

00:16:09 then it actually does become reasonable,

00:16:10 and then it is real.

00:16:11 And so that’s a good example.

00:16:13 That doesn’t happen.

00:16:13 I’m also in a bioengineering department.

00:16:15 We don’t imagine that a bridge is soundly built

00:16:18 and then it is soundly built.

00:16:19 That’s something that, it doesn’t come up

00:16:21 in too many realms of human existence,

00:16:23 but love is one of them.

00:16:24 And the ability to have a fixed idea

00:16:29 and to say it’s true, and then it is true.

00:16:32 A bridge is a kind of manifestation of love.

00:16:34 So maybe it does work a little bit,

00:16:36 but it can break down like Chernobyl did.

00:16:38 You can’t just say it’s safe.

00:16:40 You have to also prove it’s safe.

00:16:43 But on Finnegan’s Wake, I think,

00:16:45 maybe correct me if I’m wrong,

00:16:47 you’re using kind of Finnegan’s Wake

00:16:48 to give one perspective on what madness is,

00:16:52 of what’s going on in the mind.

00:16:53 How much of that is that we’re simply unable

00:16:59 to communicate with the person

00:17:01 on the other side of their mind?

00:17:03 Like there’s almost like a little person inside the brain

00:17:07 and they have some circuitry that’s used

00:17:10 to communicate emotion, communicate ideas

00:17:12 to the outside world.

00:17:14 And there’s something about that circuitry

00:17:15 that makes it difficult to communicate

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

00:17:18 So if you look at what shows up in schizophrenia,

00:17:21 with many cases, what we call thought disorders,

00:17:25 what we call the individual speech symptoms

00:17:30 of schizophrenia, Finnegan’s Wake is loaded with them.

00:17:33 And it’s just full of them.

00:17:35 We talk about clang associations in schizophrenia

00:17:39 where the word that is said echoes in some way

00:17:44 the previous word.

00:17:44 And we call that a clang association

00:17:46 because there’s no other reason

00:17:47 than the similarity of the sound,

00:17:49 like a clang of a garage door being hit.

00:17:53 And it has a, and sometimes it’s not even a word,

00:17:56 and we call that a neologism, a new word being created.

00:17:59 And of course, Finnegan’s Wake is full of that.

00:18:02 And then we also, in schizophrenia,

00:18:05 where there’s what we call loose associations

00:18:06 or tangential thought processes,

00:18:10 of course, full of that where things just go off

00:18:11 in directions that are not linear or logical.

00:18:15 And you can’t read Finnegan’s Wake, I think,

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

00:18:21 you can’t read it without thinking about schizophrenia.

00:18:24 And then when we look at the families of people

00:18:27 with schizophrenia, and Joyce was no exception,

00:18:30 there very often are people within the family

00:18:32 who are on the spectrum.

00:18:33 Some have it.

00:18:34 Some are able to see it from a distance,

00:18:39 from a safe distance.

00:18:40 There’s an association between schizophrenia

00:18:43 and what we call schizotypal personality disorder

00:18:46 where people are not quite in this severe state

00:18:49 of schizophrenia but have some magical thinking,

00:18:51 have some unusual thought patterns.

00:18:54 Very often, those are family members

00:18:56 of people with schizophrenia.

00:18:57 So this points to this, again, to this idea

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

00:19:05 very genetic biological illness that human beings dwell

00:19:09 on different spots along that spectrum.

00:19:11 I should mention that we have my friend, Sergey,

00:19:14 pulling up stuff, young Sergey or old Sergey,

00:19:16 I don’t know what to call you,

00:19:17 but there’s drafts of Finnegan’s Wake.

00:19:21 Yeah, I actually saw pictures of this from,

00:19:25 I think it was on Instagram or something.

00:19:27 These are early drafts of Finnegan’s Wake.

00:19:29 And it’s so beautiful to see.

00:19:30 For people who are just listening,

00:19:31 there’s just random paragraphs and writing

00:19:34 all over the page with stuff crossed out.

00:19:37 And it’s great to see that Joyce himself

00:19:40 was thinking in this kind of way

00:19:41 as you’re putting it together.

00:19:44 How much do you think he was thinking

00:19:45 about the schizophrenic mind?

00:19:48 I think a lot.

00:19:49 I think it’s known that his daughter suffered

00:19:51 from schizophrenia.

00:19:52 And this is, what’s depicted here on the page

00:19:56 is something that I’m sure he either felt himself

00:20:00 in some level was able to access

00:20:03 this nonlinearity of processing

00:20:06 or had seen enough in family that he knew what it was

00:20:10 and was able to reflect it down

00:20:13 in black and white on the paper.

00:20:14 So what he was able to do was quite authentic

00:20:17 in that sense.

00:20:19 Of course, I don’t want to pigeonhole him.

00:20:21 He was doing much more than that.

00:20:23 It was much more than talking about altered human

00:20:29 thought processes and thought disorders.

00:20:31 But that was an aspect that he was so good at representing

00:20:34 that it had to be intentional to some extent.

00:20:37 And a tiny tangent.

00:20:38 What does your own writing look like for this book?

00:20:42 Because it’s extremely well written.

00:20:44 How many edits?

00:20:46 Did you just drink some whiskey

00:20:48 and like I’m imagining Hemingway style?

00:20:51 What’s a very different, the writing is very different.

00:20:53 I mean, it’s really, really well written,

00:20:55 which was like, I was reading it.

00:21:00 It makes you realize,

00:21:01 because I was expecting sort of a science kind of,

00:21:03 which it is like elucidating something

00:21:08 about the human mind kind of thing.

00:21:09 But you could also probably write really strong novels.

00:21:15 So maybe that’s in the future.

00:21:17 But anyway, what is your, how many edits?

00:21:19 What’s your style?

00:21:20 Does it look like that?

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

00:21:22 Unfortunately, I used a laptop,

00:21:24 so I didn’t have this sort of a beautiful record.

00:21:26 No typewriters, cigarette, and whiskey.

00:21:29 I did explore which was their particular altered state

00:21:33 that would help me to be most creative.

00:21:34 And I found actually, I actually did the best

00:21:38 while sober, but slightly disinhibited

00:21:42 in the late hours of the night or early morning.

00:21:46 Yeah, particularly late hours of the night there.

00:21:50 I have a friend who would tell me

00:21:52 that she thought that very early in the morning,

00:21:54 her inner critic was still asleep

00:21:57 and she could write more effectively

00:21:59 before her inner critic woke up.

00:22:01 And I actually found that outstanding advice for me

00:22:03 that I often found that I was looser

00:22:07 and could write more in the morning.

00:22:09 But the other interesting thing is each chapter,

00:22:12 each story, it’s about a different human being

00:22:15 with a different class of psychiatric disorder.

00:22:18 That’s what each story, each chapter is anchored in.

00:22:22 But I’m trying to use words and style of writing

00:22:27 and diction that captures the feeling of the disorder.

00:22:32 And so it’s different in each story.

00:22:34 In the story about mania, which is a very expansive,

00:22:39 exuberant, at least briefly uplifting state

00:22:43 where the words come out in a torrent

00:22:45 and they’re complex and pressured and elaborate.

00:22:48 I try to capture that feeling

00:22:50 with the words used in that chapter.

00:22:52 And then in the schizophrenia or psychosis chapter,

00:22:56 where things slowly fragment over time

00:22:58 and become looser and separated,

00:23:01 I try to capture that in the writing too.

00:23:03 So for each, it wasn’t as if there was a single mode

00:23:06 I could be in for the whole book.

00:23:08 For each chapter, I had to put myself into a different mode

00:23:11 to capture that inner feeling of the disorder.

00:23:14 When you put yourself in that mode, does that change you?

00:23:17 Yeah, I couldn’t turn it on and off right away.

00:23:19 I had to, first I would start by thinking about the person

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

00:23:26 and the stories that are put forth.

00:23:29 The symptom descriptions are real,

00:23:31 they’re from the patients.

00:23:32 Of course, all details change to protect privacy,

00:23:35 but the actual symptom descriptions are real.

00:23:38 And I would sit with them and really try to inhabit

00:23:41 the space of the mind of that person that I knew.

00:23:45 And that’s not instantaneous.

00:23:47 It would take some time.

00:23:48 I needed quiet, I needed to be still.

00:23:51 That’s another reason late at night is good.

00:23:53 Sergey posted that drowsiness gives creativity boosts,

00:23:56 according to Andrew Huberman.

00:23:58 Thank you, Andrew.

00:23:59 He’s not wrong, he’s not wrong.

00:24:03 Why projections?

00:24:04 Is it, I mean, instead of putting words into your mouth,

00:24:09 because I can imagine a lot.

00:24:11 I mean, to me, I will start putting words in your mouth,

00:24:15 despite what I just said.

00:24:18 So, I mean, to me, projections,

00:24:20 working on neural networks, for example,

00:24:22 from an artificial neural networks,

00:24:23 from a machine learning perspective,

00:24:25 it’s often, that’s exactly what you’re doing.

00:24:27 You have an incredibly complex thing

00:24:29 and you’re trying to find simple representations

00:24:32 in order for you to make sense of it.

00:24:34 So I was kind of thinking about in that way,

00:24:36 which is like this incredibly complex neural network

00:24:43 that is kind of projecting itself onto the world

00:24:46 through this low bandwidth expression of emotion and speech

00:24:51 and all that kind of stuff.

00:24:52 And the way it’s, we only have that window into your soul,

00:24:57 the eyes and the speech and so on.

00:24:58 So in that way, when there’s any kind of disorder,

00:25:03 we get to only see that disorder through that narrow window

00:25:08 as opposed to the full complexity of its origins.

00:25:11 The word projections definitely serves that purpose here,

00:25:13 but it’s got a few other really appropriate

00:25:17 other connotations as well.

00:25:19 So the first thing is a projection

00:25:20 in terms of neuroscience is this long range connection

00:25:24 that goes from one part of the brain to another.

00:25:26 And so it’s what binds two parts of our brain together.

00:25:30 There are projections, long range connections

00:25:33 of axons, these are the outgoing threads

00:25:36 that connect one part of the brain to another part.

00:25:39 There’s a projection that links, for example,

00:25:41 auditory cortex where we hear things to reward centers

00:25:45 where we can feel, where feelings of pleasure

00:25:48 and reward are initiated.

00:25:50 And it’s been shown that if you have reduced connectivity

00:25:53 along that dimension, you are less able to enjoy music.

00:25:56 And so these connections, these projections matter.

00:25:58 They define how effectively two parts of the brain

00:26:01 can engage with each other and join together

00:26:04 to form a joint representation of something.

00:26:07 So that’s one meaning, it’s pure neuroscience.

00:26:09 The word projection is used all the time.

00:26:11 And it happens to be something that optogenetics,

00:26:13 a technique that maybe we’ll talk about a little later

00:26:16 that works particularly well with,

00:26:17 we can use light to turn on or off the activity

00:26:19 along these projections from one spot of the brain

00:26:22 to another.

00:26:23 And this is particularly referring

00:26:24 to the long range connections.

00:26:25 It’s particularly straightforward

00:26:27 along these long range projections

00:26:28 that connect different parts of the brain,

00:26:29 but it works over shorter range too.

00:26:32 But then there’s this other meaning of projections

00:26:34 which you were bringing up, which is very relevant,

00:26:35 which is at some point you can reduce something

00:26:39 from one level of dimensionality to another,

00:26:41 and you can project down into a lower dimensional space,

00:26:43 for example.

00:26:44 And then finally, there’s a psychiatric term projections

00:26:49 which comes up all the time, which is we very often

00:26:54 will look at our internal states

00:26:56 and to understand somebody else,

00:26:57 we’ll project them onto somebody else.

00:27:00 We’ll try to understand someone else’s behavior

00:27:02 and make sense of it by projecting our own inner feelings,

00:27:06 our own sort of narrative onto them

00:27:10 and use that as a way to help us understand them better.

00:27:15 And we’ll do the reverse too.

00:27:16 We’ll take things we see in the outside world

00:27:18 and we’ll bring them into ourselves

00:27:19 and see how well they map, how well they align.

00:27:21 That’s called introjection.

00:27:23 So projections turns out to be a really rich word.

00:27:25 And then finally, of course, there’s the very common

00:27:28 sense of it as a projector that illuminates

00:27:31 by conveying information across space with light.

00:27:35 So for English, for English language,

00:27:38 perfect word to use for this book.

00:27:40 But what’s funny is not every,

00:27:43 there are a lot of international translations now

00:27:45 and all those rich connotations

00:27:46 aren’t captured in other languages.

00:27:48 And so for some translations, connections is used

00:27:53 instead of projections.

00:27:54 In fact, even in England,

00:27:56 the British version is connections instead of projections

00:27:58 because apparently projections

00:28:00 doesn’t have the full connotation, I was told.

00:28:02 So you have to sacrifice some of the rich ambiguity

00:28:06 of meaning with connections, that’s interesting.

00:28:09 I mean, connect, man, words are so interesting.

00:28:12 They have so many meaning.

00:28:14 I love language and how much is lost in translation.

00:28:16 I’m very fortunate enough to be able to speak.

00:28:19 I’m not good at languages.

00:28:20 I was just, I guess, forced to by life’s circumstance

00:28:24 to learn two languages, Russian and English.

00:28:27 And it’s just so interesting to watch

00:28:29 how much of culture, how much of people,

00:28:31 how much of history is lost in translation.

00:28:35 The poetry, the music, the history, the pain,

00:28:39 the way the scientists actually express themselves,

00:28:41 which is funny.

00:28:43 I mean, it’s so sad to see how much brilliant work

00:28:52 that was written in Russian.

00:28:53 There’s a whole culture of science in the Soviet Union

00:28:56 that is now lost.

00:28:58 It makes me wonder, in the modern day,

00:29:01 how much incredible science is going on in China

00:29:05 that is lost in translation.

00:29:07 And I’ll never, I mean, that makes me very sad

00:29:09 because I’ll never learn Chinese in the same way

00:29:13 that I’ve learned English and Russian.

00:29:15 Maybe, whenever I say stuff like that,

00:29:17 people are like, well, there’s still time.

00:29:19 But, you know, yeah, that’s actually fair,

00:29:23 that I think the 21st century, both China and U.S.

00:29:29 will have very important roles in the scientific development

00:29:33 and we should actually bridge the gap through language.

00:29:36 And that doesn’t just mean convincing Chinese

00:29:39 to speak English.

00:29:40 That means also learning Chinese.

00:29:43 Well, we need these bridge people who can do both.

00:29:45 You know, Nabokov, for example, writing in English

00:29:50 beautifully, one of my favorite poets, Borges,

00:29:53 who I mentioned earlier, he wrote both in English

00:29:56 and in Spanish, I think beautifully in both.

00:30:00 We need those people who can serve as bridges

00:30:03 across cultures who really can do both.

00:30:06 You mentioned Borges, so you open your book

00:30:10 with a few lines from a poem by Jorge Luis Borges,

00:30:14 a love poem.

00:30:15 I’m gonna read parts of it because it’s a damn good poem.

00:30:18 It’s called Two English Poems.

00:30:20 I mean, there’s, I’d like to understand why you used it

00:30:24 and the specific parts you used, which is interesting.

00:30:27 But then when I read the full thing,

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

00:30:36 of what it means to delve deep into understanding,

00:30:40 offering yourself to the task of understanding

00:30:42 another human being.

00:30:43 But if you look at the full context of the poem,

00:30:46 it’s also a damn good description of being hit by love

00:30:49 and overtaken by it and sort of,

00:30:52 and trying to figure out how to make sense of the world

00:30:56 now that you’ve been stricken by it.

00:30:59 It says a bunch of things about chatting

00:31:03 and significantly with friends and all those kinds of things

00:31:06 and then the poem reads, the big wave brought you.

00:31:10 I get, this is the moment, I guess, of the universe

00:31:14 where the two people you fall in love.

00:31:16 Maybe I’m totally misreading this poem, by the way.

00:31:18 Doesn’t matter, you can’t misread a poem.

00:31:20 So it goes on, words, any words, your laughter,

00:31:25 and you’re so lazily and incessantly beautiful.

00:31:28 We talked and you have forgotten the words.

00:31:31 The shattering dawn finds me in a deserted street

00:31:34 of my city, your profile turned away.

00:31:37 The sounds that go to make your name.

00:31:40 The lilt of your laughter.

00:31:42 These are the illustrious toys you have left me.

00:31:45 So these little memories of these peculiar little details,

00:31:48 he remembers, those are the illustrious toys.

00:31:51 I apologize to mix my own words with the poem,

00:31:53 but you should definitely read it.

00:31:55 I turn them over in the dawn, I lose them.

00:31:58 I find them.

00:31:59 I tell them to the few stray dogs

00:32:01 and to the few stray stars of the dawn.

00:32:05 Your dark, rich life.

00:32:09 I must get at you somehow.

00:32:11 I put away those illustrious toys you have left me.

00:32:14 I want your hidden look, your real smile.

00:32:18 That lonely, mocking smile your cool mirror knows.

00:32:22 I want your hidden look, your real smile.

00:32:26 So this is the first part of the poem,

00:32:28 and then it goes on, which is some of the parts

00:32:30 that you reference.

00:32:33 Second part is, what can I hold you with?

00:32:36 I offer you lean streets, desperate sunsets,

00:32:38 the moon of the jagged suburbs.

00:32:40 I offer you the bitterness of a man

00:32:42 who has looked long and long at a lonely moon.

00:32:45 I offer you my ancestors, my dead men,

00:32:48 the ghosts that living men have honored in bronze.

00:32:51 My father’s father killed in the frontier of Buenos Aires,

00:32:55 two bullets through his lungs, and so on, so on.

00:32:57 I offer you whatever insights my books may hold,

00:33:00 whatever manliness or humor in my life.

00:33:02 I offer you the loyalty of a man who has never been loyal.

00:33:05 I offer you that carnival of myself

00:33:08 that I have saved somehow, the central heart

00:33:10 that deals not in words, traffics, not with dreams,

00:33:14 and is untouched by time, my joy, and adversities.

00:33:18 And I think this is the part that you include in the book.

00:33:22 I offer you the memory of a yellow rose seen at sunset,

00:33:25 years before you were born, I, damn, that’s a good line.

00:33:30 Okay, I offer you explanations of yourself,

00:33:35 theories about yourself,

00:33:36 authentic and surprising news of yourself.

00:33:39 I can give you my loneliness, my darkness,

00:33:42 the hunger of my heart.

00:33:43 I’m trying to bribe you with uncertainty,

00:33:45 with danger, with defeat.

00:33:47 That is a man who’s in love and longing.

00:33:49 If I’ve taken, but I just wanna go back to,

00:33:52 maybe you could say why you wanted to include that poem,

00:33:55 but also your dark, rich life, I must get at you somehow.

00:34:00 I put away those illustrious toys you have left me at.

00:34:03 I want your hidden look, your real smile,

00:34:06 that lonely, mocking smile, your cool mirror nose.

00:34:09 Sometimes I meet a stranger, and I just,

00:34:13 it’s like a double take.

00:34:15 It’s like, who are you?

00:34:17 Have we met before somewhere?

00:34:19 Who’s that person behind there?

00:34:22 And I wanna get at that, whatever that is.

00:34:25 And of course, maybe that’s what love is,

00:34:27 because maybe that’s the whole pursuit,

00:34:30 like a lifelong pursuit of getting at that person.

00:34:32 Maybe that’s what that is,

00:34:33 and like that insatiable sort of curiosity to keep getting.

00:34:37 Like, well, who is that person in your own private life?

00:34:40 Yeah, so that, absolutely, I think that,

00:34:42 it was a beautiful description of what you just said,

00:34:44 when there’s that first moment,

00:34:46 and then you wanna dive deeper.

00:34:48 You want to know what the hidden mysteries are.

00:34:52 In a way, it’s a love poem.

00:34:55 As a scientist, though, it also,

00:34:58 it’s a bit of how a scientist can love science,

00:35:01 and that wanting to dive deeper is,

00:35:07 it’s almost like, again, where the,

00:35:09 it could be a love affair

00:35:10 with investigating the human mind, for example.

00:35:13 And that was one reason it spoke to me also.

00:35:16 Again, thinking about the broader sweep

00:35:19 of where the human mind came from,

00:35:20 and the steps it took to get where it is today,

00:35:25 what was given up along the way,

00:35:26 what compromises were made.

00:35:28 And here’s where the darkness of the poem

00:35:29 starts to come in a little bit, too.

00:35:31 It doesn’t shy away from the negativity,

00:35:35 from the confusion, from the danger.

00:35:39 And then at the very end,

00:35:42 the boardface is offering up scenes from his life,

00:35:46 parts of himself, and this is how we connect with people.

00:35:49 We offer up parts of ourselves, just here it is,

00:35:51 and then we see how well does that map onto what you have.

00:35:54 And it’s that offering up that I liked,

00:35:57 and not the good stuff, or not only the good stuff.

00:36:00 The yellow rose is nice,

00:36:01 but he’s offering up the bad stuff, too.

00:36:03 And that, to me, was important for the book,

00:36:06 because I’m offering up hard stuff, too.

00:36:10 In fact, a lot of it.

00:36:11 And also, hard stuff from within me,

00:36:13 from my own personal side, too.

00:36:15 And that was, there’s a lot of vulnerability

00:36:17 that comes with that, but that comes with love,

00:36:20 that comes with writing.

00:36:21 You have to be open, you have to be vulnerable.

00:36:23 And so, I thought that reflected what I was trying to do,

00:36:28 and I thought it was, as an epigraph,

00:36:29 it kind of made it clear how vulnerable I was

00:36:33 in taking this step, but also what could come out of it.

00:36:38 And also, in a meta way,

00:36:39 because I was not familiar with this poem,

00:36:41 it made me curious of the poem itself

00:36:47 to pull at that thread of finding out more.

00:36:51 You picked a very particular part

00:36:53 that kind of made you want to pull at that thread,

00:36:57 and see where did these few lines come from?

00:37:02 Because I read it as a curiosity of a scientist,

00:37:05 those lines alone.

00:37:08 And also, as a desperate human being,

00:37:13 searching, like offering himself for an understanding,

00:37:17 or connection with another human being.

00:37:19 And then, because I wasn’t sure if it’s a love poem or not,

00:37:21 or if it’s desperation, or if it’s curiosity,

00:37:23 whatever it is, and then you see the love poem.

00:37:26 I mean, I don’t know, that’s gonna stick with me

00:37:28 for a while, your dark, rich life.

00:37:32 And then a few lines in here are just,

00:37:35 I mean, those are, I’m gonna just use them

00:37:38 as pickup lines at a bar.

00:37:40 I offer you the memory of a yellow rose

00:37:42 seen at sunset years before you were born.

00:37:47 No, that’s a pickup line I’ve never heard,

00:37:48 if I’ve ever heard one, anyway, sorry.

