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Welcome to SNI Digital Innovations in Learning in association with UCLA Neurosurgery. Linda Liao, chairwoman and its faculty are pleased to bring you the UCLA Department of Neurosurgery 101
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lecture series on neurosurgery and clinical and basic neuroscience.
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This series of lectures are provided free to bring the advances in clinical and basic neuroscience to physicians and patients everywhere. One out of every five people in the world suffer from a
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neurologically related disease.
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The lecture and discussion is on stereotactic and functional neurosurgery of serendipity, science, and spiral staircases. Lessons on life in the esoteric origins. Functional neurosurgery by Dr.
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Gross. I think I would make a suggestion here. I said, the lecture is on - OK. OK, so just do the whole thing over. What's his name, Robert Gross? Yeah, but you don't need that. You'll come
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to that to the next - Hi
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Let's start there. It's still recording.
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The lecture and discussion is on stereotactic and functional neurosurgery, on serendipity. Well, you did the same thing. You said, oh, no, I said, you have to say the lecture - no, first of
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all, it's of. Oh, it is of. OK, did I say on both times? Yeah, I think so. I'm sorry. And so that you say the lecture's title is of -
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The lecture and discussion title is on stereotactic that's not it. The category is that don't say that the lecture and discussion is on stereotactic and functional neurosurgery. The title is okay.
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The lecture and discussion is on stereotactic and functional neurosurgery.
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The title is serendipity science and spiral staircases, lessons on life in the esoteric origins functional neurosurgery.
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Robert E. Gross of the lecturer speaker is the speaker is Robert E. Gross MBNA
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Bowman chair and professor department of neurosurgery director and co-founder Emery neuromodulation and Technology Innovation Center E-N-T-I-C-E director translational
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neuro engineering laboratory director stereotactic functional neurosurgery and epilepsy surgery I better do that over well okay
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The lecture is Robert E. Gross,
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MBNA Bowman Chair and Professor of Department of Neurosurgery, Director and Co-Founder, Emory Neuromodulation and Technology Innovation Center, Director Translational Neuroengineering Laboratory,
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Director Stereotactic Functional Neurosurgery and Epilepsysurgery, from Emory University School of Medicine, Atlanta, Georgia, United States of America
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And, you know, you start thinking about what you've learned along the way. When we mentor students, this is important to us and even why we're doing this, you know, you get these sort of
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existential crises. And so, you know, I've done a lot of thinking about this, and I was also invited to talk about the history and something else happened along the way, which I'll get into do
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But so, this is a little bit more ethereal, usual disclosures. So I have always been a fan of both stories, so I'm going to tell you some stories. And Maxims, this helps me understand things,
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you know, you bake them into one way, one thought idea, and then you don't have to think about it. Like for example, you're damned if you do, and you're damned if you don't, but you're more
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damned if you don't than if you do. So that has been my approach to handling trauma.
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And
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another one of my favorites that I learned that I made as a resident, riffing off of President Lincoln's saying that you can't please all the people all the time, but you can displease all the
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people all the time.
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So I'm a big fan of Maxims and my lab actually for my birthday a couple of years ago put them all on a calendar, which is really great. But here are some of them that you'll encounter in this talk
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This one from Steve Covey and the seven habits of highly effective people. I gave a lecture to our residents a few years ago called the seven habits of highly functional neurosurgeons. And I think
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it's really important to, especially as residents, as you're going out there and you're starting on your career and you're nervous about how you're going to make a name for yourself and establish
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your practice and balance family life and have some fun Not that family life isn't fun, but it was Jerry Seinfeld that said there's no such thing as fun for the whole family.
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So these are important things to think about as you're going out. And so begin with the end in mind comes from that. So that's one way of thinking, and it's important to think that. Think things
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through to where the goal line is before you get going on them. On the other hand, one of the things that has guided me my whole career is simply following my nose. And I'm a big fan of that, and
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I'll show you how I followed my nose in my own career. Now, when you're beginning with the end in mind, you're imagining what the end is, but you don't know what the end is, okay? And what we're
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learning, especially these days in the pandemic, if it has made one thing crystal clear, and that is it is difficult to make predictions, especially about the future So it usually takes people.
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15 seconds to get that joke, but, um, so, um, I'm gonna make it up. It's probably attributed to Yogi Berra or, or Mark Twain. Everything is, um, so, so, um, so there you go.
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So, um, but, but it's really true is that, especially in your life, because, you know, back as, as, uh, I know that, uh, that Itzak is a nose of Yuval Noa Harari. So, and, uh, and I'm
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a fan of his writing, um, as he describes in, in Sapiens, uh, that, um, back, you know, 2000 years ago, you knew what your life was going to be. In fact, you knew what your grandchildren's
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life and your great grandchildren's life was going to be because you knew what your great grandparents life was and things didn't change very quickly. It took a millennia for things to change. But
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now you'd only not, not know what your grandchildren's world is going to be like or your children's world. You don't You don't want to know what your world is going to be like in five years from now.
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So when you're beginning with that end in mind, you're fantasizing what that end is. So you really need to be aware of where you are on that path because man plans and God laughs, okay? So, and
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you will see that you've already seen that, okay? And so just remember this. And then finally, not finally, this is one more after this, but as you start to walk on the way, the way appears So
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that's what being very cognizant of the present, where you are right now is, okay? So you can plan, you need to plan. And I would always describe to my residents and my lab students and my
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graduate students, even before I knew of this saying from Rumi, I would say, make a plan to go to San Francisco or LA. I'm gonna go to LA from Atlanta. That's my goal. I wanna go there, 'cause
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if I just sit at home on my couch, I know it's gonna happen But if I go to LA, I know something's going to have - I'm gonna have fun in LA. It's like it's gonna take me out and show me the town.
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So you make a plan and you plan, you know, when I was a kid, you would go to AAA and get a triptych. And it would tell you every stop along the way and the map for each one. And so you get going
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on that plan. But you get halfway to LA and you hit San Antonio or Santa Fe and someone says, oh, are you here for the art festival? No, no, what art festival? Oh, there's an art festival in
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two days. You can't miss that Oh, but I got to get to LA, I'm on the strip deck. All right, fine. 'Cause you didn't see that intersection. You couldn't see that intersection from Atlanta. You
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get there and you say, all right, fine, I'll go to Santa Fe. You go to Santa Fe, you meet the love of your life, you settle down and become an artist. So you never got to LA, but if you didn't
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make that plan, if you didn't begin with the end in mind, you wouldn't have gone on the path that led you to that spot. So always be aware of just where you are on that path. and especially as
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neurosurgery residents. You know, when you, I'm sure half of you wanted to be a neurosurgeon when you were five. You will see that that was not my story, okay? And so you want to always be at
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the line of scrimmage and make the call, you made a plan, you made a, you made a, you know, the, you know, go down whatever football people do, whatever you call them. And you make an audible
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at the line of scrimmage and then you start to play and you start to run and then you really have to figure out what you're doing. And that's to me what being a neurosurgeon is, is figuring it out
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along the way. Don't plan every little step from the beginning because it's not gonna happen like that. Another one of my favorites is that, you know, no good plan survives first encounter with
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the enemy. And so, you know, always remember that. And then finally, as you go along this path, good judgment comes from experience Does anybody know the rest of that?
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Experience comes from bad judgment, okay? So good judgment comes from experience, but experience comes from bad judgment. So you are going to make mistakes. You have to make mistakes. If you
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don't make mistakes, then you're not trying or doing enough, okay? So you will make mistakes and you have to learn and to be a good neurosurgeon, you have to learn from one trial, one trial
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learners. And that's what I look for. Like when a fellow comes in on the first day, Nick, our young, texted me yesterday, these fellows are great, you know? So are they an end of one learner?
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Then what happens as a neurosurgeon is this weird thing, right? You get rid of all your complications that you've seen once. So every time you have a complication by definition, it's a unicorn,
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okay? So wow, that's weird, that's never happened to me before. That's what all your complications will be. But that's if you're being successful. And then when I would say this, My former
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partner, John Willy, would say. but hopefully someone else's experience. So ideally, you're learning from your peers, oh, you saw that mistake, you don't have to figure that out for yourself.
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My daughter,
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she has to learn from her. She does not believe, you tell her all you want that lighting the fireplace, you need to come get us, you can hurt yourself. She goes, she turns on the gas, she
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doesn't open the door to the fireplace, she goes to the drawer, what's around, finally finds the lighter, comes back, opens the door, there's no, she doesn't know anything about a flu, she
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lights it, boom!
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We spent the rest of the night in the ER, fortunately she only had some corneal abrasions, but she burnt off all her eyelashes. And so she has to learn from her own experience, but hopefully you
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learn from other people's experience too. So there are many more. All right, so let me start with exemplifying some of these things along my journey. I went to Brown in 1977, was somewhat
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nondescript. I was good in science, didn't have a plan, didn't have a goal, didn't know what I wanted to. Actually, my goal was to play right field for the New York Mets, that's not happening.
