back to indexDr. Karl Deisseroth: Understanding & Healing the Mind | Huberman Lab Podcast #26
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Welcome to the Huberman Lab Podcast,
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where we discuss science and science-based tools
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for everyday life.
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I'm Andrew Huberman, and I'm a professor of neurobiology
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and ophthalmology at Stanford School of Medicine.
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Today, I have the pleasure of introducing the first guest
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of the Huberman Lab Podcast.
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My guest is Dr. Karl Deisseroth.
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Dr. Karl Deisseroth is a medical doctor.
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He's a psychiatrist and a research scientist
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at Stanford School of Medicine.
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In his clinical practice, he sees patients dealing
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with a range of nervous system disorders,
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including obsessive compulsive disorder, autism,
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attention deficit disorders, schizophrenia, mania,
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anxiety disorders, and eating disorders.
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His laboratory develops and explores tools
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with which to understand how the nervous system works
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in the healthy situation,
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as well as in disorders of the mind.
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Dr. Deisseroth's laboratory has pioneered the development
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and use of what are called channelopsins,
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proteins that come from algae,
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which can now be introduced to the nervous systems
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of animals and humans in order to precisely control
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the activity of neurons in the brain and body
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with the use of light.
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This is a absolutely transformative technology,
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because whereas certain drug treatments
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can often relieve certain symptoms of disorders,
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they often carry various side effects.
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And in some individuals, often many individuals,
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these drug treatments simply do not work.
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The channelopsins and their related technologies
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stand to transform the way that we treat
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psychiatric illness and various disorders
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of movement and perception.
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In fact, just recently, the channelopsins were applied
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in a human patient to allow an adult,
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fully blind human being to see light
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for the very first time.
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We also discuss Dr. Deisseroth's newly released book,
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which is entitled, Projections, a Story of Human Emotions.
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This is an absolutely remarkable book
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that uses stories about his interactions with his patients
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to teach you how the brain works
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in the healthy and diseased state,
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and also reveals the motivation for and discovery of
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these channelopsins and other technologies
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by Carl's Laboratory that are being used now
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to treat various disorders of the nervous system,
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and that in the future are certain to transform
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the fields of psychiatry, mental health,
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and health in general.
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I found our conversation to be an absolutely fascinating one
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about how the brain functions in the healthy state
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and why and how it breaks down in disorders of the mind.
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We also discuss the current status and future
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of psychedelic treatments for psychiatric illness,
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as well as for understanding
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how the brain works more generally.
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We also discuss issues of consciousness,
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and we even delve into how somebody like Carl
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who's managing a full-time clinical practice
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and a 40-plus person laboratory
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and a family of five children and is happily married,
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how he organizes his internal landscape,
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his own thinking in order to manage that immense workload
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and to progress forward for the sake of medicine
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and his pursuits in science.
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I found this to be an incredible conversation.
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I learned so much.
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I also learned through the course
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of reading Carl's book, Projections,
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that not only is he an accomplished psychiatrist
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and obviously an accomplished research scientist
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and a family man, but he's also a phenomenal writer.
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Projections is absolutely masterfully written.
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It's just beautiful, and it's accessible to anybody,
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even if you don't have a science background.
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So I hope that you'll enjoy my conversation
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with Carl Deisseroth as much as I did,
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and thank you for tuning in.
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Before we begin, I want to point out
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that this podcast is separate
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from my teaching and research roles at Stanford.
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In my desire and effort to bring zero cost
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to consumer information about science
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and science-related tools to the general public,
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I'd like to acknowledge the sponsors of today's podcast.
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Our first sponsor is Roca.
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Roca makes eyeglasses and sunglasses
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that in my opinion are the very highest quality out there.
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The company was founded
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because when I put them on for the first time,
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Today's episode is also brought to us by Athletic Greens.
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I started taking Athletic Greens way back in 2012,
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and I've taken it ever since,
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so I'm delighted that they're sponsoring the podcast.
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The reason I started taking Athletic Greens
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and that I continue to take Athletic Greens
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And now my conversation with Dr. Carl Deisseroth.
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Well, thanks for being here.
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Thanks for having me.
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It's been a long time coming for me
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because you may not know this,
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but one of the reasons I started this podcast
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was actually so I could have this conversation.
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It's but one, there are other reasons,
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but one of the goals is to be able to hold conversations
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with colleagues of mine that are doing incredible work
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in the realm of science,
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and then here we also have this really special opportunity
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because you're also a clinician, you see patients
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in and out for a long time.
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So for people that might not be so familiar
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with the fields of neuroscience, et cetera,
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what is the difference between neurology and psychiatry?
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Well, I'm married to a neurologist and I am a psychiatrist
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and we make fun of each other all the time.
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So this is a lot of neuroscientists
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and a lot of brain clinicians actually think
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these two should be the same field
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at some point in the future.
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They were in the past, they started together.
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Psychiatry though focuses on disorders
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where we can't see something that's physically wrong,
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where we don't have a measurable,
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where there's no blood test that makes the diagnosis,
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there's no brain scan that tells us this is schizophrenia,
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this is depression for an individual patient.
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And so psychiatry is much more mysterious
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and the only tools we have are words.
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Neurologists are fantastic physicians,
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they see the stroke on brain scans,
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they see the seizure and the pre-seizure activity
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with an EEG and they can measure and treat
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based on those measurables.
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In psychiatry, we have a harder job, I think.
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We use words, we have rating scales for symptoms,
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we can measure depression and autism with rating scales,
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but those are words still.
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And ultimately that's what psychiatry is built around.
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It's an odd situation because we've got the most complex,
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beautiful, mysterious, incredibly engineered object
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in the universe and yet all we have
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are words to find our way in.
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So do you find that if a patient is very verbal
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or hyperverbal that you have an easier time diagnosing them
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as opposed to somebody who's more quiet and reserved
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or I could imagine the opposite might be true as well?
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Well, because we only have words,
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you've put your finger on a key point.
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If they don't speak that much in principle, it's harder.
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The lack of speech can be a symptom.
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We can see that in depression,
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we can see that in the negative symptoms of schizophrenia,
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we can see that in autism.
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Sometimes by itself, that is a symptom of reduced speech.
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But ultimately you do need something.
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You need some words to help guide you.
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And that, in fact, there's challenges
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that I can tell you about where patients with depression
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who are so depressed they can't speak,
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that makes it a bit of a challenge to distinguish depression
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from some of the other reasons they might not be speaking.
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And this is sort of the art and the science of psychiatry.
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Do you find that there are patients that have,
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well, let's call them comorbidities or conditions
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where they would land in both psychiatry and neurology,
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meaning there's damage to a particular area of the brain
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and therefore they're depressed?
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And how do you tease that out as a psychiatrist?
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Yeah, this happens all the time.
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Parkinson's disease is a great example.
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It can be debilitating in so many ways.
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People have trouble moving, they have trouble walking,
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they have trouble swallowing,
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and they can have truly severe depression.
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And this is, you might say,
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oh, well, they've got a life-threatening illness,
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but there are plenty of neurological disorders
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where depression is not a strongly comorbid symptom,
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like ALS, Lou Gehrig's disease, for example.
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Depression is not as strongly comorbid in that disease,
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but in Parkinson's, it is extremely common.
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And as you know, in Parkinson's disease,
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we have loss of the dopamine neurons in the midbrain.
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And this is a very specific population of cells
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that's dying and probably that leads
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to both the movement disorder and the depression.
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There are many examples of that
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where these two fields come together
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and you really need to work as a team.
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I've had patients in my clinic
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that I treat the depression associated
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with their Parkinson's and a neurologist treats the movement
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associated with the Parkinson's and we work together.
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Do you think we will ever have a blood test
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for depression or schizophrenia or autism?
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And would that be a good or a bad thing?
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I think ultimately there will be quantitative tests.
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Already efforts are being made to look at certain rhythms
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in the brain using external EEGs
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to look at brainwaves effectively,
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look at the ratios of certain frequencies
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to other frequencies.
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And there's some progress being made on that front.
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It's not as good as it could be.
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It doesn't really give you the confidence
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for the individual patient that you would like.
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But ultimately what's going on in the brain
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in psychiatric disease is physical
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and it's due to the circuits and the connections
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and the projections in the brain that are not working
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as they would in a typical situation.
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And I do think we'll have those measurables at some point.
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Now, is that good or bad?
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I think that will be good.
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One of the challenges we have with psychiatry
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is it is an art as well as a science
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to elicit these symptoms in a precise way.
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It does take some time and it would be great
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if we could just do a quick measurement.
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Could it be abused or misused?
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Certainly, but that's, I think, true for all of medicine.
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I want to know, and I'm sure there are several,
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but what do you see as the biggest challenge
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facing psychiatry and the treatment of mental illness today?
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I think we have, we're making progress
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on what the biggest challenge is,
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which I think there's still such a strong stigma
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for psychiatric disease that patients often don't come to us
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and they feel that they should be able
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to handle this on their own.
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And that can slow treatment.
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It can lead to worsening symptoms.
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We know, for example, patients who have untreated anxiety
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issues, if you go for a year or more
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with a serious untreated anxiety issue,
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that can convert to depression.
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You can add another problem on top of the anxiety.
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And so it would be, why do people not come for treatment?
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They feel like this is something they should be able
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to master on their own, which can be true,
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but usually some help is a good thing.
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That raises a question related to something
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I heard you say many years ago at a lecture,
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which was that, this was a scientific lecture,
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and you said, we don't know how other people feel.
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Most of the time, we don't even really know how we feel.
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Maybe you could elaborate on that a little bit
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and the dearth of ways that we have to talk about feelings.
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I mean, there are so many words, I don't know how many,
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but I'm guessing there are more than a dozen words
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to describe the state that I call sadness.
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But as far as I understand, we don't have any way
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of comparing that in a real objective sense.
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So how, as a psychiatrist, when your job is to use words
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to diagnose, words of the patient to diagnose,
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do you maneuver around that?
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And what is this landscape that we call feelings or emotions?
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This is really interesting.
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People, here we have, there's a tension
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between the words that we've built up in the clinic
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that mean something to the physicians.
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And then there's the colloquial use of words
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that may not be the same.
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And so that's the first level we have to sort out.
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When someone says, I'm depressed,
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what exactly do they mean by that?
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That may be different from what we're talking about
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in terms of depression.
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So part of psychiatry is to get beyond that word
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and to get into how they're actually feeling,
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get rid of the jargon and get to real world examples
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of how they're feeling.
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So, how much do you look forward into the future?
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How much hope do you have?
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How much planning are you doing for the future?
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So these, here now you're getting into actual things
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you can talk about that are unambiguous.
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Someone says, yeah, I can't even think about tomorrow.
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I'm not, I don't see how I'm gonna get to tomorrow.
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That's a nice, precise thing that, it's sad, it's tragic,
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but it's also, that means something,
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and we know what that means.
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That's the hopelessness symptom of depression.
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And that is what I try to do
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when I do a psychiatric interview.
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I try to get past the jargon
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and get to what's actually happening in a patient's life
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and in their mind.
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But as you say, ultimately, and this shows up across,
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I address this issue every day in my life,
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whether it's in the lab where we're looking at animals,
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whether fish or mice or rats
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and studying their behavior,
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or when I'm in a conversation
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with just a friend or a colleague,
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or when I'm talking to a patient,
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I never really know what's going on
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inside the mind of the other person.
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I get some feedback, I get words, I get behaviors,
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I get actions, but I never really know.
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And as you said at the very beginning of the question,
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often we don't even have the words and the insight
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to even understand what's going on in our own mind.
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I think a lot of psychiatrists are pretty introspective.
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That's part of the reason they end up in that specialty.
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And so maybe we spend a little more time
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than the average person thinking about
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what's going on within,
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but it doesn't mean we have answers.
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So in this area of trying to figure out
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what's going on under the hood through words,
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it sounds like certain words would relate
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to this idea of anticipation and hope.
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Is it fair to say that that somehow relates
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to the dopamine system in the sense that
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dopamine is involved in motivated behaviors?
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I mean, if I say, for instance,
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and I won't ask you to run a session with me here for free.
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We'll do that off camera.
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If I were to say, I just can't imagine tomorrow.
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I just can't do it.
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So that's not action-based,
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that's purely based on my internal narrative.
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But I could imagine things like,
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I have a terrible time sleeping,
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I'm not hungry, I'm not eating.
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So statements about physical actions, I'm guessing,
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also have validity.