00:37:51 But this is universal.

00:37:52 You see it in so many forms of art.

00:37:55 Like, we’re in Texas now,

00:37:57 you see this in country and western songs.

00:38:00 It’s often a list of things.

00:38:02 Like, here’s how I describe myself.

00:38:03 There’s this, and there’s that,

00:38:04 and there’s the other thing, and here you are.

00:38:06 These things matter to me,

00:38:07 and I hope they matter to you, too.

00:38:09 It’s a pretty universal form,

00:38:11 but he did it in this very artful

00:38:14 and very vulnerable way.

00:38:16 It was both beautiful, and you could feel the hurt

00:38:20 coming from him, too, and that was important.

00:38:22 The dark stuff, too.

00:38:24 I offer you my ancestors, my dead men,

00:38:26 the ghosts that living men have honored in bronze,

00:38:29 and talking about two bullets through his lungs,

00:38:32 bearded and dead, wrapped by his soldiers

00:38:36 in the hide of a cow,

00:38:37 a mother’s grandfather just 24,

00:38:40 heading a charge of 300 men in Peru,

00:38:43 now ghosts on vanished horses.

00:38:46 So all of it, the whole history of it.

00:38:50 Since it is a love poem, what do you think about love?

00:38:55 Carl, what’s the role of love in the human condition?

00:38:58 We’ll talk about the dark stuff.

00:39:00 But maybe love is the dark stuff, too.

00:39:02 I mean, it’s the most powerful connection we can form,

00:39:06 and that’s what makes it so important to us.

00:39:11 It’s the strongest and most stable connection

00:39:16 that we can form with another person,

00:39:17 and that matters immensely.

00:39:19 It matters for the human family to have evolved

00:39:24 to be something that could survive against the odds

00:39:27 that we’ve faced over the years.

00:39:29 That unreasonable bond that becomes reasonable

00:39:35 by virtue of its own existence.

00:39:38 And of course, that joy, the wild, raw joy of love,

00:39:45 is not a bad thing, either.

00:39:46 So you put these together,

00:39:48 the strongest bridge we can form,

00:39:51 and the reward and the joy that it brings.

00:39:54 That’s what love is to me,

00:39:56 and from my perspective, this is something that,

00:40:02 it can be hard to capture fairly,

00:40:05 because you wanna talk about the positive

00:40:07 and the negative sides at once.

00:40:09 They need to be wrapped up together

00:40:10 for a full, honest description of what it is,

00:40:13 and that’s hard to do in a compact form.

00:40:16 And so you have to take time to talk about love.

00:40:19 You have to take time to do it justice.

00:40:23 It takes a book, or at least a poem.

00:40:25 Or several thousands of them.

00:40:28 I don’t know, could you pull up,

00:40:30 there’s a video I saw, yeah, like right here.

00:40:33 So can you pause for a second?

00:40:37 So there’s March of the Penguins.

00:40:39 So you always see penguins huddling together against,

00:40:44 I mean, sorry if I say just metaphors and everything,

00:40:46 but them huddling together against the harshness

00:40:50 of the conditions around them.

00:40:52 That’s very kind of, that’s like a metaphor for life,

00:40:55 like finding this connection.

00:40:57 That’s kind of what love is.

00:40:59 It’s like it allows you to forget whatever the absurdity,

00:41:02 whatever the suffering of life is,

00:41:03 together you get to like huddle for warmth.

00:41:06 And that’s why I love sort of just the honesty

00:41:11 and the intensity of the way penguins,

00:41:13 just in the middle of like the cold do this.

00:41:15 And then this video I saw, a lonely,

00:41:18 this is misinformation.

00:41:20 So the name of the video is Lonely Deranged Penguin.

00:41:23 I don’t know if he’s deranged.

00:41:26 So if you play it.

00:41:27 So he left his pack and there’s a nice like voiceover

00:41:34 and you don’t need to play it,

00:41:36 but he for some reason left the pack

00:41:38 and journeyed out into the mountains.

00:41:41 And so the narrator says that he’s deranged,

00:41:44 he’s lost his mind.

00:41:46 Now I’d like to project the idea that he’s actually,

00:41:50 there’s so many stories you could think of.

00:41:52 He’s returning to his homeland.

00:41:55 He’s an outsider thinking,

00:41:56 journeying out into the unknown,

00:41:58 thinking he may be able to discover

00:42:00 something greater than the tribe.

00:42:02 He might be looking for a lost love.

00:42:04 Why is he deranged immediately?

00:42:06 Why has he lost his mind?

00:42:07 Anyway, but this, people should look up this video

00:42:10 because to me, I might be the only one

00:42:12 who romanticizes this, but it’s such a nice kind of,

00:42:17 it’s both a picture of perhaps a mental disorder,

00:42:21 which is what the video kind of describes.

00:42:23 And it may be some deeper explanation

00:42:25 that’s not, that has to do with the motivation of a mind.

00:42:32 But yeah, I don’t know if you have a deeper analysis

00:42:35 on this penguin.

00:42:36 Well, I, like you as a psychiatrist,

00:42:40 I would want to sit down with a penguin and go through,

00:42:44 I want to see the notes from his prior therapist.

00:42:47 But this actually is relevant,

00:42:51 not knowing what was that penguin’s motivation.

00:42:54 We have very clear situations

00:42:57 where there are both within an individual,

00:42:59 we go through periods of time when we stay in one place

00:43:03 and we reap the benefits from what we’ve built.

00:43:06 And then we go through periods of foraging, of wandering.

00:43:11 Even if there may be resources where we are,

00:43:15 we have periods of time in our lives

00:43:17 where we wander, where we go in an exploratory mode.

00:43:22 And different people express that trait in different ways.

00:43:26 This is not a human specific trait.

00:43:27 If you go down to the tiny little nematode worm,

00:43:31 C. elegans with 302 nervous system cells,

00:43:34 they go through these phases of foraging and rest

00:43:37 and different individuals have different propensity

00:43:39 to forage or to rest and stay in one place.

00:43:42 At the level of the species, that’s really good

00:43:45 that there’s that diversity in their willingness to forage.

00:43:51 Some stay where they are,

00:43:52 the species is somewhat on a firm footing then,

00:43:56 but some carry a burden, a risk for themselves,

00:44:00 but it’s good for the species that they’re explorers

00:44:03 and they will venture out.

00:44:05 The migration patterns that different species blunder into

00:44:09 and that turned out to be really good,

00:44:10 they weren’t logically derived.

00:44:13 They most certainly started

00:44:15 from something like this, an exploration.

00:44:18 And humans do this too, you think?

00:44:19 And we do it too.

00:44:20 In fact, it’s something we do extremely well.

00:44:23 Let’s talk about psychiatry a little bit.

00:44:28 So in my book, you’re a rockstar.

00:44:30 First of all, for people who don’t know,

00:44:33 aside from sort of the neurological view of the brain

00:44:38 and neuroscience view of the brain,

00:44:40 you’re also one of the great psychiatrists of our time.

00:44:43 I’ve always, not always, but when I was younger,

00:44:45 I dreamed about being a psychiatrist.

00:44:49 So it’s like getting to meet your heroes

00:44:53 and also getting to meet the people who,

00:44:59 the best at the top of the world

00:45:01 at the thing you’ve failed to pursue.

00:45:03 So I’m getting a free therapy session on top of that.

00:45:07 Okay, so what big picture, what is the practice,

00:45:11 the goal, the hope of modern psychiatry?

00:45:13 If you could try to describe the discipline

00:45:17 as you see it, maybe historically

00:45:20 throughout the 20th century,

00:45:23 in contrasting to what it is today.

00:45:25 Or maybe if you want to describe

00:45:27 to what you hope psychiatry becomes

00:45:29 or longs to become in the 21st century.

00:45:34 It’s been an interesting journey.

00:45:36 Psychiatry started out pretty firmly grounded

00:45:39 in neurology and pathology.

00:45:40 Some of the initial founders effectively of the field

00:45:44 were very well grounded in microscopy, looking at cells,

00:45:49 working with patients, particularly on the neurological side,

00:45:52 and this certainly included Freud

00:45:54 and some of his contemporaries.

00:45:58 But they rapidly discovered that what they could work with

00:46:03 at the level of cells and microscopy

00:46:05 was so far from the realm of what they could get

00:46:09 from a human being and what they were getting

00:46:12 from the human being was so much more interesting

00:46:14 and was so mysterious and so unknown

00:46:17 that many of them just said,

00:46:18 we’re gonna inhabit this domain

00:46:20 and we’re gonna work with the people with their words

00:46:23 and understand what we can based on verbal communication,

00:46:27 because that was the only tool that people really had.

00:46:30 And that was a very important step for the field.

00:46:37 I would say one of the interesting things

00:46:39 that came from the early decades of psychiatry

00:46:42 really was this distinction

00:46:44 between the conscious and the unconscious mind

00:46:47 and paying particular attention to the unconscious mind

00:46:51 as something that was worthy of consideration

00:46:54 that might be important in explaining people’s actions

00:46:58 and that perhaps even insight into that was valuable

00:47:01 in its own right.

00:47:02 And out of that, psychoanalysis became a practice

00:47:07 that was not always focused on cures or treatments,

00:47:12 but was more focused on insight.

00:47:14 What does it mean?

00:47:15 How can we help people understand

00:47:17 why they’re feeling something or thinking something

00:47:19 or dreaming something?

00:47:22 And that insight separate even from treatment

00:47:24 was an interesting thing.

00:47:26 As long as one was honest about that

00:47:28 and said we’re going for understanding,

00:47:31 we’re going for insight.

00:47:32 Maybe it’s useful to just pause on that.

00:47:34 If we look at the father of psychoanalysis, Zygmunt Freud,

00:47:40 what do you make of the ideas that he had?

00:47:43 So you mentioned taking the unconscious,

00:47:46 the subconscious seriously.

00:47:49 That’s like step one,

00:47:50 like that there could be worlds

00:47:52 we do not have direct access for

00:47:53 and we probe at them through conversation

00:47:57 or is that too simplistic

00:48:00 to call psychoanalysis conversation?

00:48:03 That’s not too simplistic, but that’s right.

00:48:05 And I think that was valuable.

00:48:06 Where Freud ended up breaking

00:48:09 from some of his contemporaries,

00:48:10 he was very focused on this unconscious

00:48:13 as being so tightly linked to libido.

00:48:15 And really from his perspective,

00:48:18 you couldn’t really separate the operation

00:48:20 of the unconscious mind from these aspects

00:48:22 of the libidinous aspects.

00:48:24 And that was one reason.

00:48:25 What’s a libidinous aspect?

00:48:25 You know, sexually related drives.

00:48:29 Carl Jung, who was his contemporary,

00:48:33 that’s one factor that led to them separating

00:48:36 was Carl Jung felt there was a lot more

00:48:39 to the unconscious than this libidinous aspect of it.

00:48:42 And he saw it as a much more complete

00:48:47 alternate representation of the conscious self,

00:48:50 one that maybe reflected a whole range

00:48:53 of different motivations and desires.

00:49:00 And to properly treat it one had to consider all of them

00:49:04 rather than the ones that Freud was focused on.

00:49:06 Carl Jung, shut your mouth.

00:49:08 Thank you.

00:49:09 Thank you for the high level of images

00:49:13 that Sergei’s pulling up.

00:49:14 For people who are just listening,

00:49:15 he pulled up a quote from Sigmund Freud’s meme,

00:49:19 your mom quote Freud.

00:49:23 So the shadow, the Carl Jung shadow encompasses everything,

00:49:28 not just the desire to have sex with your mother

00:49:31 or sex period.

00:49:32 That’s right, that’s right.

00:49:34 If you look at those two folks en masse,

00:49:38 I mean, there’s a kind of,

00:49:39 it’s almost like a technique for philosophical exploration

00:49:44 of human mind, human motivations.

00:49:47 So it’s not even like necessarily,

00:49:49 it’s also doubles as a methodology for helping people,

00:49:53 but it’s almost like a,

00:49:56 it’s a kind of philosophical method.

00:49:59 Right, this is the fascinating thing about psychoanalysis.

00:50:03 And even though it’s, I would say,

00:50:06 mostly not considered a treatment today,

00:50:10 it persists for a couple of reasons.

00:50:11 One is it’s thought that it gives people some insight.

00:50:15 But second, there’s been a huge influence on literature,

00:50:19 on philosophy, on art.

00:50:22 And the opening up of discussion

00:50:24 about what was below our conscious mind

00:50:27 was so fertile in the implications

00:50:31 that it sort of reverberated and still does

00:50:34 throughout all these different realms of human endeavor

00:50:37 from different artistic experiences that people have

00:50:42 that can be colored by this concept of the unconscious.

00:50:50 Now, the other thing that was interesting

00:50:51 is this distinction,

00:50:55 you know, what are the parts of the unconscious?

00:50:57 And so there were these id and ego

00:51:00 and superego subdivisions that,

00:51:05 you know, that Freud, for example, would talk about them.

00:51:09 And the id was the primary, the primal drives

00:51:13 that an infant would have or that a very young child

00:51:16 just warmth and feeding and then later

00:51:19 the sexual or libidinous aspects.

00:51:22 And for Freud, the later happened very quickly.

00:51:25 That’s the controversial thing about him, I think.

00:51:29 I guess he thought like even children had sexual desires,

00:51:32 that they’re like dealing with, contending with.

00:51:35 So it’s the full thing.

00:51:36 Hungry, wanting to eat, wanting to poop,

00:51:38 wanting to have sex.

00:51:39 Yeah, and he was extremely focused on that aspect.

00:51:43 But then there was the superego,

00:51:46 which brought on these later sort of moralistic

00:51:51 sort of codes of conduct.

00:51:52 And that, of course, was very often in tension,

00:51:56 but all this could play out subconsciously.

00:51:58 And then the ego, this third aspect was mediating,

00:52:01 and Freud’s conception mediated this tension

00:52:04 between the different parts.

00:52:06 Now, I think that’s interesting.

00:52:08 I will say that in some ways, it’s maybe unnecessary

00:52:14 from the perspective of modern neuroscience

00:52:16 to divide things up that way from the moralistic drives

00:52:23 and the primal gratification drives.

00:52:27 In some ways, they’re all drives,

00:52:29 and maybe they’re even all primal drives.

00:52:31 The moralistic drives, they’re taught,

00:52:34 and they’re taught in ways that ultimately relate

00:52:37 back to survival, and you could even say,

00:52:42 selfish aspects of health and life

00:52:46 for the self and family.

00:52:47 And so this is, I think it’s maybe an artificial distinction.

00:52:53 The concept of the unconscious is very valuable

00:52:56 and very interesting, but these categorizations

00:52:59 of id and superego may not map onto neurobiology

00:53:05 in any particular way.

00:53:07 If there’s a town hall of competing drives and desires,

00:53:10 and they interrelate to each other,

00:53:13 they involve different aspects of the brain

00:53:16 and the history of the person,

00:53:18 and actions and choices come out of the result

00:53:22 of that overall shouting in the town hall.

00:53:25 So in some sense, Carl Jung was a step into the direction

00:53:27 of liberating yourself from such harsh categorizations.

00:53:32 Do you think, I mean, you have Daniel Kahneman

00:53:35 with System One and System Two.

00:53:37 There’s just these very compelling categorizations

00:53:40 of the human mind that seem to be sticky

00:53:46 in the superego, no, in how we talk about these ideas

00:53:51 and so on.

00:53:52 Do you think those are helpful or do they get in the way?

00:53:55 Is it some kind of balance in terms of deeper understanding

00:53:57 of how the mind actually works?

00:53:59 You know, it’s from modern neuroscience,

00:54:02 whenever we seem to get closer to addressing a question

00:54:08 like this at the level of cells,

00:54:10 it seems to get farther away.

00:54:12 And I’ll give you an example of what I mean by that.

00:54:14 So one thing I’m doing in my laboratory

00:54:16 and many people are doing is we are listening in

00:54:20 on the activity of cells, neurons in the brain

00:54:24 of mice or rats or fish or monkeys.

00:54:27 Individual cells.

00:54:28 Individual cells, exactly.

00:54:29 Of which there are, in our brain, many billions.

00:54:33 And when we do and we try to predict

00:54:37 what action will be taken by an animal

00:54:40 to address this question, where does the choice arise?

00:54:43 Where does the impetus to make a particular selection

00:54:47 of one action versus another action,

00:54:48 where does that start in the brain?

00:54:50 If you’re recording, listening in on the activity of cells

00:54:52 all across the brain, where’s the earliest spot

00:54:56 you can pick up a choice being made?

00:55:00 Well?

00:55:01 That’s so awesome.

00:55:02 Yeah, at one level, you might think,

00:55:04 how excited would Jung have been to see this

00:55:07 or Freud or the early psychoanalyst

00:55:10 to see where this starts.

00:55:12 But it’s not so simple because an emerging theme

00:55:15 in very recent neuroscience,

00:55:17 literally over the last few years,

00:55:19 is that things sort of all start together

00:55:23 all across the brain.

00:55:24 And so you can be recording from the cortex,

00:55:27 this rim of cells at the surface of the brain,

00:55:29 or you can be recording deeper

00:55:31 in a structure called the striatum,

00:55:33 which is a little older.

00:55:34 It’s more tightly linked to action.

00:55:38 And then structures called the thalamus,

00:55:40 other parts of the brain.

00:55:41 And if you record from these,

00:55:43 these all sort of represent the action and the choice

00:55:48 more or less all at about the same time, very close.

00:55:51 And so you can’t point to a particular spot and say,

00:55:56 here’s where the choice or the action originates.

00:55:59 It’s a group.

00:56:00 Finding the free will neuron.

00:56:03 It’s relevant to that question.

00:56:05 Nobody is close to being able to point to such a thing.

00:56:08 Well, close is a relative term.

00:56:11 And nobody, what I tweet today,

00:56:16 all generalizations are wrong.

00:56:19 So including this one.

00:56:21 Let’s actually talk about that.

00:56:22 So the study of individual cells.

00:56:25 If you could linger on your sense

00:56:27 that as you get closer to that understanding,

00:56:30 it feels like you’re getting farther away.

00:56:33 Why is that?

00:56:34 Because that often is the feeling

00:56:36 until you’re actually there.

00:56:38 So like, you know, see that’s when I’m running

00:56:42 and I know there’s only a mile left,

00:56:44 it just feels like that mile

00:56:46 is just getting longer and longer,

00:56:49 but eventually you finish.

00:56:50 So maybe we’re getting close

00:56:51 to cracking open these beginnings of a sense,

00:56:54 like we’ll talk about consciousness

00:56:56 or these very difficult, big questions

00:56:59 about the human mind.

00:57:00 Where do they start?

00:57:02 You’re right to say we shouldn’t generalize

00:57:04 or make absolutist statements,

00:57:06 but I would say right now,

00:57:09 the reason things are looking even harder to crack

00:57:12 than we had initially thought,

00:57:14 we now have the data streams

00:57:16 that we’ve wanted for so long

00:57:18 in terms of activity patterns all across the brain

00:57:22 at the level of cells.

00:57:23 We can literally see what the cells are doing.

00:57:26 Immense data sets.

00:57:27 You know, we get, these are time series

00:57:30 of one individual cell with sub second resolution

00:57:34 and you can collect this from enormous numbers of cells

00:57:36 across the brain.

00:57:38 So very rich data sets that we’ve wanted for a long time

00:57:40 and yet having these has not led

00:57:44 to an understanding of truly where actions

00:57:48 initiate in terms of regions or locations.

00:57:51 And let’s get a few questions on that.

00:57:54 Is the answer, high level question by your intuition,

00:57:59 is the answer within the data?

00:58:01 Or do we need different kind of data?

00:58:04 So we should also say that when you collect data

00:58:07 about the brain, there’s like the richness

00:58:10 of information you’re collecting,

00:58:12 but there’s also human doing stuff.

00:58:14 And information, so static information about the human

00:58:20 and dynamic information about the human

00:58:23 and you can get them to do different stuff

00:58:25 and you can select different humans

00:58:27 and that’s part of the collection of data aspect.

00:58:30 So like when you’re collecting data about the brain,

00:58:33 there’s some truths that you can,

00:58:36 you know, in machine learning is like annotations,

00:58:38 like supervised learning.

00:58:39 There’s some true things you can hold on to

00:58:42 before you look at the full rich mess complexity

00:58:46 of the human mind.

00:58:47 So given the data you’ve looked at,

00:58:50 do you think the answer for the origin of free will

00:58:54 in the human mind can be found?

00:58:58 Well, one amazing thing is that nobody’s found it,

00:59:04 but we have these rich data sets

00:59:05 and then there’s a conundrum which is,

00:59:09 is it in the data and we just don’t know

00:59:11 how to look at it.

00:59:12 Maybe we don’t know the right scale,

00:59:13 the right projection to make of the data,

00:59:15 the right way to interpret it.

00:59:17 And here’s where causal testing becomes very valuable

00:59:21 because then instead of just passively observing,

00:59:25 well, here are the activity patterns

00:59:28 and then here’s the choice made by the animal.

00:59:32 As we’ve gotten more powerful at reaching in

00:59:36 and causing things to happen in the brain,

00:59:38 turning up or down the activity

00:59:40 of certain types of cells or defined populations of cells

00:59:44 and seeing how that affects actions,

00:59:46 these causal perturbations have turned out

00:59:48 to be very valuable.

00:59:50 We’re just now getting to the point

00:59:52 where we can apply these in very wide swaths of the brain

00:59:58 at cellular resolution and so we’re gonna be able,

01:00:01 hopefully to make some headway on this question

01:00:03 with causality and that’s the one thing

01:00:07 that optogenetics provides us this way of using light

01:00:10 that we develop to control cells.

01:00:12 This is an untapped, relatively untapped

01:00:15 at this broad brain wide scale

01:00:17 and hopefully we can get there in the near future.

01:00:18 But I would say that the answer may be in the data

01:00:22 but we don’t know how to find it.

01:00:24 Well, there’s this interactive element

01:00:26 like where you can cause stuff that’s really powerful

01:00:28 because you get to, I mean,

01:00:31 as opposed to collecting data passively,

01:00:33 you get your collecting data actively.

01:00:35 So can you maybe describe one of the many things

01:00:38 you’re known for, one of the big things

01:00:40 is called optogenetics, what is it?

01:00:43 Optogenetics is a way of causing things to happen.

01:00:46 It’s a way of determining what actually matters

01:00:50 in terms of the activity of the brain

01:00:52 for the amazing things it does,

01:00:55 sensation, cognition, action.

01:00:58 And what it does is it provides activity.

01:01:01 It’s a way of playing in, if you will,

01:01:04 activity patterns into precisely defined cells.

01:01:07 And the way we do it is pretty cool, I think.

01:01:09 It’s, you know, right away there’s a problem

01:01:12 if you think about how do we do this?