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So I went to there, so I said, okay, I'll do engineering. That seems to be something for someone good in math and physics. I couldn't even wake up for the final exam. So I switched to computer
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science, which would have been a great thing to stay in in 1977, right? But that was not what was on the path for me. I decided to take an introductory psychology course just to try it. We didn't
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have any distribution requirements at Brown. It's one of the, you know, it's great, but it's also really ridiculous to give 18 year olds who haven't even finished myelinating their frontal lobe
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for the next seven years, full choice of what they do, not a good idea. So I took this psychology course, And there, so. November 29th,
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1978, the day, I'm sorry, November 30th, the day after my birthday, and I know that because it was a memorable birthday. My, you know, I stayed out late doing, you can imagine what. And so I
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sauntered into the psychology class at nine o'clock, a little bit late. And I was happy to see that the lights were off. So I could just slide into the back of the room and nobody would notice me
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And there was a film by Michael Gazanaga, who went on
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to become really the great head of cognitive neuroscience. And this is a recent film. I could never find the film that I saw. But he's a fan of doing these films where he's like out, walking
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around. So in this film, he's at Cornell at the time. And first it shows him in his office. And then it shows him sitting on a park bench in front of their big slope, their big hill And then he's
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in a tree. So I'm like, okay, this is weird. I mean, I'm a little hungover, but this is just a little weird. And then the next thing, you know, he has you in the operating room. So in this
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film here, this is about split brain patients. So he's doing corpus, he's studying patients that have had corpus callisotomies. And I'll just advance this.
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So, here they depict a calicotomy and this would all be well and fine if this is what they did in the film and they showed it there. But no, what they showed in the film was this. So I was like,
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whoa, I'm like blown off my chair, like, you know, I'd never seen a brain before. And I'm like, wow, that's crazy. So that got my attention. Now you would think that I would tell you that
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that's when I decided to become a neurosurgeon Okay, but it's not so, even though it was a calisotomy that shook me out of my torpor. So he goes on and, you know, in this film, he's doing all
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this testing with these patients. So the Ticistoscope showing hemisphere dominance. And I got really intrigued by this. And I got very intrigued by sort of the Eastern, Western, right hemisphere,
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left hemisphere where I went with this was not into the calisotomy zone but
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I had just read a book calledThe Eden Express by Mark Vonnegut, Kurt Vonnegut son. So in that book, Mark Vonnegut takes some psychotropic drugs. And he does not have a pleasant experience, a
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psychedelic experience,
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he goes into psychosis. And this is all about his trip into psychosis and back again, so it's fascinating. So I got put the hemispheric dominance and the psychosis together And this is what really
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intrigued me. And so I went from there to my honors thesis that I worked with a psychiatrist down in the bottom right, Robert Becker and a pharmacologist. So I started out right at the beginning,
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being very ambitious in what I did. I did not follow any garden path. This was my path. And I put these two guys together. One was a straight pharmacologist, one was a psychiatrist. And I did
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this thesis, the honors thesis, the differential effect of stimulus control on a hallucinogen LSD. and the hallucinogen plus an angiogenic agent, LSD plus pentaline tetrazole. So my hypothesis
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was that LSD gives you a serotonergic state and it's pleasant, but if you mix that with stress that that triggers some people. And you could be taking a psychotropic drug and being a very stressful
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situation and have a bad trip, or you could be a very highly anxious person and take that same drug and immediately trigger a bad trip And I've seen this happen, actually subsequent to this
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hypothesis. So, and my idea was that this would model the form, that if you added these two drugs together, you would get different pharmacology that was more consistent and be more of a model of
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schizophrenia. So where did I go from there? So from there, I went to Chicago to work at the University of Chicago and the Illinois Psychiatric Institute with Herbert Meltzer, the father of the
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dopamine hypothesis with schizophrenia. So that's what I did in my senior year after I graduated, really did not think about going to medical school. I was thinking about just going to graduate
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school, psychiatrists I worked with before that said, just one year and a know everybody that's worked with me has gone to medical school. And I said, well, I'm gonna be your first exception.
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And but during the middle of this year, I came to understand what biological psychiatry was. And I decided that yes, I'm gonna be a biological
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psychiatrist. And so I applied to medical school and I got into medical school. And the next thing that happened was I became very interested in dopamine. And I saw these papers, this actually the
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top paper I saw when I was in college. This is from 1976 or something about grafting in the brain. And so I'm sitting in my lab as an MD-PhD student. Actually, I walked into the only reason I got
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into Einstein. was because when I met with Wagner Bridger, the psychiatrist that was interviewing me, I walked into his office and he's sitting at his desk with his feet up, white-haired guy
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smoking a cigarette, which you could do back then. And I walk in and he's referring to my honesty, so he says, You beat me to it. So that's why I got in there. So I was going to do psychiatry,
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but I started thinking about grafting 'cause I saw these papers about dopaminergic grafting and it just blew my mind that you could take brain cells from one animal and stick them into another animal.
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That was crazy. So I actually hatched this idea
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that I remember sitting around in the room in my lab saying, You know what I'm gonna do? I'm going to do cerebral transplantation on patients. And with the money I
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bill for doing that procedure, I'm gonna use it to fund my lab. Now, how ridiculous is that? Okay, so that's how naive I was. So now, you know, hopefully we'll talk about mentorship in a
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little while. I didn't have a mentor that told me that that was crazy, that that was a crazy idea. But that's the idea that I had at that time. But nevertheless, I did not think about being a
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neurosurgeon. I don't even remember what, I mean, it just never crossed my mind to be an actual neurosurgeon. So I went from there and I kept following my nose. So I first was working on dopamine
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receptors because I was interested in dopamine And then I forced for any molecular biology. I said, I just can't learn everything. I'm not going to know anything about DNA and RNA. And then I read
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this book. And books are really, really critical in your life, whether it's, you've all know a Harari or whatever, I could talk about the thousand books. But this book I read then, The Eighth
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Day of Creation, which was about the makers of the revolution in biology, about the founding of molecular biology. And what that book shows is that this new field, And in fact, really all
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innovation is due to collisions. Okay, you've got to bring things together. Why did I want to become an MD PhD? Because I wanted to bring those things together. So it's all about synapses,
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bringing things together and colliding them. And that's how molecular biology came to exist as a field, but even more important, it's people that collide. Okay, it's all the people that you run
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into in your career that you can't plan to run into, that you do happen to run into, that generate these collisions and that lead to innovation It rarely comes out of one person thinking in
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isolation. You gotta get on the path and interact with people. So I switched to molecular biology at that point. And I kept following my nose and by the time I followed my nose all the way down as
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far as it would go, it was to see elegance. Okay, so I started out in psychosis, in man, and I ended up with a worm that has 389 neurons And that was then my. I fell in love with developmental
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neurobiology, and that's what I was going to do. And so I went in to see my director of the MD-PhD program, and I told her, look,
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I was interested in medical school, really just long enough to get into medical school. And I have no interest in that anymore. It bored me to tears the first two years. I had to read molecular
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pharmacology journals as a reward for doing an hour of work. I'm just gonna take my PhD certificate and go. So she convinced me, and honestly, my ex-wife at the time, so they convinced me, look,
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it's only 13 months to finish it out when you started. You'll get paid, whatever they said, 10, 000 more for doing the same thing. You don't have to do it, just finish it. And I figured, all
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right, back then, it was only 13 months. Nowadays, from my program, it would be 22 months. I wouldn't be standing here.
