00:00Initially, nobody tried to hide it. So stereotactic functional research ring really was initiated to replace. They were stimulating with 10 volts on each side. And I used to say to Lozano, my car has 12 volts on one side. Are there electrodes in the brain? Well, one should, of course, not forget the pre-psychosurgical history in the realm of stereotaxis. So when Horsley initiated cortical surgery, right? So when people say today that it was the neurosurgeons alone, this is a myth. I have seen orgasm during surgery. I have seen sexual fantasy. I have seen many, many things. People crying, people laughing, people, you know, during intraoperative stimulation. Welcome to stimulating brains. 01:25Hello, and welcome to stimulating brains. As you could probably tell from the teasers, this episode is a special one, not only because we get to discuss the resonance of psychosurgery in the history of stereotactic and functional neurosurgery, but also because we get to do that with a celebra troika of world experts. Join us as Dr. Jochen Kraus, Dr. Marwan Harith and Dr. Christian Moll remember and reflect on the history of this field, but also infect us with this idea of a serendipitous model that can drive discovery. 02:00Now to address the elephant in the room, you're probably wondering, this doesn't sound like Andy. And you'll be correct in assuming so. My name is Ala. I'm a PhD student at Western University Canada, and I am delighted to be the one who prepared this episode for today. I leave you off with Andy, who will guide and facilitate the rest of this episode. And I hope that you enjoy it as much as I did. Thank you. Thank you so much, Joachim, Marwan and Christian, for joining me for this special episode of the podcast about the history of functional neurosurgery, but also potentially psychosurgery. And then also another topic we have today is serendipity. And I think that's a really important topic in discovery science 03:02and especially in neurosurgery. Since Marwan and Christian have been on the podcast before, in episodes one and three, actually, we hear Joachim for the first time here. So to break the ice and before we get into the science, I always ask about free time and hobbies. So since you're new, maybe you want to share a bit about what you do and what you do in your free time. I must say I do a lot of different things besides medicine. And well, I would call these hobbies, but it's just being involved in different types of nature. I listen to a lot of music. I love to go to concerts. I love to go to art shows and I love to go hiking, kayaking. One problem I have with music is that I always cut in between forms. So it doesn't matter if it's metal music or classical music. 04:01And Marwan knows he'll come with me one time to concert. And so I really had great joy listening to music. One reason is I cannot listen to music while I'm doing surgery. It's completely impossible. I would be completely distracted. But if I would not be that heavily involved in neurosurgery, I think I could do a lot of different things. Great. Okay. So music and then metal music. Did I hear that right as well? It's extreme forms. Actually, it's not really metal music. It's some kind of, I would say, extreme metal music. Can you name some groups or bands? Well, Mayhem. Okay. More that kind of drone music, Earth, Sun. There's a lot of fantastic stuff out there. I read. I read this covered just a couple of years ago, going to festivals again. 05:00And just great joy. Amazing. That sounds great. Would you have listened to music while operating, Marwan? I don't listen to music while operating. Okay. I don't like it. I want to concentrate. I'm like Joachim. Okay. I mean, our eyes completely forbidden. I say. It's forbidden now. Okay. I see. Yeah. And then can you share a bit who are your key mentors in your career? Joachim. Well, I've been into a lot of different fields to be true. Actually, I started my thesis on the Basal Ganglia in neuropharmacology. So my key mentor was Professor Meyer from Freiburg. And at that time I wanted to be a pharmacologist. Actually. Then somehow I got into neuro energy and I always had a very big interest in movement disorders. 06:03So it was I was very lucky and fortunate that I met Professor Munding up in 1985 in Freiburg. And then I joined his department and somehow this was a key vision for my further career. Of course. And I looked at all of the films. I saw the videos he had from all the patients. It was also my start of being interested in history. And then, of course, I went to micro surgery with Professor Segar. Again, I focused a little bit on movement disorders with peripheral denervation and so on. And then I had another jump to a different aspect working with Bob Grossman and Joe Jankovic in the United States for two years. And then I started doing panendotomy, thalamotomy, which I did already before in Freiburg. And later the next big influence, I must say, was Tedios Mitak, who taught me how to do vascular neural surgery. 