01:01:13 How could we play in well defined activity patterns

01:01:16 and provide a stream of activity into this cell

01:01:20 and that cell and that cell but not these other cells?

01:01:22 So just for context, we’re talking about the brains

01:01:25 of mice, monkeys, humans,

01:01:32 and then the goal is to try to control accurately

01:01:35 the behavior of a single neuron

01:01:38 and then to be able to monitor single collection

01:01:42 of single neurons to then say, well,

01:01:45 to draw some deeper insight about the origins,

01:01:50 first of all, the function of different parts of the brain,

01:01:53 different neurons, different kinds of neurons,

01:01:54 but also the origins of the big things,

01:01:57 the flap of the butterfly wing that leads

01:02:00 to an actual behavioral thing.

01:02:03 Yeah, so if you could, exactly, so if you could turn on

01:02:06 or off the brain or parts of the brain or cell types

01:02:10 or individual cells at the natural rate and rhythm

01:02:15 and timing of normal brain activity,

01:02:18 that would be immensely valuable

01:02:19 because you could determine what actually mattered,

01:02:21 what could cause complex things to happen

01:02:23 and what could prevent complex things from happening

01:02:26 in a specific way.

01:02:27 But right away, you’ve got a problem if you wanna do this

01:02:29 and scientists, neuroscientists have wanted to do this

01:02:33 for a long time.

01:02:34 Francis Crick of Double Helix of DNA fame,

01:02:37 he wrote a famous paper in 1999.

01:02:40 He got interested in neuroscience later in life

01:02:43 and he said, what we need in neuroscience is a way

01:02:47 that we could turn on or off the activity

01:02:50 of individual types of neurons in a behaving animal.

01:02:56 And he even said the ideal signal would be light

01:03:00 because it would be fast, it could penetrate

01:03:04 through the brain to some extent.

01:03:07 And he had no idea how to do it.

01:03:10 He said this would probably be very farfetched,

01:03:13 but it would be a good thing.

01:03:15 And so that’s what you’re actually saying,

01:03:17 like if you wanna do this kind of thing

01:03:19 and you imagine like, how do I get inside the brain?

01:03:22 It’s pretty difficult.

01:03:24 It’s pretty difficult and then even once you get in,

01:03:26 it’s hard because all brain cells are electrical,

01:03:29 all neurons are electrically activated.

01:03:31 And so if you wanted to use electricity

01:03:34 as what you were putting in,

01:03:37 you won’t have any specificity at all.

01:03:39 If you have an electrode, a wire,

01:03:41 and you put it in the brain and you send current through it,

01:03:44 all the cells near the electrode will be stimulated.

01:03:48 That’s like trying to control fish

01:03:50 by spraying them with water.

01:03:53 Yeah, right, because there’s already a lot of electricity

01:03:56 going around anyway and you’re adding more,

01:03:58 but there’s no specificity

01:04:00 even among the different kinds of cells either

01:04:02 because all around the wire that you’ve put in,

01:04:05 there are gonna be so many different cells

01:04:06 doing totally different things,

01:04:08 many of them in opposition to each other.

01:04:10 We know that’s one way the brain is set up.

01:04:12 There are parts of the brain

01:04:14 where neurons side by side

01:04:16 are doing completely different things

01:04:17 and maybe even antagonistic to each other.

01:04:20 So what do you do?

01:04:21 How do you play in activity with any kind of specificity?

01:04:23 Well, what you do is use,

01:04:26 what we found is what you can do is

01:04:28 make some cells responsive to light.

01:04:33 Now, normally no cells deep in the brain

01:04:36 really respond to light.

01:04:37 They’re not built for that.

01:04:39 There’s no reason for them to respond to light in there,

01:04:42 which is a great situation to start with

01:04:45 because any light sensitivity you can provide to some cells

01:04:48 will be a huge signal above the noise.

01:04:51 And so that’s what we do with optogenetics.

01:04:53 We take genes, bits of DNA from microbes,

01:04:59 single celled organisms,

01:05:02 and these single celled organisms like algae,

01:05:05 they make little proteins

01:05:09 that sit in the surface of their cells

01:05:11 that receive light, capture a photon of light

01:05:15 and open up a little hole in the membrane of the cell

01:05:18 and let charged particles, ions like sodium and potassium

01:05:21 flow across the membrane of the cell.

01:05:24 And that, these algae and bacteria,

01:05:27 they do this for their own reasons

01:05:28 because that helps them move,

01:05:30 it helps them make and use energy.

01:05:34 But that’s a beautiful thing for neuroscience

01:05:36 because movement of ions,

01:05:38 charged particles across the membrane of the cell

01:05:40 is exactly the kind of electricity that neurons work with.

01:05:43 So if we can take this bit of DNA

01:05:47 that encodes this beautiful protein

01:05:48 that turns light into electricity from algae,

01:05:51 and if we can put it into some neurons,

01:05:54 but not other neurons, which we can do using genetic tricks,

01:05:58 then you’ve got a situation,

01:05:59 then you can shine on the light

01:06:01 and only the cells that have the gene

01:06:03 and that are expressing the gene

01:06:05 will be the initial direct cells

01:06:08 that are activated by the light.

01:06:09 And so that’s the essence of optogenetics

01:06:10 is the ability to do that.

01:06:12 We get that initial specificity

01:06:14 that you could never get with an electrode.

01:06:15 So let me say that this is,

01:06:18 we recently got the Alaska Prize for this.

01:06:22 It’s a brilliant idea.

01:06:25 So I talked to Andrew Huberman,

01:06:28 who’s a friend of yours, friend of mine,

01:06:32 so not to jinx things,

01:06:33 but he believes that you deserve the Nobel Prize for this.

01:06:36 So, I do too, but what, my votes.

01:06:42 Anyway, the thing is, it doesn’t matter.

01:06:44 Prizes will be all forgotten, all of us will be forgotten.

01:06:47 When the cool idea is a cool idea,

01:06:49 that’s a really powerful idea.

01:06:51 It’s actually, the origins of it

01:06:53 you might be interested in are even, are very deep.

01:06:57 There was a botanist in St. Petersburg

01:06:59 named Andre Fomensen.

01:07:01 In 1866, he published a paper

01:07:05 on the single celled green algae.

01:07:07 And he was the botanist who first noticed

01:07:09 that they moved in response to light.

01:07:12 These are tiny single celled algae that have flagella,

01:07:14 so they swim through the water.

01:07:16 And he noticed this, he was a botanist,

01:07:20 and he published this.

01:07:21 It was a paper, you know, he wrote in German,

01:07:26 but he published it in a French journal,

01:07:27 and he was doing it from St. Petersburg,

01:07:29 so it was a very international effort.

01:07:32 But you have to go back to 1866,

01:07:34 and that, I like to highlight how far back

01:07:37 that discovery goes is back to Andre Fomensen.

01:07:40 And this is a, it highlights the value

01:07:44 of just pure basic science discovery.

01:07:45 That always originates somewhere

01:07:48 in the Eastern European block.

01:07:50 But I don’t think he expected the splicing

01:07:53 of genetic material from the algae into the human brain.

01:07:57 And one of the cool things we’ve been able to do now

01:07:59 with modern methods is to really study these proteins.

01:08:02 And so we’ve discovered some of these proteins,

01:08:04 other groups have as well.

01:08:05 We’ve dived deep into their structure,

01:08:07 just like the double helix structure of DNA

01:08:09 was uncovered with X ray crystallography.

01:08:12 We used the same method in X ray crystallography

01:08:14 to see how these beautiful little proteins work.

01:08:18 We reengineered them for all kinds of function.

01:08:20 We can make them, instead of responding to blue light,

01:08:22 we can make them respond to red light.

01:08:24 We can speed them up, slow them down.

01:08:26 We can make them, with genetic engineering,

01:08:28 we can make them have different ions flow through them.

01:08:32 And so it’s this convergence, as you said,

01:08:34 like the botanist in 1866 couldn’t have predicted

01:08:36 what we could do with this.

01:08:38 And the fact that we’ve been able to discover

01:08:40 how these beautiful proteins work

01:08:42 and then apply them to neuroscience

01:08:45 is really a thrilling story.

01:08:46 Is it possible to achieve scale, do you think, with this?

01:08:49 Meaning, like what is the progress of the next 50 years,

01:08:53 100 years looks like in terms of the precision

01:08:56 and the scale of control of using light?

01:08:59 It’s going so fast it’s hard to predict.

01:09:02 I’ll give you a sense of it though.

01:09:06 First paper we published in 2005,

01:09:11 that was just encultured neurons.

01:09:12 By 2007, so that was in a dish.

01:09:14 By 2007, we had it working in behaving mice.

01:09:17 By 2009, we had it pretty general.

01:09:20 So we had methods to really make it a versatile method.

01:09:23 It could be applied to essentially any cell.

01:09:26 By 2012, we could get to single cell resolution.

01:09:29 We used light guidance strategies

01:09:31 to target individual cells in the brain of a living mouse.

01:09:36 By 2019, we were able to control up to 20 to 50

01:09:42 individually specified single cells

01:09:44 in the brain of a mouse in ways that specifically changed

01:09:48 its behavior, that could bias its decisions one

01:09:50 way or the other.

01:09:51 In fact, we could take a mouse and without any visual stimulus

01:09:58 at all, we could make it act as if it

01:10:01 had seen a particular visual stimulus

01:10:03 by playing in, using the single cell resolution optogenetics,

01:10:07 a specific pattern of activity into 20 or 25

01:10:11 individually specified cells.

01:10:12 That’s 2019 to your question of scale.

01:10:15 Now in 2022, we’re controlling hundreds

01:10:18 of individually specified single cells

01:10:20 over all of visual cortex of a mouse, all the part

01:10:24 of the brain that is the initial direct target

01:10:28 of the incoming information from the retina.

01:10:31 Are you constrained to specific types of cells currently?

01:10:34 Like you mentioned, long range is easier.

01:10:36 Is there constraints on which cells?

01:10:39 Now there really isn’t.

01:10:41 Now that we have this individual cell guidance,

01:10:43 we can target any individual kind of cell very reliably.

01:10:48 And so now to your question of scale, how far can we go?

01:10:55 Well, things are moving quickly.

01:10:58 It’s hard to say.

01:11:00 We can access individual cells across the entire brain now.

01:11:04 If you look 10, 20 years in the future,

01:11:09 I think we’ll surprise ourselves.

01:11:11 But the fact that we’re already able to cause

01:11:14 specific perceptions to happen and specific actions

01:11:17 means we’re essentially where we want to be.

01:11:19 And now it’s a matter of just more experiments,

01:11:25 more discoveries.

01:11:26 But the basic principles are clear now.

01:11:29 The basic capability is there.

01:11:32 Is there a pathway to doing the same for humans?

01:11:36 Optogenetics is primarily, it’s a discovery tool

01:11:38 that really is well suited for use in mice and rats

01:11:41 and monkeys because it involves putting in a gene

01:11:48 and also delivering light.

01:11:49 And those are two things that you can do in human beings,

01:11:52 but you’d want to do in a very careful way.

01:11:55 Now that said, there is actually just less than a year ago,

01:11:59 my friend Botan Droska in Switzerland,

01:12:02 he did the first human optogenetics therapy.

01:12:07 And he published this in the journal Nature Medicine.

01:12:10 So about 10, 12 years ago, he and I

01:12:14 published a paper together where we gave him

01:12:17 one of our optogenetic tools, one

01:12:21 of these light activated regulators of ion flow.

01:12:26 These are called microbial opsins, by the way, opsins.

01:12:29 And he put one of those into an extracted retina

01:12:33 from a human being who had died.

01:12:35 So it was a cadaveric retina.

01:12:37 And he was able to show that optical control in this paper

01:12:43 was able to turn on or off individual cells

01:12:45 in the human retina.

01:12:46 So that was a while back.

01:12:48 He spent about 10 years of going through all the regulatory

01:12:53 hoops and hurdles and going through primate studies.

01:12:56 And finally, he was able to take a human being

01:13:00 with a retinal degeneration syndrome, so someone

01:13:03 who was blind in both eyes.

01:13:06 And he gave one of these opsins into one eye of this human

01:13:12 being who was blind and with the goal

01:13:16 of conferring light sensitivity onto this retina that

01:13:20 was not able to see light.

01:13:23 And he was able to make this person see through that eye.

01:13:26 So he took a blind person.

01:13:27 And the blind person could see now,

01:13:29 could reach for objects selectively on a table.

01:13:33 And he published this in Nature Medicine.

01:13:36 And it was, you know, that’s an amazing thing.

01:13:39 Do you know the title of the paper?

01:13:40 What’s his name again?

01:13:41 Rosca, R O S K A.

01:13:43 And you look up the Nature paper.

01:13:45 Nature Medicine.

01:13:46 Nature Medicine.

01:13:47 So that’s sort of proof of principle.

01:13:49 Now, the retina is very accessible.

01:13:51 It’s near the surface.

01:13:52 You can use natural light, or you

01:13:54 can use brighter natural light.

01:13:57 I’m myself, I see optogenetics as a discovery tool.

01:14:01 It’s a way to figure out the principles by which the brain

01:14:04 works and how it operates.

01:14:05 Partial recovery of visual function

01:14:07 in a blind patient after optogenetic therapy.

01:14:10 So he went through the full process of doing primates

01:14:14 and then going, wow, that’s dedication

01:14:17 and that’s really exciting to see.

01:14:20 As beautiful as that is, and I’m glad he did all that work,

01:14:23 there are so many other ways that optogenetics

01:14:27 could help with therapies.

01:14:28 Once you know the principles, then any kind of therapy

01:14:31 can become more powerful.

01:14:32 Once you know the causal cells in a symptom,

01:14:36 like in lack of motivation or inability

01:14:40 to enjoy things or altered sleep or altered energy,

01:14:43 once you know the cells that are causal,

01:14:46 then you can make medications that address those cells.

01:14:49 You could address brain stimulation treatments that

01:14:52 might address those cells.

01:14:53 Also, diagnosis, very effective systematic way of diagnosing,

01:14:58 or at least providing you rich data

01:15:01 to some of these deep questions about schizophrenia,

01:15:04 about bipolar, all of those kinds of things.

01:15:08 The tools are low resolution currently

01:15:11 for determining the degree to which you have a thing

01:15:15 and whether you have a thing at all.

01:15:17 Yeah, exactly.

01:15:18 And so the hope is that’s a great example

01:15:23 of how you can cure or you can provide

01:15:27 some relief for a symptom of a person who has

01:15:30 a serious degenerative disease.

01:15:33 But the principles are what we’re after,

01:15:36 and that’s why I spend, even though I’m a psychiatrist,

01:15:39 even though I still see patients, I’m not myself

01:15:42 trying to drive any clinical trials in the lab.

01:15:45 I’m trying to discover, and then any kind of therapy

01:15:49 could result from that.

01:15:50 What do you think about my friend,

01:15:54 Elon Musk, and his efforts with Neuralink?

01:15:58 So this is another, there’s a lot of things to say here,

01:16:02 because there’s a lot of ideas under the umbrella

01:16:05 of Neuralink, but one of them is to use electrical signals

01:16:09 to stimulate, and then you also record,

01:16:13 you collect electrical signals from the brain

01:16:15 at a higher and higher resolution,

01:16:17 and you go implant surgically the methods

01:16:22 by which you do the stimulation and the data collection.

01:16:26 So it’s possible for the ideas of optogenetics

01:16:30 to play well with this, and we can even zoom out

01:16:34 outside of just Neuralink, and just the whole idea

01:16:36 of brain computer interfaces.

01:16:39 What are your thoughts?

01:16:41 Well, I think the engineering that they’ve done

01:16:43 is actually pretty cool.

01:16:44 So I like the.

01:16:46 Robots.

01:16:47 Yeah, from the design perspective,

01:16:49 and it was a design approach that wasn’t being taken

01:16:53 in academia, and it’s great that they did it,

01:16:55 and I think it’s pretty cool.

01:16:57 So I’ll say that.

01:16:59 Also, there are many ways that you can record

01:17:01 from many thousands of neurons, and that’s not the only way.

01:17:06 It’s a very interesting way.

01:17:08 We and others are using brain penetrating electrodes

01:17:12 that actually get quite deep.

01:17:14 This whole structure of the brain is very interesting.

01:17:16 There’s the surface cortex, where it’s the most recently

01:17:20 emergent part of the brain in evolution.

01:17:23 Mammals have it.

01:17:24 Reptiles have something a little bit like it,

01:17:27 but it’s not really the full thing.

01:17:29 This is a very recent thing.

01:17:31 That’s what we can access with some of these,

01:17:33 like the Neuralink approach,

01:17:35 and with some of these short electrodes.

01:17:38 This part of the brain, the cortex,

01:17:39 is only a few millimeters thick.

01:17:40 There’s so much that’s deep, though, that’s so important.

01:17:42 There’s the striatum, there’s the thalamus.

01:17:44 There are the parts of the brain that drive motivation,

01:17:49 that drive hunger and thirst and social interaction

01:17:52 and parenting and flight and fear and anxiety.

01:17:58 All these things are, there’s so much that’s deep

01:18:00 that these surface approaches are not getting to.

01:18:02 And so we and others are using these very long electrodes

01:18:06 that help us get deep, and we can still record

01:18:08 for many cells, many thousands of cells.

01:18:11 We can have multiple of these at once in the same animal.

01:18:15 And so there’s a diversity of methods to get to this goal.

01:18:18 I think it’s great that people coming from

01:18:24 outside academia will bring ideas

01:18:26 that weren’t being worked on, at least approaches.

01:18:29 They may turn out to be synergistic.

01:18:31 These things do work very well with optogenetics

01:18:33 because all these electrical recording methods,

01:18:37 that’s one channel of information flow.

01:18:39 Light delivery is a separate, more or less independent.

01:18:43 There can be some artifacts that happen,

01:18:45 but if you’re careful,

01:18:46 it’s another independent pathway of information flow.

01:18:49 And we’ve done really fun experiments in mice

01:18:53 where we play in patterns of activity with light,

01:18:56 and we record activity from across the brain of a mouse

01:18:59 electrically, and so using optical and electrical together

01:19:02 is extremely powerful.

01:19:04 So like optoelectric brain computer interfaces.

01:19:09 Which, by the way, there’s efforts on the computing side

01:19:13 to build optoelectric servers,

01:19:16 so like where you have both electricity.

01:19:17 So because optics is really interesting,

01:19:20 light is a very interesting method of communication

01:19:22 that’s, like you said, orthogonal in many ways.

01:19:26 It doesn’t have some of the constraints of bandwidth

01:19:28 that electricity does going through wires,

01:19:32 but you’re able to,

01:19:34 but less ability to control precisely at scale.

01:19:38 So like there’s challenges and there’s benefits,

01:19:40 and having those two interplays

01:19:42 really, really, really fascinating,

01:19:44 especially when obviously on the other side

01:19:46 of your signal is a biological mesh, mush, mushy mesh.

01:19:51 Well, the mushy mesh is kind of interesting

01:19:54 because there are problems with light.

01:19:56 Light scatters in the brain,

01:19:57 so the photons don’t just go linearly through.

01:20:01 Whenever they hit an interface between fat and water,

01:20:04 lipid and water, they bounce off in different directions.

01:20:08 And so you can come in with all the resolution you want.

01:20:10 You could play in an incredibly detailed,

01:20:13 high resolution pattern of light,

01:20:15 but the photons start scattering quite quickly,

01:20:18 and by the time you’ve gone a couple of millimeters deep,

01:20:20 you’ve lost almost all that fine spatial information.

01:20:24 So, but we’ve developed workarounds.

01:20:26 The longer wavelength light you use,

01:20:29 if you get into the infrared, there’s less scattering.

01:20:31 You can use two photon methods or three photon methods

01:20:33 where the photons have to arrive all together

01:20:36 at the same time.

01:20:37 You can put in fiber optics.

01:20:39 We developed these fiber optic methods in 2007

01:20:42 where you can access these deep structures

01:20:44 with fiber optic methods,

01:20:45 and you can put many of these fiber optics

01:20:46 at the same time in an animal.

01:20:48 We’ve used holographic methods, 3D holograms,

01:20:53 to play in hundreds of individual cell size spots of light,

01:20:56 and we can change those quickly.

01:20:59 So there are a lot of tricks,

01:21:00 a lot of interesting optics engineering

01:21:01 that has come together with neuroscience

01:21:03 in a pretty exciting way.

01:21:04 Well, that is engineering, too.

01:21:06 It was just super, super, super exciting.

01:21:07 I should mention, because I remember I mentioned Elon.

01:21:10 I recently got, for the first time ever, got COVID.

01:21:15 Well, how did I go so long without,

01:21:21 finally, so I’m all vaccinated and everything like that.

01:21:24 And so I got, because I think he mentioned it publicly

01:21:27 so I can mention it,

01:21:28 but I won’t mention anybody else involved.

01:21:30 But hanging out, we all got, Elon got COVID.

01:21:33 And the interesting thing about,

01:21:35 maybe you can comment about this.

01:21:36 So I was only sick for like a half a day.

01:21:38 I got a fever of like 104.

01:21:40 I just went up and then crashed.

01:21:44 And then I was, now maybe I’m just seeing

01:21:47 the silver lining of everything,

01:21:48 but afterwards, I have like a greater clarity

01:21:54 about the world.

01:21:57 You just think it’s greater clarity.

01:21:58 Maybe, maybe I just, it was so,

01:22:01 maybe so intensely the mind fog kind of thing

01:22:06 for such a short amount of time.

01:22:07 But the people who were involved were also reporting this.

01:22:12 It’s kind of interesting.

01:22:13 It’s like, because I do know like the immune system

01:22:18 is involved with the brain in very interesting ways.

01:22:21 So like the human mind also incorporates all these other,

01:22:24 it’s not just the, it’s not just the nervous system.

01:22:28 And I just wonder, because everyone always says,

01:22:30 no, not like, everyone always says like COVID

01:22:32 does all these bad things or whatever the disease is

01:22:34 or whatever the virus.

01:22:36 But I wonder like, I hate to be a Steven Pinker on this,

01:22:39 but like, I wonder what the benefits of certain disease are

01:22:42 if you’re able to recover.

01:22:43 Like what, is there some like, again,

01:22:46 don’t want to romanticize it,

01:22:47 but if your system goes to some kind of hardship

01:22:50 and you come out on the other end,

01:22:51 I wonder sometimes if there’s a greater,

01:22:54 maybe killed off a bunch of neurons

01:22:56 that didn’t need anyway,

01:22:57 and they were actually getting in the way.

01:22:58 There were the hater neurons.

01:23:00 I don’t know.

01:23:01 Well, that was your inner critic that I was talking about.

01:23:02 Exactly.

01:23:03 You killed off your critic.

01:23:05 Well, you know, there are mechanisms for what you,

01:23:07 the potential mechanisms for what you’re talking about.