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I figured one year I could do anything for one year. So they pushed me into a certain hospital. I was repulsed by the whole thing. I mean, I was nauseated, but I figured, all right, if I'm
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gonna do it, I'm gonna do the hardest thing first, second hardest thing second, the third hardest thing third. So what's gonna be the hardest thing for me to do? Surgery, okay? I'll just get
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through that first. So I go to the surgery, general surgery,
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gunshot wounds, Jacobi hospital, colis mastectomies, bowel operations, and within 48 hours I fell in love with it. So that was my Santa Fe experience. I had to get to, I had no idea. I mean,
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there was foreshadowing, okay? But as far as doing it, I had no idea that I would love to do it. And so I said, instead of dropping out of medical school, I'll do surgery. Well, can't do,
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General surgery. I'm a neuroscientist, so neuroscience plus surgery equals, well, what about neurosurgery? So I went and talked to the surgeon at Jacoby Hospital and I said, so I might be
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interested in this area. What's the interaction between neurosurgery and the neuroscience department? And he said, you know, I'm sorry, what? So I thought, okay, that's disappointing. That
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wasn't exactly what I thought, but then I thought to myself that here is an opportunity. I will be a cellular and molecular neurosurgeon. And I harkened back to that fetal grafting. So that became
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my idea, that idea that I had eight years, seven years before, I will do fetal grafting for Parkinson's disease. That'll be great. Now this is 1989,
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all right? So this is before paladotomy in DBS. So there was no surgery for part. There was no such thing as functional neurosurgery for all intents and purposes back then. So I
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interviewed for neurosurgery
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spots. I didn't tell anybody that this was my plan, you know? And 'cause I was smart enough to know that that was not gonna play well. If I had told people my plan was to do fetal transplantation
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when I'm done and that's why I'm becoming a neurosurgeon, again, I would not be standing here, okay? But this idea actually came, you know, so Michael Appuzo, you know, you know, well of from
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down the street, then published these papers on cellular molecular neurosurgery in 1997. So it wasn't such a crazy idea that I did have in isolation. And so I went about doing this and I carried my
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molecular cellular work into the lab, started working with stem cells, materialized right in front of me in 1992 was the first paper published on stem cells. And so I started working in the lab on
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stem cells. And I was said, okay, I'm going to restore the nervous system with by making dopaminergic neurons. So I started treating these stem cells in the culture disc with various stuff like
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bone morphogenetic proteins. And I was really disappointed that I made astrocytes. I'm like, okay, I don't want to make astrocytes. I want to make neurons. So I put this stuff in the drawer and
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for like two weeks. And finally, I said, you know what, I've had a color picture. These things were just radiant said I can't ignore this. Okay. So you have to. So I don't look a gift towards
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the mouth. That was what was on my path in front of me wasn't what I planned, but it was what I got. And so I did that and I published this nice paper on turning bone morphogenetic, turning stem
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cells into astrocytes about
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four or five years later, Angelo Viscove, who is a stem cell researcher in Italy, comes up to me and he says, I'm at a society for neuroscience meeting. And he says, Oh, we're just starting our
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clinical trialfor glioma. I said, Oh, well, congratulations for you. He said, She says, Guess what we're doing. And I said, I have no idea what you're doing. I said, Guess. I said,
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I don't know what your trial is. He said, Well, you invented it. I said, What are you talking about? He said, Bone morphogenetic proteins. They said, Okay. He said, In your paper, you
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showed that bone morphogenetic proteins cause stem cells to go exit cell cycle. So we're studying this in a glioma model. And I was like, Wow, I totally missed that. Because I had in my idea, I
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was thinking, I actually was working on some on our cell lines, our tumor cell lines. I saw that this might have some application, but I said, No, I don't wanna treat brain tumors. don't even,
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they're not even made of neurons, okay? They're not, you know, most of them aren't even exoderm, ectoderm, you know, I love neurons. So I went into functional neurosurgery because I love to
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interact with neurons and not tumors, but I missed that opportunity along the way. I guess if it worked, you would know about it. So it probably didn't work. So my plan going then into residency
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was to go and work with these guys So I'm just Bjorkland and Oli Linvall to do transplantation. So I, in my first or second year of residency, I wrote them a letter. That's what we did back then
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and said, I'd like to come and work with you after I'm done with my residency. And they said, or maybe I said during my research year, I don't remember. They said, yes, that's great. Come on,
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so that I was going to execute my plan. So that was my plan, but this is what other plans were. And that was Marwen Harris and Laurie Layton So this is 1992, so I started my residence in 1990.
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And all of a sudden, out of nowhere, came functional neurosurgery. So I saw this paper and I was like, this is a journal neurosurgery. Holy shit, you could actually do surgery for Parkinson's
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disease. Like I can actually talk about it out loud, not fetal cell transplantation. So this changed my life right at that time. I actually grabbed one of my faculty members, potlessala and took
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them out to Loma Linda, where a guy named Robert Iacono was doing a lot of paladonomies. So we went out to see the operation, and I had this idea we might start that up at Albert Einstein, which
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was of course delusional. And it took them decades before they got that going. But this exemplifies Wayne Gretzky's saying that, What was the secret to your success? I skate to where the puck is
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going to be, not where it has been. So that's what I ended up doing here. there to get the puck when it came, instead of saying, oh, the pucks over there, I'm going to go after it. Now, how
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did I get there? It was purely by following my nose. Okay, I did not conspire to be there. I didn't know that there was a puck. You know, for every Wayne Gretzky skating to where the puck is
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going to be, there's everybody else skating to where the puck is not. Okay, so, you know, is it some magical ability he has? He's a, you can see he's clairvoyant. Um, you know, I don't know,
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but you do have to figure out in your own lives, whether the puck is where you're skating to. Okay. And, and, you know, take a chance, you know, he would take a chance. He'd like the people
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like, what the hell are you skating over there for? Don't worry about it. And that's where the puck is. So you have to take a chance to go where, to where the puck might be, not necessarily
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where it's going to be, so that you can be in a position to take whatever happens to you along that way.
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That's when I first got introduced to Roy Bekay. How many people here know who Roy Bekay is?
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Two, okay. Okay, so mail-in-the-long. How many know who mail-in-the-long is? Same two. Not in medical school. You don't learn who mail-in-the-long is? Okay. How many know who Jerry Vitak is?
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Nobody, two. How many know who Ben Allen, Louis Benabit is? About four, okay So BK and DeLong were at Emory at the time. DeLong as a neurologist, BK was a neurosurgeon. And they took advantage
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of this situation. And so now all of a sudden my plan became to go to do a fellowship. So my idea was to go do a fellowship at Emory where this dream team of these three people, the neurosurgeon
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Roy BK, the neurologist on the right, mail-in DeLong, who invented the pathways that you study in medical school. Okay, the heuristic that you use to remember what the subthalamic nucleus done
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does. What you study as residents, the passenger boards, that's the long who put that together. And Jerry Vitek is a chair out at Minnesota. Or go to Toronto where this young neurosurgeon,
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Andres Lozano was, and
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this old neurosurgeon, Ron Tasker. So Ron Tasker was a functional neurosurgeon through the dark era. Okay, so there were some people doing oblations, thalomotomies, maybe something, blading
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something else, while this whole area was not an existence, Ron Tasker was one of them. And Andres Lozano was, had just come to Toronto about three years before, from the MNI, where he did
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epilepsy surgery and was trained by Olivia. And his plan, his sent for her LA, was to go do epilepsy surgery in Toronto. But he ran into, as often as the case, a neurologist who didn't believe
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in neurosurgery. for epilepsy and he totally slammed the door on that. And so Lozano took advantage of the opportunity he had of working with Tasker and that was perfect because Tasker is an
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iconoclast. He just doesn't like authority. He called me into his office one day. I was commuting from New York back and forth to Toronto 'cause my ex-wife was in school in New York. And one day I
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got a speeding ticket and I told him in the clinic office with him
33:43
and I said, Oh, Dr. Taskar, I got a speeding ticket. And he's like, Come with me. So he calls me into his office like shit. No, I didn't know, he's gonna get angry at me for that. He closes
33:54
the door and he says, Those effing gumshoes. So he really didn't like authority. And he was not playing well with the neurologists. And that's one difference between functional neurosurgeons and a
34:06
lot of other neurosurgeons is that we play well with neurologists and psychiatrists. 'cause what we do intimately involves them. Lozano coming from MI was a
34:16
team player with neurologist, pathologist, physiologist, psychiatrist. So he availed himself of that opportunity and that's what got him off going with paladotomy initially. So I had to choose
34:27
between these two people. I had come down to Emery to interview with Bekay. And when I got there, Bekay is, he's late. I mean, I'll spill the beans He died of cancer about eight years ago,
34:41
actually nine years ago, in
34:45
2013. But he was at Emery, and he interviewed me when I came down. And you could see he's a robust guy, brilliant man, but one of few words. And so he says to me, so why are you here? So I
35:00
said, well, I came to interview for a fellowship. You would know why I was here, what, six months? as I know, a year. Okay, and he never wrote me back after that and yet I wrote to Toronto
35:17
and Toronto my again my ex-wife. I think I would have stayed married to her, but She said, you know, I was like, I don't want to go work with Tasker. I don't even know about Lozano He's a
35:28
physiological surgeon. I do set sail work. I do molecular work. That's physiology I'm interested in physiology. It's like just send an
35:35
application All right, so I send an application and I won their Boterell Fellowship and Lozano calls me up and Now I'm an MD PhD with this plan to do research, but I don't see anybody at Albert
35:47
Einstein doing research and I figure you know I could work till five doing surgery and then I could work the rest of the day doing research and And I speak to Lozano on the phone and he tells me he
35:59
spends two weeks in the operating room and then two weeks in the lab And I was like I knew you could do it So I went up to Toronto to work with them. Now these two centers were really equivalent.
36:12
This is on the left, the paladotomy work with the long and bouquet. And on the right is Lozano's paladotomy work with Tony Lang, the, actually he's not even on, this is just a methods paper, but
36:24
he worked with Tony Lang, the neurologist, very, you know, editor of the Movement Disorder Journal, big figure in neurology. And so he, you know, began his extraordinarily prolific career
36:36
working up there. So I went up to Toronto. This shows a picture of me with Tasker, and, and immediately to my right, anybody recognize him? So that's Ali Razai, who was, who's at West Virginia,
36:50
who's a big figure in our field as well. So he was, he came the year after. I stayed for two years and I did, I was going to take a job in Toronto. So they offered me, well, Tasker was resigned,
37:01
it was having to step down because he was 65. So they recruited me to stay in Toronto and and. I was ecstatic to be able to have that opportunity and was planning on doing that. And so I had to
37:15
stay an extra year to go through the board certification up there as some of you know about. So I stayed up there and I started working on paladotomy. And these are some of the papers that I
37:28
published as my ex-wife is the second author up there. And so it was a very productive period of time and it was really a great experience But what happened, but that was an end game. So paladotomy
37:41
was on the way out. I was the last person to do paladotomies. Was I the year after did almost no paladotomies. Thalomontomies, I did, no thalomontomies. And when I went to Toronto to do
37:53
paladotomies, I had no idea about what DBS was. I remember sitting at the desk when Lozano said something about DBS and I was like, make a note, look that up I was embarrassed to tell them that I
38:06
didn't know what it was. This is what happened to DBS. And Alim Louis Benibid, the father of STN DBS, truly. And he was a biologist and a physicist. So he exemplified the collisions that it
38:26
takes to open up new areas. And in fact, he was trying to decide whether to become a physicist or not. And he went to medical school, he did his PhD with Floyd Bloom down at the Salk Institute.
