Karl Deisseroth: Depression, Schizophrenia, and Psychiatry | Lex Fridman Podcast #274

where the darkest places you've ever gone in your life the following is a conversation with carl deisseroth professor of bioengineering psychiatry and behavioral sciences at stanford university he's one of the greatest living psychiatrists and neuroscientists in the world he's also just a fascinating human being we discuss both the darkest and the most beautiful places that the human mind can take us he explores this in his book called projections a story of human emotions i highly recommend it it's written masterfully this is the lex friedman podcast to support it please check out our sponsors in the description and now dear friends here's carl that's roth you open your book called projections a story of human emotions with a few beautiful words that summarize all of humanity the book draws insights about the human mind for modern psychiatry and neuroscience so if it's okay let me read a few sentences from the opening you got to give props to beautiful writing when i see it quote in the art of weaving warp threads are structural and strong and anchored at the origin creating a frame for crossing fibers as the fabric is woven projecting across the advancing edge into free space warp threads bridge deformed past to the ragged present to the yet featureless future yet featureless future well done well done sir the tapestry of the human story has its own warp threads rooted deep in the gorges of east africa connecting the shifting textures of human life over millions of years spanning pictographs backdrop by creviced ice by angulated forestry by stone and steel and by glowing rare earths the inner workings of the mind give form to these threads creating a framework within us upon which the story of each individual can come into being personal grain and color arise from the cross threads of our moments and experiences the fine weft of life embedding and obscuring the underlying scaffold with intricate and sometimes lovely detail here are stories of this fabric fraying in those who are ill in the minds of people for whom the warp is exposed and raw and revealing what have you learned about human beings human nature and the human mind from those who suffer from psychiatric maladies for those for whom this fabric is warped and one thing we learn as biologists is that when something breaks you see what the original unbroken part was for and we see this in genetics we see this in biochemistry it's known that when you have a mutated gene sometimes the gene is turned up in strength they're turned down in strength and that lets you see what it was originally for you can infer true function from dysfunction and this is a theme that i thought needed to be shared and needed to be made communicable to the to the lay public to everybody people who which is i think uh almost all of us who think and care about the inner workings of our minds but who also care for those who have been suffering who have mental health disorders who face challenges but then more broadly it's a very much larger story than the present there's a a story to be told where the protagonist really is the human mind and that was one thing i wanted to share as well in projections is that broader story but still anchored in the moment of patience of people of experiences of the moment is there a clear line between dysfunction and function disorder and order this is always debated in psychiatry probably more so than any other you know medical specialty i'm a psychiatrist i'm i treat patients still i see acutely ill people who come to the emergency room where there's no doubt that this is not something that's working well where the manifestation of disease is so powerful where the person is suffering so greatly where they cannot continue as they are but of course it's a spectrum and there are people who are closer to the to the realm of being able to work okay in their jobs but suffer from some small dysfunction and everywhere in between in psychiatry we're careful to say we don't call it a disease or a disorder unless there's a disruption in social or occupational functioning but of course psychiatry has a long way to go in terms of developing quantitative tests we don't have blood draws we don't have imaging studies that we can use to diagnose and so that line ultimately that you're asking about between order and disorder function and dysfunction it's operational of the moment how are things working can we just like linger on the terms for a second so this uh disease uh dysfunction how careful should we be using those words can we just even in this conversation um from a sort of technical perspective but also a human perspective how um quick should we be in saying that schizophrenia uh depression autism as we kind of go down this uh across the spectrum of different maladies like just to use the word dysfunction and disease i would say to give ourselves license to capture the whole spectrum let's say disorder because that that captures truly i think the essence of it which is we need to talk about it when it's not working when there's disorder and that that's the fairest and you know most uh inclusive term to use so is it fair to assume that basically every member of the human species suffers from a large number of disorders then well and we just have to pick which ones are are debilitating and for each person you know if you if you look at the numbers there are uh you know if you look at how our mental health disorders are currently defined you can uh look at population prevalence values for all these disorders and you can come up with estimates that somebody will have a lifetime prevalence of having a psychiatric disorder that approaches 25 or so and so that's and in some studies it could be more some studies it could be less now what do we do with that number what does that mean and in some ways that's the essence of what i was hoping to approach with uh the book is to reflect on this spectrum that exists for all the disorders there is and taking nothing away from the severity and the suffering that comes at the extreme end of these illnesses but nearly every one of them exists on a spectrum of severity from nearly functional to completely dysfunctional life-threatening and and even fatal and so that that that number 25 more or less it doesn't capture uh that that spectrum of of uh severity to regard that number where do those numbers come from is it self-report is it people who show up and say i need help is it somebody else that points out that person needs help or is it like estimates that even go beyond that for people who don't ask for help or suffering quietly alone when you look at self-report numbers that then those numbers get even higher beyond 25 percent or more those the most rigorous studies are done with structured psychiatric interviews where people who are trained in eliciting symptoms carefully do complete psychiatric inventories of of individuals and these are time-consuming laborious studies that not often repeated when they're done they're they're done well but very often you'll see a report or something in the news of a very high number for some disorder or or symptom and very often if it's shockingly high that's coming from a self-report of a person and so that's another another issue that we have again take nothing away from the severity and reality and and biological nature of these disorders which are very genetic very you know we we understand that these are very biological and yet we lack right now the lab tests and the blood draws to make the diagnoses we'll talk about it just how biological they are because it's a that too is a mystery i mean you know in terms of from a perspective of how to probe into the disease how to understand it and how to help it so some of it could be neurobiological some of it could be uh just the the dance of human emotion and interaction and the it's like uh well it is love when it works and is love when it breaks down uh biological or is it something else so we're gonna talk about it but let me just like to linger in terms of disorder what about genius you know that sort of uh cliche saying like the madness and genius that they kind of danced together uh what about if the thing we see is this order is actually genius unheard or misunderstood well here again the numbers help us and here's where being rigorous and quantitative actually really helps if you look at disorders like autism and bipolar disorder and eating disorders anorexia nervosa for example these uh you know particularly bipolar and anorexia these can be fatal they can cause immense suffering but they are heavily genetic all three of these and what's very interesting is each one of these three is actually correlated positively positively with measures of intelligence of educational attainment and even of income and so you look at this severe disorders in many cases causing quite immense morbidity and mortality and yet they are positively correlated at the population level with positive things can you say the the three again autism autism anorexia and bipolar disorder bipolar right what's that book forgot the book name but uh is intelligence a burden uh well you know people can get into trouble when they think they're smarter than they are i will say that i don't know sometimes like in the deepest meaning of that statement i think ignorance is bliss i'm a big fan of prince michigan from the idiot and um i learned from brother karmazov optimism can be seen as naivete and dumbness but i think it's a it's a kind of deep intelligence maybe inability to reason uh sort of about the mechanics of the world but instead kind of feel the world and it seems like that's a one of the paths to happiness there is how much you think versus how much you feel this comes up all the time in medicine we encounter this all the time when you day after day you encounter this you know the the abyss of suffering from patients how much do you let yourself feel or how much do you make it abstract and and objective and try to make it clinical and that range how you're able to move yourself on that on that spectrum is very important for survival as a physician and the way you you protect yourself and your feelings turns out to be very important so you quote finnegan's wake uh mad props for that james joy's book i took a class on james joyce in college i think i read parts of finning and way i might have been on drugs of some kind or i um i somehow got an a in that class which probably refers to some kind of curve where nobody understood anything the only thing i understood and really enjoyed is the short stories the dead and then ulysses i kind of uh i think read a few cliff notes that kind of got to the point and then finnegan's wake was just a hopeless person i it's a you for people who haven't looked at it maybe you can elucidate to me better but i felt like i was reading things words and the words made sense like standing next to each other but when you kind of read for a while you realize you didn't actually understand anything that was said right but did you have a feeling though that's one that's one thing i found interesting about finnegan's week i i never fully understood it but the words caused feelings in me which i found fascinating and and sometimes i i couldn't predict it from the the semantic you know black and white context of what i was seeing in front of me on the page but the rhythm or the melody would make me feel certain ways and that's that was what i always was intrigued by with joyce of course that was his he he existed on a spectrum too and he wrote as you say you know more accessible uh works you know i learned a lot about irish history from you know portrait of the artist as a young man and there was just he could be as objective as he wanted to be but then when he let himself loose he was in this realm where the words had their own purpose separate from from you know semantic meaning from their their dry uh you know dictionary definition you know there's a funny story that was told it doesn't matter if it's true or not but they they said that uh james joyce when he was young when he was in his teen years would go around instead of ireland drinking and so on and telling everybody that he's going to be one of if not the greatest writers of the 20th century and uh he turned out to be that so the that i always think about that little story that somebody told me because i have a lot of people come up to me including myself i'm a bit of a dreamer i and you know you get into certain moods where you say i'm going to be the greatest anything ever you you get like people tell you this uh young especially young people and it kind of it makes me feel all kinds of ways but that story reminds me that like you just might be one of the greatest writers of the 21st century for example if somebody were to tell me that and like don't just don't immediately disregard that because one of the people that say that that's almost like a pre-condition that's like a requirement just to believe in yourself maybe it's not a full requirement but it's it's an interesting story i think when someone tells you that then it creates uh one sees an opportunity and then it would be a tragedy if the opportunity weren't captured right and so then that creates a um some some impetus uh some motivation to do something something good i think the mind it's like uh you know i guess that's what like books like the books or whatever i don't even know if it's a book the secret plugs into uh they kind of make a whole industry out of it but there is something about the mind believing something making it a reality it is just time and time again with steve jobs like your belief in yourself your belief in an idea sort of embracing the me versus the world embracing the madness of this idea and making it a life pursuit somehow morse reality around for some tiny fraction of the population for everybody else you descend into uh you know all the beautiful ways that failure materializes in our lifetime you know you mentioned love earlier i mean that's that's a great example of how belief in something makes it real right it's it's not reasonable on the face of it but because you believe it's reasonable then it actually does become reasonable and then it is real and so that's a that's a good example that doesn't happen i'm also in a bioengineering department we don't imagine that a bridge is soundly built and then it is soundly built that's something that it doesn't come up in too many realms of human existence but love is one of them and and these the ability to to have a fixed idea and to say it's true and then it is true a bridge is a kind of manifestation of love so maybe it does work a little bit but you know they can break down like chernobyl did you can't just say it's safe you have to also prove it safe uh but on finnegan's wake i think maybe correct me if i'm wrong you're using kind of finnegan's wake to give one perspective on what madness is of what's going on in the mind how much of that is uh that we're simply unable to communicate with the person on the other side of of their mind like there's almost like a a little person inside the brain and they have some circuitry that's used to communicate emotion communicate ideas to the outside world and there's something about that circuitry that makes it difficult to communicate with a little person on the other side so if you look at what shows up in schizophrenia with many cases the what we call thought disorders what we call uh the the individual speech symptoms of schizophrenia finnegan's wake is is loaded with them and it's it's just full of them we we talk about uh clang associations in schizophrenia where the word that is said is echoes in some way the previous word and it's we call that a clang association because there's no other reason than the similarity of the sound like a like a clang of a of a garage door being hit and it has a and sometimes it's not even a word and we call that a neologism a new word being created and of course finnegan's wake is is full of that and then uh we we also in schizophrenia where there's what we call loose associations or tangential thought processes of course full of that where things just go off in directions that are not linear or logical and you can't read finnegan's wake i think without um certainly a psychiatrist you can't read it without thinking about schizophrenia and then when we look at the families of people with schizophrenia and joyce was no exception there very often are people within the family who are on the spectrum some have it some are able to see it from a distance from a safe distance there's an association between schizophrenia and what we call schizotypal personality disorder where people are not quite in this severe state of schizophrenia but have some magical thinking have some unusual thought patterns very often those are family members of people with schizophrenia so this points to this again to this idea that that there is a range even along this very severe very genetic biological illness that human beings dwell on different spots along that spectrum i should mention that we have my friend sergey pulling up stuff young sergei or old sergey i don't know what to call you but uh there's drafts of finn can squake yeah i actually saw pictures of this from um i think it was on instagram or something these are early giraffes of finnigan's wave and it's so beautiful to see for people who are just listening there's just random paragraphs and writing all over the page with stuff crossed out and it's great to see that joyce himself was thinking in this kind of way as um as you're putting it together how much do you think he was thinking about schizophrenia this schizophrenic mind i think a lot i think you know it's it's known that his daughter suffered from from schizophrenia and uh the this is what's depicted here on the page is something that i'm sure he either felt himself and some some level was able to access this non-linearity of of processing or had seen enough in family that he he knew what it was and was able to to reflect it down in black and white on the paper so it was what he was able to do is was quite authentic in that sense of course i don't want to pigeonhole him he was doing much more than that it was much more than than talking about altered human thought processes and thought disorders but that was an aspect that he was so good at representing that it had to be intentional to some extent and a tiny tangent what does your own writing look like for this book because it's extremely well written how many edits did you just drink some whiskey and uh like i'm imagining hemingway style what's a very different the the writing is very different i mean it's really really well written which was like i was reading it it makes you realize because i was expecting sort of a science kind of which it is like uh you know elucidating something about the human mind kind of thing but you could also probably write really strong like novels uh so maybe that's in the future but anyway what is your how many edits how many what's your style does it look like that is it more structured organized unfortunately i used a laptop so i didn't have this sort of uh beautiful recorder typewriter cigarette and whiskey i did explore i was you know which was there a particular altered state that would help me to be most creative and and i i found actually i i actually did the best while uh you know sober but slightly disinhibited in the late hours of the of the night or early morning yeah particularly late hours of the night there you know i i i have a friend who would tell me that she thought that very early in the morning her inner critic was still asleep and she could write more effectively before her inner critic woke up yeah and i actually found that uh outstanding advice for me that i often found that there was i was looser and could write more in the morning but the other interesting thing is is each each chapter each story it's about a different uh human being with a different class of of psychiatric disorder that's what each story each each chapter is anchored in by trying to use words that and style of writing and and uh you know diction that captures the feeling of the disorder and so it's different in each story in the story about mania which is a very expansive exuberant uh at least briefly uplifting state uh where the words come out in a torrent and they're complex and pressured and elaborate i try to capture that feeling with the the words used in that chapter and then in the schizophrenia or psychosis chapter where things slowly fragment over time and become looser and and and separated i tried to capture that in the writing too so for each it wasn't as if there was a single mode i could be in for the whole book for each chapter i had to put myself into a different mode to capture that uh inner feeling of the disorder when you put yourself in that mode does that change you yeah i couldn't turn it on and off right away i had to first i would start by thinking about the person uh or the people one or two people based on real patients and the stories that are that are put forth uh the symptom descriptions are real they're from the patients of course all details change to protect uh privacy but the actual symptom descriptions are real and i would sit with them and really try to inhabit the space of the mind of of that person that i knew and that's not instantaneous it would take take some time i needed quiet i needed to be still that's another reason late at night is is good sergey posted that drowsiness gives creativity boosts according to andrew huberman thank you andrew uh it's