01:23:10 There are, there’s actually been a fair bit of research

01:23:13 on post COVID neurological function.

01:23:18 Actually, my wife, Michelle Monjay, who’s at Stanford,

01:23:20 she’s done a lot of this work.

01:23:22 Akiko Iwasaki at Yale has done a lot of this.

01:23:25 But what they found is that there’s a loss of myelin.

01:23:30 This is the coating of those long range projections

01:23:33 that go from one part of the brain to another.

01:23:35 Myelin is this sort of insulator

01:23:37 that coats these long range projections

01:23:39 and makes the impulses go faster and more reliably.

01:23:43 And there’s altered function of the myelin producing cells

01:23:49 and altered myelin in the case of COVID.

01:23:52 They’ve looked in both mouse and human brains.

01:23:56 And, but of course it could be very idiosyncratic.

01:23:59 Many people have cognitive problems post COVID.

01:24:03 You’re definitely aware of that.

01:24:04 So many people report this persistent brain fog

01:24:07 and the ability to function.

01:24:08 But it depends on where the inflammation was.

01:24:11 Maybe the people who have dysfunction post COVID,

01:24:14 they had a global effect.

01:24:17 Maybe you lost some of these projections

01:24:20 that were restraining you in some way.

01:24:23 And these plausibly exist.

01:24:25 And it’s known that there are cell populations

01:24:30 in the prefrontal cortex that actively restrain

01:24:33 deeper structures from expressing what they do.

01:24:36 And it’s theoretically possible that you had a lucky.

01:24:40 Somebody has to get lucky, right?

01:24:42 Somebody has to get lucky, yeah.

01:24:44 Why not me?

01:24:45 All right, if we can actually go back to this idea

01:24:48 of trying through optogenetics

01:24:53 to find origins of when the wave first starts.

01:24:59 Origins of a decision.

01:25:01 Origin of idea.

01:25:07 Origin of maybe consciousness

01:25:10 or the subjective experience.

01:25:12 So origin of things in the mind.

01:25:15 So one thing, Carl Jung, is there a God neuron?

01:25:21 Is there a belief neuron?

01:25:24 Is there, so through this methodology of optogenetics,

01:25:27 can you start getting to where a belief begins

01:25:34 or an idea begins?

01:25:37 And especially looking at the strongest of our beliefs.

01:25:41 Maybe beliefs of love and hate,

01:25:43 but religious belief into something really grand,

01:25:51 on the grandest of scale.

01:25:52 Yeah, neuroscience and neurology point us a little bit.

01:26:00 We don’t have an answer to that, but for example.

01:26:02 A lot of these questions I’m gonna ask you,

01:26:04 there’s no good answer, but you’re providing the tools

01:26:07 that give us hope to find the answer one day.

01:26:09 Yeah, and we have early clues.

01:26:11 So for example, when patients with epilepsy

01:26:14 have experiences of religiosity as part of their seizure

01:26:19 or the aura before their seizure,

01:26:22 very often those are in the temporal lobe,

01:26:26 in these parts of the brain that are at the side.

01:26:30 And so that’s an initial clue.

01:26:33 There are also parts of the brain that are involved

01:26:37 in the definition of the self

01:26:41 and defining the borders or boundaries of the self.

01:26:45 And we know this, this is some experiments that we did

01:26:48 in my lab, there’s a part of the brain

01:26:50 where if there’s a rhythm of a particular type,

01:26:55 you can cause a separation of the sense of self

01:26:59 from the sense of the body.

01:27:02 What’s normally bound up and unitary,

01:27:04 we normally think of ourself and our body

01:27:06 as pretty tightly bound up together,

01:27:08 those can be separated, it turns out.

01:27:09 We can’t take that for granted.

01:27:11 And there are certain conditions,

01:27:12 certain patterns of activity in one part of the brain

01:27:14 called the retro splenial cortex,

01:27:17 where you can actually separate those two out.

01:27:20 And so if you think about these very big questions,

01:27:25 you know, what is, where are the origins of religiosity?

01:27:29 Where, how do we define the boundaries of who we are

01:27:33 relative to others and to the world?

01:27:36 How do we link ourself to our body

01:27:40 and how can that become separated?

01:27:42 These are actually, believe it or not,

01:27:44 now accessible and rigorously and quantitatively so.

01:27:48 We did an experiment with optogenetics

01:27:50 where we provided this abnormal rhythm

01:27:54 to this particular part of the mouse brain

01:27:57 and we saw this separation of detection of a stimulus

01:28:02 and caring about it.

01:28:04 So that’s like stimulating something about the mouse brain

01:28:07 that affects these neurons that give the conception of self.

01:28:11 So you’re able to dissociate the experience

01:28:15 from the impact of the experience onto you.

01:28:17 That’s right, exactly right.

01:28:19 So like these are the goals of meditation.

01:28:23 These are the goals whenever I get drunk,

01:28:25 pretty much effective.

01:28:27 I mean, that’s not a scientific statement,

01:28:28 just an experiential anecdotal one.

01:28:32 Also psychedelics seek to this,

01:28:35 to attain this kind of state.

01:28:37 That’s so interesting.

01:28:39 Well, you mentioned psychedelics, you know,

01:28:40 DMT and 5MeO DMT, these create this religious experience,

01:28:45 this connection, people describe them

01:28:47 as a strong connection to God.

01:28:49 That in theory, these are accessible with modern methods.

01:28:53 Now that we have these rich recording methods,

01:28:56 we can explore what are the precise millisecond resolution,

01:29:01 cellular resolution, brain wide manifestations

01:29:05 of these altered states.

01:29:06 So like you could look at an altered state like on DMT,

01:29:11 record it across many people,

01:29:14 and then from there see where do these experiences

01:29:18 originate in the brain in terms of single neurons,

01:29:21 and then how do they propagate

01:29:25 and interact with everything else?

01:29:26 And if there’s some kind of common signal,

01:29:30 like how do you narrow down the set of neurons

01:29:34 that are responsible for particular experience

01:29:36 or for a particular behavioral effect?

01:29:38 Yeah, here’s where optogenetics is so useful

01:29:40 because anytime you give an agent like ketamine or PCP,

01:29:46 which we used for our dissociation experiments

01:29:49 that I was mentioning,

01:29:50 or you have a psychedelic LSD or DMT

01:29:55 for this altered perceptual state,

01:29:57 if you give either of those,

01:30:00 these change everything across the brain, okay?

01:30:03 So just the fact that you maybe give them to a mouse,

01:30:06 let’s say, or eventually to a human,

01:30:09 you won’t know yet which cells to home in on

01:30:13 as the causal players in all this

01:30:17 just by recording the activity.

01:30:19 But then what we found is that optogenetics

01:30:21 providing a causal pattern of activity

01:30:23 guided by what you see can let you test hypotheses.

01:30:28 And we saw this rhythm with ketamine and PCP

01:30:31 for dissociation, and then we said, okay,

01:30:33 let’s test what’s causal.

01:30:35 We came in and provided that rhythm.

01:30:38 We tried a few different things,

01:30:39 but only one of the causal tests we tried

01:30:41 actually caused the behavioral dissociation.

01:30:45 And so that’s how we home in on what actually matters.

01:30:47 And is it repeatable once you see the causality?

01:30:49 So like that’s one definition of causality

01:30:51 is like you try and it repeats across different mice

01:30:55 and all that kind of stuff.

01:30:55 Exactly.

01:30:58 And so you could do that for DMT.

01:30:59 You could do that for the really fascinating

01:31:02 mind expanding, thank you, thank you.

01:31:06 So the meme for people just listening,

01:31:08 this is again another disagreement

01:31:10 between Freud and Carl Jung.

01:31:13 Religion and spirituality.

01:31:15 This is the, I guess the ring scene from Lord of the Rings.

01:31:18 Religion and spirituality, Freud says,

01:31:20 cast it into the fire, destroy it.

01:31:23 Carl Jung says, no.

01:31:25 So for people who don’t know,

01:31:26 Sergei is the Slavic Lord of the Meme.

01:31:31 Thank you, I appreciate that.

01:31:33 So what we’re talking about,

01:31:34 so there is, I mean, I think a connection

01:31:36 between DMT and religious experiences

01:31:38 are some of these psychedelics.

01:31:40 Do you think it’s possible to

01:31:44 sort of stimulate religious experiences?

01:31:47 And so religious experiences are one of the most

01:31:50 deep kind of experiences.

01:31:52 And so here you could first understand

01:31:57 where they originate, how they propagate

01:32:00 through the brain, and then to stimulate them.

01:32:05 And so this is, and these can happen

01:32:06 in people who had no predisposition.

01:32:10 People who are as agnostic or atheistic as you’d like,

01:32:15 they can have these, they can feel connected

01:32:17 to God in these states.

01:32:20 Now, to be clear, I’m not advocating these.

01:32:21 We don’t know what’s safe in human beings,

01:32:24 but we definitely have not yet.

01:32:26 But we definitely can do these experiments in mice,

01:32:29 and that was already very productive

01:32:32 in understanding dissociation.

01:32:33 So we can already imagine making headway on these methods.

01:32:37 And then I had a, and this does map

01:32:39 onto the non psychedelic human experience.

01:32:42 I had a patient who was actually described

01:32:45 in the book Projections.

01:32:47 This was the patient that’s in the mania chapter,

01:32:49 the bipolar chapter.

01:32:51 Here was a guy who had never had a psychiatric illness

01:32:56 or symptom in his life.

01:32:57 He was a retirement age gentleman,

01:33:00 and nobody in his family either.

01:33:02 So no family history, no personal history

01:33:05 of any psychiatric illness, and he’d never been religious,

01:33:07 particularly before either.

01:33:08 Certainly no passionate type of religion.

01:33:13 But he, not through any psychedelic or drug,

01:33:15 he had a stressful experience,

01:33:18 actually a post 9 11 change in how he was thinking.

01:33:21 And he was pushed into a mania, a manic state,

01:33:24 revealing that he had bipolar,

01:33:26 never before known in this case, in this person.

01:33:30 And his mania, his elevated state in bipolar

01:33:33 included this profound religiosity,

01:33:37 which he had never had before.

01:33:38 And he was preaching in a elevated,

01:33:44 vigorous way to his family.

01:33:46 And so this state can be created in people

01:33:50 even late in life who had no predisposition for it

01:33:52 and even without a neurochemical.

01:33:54 So the causality of that is very interesting to explore.

01:34:00 How did the manic state unleash this religiosity?

01:34:05 But you see that in other realms of psychiatry too.

01:34:08 OCD can manifest as religiosity also.

01:34:11 You can take people who never really had

01:34:13 a religion, never played a powerful role in their life,

01:34:18 but then when their obsessive compulsive symptoms

01:34:21 become severe, they can manifest in this.

01:34:23 I think I’m in that group, so I’m a bit OCD.

01:34:26 We have, I think this is subreddits,

01:34:29 when there’s oddly satisfying things.

01:34:32 So there’s certain things that are really satisfying

01:34:35 to my OCD, in my mild OCD.

01:34:39 I think it’s pretty much a religious experience.

01:34:41 So I understand that if it’s not direct,

01:34:45 it’s at least rhymes.

01:34:48 So maybe can you speak to the,

01:34:51 Sergei’s probably desperately scrambling

01:34:54 to pull up oddly satisfying, thank you.

01:34:57 People can check it out themselves.

01:34:58 It is, as the subreddit promises, oddly satisfying.

01:35:03 Can we talk about bipolar and maybe depression?

01:35:08 Well, let’s talk about, I mean, I don’t know if there’s

01:35:11 a nice way to discuss the differences

01:35:13 in the full landscape of suffering that’s here,

01:35:17 but maybe what is depression?

01:35:20 And what are the types of depression?

01:35:23 What kind of depression have you seen and experienced

01:35:28 and researched and how can people overcome it?

01:35:31 How can humans overcome it and deal with it,

01:35:33 live with it and overcome it?

01:35:36 So this is my clinical specialty.

01:35:38 I see patients in my outpatient clinical work

01:35:42 with treatment resistant depression.

01:35:44 So very hard to treat severe illness

01:35:48 where medications haven’t been working.

01:35:51 I also see patients with autism spectrum disorders.

01:35:54 These are my two clinical focal areas,

01:35:58 but then I do emergency room work as well.

01:36:02 But the depression, why do I focus on that?

01:36:06 It’s so, one feels tantalizingly close to helping

01:36:13 these people who are suffering so deeply.

01:36:16 And that’s why I focused on it is these are people who,

01:36:20 there may not even be anything situational

01:36:23 that’s difficult or challenging in their life.

01:36:25 You can have people who seem to have everything

01:36:28 that you would want.

01:36:28 Every objective measure of their life is fine,

01:36:30 yet they can be just hit with this unstoppable hopelessness

01:36:41 and inability to see into the future,

01:36:44 a discounting of the value of their own action.

01:36:47 Anything they can imagine themselves doing seems worthless

01:36:50 or they are unable to enjoy things.

01:36:54 We call this anhedonia.

01:36:56 There’s no reward, no pleasure, not in food,

01:36:59 social interaction, movies, books,

01:37:02 anything that they would enjoy, positivity gone.

01:37:05 They can have a profound negative internal state,

01:37:09 psychic pain, and these things can seem,

01:37:13 and in the severe cases, are inescapable.

01:37:17 So what is going on?

01:37:19 Why is this state part of human existence?

01:37:23 It’s got a strong biological, genetic link, we know that.

01:37:27 It’s been linked to certain genes,

01:37:29 certain regions of the chromosomes, and twin studies.

01:37:33 There’s a clear genetic link.

01:37:35 It doesn’t explain everything, but it’s a big part of it.

01:37:37 Genetics are a strong contributor.

01:37:41 And although you can have depression

01:37:44 without anything terrible going on in your life,

01:37:46 the symptoms can be made worse by stressors, by trauma.

01:37:54 But at a very deep level,

01:37:55 there’s nothing we can measure in a person objectively,

01:37:58 so we don’t have, there’s not a known chemical,

01:38:01 not a known structure that’s different,

01:38:04 not a known brain activity pattern

01:38:06 that we can pick up with EEG.

01:38:08 A lot of people are exploring this,

01:38:09 but right now we have no objective measures.

01:38:11 All we do is talk to people and we elicit these symptoms.

01:38:15 We explore them, distinguish them from other possible causes,

01:38:20 and then what do we do?

01:38:22 Well, we have a lot of things that we can do.

01:38:24 Well, we have a range of treatments.

01:38:27 We have medications that can help people,

01:38:30 do help people, but not everybody.

01:38:33 And if they don’t work,

01:38:34 then we can go to brain stimulation methods.

01:38:36 We can do things even like electroconvulsive therapy,

01:38:39 which is very effective,

01:38:42 but it’s sort of the final thing we go to in the end.

01:38:47 And so we have treatments.

01:38:49 They work for some people.

01:38:52 They don’t do everything we’d like.

01:38:53 But here’s the problem is at a very deep level,

01:38:56 we don’t understand really what’s going on in the brain.

01:38:59 We don’t have a physical interpretation of the problem.

01:39:03 We have all these symptoms,

01:39:04 but we can’t yet point to a set of cells

01:39:07 or a set of circuits or an activity pattern

01:39:10 that is causing major depression,

01:39:12 this disease state per se in human beings.

01:39:15 Why do you think you can’t yet

01:39:17 from an optogenetics perspective?

01:39:19 Is it because there’s so many possible causes?

01:39:22 Is it so many things involved?

01:39:24 So I think the answer is there are many things involved

01:39:27 and all these different symptoms that I’ve mentioned,

01:39:30 those we can study and those we can fix,

01:39:32 the individual symptoms.

01:39:34 And we can do this in animals to be clear.

01:39:37 So in a mouse, for example,

01:39:39 we can instantaneously and precisely

01:39:42 turn up or down the motivation of an animal

01:39:46 to overcome a challenge.

01:39:48 We can turn up or down its ability

01:39:50 to be motivated by, or we think experience reward

01:39:54 from situations or actions.

01:39:59 We can increase its apparent energy level,

01:40:03 its drive to meet challenges.

01:40:07 We can turn up or down social interaction.

01:40:10 All these individual features of depression,

01:40:12 individual symptoms, we now can point to exact projections

01:40:17 and cells that are causal in mediating these.

01:40:20 But we don’t know is why all these different symptoms

01:40:24 show up together in major depression

01:40:27 and the human disease syndrome.

01:40:29 And that’s the mystery.

01:40:30 It’s sort of, in other fields of medicine,

01:40:33 someone with congestive heart failure

01:40:35 who comes into the clinic,

01:40:36 they have very different symptoms.

01:40:38 They have shortness of breath and they have swollen feet.

01:40:42 Couldn’t be two more different across the body

01:40:46 sets of symptoms.

01:40:47 Neither one obviously related to the heart,

01:40:49 but they’re both happening

01:40:50 because the heart is not working as a pump, okay?

01:40:53 And now, thankfully in cardiology,

01:40:57 we understand these disparate symptoms

01:40:59 that seem totally unrelated can be completely understood

01:41:03 because there’s an altered pump action of the heart.

01:41:05 That’s what we are hoping for in psychiatry

01:41:10 and in the study of depression or any disease.

01:41:13 These different symptoms,

01:41:14 the inability to enjoy things, the hopelessness.

01:41:20 What’s the unifying principle?

01:41:22 Yeah, unifying.

01:41:23 I mean, is there some truth to that Tolstoy quote

01:41:26 that all happy families are alike

01:41:28 and each unhappy family is unhappy in its own way?

01:41:31 So basically, I mean, this is the human condition.

01:41:37 And basically, the physicists long to find

01:41:42 a theory of everything, isn’t understanding depression

01:41:47 essentially require you to really have

01:41:51 the big theory of everything for the human mind?

01:41:55 I think we, it would certainly be nice to have that,

01:41:58 a theory of everything.

01:41:59 Don’t get me wrong.

01:42:00 I don’t think we need it.

01:42:01 The understatement of the century, it would be nice.

01:42:05 Well, it’s also a good question if it’s possible.

01:42:07 Yeah, yeah.

01:42:08 Well, that I have some thoughts on too.

01:42:11 But to this specific question,

01:42:14 I don’t think we need a theory of everything.

01:42:16 I think there will be unifying principles we can get to.

01:42:20 But even shy of that, we can treat symptoms

01:42:23 and that’s a big step.

01:42:24 And as you say, different unhappy families are different,

01:42:27 different unhappy people are different.

01:42:30 If we have somebody who comes to the clinic

01:42:31 and I see someone with a profound anhedonia

01:42:34 as one of their main symptoms,

01:42:36 inability to enjoy things,

01:42:38 and if I know based on optogenetics work and animal work

01:42:41 that a particular medication can treat anhedonia,

01:42:44 even if it doesn’t fix major depression in everybody,

01:42:47 if I treat that one symptom in that one person,

01:42:50 that’s a good thing.

01:42:51 And so we don’t need the theory of everything

01:42:55 and we don’t even need the unifying principle

01:42:58 to help people with insights that come from optogenetics.

01:43:01 How much does talking help for diagnosis

01:43:05 and for treatment, would you say, for depression?

01:43:09 It’s a big part of what we do.

01:43:11 Every good psychiatrist should be pretty adept

01:43:15 in these verbal communications and talk therapy

01:43:18 as part of what they do.

01:43:20 I give medications, I deliver brain stimulation treatments,

01:43:22 but a big, big part of everything I do with every patient

01:43:26 is talk therapy because it works so well together

01:43:31 with these other modalities.

01:43:33 Even alone, it can help people with moderate

01:43:36 or mild depression by itself.

01:43:39 People with severe depression,

01:43:41 people with other psychiatric illnesses that are severe,

01:43:46 you don’t wanna do talk therapy alone,

01:43:47 that’s not gonna do it.

01:43:48 But it still is crucial to do together with the others.

01:43:52 And it’s critical because it’s part of how

01:43:56 you reshape cognitions, complex activity patterns,

01:44:01 and you won’t get to that with a medication

01:44:03 or a brain stimulation treatment.

01:44:05 Do you have advice for people who suffer

01:44:07 from mild forms of depression or feel as they might,

01:44:12 both for those people, and do you have advice

01:44:14 for people who love the people who suffer

01:44:19 from depression and want to help?

01:44:22 Yeah, one of the incredibly frustrating things

01:44:26 about depression is the very nature of it makes it hard

01:44:30 for the people who suffer to get treatment

01:44:34 because they’re hopeless,

01:44:35 so they don’t think treatment will help.

01:44:37 They have low energy, so they’re not motivated

01:44:40 to participate in treatment in many cases.

01:44:43 Sometimes they’re actively suicidal.

01:44:46 That certainly doesn’t help.

01:44:48 They have all these things that seem to prevent treatment

01:44:53 from being effective.

01:44:54 So the loved ones, that’s where the loved ones

01:44:56 are so important, is helping them overcome these barriers

01:44:59 to treatment, the motivation, the safety, and the insight.

01:45:05 That’s critical, and particularly for the severe cases.

01:45:09 For the mild cases, where people still have some insight

01:45:13 and motivation and energy to get something done,

01:45:17 there are many things you can do.

01:45:20 Exercise is extremely important in mood maintenance.

01:45:25 Regulation of sleep and getting sufficient

01:45:28 and regular enough sleep is very important.

01:45:31 And talk therapy can be helpful in those mild

01:45:33 or moderate cases, just looking at cognitions,

01:45:36 looking at patterns of thought that people

01:45:40 may have fallen into, where they catastrophize,

01:45:43 where they spiral from small things into big things.

01:45:49 A little bit of talk therapy, 10, 12 sessions,

01:45:52 can help people identify those patterns they may have

01:45:55 in themselves that are taking occasional negative thoughts,

01:46:00 which everybody has, and magnifying those

01:46:03 into more persistent negative states.

01:46:08 If you work at this, and it’s kind of like homework,

01:46:10 this is what we call cognitive behavioral therapy.

01:46:14 It’s very structured, very organized.

01:46:15 You work hard.

01:46:16 It requires insight and motivation,

01:46:18 and you have to be motivated.

01:46:20 But if you are, then you can identify these triggers

01:46:23 that send you down particular pathways.

01:46:25 And work to intercept them.

01:46:27 And that is amazingly very effective

01:46:30 in mild to moderate cases.

01:46:32 So you basically have to train yourself

01:46:35 to see the world as a collection of triggers.

01:46:40 And you have to first understand, like collect the data,

01:46:44 like basically see every experience

01:46:48 as a thing that creates a follow on emotion, a feeling.

01:46:53 And like, I’ve learned this, you know, like on social media,

01:47:00 where like early on, you know, like all of us,

01:47:05 you know, I’ll say something,

01:47:08 I kind of respond to negativity with negativity.

01:47:12 And then you observe the results of that.

01:47:16 And then over time, you think, wait a minute.

01:47:21 This thing that I’ve been doing where

01:47:24 when somebody says, you suck, and you say, no, you suck.