38:38
And he really had that perspective of an experimental physicist colliding with neurosurgery. And in fact, although he's extraordinarily well-known in our field as a functional neurosurgeon, it
38:53
wasn't until his 1983
38:56
that he even published a paper, his first paper is 1968. So '78, it was 15 years before he even published single paper that could be reminiscent of functional neurosurgery. So he was all about
39:09
intracranial pressure monitoring, so he, too, was not really aiming for where he ended up, but he was in the right place when the puck arrived. So we think of Benabit, if I were to ask you and
39:21
you were to guess who might be the first person to do DBS for movement disorders, you'd probably, many people would say Benabit. In fact, that's not the case DBS was first done in the 1950s by Jay
39:35
Lawrence Poole, who was a surgeon in New York, who did a lot of things extremely, he had the biggest practice in New York. I'm actually descended pedigree wise from him, not only Dennis Spencer,
39:46
but also from him, because Yost Mickelson inherited his practice at Columbia, and had the biggest practice in New York and Yost Mickelson came to Albert Einstein to become the chair So I'm a second
39:59
generation descendant of Lawrence pool. And so he did this. He was the first person to put one of these electrodes in. put it
40:09
in for psychiatric disease. So he put it into a woman who had psychiatric problems. And then he did it for a patient with Parkinson's disease back in the 1950s. So tried in another case of
40:24
psychotic in 1948 and stimulated the cingulate gyri.
40:31
And also Robert Heath was another person who was infamously putting electrodes into the medial septal region in patients with psychiatric disorders. And in fact, he famously tried to cure someone of
40:45
homosexuality by exposing them to the rewarding effects of DBS in the medial septum while exposing this person to a prostitute. So he was run out of town, but not for that actually, but it's a
40:60
really interesting story. I highly recommend reading this book And there's also a movie from this. She's a neuroscientist. Danish neuroscience as Lone Frank. This is just a fantastic book. It's
41:10
gripping. I highly recommend you reading it. But Benabid was in the operating room when he was doing a thalomotomy. And although actually it was well known in the field that when you stimulate the
41:23
brain before you do the thalomotomy, that it suppresses the tremor. But he didn't know that. And so he experienced this while he was doing it And I had this video made by Stefan Shebardes, who's
41:39
his protégé. And I'm not gonna show it except to just show you a second.
41:52
But the problem of religion is either you have to get out, and I think that you have to do it, or it's easy enough to watch, and then you have what you want to
42:05
do, plus, and even one
42:07
question So, the need was, how could I, does it exist, did I find something where we should set it as well as a pressure left for a moment of sense
42:24
Oops did you have to
42:29
Oh, yes. Got it. Got it. Thanks. Thanks. All right. So I'm not going to play this whole two-hour interview, but it's fascinating. And so what he described was the experience of finding that
42:40
the tremor suppressed at, well, actually what he did was he was stimulating the patient and he said, Why do we have a stimulator that can go all the way up to a hundred and we're only stimulating
42:52
at one hertz to see the motor pathway and at 50 hertz to see the sensory pathway. Let me try to explore some of these other things. And so he started doing that just because he was open minded and
43:04
sort of bought a beginner's mind to it. And he started to explore that and he found that the tremor stopped at a hundred and he actually apologized to the patient for doing that. And the patient
43:13
said, No, that's great. And so he tried it again. She said, Can I try it again? And the patient said, Yes, please. So he tried it again and he actually found out that he could completely
43:23
suppress the tremor. Now. People had observed this for years before. So what was the difference with Benabit? The difference was that he was aware that Medtronic had a single contact electrode
43:37
that was available for pain. And he said, well, maybe we could actually try this in a patient and it had been done before. He even this patient, this reference here that's in his paper, Orlando
43:49
Andy had done thalamic stimulation for control of movement disorders. But he brought a new mind to it and a physicist mind So he completely explored this. One of my things that I like is that I
44:02
don't mind being second, I just hate being last. Sometimes being second is a great place to be because it's been proven that it can work and you can jump into the fray. In fact, that bone
44:12
morphogenetic protein paper, I was scooped on that. Okay, someone else published a paper in glia on that before I published it. I was like, okay, you published in glia, I'll publish mine in
44:21
neuron
44:23
So it's often - You know, it's not about the race. It's about doing what you do with what you have in front of you. And so he fully explored this and he published this paper. And first paper was
44:35
in 1987. Then this seminal paper on VIM stimulation was in 1996. That was the year I was in fellowship. Okay, so I was in fellowship when that puck arrived too. So my second puck was being there
44:50
when DBS hit the puck And I actually was
44:54
involved in the very first subthalamic nucleus deep brain stimulator in North America with Lozano at that time. 'Cause Benabit had started it in France and we just brought it over. So I just again
45:06
happened to be in the right place. Now what about paladotomy though? Did it completely disappear? Well, paladotomy has a long history. I know you guys probably get talks on history, but I'll
45:19
just quickly run through the history of the stereotactic frame. Victor Horsley working with Clark, again, a collision of a neurosurgeon and a physiologist and really an engineer to make this frame.
45:32
The frame was conceived by Horsley, but patented and implemented by Clark. So he could not have done this alone. He coined the term stereotaxic and he started to explore, as they said, every
45:44
cubic millimeter of the brain could be studied and recorded, but he was interested in the cerebellum
45:50
Spiegel and Wysus picked up on this frame, which was never used in a human, okay? And they developed based on the same principles, the idea of doing this in a patient. So on the left is shown
46:03
Ernst Spiegel, who was a neurologist at Temple, and on the right is shown the technician, Henry Wysus. So again, a great collaboration of a neurologist and a physiologist and a neurosurgeon. But
46:15
they were first working in psychiatric disorders So they actually did this first in a patient with mental, so-called mental disorders. they coined the term stereotactic, which is different than
46:26
stereotaxis. Stereotaxic is the arrangement in space of the brain. Stereotactic is the verb from a neurosurgeon to touch in space, okay, because that's what we do. We're not just interested in
46:39
the arrangement. We want to touch the brain. In fact, this I always make fun of my partners because I say that functional neurosurgeons are the only real neurosurgeons. Everybody else works to
46:51
avoid touching the brain if at all possible. When a spine or the nervous system, when the spine surgeon touches the nervous system, it's called an error. The cerebovascular people will even go in
47:03
through the blood vessels, anything to avoid touching neural tissue, functional neurosurgeons. Every single time I do any procedure, whether it's brain, I don't do pain, but my partner Nick
47:16
Bullis does peripheral nerve, We intentionally interact with the nervous system every single time. So we are the only true neurosurgeons. So they first used this for psychiatric surgery, but then
47:30
Irving Cooper came around. Anybody know who Irving Cooper is?
47:35
Nope, raise your hand. Okay, Irving Cooper, infamous neurosurgeon. Another great book to read is The Vital Probe. It gives you an idea of his ego. And so Irving Cooper was really intent The
47:51
same challenge as Bennibid was facing. 25 years ago, I agonized over the question of which risk is greater, the disease or the operation. So Bennibid was looking for a way to stop tremor without
48:02
hurting people, like thalomonomy does sometimes do. He was looking for a way to stop tremor and stop Parkinson's disease without hurting people. People were cutting out the motor cortex to treat
48:13
tremor. Imagine tremor before Levodopa, okay? These patients were falling all over the place So they would extra pay. the cerebral cortex, and it worked. Unfortunately, if and when motor
48:26
function came back, so did the tremor. So he was on his way to do a pyridectomy to cut the pyramid when he encountered bleeding in the anterior choroidal artery. And so he stopped, he ligated it,
48:40
and he left the operating room. Okay, serendipitous, the currents. Patient woke up without any tremor, without any rigidity He said, What the heck is going on here? So he looked at the
48:52
territory bathed by the enter choroidal and concluded that it was the globus palatus, then started to do chemo-paladectomies, put in a catheter, blow it up, put in prokene oil in some contrast,
49:06
and then he moved to cryopaladomies.
49:10
And then he came to the meeting of the double ANS, the first year it was the double ANS, That was the. RV Cushing Society, and it turned into the AAS. And so
49:26
Cooper went there with 1, 000 patients to talk about the results from paladotomy. And he presented this work, and Spiegel and Wysus were there, and Spiegel told Wysus, the neurosurgeon, to go up
49:39
there, and he was commenting on it, and he said, tell Dr. Cooper that he can't be right, because it doesn't accord with my models of the basal ganglia So Wysus got up and faithfully told Cooper
49:53
that he couldn't be right, and Cooper got up and rebutted afterwards, much like I rebutted Dr. Fried back there, and said, well, you go home and tell Dr. Spiegel it's time to remake his models.
