00:00And he said, look, you know more about depression than anybody on the planet, which was generous. He goes, there's a logic to what you want to do. I know I can do it safely. So something to do is to put yourself in the position of if this is somebody that you personally cared about, knowing what you know, knowing what I can do, knowing that if it doesn't go according to plan, we turn it off and take it out. And he felt confident about that. Would you do it? And the answer was yes. And that's what I remember. That was a moment that I really realized you can have an idea, but that surgeons are amazing people because they go that extra step. Welcome to Stimulating Brains. Hello and welcome back to Stimulating Brains. 01:11Today I will talk with Helen Myberg, who does not need an introduction in this field, but is the director of the Center for Advanced Circuit Therapeutics at Mount Sinai. Of course, we will talk about her landmark paper together with Andres Lozano in 2005. And we will also talk about the brain simulation. But we'll also cover different topics that go into the past, a bit similar as in the last episode, but also into the many inventions that Myberg Lab has put into our field over the last decade. I mean, I've told you I'd love to talk also a bit about the past, your past or your education and, you know, who stuck out? What were the experiences? Who were the mentors that stuck out? 02:02Okay. So, you know, it's interesting trying to kind of put a reverse lens on your life and look to see some kind of consistent roadway or some kind of pattern so that you can say I kind of knew where I was going as opposed to a very ill-formed idea that really was not an idea. I had a relationship. I grew up in a family where my father was a practicing physician. But my mother's brother was an academic nuclear medicine physician. So he was a scientist practitioner. And he was really an extraordinary scientist, but actually switched to medicine. And I watched his kind of tension between being, really being a scientist and that's where he wanted to be. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. 03:00Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. Right. I was in college. I would go down and he was doing things with the neurosurgeon. And so I had exposures that I didn't even know were relevant, but were quite impactful. So from an influential point of view, we did an experiment in my junior year of college where we did the original Oaks and Milner hypothalamic intracranial cell skin and condition rat, the bar class, for reward. And I can't say that that grabbed me, but that was certainly an eventful experiment of four years at the university. And a similar class, I wrote a paper on the bottom. 04:03And again, why? Because something about the idea that damage the brain and fix it, was such an oxymoron. In medical school, it became very clear I liked behavior. I thought I liked psychiatry because of the problems. And then realized I totally hated the language. And as I tried to figure out, well, how can I study this another way? I just thought, that's not how it works. Here's a decision tree. And it was like, okay, there's a jump here. Behavioral neurology is kind of a compromise. And I did a rotation from Los Angeles, went to Boston, and had a month with mommy and dad. And because I had read his work, then I knew that that was at least taking a descriptive but organized approach to complex behavior. 05:03And again, this was really at the very early days of clinical imaging. So when I got to Hopkins, it was to learn the methodology of PET scanning. So I was postdoc, but I was in nuclear medicine. So I left neurology to essentially train again as a clinician scientist and did a total one of a PhD thesis on opiate receptor imaging. So I again had a mentor in nuclear medicine, mostly doing epilepsy. But on the side, work I'd read by Bob Robinson. And I was in stroke depression. And Sergio Starkstein were on another floor. So again, piecing together my psychiatry interests, but they had no access to the scanners. I was doing epilepsy and doing receptor mapping and was in the radiology department and was 06:02able to do both. And it was, again, a very influential and uncomfortable conversation. Yeah. And I remember my neurology mentor from medical school, Leslie Weiner at USC in Los Angeles, went to visit him and he asked what I was doing and said, I told him and he goes, no, you know, what are you studying? And he was the one who painfully reminded me that, look, I wasn't a receptor pharmacologist and I wasn't an opiate physiologist and I wasn't a nuclear chemist or a physicist. And so I kept getting kind of. Slammed or at least how it felt. He said, you're a neurologist. What do you want to know about what do you want to study? Is it epilepsy? Is it depression? You're doing so many things. What do you want to know about and do that? And you'll do it with one method. And then you'll get a question and that method won't work and you'll adopt another method. 07:01So pick the topic because that's what you do. Don't pick the method. And that was probably. And that was probably among everything that anybody ever said to me, the most valuable piece of advice. Yeah. So start with the topic, not with the method is, I think, great advice. I must say, ask a research question or ask a research topic. And yeah, that makes a lot of sense. I could guess now that this and other experiences, but also a lot of the literature and experiments you did in the imaging world at some point led to the milestone that surely was culminated in the 2005 neuron paper where you did the first modern day deep brain or the first deep brain stimulation in depression patients. And I remember vividly a keynote you gave at OHBM in 2013 in Seattle. You said something like, what do you do? If you stick an electrode into a person's brain, you hope all goes well. 08:02Maybe you can share with us a bit these very initial excitements, but also, you know, tensions that were there. How did it feel like? How were the first experiences back then? Oh, again, you know, opportunity and timing and enough knowledge to either be dangerous or feel justified. And I was very fortunate. I was very fortunate to actually be in Toronto. And at the time that it just kind of seemed there was a question to ask and there was a technology to use. And there was a neurosurgeon who liked to and could do novelties. And again, if we had not spent the previous five, six years working on the interaction between this area 25 subclosal cingulate. And it's kind of apparent hijacking of the cortex. 09:05And we're conceptualizing that these systems were yoked. And this, again, was pre-default mode. This was pre-FMRI, even though these concepts were actually running in parallel and obviously have beautifully converged and been mutually informative. But that at the point where. If you need to drug or drive down this area because it seemed in all the experiments to be associated with a necessary effect for depression patients to recover, regardless of the treatment. Everything that was known about DDS and Parkinson's at the time was that all you did was block where you were stimulating. So, again, naive, wrong, partly wrong. True enough to justify. I experiment. If, in fact, we had known how it really worked, I probably wouldn't have felt comfortable to do it. 10:06So, again, enough knowledge to justify. I knew where we wanted to go. I knew what I wanted to have happen. I knew that. Things could go wrong because I also knew what the connections were of that region, and I figured we would have problems with autonomic instability in the operating. Or some untoward subcortical problem. But that we could turn it off so we could watch for that. Yeah. But this is, again, that moment of theory, third person, design it, know in principle it would work, have a surgeon, then learn that surgeons will do anything because they can. I mean, they take very knowledgeable this. But, again, they can put these electrodes. Pretty much anywhere they want. And this was not a hard target, even though we didn't have a very well formed target. 