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And there are now ways to measure
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the accuracy of those statements.
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Like for instance, if I gave you permission,
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you could know if I slept last night
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or whether or not I was just saying
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I had a poor night's sleep.
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Yes, that's right.
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So in moving forward through 2021
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and into the next 10 and 100 years of psychiatry,
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do you think that the body reporting
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some of the actions of a human
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are going to become useful and mesh with the words
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in a way that's going to make your job easier?
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I do think that's true.
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And the two things you've mentioned, eating and sleeping,
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those are additional criteria
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that we use to diagnose depression.
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These are the vegetative signs,
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we call them of depression, poor sleep and poor eating.
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And if you have a baseline for somebody,
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that's the real challenge though.
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What's different in that person?
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Some people with depressed, they sleep more.
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Some people who are depressed, they sleep less.
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Some people who are depressed,
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they're more physically agitated and they move around more.
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Some people who are depressed,
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they move less even while they're awake.
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And so you need, here's the challenge
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is you can't just look at how they are now,
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you have to get a baseline and then see how it's changed.
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And that can be a challenge that raises ethical issues.
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How do you collect that baseline information
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from someone healthy?
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I don't think that's something we have solved.
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Of course, with phones and accelerometers and phones,
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you could in principle collect a lot of baseline information
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from people, but that would have to be treated
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very carefully for privacy reasons.
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And in terms of measuring one's own behavior,
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I've heard of work that's going on,
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Sam Golden up at the University of Washington
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who works on aggression and animal models
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was telling me that there's some efforts that he's making
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and perhaps you're involved in this work as well.
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I don't know of devices that would allow people
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to detect for instance,
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when they're veering towards a depressive episode
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for themselves, that they may choose
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or not choose to report that to their clinician.
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Maybe they don't even have a clinician.
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Maybe this person that you referred to at the beginning,
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this person who doesn't feel comfortable
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coming to talk to you,
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maybe something is measuring changes
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in the inflection of their voice
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or the speed at which they get up from a chair.
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Do you think that those kinds of metrics
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will eventually inform somebody, hey, you're in trouble?
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This is getting to this question of,
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back to the statement that I heard you make
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and rung in my mind now, I think for more than a decade,
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which is oftentimes we don't even know how we feel.
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Yeah, that I do like because that gives the patient,
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the agency to detect what's going on.
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And even separate from modern technology,
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this has been part of the art of psychiatry
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is to help patients realize
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that sometimes other people observing them
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can give them the earliest warning signs of depression.
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We see this very often in family.
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They'll notice when the patient is changing
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before the patient does.
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And then there are things the patient may notice,
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but not correctly ascribe to the onset of depression.
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And a classic example of that
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is what we call early morning awakening.
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And this is something that can happen very early
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as people start to slide into depression.
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They start to wake up earlier and earlier,
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just inexplicably, they're awake.
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So this is like 2 a.m., 3 a.m. time waking?
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It could start, yeah, it could start at 5 a.m.,
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could go to four, to three.
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And unable to fall back asleep.
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Unable to fall back asleep, exactly.
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So that's, and that, they may not know what to do with that.
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It could just be, from their perspective,
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it's just something that's happening.
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But if you put enough of that information together,
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that could be a useful warning sign for the patient
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and it could help them seek treatment.
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And I think that is something that could be really valuable.
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So in this framework of needing words to self-report
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or machines to detect how we feel
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or maybe inform a psychiatrist how a patient feels,
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I want to touch on some of the technologies
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that you've been involved in building.
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But as a way to march into that,
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are there any very good treatments for psychiatric disease?
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Meaning, are there currently any pills, potions,
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forms of communication that reliably work every time
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or work in most patients?
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And could you give a couple of examples
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of great successes of psychiatry if they exist?
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Yeah, we are fortunate, and this, coming back to my,
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you know, the joking between my wife and myself
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in terms of neurology and psychiatry,
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we actually, in psychiatry, despite the depths of our,
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the mystery we struggle with,
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many of our treatments are actually, you know,
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we may be doing better than some other specialties
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in terms of actually causing, you know,
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the therapeutic benefit for patients.
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We do help patients, you know, the patients who suffer from,
link |
by the way, both medications and talk therapy
link |
have been shown to be extremely effective in many cases.
link |
For example, people with panic disorder,
link |
cognitive behavioral therapy, just working with words,
link |
helping people identify the early signs
link |
of when they're starting to move toward a panic attack,
link |
what are the cognitions that are happening?
link |
You can train people to derail that,
link |
and you can very potently treat panic disorder that way.
link |
How long does something like that take on average?
link |
For a motivated, insightful patient,
link |
you can have a very cookbook-y series of sessions,
link |
you know, six to 12 sessions,
link |
or even less for someone who's very insightful and motivated
link |
and can have a very powerful effect that quickly.
link |
And that's just with words.
link |
There are many psychiatric medications
link |
that are very effective for the conditions
link |
that they're treating, anti-psychotic medications.
link |
They have side effects, but boy, do they work.
link |
They really can clear up,
link |
particularly the positive symptoms of schizophrenia,
link |
for example, the auditory hallucinations, the paranoia.
link |
People's lives can be turned around by these.
link |
We should clarify positive symptoms.
link |
You mean not positive in the qualitative sense.
link |
You mean positive meaning that the appearance
link |
of something abnormal.
link |
Exactly, yeah, and thank you for that clarification.
link |
When we say positive symptoms,
link |
we do mean the addition of something that wasn't there before
link |
like a hallucination or a paranoia.
link |
And that stands in contrast to the negative symptoms
link |
where something is taken away.
link |
And these are patients who are withdrawn.
link |
They have what we call thought blocking.
link |
They can't even progress forward in a sequence of thoughts.
link |
Both of those can be part of schizophrenia.
link |
The hallucinations and the paranoia
link |
are more effectively treated right now,
link |
but they are effectively treated.
link |
And then, you know, this is a frustrating
link |
and yet heartening aspect of psychiatry.
link |
There are treatments like electroconvulsive therapy,
link |
which is where, you know,
link |
it's extremely effective for depression.
link |
We have patients who nothing else works for them
link |
or they can't tolerate medications.
link |
And you can administer
link |
under a very safe controlled condition
link |
where the patient's body is not moving.
link |
They're put into a very safe situation
link |
where the body doesn't move or seize.
link |
It's just an internal process that's triggered in the brain.
link |
This is an extraordinarily effective treatment
link |
for treatment-resistant depression.
link |
At the same time, I find it as heartening as it is
link |
to see patients respond to this
link |
who have severe depression.
link |
I'm also frustrated by it.
link |
Why can't we do something more precise than this
link |
for these very severe cases?
link |
And people have sought for decades to understand
link |
how is it that a seizure is leading
link |
to the relief of depression
link |
and we don't know the answer yet.
link |
We would love to do that.
link |
People are working hard on that,
link |
but that is a treatment that does work too.
link |
In all of these cases, though, in psychiatry,
link |
the frustrating thing is that we don't have
link |
the level of understanding that a cardiologist has
link |
in thinking about the heart.
link |
You know, the heart is, we now know, it's a pump.
link |
It's pumping blood.
link |
And so you can look at everything about how it's working
link |
or not working in terms of that frame.
link |
It's clearly a pump.
link |
We don't really have that level of
link |
what is the circuit really there for in psychiatry?
link |
And that's what is missing.
link |
That's what we need to find
link |
so we can design truly effective and specific treatments.
link |
So what are the pieces that are going to be required
link |
to cure autism, cure Parkinson's, cure schizophrenia?
link |
I would imagine there are several elements and bins here,
link |
understanding that the natural biology,
link |
understanding what the activity patterns are,
link |
how to modify those.
link |
Maybe you could just tell us what you think.
link |
What is the bento box of the perfect cure?
link |
Yeah, I think the first thing we need is understanding.
link |
We need, almost every psychiatric treatment
link |
has been serendipitously identified.
link |
Just noting by chance that something that was done
link |
for some person also had a side effect.
link |
Like lithium or something.
link |
Like lithium is a good example.
link |
Is it true that it was the urine of guinea pigs
link |
given lithium that was given to manic patients
link |
that made them not manic?
link |
I don't have firsthand knowledge of that,
link |
but I would defer that.
link |
But it's true for essentially every treatment.
link |
You know, the antidepressants originally, you know,
link |
arose as anti-tuberculosis drugs, for example.
link |
I did not know that.
link |
And so this is a classic example for,
link |
and this is across all of psychiatry.
link |
And of course there's the seizures as well.
link |
That was noticed that patients who had epilepsy,
link |
they had a seizure and also had depression
link |
that they became much, at least for a while,
link |
they were improved after the seizure.
link |
I don't want to take you off course of the question,
link |
answering the question I asked,
link |
but I've heard before that if autistic children get a fever,
link |
that their symptoms improve.
link |
I've done a fair bit of work with autism.
link |
In my clinical practice, I work with adult autism,
link |
and I have heard statements like that
link |
and descriptions like that
link |
from patients and their families.
link |
That is very hard to study quantitatively
link |
because often with the children,
link |
you have this not as quantitative as you'd like
link |
a collection of symptom information from home.
link |
But I have heard that enough
link |
that I think there may well be something to that.
link |
And what is, anytime you have a fever, what's going on?
link |
Well, we know all the cells in the brain,
link |
and I know this as an electrophysiologist,
link |
if you just change the temperature by a few degrees,
link |
everything changes about how neurons work.
link |
And that's even just a single neuron.
link |
It's even more likely to be complex
link |
and different with a circuit of neurons
link |
that are all affecting each other.
link |
Just elevate the temperature a little bit,
link |
everything's different.
link |
And so it's plausible for sure that things like that
link |
could happen and do happen.
link |
And yet, when you think about autism, to take your example,
link |
yes, we see changes,
link |
but what is the element in the brain
link |
that's analogous to the pumping heart?
link |
When we think about the symptoms of depression,
link |
that's maybe, we think about motivation
link |
and dopamine neurons.
link |
When we think about autism, it's a little more challenging.
link |
There's a deficit in social interaction
link |
and in communication.
link |
And so where is that?
link |
Where is that situated?
link |
What is the key principle governing the social interaction?
link |
This is where we need the basic science
link |
to bring us a step forward.
link |
So we can say, okay, this is the process that's going on.
link |
This is what's needed for the incredibly complex task
link |
of social interaction,
link |
where you've got incredibly rich data streams
link |
of sound and meaning, eye contact, body movement.
link |
And that's just for one person.
link |
What if there's a group of people?
link |
This is overwhelming for people with autism.
link |
What's the unifying theme there?
link |
It's a lot of information.
link |
And that maybe is unmatched in any realm of biology,
link |
the amount of information coming in
link |
through a social interaction, particularly with words
link |
And so then that turns our attention as neuroscientists.
link |
We think, okay, let's think about the parts of the brain
link |
that are involved in dealing with merging complex data
link |
streams that are very high in bit rate
link |
that need to be fused together into a unitary concept.
link |
And that starts to guide us and maybe we can,
link |
and we know other animals are social in their own way
link |
and we can study those animals.
link |
And so that's how I think about it.
link |
There's hope for the future,
link |
thinking about the symptoms as an engineer might,
link |
and trying to identify the circuits that are likely working
link |
to make this typical behavior happen.
link |
And that will help us understand how it becomes atypical.
link |
So that seems like the first, to me,
link |
the first bin of this, what I call the bento box,
link |
for lack of a better analogy,
link |
that we need to know the circuits.
link |
We need to know the cells in the various brain regions
link |
and portions of the body
link |
and how they connect to one another
link |
and what the patterns of activity are
link |
under a normal quote unquote healthy interaction.
link |
If we understand that,
link |
then it seems that the next step,
link |
which of course could be carried out in parallel, right?
link |
That work can be done alongside work
link |
where various elements within those circuits
link |
are tweaked just right.
link |
Like the tuning of a piano in the subtle way,
link |
or maybe even like the replacement of a whole set of keys
link |
if the piano is lacking keys, so to speak.
link |
You've been very involved in trying to generate those tools.
link |
So tell us about channelopsins,
link |
why you created them,
link |
and where they're at now in the laboratory
link |
and perhaps also in the clinic.
link |
Well, this is a, first of all,
link |
I give nature the credit for creating channelopsins.
link |
These are beautiful little proteins that are made by algae,
link |
single-celled green algae.