50:06
So we tend to think about science leading what we do, but it's not really that case. It's empiricism that leads what we do, and the hypothesis is what we put on afterwards to explore.
50:20
So, you know, you need to be aware of that. And I call this actually, at some point, I will write the book entitled, why functional neurosians are always right, but for the wrong reasons.
50:33
Because invariably, we don't really know what we're talking about. It's really empiricism, and you should remember that. That's part of being on the path. Now, paladotomy was also being heralded
50:46
by Lars Lexel, who was a surgeon doing psychiatric and movement disorder surgery
50:53
in Sweden. And he, of course, invented the gamma knife. And what are they invented for?
51:01
Anybody know? Psychiatric disease, okay? So, psychiatric disease was what motivated most functional neurosurgeons back then. Of course, every functional neurosurgeon now wants to do psychiatric
51:14
disease too but psychiatric disease. and Parkinson's disease were just raging problems before the therapeutic error. And so was Parkinson's disease in the pre-Livodopa error. And so he published a
51:30
paper on paladotomy, but then what happened in the 1960s was that levodopa came around. And with that came the dark ages of functional neurosurgery. That's why, if you look at the number of papers
51:44
published on paladotomy and thalomotomy, it absolutely plummeted after the 1960s. And that's what the field was like when I encountered it when I was in medical school. That's why I say there was
51:57
no functional neurosurgery when I matched into residency in 1990. But of course, levodopa has complications and took a good 10 years for neurologists and other people and neurosurgeons to figure out
52:11
that it wasn't the panacea that they thought it was Now you have to leave adopa dependent dyskinesia. And that was as much of a problem as the movement disorder was to begin with. And so when
52:23
Lexel's student, Laytonin came back to the situation and he was taking care of these patients. The neurosurgeons were taking care of the neurological patients because neurologists as per Laytonin
52:35
student, Hari, so you'll meet in a second, said neurologists had given up on these patients. So it was Laytonin that realized that he should revisit this and that Lexel had published a paper about
52:49
moving the target to a more effective place, the posterior, posterior ventral paladim. And so, Laytonin said
52:59
about doing a paladotomy series in the post-leave-adopa era, and that's when he published this paper, which I intersected with when I was in residency. And this is what reinvented the field of
53:13
neurosurgery, functional neurosurgery
53:16
This has had a tremendous impact. And it's not just Laytonin, but Marwen Harris, who is now emeritus in Sweden, but was at Queen Square for many years. These are the number of people that learned
53:29
how to do paladotomy from Laytonin. And that included also my friend and colleague, Mayland DeLong. So Mayland DeLong approached it from a completely different angle He approached it from the
53:45
science angle. So Mayland DeLong was born in LA, grew up in LA. He attended Stanford University, Harvard Medical School. And then he went off as a fellow to the NIMH where he worked with the
53:59
famous Edward Everts who was recording from all over the nervous system. And when DeLong came to him and said, what should I work on? He said, well, everybody in the lab has already grabbed the
54:11
good stuff So why don't you work on the basal ganglion? No one else wants to deal with that. So DeLong went and sat in a dark room and started working with monkeys and recording from their Globus
54:21
Palatus and published this paper as a single author in 1970, 1971, on the activity of the Globus Palatus during movement. So he began to characterize this and he was
54:39
ultimately began to explore the subthalamic nucleus. He eventually moved to Hopkins where he continued his work on the subthalamic nucleus. And then what happened, I'll get back to this in a second,
54:50
what happened to him was that he interacted with the MPTP model. So while he was working on monkey's MPTP here in California near the Parkinson's Institute was discovered to cause acute Parkinsonism.
55:09
The long put that in the monkeys and that's what led him to discover the role of the subthalamic nucleus in Parkinson's disease. Heretofore, a complete backwater, little tiny nucleus. If you look
55:19
at the old drawings, I'll show one in a second. It does hardly even shows up on the map. So the long moved from Hopkins to Emory in 1990. And there he interacted with Roy Bekay. So Roy Bekay went
55:37
to Beloit University. Roy was a football player. He actually played both offense and defense and was captain of the team and was valedictorian at Beloit. So this is a man of substantial talents.
55:53
He went to Northwestern and then he went to University of Washington, where he worked with a
56:00
ward up there and you know, Itzak came from the same tradition. And so he learned physiological surgery, mainly around epilepsy. tremendous epilepsy center. They were doing non-human primate
56:15
models of epilepsy, one of the only centers doing that work. And so Bekay learned how to do monkey work and monkey work in epilepsy. He was an NIH fellow there for a time, and then Bekay went to
56:29
Emory in 1982, where he was there to catch the male in the long puck. Okay, so he didn't recruit him. He was just there. He was doing some thalomotomies, but he wasn't doing palagogies, wasn't
56:42
operating on Parkinson's disease when the long came to be professor and chair of neurology in actually 1990. So collision of another two people and coincidence, serendipity. So that's what led them
56:58
to publish their first paper on, which is really just a letter to the editor on paladotomy, saying we are extremely encouraged by Dr. Layton and colleagues. We are beginning our own program using
57:08
micro-electured recordings. for physiological guidance. So no one else was using microelectric recording, but DeLong was because that's what he would do in monkeys. So he all but invented, I mean,
57:20
he did invent the area of single unit recording for this. And so what happened to that was it disappeared. Now, why did paladotomy disappear? DeLong, BK, we're doing fantastic job. Lozano,
57:34
Lang, we're doing fantastic work. And it ran into the same buzzsaw as thalomotomy ran into, and that was DBS. So having ablated the paladum, they say it was an easy step to say, well thalomodum,
57:49
thalamic stimulation works for thalomotomy. Instead of thalomotomy, maybe palatal stimulation will work instead of paladotomy. And so Jean Siegfried did this in Zurich and indeed it worked very
58:01
well. And then
58:05
Benabid jumped into the fray again So having done.
58:10
the lamex stimulation, which was as good as thalomotomy. And with Delong having outlined the role of the sum of the laminucleus, which you can't even find on this diagram. Okay, so Delong, put
58:22
this on the map. And this is the map that you're all familiar with, right? You learn that, you have to regurgitate it for your boards. And it puts STN right in the middle over here as the foot on
58:33
the pedal of the STN and of the GPI And he also described these parallel segregated circuits that go through and that there's all these circuits involve the brain, the cortex, frontal lobe, the
58:48
striatum, the paladum, the thalamus, back to the cortex. So Delong is responsible for all of this work. And he was, as I said, right in the right place at the right time to then take the
59:01
recordings that he was doing in normal monkeys and implement that in MPTP monkeys and he discovered the role of the STN. And he found that if he actually leezed in the STN, that it would cure
59:13
experimental Parkinson's disease in these monkeys. So if the pallidum is the break, the STN is the foot pushing the break. So he defined this work in this groundbreaking paper in 1990 about how to
59:26
treat experimental Parkinson's disease. Now enter a benefit. So why not just do subthalamic subthalamonomies or subthalamic nucleotomies? And
59:37
the answer is that everyone was scared to death of doing, of injuring the subthalamic nucleus because it was very well known to cause hemibals. I was sitting next to a famous person when I was in
59:49
Toronto, Claude Bertrand, who was doing subthalamonomies, which is actually ablating the area below the thalamus and behind the subthalamic nucleus, which is very effective. And I said, Dr.
59:60
Bertrand, if you were a little bit less good, you might have found the role of the subthalamic nucleus yourself. we were scared to death of the subthalamic nucleus. So they avoided it, but
1:00:13
Benabid said, okay, well, if thalamic stimulation works instead of thalomotomy and more safely, maybe STN stimulation will work instead of STN lesion. And so he did that, and that is truly
1:00:25
groundbreaking. And he published this first paper in 1993 about stimulating the subthalamic nucleus. As he has said, both about this and about other things And so why did paladotomy go away? The
1:00:39
best fate of a good therapy is to be replaced by a better therapy. And so that's what we saw in subthalamic DBS. He published three patients, then he published a handful of patients, then his
1:00:50
five-year follow-up in 2003, and the rest is history. As Lozano says, and this is, again, why functional neurosurgers are always right, but for the wrong reason. Why was it actually working?