11:03But we're close enough. Or at least we thought being close enough would be good enough. And as we planned it all out and got funding and have permission. That's when this piece kind of became. I'm really going to do this. Yeah. And I think then is the point where. You think you've got the roadmap and the blueprint and what you're going to do. And. Finally, get a patient and then it really fits is what will happen if something goes wrong. And this is where, again, you don't do these things alone. And even though. Everybody wants to do something new and push the envelope. Under Susanna was incredibly helpful. And I remember a conversation with him where he basically sat me down and said, because I said, look, I don't know what I'll do if we hurt this person. Again, she didn't have options. But. We certainly don't want to want to do harm. 12:00You know, and there are complications. As remote as they are of putting electrodes in the brain, invading the brain is. Is. Is. Has risk. And he said, look. You know more about depression than anybody on the planet. Which was generous. He goes, there's a logic to what you want to do. I know I can do it safely. So something to do is to put yourself in the position of it. This is somebody. That you personally cared about knowing what you know, knowing what I can do. Knowing that if it. If it doesn't go according to plan, we turn it off and take it out. And I. And he felt confident about that. Would you do it? And the answer was yes. And he goes, so let it go. You know, it will be there. And it'll evolve in front of us. Or, you know, something like that. I mean, that's what I remember. And that was. That was a moment that I really realized. You can have an idea. But that surgeons are amazing people because they go that extra step. 13:01Sure. And I know when I talk to my psychiatry colleagues, they always say, boy, you know, we're all studying this. But you decided actually to do it. I couldn't have done that. And I look at it as, you know, I had tried to be a nurse surgeon. So again, back to, you know, how funny, how does the world work? You know, I started doing nuclear medicine because my uncle did. I ended up finding this hybrid place because. Because I didn't have a home. I tried to be a neurosurgeon as one of my choices and settled for neurology because I didn't like operating myself. Spend all that time. Sure. And then X number of years later, I'm telling neurosurgeon what I want them to do. And actually, the amazing thing is they are happy to do it. And so it is a mosaic. It is a hybrid. And that you need all these pieces. And that. And that. And that's why I couldn't have made that last decision myself, because I would have. I actually am a risk averse person. 14:03I think that's why I did a lot of imaging. I mean, if you get me in there, I'm as dogged as anyone. But left to my natural ways, I'm pretty risk averse. So I didn't see it as a risky experiment. Not just because, well, it's not me putting the electrode in. It should have worked. It's anything that I knew was true. So. I did that computation. But I still. Right before was. I was terrified. Sure. You know, I was terrified. Not for. Not for the experiment. I was terrified for the patient. Of course. And this is where, like any physician's relationship with the patient, you have to go to be honest. But you actually have to protect them. And then you have to hold in yourself your worry. And just know that you've got a room of people. That are there for the patient. And first. And the experiment. Second. And it'll go how it goes. 15:00And you just need to be adaptive. If you need to. And luckily, it turned out even better than I could have hoped. Because all we really wanted in that operating room that first day was to get it where we in where we wanted it. And to have nothing bad happen. The fact that things happened in the OR. When we were looking for bad things. The staff. Turned out to be really interesting and good things was just an absolute bonus. And the start of everything. You were in the operation room, I assume. Or I'm sure. Oh, yeah. How was that moment to test? So the operating room is really interesting because there's lots of people running around. The patient is awake on the bed and draped and attached to the stereotactic head frame. So when we were on the mics. We would plan the surgery. So Dr. 16:00Lozano and Dr. Claremont. His postdoc at the time. Three of us kind of used our approximate maps. Not like the kind of maps that you use. Or even that we use now. I mean, it was really eyeballing. Sure. A pretty low resolution MRI. And basing it on our PET scan. Blobs. So kind of amazing. In retrospect. Yeah. to be on the non-scrub side of the patient and to talk to the patient and Andres and Clement were on the scale side. And when we got ready to test because the electrodes were in, it was really, you know, the instruction to the patient because this is the ultimate placebo-controlled experiment because we don't know what's going to happen and the patient doesn't know what's going to happen. So it's a virgin experience for everybody. And as we started on the first contact and went at very low current and we decided we do high frequency like Parkinson's because we wanted to block the activity supposedly, 17:05we just would ramp it up and first contact, we got nothing. So then we moved to the next contact and we tried it again. I can't remember if it was the second one or the third one, not much is happening. And we didn't want anything to happen because we figured we'll use the location to decide how to stimulate. Because this is going to be a chronic effect because depression is a chronic treatment. And we get to one of the contacts, we start to ramp up the current, we get to about, you know, five, five milliamps. And all of a sudden the patient starts to describe that she feels something. And it's kind of like, well, what is it? And she felt calm. And, you know, kind of figuring out, is she falling asleep? Does it feel like valium? We started asking her questions. She got very kind of short with me. And she says, look, you're trying to get me to describe the difference between a laugh and a smile. I'm going, what are you talking about? 18:00And she's going, how do I explain it? She goes, the void is gone. And I'm going, what's a void? And all of a sudden there's this descriptions of things that had gone away that she had never described as being present. And then we turned down the question. And she goes, oh, I must have been imagining it. And then we tried it again. And, and, and then she started to get more descriptive and more metaphorical. And it was interesting because instead of what we might've done, which was sit and spend a lot of time, we presumed that it would be like Parkinson's that, gee, this is good. Check the other contacts. Some contacts were better than others. But there was clearly localizable change in behavior. But it was extraordinary in that it was transient and subtle and metaphorical and clearly not 19:08the generation of euphoria, but the generation of relief. And how do you describe the moment when you no longer hurt? That is an ethereal thing. And it's a non-psychiatry. It's a non-psychiatrist is a non-philosopher. This was a spiritual thing to watch. I mean, only because we looked at my notes and looked at, had this experience with many, many patients had to get into the weeds of what does it feel like? We become sort of, it's not even armchair psychiatrist because this isn't part of what they talk to psychiatrists about either. So it's another example of a language. And the language of psychiatry, which I rejected wasn't even adequate to characterize what we were seeing. And we spent the last number of years trying to figure out what are we seeing because it's 20:02so fundamental. But we saw it that first day early on. And I don't even think we appreciated what we were seeing. But it's a pretty salient memory. And that's when you realize that. Yeah. Yeah. Yeah. And you realize that this is really hard, but that it's worth doing because those patients, patients we have now have come out of this state. And while it's not immediately