01:47:29 That never produces the result you thought it might.

01:47:32 And so might not want to just, don’t say you suck back.

01:47:38 And I do this through a lot of things in life.

01:47:41 I’m very fortunate to not suffer from depression,

01:47:46 but first of all, I have had and have people in my life

01:47:51 who do, and also, you know, all of us have depression

01:47:57 who don’t suffer from depression, have depression out.

01:48:00 Like, it’s always knocking on the door.

01:48:03 Right, yeah.

01:48:04 And so you have mild, I mean,

01:48:09 if you’re very careless with the triggers all around you,

01:48:14 then you’re just, I think all of us have the capacity

01:48:17 to really suffer from that kind of chemical

01:48:22 or psychological or philosophical existential crisis.

01:48:27 But then it raises a question, why are we built this way?

01:48:30 It seems like it doesn’t make sense, right?

01:48:32 And here’s where some of us thinking about

01:48:34 where we came from as the human family

01:48:38 is kind of interesting.

01:48:40 It doesn’t make sense that somewhere on that spectrum

01:48:45 that it’s good to detect that there’s an array

01:48:48 of adverse forces out there in the world right now

01:48:51 at this moment and to withdraw, to hunker down,

01:48:58 to not fight, not strive, not try to meet the challenge

01:49:02 and outweigh these negative forces

01:49:06 that are present out there.

01:49:08 And that makes a lot of sense, and all animals

01:49:13 that have been studied in one form or another show this.

01:49:15 Even the worm that I mentioned earlier,

01:49:18 C. elegans with 302 neurons, it can effectively give up

01:49:22 in challenging situations.

01:49:24 We’ve done this with zebrafish,

01:49:25 tiny little transparent fish.

01:49:28 You can give them a challenging situation

01:49:30 and they will give up, but then if you stimulate

01:49:33 a couple very specific brain regions in particular ways,

01:49:37 you can motivate them to overcome the challenge.

01:49:40 And if you inhibit those regions,

01:49:41 they give up much more easily than they would otherwise.

01:49:44 You can do this in mice, you can do this in rats.

01:49:47 So this is an ancestral conserve pattern

01:49:49 to detect that things are pretty bad out there

01:49:54 and to conserve energy, to hunker down,

01:49:58 to wait out the storm.

01:50:00 So as you, unfortunately, many of our maladies

01:50:04 have useful roots that contribute to our survival.

01:50:10 So both depression and motivation have uses.

01:50:14 And sometimes it’s nice to just shut the hell up

01:50:18 and huddle with the penguins versus,

01:50:22 for some unknown reason, venture out on your own

01:50:24 into the mountains like a David Goggins type character.

01:50:28 So what’s the difference to you between,

01:50:31 you see patients, between sort of rigorous psychoanalysis?

01:50:38 I don’t know if you consider talk therapy

01:50:41 and psychoanalysis, are they neighbors,

01:50:42 are they overlapping?

01:50:43 They’re neighbors.

01:50:45 Psychoanalysis is, they’re relatively,

01:50:49 it’s not nearly done as much as the talk therapy,

01:50:51 like the cognitive behavioral therapy I mentioned.

01:50:56 The psychoanalysis is a little more niche now

01:51:00 and partly because it’s not, the data isn’t,

01:51:05 in terms of actual treatment of actual therapeutic effects,

01:51:09 data not as supportive as for cognitive behavioral therapy.

01:51:13 But it’s still interesting as for insight,

01:51:15 people, a lot of people still do it

01:51:17 to gain insight into themselves.

01:51:19 And in general, it’s a good sort of conversation starter.

01:51:23 Those methods, they’re good for getting things out.

01:51:27 We don’t focus on dreams typically these days

01:51:30 in psychiatry, but they’re great conversation starters.

01:51:32 They’re great ways to get things out if people have,

01:51:37 and so we like to use those methods

01:51:39 just to get the ball rolling sometimes,

01:51:41 get people to open up a little bit.

01:51:42 But the actual treatment tends not to involve

01:51:45 these psychoanalytic approaches where you are really

01:51:49 probing the unconscious mind and its manifestation

01:51:53 through dreams, for example, as the goal.

01:51:58 That’s not the goal.

01:51:59 Modern talk therapy, we’re really focusing on treatment,

01:52:01 how to get people to feel better.

01:52:03 See, I use that as a conversation opener,

01:52:05 the Freudian thing where I try to delve at a bar

01:52:09 of the deep sexual desires in a person’s subconscious

01:52:13 and I find that opens up possibilities very quickly.

01:52:16 Now, what’s, I mean, this is a silly sounding question,

01:52:20 but what’s the difference between

01:52:22 cognitive behavioral therapy and conversation?

01:52:25 So, because I personally, as a fan of conversations,

01:52:30 as a fan of just, I like listening to podcasts

01:52:34 versus like audio book, I like both,

01:52:36 but they’re very different and I like conversation.

01:52:38 I like, it makes me personally very anxious,

01:52:41 so I like to be the listener, like a third wheel,

01:52:45 like overhearing a conversation kind of thing,

01:52:47 but it’s a really powerful method for humans

01:52:51 to explore each other’s mind, just raw conversation.

01:52:54 So, do you think it can be more productive

01:52:58 to be very systematic about it or is conversation itself

01:53:01 the art form of helping each other,

01:53:04 understanding each other and helping each other?

01:53:06 There are forms of talk therapy

01:53:08 that are essentially conversational

01:53:10 or they much more approach pure conversation.

01:53:13 There’s a befriending therapy,

01:53:17 there’s interpersonal therapy.

01:53:18 These are approaches that are purely talk therapy,

01:53:23 but they’re not as structured

01:53:25 as cognitive behavioral therapy.

01:53:26 Cognitive behavioral therapy is,

01:53:28 there are manuals, there are guidelines.

01:53:31 You can almost go through it in a very cookbooky way.

01:53:33 There’s homework that you get done.

01:53:35 So, it’s in its fullest form,

01:53:38 it’s very different from these

01:53:39 more conversational strategies.

01:53:42 But what’s interesting is sometimes people compare them

01:53:44 and so you’ll see almost like randomized controlled studies

01:53:49 comparing cognitive behavioral therapy

01:53:51 with interpersonal therapy, for example.

01:53:53 And they both can work and actually in some studies,

01:53:56 they look comparable.

01:53:59 So, to your point, conversation and insights

01:54:03 that come from conversation, if done well,

01:54:05 if done artfully, can be as powerful.

01:54:09 This reminds me of Robin Williams.

01:54:10 I have to ask you several questions here on that.

01:54:13 But one of my favorite movies is Good Will Hunting.

01:54:16 I don’t know if you’ve seen it with Robin Williams.

01:54:19 So, as a psychiatrist yourself,

01:54:21 can you do a deep analysis of this other famous psychiatrist

01:54:25 which is the movie character played by Robin Williams

01:54:29 at Good Will Hunting?

01:54:30 Is it just a caricature between a psychiatrist

01:54:33 and patient relationship?

01:54:35 Or is there something to you that was moving

01:54:39 about his ability to connect

01:54:41 to this obviously struggling young kid?

01:54:45 I think you hit on the key thing there

01:54:46 which is the depth of the connection.

01:54:48 If there’s too powerful a connection,

01:54:55 that can impair therapy

01:54:58 because it could impair open communication.

01:55:01 If someone, if a patient has a, sees the role,

01:55:05 sees the relationship in a particular way,

01:55:08 like in a friendly way maybe,

01:55:09 or like a parental child type way,

01:55:15 that can cause problems because then what they choose

01:55:17 to share, what they choose to bring up is selected

01:55:21 to be appropriate for that view of the relationship.

01:55:26 And so, I and many other talk therapists actually prefer

01:55:32 not to let things get, not let the connection get that deep.

01:55:37 You wanna have trust.

01:55:39 You wanna have a therapeutic alliance, we sometimes call it.

01:55:44 But it’s got to be enough of a blank slate

01:55:47 that the patient is not consciously

01:55:50 or unconsciously constrained in what they choose to share.

01:55:55 And so, great movie, great actors, all good,

01:56:01 no complaints except realistically,

01:56:06 the relationship should be a little more arm’s length

01:56:09 than that.

01:56:11 Let’s pretend this is real life.

01:56:13 Sometimes can’t you leave a little bit of yourself

01:56:16 in the interaction with the patient?

01:56:18 I mean, it’s another human being.

01:56:20 Yes, so there’s a balance.

01:56:22 And actually you do need some of it

01:56:24 because let’s say this person is having challenges,

01:56:28 interpersonal challenges in their life.

01:56:32 The best way to notice what those are

01:56:36 and to identify them and to work with them

01:56:39 is if you can elicit some of those problems

01:56:43 in the office, in the therapeutic interaction.

01:56:47 And this is really powerful.

01:56:49 As long as you’re alert to it, aware of it,

01:56:54 and you don’t let it go out of hand,

01:56:56 this transference, we call it,

01:56:58 is when you transfer in between

01:57:04 the current therapeutic relationship

01:57:06 and external relationships

01:57:08 that the patient may have had with others.

01:57:10 And so if the therapist starts to feel

01:57:14 an inner feeling like anger, let’s say.

01:57:17 So let’s say you have a patient

01:57:18 who is stirring frustration in you

01:57:22 or even in extreme cases, anger,

01:57:24 the best thing for the therapist to do in that case

01:57:26 is to recognize it and to realize

01:57:31 that’s probably being stirred by other people

01:57:33 in the patient’s life.

01:57:34 And that could be the source of a lot of problems.

01:57:37 And so instead of trying to wall it off,

01:57:39 and say, oh, I shouldn’t be feeling that,

01:57:42 I better be a better therapist instead,

01:57:44 and recognize it and use it,

01:57:47 and help the patient that way.

01:57:48 And so you’ve gotta be a human being.

01:57:49 You’ve gotta be a person who feels.

01:57:52 You’ve gotta be open.

01:57:53 But be in control of it and be aware of it.

01:57:56 If I may, I just wanna read,

01:57:58 because it’s one of my favorite scenes.

01:58:00 Probably one of the greatest scenes,

01:58:02 one of the greatest scenes in movie history

01:58:04 because Robin Williams does a single take.

01:58:08 Is that right?

01:58:09 I didn’t know that.

01:58:10 So this is a very interesting interaction between them.

01:58:12 So Will, and I’m sure this is a common interaction,

01:58:17 maybe with a therapist and a patient,

01:58:19 maybe with a father and son,

01:58:21 where Will, the young character,

01:58:23 the young, brilliant mathematician,

01:58:25 and Sean is the therapist, the older therapist,

01:58:28 where Will looks at a painting that Sean painted

01:58:31 and then does a deep, critical analysis of the painting

01:58:35 that basically describes pretending

01:58:40 as if he can understand another human being completely

01:58:43 by just looking at their painting.

01:58:45 And then Sean gives this whole speech

01:58:49 that contrasts sort of raw intelligence

01:58:52 and the wisdom of experience.

01:58:54 And Sean says, single take.

01:58:56 He says, you’ve never been out of Boston, right?

01:58:59 And Will says, nope.

01:59:01 All this in a sexy Boston accent, by the way.

01:59:03 And then Sean gives the speech.

01:59:07 If I asked you about art,

01:59:08 you’d probably give me the skinny

01:59:10 and about every art book ever written.

01:59:12 Michelangelo, you know a lot about him.

01:59:15 Life’s work, political aspirations,

01:59:17 him and the Pope, sexual orientation,

01:59:19 the whole works, right?

01:59:21 But I bet you can’t tell me what it smells like

01:59:23 in the Sistine Chapel.

01:59:26 You never actually stood there

01:59:27 and looked up at that beautiful ceiling, seeing that.

01:59:31 If I asked you about women,

01:59:32 you’ll probably give me a syllabus

01:59:34 of your personal favorites.

01:59:36 You may have even been laid a few times.

01:59:40 The language here is just beautiful.

01:59:42 But you can’t tell me what it feels like

01:59:45 to wake up next to a woman and feel truly happy.

01:59:49 You’re a tough kid.

01:59:50 If I asked you about war,

01:59:51 you’d probably throw Shakespeare at me, right?

01:59:54 Probably not, but let’s say.

01:59:57 Once more into the breach here, friends.

01:59:59 But you’ve never been near one.

02:00:02 You’ve never held your best friend’s head on your lap

02:00:05 and watched him gasp his last breath,

02:00:07 looking to you for help.

02:00:09 If I asked you about love,

02:00:11 you’d probably quote me a sonnet.

02:00:14 But you’ve never looked at a woman

02:00:16 and be truly vulnerable,

02:00:18 known someone who can level you with their eyes,

02:00:21 feeling like God put an angel on earth just for you,

02:00:25 who could rescue you from the depths of hell

02:00:27 and you wouldn’t know what it’s like to be her angel.

02:00:32 To have that love for her,

02:00:34 be there forever, through anything, through cancer.

02:00:38 And you wouldn’t know about sleeping,

02:00:40 sitting up in a hospital room for two months,

02:00:42 holding her hand because the doctors could see in your eyes

02:00:46 the terms visiting hours don’t apply to you.

02:00:49 You don’t know about real loss

02:00:51 because that only occurs when you love something

02:00:55 more than you love yourself.

02:00:57 I doubt you’ve ever dared to love anybody that much.

02:01:01 I look at you.

02:01:03 I don’t see an intelligent, confident man.

02:01:05 I see a cocky, scared, shitless kid.

02:01:08 But you’re a genius, Will.

02:01:10 No one denies that.

02:01:12 No one can possibly understand the depths of you.

02:01:14 But you presume to know everything about me

02:01:16 because you saw a painting of mine

02:01:18 you ripped my fucking life apart.

02:01:21 You’re an orphan, right?

02:01:23 Do you think I know the first thing

02:01:25 about how hard your life has been,

02:01:27 how you feel, who you are because I read Oliver Twist?

02:01:31 Does that encapsulate you?

02:01:33 Personally, I don’t give a shit about all that

02:01:36 because you know what?

02:01:37 I can’t learn anything from you

02:01:39 that I can’t read in some fucking book

02:01:41 unless you want to talk about you, who you are.

02:01:45 And I’m fascinated, I’m in.

02:01:47 But you don’t want to do that, do you, sport?

02:01:50 You’re terrified of what you might say.

02:01:53 Your move, chief.

02:01:55 Well done, sir, I know it’s a movie.

02:01:57 It’s interesting, right?

02:01:58 So some of that conversation

02:02:00 is at some intellectual level, too.

02:02:03 It’s not just emotional, it’s something,

02:02:06 it’s like, the reason I kind of connect with that is

02:02:10 that’s a lot of work for a therapist.

02:02:14 Like, to really understand another,

02:02:16 because he’s, I mean, from, okay, I know this is fictional,

02:02:19 but just, there’s calculation happening.

02:02:22 He deeply cares to say the words

02:02:26 that the other person needs to hear,

02:02:27 but also a little bit loses himself in the pride,

02:02:32 but then catches himself again,

02:02:35 switches from anger to connection.

02:02:38 Yeah.

02:02:39 A lot is brought up there.

02:02:40 You’re right, there has to be some emotion

02:02:42 in the therapist to care enough to keep going,

02:02:46 to keep probing, to open up as he’s doing so, right?

02:02:51 He revealed a lot about himself, his own vulnerabilities,

02:02:53 but that gave him authenticity.

02:02:56 He had to open himself up

02:02:58 so that the kid would see the authenticity

02:03:01 and open himself up in return.

02:03:05 So how do you do that as a psychiatrist, as a therapist?

02:03:10 You have to be careful.

02:03:11 You don’t wanna do too much,

02:03:13 but opening up a little bit does help.

02:03:17 It does create a chance.

02:03:20 You’re offering up something

02:03:21 and that helps the patient come back in return,

02:03:24 and it gives you that believability and authenticity.

02:03:28 Do you pay the price for that, for opening it up?

02:03:31 You can.

02:03:32 You have a family.

02:03:33 You have an incredibly difficult research.

02:03:38 You’re doing a lot of things in your world.

02:03:40 I mean, it’s the price you pay for like.

02:03:43 Well, this was one of the terrifying things

02:03:45 about writing the book was I do open up

02:03:50 in a little bit about my own personal life,

02:03:52 my own personal challenges,

02:03:53 and that was a considered decision

02:03:55 because I could have done the patient work

02:04:01 and the science work

02:04:02 and the history of the human family work

02:04:04 and tied it all together,

02:04:07 but it wasn’t, and in an early draft, it was like that,

02:04:13 but it wasn’t real yet.

02:04:15 It wasn’t something that everybody could connect with,

02:04:19 and I said, then I realized, look, if I’m gonna do this,

02:04:23 I’ve gotta open up myself,

02:04:26 and then people can connect with me

02:04:28 and see what I’m really saying, and so I did,

02:04:31 and that was not something that I’d gone in planning to do.

02:04:37 In retrospect, I learned a lot about myself.

02:04:39 It was actually really, I think, a good thing that I did,

02:04:42 but it was scary.

02:04:43 Where are the darkest places you’ve ever gone in your life?

02:04:51 You know, I had, things haven’t always been easy,

02:04:55 personally or professionally.

02:04:57 I had moments, you know, I was effectively a single dad

02:05:00 for a while, a number of years,

02:05:03 and these came at probably the hardest,

02:05:05 also, professional lifetimes for me, too,

02:05:09 the absolute hardest days of late medical school,

02:05:13 internship, taking call, getting up at 3 a.m.,

02:05:18 surgery, medicine, rounds, unforgiving environments,

02:05:24 and then all the while, personal life,

02:05:28 stripped down to the bare, and these were low moments,

02:05:32 and then I was hit particularly hard by

02:05:35 just experiences on the clinical ward,

02:05:39 connecting too deeply with patients,

02:05:42 like a child with a brain tumor,

02:05:44 and feeling it too strongly, and those things,

02:05:49 when you get down to those lowest of the low moments,

02:05:51 when everything is stripped away,

02:05:53 and there’s only this raw core,

02:05:58 well, that’s pretty hard.

02:06:00 That was probably the lowest moment,

02:06:02 and you learn a lot about yourself in those moments,

02:06:04 you know, what’s left, and then what are the roots out

02:06:09 from there, and that can be powerful to see in yourself.

02:06:15 Have you thought about killing yourself?

02:06:18 I have not.

02:06:20 I have not.

02:06:21 Have you seen that thought in the distance?

02:06:25 I am fortunate that that has not come to my mind,

02:06:28 and I have not seen it, even in the distance,

02:06:32 and in some ways, I’ve wondered if that’s made me,

02:06:36 am I a less effective psychiatrist because of that?

02:06:40 I’ve been, I’ve felt everything stripped away.

02:06:44 I’ve been at the lowest of the low, and yet, that.

02:06:48 There’s still hope.

02:06:49 There’s a light of hope still at the end of the tunnel.

02:06:52 So you never lost, even for brief moments, that.

02:06:56 Never did.

02:06:57 I don’t know why.

02:06:59 You don’t know why.

02:06:59 There was no reason.

02:07:00 You don’t know why.

02:07:01 No reason to feel hope at that moment, honestly.

02:07:03 Uh, so it was just the light without reason.

02:07:07 Yeah, that’s right.

02:07:10 What wisdom do you draw from that time?

02:07:15 About, so first of all, you said something funny,

02:07:19 which is, I wonder if it, that it’s somehow

02:07:23 not having thoughts of suicide limits your capacity

02:07:28 to truly understand somebody who is having those thoughts.

02:07:34 So how many demons must a psychiatrist have

02:07:39 in order to be a good psychiatrist?

02:07:42 You know, this is a really interesting question.

02:07:45 I think everybody knows, and I can say this,

02:07:47 that psychiatrists can be a little unusual.

02:07:50 We think about ourselves, right?

02:07:53 We think about our brains.

02:07:54 That may be one reason why we become psychiatrists

02:07:56 is we think, oh, that’s interesting going on in there.

02:07:59 What’s that about?

02:08:00 So a little introspective, a little introverted maybe,

02:08:03 and that’s what can make us good when we’re good.

02:08:07 And, but also that may select for people

02:08:12 who have some unusual aspects,

02:08:14 but you don’t have to have all of them.

02:08:17 There’s a lot that can go wrong in the psychiatric realm.

02:08:21 I think having some of those, some of it,

02:08:24 but not all of it is enough.

02:08:26 You get to see how low things can get.

02:08:29 You can get, you get empathy from that,

02:08:35 even if the symptoms are not the same.

02:08:38 Just empathy for struggle, for suffering.

02:08:41 That’s right, that’s right.

02:08:42 Do you yourself have to practice observing triggers

02:08:46 just as a human operating in this world?

02:08:49 I’ve definitely, those skills that have come from therapy,

02:08:53 I’ve found them useful, yeah.

02:08:55 If I noticed that, we’ve all been through experiences

02:09:00 where we wonder, oh, I got really mad in that interaction.

02:09:03 Why did I get that mad?

02:09:05 Yeah, sure, maybe I could have been irritated,

02:09:06 but man, why did I?

02:09:08 And then thinking about it and realizing,

02:09:12 okay, back up here, think about the broader context.

02:09:18 Think about how that relates to prior events in my life.

02:09:23 Okay, yeah, so this is a thing for me

02:09:25 when something of this class happens, then it triggers me.

02:09:30 So going forward, I’m gonna be aware of that.

02:09:33 And I’ve definitely used that

02:09:35 because you don’t wanna be out of control of those emotions.

02:09:40 You wanna identify them.

02:09:41 You wanna know where they come from

02:09:42 and you wanna head them off

02:09:44 as a civilized human being living on this earth,

02:09:48 trying to get along with other people.

02:09:50 You wanna understand those moments.

02:09:51 Let me return to Robin Williams for a second

02:09:56 and looking at Robin Williams, the actor,

02:10:00 sorry, the human,

02:10:03 because you mentioned for depression,

02:10:06 you can have everything going well.

02:10:08 And I think there’s just famous cases of just public figures

02:10:12 because a lot of people know them,

02:10:15 where they suffer quietly

02:10:19 and it seems like from the outside perspective

02:10:22 that they have everything going for them,

02:10:24 that they’re at the top of their career.

02:10:27 Two people that come to mind

02:10:28 are Robin Williams and Anthony Bourdain.

02:10:32 What insight do you have in why either of those have taken,

02:10:36 why Robin Williams, a comedian,

02:10:39 one of sort of the most jolly humans?

02:10:42 Obviously, there was always the darkness

02:10:43 that he was channeling in order to present the happiness,

02:10:50 but it feels like that realness is only possible

02:10:53 when you’re deeply self honest and analytical

02:10:56 and then if you’re deeply self honest,

02:10:59 you’re going to realize that there’s a lot

02:11:00 of beautiful things about life that you can discover

02:11:03 and if you do that,

02:11:05 how can you possibly then take your own life?