1:01:02
Well, then you have to go back into the animal model to figure it out And so as Laundry's Lozano has said,
1:01:08
And Osif probably recognizes this. First you show it works in patients, then you do it in an animal model. So, and that's where we are today. And in that clip that I was showing you a benefit,
1:01:18
what he says at the end is that here we are in 2018, okay? You know, 1993, 18
1:01:25
years later, how long? And we still don't know how sub-talamine nucleus DBS works. And that is true of almost everything we do. And so we saw the second fall of paladotomy, the first one from
1:01:39
Levodopa and the second one from STN stimulation, the publications came up and then they crashed back down again. So no one's doing paladotomies. All
1:01:49
right, in my last few minutes, I have to bring you back to spirals, spiral staircases. 'Cause I promised we were gonna talk about spiral staircases. So this is a spiral staircase. And all of
1:01:60
what I'm telling you is about how science comes and goes and comes and goes And that's what I have seen. in my short 25-year career is things coming and going. And of course, we like, and humans
1:02:15
are fascinated with spirals. So for example, the Egyptian God of life has a ram's horn on that. And of course, that then thence is named Ammonite and of course, our favorite structure, the Cornu
1:02:28
Ammonus. Okay, so spirals are at the heart of what we do and how we exist. And it's probably more than metaphorical So what we're seeing with paladotomy then is it went, it came, it went, it
1:02:42
came back again, it left again, and wouldn't you know it, it's coming back again, okay? Because now we have focused ultrasound,
1:02:52
a new way to do paladonomies. We talked in the first session about how it doesn't matter how you do it, a thermal ablation is a thermal ablation. So we're doing paladonomies now with focused
1:03:00
ultrasound. You guys have it, right? And I'm
1:03:05
doing my first case the day after tomorrow. So after six years of working on it at Emory, we finally have it implemented and ready to go. So is this the secondary resurrection? Are we resurrecting
1:03:18
thalomonomies? Of course, you know the all the data that goes around focused ultrasound thalomonomy, but we do need to remember that there's nothing fundamentally different about thalomonomies made
1:03:30
with focused ultrasound. It's not magical. It's destroying a brain region compared to RF thalomonomies or prokane oil thalomonomies. And as we go to do bigger lesions, patients are going to get
1:03:41
more sick. They'll be better, but they'll be more sick and you'll have the same problem benefit talk about, how do I get rid of the tremor without hurting people? And same with paladotomy. And as
1:03:51
we get into bilateral thalomonomies, bilateral paladotomies, it's just something we need to be very aware of. So that's coming around. Now, what about cell transplantation? Okay, so I started
1:04:03
my journey you know, in 1990 to do cell transplantation. In fact, Roy Bekay was very involved in this area and that was one of the appeals of my going to Emory in the beginning was to do cell
1:04:17
transplantation with him. I really wanted to do that. He published this paper. He was the first person again to use MPTP and then use fetal cells in an MPTP model. And in fact, my chairman, Dan
1:04:30
Barrow, was a student, was a resident and worked with BK in the lab and published a couple of papers on transplantation.
1:04:39
BK was involved in putting to death the idea that adrenal medullary grafts actually are effective. They're not and safe. They're not. And so he ended the use of adrenal medullary grafts. But he
1:04:54
also, although this was my original plan to do fetal transplantation,
1:05:01
He also participated in opining about the end of fetal cell transplantation, right? Because I'm starting my residency in 2000. I come out, I want to do that when I'm done still in 1996 and in 2001,
1:05:16
2003, two papers published that ostensibly show that fetal cell transplantation does not work. Now, again, I caution you that is this a trial of the trial or of the therapy? Because both of these
1:05:30
trials are fundamentally flawed They did not understand how the technology worked. They did not know how or went to administer immunosuppression. They did not know what cells to use and how to put
1:05:41
them in, but they both set the field back by 20 years. And so Bekay wrote, Is transplantation to treat Parkinson's disease dead? So I was somewhat disappointed as I came out in my career. And I
1:05:54
had to decide what to do when I was finishing up in Toronto. And as I said, they were off, they were recruiting me there They offered me a job. Just to shore up my position in negotiating, I
1:06:06
happened to send an application now this time to University of Utah. And they came back, they called me and they said,
1:06:14
We don't talk to you about this job. I said, You know what, I've got a contract in my bag. It's just not signed yet. And so, Ron Applebaum said, You don't want to even listen? I said, Well,
1:06:25
can't hurt to listen. So I listened. I ended up going out there and visiting them and it's beautiful. You get the snow cap mountains I mean, it was incredible. I mean, I could go back to skiing.
1:06:36
I knew how to ski, you know? And, you know, maybe I can enjoy this beautiful outdoors. And so I went again out to dinner to decide about this thing with this X-Y for again.
1:06:50
And so we made the pros and cons list. So we made the list of pros for staying in Toronto, this long, cons, this long, pros for going to Utah, long cons. this long. And we said, okay, well,
1:07:05
that's not a decision we even need to talk about. It's made. It's just not done. Okay, we'll go to Toronto. Driving back the next day, in the car, it's two hours back to Toronto, she says to
1:07:15
me,
1:07:17
why are you being so quiet? And I don't know, some of you minimalist people, because you'll probably all get accused of this too. So I said, I'm not being quiet. So half an hour later goes by,
1:07:29
not a word is exchanged. She says, why are you being so quiet? I'm not being quiet, damn it. And then I said, let's go to Utah. So that's how I made this decision to go to Utah. Got feelings,
1:07:42
okay? My brain, my left hemisphere, design and good described the, you know, the person in charge in your left hemisphere, decided Toronto was the best thing. Somewhere in that right hemisphere,
1:07:56
it analyzed the data, did a little bit of artificial, or really maybe some real intelligence on it, and predicted that that was the best. place for me to go. And so off I went to Utah. And one
1:08:06
of the reasons I went there was to work with these four people, because I was doing stem cell research. And I believed in stem cell plant transplantation. And so Mark Noble, who reviewed my paper
1:08:17
on neuron and said, no changes needed, as he told me, Chris Prussell, Margot Mayer Prussell, Amanda Rouse. So I matriculated into into that lab. I started doing work. I won the one of the
1:08:29
first Michael Defox Awards to do axonal guidance with transplantation. So how to make the axons get to where you want them to go. And then a couple of funny things happen. I was there for three
1:08:42
years. And these guys, all four of them left. Okay, three years, all four gone. They had a Meg. Everybody but one person worked on the Meg gone. Okay, psychologist, I was working with the
1:08:57
neurologist that was working and moving to sort of gone. The neurologist I was working on epilepsy gone in three years. 19 people left before I became the 20th. So that's what was going on. I was
1:09:10
like, okay, well, this didn't work out, but I will tell you that I never once regretted making the decision to go there because I made it, not because I failed to take into account one factor or
1:09:19
another. We'll rate them appropriately. I made that with my brain computer. I made that with my gut, okay? And so I never regretted going there and then a very funny thing happened Roy Bekay
1:09:32
decided to leave Emory and go back to his native Chicago to work with his good buddy,
1:09:40
Jeff Cordover, and
1:09:42
he grew up there. And so he decided to go back to Chicago. And so Dan Barrow called me on the phone and said, we'd like you to come down. And I went down there, I negotiated. I learned how to
1:09:56
negotiate, by the way, the first package I negotiated in Utah, I mean, embarrassed to even tell you what was in it. The second package was a package that something that you need to negotiate for.
1:10:08
And although he had me at hello because I was planning, I loved Emery for already decades by then. And so I went down to Emery. I probably would have ended there if I went to Toronto. It didn't
1:10:20
matter where I chose, I was going to end there. So you can't fight the inevitable. I went to Emery, all loads lead there. And Roy Bekay, who was a robust figure, was very big shoes to fill,
1:10:33
and I worked hard to do that. I went there to work with legendary colleagues like Melon DeLong, and I continued my lab work on axon-guided molecules and regeneration. And I finally got the chance
1:10:46
to do actual clinical transplantation, because wouldn't you know it, Roy Bekay had been working with a company, ultimately bought by Bear Healthcare, doing spheramine implantation of collagen
1:10:58
carrier beads, carrying retinal pigment epithelial cells, And so I walked right into that project and I ended up having the opportunity to publish this randomized clinical trial. On this, it
1:11:11
didn't work one lick, okay? No difference at four years between that and sham surgery. But with the money I made from doing that surgery, okay, the amount of money it paid per surgery, I was
1:11:27
able to support my lab for over five years So as stupid and naive as that idea that I had in 1980, that I didn't check with anybody, was it actually turned about to be exactly what happened, okay?
1:11:45
So in your mentorship decisions, you have to be aware of both the value of mentorship but don't let it take away your big hairy audacious goal, okay? your dream. As stupid as someone might say it
1:12:01
is. If it seems good to you and you develop a track record for being able to predict what's good and what's not good, then you need to stick with it because you will only be upset when someone else
1:12:12
does it and you didn't do it, like Angela Viscovey and that glioma trial, for example. So it was not such a crazy idea after all. This is some of the work we published over the years on the role
1:12:25
of axon guidance molecules. I don't think that idea was an idea, it's right time, but it's probably a good idea later, it's just not ready for prime time. But, fetal cell transplantation, or at
1:12:37
least transplantation of dopamine neurons, is on that spiral staircase, okay? It's gone dead for 20 years and it's back. I'm working with two companies right now to do different types of embryonic
1:12:50
stem cell, IPS-derived dopaminergic neurons for Parkinson's disease. So that idea of doing fetal cell transplantation, which started my career. is actually at the end of the career. And finally,
1:13:04
spiral number three, I started out in psychiatric disorders, right? That's what I wanted to do is become a biological psychiatrist. I got off that train many, many years ago. I was at Emory,
1:13:16
came to Emory in 2001 in 2003. Helen Mayberg, who went to Toronto right as I was leaving in 1998, decided to move to Emory in 2003 So another puck slammed right into, was able to start doing the
1:13:34
depression surgery with her. You could see these types of results.