well, when you get people well with this device, it's long lasting. I mean, like years, not six months, not a year. We're now we have people 10, 12, 13 years with the device. Yeah. And so how can you not want to try to figure out what that is? And I think from that, the rest was history, but there was not, not everything was done 21:01yet. And I told you a few times already that I'm always amazed if I look back, your lab somehow often was the first to do things that I sometimes think about. We should do that. Usually you've already done it. So a list of some things, for example, you used MNI space coordinates instead of ACPC coordinates in your papers or for planning. You used of course, pet activation maps, fMRI activation maps to inform targets. And you also went on to use tractography for analysis. And then later with STEM vision also in the OR for seeing which, which bundles you want to hit. And now we met in Stanford. I heard you're using segmented leads for segregation of the internal capsule. And I even haven't mentioned the electrophysiology part, right? So you also do a lot on that. And of course it's not all you. You lead the center and so on. But what are the strategies to use all these techniques and to integrate things? Well, I think it comes down to something my father told me, continues to tell me that 22:03he observes. He goes, it's really important to ask the right question. One. And I think, you know, being driven by observation, which comes down to the patient is fundamental. But I think that you, you, you surround yourself with people that can help you answer the question. So it's, I mean, a, the only thing I will take credit for, for actually knowing how to do myself is doing test scanning. I know how to do that. I know every in and out of those methods, but now I kind of feel not like an imposter, but the fact that I know the question, but I, I know the question. But I, I know that the tools have become way more complicated than one person or one team can do. And how can we leverage the community? You know, one of the things I still admire about your lab and your way of thinking and really resonate with it is your generosity. 23:04And I think it reflects, you know, our respective ages that young people are, are, I think are more open. And I, I appreciate that. I like to think. And to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to So now I realize that the questions, if I'm trying to solve a problem and I've got an unknown, I've got to have an equation to solve it. And the equations in this metaphor are tools. 24:01So if now timing is important and I can't get timing with the tool the way I'm doing it, then I've got to find another tool. Which means I've got to get people interested in the problem, which gets back to ask a good question because some people want to help you. And part of, it's not just, you know, being a good salesman. I think everyone resonates with this problem. The idea that you would be in a state of mental pain and not be able to get out. What is that? Is universal. And it can be metaphorical, like how we're stuck now in our current kind of purgatory state of not, you know, the understanding. You mean the COVID situation? But that everybody that hears the story and at every stage of my work is about everybody knows somebody who's depressed. Hmm. True. People have friends that have committed suicide or they've been sick themselves or a family member or a friend or a colleague. 25:07It is something that people suffer from. I don't personally have depression. So why do I say it? I don't know. It was interesting. It's interesting and hard, but fundamentally seem neurological. But back to your other point, I think that as the question is getting an answer, and it isn't like I believe in the theory of everything, but that for this problem, it seems as though there are pieces that can be solved. And the only way they're solved is by teamwork and trying to integrate the pieces. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. for what they want to do by seducing them in some ways to be interested in your problem 26:06while also letting them be the lead and it's a very complex constant iterative thing where you're not controlling and i'm old i want to solve and i want to solve this problem so i can go do something else that might be fun you know my husband would like it but i did something else for a while and uh i keep telling maybe you know this is this is important if only to finish a chapter of the rest and and now i have a team where you know we're trying to integrate and and it's back to involving neurology so kind of come full circle in a um i was fortunate enough to see i think two talks of you at harvard university in 2016 and um i think one focused more on deep brain stimulation and the other one more on individual patients and experiences you made with uh depression patients 27:01that you treated and i think both talks were brilliant and it really showed the two sides here of um being both uh an academic researcher but also um a caring physician and um i think it was also that that talk that where you mentioned rounds you did with mom and so on so these people apparently influenced um how you thought about the brain and how you thought about the brain you just mentioned uh uh that the terms that psychiatry used you didn't see them in good light so so how did that shape how you would approach clinical translational questions well i think you know i mean it's long-winded but you know informative you know maybe but that i really as i started studying depression i was a voyeur so one of the things about imaging is that to be really an expert one has to go deep in the method and in some ways you almost have to approach the problem from the third person 28:00and and that for many years i mean really starting at hopkins where i was in multiple departments and my clinical work was general neurology and my research work was highly technical and on depression i basically had a split life and as i changed institutions i was trying to merge them because i was studying depression in parkinson's actually my first grants were on that where i said well you know i'll be in the clinic i'll see moving disorder patients and i'll be able to study depression right there and i found that was a total mess because the patients were extremely sick you couldn't isolate out the part you wanted to do it wasn't clinical research i was trying to do mapping and it just wasn't ready and so i basically started to do that and i was trying to do mapping and i was trying to do mapping and i basically split my activities between my my first person interacting with patients 29:03from my third person mapping experiment and that worked so i had to have very very competent clinical collaborators and to trust them because i couldn't get the patients myself and that was both a good thing and a bad thing because i could focus on just the science but i had an episode happen when i was doing some studies in texas i was in peter fox's lab i was one of the um the first scientists when the um brain imaging center the research imaging center started that was 91 in texas and antonio right yeah okay yeah and um that was pre um organization for human brain mapping i mean this was you know sort of i'm sort of a dinosaur but um and i wasn't even first generation dinosaur 30:02sort of second generation but i would go down i would do all the injections myself i would do the scans with the tech um myself and i would meet the patient i wouldn't train the patients i'd meet the patient and it was when we were doing you know a group of patients and studying um any depressant effects but we still had a PET scan study of people just kind of mapping variability and i met this um older man that had a very very bad depression he's about the sickest patient i had seen coming through and it really struck me with his suffering and also how many things he had failed enough so that actually i'd been giving a talk at mass general and i was in the ether dome in this big historic place and everybody making the fuss and to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to 