02:11:07 I mean, you go through all of these thoughts

02:11:10 and I think a lot of people really loved Robin Williams,

02:11:16 which is why it was really difficult to see

02:11:18 how can even him, how can even Robin Williams

02:11:21 take his own life?

02:11:22 So I don’t know if there’s something to be said

02:11:24 about the nature of depression

02:11:25 from just looking at his case.

02:11:29 I think the action of suicide is not well understood.

02:11:33 It doesn’t always, although often,

02:11:35 is correlated with depression.

02:11:37 There are cases of suicide where there is not

02:11:40 clear depression, that’s in the minority.

02:11:42 By the way, if I just,

02:11:44 because you said it so interesting,

02:11:46 action of suicide, because there’s also thoughts of suicide

02:11:49 and probably those, they’re probably somewhat understood,

02:11:54 but it’s an interesting, because you can think of suicide,

02:11:59 if you have suicidal ideation,

02:12:00 you can think of that for so many reasons.

02:12:04 That’s right.

02:12:04 And I mean, thoughts sometimes, like painful thoughts,

02:12:16 angry thoughts, or thoughts in general,

02:12:19 can be very different, like fantasies, for example.

02:12:21 You can fantasize, like sexual fantasies.

02:12:24 You can fantasize, I was just for humor’s sake

02:12:28 wanted to mention stuff, but then people think I’m serious,

02:12:30 so I’m not gonna mention anything.

02:12:32 But sexual fantasies, and then there’s,

02:12:34 I know there’s people that have sexual fantasies

02:12:36 and they don’t wanna actually do that in real life.

02:12:38 That sexual fantasy serves some kind of purpose

02:12:41 in imagination only, and in that same way,

02:12:44 suicide might serve a purpose in imagination only,

02:12:46 is very unlikely to lead to action.

02:12:48 And yet there’s other thoughts that maybe are more amorphous

02:12:52 that do lead to action, and that leap,

02:12:56 yeah, that, oh boy, that’s a fascinating,

02:12:58 and that’s such a philosophically powerful thought

02:13:02 to not exist, like that question, that’s the,

02:13:05 is it Sarcher or Camus, Camus?

02:13:08 Well, the myth is Sisyphus, Camus, who says,

02:13:11 like basic question of why live?

02:13:15 Good question.

02:13:16 Yeah, right.

02:13:18 So that’s a great question, actually,

02:13:20 and there are other related questions.

02:13:22 Some people may have the thought of suicide

02:13:26 because there seems no point, there’s no joy in life.

02:13:33 That’s one reason that some people can put forward.

02:13:36 Sometimes there’s an, it’s not just the absence of joy,

02:13:39 there’s an active pain, an active psychic pain

02:13:43 in some people, and that, the inescapability of that

02:13:47 is enough to drive the thoughts of suicide.

02:13:50 And then there are interpersonal and cultural reasons

02:13:53 as well that can show up.

02:13:54 But the act, this act of ending of the self is,

02:14:00 in all these cases, there’s no real way to study this

02:14:02 in animals, no other animal as far as we know

02:14:05 that we can study has this concept of this is myself,

02:14:10 the situation is not tolerable, therefore,

02:14:13 I will end the self.

02:14:15 To our knowledge, this is not something

02:14:16 that can be studied in other animals.

02:14:18 So it remains this very poorly understood action.

02:14:26 And in predicting it, so what do we do as psychiatrists?

02:14:29 We have this challenge.

02:14:30 People come to the emergency room, they say they’re suicidal

02:14:33 or their friends say they’re suicidal

02:14:35 or they’ve taken some action that didn’t lead to death.

02:14:40 What do we do?

02:14:41 Well, there’s a whole range of options.

02:14:43 Was it a suicidal gesture in the sense

02:14:46 of not intending death or was the intent death?

02:14:51 And if it was the intent was death,

02:14:53 what were the reasons?

02:14:54 Are the reasons transient?

02:14:55 Are they gone now?

02:14:56 What’s the probability that it’ll be repeated?

02:15:00 So we do all these things just to decide

02:15:02 what sort of treatment should be carried out,

02:15:04 but nowhere is there a deep understanding of the biology,

02:15:09 of the cells and circuits and activity patterns

02:15:12 that underlie the action to end the self.

02:15:16 It’s a very, it’s this frustrating thing.

02:15:21 It’s so timely, it’s so common, it shows up in veterans,

02:15:26 it shows up in kids, it shows up in people

02:15:29 at every stage of life, and yet we’re very bad

02:15:33 at understanding it and we’re relatively poor

02:15:36 at predicting it and our tools are not very powerful.

02:15:40 We can put people in a locked unit,

02:15:42 we can give them care, therapy for a while.

02:15:44 At some point, we release them

02:15:47 and there’s only so much we can do.

02:15:48 It’s one of the most frustrating things,

02:15:50 the suffering that is linked to suicidality.

02:15:53 But it is a decision and it is an action

02:15:56 and if you look at optogenetics,

02:15:58 you should be able to one day sort of understand

02:16:01 the dynamics of such weighty decisions.

02:16:05 The individual causes then, if someone is anhedonic,

02:16:07 if there is no joy in life, that very likely

02:16:11 is addressable by optogenetics.

02:16:12 We know how to turn that dial very robustly in animals.

02:16:17 The motivation to overcome challenges,

02:16:20 that we have some hope of understanding.

02:16:25 Psychic pain, internal negative states,

02:16:28 we have actually a handle on that as well.

02:16:30 There’s a structure in the brain called the habenula

02:16:32 and some linked structures around it

02:16:35 that seems to generate this negative internal state.

02:16:39 It’s active when a state of acute disappointment,

02:16:42 acute outcomes that go wrong, not as expected.

02:16:49 Moments of unexpected pain.

02:16:52 The habenula is there, it seems,

02:16:54 it’s active to report on internal negativity

02:16:59 with its action.

02:17:00 And so you could imagine strategies

02:17:02 to target this brain structure

02:17:03 that might have the effect of reducing psychic pain,

02:17:07 reducing the negativity of internal states.

02:17:09 That is a very concrete hope.

02:17:11 It’s precise, it’s anatomical.

02:17:14 Optogenetics has given us all the firm foundation we need

02:17:17 to go after that question.

02:17:19 So I think there is hope.

02:17:21 If you look at the individual causes,

02:17:22 the individual symptoms relating to suicide,

02:17:25 and then it’s like a puzzle,

02:17:26 you put together the puzzle pieces.

02:17:29 By the way, I do think my habenula is

02:17:34 very functioning, very actively.

02:17:37 And I wonder if it’s like,

02:17:39 because you can also learn to channel these things, right?

02:17:43 Some of the things we suffer from,

02:17:45 I mean, there’s degrees of suffering,

02:17:48 can be a source of progress and personal growth

02:17:54 and development and all those kinds of things.

02:17:57 I mean, I, what is it?

02:18:01 Nietzsche suffered from stomach issues.

02:18:07 I wonder if he’s written some of those things

02:18:09 if his stomach was all great.

02:18:12 I mean, there’s, I kind of think that

02:18:18 a difficult life in some form,

02:18:19 you can get, you get to choose in some regard

02:18:21 and some of you don’t.

02:18:22 The difficulties you have and the ones you do have,

02:18:25 it’s nice to use if possible.

02:18:27 Sometimes it’s nice to treat,

02:18:28 sometimes it’s nice to use.

02:18:31 Well, the way you phrase it, I think you’re using it.

02:18:33 I could be wrong, but if you,

02:18:35 you phrased in this semi humorous way about your habenula,

02:18:39 it seems to me that you’re using that to good effect.

02:18:43 Now, but one never really knows

02:18:46 what someone else’s internal state is.

02:18:48 As I look at you, I don’t know the depths of what’s going on

02:18:51 and it’s possible that it’s a much harder situation

02:18:56 in there.

02:18:57 Yes.

02:18:58 So that’s, I actually worry about this a lot.

02:19:00 So I’m extremely self critical,

02:19:02 like in the privacy of my own mind,

02:19:04 which is an interesting thing

02:19:05 when you get to meet the internet

02:19:07 and the internet will tell you you suck.

02:19:11 But for now, now this is what I worry about

02:19:15 and I’m very paying attention.

02:19:16 For now it’s really, I just have this like very negative

02:19:19 voice, but that voice seems to be very useful

02:19:23 for productivity and so I channel it.

02:19:26 I just put it on the table and let that voice like

02:19:29 talk to me, but I’m very, I’m like monitoring that voice

02:19:33 because looking at Robin Williams, you know,

02:19:35 you get older, your brain changes or like you’re,

02:19:38 and then that voice can now all of a sudden grow, right?

02:19:43 And then where you can’t control as much,

02:19:45 you have to be very careful with these kinds of things.

02:19:47 You’re very right about that.

02:19:50 So my negativity, I have this,

02:19:53 I never think I’ve done enough is sort of where my

02:19:56 negativity comes from inside.

02:19:57 I never think that I’ve met the potential of the moment.

02:20:04 I haven’t done, I haven’t, you know,

02:20:08 made the most of the opportunities that are available.

02:20:12 Still early, I haven’t, you know,

02:20:15 progressed as far as I should.

02:20:16 And exactly as you’re saying, that works for a while.

02:20:20 But then what happens as you get later in life

02:20:23 and there’s less runway to, you know, fix that.

02:20:28 And then maybe then that negative voice is a problem.

02:20:33 But also at that point, the negative voice

02:20:34 starts having more and more of a point.

02:20:36 When you’re being very successful,

02:20:39 it’s easy to be like, no, okay, well,

02:20:43 like because later in life, you’re really literally

02:20:46 just sitting there on a rocking chair doing nothing.

02:20:49 And then it’s, or maybe any kind of tragedy happens.

02:20:53 Loss of a loved one, loss of a job,

02:20:57 loss or you get screwed over in some kind of way.

02:21:01 I don’t know.

02:21:02 And then all of a sudden the negative voice

02:21:04 is just you and the negative voice

02:21:05 for days and days and days.

02:21:07 And so I don’t know, to go back to your example

02:21:10 of Robin Williams, I don’t know what was going on inside him.

02:21:13 I don’t know the nature of his internal state.

02:21:15 Was it active psychic pain that?

02:21:18 May I mention, may I interrupt to just say

02:21:20 that Sergei posted an examination of Robin Williams.

02:21:23 His brain tissue suggested that he suffered from quote,

02:21:27 diffuse LEWY, Lewy body dementia, LBD.

02:21:33 Depression is a symptom of LBD and it’s not about psychology.

02:21:38 It’s rooted in urology.

02:21:40 This is words from Sergei.

02:21:42 His brain was falling apart.

02:21:43 Yeah, Lewy body dementia.

02:21:45 This is a very interesting neurological disorder

02:21:47 where among other things, there’s neuron death indeed.

02:21:51 So you’ve got frank neuron loss.

02:21:54 It’s not just a matter of some longstanding psychic pain,

02:21:58 but you’ve got a progressive loss.

02:22:00 And so clearly you’ve got a situation

02:22:03 where he could have finally reached a point

02:22:04 where the balance that he’d worked out

02:22:07 between negativity and positivity was disrupted due to loss.

02:22:12 The wrong cells died, the wrong projections were cut.

02:22:15 By the Lewy body dementia.

02:22:16 Certainly dopamine neurons die in Lewy body dementia.

02:22:19 Those are neurons that give rise to much of the feelings

02:22:23 of reward and pleasure that we experience among other roles.

02:22:27 So clearly in his case, there could have been

02:22:30 a very concrete cellular neurological issue

02:22:34 that was progressive and pushed him to that point.

02:22:37 But were you about to make a point about broader

02:22:41 that if there is not a neurological degeneration?

02:22:45 Yeah, so in his case, not knowing that,

02:22:48 it could have been simply that,

02:22:49 let’s say he had an internal psychic pain state

02:22:52 and he was in sort of a compensated mode

02:22:56 for much of his life, able to generate enough joy

02:22:58 from his comedy and his social interactions.

02:23:02 But eventually later in life, those things drop away,

02:23:06 the balance shifts.

02:23:08 You get tired of fighting the pain for that long.

02:23:10 So you’ve got this time dependent non stationarity

02:23:14 that happens and then the same symptom

02:23:18 becomes no longer tolerable in the end.

02:23:21 What is autism?

02:23:22 What do we know about autism?

02:23:25 Human beings exist on a spectrum of how social we can be.

02:23:30 And this is pretty interesting actually, scientifically,

02:23:34 but also very important clinically.

02:23:38 There are hyper social states where people

02:23:40 are almost too social.

02:23:42 There are chromosomal deletion states

02:23:44 where people have instant affinity and bonding

02:23:47 and rich deep seeming connections with people, very verbal.

02:23:52 On the other end, people with autism spectrum disorder

02:23:57 are not able to keep up with social interactions

02:24:05 and it’s a spectrum.

02:24:06 Some have mild to moderate difficulties.

02:24:09 They may have inability to understand

02:24:13 what the next thing to do in a social situation is,

02:24:16 but may have perfectly good language abilities.

02:24:19 And as you progress further along the spectrum,

02:24:21 that gets more and more severe

02:24:23 so they can’t make eye contact because it’s too overwhelming

02:24:28 to think about what has to be done next

02:24:29 if a person looks in a particular way.

02:24:32 And then as you go farther,

02:24:33 then language and social communication themselves break down

02:24:38 so there’s no reciprocity, there’s no shared enjoyment.

02:24:41 And that this gets very hard then

02:24:43 as you get to this far end of the spectrum

02:24:45 where there’s really an absence of social cognition at all

02:24:50 and social bonding.

02:24:52 So why does this exist?

02:24:54 What is it?

02:24:55 It’s very genetic.

02:24:56 As I mentioned, it’s one of the top three or four

02:25:00 most biological in the sense of most genetically determined

02:25:03 of the psychiatric illnesses.

02:25:05 It does have these interesting positive correlations,

02:25:08 slight positive correlations

02:25:09 with intelligence and education.

02:25:13 And the reason for that

02:25:16 is kind of interesting to think about.

02:25:18 Is there something good about it?

02:25:19 Just like, or at least with at least part of the spectrum,

02:25:23 is there something good about it?

02:25:23 Just as we were talking about for depression,

02:25:26 as you could say for mania,

02:25:27 as you could say for schizophrenia.

02:25:30 And here it’s kind of interesting

02:25:33 to think about the underlying science

02:25:37 of what it means to be good at a social interaction.

02:25:41 Someone who’s very good at a social interaction

02:25:44 is incredibly good at dealing

02:25:45 with unpredictable information,

02:25:48 is able to handle this torrent of information

02:25:51 coming through rapidly changing

02:25:56 model of the other person and of the interaction

02:25:58 and their model of you, your model of them.

02:26:02 With each word that changes,

02:26:03 with each new bit of information

02:26:05 that comes in through the conversation,

02:26:06 each bit of body language, all this is rapidly changing.

02:26:09 And some people are able to keep up

02:26:12 with that firehose of information perfectly well.

02:26:15 But that’s a special brain state to be in.

02:26:17 That’s working with unpredictability.

02:26:20 That’s the only way that can be done

02:26:24 is most likely by constantly running models

02:26:29 of what the other person might be about to say.

02:26:32 So you can’t stop and think, oh, what did that word mean?

02:26:34 What did that shift in eye contact mean?

02:26:37 What do they mean together?

02:26:38 There has to be some advanced work going on

02:26:41 where you’re predicting what’s going on

02:26:42 if you’re to keep up with a rich

02:26:43 and fast social interaction.

02:26:46 Now, on the flip side, there are brain states

02:26:51 that maybe don’t have to work so fast

02:26:53 but that are extremely important still.

02:26:54 Dealing with something that’s not moving

02:26:57 or that’s predictable, still complex,

02:27:00 like mathematical proof or a very complex arrangement

02:27:05 of geometrical shapes, a large number

02:27:08 of individual nonmoving things.

02:27:11 There’s possibly a way of being that’s particularly good

02:27:14 at dealing with these static, unmoving,

02:27:16 or predictable situations and less so

02:27:19 with these rapidly changing social situations.

02:27:22 And so the way I conceptualize autism

02:27:25 is these are people whose brains are not so good

02:27:31 with the high bit rate, unpredictable information,

02:27:34 but may be quite good at given enough time,

02:27:38 given the grace to work with the system,

02:27:45 to look at it from different angles,

02:27:47 to take different perspectives with a confidence

02:27:49 that it’s not changing in between perspectives.

02:27:53 That’s a brain state that’s valuable.

02:27:55 It’s something that has probably contributed

02:27:59 to a lot of the success of the human family,

02:28:01 being able to design something,

02:28:02 being able to consider all the different contributions

02:28:09 to a static, predictable system.

02:28:13 So autism, in a sense, is a spectrum

02:28:17 that has identifiable characteristics

02:28:21 about the way people deal with dynamic information,

02:28:25 often expressed itself as like social dynamic information.

02:28:29 But you critically, your use of the word often there

02:28:31 is really, I think, smart,

02:28:32 because it’s not just social interaction

02:28:35 that is a challenge in autism.

02:28:37 And so many people conceptualize it purely

02:28:39 as a social dysfunction disorder.

02:28:44 But it’s really any unpredictable information

02:28:47 that’s a problem, that’s a challenge

02:28:49 for people on the spectrum.

02:28:50 They react very negatively to unexpected sounds,

02:28:56 even if not social sounds, unexpected lights,

02:28:59 unexpected touches, and so it’s really

02:29:02 unpredictable information that is, in my view,

02:29:05 the core problem with the processing in autism,

02:29:08 not just social.

02:29:09 Social just shows up because it’s so unpredictable.

02:29:11 Yeah, it’s so interesting.

02:29:12 I mean, I try to not to think about that stuff.

02:29:16 I’m afraid of thinking about disorders

02:29:22 and things like that because just like I don’t like

02:29:25 sort of economics or game theory,

02:29:28 I want to be careful with it because it,

02:29:32 whenever you have a category or a model,

02:29:34 it’s too easy to just, for everything,

02:29:37 I mean, it’s the OCD thing.

02:29:39 I like models too much.

02:29:40 I like categories too much.

02:29:42 The moment you acknowledge yourself,

02:29:44 well, I have an eating disorder, for example,

02:29:46 or something like that, as opposed to just being a,

02:29:49 well, I’ll just leave it at that

02:29:51 from my own critical understanding of myself.

02:29:54 Let’s just say I don’t know how to moderate eating fruit.

02:29:56 People make fun of me.

02:29:57 They think all fruit is healthy.

02:30:00 I know.

02:30:03 I don’t know how to moderate anything,

02:30:05 but even fruit, apples and cherries, is a nightmare.

02:30:10 Anyway, that’s such a psychiatrist thing to say.

02:30:14 Very interesting.

02:30:15 Thank you.

02:30:18 But there’s characteristics and it’s interesting

02:30:22 to think about, like for example,

02:30:24 I have trouble making eye contact,

02:30:26 but I actually, as you said it now,

02:30:29 it’s not that I’m shy at all in that sense.

02:30:35 It’s literally, I’m getting way too much information

02:30:38 and it’s distracting me.

02:30:40 Like I need to just close my eyes so I can,

02:30:44 like all the things that people seem to be able to do

02:30:46 in parallel, it’s just, you just asked me a question.

02:30:51 For me to think about the answer to that question,

02:30:53 I can’t have all this cool, rich visual information

02:30:56 coming my way.

02:30:57 That’s literally, because I often close my eyes to think.

02:31:01 It’s not because I’m afraid of something, whatever.

02:31:04 It’s just like too much information happening here.

02:31:06 Well, that’s a beautiful description.

02:31:08 It’s amazing that that is how you experience

02:31:12 the eye contact aspect.

02:31:15 I think that’s, I mean, you’ve articulated

02:31:18 what captures it for so many people,

02:31:22 which is that it’s overwhelming.

02:31:23 There’s just too much information just coming in

02:31:26 through the eyes and to keep up with it,

02:31:30 to know you’re gonna be expected to keep up with it,

02:31:33 first of all, so there’s that aspect.

02:31:35 You know, you’ve learned socially

02:31:37 that there’s gonna be an expectation

02:31:38 if you’re making eye contact.

02:31:40 People are gonna think you’re keeping up with it,

02:31:42 and you don’t want to because you wanna focus

02:31:45 on other things and make progress in other dimensions.

02:31:50 Yeah, and so then there’s a strong desire

02:31:52 to look away or to close the eyes

02:31:53 because it’s overwhelming, it’s a distraction,

02:31:57 and it’s gonna cause errors of understanding.

02:32:00 And of course, our eyes, that’s part,

02:32:02 the way we use our eyes is part of the human communication,

02:32:04 so you have to kind of be aware of that,

02:32:07 of that element of it.

02:32:10 So yeah, I mean, but it’s fascinating.

02:32:12 You should be aware of your own self

02:32:13 in those little characteristics,

02:32:16 whether it’s classified on some aspect

02:32:19 of the autism spectrum or just in general,

02:32:22 whether it’s eating, whether it’s depression,

02:32:26 whether it’s even like schizophrenia

02:32:29 that I hope we get a chance to talk to a little bit.

02:32:32 Yeah, but those things are all made up

02:32:35 of different symptoms and characteristics,

02:32:40 and use them as a superpower, I suppose,

02:32:43 is the best we can hope for in mild cases, I guess.

02:32:47 I do think both brain states can’t coexist

02:32:50 at the same time.

02:32:51 The way of dealing with something unpredictable

02:32:52 and dealing with something predictable,

02:32:55 those are different ways of being,

02:32:56 here’s a huge opportunity for very creative

02:33:01 model building in theoretical neuroscience

02:33:04 and linking that to these data streams

02:33:07 we’re getting across the brain that we talked about earlier,

02:33:11 these immense data sets of activity across the brain.

02:33:15 Here’s where I think there could be

02:33:17 a real convergence of theoreticians and experimentalists

02:33:19 to say, okay, given what we know about wiring of the brain,

02:33:24 here is what the brain state is likely to be

02:33:27 that deals well with unpredictable information,

02:33:30 and here’s the brain state

02:33:31 that deals with predictable information.

02:33:33 Here’s why they’re incompatible, at least at the same time.

02:33:36 Here’s why you’ve gotta be able to detect

02:33:39 which state you should be in.

02:33:40 Here’s how you could switch between them.

02:33:42 Here’s the kind of cells that you would predict,

02:33:44 almost like predicting the Higgs boson.

02:33:46 Here’s the kind of circuitry that I would predict

02:33:49 should govern the switching,

02:33:51 or might make one state too sticky, too hard to get out of.

02:33:58 That is a huge opportunity for an interaction

02:34:01 from the theoretical and experimental side together.

02:34:04 Make one state too sticky.

02:34:07 The sort of measure the stickiness of the state

02:34:12 and how to lessen the stickiness.

02:34:14 Get some oil in the machine.

02:34:16 Yes, yeah, what would predict the kind of oil

02:34:19 that would work well.