1:13:46
I mean, they're just spectacular. You could just see the different look on this woman's face as she gets treated. We published a number of papers together. This is not dead. The clinical trials
1:13:53
brought in for subgenual singulate Show that it didn't work or is a failed clinical trial. ventral, capsule, ventral stimulation failed clinical trial. Are these trials of the therapy or of the
1:14:06
clinical trial? They were trials that failed. They don't mean the therapy doesn't work, and hopefully this will be coming around again. We are in very close discussions to launch that. So finally,
1:14:19
one of my goals after all of this serendipity is frankly to look this gift horse in the mouth and say how can we make sure that this stuff happens on purpose, not just waiting for one person to slam
1:14:31
it to another person, not waiting for these chance encounters. And so we started an organization, a center at Emory called Entice Emory Neuromodulation Technology and Innovation Center with Georgia
1:14:43
Tech, specifically to collide people together, like the CERN Large Hadron Collider, you slam protons together and you look and see what happens. Protons are slamming together randomly in the
1:14:55
universe all the time. This doesn't happen very often and no one is there. to capitalize on the results. So you slam these things together, collisions, which we've talked about the whole time,
1:15:06
and you look at the results and you cultivate the results. You know, you don't wait for so-and-so to see so-and-so a year later and say, Hey, didn't you guys talk about something a year ago? Oh
1:15:15
yeah, yeah, we need to get together. Okay, you have an idea, we're gonna cultivate it. And so we collide, we build together, clinician scientists, engineers, come up with concepts and we
1:15:25
cultivate them We have working forums, working groups, retreats, and we recruited some great people purposefully. So, Helen Mayberg and Melon DeLong and I all ended up at Emory for different
1:15:38
reasons. We didn't come to work with each other, but we found ourselves there. So we said, What can we do if we recruit peopleon purpose to come there? So for example, we recruited Chase and
1:15:47
Penderina from Stanford to work on brain machine interface, brought them together with Nick, our young, okay? probably never would have run into each other. I slammed them together and Emery said,
1:15:59
You're an engineer, you're an engineer, you guys work on this. We are doing our first brain gate implant over the summer, okay? So it took 20 years for that to happen, but it eventually happened
1:16:11
by purposefully doing that. We've submitted grant proposals just already three years ago in the order of12 million. We bought in7 million of grant proposals by purposefully working with people to
1:16:24
harvest those things. And now we formed what we call the brain restoration center to do that in a bigger way to not only work on idea generation, but is so much more than getting ideas to the market.
1:16:36
If you don't have a commercializable therapy, so why did fetal cells die? Was it because fetal cells don't work? They actually work, but you can't make any money doing that. But you can make
1:16:47
money if you take an embryonic stem cell, make the same dopamine neuron, but put a proprietary gene that has nothing to do with it in there, then you can patent it and it's yours and you can make
1:16:57
money. So you need to have a commercializable plan in order to make something work, but it takes all of these steps to get through the Valley of Death to the other side. So that's what we plan to
1:17:09
do in the center to scope out all of those things. So there's all these different ways in which DBS works now and that we apply it to. CMDBS,
1:17:21
deep depression, connectivity-based partialation, all involving technology, Alzheimer's disease even,
1:17:31
optogenetics, probably gonna come in some way, shape, manner, or form. I'm working with a company on chemogenetics for epilepsy, post-traumatic stress disorder, which Dr. Langevin is very
1:17:42
interested in. So all of these things are things that we can do as we slam all of the technology and all of these people together and work very hard at it. So I talked about maxims I think, at the
1:17:55
end of the day - You know, hopefully you learned something from my experience. That's why I share that with you so that you don't have to learn all these lessons on the way. So take out of it what
1:18:06
you can, what you will. I'm sure you'll remember at least one thing from it. I'm not sure what it is. That's probably all you'll remember. But that's why we do this to help you guys to develop
1:18:16
good judgment from our experience. Thank you for listening to me.
1:18:34
Is that amazing talk? So speaking of skating to where the puck is going to be,
1:18:41
probably the elephant in the room, and I think this is where functional neurosurgery probably has huge implications for humanity, is ultimately we're going to be going beyond disease in treating
1:18:52
enhancement of function. You know, already Lozano gets requested to do implants on rich people to enhance memory Three of your thoughts on that, because that's coming down the pipeline pretty soon.
1:19:04
So, against the background of that, it's very difficult to make predictions, especially about the future, I was recently participating in a session called The Future of Neuro Devices. It was by
1:19:20
this thing called The Neuroscience School of Advanced Studies in Switzerland. It was very nice, a treat
1:19:27
And the very first night of this thing, there are about 15 of us there. People from industry, from science, from clinicians. And we talked about the landscape of neuro devices. And I'm
1:19:39
extraordinarily, who thinks I'm gonna say optimistic? Pessimistic about the landscape for neuro devices. And here's why. The market is too small to support the development. Take, for example,
1:19:54
functional electrical neuromodulation, which is a way to stimulate the arm basically in cases where upper arm function is damaged, pioneered by the Case Western Reserve. They spun out a company.
1:20:08
They successfully showed that it works in clinical trials. But the problem was that it doesn't work. If you've got C2, C3, C4 injury, you've got bigger problems than that. Okay, if you've got
1:20:20
C7, C8, it doesn't matter. Okay, it only works for C5, C6, C6, C7. So one small part of the skeletal axis They didn't have a market. No market, no margin, no mission, no market, no margin.
1:20:37
If you look at the
1:20:40
incidents of disease, you will see that the only things that might potentially have a big enough market if you're aiming for a single market with a device is Alzheimer's disease and hence Lozano,
1:20:53
but I will just say that is just not the right approach. We are not treating a global disorder with a focal stimulation and psychiatric disease. Depression, big market, Abbott will raise money for
1:21:07
a clinical trial by saying how big the market is. At the same time as they approach the FDA for orphan device status because so few patients will actually go for it, we have to screen 100 patients
1:21:20
to get one that's appropriate for that. So even for depression, the market is too small. The manufacturers of DBS, so that's one device that could be used for everything ostensibly. And they know
1:21:31
they have said, they will acknowledge that there's not room enough for three players in the market, okay? It's not big enough. So where does that leave us with developing new technologies? One,
1:21:44
it leaves us with decreasing the cost, okay? I lost another debate. I'm great at losing debates. With a psychiatrist from UCLA, I don't remember who it is, but you probably know who it is, who
1:21:57
does VNS for depression And I was assigned the topic of invasive neuromodulation is more effective, and he was assigned non-invasive. And I went first and I established beyond a shadow of a doubt,
1:22:10
just like larger sections in epilepsy are better. I established beyond a shadow of a doubt that invasive neuromodulation is more effective. And he got up and he said, Thank you. You just took the
1:22:19
first part of my talk. You're right, it is more effective. But here's the problem. You look at the number of patients with this disease that you wanna treat, and you look at the cost of your
1:22:29
device. times that number of patients and neurosurgery, which doesn't even show up on the Medicare budget, will take over the Medicare budget. TMS is neuromodulation for the masses. It's much
1:22:43
less effective, but it's much cheaper. And even that is too hard to implement over a large group of people. So you've got to figure out a way to find that breakpoint in a market-based economy where
1:22:56
devices or whatever you're doing, development hits a price point that's reasonable. One of the device developers or therapy developers said to me, well, we think this is gonna sell for a million
1:23:08
dollars of therapy. I said, then I'm out, you know, I'm out, let's forget it. Why would you even spend your time doing that? But to answer your question directly, what's the biggest market? I
1:23:19
am gonna go out on a limb now, okay? The biggest market is going to be wealthy people that will do anything to get a leg up on the person next to them. So I am involved with a company near
1:23:32
therapeutics. I have stock options. I'm helping them develop their therapy and develop the clinical trial for brain stimulation for memory. And we are treating traumatic brain injury, okay? Maybe
1:23:44
we'll go to Alzheimer's disease, but we're not gonna offer that to the, you know, that's not what we're doing. But what it does is it takes your memory function. Everybody's got a range of memory
1:23:54
function, okay? One day they're here and one day they're here. Maybe its ox memory is up here and goes back and forth from up there and maybe mine goes back and forth down over here. But everybody
1:24:05
can be made better on their bandwidth by stimulating them appropriately and improving their function when they're in a bad encoding state. That's the idea behind this neotherapeutics and Michael
1:24:15
Kahan and the whole DARPA program. That's true of people down here that might have TBI and it's also true of people up here. So the question is then, you know, okay, if it's going to work and
1:24:28
there are people that want it. who's gonna put it in? I'll say right now, there is definitely a neurosurgeon here in the United States. I don't know this, I don't know who it is, but I would
1:24:38
give this 9999 chance. There's already a neurosurgeon on Elon Musk's payroll, okay? Phil Kennedy, okay, if you look at that movie,
1:24:49
what's it called? I don't know, there's a movie on Netflix right now. I'm gonna watch it on the way home. Phil Kennedy, when I came to Emory 22 years ago, I intended to work with Phil Phil had
1:24:59
done brain
1:25:02
machine interface with Roy Bekay. He published the first paper on patients operating computer cursors with his neurotrophic electrode. Phil Kennedy was an engineer and eventually became a
1:25:11
neurologist. I couldn't, Roy did that protocol. Three patients were implanted. He left, I couldn't get it through the IRB again. Phil went on, he went to start working at a local community
1:25:21
hospital, but he couldn't get the IRB to approve it or anybody to do it So Phil, who was interested in making - a brain machine interface for language dysfunction in the Broca's region went down to
1:25:35
Belize and found a surgeon who was willing to implant the electrode in Phil Kennedy. So Phil got a brain machine interface in his Broca's area, subsequent abscess down the line. He was a phasic for
1:25:50
a while. Now he's pretty much back to normal. Although you can hear it, he presented at AANS a couple of years ago And so yeah, you'll find a neurosurgeon to do it. In fact, you'll find many
1:26:01
neurosurgeons. And I'll tell you where they'll do it too. I was at Benabids Clinitech out in Grenoble. So this is a private public partnership. They have built what you can just imagine as the
1:26:13
James Bond facility, 007 facility for medical devices. I don't think it's 20 stories underground, but you need a fingerprints and retina scans to get into it.