link |
And it's a great story in basic science
link |
that our understanding of animal behavior,
link |
sensation, cognition, and action in our brains,
link |
all the way back to a botanist in the 1850s and 1860s
link |
in Russia is where the story begins.
link |
So this was a botanist named Andrei Fominzin
link |
who worked at St. Petersburg.
link |
And he had noticed in the river near his laboratory
link |
that there were algae that he could look at
link |
in a dish, in a saucer.
link |
He could put them there.
link |
And when he had light shining from the side,
link |
the green tinge in the saucer of water would move
link |
to a particular distance from the light
link |
that he was shining from the side,
link |
which was an amazing thing.
link |
If he made the light brighter,
link |
the green tinge would back off a little bit
link |
to a more optimal location.
link |
So just the right light level.
link |
So this was plant behavior.
link |
It was light-driven plant behavior.
link |
And he delved into this a little bit.
link |
He identified that with microscopy,
link |
he could see that there were little single-celled algae
link |
with flagella that were swimming to the right light level.
link |
So behaving plants, and this has been the secret
link |
that's helped us unlock so many principles
link |
of animal behavior.
link |
So it turns out these algae achieve this amazing result
link |
with a single gene that encodes a single protein.
link |
It's just a little biomolecule that does a job in a cell.
link |
And these are proteins that sit in the surface of cells
link |
in their surface membrane.
link |
And when a photon, a light particle, hits them,
link |
they open a little pore, a little hole in the membrane,
link |
and charged particles, ions, like sodium,
link |
rush across the pore.
link |
Now, why do they do that?
link |
They do that to guide their flagella.
link |
That signal coming in, those ions coming in
link |
through the pore in response to light,
link |
guide their flagellar motor that guides them
link |
to a particular spot in the saucer, okay?
link |
Now that's plant behavior,
link |
but it turns out, as you know,
link |
this movement of ions across the membrane,
link |
this happens to also be neural code in our brains
link |
Sodium ions rushing into cells turns them on,
link |
makes them fire away, fire action potentials,
link |
communicate to the next cell down the chain.
link |
And this is an amazing opportunity
link |
because we can borrow these proteins.
link |
In fact, we can take the gene
link |
that directs the creation of the protein,
link |
and we can use genetic tricks, modern genetic tricks,
link |
to put that gene into neurons in the brains of mammals,
link |
and then use light to turn those cells,
link |
the specific cells that we've put this gene into,
link |
There are other opsins, we call them,
link |
that you can use to turn cells off.
link |
It's all fast, real time.
link |
You can play in patterns of activity in real time
link |
into cells or kinds of cells, just as a conductor.
link |
It elicits the music from the orchestra,
link |
the strings and the woodwinds.
link |
And you can see what matters,
link |
what matters for sensation, what matters for cognition,
link |
what matters for action, and we call this optogenetics.
link |
And I must say it was quite an honor and a privilege
link |
to watch optogenetics move from idea to discovery
link |
to the laboratory.
link |
I think we were postdocs at the same time,
link |
which is living proof that people move at different rates.
link |
Because that's a joke at my expense, by the way.
link |
We end up in the same spot.
link |
And we're less physically, if not professionally,
link |
but nonetheless, it's been a marvelous story thus far.
link |
And I'd like to, maybe you could give us,
link |
I'd like to just touch on a couple examples
link |
of where the technology resides in laboratories now.
link |
So maybe the range of animals that it's being used in
link |
and some of the phenomenon that channel rhodopsins
link |
and their related genes and proteins
link |
are starting to elicit what you've seen.
link |
And then I'd like to talk about their applicability
link |
to the clinic, which is, I think,
link |
the bigger mission, if you will.
link |
Yeah, so this whole thing,
link |
it's been about now going on 17 years
link |
that we've been putting channel rhodopsins into neurons.
link |
It started, just like Andrei Fominsson's work in a dish,
link |
by 2000, that was in 2004, in 2007,
link |
we were putting these into behaving mice
link |
and we were able to, with a switch,
link |
cause them to move one direction or another.
link |
So basically, you're controlling the mouse's behavior.
link |
Yeah, exactly, in real time.
link |
So we could make a mouse that was just sitting there
link |
doing nothing to then turn left very consistently,
link |
in fact, go around in a circle
link |
and as soon as we turn off the light, it would stop.
link |
That was an eye-opening moment.
link |
It took really a few years to make optogenetics work.
link |
There was a lot of putting all the,
link |
there were a lot of problems that had to be solved.
link |
These channel rhodopsins actually don't move many ions.
link |
They have a small current, small conductance, as we say.
link |
And so we had to figure out ways to pack a lot of them
link |
into cells without damaging cells
link |
and still make them targetable.
link |
So we don't want them to just be in all the cells
link |
cause then it becomes just like an electrode.
link |
You're just stimulating all the cells that are nearby.
link |
We had to keep that specificity,
link |
make them targetable to just one kind of cell or another
link |
while still packing in large numbers of them
link |
And we had to get in the light in safe and specific ways.
link |
And so it took probably about four or five years
link |
to really create optogenetics between 2004 and 2009.
link |
By the end of that time though,
link |
we had all the basic light delivery,
link |
gene delivery principles worked out
link |
and people started to apply the technology
link |
to fish, to rats, to mice,
link |
to non-human primates like monkeys.
link |
And just a couple months ago,
link |
my colleague Botond Roska in Switzerland
link |
succeeded in putting channel rhodopsins
link |
into the eyes of human beings.
link |
And making a blind person see.
link |
And so that's pretty cool.
link |
This was a patient with retinal degeneration
link |
and he provided a channel rhodopsin
link |
into the eye of this patient
link |
and was able to confer some light sensitivity
link |
onto this patient that wasn't there before.
link |
An amazing paper and discovery.
link |
I realized it was one patient,
link |
but it's such an important milestone.
link |
Well, as you say, it's a very important milestone.
link |
And the history of that is very deep.
link |
Almost 10 years earlier, Botond, Roska, and I
link |
had published a paper in science in human retina,
link |
but explanted, taken from cadavers
link |
from someone who had died living retina,
link |
taken out, opsins put into this retinal tissue
link |
and showing that it worked,
link |
recording from the cells,
link |
showing that in these human neurons,
link |
retinal neurons, that you could get light responses.
link |
But then from that moment,
link |
almost 10 years of how clinical development goes,
link |
and this is a gene therapy,
link |
so you've got all the regulations
link |
and concerns and all that.
link |
It took almost 10 years to get to this point now
link |
where a living human being has a new functionality
link |
that wasn't there before.
link |
Now that's incredibly inspiring,
link |
and it's a beautiful thing.
link |
I would say though, that the broader significance
link |
of optogenetics is really still understanding
link |
because once you understand how the circuitry works
link |
and which cells actually matter,
link |
then any kind of treatment becomes more grounded
link |
and logical and specific and principled.
link |
And whether it's a medication or a talk therapy
link |
or brain stimulation treatment
link |
with electrical or magnetic means,
link |
if you actually know what matters,
link |
that is incredibly powerful.
link |
not intended to disparage the beautiful retinal work
link |
and conferring vision on someone who couldn't see,
link |
of course, that's wonderful.
link |
But, and that's direct, what you might call
link |
direct optogenetics in patients.
link |
Indirect is everything that comes from understanding.
link |
Okay, we know these cells matter now for this symptom.
link |
Well, how can we target those cells
link |
and help them work better in patients by any means?
link |
And I think that's the broader significance
link |
of optogenetics clinically.
link |
You and I know Boton well,
link |
and you and Boton share this incredible big vision
link |
that I think only a clinician can really understand,
link |
being in close contact with and the suffering of patients
link |
as a ultimate motivator of developing technologies,
link |
which makes me have to ask,
link |
did you decide to become a scientist
link |
to find cures for mental disease?
link |
It's a really important question
link |
to actually look back and see the steps
link |
that brought you to a particular place.
link |
And that was not what brought me initially to science.
link |
And it's okay to, I think, to embrace the twists and turns
link |
that life brings to you.
link |
But I was always interested in the brain.
link |
And so that was something that for me started
link |
from a very early age.
link |
I was, you know, we talked about being introspective.
link |
I noticed very early on,
link |
I had a deep love of poetry and stories.
link |
And I was a voracious reader and I was amazed
link |
by how words could make me feel in particular ways,
link |
just even separate from their, you know,
link |
of course, dictionary meanings,
link |
the rhythm and how they work together,
link |
even separate from meaning.
link |
And I was stunned by poets that could use words
link |
in new ways that were even divorced
link |
from their meaning at all,
link |
and yet could still trigger specific emotions.
link |
And I was, this was always fascinating to me.
link |
So, you know, I wanted to understand that.
link |
And so I was interested,
link |
and I became interested in the brain.
link |
And I thought, well, I'm gonna have to study the human brain
link |
because only human beings can describe
link |
what's going on inside enough.
link |
So in college, I began to steer myself toward medicine
link |
and with the idea of becoming a neurosurgeon.
link |
And so I came here to medical school
link |
and did an MD PhD program,
link |
planning neurosurgery all the way through.
link |
The first rotation I did at the end of medical school,
link |
as you know, you do rotations,
link |
you go through different specialties,
link |
and some of these are required rotations
link |
that everybody has to do.
link |
Some are elective where you can pick what you wanna do.
link |
I elected to do neurosurgery first,
link |
even before regular surgery,
link |
I was not sure I wanted to do it.
link |
I had a fantastic time.
link |
There was an amazing patient who had a thalamic damage,
link |
and there was a neglect syndrome
link |
where the patient was not able to be aware of something
link |
that was right in front of him.
link |
Even though their vision was perfectly fine.
link |
Even though their vision was perfectly fine, exactly.
link |
And so I was, and I loved the operating room.
link |
I loved the rhythm of suturing and the precision of it.
link |
And I loved being able to help patients immediately.
link |
But then a required rotation was in psychiatry,
link |
which I was not looking forward to at all.
link |
And that completely reset my whole life,
link |
that experience in psychiatry.
link |
And it was at that moment that I saw this is,
link |
first of all, the greatest need,
link |
the depth of suffering and the depth of the mystery together.
link |
And also it was, I almost feel a little guilty about this.
link |
It's so interesting too.
link |
Yes, yes, we can help.
link |
Yes, there's need.
link |
But as a scientist, this is amazing
link |
that someone's reality can be different from my own.
link |
With everything physically, as far as we can tell,
link |
the same with the measures we have,
link |
and yet we've got a different reality.
link |
That is an amazing thing.
link |
And if we can understand that and help these people,
link |
that would be just more than anybody could ask for it.
link |
And so that's how I ended up taking this path,
link |
just a required rotation in psychiatry.
link |
It all started with poetry.
link |
And it started with poetry.
link |
Out of respect for poetry,
link |
are there any favorites that you spend time with
link |
on a regular basis?
link |
I mean, the ones who got me down this path
link |
early on, I remember in childhood in high school,
link |
Borges had an immense influence on me.
link |
I studied Spanish all the way through and reading his work.
link |
He was a great writer.
link |
He wrote both in English and in Spanish,
link |
and being able to appreciate his poetry
link |
both in English and in Spanish was a pretty amazing thing.
link |
Not many poets can do that.
link |
I wouldn't say now.
link |
At one point, I was effectively fluent in Spanish,
link |
and I'm pretty good with medical Spanish still,
link |
because we use Spanish all the time in the clinic here.
link |
I wouldn't claim full fluency,
link |
but it's something I definitely use all the time.
link |
That's been very helpful in the clinic.
link |
Yeah, Borges is wonderful.
link |
As the son of an Argentine, I grew up hearing about it,
link |
and I learned that Borges' favorite city was Geneva.
link |
So I spent time in Geneva only for that reason.
link |
It also turns out to be an interesting city.
link |
So you developed methods to control neurons
link |
with these algae proteins using light.
link |
In 2015, there was what I thought was a very nice article
link |
published in the New Yorker describing your work
link |
and the current state of your work
link |
in the laboratory in the clinic,
link |
and an interaction with a patient.
link |
So this is, as I recall, a woman who was severely depressed.
link |
And you reported in that article
link |
some of the discussion with this patient,
link |
and then in real time,
link |
increased the activation of the so-called vagus nerve,
link |
this 10th cranial nerve that extends out of the skull
link |
and innervates many of the viscera and body.
link |
What is the potential for channelrhodopsins,
link |
or related types of algae engineering,
link |
to be used to manipulate the vagus?
link |
Because I believe in that instance,
link |
it wasn't channelopsin stimulation,
link |
it was electrical stimulation, right?
link |
Or to manipulate, for instance,
link |
a very small localized region of the brain.
link |
Let me frame it a little bit differently
link |
in light of what we were talking about
link |
a couple of minutes ago.
link |
My understanding is that if somebody has severe depression
link |
and they take any number of the available
link |
pharmaceutical agents that are out there,
link |
SSRI, serotoninergic agents,
link |
increased dopamine, increased whatever,
link |
that sometimes they experience relief,
link |
but there are often serious side effects.
link |
Sometimes they don't experience relief,
link |
but as I understand it,
link |
channelopsins and their related technology, in principle,
link |
would allow you to turn on or off
link |
the specific regions of the brain
link |
that lead to the depressive symptoms,
link |
or maybe you turn up a happiness circuit
link |
or a positive anticipation circuit.
link |
Where are we at now in terms of bringing this technology
link |
to the nervous system?
link |
And let's start with the body and then move into the skull.
link |
Yeah, so starting with the body is a good example
link |
because it highlights the opportunity
link |
and how far we have to go.
link |
So let's take this example of vagus nerve stimulation.
link |
So the vagus nerve, it's the 10th cranial nerve.