not wrong he's not wrong why projections is it uh i mean there's some instead of putting words into your mouth because i can imagine a lot i mean i to me you know i will start putting words in your mouth despite what i just said so i mean to me projections working on neural networks for example from artificial neural networks from a machine learning perspective it's often that's exactly what you're doing you have an incredibly complex thing and you're trying to find simple representations in order for you to make sense of it so i was kind of thinking about in that way which is like um this incredibly complex neuronal network that is kind of projecting itself onto the world through this low bandwidth expression of emotion and speech and all that kind of stuff and the way it's we only have that window into your soul the eyes and the speech and so on so that in that way we're um when there's any kind of disorder we get to only see that disorder through that narrow window as opposed to the full complexity of its origins the word projections definitely serves that purpose here but it's it's got a few other really appropriate other connotations as well so the first thing is a projection in terms of neuroscience is this long-range connection that goes from one part of the brain to another and so it's what binds two parts of our brain together there are projections long-range connections of axons these are the outgoing threads that connect one part of the brain to another part there's a there's a projection that links for example auditory cortex where we hear things to reward centers where we can feel where feelings of pleasure and reward are initiated and it's been shown that if you have reduced connectivity along that dimension you are less able to enjoy music and so these connections these projections matter they define how effectively two parts of the brain can engage with each other and join together to form a joint representation of something so that's one meaning it's pure neuroscience the word projection is used all the time and it happens to be something that optogenetics a technique that we maybe we'll talk about a little later it works particularly well with we can use light to turn on or off the activity along these projections from one spot of the brain to another and this is particularly referring to the long range connections it's particularly straightforward along these long range projections that connect different parts of the brain but it works over shorter range too but then there's this other meaning of projections which you were bringing up which is very relevant which is at some point you you can reduce something from one level of dimensionality to another you can project down into a lower dimensional space for example and then finally there's a psychiatric uh term projections which comes up all the time which is uh we very often uh will look at our internal states and to understand somebody else we'll project them on to somebody else we'll try to understand someone else's behavior and and make sense of it by projecting our own inner feelings our own uh sort of narrative onto them and use that as a way to help us understand them better and we'll do the reverse too we'll take things we see in the outside world and we'll bring them into ourselves and see how well they map how will they align that's called introjection so projections is a turns out to be a really rich word then finally of course there's the very common sense of it as as a projector that that illuminates by conveying information across space with light so for english for english language perfect word to use for this book but what's funny is not every there are a lot of international translations now and and all those rich connotations aren't captured in other languages and so for some translations uh connections is used uh instead of projections in fact even in england the british version is connections instead of projections because apparently projections doesn't have the full connotation i was told you have to sacrifice some of the rich um ambiguity of meaning uh with connections that's interesting i mean connect and words are so interesting they have so many i love language and how much is lost in translation i'm very fortunate enough to be able to speak i'm not good at languages i was just i guess forced to by life circumstance to learn two languages russian and english and it's just so interesting to watch how much of culture how much of people how much of history is lost in translation the poetry the the music the history the pain the way the scientists actually express themselves which is funny i mean just it's so sad um to see how much brilliant work that was written in russian there's a whole culture of science in the soviet union that is now lost it makes me wonder in the modern day how much incredible science is going on in china that is lost in translation and i'll never i mean that makes me very sad because i'll never learn chinese in the same way that i've learned english and in russian maybe whenever i say stuff like that people are like well there's still time but uh you know uh yeah that's it's that's actually fair that uh i think the 21st century both china and us will have very important roles in the scientific development and we should actually bridge the gap through language and that that doesn't just mean convincing chinese to speak english that means also learning chinese well we need these bridge people who can do both you know the um you know nabakov for example writing in english beautifully uh uh you know one of my favorite poets porques who you know mentioned earlier he wrote both in english and in spanish i think you know beautifully in both we need those people who can serve as bridges across cultures who really can do both you mentioned borges so you open your book with a few lines from a poem by jorge luez borges a love poem i'm going to read parts of it because it's a damn good poem yeah it's called two english poems i mean there's i'd like to understand why you used it and the specific parts you used which is interesting but then when i read the full thing so i think you used it as as a sort of beautiful description of what it means to delve deep into understanding uh offering yourself to the task of understanding another human being but if you look at the full context of the poem it's also a damn good description of being hit by love and overtaken by it and uh uh sort of and trying to trying to figure out how to make sense of the world now that you've been uh stricken by it it says a bunch of things uh about chatting and significantly with friends and all those kinds of things and then the poem reads the big wave brought you i get this is the moment i guess of the universe where the two people you fall in love maybe i'm totally misreading this poem by the way it doesn't matter you can't misread a poem so it goes on words any words you're laughter and you're so lazily and incessantly beautiful we talked and you have forgotten the words the shattering dawn finds me in a deserted street of my city your profile turned away the sounds that go to make your name the lilt of your laughter these are the illustrious toys you have left me so these little memories of these peculiar little details he remembers those are the illustrious toys i apologize to mix my own words of the poem but you should definitely read it i turn them over in the dawn i lose them i find them i tell them to the few straight dogs into the few stray stars of the dawn your dark rich life i must get at you somehow i put away those illustrious toys you have left me i want your hidden look your real smile that lonely mocking smile your cool mirror knows i want your hidden look your real smile i am so i this is the first part of the poem and then it goes on which is some of the parts that you reference second part is what can i hold you with i offer you lean streets desperate sunsets the moon of the jagged suburbs i offer you the bitterness of a man who has looked long and long in a lonely moon i offer you my ancestors my dead men the ghosts the living men have honored in bronze my father's father killed in the frontier of buenos aires two bullets through his lungs and so on so on i offer you whatever insights my books may hold whatever manliness of humor my life i offer you the loyalty of a man who has never been loyal i offer you that kernel of myself that i have saved somehow the central heart that deals not in words traffics not with dreams and is untouched by time my joy and adversities and i think this is where the part they include in the book i offer you the memory of a yellow rose cena sunset years before you were born i damn that's a good line okay [Laughter] i offer you explanations of yourself theories about yourself authentic and surprising news of yourself i can give you my loneliness my darkness the hunger of my heart i am trying to bribe you with uncertainty with danger with defeat that is a man who's in love and longing if i've taken but i just want to go back to maybe you could say why you want to include that poem but also your dark rich life i must get at you somehow i put away those illustrious toys you have left me out when you're i want your hidden look your real smile that lonely mocking smile your cool mirror knows what sometimes i meet a stranger and i just it's like it's like a double take it's like who are you have we met before somewhere who's that person behind there and i want to get at that whatever that is and of course maybe that's what love is because maybe uh maybe that's the whole pursuit like a lifelong pursuit of getting at that person maybe that's what that is and like that uh insatiable sort of curiosity to keep getting like who's that person then you're on private life yeah so that absolutely i think that it was a beautiful description of what you just said when there's that first moment and then you want to dive deeper you want to know what the what the hidden mysteries are in a way it's it's a it's a love poem as a as a scientist though it also it's a bit of how a scientist can love science and and that wanting to dive deeper is it's almost like again where the it could be a love affair with investigating the human mind for example and and that was one reason it spoke to me also again thinking about the broader sweep of where the human mind came from uh the steps it took to get where it is today what was given up along the way what compromises were made and here's where the darkness of the poem starts to come in a little bit too it doesn't shy away from the negativity from the confusion from the danger and then at the very end the board faces offering up scenes from his life parts of himself and this is how we connect with people we offer up parts of ourselves just here it is and then we see how well does that map on to what you have and it's it's that offering up that i liked and not not the good stuff or not only the good stuff the yellow rose is nice but but he's offering up the bad stuff too and that that to me was important for the for the book because i'm offering up hard stuff too and in fact a lot of it and also hard stuff from within me from my my own personal side too and that was there's a lot of vulnerability that comes with that but that's that comes with love that comes with writing you have to be open you have to be vulnerable and so i thought that reflected what i was trying to do and i thought it was a as an epigraph it kind of made it clear how vulnerable i was in taking this step but also what what could come out of it and also in a meta way because i was not familiar with this poem it uh it made me curious of the poem itself to pull at that thread of finding out more so you picked a very particular part that kind of made you want to um pull at that thread and and then and see where did this where did these few lines come from because i i read it as a curiosity of a scientist those lines were alone and also as a desperate uh human being searching like offering himself for an understanding or connection with with another human being and then because i wasn't sure if it's a love poem or not or if it's desperation or if it's curious whatever it is and then you see the love poem i mean i don't know that that's gonna stick with me for a while the your dark rich life and then a few lines in here are just i mean those are i'm going to just use them as as pick up lines at a bar i offer you the memory of a yellow rose seen at sunset years before you were born now that's a pickup line i've never if if i've ever heard one anyway sorry but this is universal you know you see it in so many forms of of art you know like you know we're in texas now you see this in country uh country and western songs it's it's often a list of things like here's how i describe myself there's this and there's that and there's the other thing and here you are these things matter to me and i hope they matter to you too it's a it's a pretty universal form but it's but he did it in this very artful uh and very vulnerable way it was it was both both beautiful and you could you could feel the hurt coming from him too and that was important the dark stuff too i offer you my ancestors my dead men the ghosts the living men have honored in bronze and talking about two bullets through his lungs bearded and dead wrapped by his [Applause] soldiers in the height of a cow my mother's grandfather just 24 heading a charge of 300 men in peru now ghosts on vanished horses so all of it the whole history of it um since it is a love poem what do you think about love carl what's what's the role of love in the human condition we'll talk about the dark stuff yeah but uh maybe love is the dark stuff too i mean it's it's the most powerful connection we can form and that's that's it's that's what makes it so important to us it's the it's the strongest and most stable connection that we can form with another person and that matters immensely it matters for for the human family to have evolved to be something that could survive against the odds that that that we've faced over the years that un reasonable bond that becomes reasonable by virtue of its own existence and of course that joy the the wild raw joy of love is not a bad thing either so you put these together the four the strongest bridge we can form and the reward and the joy that that it brings that's that's what love is to me and from you know my perspective this is something that you know it can be hard to capture fairly because you want to talk about the positive and the negative sides at once they need to be wrapped up together for full honest description of what it is and that that's hard to do in a in a compact form and so you have to take time to talk about love you have to take time to to do it justice um it takes a book or at least a poem or several thousands of them i don't know so is there could you pull up there's a video i saw yeah like right here so can you pause for a second uh so so there's march of the penguins so you always see like penguins huddling together against i i mean sorry if i see just metaphors and everything but uh them huddling together against the harshness of the conditions around them that's very kind of that's like a metaphor for life like finding this connection that's kind of what love is it's like it allows you to forget whatever the absurdity whatever the suffering of life is together you get to like huddle for warmth and that's why i love the uh sort of just the uh the honesty and the intensity of the way penguins just in the middle of like the cold do this and then this video i saw a lonely this is this is misinformation so the name of the video is lonely deranged penguin i don't know if he's deranged so if you play it so he left his pack and uh and there's a nice like voiceover and you don't need to play it but he for some reason left the pack and journeyed out into the mountains and so the the narrator says that he's deranged he's lost his mind now i'd like to project the idea that he's actually there's so many stories you could think of he's returning to his homeland he's an outsider thinking journeying out into the unknown thinking he may be able to discover something greater than the tribe he might be looking for a lost love why is he deranged immediately why has he lost his mind anyway but this you people should look up this video because to me i might be the only one who uh romanticizes this but it's such a nice kind of it's both a picture of perhaps a mental disorder which is what the video kind of describes and it may be some deeper explanation that's not that that has to do with the motivation of a of a mind yeah i don't know if i don't know if you have a deeper analysis on this penguin well i i like you as a psychiatrist i i would i would want to sit down with a penguin and go i want to see the notes from his prior therapist and but this this actually is relevant not knowing what was that penguin's motivation we have very clear situations where there are both within an individual we go through periods of time when we stay in one place and we reap the benefits from what we've built and then we go through periods of foraging of of of wandering even if there may be resources where we are we we have periods of time in our lives where we want or where we where we go in an exploratory mode and different people express that trait in different ways this is not a human specific trait if you go down to to the tiny little nematode worm c elegans with 302 nervous system cells they go through these phases of foraging and rest and different individuals have different propensity to forage or to rest and stay in one place at the level of the species that's really good that there's that diversity in their willingness to forage some stay where they are the species is somewhat on a firm footing then but some carry a burden a risk for themselves but it's good for the species that they're explorers and they will venture out the migration patterns that different species blunder into and that turn out to be really good they weren't logically derived they most certainly started from something like this an exploration humans do this too you think and we do it too in fact it's that's something we do extremely well let's talk about psychiatry a little bit so my book you're a a rock star first of all for people who don't know you're one aside from sort of um the neurological view of the brain and neuroscience view of the brain you're also one of the great psychiatrists of our time i've always not always but when i was younger i dreamed about being a psychiatrist um so it's like it's like getting to meet your heroes and also um you know getting to meet the people who uh the best at the top of the world at the thing you've failed to pursue so there so there's i'm getting a free therapy session on top of that okay so what uh big picture what is the practice the goal the hope of modern psychiatry if you could try to describe the discipline as you see it maybe historically throughout the 20th century in contrasting to what it is today or maybe if you want to describe to what you hope psychiatry becomes or longs to become in the 21st century yeah it's been an interesting journey uh it psychiatry started out pretty firmly grounded in neurology and pathology some of the initial founders effectively of the field were very well grounded in microscopy looking at cells working with patients uh particularly on the neurological side and this certainly included you know freud and some of his contemporaries and but they rapidly discovered that what they could work with at the level of cells and microscopy was so far from the realm of what they could get from a human being and what they were getting from the human being was so much more interesting and had was so mysterious and so unknown that many of them just said we're going to inhabit this domain and we're going to work with the people with their words and understand what we can based on verbal communication because that was the only tool that people really had and that was a very important step for the field i would say one of the interesting things that came from the early decades of psychiatry really was this distinction between the conscious and the unconscious mind and paying particular attention to the unconscious mind is something that was worthy of consideration uh that that might be important in explaining people's actions and that perhaps even insight into that was valuable in its own right and out of that psychoanalysis uh became a practice that it was not always focused on cures or treatment but was more focused on insight what does it what does it mean how can we help people understand why they're feeling something or thinking something or dreaming something and that insight separate even from treatment was was an interesting thing as long as one was honest about that and said you know we're we're going for understanding we're going for insight maybe it's useful to just pause on that let's if you look at the father psychoanalysis sigmund freud what do you make of the ideas that he had so you mentioned taking the unconscious the subconscious seriously that's like step one like that there could be worlds we do not have direct access for we probe at them through conversation or um is it too simplistic to call psychoanalysis conversation that's not too simplistic but that's right and i think that was valuable where where freud ended up breaking from some of his contemporaries he was very focused on this unconscious as being so tightly linked to libido and and really he from his perspective you couldn't really separate the operation of the unconscious mind from these aspects of the libidinous