1:26:25
room that just for clinic visits is three times, four times bigger than this room with one, two, three, four, five. They're like 30 different bays for just intakes of clinic. Who's going there?
1:26:35
No one's going there. They have a high field strength magnet. They have a mag. They have a clean room. They have facility. They could do everything there. So all you need to do is do that in a
1:26:47
country that doesn't have regulations. And you will get all the billionaires you read about in Yuval Noor Harari, Homo Deus, all the billionaires of which they're like a million now, you know,
1:26:58
going down to get their memory device. So I think actually that's the answer. Okay. So that's the market for this. And that will then drive those companies to then, as almost pro bono, use their
1:27:15
devices on pathologies. And that will be there above the board thing. I think we as a the society, we'll get to the point where we accept this. just like we accept plastic surgery, which
1:27:27
originally was a wartime specialty. Reece Cosgrove at our WSSFN meeting four years ago when talking about the neuroethics of this with Lone Frank, the person who wrote that book, The Pleasure Shock.
1:27:40
And Reece said, in answer to this question, we have a line in the sand that we won't cross. And I stood up and said, Reece, it's a line in the sand. All you have to do is cover it up and make
1:27:51
another line Okay, that's where we're going to go, I will predict. And that's how treatment of patients will be funded by companies that make their money on market-based devices.
1:28:07
Dr. Gross, this is Jeff Colby, program director. I apologize for not being there in person, but I just want to thank you for a fantastic lecture, incredibly thought provoking for all of us,
1:28:19
everybody from medical students to faculty about building a path and looking towards the future. Just really enjoyed the lecture. Thank you so much
1:28:34
All right, sorry, MC.
1:28:40
I was glad you brought up the depression trials you were doing with Dr. Mayberg
1:28:46
report. I was always very disappointed in how this got labeled, kind of like you said, this failed. But over the last couple of years, we've seen a shift. I know last year Dr. Chang put out a
1:28:55
paper, but wow, he's doing it. And we're just doing some interesting work up in Minnesota, seems to be more and more network-based. And I'm
1:29:02
just curious as to your thoughts on approach for that moving forward and maybe what you're thinking Yeah, so the idea of the Mearsheth and not our Peridian, of course, probing the network with
1:29:16
stereo-E-G electrodes, depth electrodes. And yeah, it's a network. Helen Mayberg shows the network. She's always shown the network. She found nodes in the network. And that's how she picked out
1:29:27
the sub-genual singulate region. Again, why functional neurosurgeons are always right, put that in there because of pet hypometabolism in gray matter, because that's where pet hypometabolism is,
1:29:40
to try to shut it down. But really what we're doing, as we found subsequently, stimulating the white matter. We're stimulating the nexus of three or four white matter pathways. So it works. Now,
1:29:53
I think exploring the network is a great scientific question that can be posed by its stereo EEG, as well as other techniques, like functional imaging, by mag, by various different approaches. As
1:30:07
for doing that to look for nodes to stimulate, you do that with all due respect when you think you don't have a therapy that works, and you're looking for a therapy that works. So to motivate that,
1:30:21
you put in your introduction that sub-genual singularity stimulation unfortunately doesn't work, and neither does ventral cordal eventual striatal stimulation That's what motivates, that's the
1:30:31
premise.
1:30:34
necessarily a correct premise. We've got 37 patients we've operated on. And when they learn the outcome of the Borden trial that it doesn't work, they laugh. And they laugh because A, it's funny,
1:30:49
and B, they can laugh. And that's not a joke. It's actually true. So this is sustained and beneficial. And my hypothesis and Helen's hypothesis and Abbott's hypothesis is that we failed to show
1:31:04
that it works in the clinical trial. Okay, the clinical trial was a failure. Now, maybe it turns out that the emperor has no clothes and that we're diluting ourselves. But we don't know that yet.
1:31:17
We have to do the trial and do it again and do it in the right way. And the right way to test how it works in depression and the way we did it is not One of the other soap boxes I get on is, because
1:31:31
I get on a couple, is. that we're testing neuro devices using models that are built for pharmacology. And they're the double-blind trial. And that's not necessarily the best way to test this. So
1:31:46
the example I use is, let's say you had fine wine from Northern California. Do you have any fine wine down here? Okay. And do you guys think you make fine wine in LA as well? Anybody? No, okay.
1:32:01
Then I'll use Georgia You know, some people in Georgia think they make good wine. So let's say I wanted to show that Georgia wine was as good as French, you know, Chateau Margot,
1:32:14
you know, 1979, okay. Well, so I designed an experiment and we're going to do a double-blind experiment. We're going to, you know, easy, taste tests, blinded, okay. So what, when are you
1:32:27
going to do your outcome metric?
1:32:30
would be the best time to do the outcome metric.
1:32:35
Okay, if you do that immediately, let's say you do it in one year, I'll give you a year. I'll give you six months to a year, and you set your outcome much or get six months to a year. Which wine
1:32:43
do you think will be better? Chateau Margot of the type that would be 1979 that you're still drinking in 22 and 22, or Chateau Elon, which is up the street for me in Georgia, at one year. I
1:32:58
guarantee you that you would spit out the Margot in an instant It's filled with tannins, it's chalky, it's disgusting. Okay, there's no question that in that time point, Chateau Elon wins. So
1:33:11
you have to choose the time point that's appropriate for the experiment. The only timeline to demonstrate that Chateau Margot is better than Chateau Elon is at 10 years or 20 years. Okay, but who's
1:33:24
going to do a trial for 10 or 20 years? So you pick a surrogate time point that is one that you can feasibly do Okay, you say, and I like, for example. with the neuro pace trial, they had as
1:33:36
much trouble getting through the FDA. I mean, I've described earlier the panel, you don't know what it took to get that panel with the FDA because the panel, the FDA actually didn't give a neuro
1:33:46
pace a panel, which they should have because it was a new therapy. They said, well, it's the same as DBS. It's not. So they didn't give a panel and they declined that they rejected it. They
1:33:56
said neuro paces rejected. So neuro paces had to appeal that decision I was involved in that
1:34:05
and, you know, it took a lot of effort. And while we were sitting there, I turned in the, in preparing for the appeal, I turned around to Marty Morrell, the CMO. And I said, Marty, if you
1:34:14
had chosen your outcome point at six months, instead of three months, we wouldn't be sitting here. And she said, we couldn't afford to do six months. We calculated how much money it would take to
1:34:25
run the trial for a six month outcome metric and we didn't have enough money. So we had to do three months.
1:34:31
External considerations to the experiment, that is the right way to do the experiment, 'cause they needed six months, just like Satomago needs 20 years. External considerations led them to do that.
1:34:43
And I call this, Nature doesn't give a shit. Okay, you don't get a, you don't get a, oh, okay, we'll give you a free pass because we understand it's not gonna make money or that your patent is
1:34:53
going to expire if you do the dose response curve, like swearming should have done. No dose response curve, let's just go with this dose We'll live or die by that. Well, you died by it, okay?
1:35:03
So all these external considerations factoring to doing what is an experiment and nature doesn't give a shit and it never gives you a break. So that's really what probably happened with Baudin. It
1:35:16
was not done, it was done in a multi-center trial with groups that didn't know how to do it, they didn't know how to target it. The outcome measure, we've already, it's been shown that the
1:35:25
outcome measure of six months is too short. They did an optimization trial in Belgium or Netherlands, I always forget, which one. I'll be in other ones. Sorry, anybody should build them in other
1:35:34
ones.
1:35:36
And they were going to do an acute discontinuation. So get it to the right place and then acutely randomly discontinue, but at six months they hadn't optimized yet. They had to take it out to a
1:35:47
year. So we know it takes a year to optimize. We've shown that in our own results. So anyway, that whole network idea is founded on a premise, which I would submit is not necessarily true What we
1:36:01
need to do is show that what we think we know the most about and think we know works definitively works or not before looking for other targets, which will suffer the same problem that we had in
1:36:13
broaden if we do it in that same way.
1:36:24
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1:36:40
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