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It comes from the brain, it goes down,
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it innervates the heart, innervates the gut.
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And by innervate, I mean it sends little connections down
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to help guide what happens in these organs
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in the abdomen and chest.
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It also collects information back,
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and there's information coming back from all those organs
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that also go through this vagus nerve,
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the 10th cranial nerve, back to the brain.
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And so this is somewhat of a super highway to the brain then
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And maybe the idea is maybe we could put a little cuff,
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a little electrical device around the vagus nerve itself
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and maybe have just like a pacemaker battery,
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have a little power source here under the clavicle,
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everything under the skin,
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and have a little cuff and drive signals
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and maybe they'll get back to the brain.
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So a way of getting into the brain
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without putting something physical into the brain.
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And why the vagus?
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I mean, it's there and it's accessible.
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That's the reason.
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That's the reason?
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That's the reason, yes.
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You're not kidding.
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So stimulating the vagus to treat depression
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simply because it's accessible.
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It started as actually as an epilepsy treatment
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and it can help with epilepsy.
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But yes, it's simply because it's accessible.
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You got to love the medicine.
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As a scientist, this is where I get to chuckle and just say,
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I'm in the field of medicine from that perspective,
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from the perspective of a scientist and outsider,
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the field of medicine as a field that goes in
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and tickles pathways because they're there.
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It's, I don't know what to say.
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It's a little shocking.
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And we all, at least in my laboratory,
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I always say you never do an experiment because you can.
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You do an experiment to test a specific hypothesis.
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I mean, there are stories people tell.
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So the vagus nerve lands on a particular spot on the brain
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called the solitary tract nucleus,
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which is just one synapse away from the serotonin
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and dopamine and the norepinephrine.
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So there's a link to chemical systems in the brain
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that make it a rational choice.
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Yes, it's not irrational,
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but I can tell you that even if that were not true,
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the same thing would have been tried.
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You actually would have done it anyway.
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Because it's accessible, yeah.
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Well, again, not to disparage what's been happening
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in this branch of medicine.
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There's immense suffering, treatments.
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Many treatments don't work and we try things.
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And this is how so many advances in medicine happen.
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You think about kidney dialysis,
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which has kept many people alive.
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That was just started by someone saying,
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hey, let's try this.
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Maybe there's something building up in the blood.
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Maybe we can dialyze something and help them.
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And it was just sort of a test pilot mentality.
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We can access the blood.
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Let's run it across a dialysis membrane,
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put it back in the body.
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Oh my God, that actually works.
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And sometimes you do need that test pilot mentality,
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of course, to do it in a rigorous, safe, controlled way,
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which is what we do.
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And so anyway, that's how we ended up
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but still with the vagus nerve stimulation.
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Okay, so what does it, does it work?
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It has, it's FDA approved for depression,
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this vagus nerve stimulation.
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But on a population level,
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if you average across all people,
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the effect sizes are pretty small.
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Some patients it has an amazing effect in,
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but some patients it doesn't work at all.
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And average across everybody,
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the effect size is pretty small.
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How do you think it's working when it does work?
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Is it triggering the activation of neurons
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that release more serotonin or dopamine?
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It could be, but I would say
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we don't have evidence for that.
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And so I just don't know.
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But what is clear is that it's dose limited
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in how high and strongly we can stimulate.
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It's because it's an electrode
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and it's stimulating everything nearby.
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And when you turn on the vagus nerve stimulator,
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the voice, patient's voice becomes strangulated and hoarse.
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They can have trouble swallowing.
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They can have trouble speaking for sure.
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Even some trouble breathing
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because everything in the neck,
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every electrically responsive cell and projection
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in the neck is being affected by this electrode.
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And so you can go up just so far with the intensity
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and then you have to stop.
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So to your initial question,
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could a more precise stimulation method
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like optogenetics help in this setting?
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In principle, it could,
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because if you would target the light sensitivity
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to just the right kind of cell,
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let's say cell X that goes from point A to point B
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that you know causes symptom relief of a particular kind,
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then you're in business.
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You can have that be the only cell that's light sensitive.
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You're not going to affect any of the other cells,
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the larynx and the pharynx
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and the projections passing through.
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So that's the hope.
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That's the opportunity.
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The problem is that we don't yet have
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that level of specific knowledge.
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We don't know, okay,
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it's the cell starting in point A going to point B
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that relieves this particular symptom.
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We want to fix this key on the piano.
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And then I see two other steps that are required.
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One is to get the channelopsin gene into the cell.
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In the case of Boton, Rosco and colleagues
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rescuing vision in this patient,
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they did that by an injection of a virus
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that doesn't damage the neurons.
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The virus itself is fairly innocuous,
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but carries a cargo,
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and it's a one-time injection.
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The cells express,
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and then they used light to stimulate.
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So let's say I'm depressed,
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which I don't think I am,
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although now sitting in front of a psychiatrist,
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you probably can see signs that maybe I am,
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But let's say we put channelopsin
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into a specific branch of the vagus
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that we understand is responsible for mood.
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How are we going to get it in there?
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And then how are we going to deliver the light?
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Because we're not talking about sunlight
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or standing in front of a light bulb necessarily,
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but what are the mechanisms for the body?
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Yeah, so we had to solve exactly these questions.
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You're saying, how do you get the light in?
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How do you get the gene in in a potent
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and robust and safe way?
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And that's now solved,
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and that's not a challenge.
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So there are very safe,
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well-tolerated gene delivery mechanisms
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that are called adeno-associated viruses, AAVs.
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And these are things that are associated
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with the common cold.
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They themselves don't cause any symptoms.
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They've been engineered,
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and there's been a broad community of viral engineering
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that's been going on for decades,
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making these safer, well-tolerated, and so on.
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We can put the channelrhodopsin gene
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into these viral vectors that deliver the gene,
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and we can have little bits of additional DNA
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that govern expression only in one kind of cell,
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These are called promoters and enhancers,
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all genetic tricks built up by a very broad community
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of great scientists over the decades.
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We can put these different bits of DNA,
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package them into this AAV, this little virus,
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and that can be then injected
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into a particular part of the body.
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And sticking with this vagus nerve example,
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we know that there are particular clumps of neurons.
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There's one called the nodos ganglion
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that has a clump of cells related to the vagus nerve,
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and you could, for example,
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target a little injection into that ganglion.
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Would that be an outpatient procedure?
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Yeah, yeah, so you come in in the morning,
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get your injection, maybe walk out a few hours later.
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Yeah, that's right, and so that's the gene.
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Then the light delivery,
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this is also something that we've worked out.
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We've worked on making very, very light-sensitive opsins.
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One challenge, and Botand would be the first to state this,
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in fact, in solving this problem for the patient,
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he had to build goggles that created much brighter light
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than the normal ambient light delivery,
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because as I mentioned earlier,
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you have to pack a lot of these channelrhodopsins in.
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They don't have much current.
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You have to really make sure
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that you've got a tense enough light
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to activate enough of them to cause a stimulation.
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And it has to be the right wavelength, correct?
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It has to be the right wavelength.
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And going back to your example
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of the algae moving toward or away the light,
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it has to be tuned just right.
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So could you, I'm imagining in my mind as a non-engineer,
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I know you're also a bioengineer,
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I'm imagining a little tiny blue light-emitting thing,
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object that's a little bigger than a clump of cells,
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or maybe about the size of a clump of cells.
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And for those who don't know,
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your credit card is about 200 microns thick on the side,
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and a micron is a thousandths of a millimeter.
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And so we're talking about a little tiny stamp
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that's basically half a millimeter in size all around.
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Each edge, half a millimeter in size.
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I can imagine that being put under my skin.
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And then I would, what, I'd hit an app on my phone,
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and I'd say, Dr. Deisseroth, I'm not feeling great today.
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Can I increase the stimulation?
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And you say, go for it.
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And then I ramp it up.
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Is that how it would go?
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I mean, that's effectively what we already do
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with the vagus nerve stimulation, the doctor in this case.
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And I have this in some of my patients in the clinic.
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I do vagus nerve stimulation.
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I say, hi, I go through the symptoms.
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I use the psychiatric interview
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to elicit their internal states.
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And then I have a radio frequency controller
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that I can dial in.
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Right there in real time.
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Right there in real time.
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You're holding the remote control
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essentially to their brain,
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although it's remote, remote control.
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Through a couple of steps, but yeah.
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And I can turn up the frequency.
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I can turn up the intensity, all with the radio frequency.
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And control, and then it's reprogrammed or re-dosed.
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And then the patient can then leave at this altered dose.
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So this is happening now?
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This is happening right now, electrically.
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You do this routinely?
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I do it routinely in my clinic, electrically.
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And you're getting the verbal content,
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which as you described earlier,
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is the indication of how well
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something is working in real time.
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So maybe you could just describe a little bit
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of the interaction with that particular patient
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or another patient.
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What's a typical arc of narrative
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as you go from no stimulation to increased stimulation?
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In most patients, the actual therapeutic effects,
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the benefits actually take many days to weeks.
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And so what I'm mostly focusing on in the office
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in real time is making sure
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I'm in a safe, low side effect regime.
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And so first I talked to the patient, you know,
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who has been on a particular dose of the stimulation
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for weeks or longer.
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And I talked about symptoms.
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How were things over the past month?
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How was your hope?
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How was your energy level?
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You know, what is your mood?
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And then we talk with the patient and we decide,
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oh, this is not yet where we'd like to be.
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And so then I can turn up the intensity of the stimulation
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in real time in the office.
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I don't, in most patients,
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I don't expect an immediate mood change.
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What I do is I increase the dose
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until a next level up while asking the patient
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Can you still breathe okay?
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Can you still swallow okay?
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And I can hear their voice as well.
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And I can get a sense.
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And you're looking at their face.
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And I'm looking at their face.
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And so I can get a sense, is there a,
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am I still in a safe side effect regime?
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And then, you know, I stop at a particular point
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that looks safe and then patient goes home,
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comes back a month later,
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and I get the report on how things were over that month.
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I asked if you're looking at their face,
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because in your book,
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you described the incredible complexity
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of social interactions.
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you described the incredible amount of information
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that the eyes inform about the brain
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and the context of somebody's inner experience,
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whether depressed or happy or otherwise.
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I want to make sure that we get back to how to maneuver them
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and manipulate the nervous system for sake of mental health.
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But what are you looking for?
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So as a vision scientist, I think, you know,
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pupils dilating is a sign of arousal,
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but that could be a positive arousal,
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positive valence, like excitement, or it could be terror.
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You're going to get the same dilation of the pupils.
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And I'm always reminding people
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that these two little goodies are two pieces of brain,
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basically, they're just outside the cranial vault.
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So they're not unlike the vagus in that sense,
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but they're more of a report than a control knob,
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although I like to think they could be
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used as control knobs too.
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So without putting you on the spot, again, to diagnose me,
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something I would never ask you to do
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with the cameras rolling,
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but what are you looking for
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that the patient might not be aware of?
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In other words, can you see depression in somebody's eyes?
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And if you know a patient or if you don't,
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can you see it in their body posture when they walk in?
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Realizing, of course, that a trained psychiatrist
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like yourself develops an intuitive sense
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that's aggregating lots of different features of a patient.
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But what about the eyes?
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What's going on there?
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The eyes are incredibly rich in information.