aspects and that was one reason you know sex sexual sexually related uh you know drives carl jung who was his you know uh you know contemporary that's one factor that led to them separating was you know carl jung felt there was a lot more to the unconscious than than this libidinous aspect of it and he saw it as a much more complete uh uh alternate representation of the the conscious self one that maybe reflected a whole range of different motivations and and desires um and to to properly treat it one had to consider all of them rather than the ones that destroyed us called young chef thank you thank you for the high level of uh of images that sergey is pulling up for people who are just listening he pulled up a as a quote from uh segment four it's a meme your mom quote uh freud uh so the the shadow the carl young shadow encompasses everything not just the desire to have sex with your mother or sex period that's right that's right if you look at those two folks on mass i mean there's a kind of it's almost like a technique for philosophical exploration of human mind human motivations so it's not even like necessarily it's also doubles as a methodology for helping people but it's almost like a it's a kind of philosophical method right this is the fascinating thing about about psychoanalysis and and it even though it's it's i would say mostly not considered a treatment today it persists for a couple reasons one is it it's it's thought that it gives people some insight but second there's been a huge influence on on literature on philosophy on art and the the opening up of discussion about what was below our conscious mind was uh so so fertile in the implications that it it sort of reverberated and still does throughout all these different realms of human endeavor from our different artistic uh you know experiences that people have can be colored by this this uh concept of the unconscious now the other thing that was interesting is is is this distinction you know what what are the parts of the unconscious and and so there were these id and ego and superego uh subdivisions that you know that that freud for example would would talk about them and and the the id was the primary the primal drives that an infant would have uh or that a very young child just warmth and feeding and then then later the you know the sexual or libidinous aspects and for freud the later happened very quickly that's the controversial thing about him i think i guess he thought like even children had sexual desires that they're like dealing with contending with so it's the full thing hungry wanting to eat wanting to poop wanting to have sex yeah and he was extremely focused on that on on that aspect but then there was then there was this the superego which brought on these later sort of moralistic uh sort of codes of conduct and and that of course was very often in intention but all this could play out subconsciously and then the ego this third aspect was mediating and for its conception mediated this tension between the different uh parts now i think that's interesting uh i will say that in some ways it's maybe unnecessary from the perspective of modern neuroscience to divide things up that way from the you know the moralistic drives and the primal gratification drives in some ways they're all drives and maybe they're even all primal drives you know the the moralistic drives they're they're taught and they're taught in ways that ultimately relate back to survival and you could even say selfish aspects of of health and life for the self and family and so this is uh i don't i think it's maybe an artificial distinction the concept of the unconscious is very valuable and very interesting um but these categorizations uh of id and and uh superego may not map onto neurobiology in any particular way if there's a town hall of competing drives and desires and there they interrelate to each other they involve different aspects of the of the brain and the history of the person and actions and choices come out of the result of that overall you know shouting in the town hall so in some sense carl jung was a step into the direction of liberating yourself from such harsh categorizations do you think i mean you have daniel kahneman with system one of system two there's just these very compelling categorizations of the human mind that seemed to be sticky in our uh in the super ego no uh in the you know the how we talk about these ideas and so on yeah do you think those are helpful or do they get in the way is it some kind of balance in terms of deeper understanding of how the mind actually works you know it's from the from modern neuroscience uh whenever we seem to get closer to addressing a question like this at the level of cells it seems to get farther away and i'll give you an example of what i mean by that so one thing i'm doing in my laboratory and many people are doing is we are listening in on the activity of cells neurons in the brain of mice or rats or fish or monkeys individual cells individual cells exactly of which there are you know in our brain many billions and when we do and we try to predict what action will be taken by an animal to address this question where does the choice arise where does the impetus to make a particular selection of one action versus another action where does that start in the brain if you're recording listening in on the activity of cells all across the brain where's the earliest spot you can pick up a choice being made well that's so awesome yeah at one level you might think how excited would young have been to see this or freud or the early you know psychoanalysts to see where this starts but it's not so simple because an emerging theme in very recent neuroscience literally over the last few years is that things sort of all start together all across the brain and so you can be recording from the cortex this rim of cells at the surface of the brain or you can be recording deeper in a structure called the striatum which is a little older it's more tightly linked to to action and then structures called the thalamus other parts of the brain and if you record from these these all sort of represent the action and the choice more or less all at about the same time very close and so it's you can't point to a particular spot and say here's where the choice or the action originates it's a finding the free will neuron that's relevant to that question nobody is is close to being able to point to such a thing well close is a relative term and nobody uh what i what i tweet today uh all generalizations are wrong [Laughter] so including this one let's actually talk about that sort of the study of individual cells if you could linger on your sense that as you get closer to that understanding it feels like you're getting farther away why is that because that that often is the feeling until you're actually there so so like uh you know see that's when i'm running and i know there's only a mile left it just feels like that mile is just getting longer and longer but eventually you finish so maybe we're getting close to cracking open these like beginnings of ascent like we'll talk about consciousness or these very difficult big questions about the human mind where do they start you're right to say we shouldn't uh generalize or make absolutist statements but i would say right now the reason things are looking even harder to crack than we had initially thought we now have the data streams that we've wanted for so long in terms of activity patterns all across the brain at the level of cells we can literally see what cells are doing immense data sets you know we get these are you know time series of one individual cell with you know sub second resolution and you can collect this from you know enormous numbers of cells across the brain so very rich data sets that we've wanted for a long time and yet having these uh has not led to an understanding of truly where actions uh initiate um in terms of regions or locations let's get a few questions on that is the answer high-level question by your intuition is the answer within the data or do we need different kind of data so we should also say that when you collect data about the the brain there's like the richness of information you're collecting but there is also human doing stuff um like and the information so static information about the human and dynamic information about the human and you can get them to do different stuff and you can select different humans and that's part of the collection of data aspects so like when you're collecting data about the brain there's some truths that you can you know in machine learnings like annotations like supervised learning there's some true things you can hold on to before you look at the full rich mess complexity of the human mind so given the data you've looked at do you think the answer for the for the origin of free will in the human mind is can be found well one one amazing thing is that nobody's nobody's found it but we have these rich data sets and and then there's a conundrum which is uh is it in the data and we just don't know how to look at it maybe we don't know the right scale the right projection to make of the data the right way to interpret it and here's where causal testing becomes very valuable because then instead of just passively observing well here are here are the activity patterns and then here's the choice made by the animal as we've gotten more powerful at reaching in and causing things to happen in the brain turning up or down the activity of certain types of cells or defined populations of cells and seeing how that affects actions these causal perturbations have turned out to be very valuable we're just now getting to the point where we can apply these in very wide swaths of the brain at cellular resolution and so we're going to be able uh hopefully to make some headway on this question with with causality and those that's the one thing that optogenetics provides us this way of using light that we develop to control cells this is an untapped relatively untapped at this broad brain wide scale and hopefully we can get there in the near future but i would say that the answer may be maybe in the data uh but we don't know how to find it well there's this interactive element like where you can cause stuff that's really powerful because you get to i mean uh as opposed to collecting data passively you you're collecting data actively so can you maybe describe one of the many things you're known for one of one of the big things is called optogenetics what is it optogenetics is a way of causing things to happen it's a way of determining what what actually matters in terms of the activity of the brain for the amazing things it does sensation cognition action and what it does is it provides activity it's a way of playing in if you will activity patterns into precisely defined cells and the way we do it is pretty cool i think it's you know right away there's a problem if you think about how do we do this how could we play in well-defined activity patterns and provide a stream of of activity into this cell and that cell and that cell but not these other cells so just for for context we're talking about the brains of mice uh monkeys humans and then the goal is to try to control accurately the behavior of a single neuron and then to be able to monitor a single collection of single neurons to then say well to draw some deeper insight about the origins first of all the function of different parts of the brain different neurons different kinds of neurons but also the origins of the big things the uh the the flap of the butterfly wing that leads to an actual behavioral thing yeah so if you could exactly so if you could turn on or off the brain or parts of the brain or cell types or individual cells at the natural rate and rhythm and timing of normal brain activity that would be immensely valid because you could determine what actually mattered what what could cause complex things to happen and what could prevent complex things from happening in a specific way but right away you've got a problem if you want to do this and and scientists neuroscientists have wanted to do this for a long time francis crick of double helix of dna fame he wrote a famous paper in 1999 he got interested in neuroscience later in life and he said what we need in neuroscience is a way that we could turn on or off the activity of individual types of neurons in a behaving animal and he even said the ideal signal would be light because it would be fast it could uh penetrate through the brain to some extent and he had no idea how to do it he said this would probably be very far-fetched but it would be a good thing and so that's what you're actually saying like if you want to do this kind of thing and then it's you imagine like how do i get inside the brain it's pretty difficult it's very difficult and then even once you get in it's hard because all brain cells are electrical all neurons are electrically activated and so if you wanted to use electricity as what you were putting in you won't have any specificity at all if you have an electrode a wire and you put it in the brain and you send current through it all the cells near the electrode will be stimulated it's like trying to control fish by spraying them with water yeah right because there's already a lot of electricity going around anyway and you're adding more but there's no uh specificity even among the different kinds of cells either because all around the wire that you've put in they're going to be so many different cells doing totally different things many of them in opposition to each other we know that's one way the brain is set up there are parts of the brain that where neurons side by side are doing completely different things and maybe even antagonistic to each other so what do you do how do you play in activity with any kind of specificity well what you do is use what we found is what what you can do is make some cells responsive to light now normally no cells deep in the in the brain really respond to light they're not built for that there's no reason for them to respond to light in there which is a great situation to start with because any light sensitivity you can provide to some cells will be a huge signal above the noise and so that's that's what we do with optogenetics we take genes bits of dna from microbes single-celled organisms and these single-celled organisms like algae they make uh little proteins that sit in the surface of their cells that receive light capture a photon of light and open up a little hole in the membrane of the cell and let charged particles ions like sodium and potassium flow across the membrane of the cell and that they these algae and bacteria they do this for their own reasons because that helps them move it helps them make and use energy but that's a beautiful thing for neuroscience because movement of ions charged particles across the membrane of the cell is exactly the kind of electricity that neurons work with so if we can take this bit of dna that encodes this beautiful protein that turns light into electricity from algae and if we can put it into some neurons but not other neurons which we can do using genetic tricks then you've got a situation then you can shine on the light and only the cells that have the gene and that are expressing the gene will be the initial direct cells that are activated by the light and so that's the essence of optogenetics is the ability to do that we get that initial specificity that you could never get with an electrode okay so let me say that this is uh we recently got uh the alaska prize for this is a brilliant idea um so i talked to um andrew huberman who's a friend of yours friend of mine um not to jinx things but he believes that he deserves the nobel prize for this so um i do too but what uh my votes anyway the thing is does it doesn't matter prizes will be all forgotten all of us will be forgotten one of the cool ideas cool idea is a cool idea that's a really powerful idea it's actually the the origins of it you might be interested in are even are very deep uh there was a botanist in saint petersburg named andrei fomensen in 1866 he published a paper on the single-celled green algae and he was the botanist who first noticed that they moved in response to light these are tiny single-celled algae that have flagella so they swim through the water and he noticed this he was a botanist and he published this it was as a paper you know he wrote in in german but he published it in a french journal and he was doing it from st petersburg so it was a very international effort but you have to go back to 1866 and that i just i like to highlight how far back the that discovery goes is back to to andre feminism and this is a it highlights the value of just pure basic science discovery that always originates uh somewhere in the eastern european bloc uh but i don't think he uh expected the splicing of genetic material from into the human brain and one of the cool things we've been able to do now with modern methods is to really study these these proteins and so we we've discovered some of these proteins other other groups have as well we've dived deep into their structure just like the double helix structure of dna was uncovered with x-ray crystallography we used the same method x-ray crystallography to see how these beautiful little proteins work we re-engineered them for all kinds of function we can make them instead of responding to blue light we can make them respond to red light we can speed them up slow them down we can make them with genetic engineering we can make them have different ions flow through them and so it's it's this convergence as you said like the botanist in 1866 couldn't have predicted what we could do with this uh and and the fact that we've been able to discover how these beautiful proteins work and then uh apply them to neuroscience is really a thrilling story is it possible to achieve scale do you think with this meaning like greater like what is the progress of the next 50 years 100 years looks like in terms of the precision and the scale of control of using light it's going so fast it's hard to to predict i'll i'll give you a sense of it though in you know first paper you know we published in 2005 that was just in cultured neurons by 2007 so that was in a dish by 2007 we had it working in behaving mice by 2009 we had a pretty general so we had methods to really make it a versatile method could be applied to essentially any cell by 2012 we could get to single cell resolution we used light guidance strategies to target individual cells in the brain of a of a living mouse by 2019 we were able to control up to 20 to 50 individually specified single cells in the brain of a mouse and in ways that specifically changed its behavior that could bias its decisions one way or the other in fact we could take a a mouse and without any visual stimulus at all we could make it act as if it had seen a particular visual stimulus by playing in using the single cell resolution optogenetics a specific pattern of activity into you know 20 or 25 individually specified cells that's 2019 it's your question of scale now in 2022 we're controlling hundreds of individually specified single cells over all of visual cortex of a mouse all the part of the of the of the brain that that is the initial direct target of the incoming information from the from the retina are you constrained to specific types of cells currently like you mentioned long range is a little easier is there constraints on which cells uh now there really isn't now that we have this individual cell guidance we can target any individual kind of cell very reliably and so now to your question of scale uh how far can we go well things are moving quickly it's hard to say uh we we can access individual cells across the entire brain now if you look 10 20 years in the future um you know i think we'll we'll surprise ourselves but the fact that we're already able to yeah to cause specific perceptions to happen and specific actions means we're essentially where we want to be and now it's a matter of just uh you know more experiments more discoveries but the the basic principles are clear now the basic capabilities is there is there a pathway to doing the same for humans optogenetics is primarily it's a discovery tool it really is well suited for use in mice and rats and and monkeys because it's uh it involves putting in a gene uh and also delivering light and those are two things that you can do in human beings but you'd want to do in a very careful way now that that said there is actually just less than a year ago um my friend bhoton raska in switzerland he did the first human optogenetics uh therapy and he published this in the journal nature medicine so about uh 10 12 years ago he and i published a paper together where we gave him one of our optogenetic tools one of these light-activated regulators of ion flow these are called microbial opsins by the way opsins and he put one of those into an extracted retina from a human being who had died so it was a catavaric retina and he was able to show that optical control in this in this paper uh was able to turn on or off individual cells in the human retina so that was a while back he spent about 10 years of going through all the regulatory you know hoops and hurdles and going through primate studies and finally he was able to take a human being with a retinal degeneration syndrome so someone who's blind in both eyes and he gave a one of these options into one eye of this human being who was blind and with the goal of conferring light sensitivity onto this retina that was not able to see light and he was able to to make this person