31:25and he committed suicide. And it would be remiss of me to say that those things are connected, but they sort of are. And the reason he was rejected was because of a 20-year prior alcohol use. And what suddenly crystallized, perhaps through that case, was the idea, this is no joke, we can sit in math and we can think we know about how the brain works and this circuit does X or Y, goes up or down, and fight among ourselves of what method we're going to use. 32:00At the end of the day, if the work doesn't lead to making a difference for people, we're playing for a living. And it became pretty clear that I was playing for a living because it was safe. And I didn't know it at the time because I was just frustrated and sad that that wasn't a good enough reason. And again, far be it from me to tell another institution what their inclusion or exclusion criteria is for a procedure. But in retrospect said, we've got to use what we learn to affect change. And if the status quo isn't good enough, can we direct our research in a way that we learn about how the brain works? And I think that that is noble and that's what many people do extremely well. So my personal... conflicts are about how do I take my intuition and my clinical training and ask questions using these technologies in a way that can affect clinical change. 33:06And that wasn't like I said at that moment, oh, you know, light bulb, I'm going to do GBS. I was trying to reconcile how can you make a lesion in these areas? Why does that work? And how does disinhibition work? And... And so all of these pieces are like this big puzzle of which you assume all the pieces are in the box. You don't know if they are. There's no picture on the top of the box to tell you how you're assembling the pieces. They're kind of grabbing them haphazardly and you're kind of trying to hope they fit together. And that was just kind of a section of I think a big puzzle that actually... probably was pretty salient in front of me. Yeah. Salient and pretty important, even though I didn't realize how important it was at the time. There's a great passage in this book by Lone Frank, The Pleasure Shock. 34:02Actually, I really like the book, to be honest. And I think back then in your early, very early days in UCLA, you also had the opportunity to be in the lab of Irvin and Mark, if that's correct? At least around the same... Yeah. Yeah. No, I worked in the lab down the hall. Okay. And... And I think in that book, there's... She basically takes up the story that the Terminal Man movie came out based on the book by Michael Critchton. And Critchton had done an internship with Frank and Irvin at Boston City Hospital in the 60s. And basically, the book ruminated one story of one patient that was inspired by a real patient. And they were treating violent behavior in epilepsy patients. Back then... And... And you... You experienced demonstrations on the street, of the counterculture... And... And even apparently were hit by demonstrators trying to enter the building. 35:04I... I think she wrote one of those who received some lumps that day was a young, ambitious... ...deacon... ...by the name of Helen Myberg. That... That was... You know... I... I forgot I had told her that story because... ...and again... You know... You forget all of the influences... But... You know... I read... Violence in the Brain... That... That... brain, that, and then when realized that part of the team was actually there, I actually worked for the wife of one of the neurosurgeons, Crandall. And so when I would go into the building, I mean, suddenly there were all these protesters because of the violence center. And so it was kind of, you know, trying to duck through and you felt like you were crossing the picket line and was sort of an irony. But again, it's like I knew about it there, again, very third person. But what a funny coincidence, because actually when I was resident, there were two papers 36:03I read that were probably influential. One was the brain paper in 83, I think, of Bob Robinson on stroke depression. And the other was in the New England Journal, which was a... a group conference statement about whether or not epilepsy patients were violent. And so that summary about that, and Engel was the lead, and Engel had been at UCLA when I was in college. And so this whole notion of purposeful violence influencing, you know, in epilepsy patients, it's kind of like what goes on now with, you know, schizophrenia. Is there violence or violence? And so all of these things kind of came together in our subconscious in the most interesting of ways. I mean, I actually did a lot of medical legal work arguing against that, you know, that 37:07you can't use a scan to determine culpability in a crime. And I realized that was really going back to epilepsy patients. And I realized that that was a very important thing. And I realized that that was a very important thing. And I realized that that was a very important thing. And I realized that that was a very important thing. And so it's, it is really interesting how there are threads that go back when I was 16 years old. Would you say that your current decisions, like, did you learn from these times where the culture was against, you know, psychosurgery and so on? And how can we prevent this from happening again? Günter Deutsch mentioned to me that the best thing we can do to prevent this happening again would be to, you know, document the cases as good as we can, right, our successes and be as scientific as possible, of course. No, I think that, you know, I looked at Moniz and I loved, there's a small museum, a small hospital in 38:04Lisbon where he has all of his papers and his contraptions. They also have all the angiograms. It's really magnificent, the museum. And that you read the history. I think we have to read history. And when we, whether or not it's making sure that we cite people properly in our own papers, nothing's original. There's just a different orientation, again, because of the tool. And, and I'm, I'm guilty of this too. You know, I've looked at who did what and is the location of where we went in our logic. I mean, our logic was our logic and wasn't previous logic. But that you can go back and even look at, at Friedman's work and Moniz's work. Yeah. The only criticism you could say is lack of documentation. And, and they didn't look to balance. Did they do what they said they did and what tools did they have to know? And I think the same is true of Robert Heath. 39:05That, you know, even to have the institution hide the data to make it so difficult. I mean, what, what, what Lauren did is really important to the historical record. Yeah. And it isn't just commentary through the lens of patients that were harmed, which is also very important. But that to actually get in the head of what was someone's motivation then? What was happening? What was the field doing? We can't have a 2020 view on what was going on in the, in the fifties. People were locked up, chained up, being given insulin, being put into comas, being tied up. You know, it was a bad time. It was a bad time without treatments. And, and I think that he had a hypothesis. He was testing it. People lost sight of that because he kind of like went sideways. 40:00Um, when he got into believing things that weren't evidence-based, were not hypothesis driven. Well, I can stick a probe in anywhere. I can do whatever I want. Got lost. But I think when you get to this fundamental intent. That's a subtle area. Yeah. It doesn't matter if now we know that that was a simplistic idea. The logic was impeccable. The data was there. You look at those pictures and it's sobering to realize we're using the same bloody device that he was using then. And he didn't have four companies helping. And you can't have hubris about what that must've been like. You can only. You can't have a single company that's doing the same thing. So I think that he grieved the idea that he lost his way because he brought his own hype. Yeah. And whatever else went on, which the record is hard to parse. So I think for us, you have to be honest about your motivation and your logic. 