02:34:21 What, in your practice, is treatment or advice

02:34:27 for the people on the autism spectrum?

02:34:31 So right now, there’s no real medical treatment.

02:34:34 There are behavioral treatments

02:34:36 that are most effective early in life.

02:34:38 They make sure people don’t fall too far behind.

02:34:42 If you’re not interacting socially,

02:34:43 you create this vicious cycle

02:34:46 where you fall farther and farther behind

02:34:48 because you’re not interacting.

02:34:49 And these therapies which are applied early in life,

02:34:52 therapists work with the kids,

02:34:55 train them to deal with these things

02:34:57 that otherwise would be aversive to them,

02:34:59 teach them how to predict things and interact,

02:35:02 and that has a big effect.

02:35:04 But it’s behavioral therapy.

02:35:06 There’s no medicine that works.

02:35:08 There are ways of reducing individual symptoms though

02:35:12 that sometimes come along with autism

02:35:13 and those do respond to medications.

02:35:15 So you can, one thing, very often,

02:35:18 my patients with autism are very anxious

02:35:21 because they live in a world

02:35:23 that they have a really hard time

02:35:25 predicting what’s gonna happen.

02:35:26 And so they find, and some of these are high functioning,

02:35:29 Silicon Valley types who they may make great livings

02:35:33 but they’re very unhappy because they’re on the spectrum.

02:35:38 They don’t understand how social interactions really work.

02:35:43 They’re very anxiety provoking

02:35:46 because they don’t know what to say.

02:35:47 They don’t have any clue how anybody else knows what to say.

02:35:50 They’re constantly worried they’re gonna say something

02:35:52 that’s completely inappropriate

02:35:54 and so they’re very anxious.

02:35:55 And I can treat their anxiety.

02:35:57 It doesn’t touch the autism per se

02:35:59 but I can help them with their anxiety.

02:36:02 What I just talked about, eye contact.

02:36:05 I am richly, even with eyes closed

02:36:08 and all those kinds of things,

02:36:09 I’m richly experiencing the world.

02:36:12 And it’s not like you’re afraid of the world

02:36:14 or you’re not able, I don’t know what to do.

02:36:16 No, I know everything.

02:36:17 In fact, I know way too much.

02:36:19 There’s so many cool options.

02:36:20 Like at any one moment, there’s all the stuff happening

02:36:24 and it’s all beautiful.

02:36:26 And at any one moment, you can do anything you want.

02:36:28 You can take off your clothes.

02:36:29 You can punch that guy over there.

02:36:31 You can run away.

02:36:33 You can go in for a hug.

02:36:35 You can say something profound and deep

02:36:38 or you can say something generic

02:36:39 or you can do so many things you can say.

02:36:42 And then it’ll go, it’ll unravel in all these kinds of ways

02:36:46 and this moment could be completely life changing

02:36:48 or it can be mundane and meaningless.

02:36:51 And all of those options are before you at any one moment.

02:36:54 And so it’s like, it’s amazing and overwhelming

02:36:59 if you allow yourself to think about it,

02:37:02 which whatever, exactly.

02:37:04 Like, well, I’m fortunate with chess,

02:37:06 you have a few set options.

02:37:08 Two dimensional, at least dimensional is constraints.

02:37:11 There is unlimited possibilities

02:37:15 and unlimited beautiful things happening all around you.

02:37:18 So I don’t think there’s a kind of sense

02:37:20 that somehow you’re limited in the places of,

02:37:28 in the way you can see the world

02:37:29 and how you can interact with that world.

02:37:31 I am overwhelmed by the lack of limit.

02:37:36 That all of us should be, have you looked around?

02:37:38 You can do whatever the hell you want.

02:37:40 Nobody will remember you anyway.

02:37:42 All of us will be dead one day.

02:37:44 You could do anything.

02:37:45 You can, I don’t know, you can get naked

02:37:49 and run around the city,

02:37:50 as long as you’re not hurting anybody,

02:37:52 and it doesn’t matter.

02:37:54 So it’s Austin, anyway.

02:37:55 Austin, yeah, exactly.

02:37:59 Seems like a to do item for anybody living in Austin,

02:38:03 for sure.

02:38:04 But the spectrum is an interesting concept

02:38:07 because that is, when I say,

02:38:10 when I refer to the spectrum,

02:38:12 I’m actually referring to, it’s a precise clinical term,

02:38:15 but you’re right, it’s been coopted more broadly

02:38:17 and it is widely used and it can be

02:38:20 an unfair categorization of someone

02:38:22 who’s socially and occupationally very healthy.

02:38:25 And that is critical

02:38:29 because we don’t define a disorder

02:38:32 unless there’s social or occupational dysfunction.

02:38:34 It doesn’t matter what the symptoms are.

02:38:36 I’ve had patients who are pleasantly hallucinating,

02:38:39 so frankly, psychotic, but doesn’t affect their lives,

02:38:43 so I don’t give that person a diagnosis

02:38:46 because there’s not social or occupational dysfunction.

02:38:49 Same with anything on this,

02:38:53 any of the diverse symptoms of autism spectrum disorder.

02:38:58 If someone has them,

02:38:59 but they’re successful socially and occupationally,

02:39:03 we don’t say that there’s a disorder.

02:39:05 But then you’re right, that the concept of the spectrum

02:39:07 does become a useful pigeonholing device,

02:39:12 which is maybe not the best thing.

02:39:15 Yeah, and the eye contact is an interesting one,

02:39:19 is an interesting one.

02:39:21 I’m torn on it.

02:39:23 I’m torn about the usefulness of eye contact

02:39:25 because people kind of make fun of it,

02:39:27 but let me just say one thing about eye contact

02:39:31 and about life in general.

02:39:33 It’s okay to be weird,

02:39:36 but like some people, when you have your eyes closed

02:39:39 and there’s that weird, what is happening to this creature?

02:39:41 Like you see a weird creature on the side of the road.

02:39:44 It’s interesting.

02:39:46 And you wanna, I mean, the weird stuff,

02:39:49 I’m gonna go back to Robin Williams with the,

02:39:51 that’s the good stuff, right?

02:39:53 He has that whole speech about him and his wife

02:39:56 and what he loves all the little peculiarities,

02:39:59 all the weird stuff.

02:40:00 And that, like let those flourish.

02:40:04 Let those, like celebrate those in yourself

02:40:06 and not in some kind of woke way,

02:40:08 but in some like very human way.

02:40:10 This is what makes us, this is the weirdness.

02:40:13 Yeah, I’m 100% on board with that.

02:40:17 And I don’t think, you know, people who are happy

02:40:22 and who have people in their lives who are happy with them,

02:40:27 these are, I think, let the weirdness flourish.

02:40:30 Let the, all the different ways members

02:40:33 of the human family can be different.

02:40:35 Let’s see them all.

02:40:36 That’s one of our, that’s one of the joys of being alive

02:40:38 is seeing all the ways we can be human.

02:40:41 And I think about it all the time.

02:40:43 Why do we have all these ways of being human?

02:40:49 And even within one individual,

02:40:53 you go through phases of life

02:40:54 where you express different sides of your way of being,

02:40:57 which is also a pretty fun opportunity, right?

02:40:59 You can go through phases where you’re in one mode

02:41:02 and phases when you’re in another mode.

02:41:05 And let that, you know, just let that flourish too.

02:41:09 Let the ways that you can be you vary as well.

02:41:13 I think that’s important for people to explore.

02:41:15 And I should, like, as if you can address the internet,

02:41:22 but I would like to sort of ask the internet

02:41:27 to celebrate the weirdness of people.

02:41:31 Like, that’s, it’s the Robin Williams,

02:41:37 people call these imperfections,

02:41:39 but they’re not, that’s the good stuff.

02:41:40 For any one individual person,

02:41:43 find the weird stuff and celebrate it,

02:41:47 as opposed to what the internet often does,

02:41:50 which is find the weird stuff and criticize it.

02:41:55 Because when you criticize the weird stuff,

02:41:57 you’re creating conformity, which is another human thing.

02:42:01 But that conformity creates a boring world.

02:42:05 You want the weird, you want the crazy.

02:42:10 That’s what fun is made of.

02:42:12 That’s the foundation of humor

02:42:16 and all of the ways in which we deal

02:42:19 with the suffering in the world,

02:42:21 with the injustices in the world,

02:42:23 is like this like huge variety of weird.

02:42:30 Yeah, I don’t know.

02:42:32 And that’s what, at the depth of psychiatry,

02:42:34 is like you wanna acknowledge the weird,

02:42:38 celebrate the weird, like step around it

02:42:41 to find the particular aspects of weird

02:42:44 that are debilitating, like you said.

02:42:47 They’re somehow negatively affecting your ability

02:42:49 to function in the world,

02:42:51 as opposed to trying to shut it all down.

02:42:54 That’s right.

02:42:56 Well, on that topic, I mean,

02:42:58 I’d love to talk to you about schizophrenia.

02:43:00 What is schizophrenia?

02:43:04 From your research and from your general understanding,

02:43:07 and what is the full landscape of suffering

02:43:10 and wisdom that schizophrenia explores?

02:43:15 Schizophrenia is a state where

02:43:19 there is a break from reality.

02:43:22 And so this can show up, as we call them,

02:43:25 the positive symptoms of schizophrenia.

02:43:27 These include hallucinations,

02:43:29 hearing something or seeing something that’s not there,

02:43:32 usually auditory hallucinations.

02:43:34 Paranoia, people can have complex fears.

02:43:38 Delusions, which we call fixed false beliefs,

02:43:41 people get an extremely unshakable

02:43:43 but completely implausible idea about something.

02:43:46 Sometimes it relates to themself, sometimes to the world.

02:43:49 These we call the positive symptoms,

02:43:51 break from reality as we know it.

02:43:54 Then there are the negative symptoms that come with it,

02:43:57 and these are progressive.

02:43:59 These are flattening of emotion, as we call it,

02:44:04 so starting to express less and less positive emotion,

02:44:07 ending more in a neutral or flat state.

02:44:12 Thought disorder, inability to work with complex patterns

02:44:16 of planning or thinking, so you can’t make plans,

02:44:19 you’d have poor working memory,

02:44:21 you can’t keep track of where you were in a conversation,

02:44:25 in a sequence of actions.

02:44:27 So poor and impaired working with the thoughts of oneself

02:44:34 and then these positive symptoms of break from reality.

02:44:37 Okay, now why do these come together?

02:44:42 What’s the neurobiology of it?

02:44:44 Again, we don’t know.

02:44:45 Schizophrenia, extremely genetically determined.

02:44:48 If you look at the numbers,

02:44:48 could be upwards of 80% genetically determined.

02:44:51 1% of the human population around the world,

02:44:57 it’s universal, okay?

02:44:58 It’s not confined to any one culture,

02:45:00 not even really biased in one culture or another,

02:45:04 about 1% around the world.

02:45:07 And has this progressive quality to it, untreated,

02:45:12 so it’s very interesting.

02:45:13 There’s a break that happens, we call it first break,

02:45:17 when someone experiences their first disruption of reality,

02:45:22 they can have a completely typical life up until that point.

02:45:25 So you might have a, and I’ve seen just heartbreaking cases

02:45:28 of like this in the Stanford emergency room

02:45:31 where a kid has come there,

02:45:33 who’s been extremely high functioning in that sense

02:45:37 of academic achievement and athletic and interpersonal,

02:45:41 and then comes to college.

02:45:43 Usually in men, it’s around 18, 19 when the first break

02:45:47 happens, some terrifying paranoia hits

02:45:52 or some auditory hallucinations start.

02:45:55 They’re getting screamed at by a voice in their head.

02:45:57 So devastating.

02:45:59 With women, comes on also often a little later,

02:46:02 sometimes in the 20s, and it can be progressive.

02:46:06 If it’s not treated, it just progresses and progresses.

02:46:09 The voices become overwhelming, the delusions

02:46:14 and paranoia extend and expand.

02:46:16 The thought, the negative symptoms particularly

02:46:18 become more and more severe.

02:46:20 So one can’t even maintain thoughts

02:46:23 in any sort of ordered fashion.

02:46:26 And then eventually, it can be fatal,

02:46:30 it can lead to suicide, it can lead to erratic behavior

02:46:33 that leads to accidents.

02:46:35 Now, it can be treated.

02:46:38 There are medications that help, fortunately.

02:46:42 They have side effects, so they’re not perfect.

02:46:44 You can have movement problems and actually a whole host

02:46:49 of different side effects that come from the medications.

02:46:51 But we can help people now with schizophrenia

02:46:55 very, very significantly.

02:46:58 But the amazing thing, and this is emblematic

02:47:00 of where psychiatry stands, we don’t have

02:47:03 the deep understanding, just like with depression,

02:47:05 we don’t have that heart as a pump level of understanding

02:47:09 that we’d like to have with schizophrenia,

02:47:11 despite it being so biological, so genetic in its nature.

02:47:15 So is there a way to return to the other side

02:47:20 of the first break?

02:47:22 So when you have a break with reality,

02:47:24 is there a way to kind of stitch it together?

02:47:27 So some people, that works, but we don’t really know how.

02:47:32 So medications, antipsychotic medications, we call them,

02:47:36 they block a particular neurotransmitter receptor

02:47:39 called the serotonin 2A receptor,

02:47:44 and they modulate dopamine as well

02:47:46 and other neurotransmitters.

02:47:49 These can take someone who’s actively hallucinating,

02:47:53 actively paranoid, put them back in a completely normal

02:47:56 state, and some people stay that way indefinitely.

02:48:01 So you can bring people back from that,

02:48:04 back to the other side, have it stitched together.

02:48:07 More typically, you’ll end up in some intermediate state

02:48:11 where symptoms are reduced powerfully,

02:48:15 but there might be still something there

02:48:16 and you’ve got a drop down in functioning

02:48:19 that may be persistent for a while.

02:48:22 But concepts, what physically is going on?

02:48:26 One idea is that it’s communication within the brain.

02:48:31 One part of the brain is not able to tell

02:48:34 other parts of the brain what it’s doing.

02:48:36 And so the auditory hallucinations

02:48:38 are very interesting in this regard.

02:48:40 They often have this conversational,

02:48:42 inner monologue like quality.

02:48:44 As we’re walking along the street,

02:48:45 we may have an inner monologue,

02:48:47 thoughts about what’s going on.

02:48:49 If we see somebody we don’t like,

02:48:50 we may have a thought,

02:48:52 wish somebody would punch that guy, something like that,

02:48:54 or maybe I should punch that guy.

02:48:55 But these are so far below where we would ever act

02:48:59 or even think of acting,

02:49:02 but they’re just things that come up.

02:49:03 And in people with schizophrenia,

02:49:07 those inner thoughts, that inner monologue,

02:49:09 is not recognized as the inner monologue of the self.

02:49:15 And so it’s perceived as something coming from the outside

02:49:20 or from inside, but from another entity.

02:49:23 Another, oh, another, I thought you meant

02:49:26 like another room inside the same building.

02:49:29 Another room inside there, yeah.

02:49:31 And so that’s, so it could be conceptualized

02:49:35 as a communication within the brain problem,

02:49:38 notifying another part of the brain what’s going on.

02:49:40 And there’s some evidence consistent with that.

02:49:44 I don’t know if you can help with this,

02:49:45 but I sometimes, so I’ve been talking

02:49:48 to quite a few homeless folks recently,

02:49:50 just, so what I do is I hang out at night

02:49:56 and talk to interesting people.

02:49:59 And some of them, and I’ve known people in the past

02:50:02 who suffer from schizophrenia,

02:50:03 and some of them, like self, will describe

02:50:07 as that as something they suffer from.

02:50:12 And they seem to understand something deeply

02:50:14 about this world.

02:50:15 I don’t know if it’s correlated

02:50:17 or maybe it’s another aspect of like depression,

02:50:23 all those things that I’ve encountered in my own life

02:50:27 is maybe just the struggle and the suffering

02:50:31 has taken you through a life

02:50:33 where you think deeply about life.

02:50:35 Like there’s like self reflection

02:50:37 that society forces on you

02:50:39 because it’s a disorder of some kind.

02:50:43 It’s interesting, I guess my only sort

02:50:46 of anecdotal observation is people who suffer

02:50:48 from schizophrenia seem to be very interesting

02:50:53 and very thoughtful in a nonlinear way about the world.

02:51:00 I’ve noticed that it’s not always positive.

02:51:04 There are unusual ways they view the world.

02:51:06 It was, but it’s always interesting.

02:51:10 That could be conspiratorial thinking too.

02:51:12 Like, but like the theories they have

02:51:15 about the way the world functions,

02:51:17 often very well read, which is also interesting

02:51:20 because they’re almost like looking

02:51:21 for helpful answers from somewhere.

02:51:23 Absolutely there.

02:51:24 And so they’re, they might be citing

02:51:26 some very interesting literature

02:51:27 and then using that to, there’s a stickiness

02:51:32 in their mind to different models of the world

02:51:34 and trying to make sense of that world.

02:51:36 And those models could include conspiracy theories.

02:51:39 Yeah, they’re very attuned to complexity

02:51:42 and they come up with unlikely explanations,

02:51:46 which is one of the things that makes them,

02:51:48 it makes it hard for them to function in the world

02:51:50 is how unlikely their explanations are.

02:51:53 But you’re right, there’s a depth of consideration

02:51:55 of the complexity of the world and a concern about it

02:52:00 and a work, an impulse to work to understand it

02:52:04 that is actually quite refreshing.

02:52:07 But the first case in the medical literature,

02:52:11 there was a classical schizophrenia.

02:52:15 There was a patient named James Tilly Matthews

02:52:17 who had this, he sketched out for his doctor

02:52:22 the experiences he was sensing

02:52:26 and he drew himself as a cowering figure

02:52:31 on the ground controlled by a loom,

02:52:34 a weaving device that was sending threads,

02:52:37 long threads, projections across space

02:52:40 from the loom to him, to his arms and to his body

02:52:44 and controlling him from afar.

02:52:47 And he called this the air loom, a loom in the air.

02:52:51 And it was such an evocative thing

02:52:54 because this was the start of the Industrial Revolution

02:52:56 or mid and it was where really industrial strength,

02:53:01 looms and weaving devices were really kind of the emblematic

02:53:05 of the most complex, powerful technological achievements

02:53:10 of the time and so that was the explanation available

02:53:13 to him to explain how his body was seemingly moved

02:53:18 without his volition and these days, of course,

02:53:22 people with schizophrenia will have more technology

02:53:25 appropriate interpretations, they’ll have delusions

02:53:29 of satellite or alien control or beamed information,

02:53:32 very, very common to have this delusion

02:53:35 of a government agency sending electromagnetic

02:53:39 or radio frequency information to control their limbs.

02:53:43 But it’s the same thing, whether it’s a thread

02:53:45 from an Industrial Revolution loom

02:53:48 or RF radiation, it’s the same thing just adapted

02:53:53 to the moment explaining, trying to explain

02:53:56 the world they live in and their relationship to the world.

02:53:58 But unconstrained by sort of the thing

02:54:01 that’s socially acceptable,

02:54:02 which is both refreshing and dangerous.

02:54:05 Yes.

02:54:08 I wrote down a question.

02:54:10 Why do we cry?

02:54:13 Are tears a window to some depths

02:54:15 that we ourselves don’t know?

02:54:17 I almost wanna make fun of myself for that question,

02:54:19 but you do talk seriously about crying in the book.

02:54:22 In fact, the whole first chapter really tussles

02:54:26 with crying as why do we do it, what does it mean,

02:54:29 why is it involuntary?

02:54:31 It seems like a weakness, right?

02:54:32 Because it’s so involuntary and it’s reflecting

02:54:35 something true and inside.

02:54:37 At the level of the individual,

02:54:39 that seems like a problem, right?

02:54:40 Wouldn’t it be better if we could control it,

02:54:42 if we could not show that emotion when it’s not useful,

02:54:48 show it when it’s useful?

02:54:49 But it’s not, it’s largely involuntary.

02:54:52 And so there’s a value to it, I think,

02:54:55 as an honest reporter of a need,

02:54:59 of hope and frailty at the same time.

02:55:03 I am a human being, there’s a frailty to myself

02:55:10 or my situation where I need social help,

02:55:12 I need help from my community.

02:55:14 I have hope that that is possible,

02:55:18 but I’m not enough for myself, I need the community.

02:55:21 That I think is what the social signal of crying is.

02:55:25 Now people have studied crying, it’s an extreme,

02:55:29 you can quantify the extent to which the presence of tears

02:55:33 on a face triggers reactions in onlookers.

02:55:37 And you can show the same face in the presence

02:55:41 or absence of tears and show that to people

02:55:44 under quantifiable and rigorous psychological conditions.

02:55:49 And tears are much more powerful at stirring

02:55:53 the desire to help in viewers

02:55:57 than any other facial feature.

02:56:01 Which is pretty interesting that it’s the honest one

02:56:04 that’s also the most powerful, right?

02:56:05 It kind of indicates there’s a certain logic

02:56:07 to our design as social beings

02:56:11 that we have an honest report.

02:56:14 That’s hard to control.

02:56:17 But is it well understood how that connects

02:56:21 to the internal state of emotion?

02:56:26 Yeah, there are long range projections that come,

02:56:30 so where is crying generated?

02:56:31 This is the confusing thing about it.

02:56:33 So that we have a little tear duct, the lacrimal gland

02:56:36 that leads to the release of fluid,

02:56:38 it ejects fluid and it comes out.

02:56:40 And those of course, that whole system was designed

02:56:43 to keep the eye clean, to wash out particulate irritants.

02:56:47 So it’s a long standing, as long as we’ve had eyes

02:56:49 and have been out of the water in our evolution,

02:56:52 we’ve needed this sort of thing.

02:56:53 So long standing biological structure,

02:56:56 recently co opted it seems by our evolution

02:56:59 as social primates.

02:57:02 Now, how could that happen?

02:57:03 Well, the lacrimal gland is controlled by structures

02:57:07 in the pons, which is a structure deep in our,

02:57:11 just above our neck, between our neck and our head.

02:57:14 And reflecting its ancient origin, right?

02:57:16 As you go farther down toward the spinal cord,

02:57:18 these are the more basic early evolved structures.

02:57:21 And in the pons, that’s where breathing is controlled,

02:57:25 tear duct contraction.

02:57:30 And what we found and with optogenetics,

02:57:34 we helped sort this out,

02:57:35 there are long range projections

02:57:36 from fear and anxiety regions in the forebrain

02:57:40 that project all the way to the pons

02:57:43 in and around those areas.

02:57:45 The reason those are there,

02:57:47 we think is to regulate the respiratory rate changes,

02:57:50 the breathing changes of fear and anxiety.

02:57:52 So we know when we’re in a state of fear and anxiety,

02:57:55 we need, we cope better if we have elevated heart rate,

02:57:58 elevated respiratory rate, more blood pumping around,

02:58:01 more oxygenated blood,

02:58:02 we’re ready to meet the threat if it happens.