see through that eye so he took a blind person and the blind person could could see now could reach for objects selectively on a table uh and he published this in nature medicine and it was you know that's an amazing thing um do you know the title of the pit what's his name again uh roska r-o-s-k-a can you look up the nature paper yeah nature medicine nature medicine so that that's sort of proof of principle now the retina is very accessible it's near the surface you can use natural light or you can use brighter natural light i'm myself i see optogenetics as as a discovery tool it's a way to figure out the principles by which the brain works and how it operates partial recovery of visual function in a blind patient after optogenetic therapy so he went through the full process of doing primate societies and then and then going well that's dedication and that that's really exciting to see yeah as beautiful as that is and i'm glad he did all that work there there are so many other ways that optogenetics could help with therapies once you know the principles then any kind of therapy can become more powerful once you know the causal cells in a symptom like in lack of motivation or inability to enjoy things or altered sleep or altered energy once you know the cells that are causal then you can make medications that address those cells you could address brain stimulation treatments that might address those cells also diagnosis very effective systematic way of diagnosing or at least providing you rich data to some of these deep questions about schizophrenia about bipolar all those kinds of things that are the tools are low resolution currently for determining what like the degree to which you have a thing and whether you have a thing at all yeah and exactly and so the the hope is you know that's a this is a great example of how you can cure or you can you know provide some relief for a symptom of a person who has a serious degenerative disease but but the principles are what what we're after and that's why i spend even though i'm a psychiatrist even though i i still see patients i'm not myself trying to drive any clinical trials in the lab i'm trying to discover and then any kind of therapy could result from that what do you think about uh my friend elon musk and his efforts with neuralink so this is another i mean there's a lot of things to say here because there's a lot of ideas under the umbrella of neuralink but one of them is to use electrical signals to stimulate and then you also record you collect electrical signals from the brain at a higher and higher resolution and you go implant surgically the methods by which you do the stimulation and the the data collection so it's possible for the ideas of optogenetics to play well with this and we can even zoom out outside of just neural link and just the whole idea of brain computer interfaces what are your thoughts well i think the engineering that they've done is actually pretty cool so i i like the uh robots yeah from the from the design perspective and it wasn't a it was a design approach that wasn't being taken in academia and it's great that they did it and i think it's it's pretty cool um so i'll say that also there are many ways that you can record from many thousands of neurons and that's not the only way it's a it's a very interesting way we and others are using uh brain penetrating electrodes that actually get quite deep this whole structure the brain is very interesting we there's the surface cortex where it's the most recently emergent part of the brain in evolution uh mammals have it reptiles have something a little bit like it but it's not really the full thing it's a this is a very recent thing that's what we can access with some of these you know like the neural link approach and with some of these short electrodes this part of the brain the cortex is only a few millimeters thick there's so much that's deep though that's so important there's the striatum there's the thalamus there are the parts of the brain that drive motivation that drive hunger and thirst and and social interaction and parenting and and flight and fear and anxiety all these things are there's so much that's deep that these surface approaches are not getting to and so we and others are using these very long electrodes that help us get deep and we can still record for many cells many thousands of cells we can have multiple of these at once in the same animal and so there's a diversity of methods to get to this goal um i think it's great that that people coming from you know the you know outside academia will bring ideas that weren't being worked on uh at least approaches they may turn out to be synergistic these things work very do work very well with optogenetics because all these electrical recording methods that's one channel of information flow light delivery is a separate you know more or less independent there can be some some artifacts that happen but if you're careful that it's another independent pathway of information flow and we've done really fun experiments in mice where we play in patterns of activity with light and we record activity from all across the brain of a mouse electrically and so using optical and electrical together is extremely uh powerful so like opto electric brain computer interfaces which by the way there's uh efforts on the computing side to build optoelectric uh servers so like where you have both electricity so because optics is really interesting light is a very interesting method of communication that's like you said orthogonal many ways it doesn't have some of the constraints of bandwidth that electricity does going through wires but you're able to but it's less ability to control precisely at scale so like there's challenges and there's benefits and having those two interplay is really really really fascinating especially when obviously on the other side of your signal is a biological um [Music] well the the mushy mesh is kind of interesting because we we have there are problems with light light scatters in the brain so the the photons don't just go you know linearly through they whenever they hit an interface between fat and water lipid and water they they bounce off in different directions and so you can come in with all the resolution you want you could play in an incredibly detailed high resolution pattern of light but the photons start scattering uh quite quickly and by the time you've gone a couple millimeters deep you've lost almost all that fine spatial information so but we've developed workarounds the longer wavelength light you use if you get into the infrared there's less scattering you can use two photon methods or three photon methods where the photons have to arrive all together at the same time you can put in fiber optics we developed these fiber optic methods in 2007 where you can access these deep structures with fiber optic methods and you can put many of these fiber optics at the same time in an animal we've used holographic methods 3d holograms to play in hundreds of individual cell sized spots of light and we can and we can change those quickly and so there are a lot of tricks a lot of interesting optics engineering that has come together with neuroscience in a pretty exciting way but it's engineering too it was just super super super exciting i should mention because i remember mentioning elon um i recently got for the first time ever got covered um how did i go so long without finally so i'm all vaccinated and everything like that and so i got uh because i think he he mentioned it publicly so i can mention it but i won't mention anybody else involved but hanging out we've all got you and got covered and the interesting thing about maybe you can comment about this so i was only sick for like a half a day i got a fever of like 104 i just went up and then crashed and then i was now maybe i'm just seeing the silver lining of everything but afterwards uh i have like a greater clarity about the world you just think it's greater clarity maybe maybe i just it was so uh maybe so intensely the mind fog kind of thing for such a short amount of time but the people were involved were also reporting this it's kind of interesting it's like uh because i i do know like the immune system uh is involved with the brain in very interesting ways so like the human mind also incorporates all these other it's not just the it's it's not just the nervous system and i i just want it because everyone always says no not like everyone always says lykova does all these bad things or whatever the disease is or whatever the virus but i wonder like i hate to be a stephen pinker on this but like i wonder what the benefits of certain diseases are if you're able to recover like what is there some like uh again don't want to romanticize it but if your system goes to some kind of hardship and you come out on the other end i wonder sometimes if there's a greater um maybe killed off a bunch of neurons that i didn't need anyway and they were actually getting in the way there were the hater neurons well that was your inner critic that i was talking exactly killed off your critic well you know there are mechanisms for what the potential mechanisms for what you're talking about there are uh there's actually been a fair bit of research on post-covered neurological function and actually my wife michelle mange who's at stanford she's done a lot of this work uh akiko iwasaki yale has done a lot of this but what what they found is that there's a loss of myelin this is the coating of those long range projections that go from one part of the brain to another myelin is this sort of insulator that coats these long-range projections and makes the impulses go faster and more reliably and there's altered function of the myelin producing cells uh an altered myelin in the case of of covert they've looked in both mouse and and human brains and but of course it could be very idiosyncratic many people have cognitive problems postcoded you're definitely aware of that so many people report this persistent brain fog inability to function but it depends on where the inflammation was you know maybe the people who have dysfunction postcode they had a global effect maybe you lost some of these projections that were restraining you in some way and and these plausibly exist and it's known that there are cell populations in the prefrontal cortex that actively restrain deeper structures from expressing what they do and it's it's theoretically possible that you had a lucky uh somebody has to get lucky right somebody has to get like all right if we can actually uh go back to this idea of trying through optogenetics to find origins of when the wave first starts origins of a decision origin of uh idea origin of maybe consciousness or the subjective experience the origin of things in the mind uh so one thing it's carl jung um is there a god neuron is there a belief neuron is there so through this methodology of optogenetics can you start getting to like where a belief begins or an idea begins and especially looking at the strongest of our beliefs maybe beliefs of love and hate but religious belief into some something like really grand on the grandest of scale neuroscience and uh neurology point us a little bit uh we don't have an answer to that but yeah a lot of these questions i'm going to ask you there's no good answer but they're you're providing the tools that give us hope to find the answer one day yeah and we have early clues so for example when patients with epilepsy have uh experiences of religiosity as part of their seizure or the aura before their seizure very often those are uh in the in the temporal lobe uh in these parts of the brain that are at the side and so that's initial clue there are also parts of the brain that are involved in the definition of the self uh and defining the borders or boundaries of the self and we know this there's just some experiments that we did in my lab there's a part of the brain where if there's a rhythm of a particular type you can cause a separation of the sense of self from the sense of the body what's normally bound up and unitary we normally think of ourself in our body as is pretty tightly bound up together those can be separated it turns out we can't take that for granted and there are certain conditions certain patterns of activity in one part of the brain called the retrosplenial cortex where you can actually separate those two out and so if you think about these very big questions you know what is where are the origins of religiosity where how do we define the boundaries of who we are relative to others and to the world how do we link our self to our body and how can that become separated these are actually believe it or not now accessible and rigorously and quantitatively so we did an experiment with optogenetics where we provided this abnormal rhythm to this particular part of the mouse brain and we saw this separation of detection of a stimulus and caring about it so that's that's like stimulating something about the model's brain that affects these neurons that give the conception of self so you're able to dissociate the experience from the impact of the experience unto you that's right exactly right so like these are the goals of meditation uh these are the goals whenever i get drunk pretty much effective i mean that's not a scientific statement just an experiential anecdotal one um also psychedelics seek to this uh to attain this kind of state that's so interesting well you mentioned psychedelics you know dmt and five meow dmt these these create this religious experience this connection people describe them as a strong connection to god in theory these are accessible with with modern methods we we now that we have these rich uh recording methods we can explore what are the precise millisecond resolution cellular resolution brain wide manifestations of these altered states so like you could uh look at an altered state like an on dmt record it across many people and then from there see where do these experiences originate in the brain in terms of single neurons and then how do they how do they propagate and interact with everything else and if there's some kind of uh common signal like how do you narrow down the set of neurons that are responsible for particular experience or for a particular behavioral effect yeah here's where optogenetics is so useful because any time you give an agent like a you know an agent like ketamine or pcp which we used for our dissociation experiments that i was mentioning or you have a psychedelic lsd or dmt for this uh altered perceptual state if you if you give either of those these change everything across the brain okay so just just the fact that you maybe give them to a mouse let's say or eventually to a human you won't know yet which cells to hone in on as the causal players in all this just by recording the activity but then what we found is that optogenetics providing a causal pattern of activity guided by what you see can let you test hypotheses and we saw this rhythm with ketamine and pcp for dissociation and then we said okay let's test what's causal we came in and provided that rhythm we tried a few different things but only one of the causal tests we tried actually caused the behavioral dissociation and so that's how we hone in on what actually and is it repeatable once you see the cause so like that's one definition of causality is like you try and repeats across different mice and all that kind of stuff exactly and so you could do that for dmt you could do that for like the really fascinating mind expanding uh uh thank you thank you for so the meme for people just listening this is again another disagreement between freud and and uh uh carl jung religion and spirituality this is the i guess the ring scene from uh lord of the rings religion spirituality freud says cast it into the fire destroy it carl jung says no so so for people who don't know sergey is the slavic lord of the meme thank you i appreciate that so what we're talking about so do there is i mean i think a connection between gmt and religious experiences or some of these psychedelics do you think it's possible to sort of stimulate religious experiences so religious experiences are one of the most deep kind of experiences and so here you could first understand where they originate how they propagate to the brain and then to stimulate them yeah yeah and so this is and these that can happen in people who had no predisposition um you know people who who are you know as agnostic or atheistic as you'd like uh they can have these they can feel connected to god in these in these states now to be clear i'm not advocating these we don't know what's safe uh in human beings but we definitely have not yet but we definitely can do these experiments in in mice and that was already very productive in understanding dissociation so we can already imagine making headway on these methods and then you know i had a and this this does map on to the non psychedelic human experience i had a patient who's actually described in in the book projections this was the patient that's in the mania chapter the bipolar chapter here was a guy who had never had a psychiatric illness or symptom in his life he was a retirement age gentleman and nobody in his family either so no family history no personal history of any psychiatric illness and he had never been religious particularly before either certainly no no passionate you know uh type of religion but he not through any psychedelic or drug he he had a stressful experience actually a post 9 11 change in how he was thinking and he was pushed into a mania a manic state revealing that he had bipolar never before known in this case in this person and his mania his elevated state and bipolar included this profound religiosity he which he had never had before and he was he was you know preaching in a elevated you know vigorous way to his family and so this this state can be created and people even late in life who had no predisposition for it and know even without a neurochemical so there's the the the causality of that is very interesting to explore how did the the manic state unleash this religiosity but you see that in other realms of of psychiatry too ocd can manifest as religiosity also you can take people who never really had a a religion ever played a powerful role in their life but then when their obsessive compulsive symptoms become severe they can manifest in this i think i'm in that group so i'm a bit ocd we have uh there's i think this is subreddits uh one is oddly satisfying things so there's certain things that are really satisfying to my ocd in my mild ocd i think it's pretty much a religious experience so i understand that there's it if it's not direct it's at least uh rhymes so maybe can you speak to the sergey is probably uh desperately scrambling to pull up oddly satisfying thank you uh people can check it out themselves it is as as the subreddit promises oddly satisfying um can we talk about bipolar it may be depression well let's talk about i mean i don't know if there's a a nice way to discuss the differences in the full landscape of suffering that's here but maybe what is depression and what are the types of depression what kind of depression have you seen and experienced and researched and how can people overcome it how can humans overcome it and deal with it live within overcome it so this is my clinical specialty i see patients in my outpatient clinical work with treatment resistant depression so very hard to treat severe illness where medications haven't been been working i also see patients with autism spectrum disorders these are my two clinical focal areas but then i do emergency room work as well but the depression why do i focus on that it's so uh one feels tantalizingly close to helping these uh people who are suffering so deeply that's and that's why i focused on it is these are people who there may not even be anything situational that's that's difficult or challenging in their life you can have people who seem to have have everything that you would want every objective measure of the life is fine and yet they can be just hit with this unstoppable hopelessness and inability to see into the future a discounting of the value of their own action anything they can imagine themselves doing seems worthless or they are unable to enjoy things we call this anhedonia there's no reward no pleasure not in food social interaction movies books anything that they would enjoy positivity gone they can have a profound negative internal state psychic pain and these things can seem and in the severe cases are inescapable so what is going on why why is this state part of the human existence it's got a strong biological genetic link we know that it's been linked to certain genes certain regions of the chromosome and twin studies there's a clear genetic link it doesn't explain everything but it's a big part of it genetics are a strong contributor and although you can have depression without anything terrible going on in your life the symptoms can be made worse by stressors by trauma and but at a very deep level there's nothing we can measure in a person objectively so we don't have there's not a known chemical not a known structure that's different not a known brain activity pattern that we can pick up with eeg a lot of people are exploring this but right now we have no objective measures all we do is talk to people and we elicit these symptoms we explore them distinguish them from other possible causes and then what do we do well we have a range of treatments we have medications that can help people do help people but not everybody um and if they don't work then we can go to brain stimulation