41:05I think we have protections that they don't have. I, sometimes it can seem onerous. The levels of, of regulation. I like to say that. I like to say that I'm not a big fan of the idea of what regulatory hoops I would have to go through in the United States. Sure. If I had my idea and done it in the United States instead of Canada, I probably would have given up because I didn't really think it was going to work. And this was too much trouble. It was, it was just dumb luck to have been in Canada where we could test the idea and then go deep. But I think this is all about. No one says this is easy. There's, there's nothing wrong with having an idea, testing it as long as you do it safely. And it turns out it was, it was a harebrained idea and it doesn't work. So you stop. Yeah. It's not about your own ego. 42:00It's about more about money. It's about getting the right answer. And, and most ideas don't get anywhere, even when they're tested. So I, I look at the historic record and go, if we document, we'll be okay. I expect if. Sure. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. In 50 years, people will look back and go, you stuck with what in people's frames. Sure. Because we'll have tools that we, we don't do it this way. I mean, but this is where we are. And, and if anybody will care, then the record will be clear. True. And I don't, I don't lose a lot of soup over it. Cause I know we take a, we take a very deliberate point of view and if we follow the data, data will always set you free. Sure. Yeah. You know, maybe if, if you think about the world as a, um, a global consciousness, I feel currently it's really in depression because it ruminates about one topic, which is COVID and it paralyzes the actions of people and of organs and of States and countries. 43:03This is the only topic. And it's a bit like it really reminded me of depressive States in the brain somehow as well. Um, I don't know if that's a good. Oh, and ruminating, hoping you'll suddenly find a solution. Yeah. Of truth and that the certainty of it. It's a good metaphor. I've had the same, um, thought because I mean, I think there's a reason that maybe even how depression is conceptualized, it's just kind of wrong, you know, that it really is about, you know, not being able to state shift. And that's, that's really all it is. I mean, you keep trying, I mean, what's the, what the, there's a expression about, you know, it's an Einstein expression, I think repeating on the state, you know, like hoping for a different solution. So where, where's the balance between iteration is Asian and good versus iteration is just 44:01getting a whole deeper. Well, now you're, uh, since 2018, the director of the center for advanced circuitry therapeutics at Mount Sinai in New York. So the integration, I think you mentioned. I mean, you're a surgery, neuro radiology, but also of course, neurology and psychiatry. If I understood correctly in one building or is that true that you're close to each other now? And so instead of having, I think what everybody's familiar with, because everybody's got a multidisciplinary team that does this, the thing though, is, is that they're virtual and that, you know, you get together and everyone does their part. But in fact, one of the things I learned at Emory was that having collisions, you know, not just around the coffee machine, but actually being able to be fluent in more than one language, at least to be able to get by is done by having everybody in close proximity. And we couldn't quite get it at Emory. 45:03So we did it in our lab, but never accomplished it despite some efforts. So when moving part of the conditions of moving was to say, let's try it. You know, if I move. I want to live, no surgery. I want the people who do DBS in a proximity, in close proximity, because not because I personally want to go back to studying non-motor problems and movement disorder, but why shouldn't we reinvent the wheel in parallel? Why shouldn't psychiatry and DBS be answering fundamentally the same questions that neurology is doing? That's just a waste of time. And it's a good thing. I think it's a good thing. It turned out that Brian Capel, my surgeon in New York, not only was he fundamentally interested in depression himself. He also shared, and I think it's a common view of neurosurgeons that you treat circuits. 46:02You don't treat diseases. This is the wrong sort of the surgeons. They treat everything. But the thing is, they, if they behave as just a, a convergence point. It's not. It's not. It's not. It's not. It's not a convergence point on a wheel that we really want to be having to where what neurology learns is fundamentally the same brain and what psychiatry is studying is the same brain, but just a different circuit and that we can have reciprocal relationships. And so we have Martin Fugui, who's a psychiatrist that's interested in OCD, but he's also interested in compulsive and behaviors and non-motor behaviors and problems. So I think that's a good thing. I think that's a good thing. I think that's a good thing. Adam Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa Dewa 47:14they're just the sole practitioner of their expertise that we can we can leverage each other now so we all live together in the same space and it's if i realized how hard it was going to be i'm not sure i would have done it but then that's kind of what happened with the dbs experiment i actually did it knowing it should have worked but i never did the computation of what i would do if it actually didn't work i hoped it would work but i didn't actually play out the hand in my mind of what would happen if it really worked long term what um and i think it's the same as this it's only rational it's going back to russ belveserini that you know psychiatry and neurology 48:00will merge because of imaging they didn't merge but they're merging actually because of neuromodulation and they're not merging because of neuromodulation with non-invasive tools those are still totally separate they merge when everybody has to meet in an operating room to do something and and it's it's sort of i mean i just thought about this i mean how ironic you know had i become a neurosurgeon this would not have happened either because i would have been whatever kind of neurosurgeon i would have been maybe i but i wouldn't have had the behavioral side of things to actually see these various components so but it's hard because you have three administrations you have every department to deal with you have the constant entropy of it pulling apart rather than pulling together but i have administrative support in a way that at least when we fail it will have been 49:06about an effort and i i think it won't evolve exactly how it is in my mind but i think it will to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to then the thing is oh you mean it's this hard or we don't do it that way or you know you get back to don't really rejection sensitive look for a solution and i think the new center is that way i think experiments have always been that way i think career you know and i've been an attending 50:03in neurology and radiology at least and you've of course worked a lot with psychiatrists and and so that surely helps right but i think you know what the other thing i i mean from a more nihilistic point of view the structure of medical education and training each discipline now i mean again when dr dalvis says they'll emerge late 70s we didn't know very much about anything in neuroscience so so it was easy to say oh these things will kind of go back into one hopper well as you know as a neurologist neurology used to just do diagnosis now the treatments are extraordinary and molecular biology is the center of the universe in neurology you know more than imaging whereas in psychiatry it's also gotten very molecular and and psychiatry to me still doesn't 51:00embrace the brain model it still holds on to the brain as a bowl of soup you know add a chemical stir i don't really need to know where um and and it's it's it's much more interested in these molecular genes and the interaction of um you know all very interesting but doesn't get into a