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And as you allude to though,
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it's not as if any one measurable
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conveys all the information you need.
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It's what we, you know, what an engineer would say,
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joint statistics, it's many things all at once,
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whether they're in synchrony or out of synchrony
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that actually turns out to matter.
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And, you know, the eye contact question,
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we all know eye contact is incredibly important.
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You don't feel you've connected with somebody
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unless there's eye contact,
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but eye contact can go awry too.
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It can be too intense or it can be mistimed
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or if there's someone with autism,
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it can be barely there at all.
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And this is one of the most striking symptoms of autism
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is the avoidance of eye contact
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almost as if it's a harmful quantity.
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And so there's an immense amount of information
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you get from the eyes,
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but it's the pairing of what's going on in the eyes
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with everything else going on, the body language,
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the verbal content of what's coming out.
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All that together is the art of psychiatry
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and social interaction.
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But, you know, sometimes you don't have the eye contact
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and this is an amazing thing.
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And I do talk about this in the book as well.
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In many cases, you know, in psychiatry,
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sometimes it's over the phone
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that you have to make key decisions.
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And as I recall, you know, vividly being as a resident,
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very often you have to take these phone calls
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from people who are not in the hospital,
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people you can't see, can't see their eye,
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can't see their body, anything about them,
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just the sound of their voice.
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And you can ask them questions
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and you have to make, in some cases, life or death decisions.
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You know, is this person truly suicidal,
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something like that, as it comes up all the time.
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And so I developed over the course of training,
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and I think all psychiatrists do this,
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is you develop a way to, whatever data stream you have,
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whether it's the eyes or whether it's just the sound
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of a voice coming over the phone,
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you learn to hone in on that data stream you have
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and focus on it and identify changes.
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And it's quite amazing.
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I found that you can actually, if you know a patient,
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you can detect very precise changes in mood
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just from the sound of the voice.
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And you can have a realization that,
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oh, this patient's depression has improved by about half,
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just by the tone of their voice.
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And same with eyes, with enough practice,
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you can get enough information from a single data stream
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to give you some information.
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But when you do have the whole picture,
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that of course is best.
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So many theories out there about excessive blinking
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and lying, lack of blinking in sociopathy.
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I like to remind people that people have varying degrees
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of lubrication of the eyes,
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which also influence the frequency of blinking
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and presumably have nothing to do with whether or not
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what they're saying is true or not.
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But incredible nonetheless,
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that the eyes are a portal to overall arousal state.
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I'm fascinated by the effects of light on circadian biology
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just overall desire to be awake or asleep, et cetera.
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So the eyes are on the outside of the cranial vault.
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The vagus is outside the cranial vault, obviously.
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What about the goodies in here?
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Parkinson's, we know at least one of the major sites
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of degeneration and failure that lead to those symptoms.
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I can name off any number of other things.
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In your book, you talk about the beautiful work
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done with optogenetics of active versus passive coping,
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that there are areas of the brain like the habenula
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that make, when active, make animals and presumably people
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passive and unwilling or uninterested
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in fighting back against pressures of life.
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Whereas another region, the raphe, you stimulate that
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and they actively cope.
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They get their grit going
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and they are able to lean into life.
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So how does one get to those structures in a focused way?
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And what does the next two to five to 10 years look like?
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Well, this is the promise on that,
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and it is on that timescale
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that I think things may start to play out.
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You know, the specificity of optogenetics
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is really only useful if you have some idea
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of how to use that specificity.
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And it's an actually, it's a frustrating aspect
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of psychiatry that in many cases,
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the most effective treatments we have
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have the least specificity.
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Electroconvulsive therapy being a great example
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where you're causing a brain-wide-
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Which looks barbaric, but as you mentioned, is effective.
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These days, it's much more clinically, you know-
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It doesn't look like one flu,
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the last seen in one flu over the cuckoo's nest.
link |
Now it's a very clinically safe and stable procedure.
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But where I would say, yeah,
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it's got this almost medieval lack of specificity,
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even if the procedure is well-controlled
link |
and clinically safe and stable,
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and it's not very specific.
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You're causing a brain-wide seizure.
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How could you be less specific than that?
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And we don't know the source of the relief.
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Presumably it's a dump of neuromodulators
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like dopamine and serotonin, but we don't-
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There certainly is a dump of neuromodulators.
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We don't know that that's the cause for the relief.
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And likewise with medications,
link |
this is also an interesting thing.
link |
Some of the most effective antidepressants,
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some of the most effective antipsychotics
link |
are the ones that have the most side effects.
link |
And many examples of this, for example,
link |
the most effective antipsychotic
link |
is something called clozapine,
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which has, it's unquestionably has the most side effects.
link |
It had terrible, terrible side effects.
link |
It's a D4 antagonist?
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It has basically every receptor.
link |
Yeah, it acts- Interesting.
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Yeah, it has prominent serotonin, prominent muscarinic,
link |
certainly acts on dopamine receptors,
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but it causes blood cell counts to change.
link |
How do people feel?
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So if I were schizophrenic
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and I was getting auditory hallucinations, et cetera,
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and I took clozapine, what could I expect to feel?
link |
Well, so you would notice side effects
link |
and you would notice resolution of symptoms both.
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So the voices would go away in a good situation,
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the voices would go away,
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but I would feel not good in my body?
link |
You would have, you might have dizziness,
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you might have drooling,
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you might have any number of physical sensations
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that would be due to these off-target effects,
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the medication acting on these other receptors.
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And I'm certainly not suggesting this,
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but what if somebody without schizophrenia took clozapine?
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They had the same side effects, presumably, yeah.
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And so it would not be something that I would recommend.
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Do psychiatrists take the drugs that they prescribe?
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I just finished for the third time
link |
Oliver Sacks' autobiography, which is marvelous
link |
and I highly recommend to people.
link |
He certainly took a lot of drugs,
link |
not as part of his professional role,
link |
but just out of curiosity,
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what is the interest or kind of role of drugs
link |
in the field of psychiatry?
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Because I would imagine for a group
link |
of very curious, introspective people
link |
who are making recommendations about what to take,
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there could actually be some benefit
link |
for understanding what the experience of those drugs
link |
was like for their patients.
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I think that's true.
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And I will say that probably many or most psychiatrists
link |
have sampled a number of these
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for exactly the reason that you're saying
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is to understand better
link |
and to help treat their patients better.
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And I've spoken to people who have really been,
link |
have found this very helpful to know,
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okay, this sleep disruption caused by this medication
link |
or the libido disruption caused by this other medication,
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wow, that is a big effect.
link |
And it really helps with empathy
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for the patients to understand.
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I'm not suggesting that physicians
link |
or anybody experiment with drugs,
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but I am relieved to hear that
link |
because I think that when you're talking about
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accessing somebody's mind and their basic physiology,
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as you've mentioned,
link |
related to appetite, libido, and sleep,
link |
you really, one is acting as a mechanic
link |
of the person's whole experience.
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They walk out of the office and they have a life experience
link |
that extends beyond the script, yeah.
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And so, yeah, and so at the same time though,
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you can't let that completely guide your clinical decisions
link |
because as I mentioned,
link |
some of these medications that have the most side effects,
link |
they are also the most effective.
link |
And clozapine is a great example.
link |
That will work in patients where nothing else works.
link |
we don't take the step of clozapine prescription lightly
link |
because of all these side effects.
link |
You have to come in for a weekly blood cell
link |
or every few weeks of blood cell check
link |
to make sure that the blood counts are not off, for example.
link |
But there are patients where no other medication works
link |
for the schizophrenia and clozapine works amazingly well.
link |
And so we do it even though there are the side effects.
link |
And so then this comes back to your question,
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what if we had better and better specificity?
link |
Well, only if we know exactly what we're doing is the point.
link |
And so, because as we become more refined,
link |
we better be right about where we're refining to.
link |
And you imagine a day where it will be a single,
link |
maybe even outpatient neurosurgery
link |
would go in through the skull or the back of the ear,
link |
deliver a small viral injection
link |
of one of these adenoviruses,
link |
a little sticker of light emitting diode.
link |
Is that it deep in the brain?
link |
Is that how you envision this someday?
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That certainly could happen.
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What I actually prefer as a vision is still medications
link |
because those are minimally invasive.
link |
If we knew what we were doing,
link |
we could make them more specific, have fewer side effects.
link |
But optogenetics that'll arm us
link |
with true causal understanding.
link |
And so we'll know,
link |
and we're already moving rapidly toward this point,
link |
we'll know, okay, this symptom,
link |
the loss of pleasure in life that we call anhedonia
link |
or the loss of motivation or energy
link |
to overcome challenges, active coping,
link |
these are largely subserved,
link |
largely controlled by this circuit or that circuit
link |
or the cell that inhabits this other circuit.
link |
And we will know that
link |
because of the work done with channel ops.
link |
Exactly. Yeah, I agree.
link |
In ways that we never could have the confidence otherwise.
link |
And so we'll know that this is the circuit
link |
that underlies the symptom or its resolution.
link |
And then we'll get to understand these cells very deeply.
link |
Okay, these cells that are causal, that do matter,
link |
What's their wiring?
link |
What are the proteins that they make?
link |
What are the little things that are on the surface
link |
of the cell that could be receptors for specific medications
link |
or combinations of receptors
link |
that would give us the specificity we need?
link |
And then armed with that causal
link |
and precise and rigorous knowledge,
link |
then you can imagine medication development
link |
becoming totally different, no longer serendipitous,
link |
but truly grounded in causality.
link |
So using channel ops as a way to probe the circuitry
link |
and figure out the sites that are disrupted,
link |
what patterns of activity are required,
link |
and then by understanding the constituents of those cells,
link |
like what they express and what they make,
link |
then developing drugs that could target those cells,
link |
not necessarily putting light-inducing diodes
link |
into the brain or walking around with wire packs
link |
attached to our skull or something like that.
link |
And I realize no one has a crystal ball,
link |
but what do you think the arc of that is?
link |
Meaning, are we going to see that in a year,
link |
in two years, three years?
link |
Let me reframe that.
link |
If, how soon will a pill-based treatment
link |
for a psychiatric disease be available
link |
that targets a specific set of cells
link |
that we know are important
link |
because of the work done with channel ops?
link |
I think that is, in some ways,
link |
it's already happening at the level of individual patients.
link |
And- Here at Stanford.
link |
And more broadly, in terms of new drugs,
link |
new multicenter clinical trials
link |
that'll play out over the next few years.
link |
And these could be drugs that are already safe and approved
link |
for other purposes, but we might say,
link |
okay, now we know that this medication,
link |
based on what we know from causal optogenetics,
link |
this could be useful for this other purpose,
link |
this psychiatric symptom.
link |
And so the path to helping patients
link |
could be relatively swift.
link |
That's very exciting.
link |
What are your thoughts about brain-machine interface?
link |
And Neuralink always comes up,
link |
although I do want to point out,
link |
I have tremendous respect for the folks at Neuralink,
link |
including someone who came up through my lab,
link |
is now there as a neurosurgeon,
link |
but the brain-machine interface is something
link |
that's been happening for a long time now.
link |
Some of the best work,
link |
among the best work being done here at Stanford
link |
and elsewhere too, of course.
link |
How is what you just described compatible with
link |
or different than brain-machine interface,
link |
meaning devices, little probes,
link |
they're going to stimulate different patterns of activity
link |
and ensembles of neurons.
link |
And what are your general thoughts
link |
about brain-machine interface as going forward?
link |
Yeah, I mean, this is, first of all,
link |
it's an amazing scientific discovery approach.
link |
As you mentioned, we and others here at Stanford
link |
are using electrodes, collecting information
link |
from tens of thousands of neurons.
link |
In humans, I should add.
link |
And even, yes, there's quite,
link |
even separate from the Neuralink work,
link |
many people have been doing this in humans
link |
as well as in non-human primates.
link |
And this is pretty powerful, it's important.
link |
This will let us understand what's going on in the brain
link |
in psychiatric disease and neurological disease
link |
and will give us ideas for treatment.
link |
It is, of course, it's still invasive.
link |
You still are talking about putting a device into the brain
link |
and that has to be treated as a situation
link |
that has some risks and a step
link |
that has to be taken carefully.
link |
I see that as something that will be part of psychiatry
link |
Already with deep brain stimulation approaches,
link |
we can help people with psychiatric disorders,
link |
and that's putting just a single electrode,
link |
not even a complex closed loop system
link |
where you're both playing in and getting information back.