methods we can do things even like electroconvulsive therapy which is uh a very effective but it's that's a sort of the final thing we go to in the end and so we have treatments they they work uh for some people they don't do everything we'd like but here's the problem is at a very deep level we don't understand really what's going on in the brain we don't have a physical interpretation of the problem we have all these symptoms but we can't yet point to a set of cells or a set of circuits or an activity pattern that is causing major depression this disease state per se in human beings why do you think you can't yet from an optogenetics perspective is it because there's so many possible causes is it so much so many things involved so i think the answer is there are many things involved and all these different symptoms that i've mentioned those we can study and those we can fix the individual symptoms and we can do this in animals to be clear so in a mouse for example we can instantaneously and precisely turn up or down the motivation of an animal to overcome a challenge we can turn up or down its ability to to to be motivated by or we think experience reward from from uh situations or actions we can increase its apparent energy level it's it's uh it's it's its drive uh to meet challenges we can turn up or down social interaction uh all these individual features of depression individual symptoms we now can point to exact projections and cells that are causal in mediating these but we don't know is why all these different symptoms show up together in major depression in the human disease syndrome and that's that's the mystery it's sort of in other fields of medicine you know someone with congestive heart failure who comes into the clinic they have very different symptoms they have shortness of breath and they have swollen feet okay couldn't be too more different across the body sets of symptoms neither one obviously related to the heart but they're both happening because the heart is not working as a pump okay and and now thankfully in cardiology we understand these disparate symptoms that seem totally unrelated can be completely understood because there's an altered pump action of the heart that's that's what we are hoping for in in psychiatry and in the study of depression or any disease these different symptoms the inability to enjoy things the hopelessness uh what's the what's the unifying unifying i mean is there is there some truth to that the tolstoy quote that all happy families are alike and each unhappy family is unhappy in its own way so basically i mean this is the human condition and and it basically that might you know the physicists long define the theory of everything it doesn't understanding depression essentially require you to really have the big theory of everything for the human mind i think we it would certainly be nice to have a theory of everything don't get me wrong i don't think we need a first date of the century it would be nice it's also a good question if it's possible yeah yeah well that that i i have uh some thoughts on too but but to your to this specific question um i don't think we need a theory of everything i think there will be unifying principles principles we can get to but even shy of that if we can we can treat symptoms and that's a big step and as you say different different unhappy families are different different unhappy people are different if we have somebody who comes to the clinic and i see someone with a profound anhedonia as one of their main symptoms inability to enjoy things and if i know based on optogenetics work and animal work that a particular medication can treat anhedonia even if it doesn't fix major depression in everybody if i treat that one symptom in that one person that's a good thing and and so i we don't need the theory of everything and we don't even need the unifying principle to help people with insights that come from optogenetics so how much does talking help for diagnosis and for treatment would you say for depression it's a big part of what we do every good psychiatrist is should be pretty adept in these verbal communications and talk therapy as part of what they do i give medications i deliver brain stimulation treatments but a big big part of everything i do with every patient is talk therapy because it works so well together with these other modalities even alone it can help people with moderate or or mild depression by itself people with severe depression people with other psychiatric illnesses that are are severe you don't want to do talk therapy alone that's not going to do it but it still is crucial to do together with the others and it's it's it's critical because it's uh part of how you re shape cognitions you know complex activity patterns and and you won't get to that with a medication or brain stimulation treatment do you have advice for people who suffer from mild forms of depression or feel as they might both for those people and do you have advice for people who love the people who suffer from depression and want to help yeah one of the incredibly frustrating things about depression is the very nature of it makes it hard for the people who suffer to get treatment because they they're hopeless so they don't think treatment will help they have low energy so they're not motivated to participate in treatment in many cases they're sometimes they're actively suicidal that certainly doesn't help they have all these things that seem to prevent treatment from being effective so the loved ones that's where the loved ones are so important is is helping them overcome these barriers to treatment the motivation the safety and the insight that's critical uh and particularly for the severe cases for the mild cases where people still have you know have some insight and motivation and energy to get something done there are many things you can do uh exercise is extremely important in in mood maintenance regulation of sleep and getting sufficient and regular enough sleep is very important and talk therapy can be helpful in those mild or moderate cases just looking at cognitions looking at patterns of thought that people may have fallen into where they catastrophize where they spiral from small things into big things a little bit of talk therapy 10 12 sessions can help people identify those patterns they may have in themselves that are taking occasional negative thoughts which everybody has and magnifying those into more persistent negative states once you if you work at this it's kind of like homework this is what we call cognitive behavioral therapy it's very structured very organized you work hard it requires insight and motivation and you have to be motivated but if you are then you can identify these triggers that send you down particular pathways and work to intercept them and that is amazingly very effective in mild to moderate cases so you're basically have to train yourself to see the world as a collection of triggers and you have to first understand like collect the data like basically see every experience as a thing that creates a follow-on emotion of feeling and like i've learned this you know like on social media where like early on you know like all of us um you know i'll i'll say something i kind of respond to negativity with negativity and then you observe the results of that over time you think wait a minute th this thing that i've been doing where when somebody says you suck and you say no you suck that never produces the result you thought it might and so might not want to just don't say you suck back and i do this through a lot of things in life i'm very fortunate to not suffer from depression but i first of all i have had and have people in my life who do and and also you know all of us have depression who don't suffer from depression have depression out like uh it's always knocking on the door right yeah and so you you have mild uh i mean uh if you're very careless with the triggers all around you then you you're just i think all of us have the capacity to really suffer uh from that kind of uh chemical or psychological or philosophical existential crisis but then it raises a question why are we built this way it seems like it doesn't make sense right um and here's where some of this thinking about where we came from uh as the human family is is kind of interesting does it make sense that somewhere on that spectrum that it's good to detect that there's an array of adverse forces out there in the world right now at this moment and to withdraw to to hunker down to not fight not strive not try to meet the challenge and outweigh these negative forces that are present out there and that makes a lot of sense uh and all animals that have been studied in one form or another show this even the worm that i mentioned earlier c elegans with 302 neurons it can effectively give up in challenging situations we've done this with zebrafish tiny little transparent fish you can give them a challenging situation and they will give up but then if you stimulate a couple very specific brain regions in particular ways you can motivate them to overcome the challenge and if you inhibit those regions they give up much more easily than they would otherwise you can do this in mice you can do this in rats so this is an ancestral conserved pattern to detect that things are pretty bad out there and to conserve energy to hunker down to wait out the storm it says use unfortunately many of our maladies have useful roots in in our uh that contribute to our survival so both depression and motivation have uses and in the pain sometimes it's nice to just shut the hell up and huddle with the penguins right uh versus for some unknown reason venture out on your own into the mountains like a david goggins type character so what's the difference to you between you see patients between sort of rigorous um psychoanalysis i don't know if you consider where you like talk therapy and psychoanalysis are they neighbors are they overlapping their their neighbors uh psychoanalysis is it's um they're relatively it's not nearly done as much as the talk therapy like the cognitive behavioral therapy i mentioned uh the the psychoanalysis is is a little more niche now and partly because it's it's not data isn't um in terms of actual treatment of actual therapeutic effects data not as supportive as for cognitive behavioral therapy but it's still interesting as for insight people a lot of people still do it to gain insight into themselves and in general it's a good uh sort of conversation starter those methods you know they're good for getting things out you know we don't focus on dreams uh typically these days in psychiatry but they're great conversation starters they're great ways to get things out if people have uh and so we like to use those methods just to get the ball rolling sometimes get people to open up a little bit but the actual treatment that tends not to involve these psychoanalytic approaches where you are really probing uh the unconscious mind and its manifestation through through dreams for example as as the as the goal that's not the goal modern talk therapy we're really focusing on treatment how to get people to feel better see i use that as a conversation opener to the freudian thing where i try to delve at a bar of the deep sexual desires in a person's subconscious and i find that opens up possibilities very quickly no um all right what's i mean this is a silly sounding question but what's the difference between cognitive behavioral therapy and conversation so um because i personally as a fan of conversations is a fan of just i like listening to podcasts um versus like audio book i like both but they're very different and i like conversation i like um it makes me personally very anxious so i like to be the listener uh like like a third wheel like overhearing a conversation kind of thing but it's a really powerful method for humans to explore each other's mind just raw conversation so do you think it can be more productive to be very systematic about it or is conversation itself the art form of of helping each other understanding each other and helping each other there are forms of talk therapy that are essentially conversational or they much more approach pure conversation there's uh there are there's a befriending therapy there's interpersonal therapy these are these are approaches that are purely talk therapy but they're not as structured as cognitive behavioral therapy cognitive behavioral therapy has is there are manuals there are guidelines you can almost go through it in a very cookbooky way there's there's homework that you get done so it's in its fullest form it's very different from these more conversational strategies but what's interesting is sometimes people compare them and so you'll see almost like randomized controlled studies um comparing cognitive behavioral therapy with interpersonal therapy for example and they both can work and actually in some studies they look uh comparable um so there's to your point conversation and insights that come from conversation if done well if done artfully can be as powerful this reminds me of robin williams so i have to ask you several questions here on that but one of my favorite movies is goodwill hunting i don't know if you've seen it with robin williams so as a psychiatrist yourself can you do a deep analysis of this other famous psychiatrist which is the movie character played by robin williams at goodwill hunting this is just a caricature between a psychiatrist and patient relationship or is there some something to you was that was moving about his ability to connect to this obviously struggling young kid i think you've hit on the key thing there which is the the depth of the connection if if there's a too powerful connection that can impair uh therapy because it could impair open communication if if someone if a patient has a sees the role sees the relationship in a particular way like in a friendly way maybe or like a parental child type way that can cause problems because then what they choose to share what they choose to bring up is selected to be appropriate for that view of the relationship and so i and many other talk therapists actually prefer not to let things get um not let the connection get that deep you want to have trust you want to have a therapeutic alliance we sometimes call it but it's got to be enough of a blank slate that the patient is not consciously or unconsciously constrained in what they choose to share and so great movie great actors it's all good no complaints except uh realistically the relationship should be a little more uh arm's length than that let's pretend this is real life sometimes can't you leave a little bit of yourself in the interaction with the patient i mean it's another human being yes so it's a balance and actually you do need some of it um because let's say this person is having challenges interpersonal challenges in their life the best way to notice what those are and to identify them and to work with them is if you can elicit some of those problems in in the office in the therapeutic interaction and this is really powerful as long as you're alert to it aware of it and you don't let it go out of hand this transference we call it is when you transfer in between the current therapeutic relationship and external relationships that the patient may have had with others and so if the therapist starts to feel an inner feeling like anger let's say so let's say you have a patient who is stirring frustration in you or even an extreme case is anger the the best thing for the therapist to do in that case is to recognize it and to realize that's probably being stirred by other people in the patient's life and that could be the source of a lot of problems and so instead of trying to wall it off and say oh i shouldn't be feeling that i better be a better therapist instead and recognize it and use it and help the patient that way and so you've got to be a human being you've got to be a person who feels and you've got to be open but be in control of it and be aware of it if if i may i just want to read the because my favorite scenes probably one of the greatest scenes one of the greatest scenes in movie history because robin williams does a single take is that right so this is a very interesting interaction between them so um will and i'm sure this is a common interaction um maybe with the therapist and a patient maybe with the father and son where will the young character the young brilliant mathematician and sean is the therapist the older uh therapist where will looks at a painting that sean painted and then does a like a deep critical analysis of the painting that basically you know describes uh pretending as if he can understand another human being completely but just looking at their painting and then sean gives this whole speech that contrasts sort of raw intelligence and the wisdom of experience and sean says single take he says you've never been out of boston right and will says nope all this in a sexy boston accent by the way uh and then sean gives the speech if i asked you about art you probably give me this skinny and about every art book ever written michelangelo you know a lot about him life's work political aspirations him and the pope sexual orientation the whole works right but i bet you can't tell me what it smells like in the sistine chapel you never actually stood there and looked up at that beautiful ceiling seen that if i asked you about women you'll probably give me a syllabus of your personal favorites you may have even been laid a few times the language here is just beautiful but but you can't tell me what it feels like to wake up next to a woman and feel truly happy you're a tough kid if i asked you about war you probably throw shakespeare at me right probably not but let's say once more into the breach dear friends but you've never been near one you've never held your best friend's head on your lap and watch him gasp his last breath looking to you for help if i ask you about love you'd probably quote me a sonnet but you've never looked at a woman and be truly vulnerable known someone who can level you with their eyes feeling like god put an angel on earth just for you who could rescue you from the depths of hell and you wouldn't know what it's like to be her angel to have that love for her be there forever through anything through cancer and you wouldn't know about sleeping sitting up in a hospital room for two months holding her hand because the doctors could see in your eyes the terms visiting hours don't apply to you you don't know about real loss because that only occurs when you love something more than you love yourself i doubt you've ever dared to love anybody that much i look at you i don't see an intelligent confident man i see a cocky scared shitless kid but you're a genius well no one denies that no one can possibly understand the depths of you but you presumed to know everything about me because you saw a painting of mine you ripped my fucking life apart you're an orphan right do you think i know the first thing about how hard your life has been how you feel who you are because i read oliver twist does that encapsulate you personally i don't give a shit about all that because you know what i can't learn anything from you that i can't read in some fucking book unless you want to talk about you who you are and i'm fascinated i'm in but you don't want to do that do you sport you're terrified of what you might say your move chief well done sir i know it's a movie it's interesting right so some of that conversation is at some intellectual level too it's not just emotional it's something uh it's like i the reason i kind of connect with that is that's a lot of work for a therapist like to really understand another because he's i mean from okay i know this is fictional but just there's calculation happening he deeply cares to say the words that the other person needs to hear but also a little bit loses himself in the pride but then catches himself again switches from anger to uh to connection yeah a lot is brought up there that you're right there there has to be some emotion in the therapist to care enough to keep going to to keep probing to open up as he's doing so right he revealed a lot about himself his own vulnerabilities but that gave him authenticity he had to open himself up so that the the kid would see the authenticity and open himself up in return so so how do you do that as a as a as a psychiatrist as a therapist you have to be careful you know you don't want to do too much uh but opening up a little bit does help it does create uh a chance you know you're offering up something and that helps the patient come back in return and it gives it gives you that that believability and authenticity do you pay the price for that for opening it up you can um you have a family you have an incredibly like difficult research like you're doing a lot of things in your world i mean it's the price you pay for like well this is one of the terrifying things about about writing the book was was i i do open up uh in a little bit about my own personal life my own personal challenges and that was a considered decision because uh i could i could have done the the patient work and the science work and the and the history of the human family work and and tied it all together but but it wasn't and i i in an early draft it was it was like that but it wasn't it wasn't real yet it wasn't it wasn't uh something that that everybody could connect with and i said then i realized look if i'm going to do this i i've gotta i've gotta open up myself and then and then people can connect with me and see what i'm really saying and so i did and that