fundamental principle of of how the brain works and again you know it's the world people are free to approach these complex problems however they want to do it but to me it's always been about get the basic architecture the basic structure of the system and then you can go deep so i've always been kind of a lower resolution person i mean and it really it probably really goes back to for a long time we just didn't as you mentioned in the 70s we didn't know too much 52:01about the brain and we still don't and i i guess it was really the development of you know we have have a software and a hardware and it's fine to study just the software because we don't understand the hardware and that's maybe how all these how all these this language developed and now we're trying to fit it back together but it doesn't fit so i have a new kind of working way i mean it's you know it's rationalization maybe but it goes back actually to what we saw in the operating room with that first patient which we had thought about the data tells me now that basically maybe all dbs does is kind of reset the system okay it's not it's not broken it's dysregulated it's it's off the track there's something about kind of the electrical reset done from the very beginning that one working hypothesis is that all it does is 53:00kind of cardiovert the brain and but in a very very specific way it's not ect these are ect failures but that you reset the brain and then you actually maintain a pacemaker and that the rest is rehab and it's the ultimate integration of everybody's right just not at the same time you cannot do psychodynamic psychotherapy you can't even do behavioral activation you know classical psychiatric rehab you know therapy if your brain doesn't work any more then you can't kind of lift weights or run on a broken limb and so the first thing you do is reset the bone reset the system open up the you know make the basic structure work and then the timing becomes how do you do graduated rehab and 54:00trying to understand how rehab works is very different if you don't fundamentally know that the organ of interest or the bone isn't aligned i mean we still have to deal with the fact that a surgeon perfectly fix a broken bone and a runner never goes exactly back to running the marathon at the same time that they did but then there are people that you can fix their bone perfectly you don't make them a runner yeah and so the big thing about we equally can't have that because we've got these tools and they can do almost um miraculous changes in these profoundly ill people it's necessary but not sufficient and if there was one example of the fact that we all need each other in the clinical neurosciences it's that even with this kind of device without a therapist 55:00or with a therapist it's not going to be a good thing for you to be able to do that so i'm going to do that and i'm going to do that and i'm going to do that and i'm going to do that and i'm going to do that without rehab people can't be who they could be and so the machine is not enough so everybody is right just not at the same time so order is important so i'll be happy if i can just figure out what that reset thing is because i think at the end of the day that's probably all we do but that's pretty important speaking about that that reset um that that rings a bell about one last topic i wanted to dive into as well which is the depression switch which is i think your current model or at least the model from recent papers that you um now basically develop the cg25 stimulation on so um my understanding is that um there are three bundles at least so a single bundle the forceps minor and the unsenat for cyclos stimulating at that crossing side seems to be associated with good outcome and you've now even migrated that into a 56:00prospective trial and have shown that if you really target these three structures um you get better rates of good clinical outcome so i think that you know fundamentally the old days were get some blobs look up in a paper and see how they connect and all we really did was reverse engineer with tractography this map so in essence just like the whole rest of the world we we've moved away from voxel based analyses to network constructs this is a structural network and it's a convergence point between several known networks actually there's a fourth component which is harder to map with tractography but there is a subcortical connections because area 25 projects to the raphe it projects to the nucleus accumbens it projects to the anterior midline thalamus and so the 57:00subcortical part may be actually fundamentally more important than the rest a little harder to but i think that this idea of dynamics of networks is certainly where the whole field is now and dynamical models and when you think about the phenomenology of the reset in the operator in the switch it almost feels as though you're watching something that's not working that's just synchronous or or overly synchronous kind of either become phase locked or or or broken broken apart it happens at a timing that can only be explained that way and so obviously we can make inferences by looking at people who did better or not by what we were stimulating or not but that's very different from a causal model of what what what is necessary and sufficient to do and what's 58:00efficient even within our system and we've been in our more recent work we've been trying to track with these prototype devices what is area 25 doing in its physiology but obviously we need ways to measure the rest of the brain sure and um behaviorally we're you know trying to explore how do how can we leverage things by how people move or how their facial expression changes or the qualities that the psychiatrists um infer from their enzymes but that the network differences is is how to actually look at that in a smart way is challenging and and we're leveraging every collaboration we've got i mean we learned a lot watching strategies that people did with epilepsy patients where you can kind of brute force machine 59:00learn the whole brain i think that gets part of the answer i don't think that gets the answer but even with and you can't put people back easily in a scanner um in a fmi scanner although i know your group has but you know one's got to be again smart the it was easy you've done already you know there are these technical limitations but my instinct is is you're watching how these these over learn patterns are going to change and how you're going to change them and how you're going to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to 01:00:00really require either brute force rehab with a therapist, or maybe they need another place in the brain to stimulate. And I think that's, you know, something you keep us busy thinking about. We met in Stanford. Brian Coppell mentioned that DBS in his brain really means disrupting an attractor state. And I think that's what you mean, right? So would you say there's an attractor state of depression that keeps this ruminating going and the low entropy, basically, low freedom, low changing? So I think, you know, if I could retrain and probably be as like a physicist to study its nonlinear dynamics, because every time, like you just said, the phenomenology is of a stable local minimum. The first effects are really popping you into another actually unstable state. So the models of bi-stability are really most attractive to really kind of describe the phenomenology. 