link |
Even just a single stimulation electrode in the brain
link |
can help people with OCD, for example,
link |
And that will become much more powerful
link |
when we get to a true brain-machine interface,
link |
collecting information back,
link |
stimulating only when you need to.
link |
If we could identify a pathological activity pattern,
link |
a particular, almost like the prodrome
link |
or the early stage of a seizure,
link |
maybe there are events that happen leading up to,
link |
on some timescale, a psychiatric symptom.
link |
We could intervene in a closed loop way,
link |
detect what's happening, what's starting to go wrong,
link |
feed that back to the brain stimulation electrode,
link |
have it be in that way more efficient and more principled.
link |
This is, I think, it's great.
link |
It's something that, of course, will be grounded again
link |
in causal understanding.
link |
We'll need to know what is that pathological pattern
link |
that we're detecting, and we need to know that it matters.
link |
And so again, that's where optogenetics is helping us,
link |
helping us know, okay, this pattern of activity
link |
in these cells, in these circuits,
link |
this does mean that there's a particular kind of symptom
link |
But armed with that knowledge, absolutely.
link |
Even the simple closed loop device detect and stimulate
link |
is going to be part of psychiatry in the future.
link |
And then, of course, as you get to more cells,
link |
more connections, the ability that we have to help people
link |
will become more powerful.
link |
One of the questions I get asked a lot is about ADHD
link |
and attention deficit of various kinds.
link |
I have the hunch that one reason I get asked so often
link |
is that people are feeling really distracted
link |
and challenged in funneling their attention
link |
and their behavior.
link |
But, and there are a number of reasons for that, of course.
link |
But what is true ADHD, and what does it look like?
link |
What can be done for it?
link |
And what, if any, role for channel opsins
link |
or these downstream technologies that you're developing?
link |
What do they offer for people that suffer from ADHD
link |
or have a family member that suffers from ADHD?
link |
This is a pretty interesting branch of psychiatry.
link |
There's no question that people have been helped
link |
by the treatments.
link |
There's active debate over what fraction of people
link |
who have these symptoms can or should be treated.
link |
This is typically Adderall or stimulants of some kind.
link |
For example, the stimulants, that's right.
link |
So ADHD, as its name suggests, it has symptoms of,
link |
it can have either a hyperactive state
link |
or an inattentive state.
link |
And those can be completely separate from each other.
link |
You could have a patient who effectively
link |
is not hyperactive at all,
link |
but can't remain focused on what's going on around them.
link |
So their body can be still,
link |
but their mind is darting around.
link |
They can be very hyperactive with their body.
link |
It happens both ways.
link |
Probably rarely is somebody hyperactive with their body,
link |
but their mind is still.
link |
Although I have to say,
link |
and this is a benevolent shout out to Botan Roska,
link |
Botan has an incredibly sharp and focused mind.
link |
And his hand movements are extremely exact also.
link |
So I do sometimes wonder whether or not our body movements
link |
and our head movements are,
link |
whether or not they're coordinated or not is a readout
link |
of how directed our attention is.
link |
I notice I have to think complex abstract thoughts.
link |
I notice I have to be very still.
link |
So my body has to be almost completely unmoving
link |
for me to think very abstractly and deeply.
link |
Other people are different.
link |
Some people, when they're running,
link |
they get their best thoughts.
link |
I can't even imagine that.
link |
My brain does not work that way at all.
link |
I have to be totally motionless,
link |
which is kind of interesting.
link |
How do you go about that?
link |
I sit much like this.
link |
I try to have time in each day
link |
where I am literally sitting almost in this position,
link |
but without distraction and thinking.
link |
And so it's kind of a,
link |
it's almost meditative in some ways,
link |
except it's not true meditation,
link |
but I am thinking while not moving.
link |
You're trying to structure your thoughts in that time.
link |
Yeah, that's right. Interesting.
link |
So, but everybody, as you say, is very different.
link |
And so with ADHD, you have,
link |
the key thing is we want to make sure
link |
that this is present across different domains of life,
link |
to show that it really is a pervasive pattern
link |
and not something specific to the teacher
link |
or the home situation or something.
link |
And then you can help patients.
link |
It's interesting that ADHD is one of those disorders
link |
where people are trying to work
link |
on quantitative EEG-based diagnoses.
link |
And so there's some progress toward making up a diagnosis
link |
with looking at particular externally detectable
link |
brainwave rhythms.
link |
So skull cap with some electrodes
link |
that don't penetrate the skull.
link |
And this can be done in an hour or two hour session.
link |
Has to be done in a clinic, right?
link |
Yeah, in the clinic, right,
link |
you have to have the right recording apparatus and so on.
link |
But that's in principle,
link |
as increasing confidence comes
link |
in exactly which measurements one could even imagine
link |
moving toward home tests, but we're not there yet.
link |
One of the reasons I get asked about it so much
link |
is a lot of people wonder if they have ADHD.
link |
Do you think that some of the lifestyle factors
link |
that inhabit us all these days
link |
could induce a subclinical or a clinical-like ADHD?
link |
Meaning if I look at people's phone use, including my own,
link |
and I don't think of it like addiction,
link |
it looks to me and feels to me more like OCD.
link |
And I'll come clean here by saying when I was younger,
link |
when I was a kid, I had a grunting tic.
link |
I used to hide it.
link |
I actually used to hide in the closet
link |
because my dad would make me stop.
link |
And I used to, I couldn't feel any relief of my mind
link |
until I would do this.
link |
And actually now, if I get very tired,
link |
if I've been pushing long hours, it'll come back.
link |
I was not treated for it,
link |
but I will confess that I've had the experience of,
link |
I always liked sports where I involved a lot of impact,
link |
fortunately not football, because I went to high school
link |
where the football team was terrible.
link |
Maybe that would have avoided more impact,
link |
but things like skateboarding, boxing, they bring relief.
link |
I feel clarity after a head hit, which I avoid,
link |
but I used to say that's the only time
link |
I feel truly clear for a long,
link |
and then eventually it dissipated.
link |
By about age 16, 17, it just disappeared.
link |
So I have great empathy for those that feel
link |
like there's something contained in them
link |
that won't allow them to focus on
link |
what they want to focus on.
link |
And these days with the phone and all these email, et cetera,
link |
I wonder, and I empathize a bit
link |
when I hear people saying like,
link |
I think I might have ADHD or ADD.
link |
Do you think it's possible that our behaviors
link |
and our interaction with the sensory world,
link |
which is really what phones and email really are,
link |
could induce ADD or reactivate it?
link |
This is a great question.
link |
I think about it a lot.
link |
And you mentioned this tic-like behavior in yourself.
link |
It's very common that people who have tics
link |
have this building up of something
link |
that can only be relieved by executing the tic,
link |
which can be a motor movement
link |
or a vocalization or even a thought.
link |
And people do, I think these days do have this,
link |
if they haven't checked their phone in a while,
link |
they do have a buildup, a buildup, a buildup
link |
until they can check it and relieve it.
link |
And there's some similarities.
link |
There is a little reward that comes with the checking,
link |
but the key question in all of psychiatry,
link |
what we do is we don't diagnose something
link |
unless it's disrupting what we call
link |
social or occupational functioning.
link |
Like you could have any number of symptoms,
link |
but literally every psychiatric diagnosis requires
link |
that it has to be disrupting someone's social
link |
or occupational functioning.
link |
And these days, checking your phone is pretty adaptive.
link |
That pretty much helps your social
link |
and occupational functioning.
link |
And so we can't make it a psychiatric diagnosis,
link |
at least in the world of today.
link |
Yeah, opting out of communication now
link |
makes you in some ways less adaptive,
link |
though I would point to you as an example
link |
of somebody who is quite good at managing his interactions,
link |
at least from the outsider perspective.
link |
I do want to ask you a little bit about you.
link |
and I realize this is only a partial list,
link |
but you're a clinician, you see patients,
link |
you run a big laboratory.
link |
How many people are in your laboratory now?
link |
That's a huge laboratory.
link |
From experience, I can say that's an enormous laboratory.
link |
You have a family of five children
link |
and you're happily married
link |
to a wonderful colleague of ours as well,
link |
who does incredible work.
link |
How do you organize at a kind of conceptual level
link |
the day and the week?
link |
And I should say what stress mitigation practices, if any,
link |
do you incorporate?
link |
I've received emails from you at three in the morning.
link |
I sometimes send emails at three in the morning,
link |
but that's when I wake up, maybe I'm depressed,
link |
but I go back to sleep.
link |
So maybe you just describe the arc of the blocks of the day,
link |
not hour by hour, necessarily the details
link |
of what are in those blocks,
link |
but how do you conceptualize the day?
link |
How do you conceptualize the week?
link |
And how do you feel about how that's lined up
link |
with your larger goals of making sure
link |
these five young people flourish, which I hear they are.
link |
But how do you go about this?
link |
What for most people would just be
link |
an overwhelming set of items?
link |
Well, of course, sometimes it's just take it day by day,
link |
and so I don't claim-
link |
So you bring the horizon into the unit of the day.
link |
I do, I do, the unit is the day, that's right.
link |
And what I try to have in each day,
link |
as I mentioned earlier, some, at least an hour of time
link |
where I can think, and that can be,
link |
it can be when kids are napping, it can be,
link |
you know, actually, because I, while driving,
link |
I can do that too, because I'm sitting still.
link |
But that's the one thing I try to preserve.
link |
When I was writing the book,
link |
I adapted that time to be my writing time,
link |
but it wasn't enough.
link |
It's, you know, so I had to add in a new block of time,
link |
which was sort of midnight to 2 a.m. writing time.
link |
And so that, carving out these even small protected times
link |
are very important.
link |
There's, of course, you know,
link |
obligations will expand to fill the time available,
link |
and you have to be disciplined in my,
link |
at least I found I had to be disciplined
link |
in truly protecting those times where one can think.
link |
So that means no phone?
link |
That means no phone, no checking of the phone.
link |
I would, you know, when I was writing the book,
link |
I would have, there's a focus mode on the MacBook,
link |
which kind of removes the border,
link |
and you just have your documents,
link |
and it's very pure,
link |
and you don't have the temptation of distraction.
link |
I'm a big believer in,
link |
because the vision and the eyes play such a prominent role
link |
in directing our cognition,
link |
something you talk about in the book really beautifully,
link |
and with a lot of depth and rigor, using visual tools
link |
to harness one's complete mental attention.
link |
When you do this practice of sitting and just thinking,
link |
sitting still and thinking, you said your eyes are open.
link |
Are you hearing your own verbal voice,
link |
although in your head?
link |
So you're actually in conversation with yourself.
link |
Yes, and hearing, literally, I mean, not quite literally.
link |
I don't actually hear a phonation, but I'm hearing words.
link |
And so I discovered this about myself.
link |
Other people, I think, may operate differently,
link |
but I'm extremely verbal in how I think.
link |
That's how all my reasoning is done.
link |
It's with sentences and construction of, you know,
link |
almost equations with words.
link |
Complete sentences?
link |
Complete sentences, or completish, anyway, mostly complete.
link |
And then, when writing the book,
link |
everything about the writing, I would always,
link |
every sentence was always played out in my mind,
link |
listening for rhythm and timing,
link |
and I would obsess over exact placement of words
link |
to get the right rhythm of the spoken sentence in my mind.
link |
I don't mean to interrupt your flow, but when you do that,
link |
and having experienced this process a bit,
link |
although differently,
link |
do you experience any kind of welling up of anxiety
link |
when you're hitting the friction points?
link |
And if so, do you have tools or ways
link |
that you quell that anxiety in real time?
link |
Because what we're really talking about here is your mind,
link |
but what we're really talking about is this process
link |
of converting the activity of neurons
link |
into something physically concrete in the world,
link |
and these intermediate steps are so mysterious to everybody.
link |
We hear, you know, just write the book, just do it,
link |
whatever that means.
link |
In fact, statements like that, to me,
link |
are kind of empty and meaningless.
link |
But when you hear your voice
link |
and you're trying to find the correct word
link |
and you keep hitting, it doesn't sound quite right,
link |
what is the experience in your body?
link |
Yeah, when it's not right, it's definitely, it's aversive.
link |
It doesn't feel good, but it's not,
link |
but there's also a hope because I know I can solve it too,
link |
and so there's this,
link |
it's almost like you're almost there, you know?
link |
There's a path that you know is there.