was it was not something that um i'd gone in planning to do in retrospect i learned a lot about myself it was actually really i think a good thing that i i did but it was scary where are the darkest places you've ever gone in your life you know i had uh things haven't haven't always been been easy personally or you know or professionally i had i had moments you know i was effectively a single dad for for a while a number of years and these came at probably the hardest also professional life times for me too the absolute hardest uh days of late medical school internship you know taking call you know getting up at 3am you know surgery uh medicine rounds unforgiving environments and then all the while you know personal life uh you know stripped down to the bear um and these were low moments and then i was hit particularly hard by just experiences on on the clinical ward connecting too deeply with patients like you know a child with a brain tumor and feeling it too strongly and and those things uh when you get down to those lowest of the low moments when everything is is stripped away and and there's there's only this this raw core well yeah that's pretty hard those that was probably the the lowest moment and you learn a lot about yourself in those moments you know what's what's left and and then what are the the the roots out from there and and that's that's that can be powerful to to see uh in yourself have you thought about killing yourself i have not i have not have you seen that thought in the distance i am fortunate that that has not come to my mind and i have not seen it in the even in the distance and i in in in some ways i've i've wondered if that's made me am i a less you know effective psychiatrist because of that i've been i've felt everything stripped away i've been at the lowest of the low and yet the the that there's still hope there's a light of hope still at the end of the day right so you never lost even for brief moments that um i never did i don't know you don't know why there was no reason you don't know why no reason to feel hope at that moment honestly uh so it was just the light without reason yeah that's right what wisdom do you draw from that time about so first of all you said something funny which is i wonder if it that it's somehow not having thoughts of suicide limits your capacity to truly understand somebody who is having those thoughts so how many demons must the psychiatrist have in order to be a good psychiatrist yeah you know this is a really interesting question i think everybody knows and i can say this that psychiatrists can be a little unusual there we we think about ourselves right we think about our brains that may be one reason why we become psychiatrists is we think oh that's interesting going on in there what's that about so a little little introspective a little introverted maybe and that's what can make us good when we're good and but also that that may select for people who have some unusual aspects but you don't have to have all of them there's a lot that can can go wrong in the in the psychiatric realm uh i think having some of those some of it but not all of it is enough you get to see how low things can can get you can get a you get empathy from that even if the symptoms are not the same um just empathy for struggle for suffering that's right that's right do you yourself have to practice observing triggers just as a human operating in this world i've definitely those those skills that have come from from therapy i've i've found i found them useful yeah if i noticed that uh we've all been through experiences where we wondered oh i got really mad in that interaction why did i get that mad you know yeah sure maybe i could have been irritated but man why did i yeah and and and then thinking about it and realizing okay you know back up here think about the broader context um uh think about what how that relates to you know prior events in my life okay yeah so this is a thing for me uh when something of this class happens then it triggers me so going forward i'm going to be aware of that um and i've definitely used that because it's you don't you don't want to be out of control those emotions you want to identify them you want to know where they come from and you want to head them off as a as a civilized human being living on this earth trying to get along with other people you want to understand those moments let me um return to robin williams for a second and looking at robin williams the the actor the uh sorry the human and because you mentioned um for depression you can have everything going well and i think there's just uh famous cases of just public figures because a lot of people know them where they they suffer quietly and it seems like from the outside perspective that they have everything going for them that they're top of their career you know two people that come to mind are robin williams and anthony bourdain what insight do you have and why either of those taken why robin williams a comedian one of sort of the most jolly humans obviously there was always the darkness that he was channeling channeling in order to present the happiness but it feels like that realness is only possible when you're deeply self-honest and analytical and and then then if you're deeply self-honest you're going to realize that there's a lot of beautiful things about life that you can discover and if you do that how can you possibly then take your own life and you go through all these thoughts and i think a lot of a lot a lot of people really loved robin williams which is why it was really difficult to see how can even him how can even robin williams take his own life so i don't know if there's something to be said about the nature of depression from just looking at his case i think the action of suicide is not well understood uh it it doesn't always although often is correlated with depression there are cases of suicide where there is not clear depression that that's in the minority by the way if i just look because you said it's so interesting action of suicide because there's also thoughts of suicide that's right and probably those that probably somewhat understood but it's an interesting because you can think of suicide if you have suicidal ideation you can think of that for so many reasons that's right and and the i mean i thoughts sometimes like painful thoughts angry thoughts or thoughts in general can be very different like fantasies for example you can fantasize like sexual fantasies you can um fantasize i was just for humor's sake wanted to mention stuff but then people think i'm serious i'm not going to mention anything but sexual fantasies and then there's i know there's people that have sexual fantasies and they don't want to actually do that in real life that that that sexual fantasy serves some kind of purpose in imagination only and in that same way suicide might serve a purpose and imagination only is very unlikely to lead to action and yet there's other thoughts that maybe are more amorphous that do lead to action and that leap uh yeah that oh boy that's a facet and that's such a philosophically powerful thought to not exist right like that question uh that's this uh is it sarcher or kamu kamu well the mythicist who says like basic question of why live question yeah right so that's a great question actually and there are other related questions some people may have the thought of suicide because there seems no point there's no joy in life that's one reason that some people can put forward sometimes there's an it's not just the absence of of joy there's an active pain an active psychic pain in some people and that the inescapability of that is enough to drive the thoughts of suicide and then there are interpersonal and cultural reasons as well that can show up the but the act this act of ending of the self is in all these cases there's no real way to study this in animals no other animal as far as we know that we can study has this concept of this is myself the situation is not tolerable therefore i will end the self to our knowledge this is not something that that can be studied in other animals so it remains this this uh uh very poorly understood action and in predicting it so what do we do with psychiatrists we have this challenge people come to the emergency room they say they're suicidal or their friends say they're suicidal or they've taken some action that that didn't lead to death what do we do well there's a whole range of options you know was it a suicidal gesture in the sense of not intending death or was it was the intent death and if it was the intent was was death what were the reasons are the reasons transient are they gone now what's the probability that it'll be repeated so we do all these things just to decide what sort of treatment should be carried out but nowhere is there a deep understanding of the biology of the cells and circuits and activity patterns that underlie the end the action to end the self it's a very it's so it's this frustrating thing it's it's so timely it's so common it shows up in veterans it shows up in kids it shows up in people at every stage of life and yet we're very bad at understanding it and we're relatively poor at predicting it and our tools are are not very powerful we can put people in a locked unit we can give them care therapy for a while at some point we release them and there's only so much we can do it's one of the most frustrating things and the suffering that is linked to suicidality but it is a decision and it is an action and if you look at optogenetics you should be able to one day sort of understand the dynamics of such weighty decisions the individual causes then if someone is anhedonic if there is no joy in life that very likely is addressable by optogenetics we know how to turn that dial very robustly in animals the motivation to overcome challenges that we have some some hope of understanding psychic pain internal negative states we have actually a handle on that as well there's a structure in the brain called the habenula and some linked structures around it that seems to generate this negative internal state that's it's active when a state of acute disappointment acute outcomes that go wrong uh not as expected you know moments of unexpected pain uh the habenula is there it seems it's active to report on internal uh negativity with its with its action and so you could imagine strategies to target this brain structure that might have the effect of reducing psychic pain reducing the negativity of internal states that is a very concrete hope it's precise it's anatomical optogenetics has given us all the firm foundation we need to go after that question so i think there is hope uh if you look at the individual causes the individual symptoms relating to suicide and then it's like a puzzle you put together the puzzle pieces well by the way i do think my uh habenula is uh very functioning very actively and i wonder if it's like because because you you can also learn to channel these things right some some of the things we suffer from i mean there's degrees of suffering can be um a source of progress and personal growth and development and all those kinds of things and i mean i um what is it nietzsche suffered from stomach issues you know i wonder if you've written some of those things if if his stomach was all great right i mean that there's i kind of think that uh a difficult life in some form you can get you get to choose in some regard and some of you don't the difficulties you have and the ones you do have it's nice to use if possible it's sometimes it's nice to treat sometimes it's nice to it's nice to use well the way you phrase it i think you're using it i could be wrong but if you you phrased in this semi-humorous way about your habenula it seems to me that you're you're using that to good effect now but one never really knows what someone else's internal state is as i look at you i don't know the depths of what's going on and it's possible uh that that it's it's it's a much harder situation in there um yes so that's i actually worry about this a lot so i'm extremely self-critical like in the privacy of my own mind which is an interesting thing when you get to meet the internet and the internet will tell you you suck uh but for for now now this is what i worry about and i'm very paying attention for now it's really i just have this like very negative voice but that voice seems to be very useful for productivity yes and so i channel it i just put on the table and let that voice like talk to me but i'm very i'm like monitoring that voice because looking at robin williams you know you get older your brain changes or like your and and then that voice can now all of a sudden grow right and then where you can't control as much just be very careful with these kinds of things you're very right about that i so my my negativity i have this uh i never think i've done enough is sort of where my my negativity comes from inside i i i never think that i've i've met the potential of the moment i haven't done uh i haven't you know made the most of the opportunities that are available still early i haven't you know you know progressed as far as i should and exactly as you're saying that works for a while but then what happens as as you get later in life and there's less runway to you know fix that and then maybe maybe then maybe then that negative voice is is a problem but also at that point the negative voice starts having more and more of a point that's when when you're being when you're being very successful it's easy to be like no okay well like later in life you're really literally just sitting there on a on a rocking chair doing nothing and then it's or maybe any kind of tragedy happens loss of a loved one loss of a job loss or you get screwed over in some kind of um some kind of way i don't know those and then also in the negative voice is just you and the negative voice for days and days and days and so i don't know to go back to your example of robin williams i don't know what was going on inside him i don't know the nature of his internal state was it a was it active psychic pain that may have mentioned may interrupt to just say that sergey posted an examination of robin williams's brain tissue suggested that he suffered from quote diffuse l-e-w-y lewy body dementia lbd depression is a symptom of lbd and it's not about psychology it's rooted in urology this is words from his brain was falling apart yeah louis body dementia this is a very interesting neurological disorder where among other things there are there's neuron death indeed so you've got frank neuron loss it's not just a matter of some long-standing psychic pain but you've got a progressive loss and so clearly you've got a situation where he could have finally reached a point where the balance that he'd worked out between negativity and positivity uh was disrupted due to loss the wrong cells died the wrong projections were cut by the lewy body dementia certainly dopamine neurons die in lewy body dementia those are neurons that give rise to much of the feelings of reward and pleasure that we experience among other roles so uh clearly in his case there could have been a very concrete cellular neurological issue that was progressive and pushed him to that point but what were you uh were you about to make a point about broader that if there isn't another neurological degeneration yeah so in his case not knowing that uh it could have been simply that let's say he had an internal psychic pain state and it was in he was in sort of a compensated mode for much of his life able to generate enough joy from his his comedy and his social interactions and and then but eventually later in life you know the the those things drop away the balance shifts you get tired of fighting the pain for that long and then so you've got this time dependent non-stationarity that happens and then the same symptom becomes no longer tolerable in the end what is autism what do we know about autism human beings exist on a spectrum of uh how social we can be and this is pretty interesting actually scientifically but also very important uh clinically there are hypersocial states where people are almost too social there are chromosomal deletion states where people have instant affinity and bonding and and rich deep seeming connections with people very verbal on the other end people with autism spectrum disorder are not able to keep up with social interactions and it's a it's a spectrum some have mild to moderate difficulties they may have inability to understand what the next thing to do in a social situation is but may have perfectly good language abilities and as you progress further along the spectrum that gets more and more severe so they can't make eye contact because it's too overwhelming to think about what has to be done next if a person looks in a particular way yeah and then as you go farther then language and social communication themselves break down so there's no reciprocity there's no shared enjoyment and that this gets very hard then as you get to this far end of the spectrum where there's really an absence of social cognition at all uh and and social bonding so why why does this exist what is it uh it's very genetic as i mentioned it's it's one of the you know top three or four most biological in the sense of most genetically determined of the psychiatric illnesses it does have these interesting positive correlations slight positive correlations with intelligence and education and the reason for that is kind of interesting to think about is there something good about it just like or at least with at least part of the spectrum is there's something good about it just as we were talking about for depression as you could say for mania as you could say for schizophrenia and here it's kind of interesting to think about the the underlying science of what it means to be good at a social interaction the someone who's very good at a social interaction is incredibly good at dealing with unpredictable information is able to handle this torrent of information coming through rapidly changing a model of the other person and of the interaction and their model of you your model of them with each word that changes with each new bit of information that comes in through the conversation each bit of body language all this is rapidly changing and some people are able to keep up with that fire hose information perfectly well but that's a special brain state to be in that's working with unpredictability that's you know uh the only way that can be done is most likely by constantly running models of what the other person might be about to say so you can't stop and think oh what did that word mean what did that shift in eye contact mean you know what do they mean together there has to be some advanced work going on where you're predicting what's going on if you're to keep up with a rich and fast social interaction now on the flip side there are brain states that maybe don't have to work so fast that are extremely important still dealing with something that's not moving or that's predictable still complex like uh you know mathematical proof or a very complex arrangement of geometrical shapes uh a large number of individual non-moving things there's a possibly a way of being that's particularly good at dealing with these static unmoving or predictable situations and less so with these rapidly changing social situations and so the way i conceptualize autism is these are people who whose brains are not so good with the high bit rate unpredictable information but may be quite good at giving enough time given the grace to work with the system to look at it from different angles to take different perspectives with the confidence that it's not changing in between perspectives that's a brain state that's valuable it's something that has probably has contributed to a lot of the success of the human family being able to design something being able to consider the all the different contributions to a static predictable system so autism in a sense is a is a spectrum that has identifiable characteristics about the way people deal with dynamic information often expressed itself as like social that's right dynamic information but you critically your use of the word often there is really i think smart because it's not just social interaction that is a challenge in autism and so many people conceptualize it purely as a social dysfunction disorder but it's really any unpredictable information that's a problem that's a challenge for for people on the spectrum they react very negatively to unexpected sounds even if not social sounds unexpected lights unexpected touches and so it's really unpredictable information that is uh in my view the core problem with with the processing and autism not just social social just shows up because it's so unpredictable yeah it's so interesting i mean um i tried to not to think about that stuff um i'm afraid of thinking disor about disorders and things like that because just like i don't like sort of economics or game theory uh i won't be careful with it because it uh whenever you have a category or a model it's too easy to just uh for every i mean it's the ocd thing i like models too much i like categories too much the moment you acknowledged yourself well i have an eating disorder for example or something like that as opposed to just being a well i'll just i'll just leave it at that for my own critical understanding of myself uh let's just say i don't know how to moderate eating fruit people make fun of me they think all fruit just fruit is healthy i know [Laughter] i don't well i don't know how to moderate anything but even even fruit uh this apples and