01:01:07And then something over time moves you into a stable and more in-slope state. I mean, I think, you know, the brain should intrinsically not be stuck in one subroutine. Depression is like, you know, Groundhog's Day, the movie. You know, it's... No matter what you do, the answer is the same. And whether or not you describe it as rumination, you keep looking for a solution and keep getting the same answer. And that pretty much makes your predictions. You're very good at prediction. It just happens to be not going toward the goal. Yeah, makes sense. And BBS actually shifts you out of this local minimum, this powerful, this rut. And then actually you reestablish your entire environment, 01:02:03which really requires you to repopulate your life experience with a brain that will respond to the world in a more normal way. And there's something about the BBS that allows that new repertoire of world interactions to evolve. And, you know, that takes time. But maybe resetting that normal prediction error coding can happen is as simple as just a small alignment. And I think that would be, you know, just the best. If in the end it turned out the BBS just was totally an enabler. And the rest, you know, look, you want to know what consciousness is, not my department. You know, you want to know how you learn or all the things that make life so incredibly amazing. Amazing. And that's the way that we are as human beings, 01:03:00who we are and give all of us, you know, a lot of people things to study. Now, this just, this just allows you to do that. And the patients say that. I mean, the patients will even tell you, look, you didn't give me anything. You know, you really want to hear that after all this work. They go, no, no, no, you took something away. Great. And it became so hard to realize that life is just really hard. Right. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. that's giving a pill, sometimes that's doing an operation. But in essence, we don't make people who we are. We allow people with a functioning brain to be whoever they want to be. 01:04:01So I don't think I should be judging whether or not this technique for depression is a success by whether or not you get a job. Sure, no, true. I judge it by whether or not you can make the decision to get a job or to sit in your basement and watch TV, as long as it's useless. And the thing is, even if you take the self-serving notion of, and we certainly struggle with this, how do you have endpoints so that something that works so well in your own lab with your own patients, and now across more than, I've worked with many psychiatrists now, so this is not about some magic. The notion that we have some cabal, but that why can't we scale it up? Maybe it's because we take too much ownership of what we do. And that fundamentally is a problem too. We don't own the whole patient. We train that we see a person in all their parts, 01:05:02but our interaction with them isn't everything. And that's a real difference between neurology and psychiatry. And I think that we may be underlined, knowing what actually our role is as we try to push on to our own treatments of how to put people in a position to be their best self, because we don't control the world. And I remember when I was at Emory, we went through the 2008, the 2012 was in the financial collapse. I mean, if you were over the age of 45 and you lost your job and you were out of work for three months, good luck. Fine. Yeah. But a new job in your own field, what do you do if you've been sick for six years and haven't worked in that long? How do you sell yourself? And now that you're well, you watch the importance of the therapist and the patient saw the therapist often. Well, and it took several years for them to realize, no, the device enabled it. 01:06:03So how do you pick your outcome measures when the world is not hospitable? I've even entertained the idea that maybe the first six months, you ought to have patients in a work camp. You ought to keep them where you provide the environment so that you don't have the variance of some patients have really supportive families. Some people return to more stress and they awoke to realize that their environment is pretty awful. And there's all those extra noise features that make for a bad experiment. But actually, it's the real life in which we live. We do these experiments and we've got to be smart so that we don't lose the ability to have this in our toolkit of treatments for the wrong reason. If it doesn't work, it doesn't work. But if it does work, which obviously I think I have evidence that it does and not just our group but other groups. 01:07:02But how do we maximize how to use it? Because the world is a tough place. Someone said that, you know, DBS for depression only works if Helen Myberg does it. And it was meant in a good way because it is a tough problem and you need a good patient selection and you need a team that can do it and the experience and so on. So you talked about scaling it up and exactly these outcome measures make it much more complex as in tremor, where you just have, you know, direct evidence on videotape. So on one hand, I'm not trashing that look. It's the most fundamental thing. You explain most of the variance. So some people think we have some magic of how we can patients that we cherry pick. There's a machine learning algorithm that good psychiatrists that have worked in this have learned. What the phenotype is. Now everybody wants phenotypes. No one says they're cherry picking for cancer when you do a receptor marker and you only give a drug to people who have that receptor marker. 01:08:03I consider that really great psychiatrist of which I've had the privilege to work with many. I've learned what the phenotype is that this SEC DBS works on and they and they select for it. And so they get better because we pick the right group of these resistant patients. On the other hand, and they we get people to remission and then there's noise of real life on top of it. So I don't have a problem with meeting new scale. I think that a even if you don't know the right patients do. You can follow. And. And criteria. And we study ECG failures without. Comorbidity that are mostly melancholic. The most important variable is getting it in the right spot. And in our own group. Even with experienced people. That explain most of the variance. 01:09:00And if that's. You know, one of the things I always like to bring up in my thoughts is we've got three variables that lead to failure. The psychiatrist. The surgeon. Say you didn't. You didn't do the surgery, right? The surgeons find the psychiatrist. So you didn't give me the right patient. And three is, well, it's a lousy scale. And why are we using some, you know, ancient, you know, endpoint that that measures too many things. You kind of look at what variables can you change? We're back to my rules of, you know, it's hard that like don't die trying on the wrong thing. The one variable I can control right now is I can figure out where to put it. And a surgeon follows instructions. That that is a controllable variable. Finding the phenotype of depression. I spend the rest of my time trying to do that. That's almost a loss cause. Even when you find a marker, nobody wants to use it. And getting it scaled up is really hard. 01:10:00The endpoints are fine if you actually do a good job on the other two. So I think that understanding this reset switch. And providing more evidence. Of the stages of recovery and which ones the DBS does and which it doesn't is a kid in Parkinson's. That look, there are dopamine sensitive behaviors. That are substituted by DBS and the SPN. And then there are other parts of the illness that are not. By that location. So if you want to deal with. And freezing. That's why people try to look at the PPN or look at some other. Target. If you really care about non-motor features. It's not going to be doing the best possible job of hitting the lateral STN. You've got to be creative to the full feature space. Depression has got. Instead of saying, oh, it's too complicated. It's heterogeneous. No, it has modules. 01:11:00It has the sort of features. Which one are you in when you're in the SCC? And which ones aren't, are you not in? And then maybe you can. Come to understand which features are less affected. And then maybe be picking different targets. Different phenotypes. But there's a logic. That's no different for this. Than there is for neurology and neurology. Necessarily do such a good job either. They get better and better. They were already pretty good at. And so again, yeah. Freezing of gauge and yeah, you're right. There are a lot of things that we can't. Modulate. Well. I think it's figuring out the problem. You cancel and not over ruminating on, on the whole picture. I mean, I think that's just kind of being an adult and when they think the patients needs kind of guide those decision trees on experimentally. So what do you think needs to be done for this for the future? 