02:58:05 All those cells are down there in the pons too,

02:58:07 right next to the lacrimal duct, the tear gland neurons.

02:58:12 And so almost certainly this fear anxiety induced crying

02:58:17 arose from a very slightly misdirected long range projection

02:58:23 that was there to regulate breathing.

02:58:27 And a little twist, just a little misdirection,

02:58:29 a little missing of one sign post to stop here,

02:58:33 going on a little farther,

02:58:35 getting to the lacrimal gland neurons gave us crying.

02:58:38 And that’s, and we just have it,

02:58:40 that peculiar sort of structure, neuronal structure

02:58:43 that resulted in that, that’s what we’re stuck with.

02:58:46 And that ends up being, in terms of social interaction,

02:58:50 one of the more important, authentic,

02:58:53 involuntary displays of interstate.

02:58:57 That’s right.

02:58:57 And social communication.

02:58:58 Yeah.

02:58:59 Oh, yeah, is there other stuff like that?

02:59:04 I mean, do you, yeah, I mean, the human face is fascinating

02:59:08 as a display of emotion, as a display of truth and lying

02:59:12 and all those kinds of things.

02:59:13 I personally, I mean, we’re all, I suppose,

02:59:19 have different sensors that are sensitive

02:59:24 to certain aspects of the human face.

02:59:25 But to me, it seems like the eyes

02:59:28 are really important communication or something.

02:59:31 You know, I’ve talked to a few sort of girls

02:59:33 about like Botox and stuff like that.

02:59:35 And it always bothers me when,

02:59:37 I guess guys can do this too,

02:59:38 but like when women speak negatively

02:59:43 of, I guess you can call them wrinkles,

02:59:46 at the tips of an eye.

02:59:49 But like to me, when you smile, when you wink,

02:59:54 not wink, but like narrow the eyes,

02:59:58 something is communicated and those,

03:00:00 that stuff is really useful, the human face.

03:00:03 And when it’s gone, something is missing.

03:00:05 And a lot of little stuff, it feels like it really,

03:00:08 it’s almost involuntary, I guess,

03:00:10 but it’s harder to describe as the presence

03:00:12 or absence of tears.

03:00:13 It’s like something about this person,

03:00:16 you can tell they’re not bullshitting you.

03:00:18 Yeah, yeah.

03:00:19 And so that was what made, presumably,

03:00:21 that tear recruitment so powerful,

03:00:24 is it just landed in this very high value real estate

03:00:28 for social communication.

03:00:29 If it had gone to, you know,

03:00:31 there’s a lot of neurons in the pons

03:00:34 that control movement of large muscles elsewhere,

03:00:40 that would have been much less effective

03:00:41 as a social signal than something around the eye.

03:00:43 So it was, however that little misdirection happened,

03:00:46 it landed in a great area for social communication.

03:00:50 And because it was coming from the fear and anxiety circuits

03:00:53 that regulate that necessary involuntary change

03:00:57 in heart rate and respiratory rate,

03:00:59 it also was involuntary and that became valuable

03:01:02 as a truth signal, as social beings.

03:01:05 So very interesting when you think about

03:01:08 the origins of the human family,

03:01:09 the origins of social structures

03:01:12 and our ability and need to call for help

03:01:14 when there’s hope, but need at the same time.

03:01:20 What is consciousness, Carl?

03:01:23 So you’re actually using techniques.

03:01:26 I mean, even putting psychiatry aside,

03:01:28 just looking at optogenetics,

03:01:31 you’re trying to understand some of these deep aspects

03:01:34 of the human mind.

03:01:36 And maybe this is a good time to return to a question

03:01:38 you mentioned you might have an opinion on

03:01:41 if there’s such a thing as a theory of everything

03:01:43 for the human mind.

03:01:44 Because surely answering of what is consciousness

03:01:47 is as, well, that’s not sure.

03:01:50 But it seems like it’s a fundamental part

03:01:53 of the human experience in the human mind

03:01:56 and solving that question will result in solving

03:02:00 the bigger thing about the human mind.

03:02:02 The flip side could be consciousness

03:02:05 is just the few neurons that are generating

03:02:07 some useful thing that make us,

03:02:10 it’s like the sense of self

03:02:12 that you talked about in the mice.

03:02:16 Maybe it’s a subset of those cells

03:02:18 that are just creating a richer sense of self

03:02:21 and that’s it.

03:02:22 So this is a great question.

03:02:26 All neuroscientists think about this

03:02:28 and a lot of non neuroscientists too.

03:02:29 It’s the reason a lot of people came to the study

03:02:34 of the brain is to think about consciousness

03:02:36 and not just being awake or alert

03:02:38 but really what’s sometimes called

03:02:40 the hard problem of consciousness

03:02:42 which is what is that nature of that inner

03:02:45 subjective sense we have?

03:02:47 Not just information processing

03:02:51 but feeling something about the information.

03:02:54 What is that inner state of subjectivity physically?

03:02:59 What is it?

03:03:00 And that’s called the hard problem of consciousness

03:03:03 and it’s not a extremely well defined question.

03:03:08 Everybody has sort of a sense of what it means

03:03:11 but it’s such a hard problem

03:03:14 because you run into paradoxes quite quickly

03:03:17 the more you think about it

03:03:18 and that is exciting also

03:03:21 because it makes us think

03:03:23 actually there’s some fundamental,

03:03:25 there’s a big thing that we’re missing.

03:03:28 The brain is not just a collection of little tricks.

03:03:30 There is a big, big concept.

03:03:32 So that’s your sense of the big

03:03:34 because a flip side could be with optogenetics.

03:03:37 You can, there’s an engineering question.

03:03:40 Can you turn consciousness on and off like a light switch?

03:03:43 Okay, so here’s where exactly consciousness

03:03:47 frames the problem extremely well

03:03:48 and it frames it the following way.

03:03:50 So I told you earlier that we can stimulate

03:03:54 20 or 25 cells in the visual cortex of a mouse

03:03:59 and we can make it behave and we can make its brain act

03:04:03 as if it’s seeing something that isn’t there.

03:04:06 We have that level of control now.

03:04:07 We can pick out 25 neurons, play in activity

03:04:10 and both behavior and in the brain,

03:04:13 it’s as if it’s seeing something specific.

03:04:16 Okay, now let’s do a thought experiment,

03:04:18 you know, a Gedanken experiment and let’s play this out.

03:04:22 Let’s say we could do the same thing

03:04:24 for every single neuron in the brain of a human being.

03:04:27 Let’s say we had total control

03:04:30 and I could do something like,

03:04:31 I could show you a rich deep color red

03:04:34 and you could look at it and you would be aware

03:04:36 that it’s red, but also you might have some feelings

03:04:38 about it, something would be stirred in you,

03:04:40 some subjective sense as you looked at that rich color red

03:04:44 and then I would take away the visual stimulus

03:04:48 and I would, in this thought experiment,

03:04:50 I would, using some hyperoptogenetics,

03:04:53 I would play in exactly the same pattern of activity

03:04:57 in every cell in your brain for as long as was needed,

03:05:00 whatever, 15 seconds, something like that,

03:05:03 that exactly matched what was going on

03:05:06 when you were feeling that inner subjective sense.

03:05:10 Okay, so in that thought experiment,

03:05:12 a question for you is would you be feeling

03:05:16 that same inner subjective sense?

03:05:18 Stimulus is gone, every neuron’s doing the same thing

03:05:20 because I’m controlling it.

03:05:23 There’s a philosophical question there.

03:05:25 If you ask me specifically, I would say yes.

03:05:29 Okay, good, most people would say that

03:05:31 because it’s hard to say no, right?

03:05:33 It’s very hard to say no.

03:05:34 If every cell in your brain is doing what it was doing,

03:05:38 what else could be different?

03:05:39 How could? Well, most normal people would say yes.

03:05:42 Of course, philosophers would then start saying no.

03:05:46 They’re the ones that say,

03:05:50 I’m in sort of parallel and sorry

03:05:53 if it’s a bit of an interruption,

03:05:54 but if there’s a robot that’s conscious in front of you,

03:05:58 if it appears conscious, then it’s conscious.

03:06:02 Like to me, of course, philosophers again speak up

03:06:07 and say, well, no, how do you know it’s conscious?

03:06:10 Well, how do you know anything is conscious?

03:06:12 And sort of as normal humans,

03:06:15 we tend to lean on the experience

03:06:19 versus some kind of philosophical concept.

03:06:22 So the great thing about what you just said,

03:06:25 the Turing test is it’s very practical.

03:06:28 If it acts conscious, it is conscious.

03:06:31 But I think that’s limiting.

03:06:32 I like the thought experiment.

03:06:34 I think it’s actually more informative.

03:06:36 And so I’m halfway to the conclusion there,

03:06:39 but let’s take it as your answer was yes,

03:06:43 that you would be feeling the same thing.

03:06:44 Okay, now here’s where it gets fun.

03:06:47 Now that every cell in your brain knows what it has to do

03:06:55 in the sense that we know it and we’re providing it,

03:07:00 your brain cells don’t need to be in your head

03:07:02 anymore at all, right?

03:07:04 The only reason they’re next to each other,

03:07:06 the only reason they’re wired together

03:07:08 is to affect each other, to stimulate or inhibit each other.

03:07:12 But we don’t need that anymore

03:07:13 because optogenetically,

03:07:15 we’re providing that activity pattern

03:07:17 for as long as needed.

03:07:18 We’re providing the effect of the communication.

03:07:20 They don’t need to be connected anymore.

03:07:22 They don’t even need to be in your head.

03:07:24 I could spread your neurons all over the continent,

03:07:28 all over the galaxy,

03:07:30 and I could still provide the same stimulus pattern

03:07:34 over 10 or 15 seconds to all those neurons.

03:07:36 And somewhere Lex Friedman would have to be,

03:07:41 even though no longer existing as a physical object anymore,

03:07:45 would be feeling that subjective feeling.

03:07:48 And it’s inescapable

03:07:49 because it’s exactly the same as the previous situation.

03:07:52 All the neurons have to be spatially,

03:07:55 like the locality constraint,

03:07:56 they have to be spatially close to each other.

03:08:01 And you talk about light opto,

03:08:03 which is funny because light is the fastest traveling thing

03:08:09 that we know of.

03:08:10 Maybe let’s not put them all over the universe

03:08:13 because we might get relativistic problems then.

03:08:14 Let’s just keep them out.

03:08:15 Let’s keep all your neurons.

03:08:17 Let’s spread them over North America, okay?

03:08:19 And let’s play them out, same pattern of activity.

03:08:22 And right, it seems absurd, right?

03:08:24 There’s no way that could be true.

03:08:25 There’s no way that Lex would be feeling

03:08:28 that internal sense

03:08:29 if his neurons were spread all over North America.

03:08:32 And yet it’s exactly the same as the previous situation

03:08:35 where you said, sure.

03:08:37 So we’ve got a paradox.

03:08:38 And this is what makes people think.

03:08:39 Is it a paradox though, sorry?

03:08:40 Well, maybe paradox is the wrong word.

03:08:42 We got a problem.

03:08:44 We got a problem because it reveals

03:08:46 that there’s something big about those,

03:08:49 that internal subjective state that we’re not explaining.

03:08:53 And we don’t really have a hope of explaining

03:08:54 in the near future.

03:08:55 But don’t you think we would still have that?

03:08:58 It’s just the word internal loses meaning,

03:09:00 but don’t you think we still have

03:09:02 that internal subjective state?

03:09:04 Or if not, then where the heck is the magic coming from?

03:09:10 Okay, well, I just think,

03:09:13 I think one of the problems

03:09:16 that I think we need to let go of

03:09:19 is we tend to, outside of the experience of consciousness,

03:09:23 the hard problem of consciousness,

03:09:25 we tend to think that we individual humans

03:09:27 are really special.

03:09:30 Not the subjective experience,

03:09:32 but the entirety of it, like the body

03:09:34 that contains the thing.

03:09:35 So the local, the constraint of all the stuff

03:09:40 has to be together, and it’s all mine.

03:09:45 That’s a very, I don’t know if that has anything to do

03:09:48 with the mechanisms that are creating this.

03:09:52 So in fact, one really nice way to break through that

03:09:56 is to either observe or create consciousness

03:10:02 that spans multiple organisms.

03:10:07 Sort of like, let’s say it’s not an organism dependent

03:10:14 phenomena, that the phenomena can,

03:10:17 that’s just a peculiar way it has evolved on Earth,

03:10:22 but it’s a phenomena that doesn’t have anything to do

03:10:26 with a specific biological system.

03:10:31 Right, so and we have different parts of our brain exist

03:10:35 and sometimes create complex awarenesses of things

03:10:41 that involve different neurons that are distributed widely

03:10:47 and that need to communicate with each other

03:10:49 to form this joint representation,

03:10:51 this state of consciousness.

03:10:53 But indeed, why do they have to be in the same head?

03:10:57 We don’t know why that would be the case that they do.

03:11:02 And so that’s a huge unanswered question in the field

03:11:06 is what is it that binds the activity of neurons together

03:11:11 so they can form a joint representation?

03:11:14 And actually this comes back to the dissociation experiment

03:11:16 we talked about before, where your sense of self

03:11:19 becomes separated from your body.

03:11:23 Those things that were fused in a joint representation,

03:11:26 the same concept, unitary, are now separate.

03:11:31 And in late 2020, we published a paper in Nature

03:11:35 showing how this could be.

03:11:37 We used optogenetics to drive this rhythm

03:11:41 that ketamine and PCP cause in retrosplenial cortex

03:11:44 and we got different parts of the brain to be out of sync

03:11:47 and when they were active, never able to be active

03:11:50 at the same time, never able to form

03:11:53 a joint representation at the same time.

03:11:56 And so we’ve got a toehold into these questions.

03:11:58 We don’t have the answers, but.

03:11:59 And that mimics the dynamics of ketamine effects.

03:12:02 Exactly, exactly.

03:12:04 And you’re able to find that kind of oscillation.

03:12:08 Wow, wow, wow.

03:12:09 I see if you get even greater and greater control

03:12:13 with more control over individual neurons

03:12:16 and understanding, like if you think of certain neurons

03:12:19 that having some role to play in the sense of self,

03:12:24 you can play like an orchestra.

03:12:27 That, to create certain degrees of consciousness,

03:12:31 degrees of subjectivity, and thereby understand

03:12:35 what is consciousness.

03:12:37 But by having a very complicated light switch essentially.

03:12:41 And here’s the challenge is the nice thing

03:12:44 about the thought experiment is it kind of highlights

03:12:50 that we’re gonna hit a point where

03:12:53 we’re addressing some very, very fundamental questions.

03:12:57 What allows the activity of two sets of neurons

03:13:03 to become mutually relevant to each other?

03:13:07 This is in some ways maybe one of the deepest

03:13:11 remaining questions in neuroscience is what allows

03:13:14 activity patterns to become relevant to each other?

03:13:18 Do they have to be in sync temporarily?

03:13:21 Do they need to be, is there some other quality

03:13:25 that we don’t know about that also needs to be present

03:13:28 to allow cells to fuse together into a joint representation?

03:13:32 Just so I understand, because it feels close

03:13:37 to some very, very deep idea.

03:13:41 So there’s a bunch of semi distributed signals

03:13:43 going on in the brain.

03:13:46 And you’re saying there could be something

03:13:50 like a theory of everything if one to exist

03:13:53 is to understand why, how and why signals

03:13:58 close to each other start becoming relevant to each other

03:14:07 as part of some very much bigger signal

03:14:10 that they’re producing.

03:14:12 How they coordinate, essentially.

03:14:16 Because it’s very distributed.

03:14:18 I mean that’s a kind of, within a distributed system,

03:14:22 how is order achieved?

03:14:25 And this is a very specific kind of distributed system

03:14:28 that is one of the most intelligent that we’re aware of

03:14:32 in the known universe.

03:14:34 In that would maybe be something also,

03:14:38 an understanding of the full conscious experience too.

03:14:42 That this kind of coordination.

03:14:44 How does the coordination between different neurons

03:14:46 that are responsible for sense of self,

03:14:49 how do they begin to form a big picture

03:14:51 that we see as a human experience?

03:14:54 That’s really, really interesting.

03:14:55 So uniting the small and the,

03:14:57 I mean that’s actually literally theory of everything.

03:15:00 Uniting the small, the sort of the theory of the neuron.

03:15:05 The functioning of the neuron with the big.

03:15:07 Just the functioning of the entire mind.

03:15:12 That’s right.

03:15:12 And I think keeping a toehold in both

03:15:14 at the cellular level of resolution

03:15:17 and the brain wide resolution will be critical.

03:15:19 If you lose touch with either,

03:15:21 I think you’ll miss the big insight.

03:15:23 So that’s what we’re trying to do.

03:15:25 Keeping grounded in the cellular resolution.

03:15:29 Trying to keep the broadest brain wide perspective

03:15:32 and meet in the middle.

03:15:35 Do you think you’ll see it in your lifetime?

03:15:36 A major breakthrough in that dimension.

03:15:39 I have hope.

03:15:40 I have hope.

03:15:42 It’s very hard to predict what will happen

03:15:43 with big things like this.

03:15:45 If we don’t get there,

03:15:46 there’ll be plenty of other exciting stuff.

03:15:48 So it’s okay.

03:15:50 But the other aspect of this whole thing

03:15:52 is that your life is pretty short.

03:15:55 Yeah, that’s true.

03:15:56 So first of all, you can die any day.

03:15:59 I tend to try to think about that,

03:16:01 that it ends, it can end any moment

03:16:03 because it really, really can.

03:16:05 And if not, it’ll be soon anyway.

03:16:08 Do you think about that?

03:16:09 Do you think about your mortality?

03:16:12 I do, yeah.

03:16:13 It comes back to what we talked about earlier.

03:16:16 I never think I’ve done enough

03:16:18 and it’s relevant to that for sure.

03:16:20 There’s a deadline.

03:16:25 Do you think there’s ever going to be a feeling

03:16:27 where you sit back and you’re really proud of yourself?

03:16:34 I hope so.

03:16:35 Like, I’ve done enough.

03:16:36 I’ve done everything there is.

03:16:39 Because the thing is,

03:16:41 a warrior has some number of battles in them.

03:16:44 And at a certain point, if you’re deeply honest,

03:16:47 it’s like, well, that was a pretty good run.

03:16:50 As far as runs goes, that was pretty good.

03:16:53 And you can hang up your helmet

03:16:55 and then go sort of drink some ale,

03:17:00 listen to some music with the old lady,

03:17:03 and say, I did pretty good.

03:17:04 You think you’ll get there?

03:17:08 You know, with something,

03:17:10 nature always has surprises for us.

03:17:12 The curious mind is always after more.

03:17:17 But biology gives us other rewards.

03:17:22 Children and family, community.

03:17:26 And one can feel good about those things.

03:17:30 Biology is full of rewards.

03:17:31 But do you think about those rewards?

03:17:34 What do you think is the why of those rewards?

03:17:37 What’s the meaning of life and this existence?

03:17:40 What’s the why of biology?

03:17:44 What does it want from us?

03:17:45 Why are all these cells very busy

03:17:47 putting together an organism

03:17:49 that seems to want to just be in a hurry to do stuff

03:17:53 and survive, but it’s not happy being survived.

03:17:57 Like you said, it’s curious.

03:17:59 It keeps wanting to get into more trouble.

03:18:01 Why?

03:18:02 Yeah, you know, we’re clearly designed for that, right?

03:18:07 We’re clearly designed to ask why and to answer.

03:18:10 And that, I think, is,

03:18:12 I don’t know the meaning of all life.

03:18:15 I think a meaning of our lives is that.

03:18:17 And this is the Aristotelian happiness.

03:18:22 An organism is happy, an animal’s happy

03:18:24 if it’s performing to its design, right?

03:18:26 If it’s doing what it was made for.

03:18:29 Yeah, well, you have to understand, what’s the design?

03:18:33 And, you know, who is the designer

03:18:39 and what were they up to and how hard is it?

03:18:43 Do you have to build the whole universe?

03:18:45 And does the design even know what the hell they’re doing?

03:18:47 Because, you know, maybe the designer built humans

03:18:51 to find out about themselves.

03:18:56 That’s what I would do.

03:18:57 Like, if I had the power to build clones,

03:19:00 I would build a lot of clones

03:19:02 and I would get them into different trouble

03:19:04 to understand, like, what am I designed,

03:19:08 what’s this body designed to do?

03:19:10 How far can I go that way?

03:19:11 Exactly.

03:19:12 And then, and I dissociate myself completely

03:19:15 from having any way to know, like, that I know that person.

03:19:19 Oh, that’s good.

03:19:19 I mean, I suppose you could do that

03:19:21 in a single person’s body, but dissociation, you could.

03:19:26 Yeah, but I do wonder what,

03:19:30 if you look at Earth as a collection of humans,

03:19:33 as a collection of biological organisms,

03:19:35 it seems that we’re busy doing something

03:19:40 and it just seems too beautiful and too special

03:19:45 to be a random, a random experiment.

03:19:50 It seems like it’s an experiment that’s cleverly designed

03:19:57 That’s right.

03:19:58 by some forces of nature

03:20:00 that are beyond our current understanding.

03:20:03 And maybe that’s part of our design,

03:20:05 is to keep asking why.

03:20:06 You said answer.

03:20:07 I’m not sure that’s part of the design, the answer.

03:20:11 I think we’re given just the sufficiently limited

03:20:15 cognitive capability that we know how to long

03:20:19 to find the answer and we lack the ability

03:20:22 to find the answer.

03:20:24 That’s basically a summary of your career.

03:20:26 No, I’m just kidding.

03:20:27 And then we give each other Nobel Prizes

03:20:29 for having even an inkling of a good step

03:20:33 towards the right direction.

03:20:35 Carl, you’re an incredible human being.

03:20:38 I’m a huge fan of who you are as a person,

03:20:41 who you are as a scientist, who you are as a writer.

03:20:43 I just thank you so much.

03:20:45 I’m so honored that you would sit down

03:20:46 and talk to me today.

03:20:47 It was amazing.

03:20:48 It’s been incredibly fun.

03:20:49 Let’s do it again sometime.

03:20:50 Let’s do it again.

03:20:51 It’s been really great.

03:20:52 Your insights and wit and modesty

03:20:55 are really quite rewarding.

03:20:58 Thank you so much, man.

03:21:00 Thanks for listening to this conversation

03:21:02 with Carl Diceroth.

03:21:03 To support this podcast,

03:21:04 please check out our sponsors in the description.

03:21:07 And now, let me leave you with some words from Carl Jung.

03:21:11 Knowing your own darkness is the best method

03:21:13 for dealing with the darkness of other people.

03:21:16 Thank you for listening and hope to see you next time.