cherries is a nightmare anyway that's such a psychiatrist thing to say very interesting um but uh but there's characteristics and and i it's it's interesting to think about like for example i have trouble making eye contact but i actually as you said it now it's not that i'm shy at all in that sense it's literally i'm getting way too much information it's distracting me like i need to just close my eyes so i can like all the things that people seem to be able to do in parallel it's just you just ask me a question for me to think about the answer to that question i can't have all this cool rich visual information coming my way that's literally because i often close my eyes to think it's not because i'm afraid of something whatever it's just like too much information happening here yeah well that's a beautiful description it's it's amazing that that is how you experience the the eye contact uh aspect i think that's i mean you've articulated what uh you know captures it for for so many people which is that it's overwhelming there's just just too much information just coming in through the eyes and to keep up with it to know you're going to be expected to keep up with it first of all so there's that that aspect you know you learned socially that there's going to be an expectation if you're making eye contact people are going to think you're keeping up with it and you don't want to because you want to focus on other things and make progress in other you know dimensions yeah and so that then there's a strong desire to look away or to close the eyes because it's it's it's it's overwhelming it's a distraction and it's going to cause errors of of understanding and of course our eyes that's part the way we use our eyes as part of the human communications you have to kind of be aware of that of that um that element of it so yeah i mean but it's fascinating you should be aware of your own self in those those little characteristics whether it's uh whether it's classified on some aspect of the uh autism spectrum or just in general whether it's eating whether it's depression whether it's um even like schizophrenia that would i hope we get a chance to talk to a a little bit yeah but those things are all made up of different care symptoms and characteristics and use use them as a superpower i i suppose this is the best we can hope for in mild cases i guess i do think both brain states can't coexist at the same time the way of dealing with something unpredictable and dealing with something predictable there those are different ways of being here's a huge opportunity for very creative model building in theoretical neuroscience and linking that to these data streams we're getting across the brain that we talked about earlier these immense data sets of activity across the brain here's where i think there could be a real convergence of theoreticians and experimentalists to say okay given what we know about wiring of the brain here is what the brain state is likely to be that deals well with unpredictable information and here's the brain state that deals with predictable information here's why they're incompatible at least at the same time here's why you've got to be able to detect which state you should be in here's how you could switch between them here's the kind of cells that you would predict almost like predicting the higgs boson here's the kind of circuitry that i would predict should govern the switching or might make one state too sticky too hard to get out of right yeah that is a huge opportunity for an interaction from the theoretical and experimental side together make one state too sticky the sort of uh measure the stickiness of the state and how to lessen the stickiness that's right get some oil in the machine yes yeah what would predict the kind of oil that would work well uh what in your practice is um treatment or advice for the people on the autism spectrum so right now there's no real medical treatment there are behavioral treatments that are most effective early in life they make sure people don't fall too far behind if you're not interacting socially you create this you know vicious cycle where you fall farther and farther behind because you're not interacting and these these therapies which are applied early in life therapists work with the kids train them to deal with these things that otherwise would be aversive to them teach them how to predict things and interact and that has a big effect but it's behavioral therapy there's no medicine that works there are ways of reducing individual symptoms though that sometimes come along with autism and those do respond to medications so you can you know one thing very often my patients with autism are very anxious because they live in a world that they have a really hard time predicting what's going to happen and so they find and some of these are high functioning you know silicon valley types who you know they might make you know great livings but they're very unhappy because they're on the spectrum they don't understand how social interactions really work they're very uh anxiety provoking because they don't know what to say they don't have any clue how anybody else knows what to say they're constantly worried they're going to say something that's completely inappropriate and so they're very anxious and i can i can treat their anxiety it doesn't touch the autism per se but i can help them with their anxiety what i just talked about eye contact i am richly even with eyes closed and all those kinds of things i'm richly experiencing the world and it's not like you're afraid of the world or you're not able i don't know what to do no i know everything in fact i know way too much there's so many cool options like at any one moment there's all the stuff happening and it's all beautiful and at any one moment you can do anything you want you can take off your clothes you can punch that guy over there you can uh run away you can go in for a hug you can say something profound and deep or you can say something generic or you could use so many things you can say and then and then it'll go it'll unravel in all these kinds of ways and this moment could be completely life-changing or it can be mundane and meaningless and all of those options are before you at any one moment and so that's amazing it's amazing and overwhelming if you allow yourself to think about it yes which uh what whatever exactly like well unfortunately with chess you have a few set options two-dimensional dimensions constraints there is unlimited possibilities and unlimited beautiful things happening all around you so i don't think there's a kind of sense that somehow you're limited in your in in the places of uh in the way you can see the world and how you can interact with that world i am overwhelmed by the lack of limit that all of us should be have you looked around you could do whatever the hell you want nobody will remember you anyway mo all of us will be dead one day you could do anything you can uh i don't know you can get naked and run around the city as long as you're not hurting anybody and it doesn't matter so it's austin anyway exactly seems like uh a to-do item for anybody living in austin for sure but you know the the spectrum is an interesting concept because that is you know when i say when i refer to the spectrum uh i'm actually referring to it's a precise clinical term but you're right it's been co-opted more broadly and it is widely used and it can be an unfair categorization of someone who's socially and occupationally very healthy and that is critical because we we don't define a disorder unless there's social or occupational dysfunction it doesn't matter what the symptoms are i've had patients who are pleasantly hallucinating so frankly psychotic but doesn't affect their lives so i don't give that person as diagnosis because there's not social or occupational dysfunction same with any anything on this you know any of the diverse symptoms of autism spectrum disorder if someone has them but they're successful socially and occupationally we don't say that there's a disorder but then you're right the concept of the spectrum does become a useful uh you know pigeonholing um device which is maybe not not the best thing yeah and eye contact is interesting one is interesting one i'm torn on it talking about the usefulness of eye contact because people kind of make fun of it but let me just say one thing about eye contact and about life in general it's okay to be weird but like some people when you have your eyes closed and there's that weird what is happening to this creature like you see a weird creature on the side of the road it's interesting yeah and you want to i mean the the weird stuff i'm going to go back to robin williams with the that's the good stuff right he has that whole speech about him and his wife and what he loves all the little peculiarities all the weird stuff and that like um let those flourish yes uh let the like celebrate those in yourself and not in some kind of woke way but in some like very human way this is what makes us this is the weirdness yeah i i'm 100 on board with that i and i don't think you know people who are happy and who have people in their lives who are happy with them these are i think let let the weirdness flourish let the let the all the different ways members of the human family can be different let's see them all that's one of our that's one of the joys of being alive is seeing all the ways we can be human and i i think about it all the time why do we have all these ways of being human uh and even within one individual you go through phases of life where you express different sides of your way of being which is also a pretty fun opportunity right you can go through phases where you're in one mode and phases in another mode and let that you know just let that let that flourish too let the ways that you can be you uh vary as well i think that's important for people to explore and i should like because if you can address the uh the uh the internet but i i would like to sort of ask the internet to celebrate the uh the the weirdness of people like that's uh that's the robin williams uh uh people call these imperfections but they're not that's the good stuff for any one individual person find the weird stuff and celebrate it as opposed to what the internet often does which is find the weird stuff and criticize it because when you criticize the weird stuff you're creating conformity which is another human thing but that that conformity creates a a boring world you want the weird you want the crazy that's what fun is made of that that that's the uh the foundation of humor and the all the ways in which we deal with the with the with the suffering in the world with the injustices in the world is like this like huge variety of weird okay uh yeah i don't know and that's what at the depth of psychiatry is like you want to uh acknowledge the weird celebrate the weird like step around it to find the particular aspects of weird that are debilitating like you said they're somehow negatively affecting your ability to function in the world as opposed to trying to shut it all down that's right well on that topic i mean i'd love to talk to you about schizophrenia what what is schizophrenia from your research and from your general understanding and what is the full landscape of suffering and uh wisdom that schizophrenia explores schizophrenia is a state where there is a break from reality and so this can show up as we call them the positive symptoms of schizophrenia these include hallucinations hearing something or seeing something that's not there usually auditory hallucinations paranoia people can have complex fears delusions which we call fixed false beliefs people get an extremely unshakeable but completely implausible idea about something sometimes it relates to themselves sometimes to the world these we call the positive symptoms break from reality as we know it then there are the negative symptoms that come with it and these are progressive these are flattening of of emotion as we call it so starting to express less and less positive emotion ending more in a neutral or flat state thought disorder inability to work with complex patterns of planning or thinking so you can't make plans you'd have poor working memory you can't keep track of where you were in a conversation in a sequence of actions so poor and impaired working with the thoughts of oneself and then these these positive symptoms of break from reality okay now why does why does this why do these come together what's the neurobiology of it again we don't know schizophrenia extremely genetically determined if you look at the numbers could be upwards of 80 percent genetically determined um one percent of the human population around the world it's it's universal okay it's not confined to any one culture not even really biased in one you know culture another about one percent around the world and has this progressive quality to it untreated so it's very interesting there's a break that happens we call it first break when someone experiences their first disruption of reality they can have a completely typical life up into that point so you might have a and i've seen you know just heartbreaking cases of like this like this in the stanford emergency room where a kid who's come there has been extremely you know high functioning in that sense of academic achievement and athletic and interpersonal and then comes to college usually in men it's it's around 18 19 when the first break happens some terrifying paranoia hits or some auditory hallucinations start they're getting screamed at by a voice in their head so devastating with women comes on also often a little later sometimes in the 20s and it can be progressive if it's not treated it just progresses and progresses the the voices become overwhelming the delusions and paranoia extend and expand the thought the negative symptoms particularly become more and more severe so one can't even maintain thoughts in any sort of ordered fashion and then eventually uh you know it can be fatal can lead to suicide it can lead to erratic behavior that leads to accidents now it can be treated there are medications that help uh fortunately they have side effects so they're not perfect you can have movement problems and uh actually a whole host of different side effects that come from the medications but we can help people now with with schizophrenia very very significantly but the amazing thing and this is emblematic of where psychiatry stands we don't have the deep understanding just like with depression we don't have that heart as a pump level of understanding that we'd like to have with schizophrenia despite it being so biological so genetic in its nature so is there a way once a wait to return to the other side of the first break so when you have a break with reality it's a way to kind of stitch it together yeah so some people that that works but we don't really know how so medications antipsychotic medications we call them they block a particular neurotransmitter receptor called the serotonin 2a receptor and they modulate dopamine as well and other neurotransmitters these can take someone who's actively hallucinating actively paranoid put them back in a completely normal state and some people stay that way indefinitely and so you can bring people back from from that back to the other side have it stitched together more typically um you'll end up in some intermediate state where there's a symptoms are reduced powerfully but there might be still something there and you've got a drop down in functioning that may be persistent for a while but concepts what physically is going on one idea is that it's communication within the brain one part of the brain is not able to tell other parts of the brain what it's doing and so the auditory hallucinations are very interesting in this regard they often have this conversational inner monologue like quality as we're walking along the street we may have an inner monologue thoughts about what's going on if we see somebody we don't like we might have a thought out where somebody would punch that guy something like that or maybe i should punch that guy but we these are so far below where we would ever you know act or even think of acting but they're just things that come up and and people with schizophrenia those inner thoughts that inner monologue is not recognized as the inner monologue of the self and so it's it's perceived as something coming from the outside uh or from inside but from a another entity another another room yeah inside the same building another room on the inside there yeah yeah and so that that's so it's a it's a it could be conceptualized as a communication within the brain problem notifying what's another part of the brain what's going on and there's some evidence uh consistent with that i don't know if you can help with this but i sometimes have been talking to quite a few homeless folks recently just that's what i do is i hang out at night um and uh talk to interesting people and some of them and i've known people in the past who suffer from schizophrenia and some of them like self will describe uh as as a as that as something they suffer from and they seem to understand something deeply about this world i don't know if it's correlated or or maybe it's it's another aspect of like depression all those things that i've encountered in my own life is maybe just the struggle and the suffering has taken you through a life where you think deeply about life like there's like self-reflection that society forces on you because it's a disorder somehow or some kind is it interesting i i guess my only sort of anecdotal observation is people who suffer from schizophrenia seem to be very interesting and very thoughtful in a non-linear way about the world i've noticed that it's not always positive uh they're the unusual ways they view the world it was but it's always interesting it's uh it could be conspiratorial thinking too yeah like but like the the theories they have about the way the world functions it often very well read which is also interesting because they're almost like looking for helpful answers from somewhere absolutely and so they're you know they might be citing some very interesting literature and then using that um there's a stickiness in their mind to different models of the world and trying to make sense of that world and those models could include conspiracy theories yeah they're very attuned to complexity and they come up with unlikely explanations uh which is one of the things that makes them it makes it hard for them to function in the in the world is how unlikely their explanations are but but you're right there's a depth of consideration of the complexity of the world and a concern about it and a work uh a an impulse to work to understand it that is actually quite refreshing um but you know the first case in the medical literature uh there was a classical schizophrenia there was a patient named james tilly matthews who had this uh he sketched out for his doctor the uh experiences he was he was sensing and he drew himself as a a cowering figure on the ground controlled by a loom a weaving device that was sending threads long threads projections across space from the loom to him to his arms and to his body and controlling him from afar and he called this the heirloom a loom in the air and it was such an evocative thing because you know this was the start of the industrial revolution or mid and it was where you know really industrial strength you know looms and weaving devices were really uh kind of the emblematic of the most complex powerful technological achievements of the time and so that was the explanation available to him to explain how his body was seemingly moved without his volition uh and these days of course people with schizophrenia will have more technology appropriate interpretations they'll have a you know delusions of satellite or alien control or beamed information very very common to have this delusion of a government agency you know sending electromagnetic or or radio frequency information to control their limbs but it's this it's the same thing it's that whether it's a thread from an industrial revolution loom or you know rf you know radiation it's the same thing just adapted to the to the moment explaining trying to explain the world they live in in their relationship to the world but unconstrained by sort of the thing that's socially acceptable which is that's right both refreshing and dangerous yes i wrote down a question why do we cry our tears a window into some depths that we ourselves don't know i almost want to make fun of myself for that question but you do talk seriously about crying in the book in fact the whole first chapter really really tussles with crying as a as why do we do it what does it mean why is it involuntary it seems like a weakness right it's because it's so involuntary and it's reflecting something true and inside at the level of the individual that seems like a problem right wouldn't it be better if we could control it if if we could not show that emotion when it's not useful show it when it's useful but it's not it's it's largely involuntary and so there's a value to it i think as an honest reporter of a need of hope and frailty at the same time i i'm a human being there's a frail a frailty to myself or my situation where i need social help i need help from my community i have hope that that is possible uh but i'm not enough for myself i need the community that that i think is what the the social signal of crying is now people have studied crying uh it's an extreme you can you can quantify the extent to which the presence of tears on a face triggers