01:12:02Like what are the things that we need to do as a field to make this more mainstream, more robust? And I think that, you know, so. Psychiatry and I think you're part of this solution. I think anyone doing imaging and tractography now that that's become kind of a mainstream. That you need to understand this, not in the abstract. That, that to have guidance of how you implant. Because you actually embrace a full circuit structure and the complexity of it. And I think people are doing that in the conversations. But it's not enough to just. say it's complicated and we're kind of in there, but to get granular because at least in our experience, I mean, surgeon didn't believe it until we proved it, that a millimeter could make a difference. Do I think, you know, and again, we lucked out that we at least have differences in the DTI maps to generate 01:13:02some hypotheses. Do I think it's as simple as you're in or out of the circuit? No, because there's a lot of overlap. But that lays foundation for figuring out the nuances. And that becomes you, it's sort of like feature selection in machine learning. You can throw in every data point if you're Amazon or Google and just machine learn the universe. And I don't know, patterns for things will pop out that maybe you didn't even know you cared about. In this space, feature selection with smaller samples is where you have to, you know, you have to go. And so I think that knowing that there's an anatomy, you know, informed by work like Suzanne Hebert and, and, and actually taking ground truth and then looking to see what part of it can I resolve with the tools we have, which you and I know we don't have the luxury of what you can do in a non-human primate track tracing, 01:14:02but that one can reverse engineer to know what you do and then test prospectively. It's gotta be iterative. And I think the fields are now moving there with anybody doing DBS, particularly in psychiatry and even in neurology, that tractography is important as an MRI as is as important as unit reporting. And that I think that that's a story. I think that people then also need to be to balance between if you don't get a hundred percent, you don't throw it away. Sure. And that you don't say, Oh, I'll build another better mousetrap. I'll pretend you don't know anything and just start from ground zero doing something else. If you have no finding, then of course you need to do that and give up on what you thought was your own good idea. But if you actually are close, but not to the finish line, it's actually not a race. So it isn't like go home. 01:15:01It's not the Olympics where you were full. You don't make the team. No, you try again and you learn from your mistakes. You don't, you don't grind in and say, well, we were right and you were wrong or I respect you. And that's back again to nobody's right all the time. Let's, this is war against the disease. This is not a competition against each other. And, and how do we take what we've learned and same for me to listen to where evidence-based criticism is and said, I bet if you do this, it would be better. Yeah. And, and do what it takes to try to do it again. Yeah. And make iterations that don't change too many variables at the same time. Makes sense. But to do that, because, you know, and I think it would be a personal failing, but I, I let it go that it would be a personal thing. If what I do was not available, look, I can change my email address. 01:16:01I don't have a listed phone number. I'll deal with the fact that people write from all over the world who are suffering and want to know, who think it's a treatment. How can they get it? Where can I send them the desperation that one has to listen to that? I don't ask for considering I don't have a clinical practice. I get this, you know, all the time. And you, you have to have no funnel road to not be empathetic to this kind of suffering and to have people think that you can solve it. I don't pretend that I can solve, you know, the world's problems. But you know, what I know and not being able to get it to a finish line is, is to live that your experiments are your experiments. You do the best you can. But if you want it to be for real, you have to have partners and those partners are industry. And we have to influence industry to do it again, whether or not we have to, you have to give them evidence and then we have to make them realize it's 01:17:01important. And there are lots of ways to do that, but they have, but that's, that's, um, I, I, I, I will be able, I would like to have a, a chapter and where I, where I felt gave it another shot and that hopefully will happen. And it's like the data, the data wants it. And, and, and the community should work to see that be successful and, and, and to help it be successful. And I think that's true for depression. I think that's true, you know, for these other disorders. And, and, and we can work together to do that. It's, it's so fascinating to me personally, you know, if you have only one patient in which you see a true effect, you know, and, and, and I'm sure you have seen such patients where, you know, you're sure this works for this patient. Then that is proof that it will work. It's maybe, you know, it won't maybe work for everybody. And it might, you know, the target might've been lucky in this one and unlucky in the other one. 01:18:02And, and so on. You know, what's interesting. I, you know, particularly as the papers, have evolved and you know everybody i feel like it's a the greek chorus in a you know uh an ancient you know theater where you know each side is you know playing commentary all the time you'll watch patients respond in blogs you know when industry trial failed people say oh yeah we knew it didn't work and then other patients going what worked for me and i'm not entitled and and the the ethical discussions about what's good enough you know if something is safe should you have access um what is the bar you know what does it mean to be a patient with a device that is working and knowing that other people don't have access and there's a powerlessness in in that in that also but i think every clinician again you can you know placebo effects are profound in many 01:19:02situations we have an ongoing naturalistic test that this is not placebo because when a device breaks or a battery dies and the patient hasn't checked it and you replace the battery and fix the device after you've lost the effect and you need to um if on the front side you can't prove it's not placebo that's a true statement because you haven't done the experiment but you have the naturalistic experiment i'm done that's that's not the that's not how we should be spending our time arguing about if it's real we should be spending our time about is it worth it you know there's discussions about well it's a first world treatment yeah yeah it is but if we can understand what we've done in these intractably ill people to get them better and keep them better it will teach us something so fundamental about what depression is that it will scale in a different direction to other parts of 01:20:06how we treat depression and how we treat people and how we treat people and how we treat people so while now it is a first world treatment and i can't i can't control that but i can work to have fundamental understanding so it could move to be non-invasive or we could learn something that could be leveraged in another way but to do that in the absence of understanding these clues would really be a missed opportunity great thank you thank you so much helen for this um uh great opportunity to to talk with you well you know it's it's very um it keeps me going to know that people are interested and and i know i get a lot of reinforcement from the patients but but in fact this is a privileged position and and this has been really fun and i hope i can continue to make something you know meaningful contributions because 01:21:07i want to thank you for listening to stimulating brains