link |
You don't quite see it, but it's there,
link |
and I keep that in mind,
link |
and so there's this propulsive force forward
link |
because I know that the solution is there,
link |
and that said, you know, there were single words
link |
that I would spend days on
link |
because I was just not happy until I got it right,
link |
and there were some things that I never quite got perfect,
link |
and so I left out of the book entirely
link |
because it was so close, but not quite there,
link |
and so at the end, I was like, no, I can't put that in.
link |
Everything you just said is entirely consistent
link |
with my experience of you
link |
and the way you go about everything.
link |
I have to ask, are your kids writers,
link |
do they like books and words and poetry?
link |
I know one of your children is going on
link |
to a career in medicine and science.
link |
Yeah, they're each different, which is amazing,
link |
yet they all, I think, do have some appreciation
link |
or a lot of appreciation for reading,
link |
but some are very musical.
link |
Two of the five are extremely musical,
link |
very, very talented with guitar and singing
link |
and vocal impressions.
link |
It's just astonishing,
link |
and some of them are great with drawing and artistry,
link |
and some are very physical and vigorous
link |
and are never happy except when leaping about,
link |
and so it's just amazing how different they are, honestly,
link |
but I think there is a shared appreciation for language.
link |
Do you think that one can train their mind
link |
in using these practices?
link |
I really like your description of the sitting,
link |
staying physically still
link |
and learning to grapple with those challenges.
link |
It's something that, especially in laboratory science,
link |
we aren't really trained to do.
link |
Like many professions,
link |
we're taught to come in and just get into motion,
link |
and I found that very relaxing
link |
as someone who probably has an underlying tick
link |
or something like that, it felt great to be in motion.
link |
One of the hardest things
link |
about becoming a university professor and running a lab
link |
was that I was no longer working with my hands,
link |
and it felt like some big important part of my life
link |
had been amputated,
link |
but what sorts of practices do you incorporate there,
link |
and do you think people can learn to get better at focusing
link |
through a dedicated practice of the sort that you describe?
link |
I think, you know, that I also,
link |
I remember the rhythms of physical work
link |
in the laboratory very well.
link |
I, my work, you know, these days as the laboratory leader,
link |
my job is returned mostly to words now again,
link |
and so it's kind of coming full circle.
link |
It was, so it's a different mode.
link |
I think you just have to embrace
link |
that different stages of life
link |
come with different modes,
link |
but you can definitely train yourself for each mode.
link |
I was not, you know, I loved, you know,
link |
as I mentioned, the rhythm of sewing
link |
and suturing and surgery,
link |
and I worked really hard on that and became good at it,
link |
and now I never do it, but it's what's the next challenge.
link |
You know, there's all the various experimental techniques,
link |
the dissections of the brain, you know,
link |
I can't tell you how many thousands of brain dissections
link |
I've done in my life, and now I don't do them at all.
link |
And then you developed a method
link |
so that we don't have to dissect brains.
link |
As you mentioned, maybe tell us for a moment about clarity
link |
and for people who will probably never set foot
link |
into a laboratory, what an incredible,
link |
yet another incredible discovery and development clarity is
link |
and why it helps us understand how the brain is structured.
link |
Yeah, so this is a different technology
link |
also developed in my lab here,
link |
and it's a part of a broader approach
link |
that we call hydrogel tissue chemistry.
link |
And what this is is it's building a gel,
link |
like a clear, jello-like substance
link |
from within all the cells of a tissue
link |
or even an animal all at once.
link |
So you're building, effectively building a gel
link |
inside all the cells at once.
link |
Now that's an odd thing to do.
link |
Well, we do it to transform the tissue
link |
into a more tractable, accessible object.
link |
And the reason that works is having built this gel,
link |
this new infrastructure inside the tissue,
link |
we can then use chemical tricks
link |
and we can link the molecules we care about,
link |
like proteins or RNAs, which are the things,
link |
as you know, right before they become proteins,
link |
we can link them, physically anchor them
link |
to this gel, which is a scaffold, basically.
link |
It's an interlocking network of polymers.
link |
We can link all these interesting molecules in place,
link |
lock them in where they were initially,
link |
in the tissue, in the cell, in all the cells.
link |
And then we can remove very vigorously
link |
everything we don't care about
link |
that's blocking our light,
link |
that's blocking our molecules coming in
link |
to exchange information with the tissue.
link |
We can get rid of everything else,
link |
like the lipids, the fats.
link |
We can effectively use detergents to get them all out.
link |
And then we can see in all the things
link |
that we're absorbing, our scattering light are gone.
link |
You can have a brain that's completely transparent,
link |
and yet all the interesting molecules
link |
are still locked into place there
link |
at the cellular and subcellular level.
link |
And so this is hydrogel tissue chemistry.
link |
The first form we described was called Clarity.
link |
We use that quite a bit still,
link |
but there are many variants now
link |
that we and others have developed
link |
on this basic concept of building this gel
link |
within the tissue and anchoring molecules into place.
link |
Literally glass clear brains.
link |
I've done this, I've taken a brain clear with this method
link |
and looked at somebody through it.
link |
And although you don't want to get it too close to your eye,
link |
you don't want to touch it to your own eye.
link |
But, and you can see direct all the way through it.
link |
That's incredible for the,
link |
it raises an important question,
link |
which is again about the human brain.
link |
I mean, as somebody who essentially started out
link |
in neuroanatomy and then got into other things,
link |
I always am bothered by the fact
link |
that we actually know very little
link |
about the microstructure of the human brain
link |
compared to the brains of other organisms.
link |
And in thinking about understanding the circuitry
link |
and the piano, so to speak,
link |
and how to manipulate it in order to relieve suffering,
link |
one wonders are the structures in these animal brains
link |
and how they behave in active coping,
link |
passive coping, ADD, et cetera, those models,
link |
how well they translate to the human condition.
link |
Do you think it's fair to say that there are entire regions
link |
of the human brain that aren't just bigger,
link |
but that exist only in the brains of humans,
link |
especially given that we have this speech,
link |
although I do wonder sometimes if, you know,
link |
animals are reporting to each other there,
link |
maybe they have little psychiatric sessions
link |
You know, I'm always careful
link |
to not assume we do things better.
link |
We certainly understand what we're doing better
link |
than we understand what animals are doing,
link |
and they certainly do things better than we do.
link |
That said, we do have amazing, wonderful brains
link |
and many structures that are very highly developed
link |
in our brains that are not nearly so developed
link |
in mice and fish, for example.
link |
Now, that said, when I look at the big picture,
link |
you know, what is the mammalian brain really doing?
link |
There are things that you would never have thought
link |
we could study in animals, in laboratory,
link |
in mammals like mice that it turns out you can, actually.
link |
And so I would never draw the line and say,
link |
here's something you can't study in mice,
link |
or here's something that has no parallel in mice.
link |
I would be very careful before making
link |
any statement like that.
link |
A good example of that is we've been able to study
link |
just in the past year come to an understanding
link |
of dissociation, and we had a paper that came out
link |
in late 2020, both mouse and human work,
link |
in which we got to sort of the circuit basis
link |
Now, what is dissociation?
link |
A lot of people might not have experienced it,
link |
but it's actually very common.
link |
More than 70% of people who've been through trauma
link |
experience dissociation.
link |
It shows up in borderline personality.
link |
It shows up in PTSD.
link |
What it is is it's a separation of the sense of self
link |
from the body, and so you can have someone who,
link |
it's not as if you're numb, you're not anesthetized.
link |
You can still, you know that something's happening
link |
to the body, but you just don't care
link |
because you don't ascribe it to yourself,
link |
which is very interesting, right?
link |
That is, how interesting is that?
link |
The self-report narrative.
link |
Almost in your book, you touch on this,
link |
and I will say is the most precise and meaningful
link |
and eloquent description of what might be consciousness,
link |
this narrative toward the self or of the self
link |
and where it might reside.
link |
So in dissociative conditions,
link |
people are feeling as kind of an absence of a merge
link |
between mind and body.
link |
Is that one way to describe it?
link |
And as I recall, this paper involved
link |
an exploration of ketamine.
link |
Ketamine was a big part of it, yeah, that's right.
link |
And so ketamine is another one of those cases
link |
where people can experience dissociation.
link |
Ketamine or PCP, we call these the dissociative drugs.
link |
They cause it just like these other
link |
psychiatric conditions can cause it.
link |
But we were able to manifest this in mice,
link |
administering these dissociative agents in mice.
link |
We could make them still able to detect stimulus
link |
but not care that it was happening.
link |
All the while, we were recording the activity
link |
of individual cells in the brain to see what was going on,
link |
what was happening along with this dissociation
link |
and then use optogenetics to see that it mattered
link |
to actually provide that pattern of activity
link |
and see, oh, that actually causes the dissociation.
link |
So we could do all that in mice,
link |
which was just a, who would have thought
link |
that you could study something like this in mice?
link |
And we were able to go back and forth with human work
link |
because here in our Stanford Comprehensive Epilepsy Center,
link |
there are a lot of what we call stereo EEG recording.
link |
Patients who come in
link |
and in the course of normal clinical care,
link |
they have electrodes recording in their brain
link |
to identify where the seizure is
link |
so they can be candidates for removing
link |
a little patch of the brain that's causing the seizure.
link |
This is done for patients who medications
link |
are not helping their seizure disorder.
link |
And there was a patient who had a dissociative state
link |
before every seizure.
link |
So this was a human being who was really dissociating,
link |
who could tell us literally as it was happening.
link |
And we could see this pattern,
link |
the same pattern that was happening in the mice
link |
in the same patch of the brain,
link |
we could see that happening in the human being
link |
at exactly the right time in the same patch of the brain
link |
that's homologous across these
link |
immense evolutionary distances.
link |
And we knew that it mattered too, both in mouse and human,
link |
because in the human, we could cause it to happen.
link |
I want to underscore the power of not just that,
link |
I want to underscore the power of optogenetics
link |
and the ability to not just remove a particular experience
link |
or behavior by lesioning or destroying,
link |
but then to go back and actually activate
link |
the same structure or group of structures
link |
and see the emergence.
link |
So it's essentially, these days you hear a lot
link |
about gain-of-function research
link |
in the context of viral manipulation,
link |
but gain-of-function is something
link |
that we do in the laboratory and you do in patients
link |
to both take away something and put it back,
link |
which gives you causality.
link |
Yeah, and so, exactly.
link |
And so with optogenetics, we were able to provide
link |
in animals without being on any ketamine or any drug,
link |
and we could cause the dissociative state
link |
by playing in a precise pattern of activity.
link |
And that, who would have thought you could do that?
link |
But there was a combined mouse and human paper.
link |
Likewise, we've been able to play in visual sensations
link |
into the brains of mice, and by observing
link |
which cells in the visual part of the brain,
link |
visual cortex, are naturally responsive to,
link |
for example, vertical bars instead of horizontal bars
link |
in the visual world, we could see which cells
link |
were normally reporting on vertical bars,
link |
and then we could use optogenetics
link |
to come and play in activity just to those cells.
link |
So these animals are not viewing anything.
link |
Not viewing anything at all,
link |
and we could activate just the vertical bar cells,
link |
and not only did the animal act
link |
as if it was seeing a vertical bar behaviorally,
link |
it was trained to do a particular thing
link |
if it saw a vertical bar, and it did that
link |
just as if it was seeing something visually.
link |
But everything in the brain that we were recording too,
link |
the internal representation of this external world
link |
was naturalistic too.
link |
It looked like the brain was seeing something visual.
link |
So that's gain of function too,
link |
playing in, providing a complex sensation,
link |
our percept that wasn't there before,
link |
and we can do that across species.
link |
So we haven't, you know, and of course,
link |
mice are social, and they do amazing acts
link |
of information processing, and so I don't,
link |
I try not to disparage our cousins too much.
link |
They certainly have helped the field of neuroscience
link |
and medicine, I should mention,
link |
and I know that people have various sensitivities
link |
about animal research, but the work that's been carried out
link |
in mice has been absolutely vital
link |
and instructional for treatment of human disease.
link |
Since we talked about dissociation
link |
and dissociative states, rather, and ketamine,
link |
I'd love your thoughts on psychedelic medicine.
link |
You know, I sort of half joke,
link |
having grown up in this area in Northern California
link |
when it was much more counterculture than it is now,
link |
that many of the things that we're hearing about now,
link |
at least from my read of the history books,
link |
There was a movement aimed at taking
link |
the very same compounds, essentially,
link |
putting them into patients,
link |
or people were obviously using them recreationally,
link |
but putting them into patients
link |
and seeing tremendous positive effects,
link |
but also tremendous examples of induced psychiatric illness.