reactions in onlookers and and you can show the same face in the presence or absence of tears and show that to to people under quantifiable and rigorous uh you know psychological conditions and tears are much more powerful at stirring the desire to help in viewers than any other facial uh feature which is pretty interesting that it's the it's the honest one that's also the most powerful right it kind of indicates there's a certain logic to our design at as social beings that we have an honest report that's hard to uh hard to control and but is it is it well understood what how that connects to the internal state of emotion yeah there are long-range projections that come so where where is crying generate this is the confusing thing about it so that we have a little tear duct the lacrimal gland that leads to the release of fluid it ejects fluid and it comes out and those of course that whole system was designed to keep the eye clean to wash out particulate irritants so it's it's a long standing as long as we've had eyes and have been out of the water uh in our evolution we've needed this sort of thing so long-standing biological structure recently co-opted it seems by our evolution as social uh primates now how could that happen well the lacrimal gland is controlled by structures in the ponds which is a structure deep in our just above our neck between our neck and our head and reflecting its ancient origin right as you go farther down toward the spinal cord these are the more basic early evolved structures and and in the ponds that's where breathing is controlled tear duct uh contraction and what we found and with optogenetics we helped sort this out there are long range projections from fear and anxiety regions in the forebrain that project all the way to the ponds in and around those areas the reason those are there we think is to regulate the respiratory rate changes the breathing changes of fear and anxiety so we know when we're in a state of fear and anxiety we need we cope better if we have elevated heart rate elevated respiratory rate more blood pumping around more oxygenated blood we're ready to meet the threat if it happens all those cells are down there in the ponds too right next to the lacrimal gl duct the tear gland neurons and so almost certainly this fear anxiety anxiety-induced crying arose from a very slightly misdirected long-range projection that was there to regulate breathing and a little twist just a little misdirection a little missing of one sign post to stop here and going on a little farther getting to the lacrimal gland neurons gave us crying and that's and we just have it that peculiar sort of structure neuronal structure that resulted in that that's that's that's what we're stuck with and then and ends up being in terms of social interaction one of the more important uh authentic involuntary displays of interstate that's right and social communication oh yeah is there other stuff like that i mean do you yeah i mean the human face is fascinating as a display of emotion as a display of truth and lying and all those kinds of things i personally i mean we're all i suppose have different uh sensors that are sensitive to certain aspects of the human face but to me it seems like uh the eyes are really important communication or something you know i've talked to a few sort of girls about like botox and stuff like that it always bothers me when i guess guys could do this too but like when women speak negatively of i guess you can call them wrinkles at the uh at the tips of of an eye but like to me when you smile when you wait not wink but like narrow the eyes to community something is communicating and those that stuff is really useful the human face and when it's gone that something is missing and a lot of little stuff it feels like can really it's almost involuntary i guess but it's harder to describe as the presence or absence of tears it's like something about this person you can tell they're not bullshitting you yeah yeah and so that was that was what made presumably that that tier recruitment so powerful is it just landed in this very high value real estate for social communication if it had gone to you know there's a lot of neurons in the in the ponds that control you know movement of large you know muscles uh you know elsewhere that would have been much less effective as a social signal than something around the eye so it was however that that little misdirection happened it it landed in a great area for social communication and because it was coming from the fear and anxiety circuits that regulate that necessary involuntary change in heart rate and respiratory rate it also was involuntary and that became valuable as a as a truth signal as social beings so very interesting when you think about the origins of the human family the origins of social structures and our ability and need to call for help when there's hope but but need at the same time what is consciousness bro so you're actually using techniques i mean even putting psychiatry aside just looking at optogenetics you're trying to understand some of these deep aspects of the human mind and maybe this is a good time to return to a question you mentioned you might have an opinion on if there's such a thing as a theory of everything for the human mind because surely answering of what is consciousness is as well that's not sure but it seems like it's a fundamental part of the human experience in the human mind and solving that question will result in solving the bigger thing about the human mind the flip side could be consciousness it's just the few neurons that are generating some useful thing that make us it's like uh the the sense of self that you talked about in the uh in the mice maybe it's a subset of those cells that are just creating a richer sense of self and that's it so this is a great question all neuroscientists think about this and a lot of non-neuroscientists too it's it's such a it's the reason a lot of people came to the study of the brain is to think about consciousness and not just being awake or alert but really what's sometimes called the hard problem of consciousness which is what is that nature of that inner subjective sense we have not just information processing but feeling something about the information that what is that inner state of subjectivity physically what is it and that's called the hard problem of consciousness and it's not an extremely well-defined question everybody has sort of a sense of what it means but it's such a hard problem because you run into paradoxes quite quickly the more you think about it and that is exciting also because it makes us think actually there's some there's a big thing that we're missing the brain is not just a collection of little tricks there is a big big concept so that's your sense of because like a flip side could be with optogenetics you can there's an engineering question can you turn consciousness on and off like a light switch okay so here here's where exactly consciousness frames the problem extremely well and it frames it the following way so i told you earlier that we can stimulate 20 or 25 cells in the visual cortex of a mouse and we can make it behave and we can make its brain act as if it's seeing something that isn't there we have that level of control now we can pick out 25 neurons play an activity in both behavior and in the brain it's as if it's seeing something specific okay now let's do a thought experiment you know a good duncan experiment and let's play this out let's say we could do the same thing for every single neuron in the brain of a human being let's say we had total control and i could do something like i could show you a rich deep color red and you could look at it and you would be aware that it's red but also you might have some feelings about it some something would be stirred in you some subjective sense as you looked at that rich color red and then i would take away the visual stimulus and i would in this thought experiment i would using some hyperoptogenetics i would play in exactly the same pattern of activity in every cell in your brain for as long as it was needed whatever 15 seconds something like that that exactly matched what was going on when you were feeling that inner subjective sense okay so in that thought experiment a question for you is would you be feeling that same inner subjective sense stimulus is gone every neuron's doing the same thing because i'm controlling it there's a philosophical question there i'm if if you ask me specifically i would say yes okay good most people would say that because it's hard to say no right it's very hard to say if every cell in your brain is doing what it was doing what what else could be different how could most normal people would say yes of course philosophers would then start saying no they're they're the ones that say um i'm i'm going to sort of to parallel and sorry if it's a bit of an interruption but if there's you know if there's a robot that's conscious in front of you if it appears conscious then it's conscious like to me uh of course philosophers again speak up and say well no how do you know it's conscious well how do you know anything is conscious and sort of as normal humans we tend to uh lean on the experience versus some kind of philosophical concept so the great thing about the the what you just said the the turing test is it's very practical if it acts conscious it is conscious but i think that's limiting i like the the thought experiment i think it's actually more informative and so i'm halfway halfway to the to the conclusion there but let's let's let's take it as your answer was yes that's that you would be feeling the same thing okay now here's where it gets fun now that every cell in your brain is knows what it has to do in the sense that we know it and we're providing it your brain cells don't need to be in your head anymore at all right the only reason they're next to each other the only reason they're wired together is to affect each other to stimulate or inhibit each other but we don't need that anymore because optogenetically we're providing that activity pattern for as long as needed we're providing the effect of the communication they don't need to be connected anymore they don't even need to be in your head i could spread your neurons all over the continent all over the galaxy and i could still provide the same stimulus pattern over 10 or 15 seconds to all those neurons and somewhere lex friedman would be would have to be even though no longer existing as a physical object anymore would be feeling that subjective feeling and it's inescapable because it's exactly the same as the previous situation all the neurons have to be uh spatially like the locality constraint they have to be spatially close to each other uh and you talk about light opto which is funny because you know light is the fastest traveling thing that we know of well maybe let's not put them all over the universe because we might get relativistic problems then let's let's just keep them on let's keep all your neurons let's spread them over north america okay and let's let's play them out same pattern of activity and right it seems absurd right there's no way that could be true there's no way that that that lex would be feeling that internal sense if his neurons were spread all over north america and yet it's exactly the same as the previous situation where you said sure wow so we've got a paradox and it and this is what makes people say paradox though sorry yeah yeah maybe products is the wrong word we got a problem we got a problem because it reveals that there's something big about those that internal subjective state that we we're not explaining and we don't really have a hope of explaining in the near future but don't you think we would still have that it's just the word internal loses meaning but don't you think we still have that internal subjective state where's uh if not then where the heck is the magic coming from okay well i just think i think they're one one of the problems that i think we need to let go of is we tend to outside of the experience of consciousness the heart problem of consciousness we tend to think that we individual humans are really special not the subjective experience but the entirety of it like the body that contains the things so the local the the constraint of all the stuff has to be together and it's all mine that's a very i don't know if that has anything to do with the mechanisms that are creating this so i and in fact one really nice way to break through that is to either achieve either observe or create consciousness that spans multiple organisms sort of so like that say it's not it's not an organism-dependent uh phenomena that the phenomena can that's just a peculiar way it has evolved on earth but it's it's a it's a phenomena that doesn't have anything to do with a specific biological system all right so and we have different parts of our brain exist and sometimes create complex awarenesses of things that involve different neurons that are distributed widely and that need to communicate with each other to form this joint representation the state of consciousness but indeed why do they have to be in the same head we don't know why that would be the case that they do and so that's a huge unanswered question in the field is is what is it that binds the activity of neurons together so they can form a joint representation and actually this comes back to the dissociation experiment we talked about before where you can your sense of self becomes separated from your your your body those things that were refused in a joint representation the same concept unitary are now separate and in late 2020 we published a paper in nature showing how this could be we used optogenetics to drive this rhythm that ketamine and pcp cause in retrospinal cortex and we got different parts of the brain to be out of sync and when they were active never able to be active at the same time never able to form a joint representation at the same time and so we've got a toehold into these questions we don't have the answers but and that mimics the dynamics of ketamine effects exactly exactly and you're able to find that kind of oscillation that wow wow wow let's see if you get even greater and greater control with more control over individual neurons and understanding like if you think of certain neurons that having some role to play in in the sense of self you can play like an orchestra um that to create this certain degrees of consciousness decreases subjectivity and thereby understand what is consciousness but by having a very complicated light switch essentially that and here's the here's the challenge is the nice thing about the the thought experiment is it it kind of highlights that we're going to hit a point where we're addressing some very very fundamental questions what what what allows the activity of two sets of neurons to become mutually relevant to each other this is this is in some ways maybe the one of the deepest remaining questions in neuroscience is is what allows activity patterns to become relevant to each other do they have to be in sync temporarily do they need to be is there some other quality that we don't know about that also needs to be present to allow cells to to fuse together into a joint representation just just so i understand because it uh it feels close to some very very deep idea so there's a bunch of semi-distributed signals going on in the brain and you're saying there could be something like a theory of everything if one to exist is to understand why how and why signals close to each other start becoming relevant to each other that's right that's right as part of some very much bigger signal that they're producing that's right how they coordinate essentially um because it's very distributed i mean that's a kind of within a distributed system how is order achieved and this is a very specific kind of distributive system that is one of the most intelligent that we're aware of in the known universe and that would maybe be something also an understanding of the the full conscious experience too that this kind of coordination how does the coordination between different neurons that are responsible for sense of self how do they begin to form a big picture that we see as a human experience that's really really interesting so uniting the small and i mean that's actually literally theory of everything uniting the small the sort of the theory of the neuron um the functioning of the neuron with the big just the um the functioning of the entire mind that's right and i think keeping a toe hold in both at the cellular level of resolution and the brain wide resolution will be critical if you lose touch with either i think you'll miss the big insight so that's what we're trying to do keeping our keeping grounded in the cellular resolution trying to keep the the broadest brain wide perspective and meet in the middle do you think you'll see it in your lifetime a major breakthrough in that dimension i have hope i have hope i'm i'm uh it's very hard to predict what will happen with with big things like this if we don't get there there'll be plenty of other exciting stuff so it's okay but the other aspect of this whole thing is that your life is pretty short that's true so first of all you can die any day i tend to try to think about that that it ends and get in at any moment because it really really can and if not it'll be soon anyway do you think about that do you think about your mortality i do yeah it's it comes back to what we talked about earlier i you know i never think i've done enough and it's it's relevant to that for sure there's a deadline yeah do you think there's ever going to be a feeling where you sit back and you're really proud of yourself i hope so like i've done enough i've done everything there is like like you know because the thing is a warrior has some number of battles in them and at a certain point if you're deeply honest it's like well this that was a pretty good run as far as runs goes that was pretty good you can hang up your helmet and then go sort of drink some ale listen to some music with the old lady yeah i'd say i did pretty good you think you'll get there i i you know with something with nature always has surprises for us we're always the curious mind is always after more but yeah true but biology gives us other rewards you know children and family community um and and one can feel good about those things biology is full of rewards but do you think uh about those rewards what do you think is the why of those rewards what's the meaning of life and this existence what's uh what's the why of biology what does it want from us why are all these cells very busy putting together an organism that seems to want to just be in a hurry to do stuff and survive but it also just doesn't it's not happening being survived like you said it's curious it keeps wanting to get into more trouble why yeah that you know that we're clearly designed for that right this is we're clearly designed to to ask why and to answer and and that i think is i don't i don't know the meaning of all life i think a meaning of our lives is that and you know this is the the aristotelian you know happiness this is an organism is happy an animal's happy if it's performing to its design right if it's it's he's doing what it was made for yeah well you have to understand what what's what's the design and uh you know who's the designer and what were they up to and how hard is it do you have to build the whole universe and does the design even know what the hell they're doing because uh you know maybe the designer built humorous to find out about themselves that's what i would do like if i had the power to build clones i'll build a lot of clones and i'll get them into different trouble to understand like what am i design what's this body designed to do how far can i go that way exactly and then and i dissociate myself completely from having anybody to know like that i know that person that's good i mean i suppose you could do that in a single person's body but dissociation you can you could yeah well but i do wonder what if you if you look at earth as a collection of humans as the collection of biological organisms it seems that we're busy doing something and it just seems too beautiful and too special to be a random a random experiment it seems like it's an experiment that's cleverly designed that's right by by some forces of nature that are beyond our current understanding and maybe that's part of our design is to keep asking why he said answer i'm not sure that's part of the design the answer no i think we're given just the sufficiently limited cognitive capability that we know how to long to to find the answer and we lack the ability to find the answer that's basically a summary of your career no i'm just kidding um and then we give each other nobel prizes for for having even an inkling of a good step towards the right direction carl you're an incredible human being um i'm a huge fan of who you are as a person who you are as a scientist who you are as a writer i just thank you so much i'm so honored that you would sit down and talk to me today it was amazing it's been incredibly fun uh let's do it again sometime it's been really great your your insights and wit and and modesty are really uh quite rewarding thank you so much thanks for listening to this conversation with carl diceroth to support this podcast please check out our sponsors in the description and now let me leave you with some words from carl young knowing your own darkness is the best method for dealing with the darkness of other people thank you for listening and hope to see you next time you