link |
In other words, many people lost their minds
link |
as a consequence of overuse of psychedelics.
link |
I'll probably lose a few people out there,
link |
but I do want to talk about
link |
what is the state of these compounds?
link |
And I realize it's a huge category of compounds,
link |
but LSD and psilocybin, as I understand,
link |
trigger activation of particular serotonin receptor
link |
mechanisms may or may not lead to more widespread activation
link |
of the brain that one wouldn't see otherwise.
link |
But when you look at the clinical and experimental
link |
literature, what is your sort of top contour sense
link |
of how effective these tools are going to be
link |
for treating depression?
link |
And then if we have the time,
link |
we could talk about trauma and MDMA and some of that work.
link |
Well, you're right to highlight both the opportunity
link |
and the peril that is there.
link |
And of course, we want to help patients,
link |
and of course, we want to explore anything
link |
that might be helpful, but we want to do it in a safe
link |
But I do think we should explore these avenues.
link |
These are agents that alter reality
link |
and alter the experience of reality, I should say,
link |
in relatively precise ways.
link |
They do have problems, they can be addictive,
link |
they can cause lasting change that is not desirable.
link |
But we have to see these as opportunities.
link |
We have to, first of all, study in the laboratory,
link |
and I'm doing this here.
link |
We have big, we have safes with many interesting psychedelics
link |
that are all very carefully regulated.
link |
We get inspections from the DEA and so on.
link |
If anyone's hoping to find these labs,
link |
they exist in outer space, so you need to be on board
link |
one of the SpaceX missions in order to access them,
link |
so don't try and come find them.
link |
Yeah, no, that's exactly true, yes.
link |
And we're doing exactly this.
link |
We're saying this is an incredible opportunity.
link |
If we could understand how the perception of reality
link |
is altered, we could create new kinds of intervention
link |
that don't have the risks and the problems
link |
of causing lasting change or addiction.
link |
Now, that said, even as these medications exist now,
link |
as you know, there's an impulse to use them
link |
in very small doses and to use them
link |
as adjunctive treatments for the therapy of various kinds,
link |
and I'm also supportive of that
link |
if done carefully and rigorously.
link |
Of course, there's risk, but there is risk
link |
with many other kinds of treatment,
link |
and I'm not sure that the risks for these medications
link |
vastly outweigh the risks that we normally tolerate
link |
in other branches of medicine.
link |
Why would they work?
link |
I mean, let's say that indeed their main effect is to create
link |
more connectivity, at least in the moment,
link |
between brain areas.
link |
So the way I think about a very,
link |
I think about the two extremes of my experience anyway
link |
is a high degree of stress and focus, for whatever reason,
link |
is going to create changes in my visual field
link |
and changes in the way that I perceive time
link |
so that I'm going to micro-slice time.
link |
I'm in a very contracted view of whatever my experience is,
link |
whereas on the opposite extreme,
link |
in a dream or in sleep, space and time are very fluid,
link |
and I'm essentially relaxed,
link |
although it might be a very interesting dream,
link |
Psychedelics seem to be a trajectory,
link |
I'm not too far off from the dream state
link |
where space and time are essentially not as rigid,
link |
and there is this element of synesthesia,
link |
of blending of the senses, you know,
link |
feeling colors and hearing light and things of that sort.
link |
You hear these reports anyway.
link |
Why would having that dreamlike experience
link |
somehow relieve depression long-term?
link |
Do we have any idea why that might be?
link |
We have some ideas and no deep understanding.
link |
One way I think about the psychedelics
link |
is they increase the willingness of our brain
link |
to accept unlikely ways of constructing the world,
link |
unlikely hypotheses, as it were, as to what's going on.
link |
The brain, in particular our cortex, I think,
link |
is a hypothesis generation and testing machine.
link |
It's coming up with models about everything.
link |
It's got a lot of bits of data coming in,
link |
and it's making models and updating the models
link |
and changing them theories, hypotheses for what's going on.
link |
And some of those never reach our conscious mind,
link |
and this is something I talk about in projections
link |
in the book quite a bit, is many of these are filtered out
link |
before they get to our conscious mind, and that's good.
link |
We think how distracted we'd be
link |
if we were constantly having to evaluate
link |
all these hypotheses about what kinds of shapes
link |
or objects or processes were out there.
link |
And so a lot of this is handled
link |
before it gets to consciousness.
link |
What the psychedelics seem to do
link |
is they change the threshold for us
link |
to become aware of these incomplete hypotheses
link |
or wrong hypotheses or concepts that might be noise
link |
but are just wrong and so are never allowed
link |
to get into our conscious mind.
link |
Now, that's pretty interesting,
link |
and it goes wrong in psychiatric disorders.
link |
I think in schizophrenia, sometimes the paranoid delusions
link |
that people have are examples of these poor models
link |
that escape into the conscious mind
link |
and become accepted as reality,
link |
and they never should have gotten out there.
link |
Now, how could something like this in the right way
link |
help with something like depression?
link |
Patients with depression often are stuck.
link |
They can't look into the future world of possibilities
link |
Everything seems hopeless, and what does that really mean?
link |
They discount the value of their own action.
link |
They discount the value of the world
link |
at giving rise to a future that matters.
link |
Everything seems to run out like a river
link |
just running out into a desert and drying up.
link |
And what these agents may do
link |
that increase the flow through circuitry
link |
if you will, the percolation of activity through circuitry
link |
may end up doing for depression
link |
is increasing the escape of some tendrils of process,
link |
of forward progression through the world.
link |
It's how I think about it.
link |
There are ways we can make that rigorous.
link |
We can indeed identify in the brain by recording.
link |
We can see cells that represent steps along a path
link |
and look into the future,
link |
and we can rigorously define these cells,
link |
and we can see if these are altered on psychedelics.
link |
And so that's one of the reasons
link |
that we're working with these agents in the laboratory
link |
to say, is this really the case?
link |
Are these opening up new paths
link |
or representations of paths into the future?
link |
MDMA, ecstasy, is a unique compound
link |
in that it leads to big increases in brain levels
link |
of dopamine and serotonin simultaneously.
link |
And I realized that the neuromodulators
link |
like dopamine and serotonin often work in concert,
link |
not alone, the way they're commonly described
link |
in the more general popular discussions.
link |
However, it is a unique compound,
link |
and it's different than the serotonergic compounds
link |
like LSD and psilocybin.
link |
And there are now data still emerging
link |
that it might be, and in some cases can be useful
link |
for the treatment of trauma, PTSD and similar things.
link |
Why would that work?
link |
And a larger question,
link |
perhaps the more important question is,
link |
psychedelics, MDMA, LSD, all those compounds,
link |
in my mind, there are two components.
link |
There's the experience you have while you're on them,
link |
and then there's the effect they have after.
link |
People are generating variations of these compounds
link |
that are non-hallucinatory variations,
link |
but how crucial do you think it is to have,
link |
let's stay with MDMA, the experience of huge levels
link |
of dopamine, huge levels of serotonin,
link |
atypical levels of dopamine and serotonin released,
link |
having this highly abnormal experience
link |
in order to be normal again?
link |
Yeah, I think the brain learns from those experiences.
link |
That's the way I see it.
link |
And so, for example, people who've taken MDMA,
link |
they will, as you say, they'll be the acute phase
link |
of being on the drug and experiencing
link |
this extreme connectedness with other people, for example.
link |
And then the drug wears off,
link |
but the brain learned from that experience.
link |
And so what people will report is,
link |
yeah, I'm not in that state, but I saw what was possible.
link |
I saw, yeah, you can, there don't need to be barriers,
link |
or at least not as many barriers as I thought.
link |
I can connect with more people in a way that is helpful.
link |
And so I think it's the learning that happens
link |
in that state that actually matters.
link |
And as you described that, that sounds a lot like
link |
what I understand to be the hallmark feature
link |
of really good psychoanalysis,
link |
that the relationship between patient and therapist
link |
hopefully evolves to the point where these kinds of tests
link |
can be run within the context of that relationship
link |
and then exported to other relationships.
link |
Exactly right, yeah.
link |
And that probably, I'm assuming,
link |
is still the goal of really good psychiatry also.
link |
It should be, when we have time,
link |
I think all good psychiatrists try to achieve
link |
that level of connection and learning,
link |
try to help patients create a new model that is stable,
link |
and that can help instruct future behavior.
link |
One of the things that I took from reading your book,
link |
in addition to learning so much science
link |
and the future of psychiatry and brain science,
link |
was amidst these, in many cases,
link |
very tragic cases and sadness,
link |
and a lot of the weight that that puts on the clinician,
link |
that there's a central cord of optimism,
link |
that where we're headed is not just possible,
link |
but very likely and better.
link |
And, you know, are you an optimist?
link |
And this is, by the way,
link |
this was a really interesting experience
link |
in writing projections because I had a dual goal.
link |
I wanted it to be for everybody,
link |
literally everybody in the world who wants to read it.
link |
And yet at the same time,
link |
I wanted to stay absolutely rigorously close to the science,
link |
what was actually known.
link |
When I was speaking about science,
link |
when I was speaking about the neurobiology of the brain
link |
I wanted to not have any of my scientific colleagues think,
link |
oh, he's going too far.
link |
He's saying too much.
link |
And so I had these two goals,
link |
which I kept in my mind the entire time.
link |
And a lot of this,
link |
trying to find exactly the right word we talked about
link |
was on this path of staying excruciatingly rigorous
link |
and yet letting people see the hope where things were,
link |
have everybody see that we've come a long way.
link |
We have a long way to go,
link |
but the trajectory and the path is beautiful.
link |
And so that was the goal.
link |
I think, of course, that sounds almost impossible
link |
to jointly satisfy those two goals,
link |
but I kept that in my mind the whole way through.
link |
And yes, I am optimistic.
link |
And I hope that came through in the book.
link |
But it certainly did.
link |
And at least from this colleague,
link |
you did achieve both.
link |
And it's a wonderful,
link |
it's a masterful book really.
link |
And one that as a scientist
link |
and somebody who is a fellow brain explorer
link |
hits all the marks of rigor and is incredibly interesting.
link |
And there's a ton of storytelling.
link |
I don't want to give away too much about it,
link |
but people should definitely check out the book.
link |
Are you active on social media
link |
if people want to follow you
link |
and connect with what you're doing now and going forward?
link |
Yeah, I have a Twitter.
link |
That's where I mainly do exchange,
link |
tell people about things that are happening.
link |
We'll provide a link to it,
link |
but that's Karl Deisseroth as I recall with a K.
link |
That's right. Yeah.
link |
And so you're on Twitter and people will hear this.
link |
Definitely check out the book.
link |
There are other people in our community
link |
that of course are going to be reaching out on your behalf,
link |
but it's incredible that you juggle
link |
this enormous number of things.
link |
Perhaps even more important, however,
link |
is that it's all in service
link |
to this larger thing of relieving suffering.
link |
So thank you so much for your time today,
link |
for the book and the work that went into the book,
link |
I can't even imagine,
link |
for the laboratory work and the development channel ops
link |
and clarity and all the related technologies
link |
and for the clinical work you're doing
link |
and for sharing with us.
link |
Well, thank you for all you're doing and reaching out.
link |
I'm very impressed by it.
link |
It's important and it's so valuable.
link |
And thank you for taking the time
link |
and for all your gracious words about the book.
link |
I hope you enjoyed today's discussion
link |
with Dr. Deisseroth as much as I did.
link |
Be sure to check out his new book,
link |
Projections, A Story of Human Emotions.
link |
It's available on Amazon, Audible
link |
and all the other standard places where books are found.
link |
If you'd like to support this podcast,
link |
please subscribe to us on YouTube.
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As well, you can subscribe to us on Apple or Spotify.
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At Apple, you also have the opportunity
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Please put any questions you have
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if you'd like us to address certain things
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In addition, please check out our sponsors.
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We also have a Patreon.
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There you can support us at any level that you like.
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Last but not least, if you're interested
link |
in understanding more about how the brain works
link |
and how it functions and how it breaks down
link |
in various conditions,
link |
check out the first episode of the Huberman Lab Podcast.
link |
The title of that episode
link |
is How Your Nervous System Works and Changes.
link |
If you're watching this right now on YouTube,
link |
you can simply click on the title card for that episode.
link |
And last but not least,
link |
thank you for your interest in science.
link |
I'll see you in the next one.