07:07So I got a lot of different twists and turns that brought me to the mix I'm actually doing both in daily work and also in my scientific research. Great. And you are a neurologist as well, correct? I'm a Facharzt. I'm Facharzt for neurology. So I started my training with neurology, then went back to neurosurgery, back to neurology. But I'm very actually proud that I'm Facharzt for neurology. Very nice. But my work, of course, is neurosurgery. Christian always talks when he talks about the history about surgical neurologists or also neurosurgery. Also, neurological surgeons, I think. So that fits your description as well, I'm sure. 08:00So, yeah. One last question, more focusing on you, Joachim. We heard from Werle Wissawander-Walle in episode 31 just recently that, and I think I've seen it in your talks quite often, that 1999 was a special year for the brain simulation with three unique papers all published in the same journal in The Lancet. And one of them was yours and involved, I think, the first three cases of palatal deep brain stimulation for dystonia. First of all, is that correct? Were these the first cases? And then also, can you tell us a little bit what led up to this trial and about the impact it had at the time? So actually, they were the first three patients who survived dystonia. And so how did I come to do that? I was in Houston in the mid 1990s. And I saw something. There were some dystonia patients. So we did regular paludotomy on the PD patients. And we started also to perform paludotomy on dystonia patients. 09:03And until then, the main target actually for dystonia was the thalamus. Many people now think that the main target was the paludotomy. But it's not true. Paludotomy was not a surgery that had been performed regularly for dystonia. It was always thalamotomy. But then Bob Grossman, he was a bit hesitant and he wasn't sure if that would work. So then I went to Switzerland from Houston. And when I came there, I had several patients who were waiting for me for surgery with cervical dystonia. And they showed me some patients where I should do peripheral denervation. And some of these patients were so severe, severe retrocholitis, problem with swallowing. So I saw peripheral denervation is not a good option. And I thought, now I have the chance to explore the GPI as a target for dystonia. We went to the editorial commission together with Jean-Marc Gugunder. 10:03And we started with the first patient. And we told the patient, we are not sure what will happen. And we hope you will improve. We have a good concept. We did the theory. It should work, but we're not sure. And the patient had a fantastic response to other patients. And that was it. And that was the birth of a palatal DVS for cervical dystonia. And also, of course, these were some of the first patients worldwide for dystonia, along with Mobeye and Oxford. Yeah. And when we were very lucky to publish in The Lancet, it was difficult to publish because people initially just did not believe it would work. And they wanted to have a bigger series. But of course, it takes some time and you always need a pilot series to start somehow. Sure. Yeah. Great. So the first cases you mentioned, Mobeye and Oxford, were then generalized dystonia, I assume? Yeah. 11:00I think at the same time, also in Toronto, Andrej Zluzano had a patient who was generalized dystonia, Philippe Coupe and Mobeye, and then Tipu shortly thereafter also in Oxford. But I must say generalized dystonia became much more readily accepted as an indication. And I would say five, two. Ten, 15 years that severe dystonia was accepted as well. Makes sense. Yeah. May I ask the question as well? Andy, of course, please. That's pretty interesting what you say. Could you perhaps specify a bit who you mean with the people just didn't believe so? Who in the community didn't believe in it? For what reasons? The neurologists? I mean, the old neurosurgeons would have believed, right? They perhaps were not the referees for your paper, but who? Actually, nobody believed it. Nobody believed it. 12:00Neurologists didn't believe. I sent a paper to Google Disorders. They said, well, this is very interesting, but maybe submit it again when you have more patients, when we see that it really works. I understood, of course, in a way. And then also all the neurosurgeons didn't believe it. I remember I was in Hamburg in 1999 and there was an old elder gentleman sitting in the audience and the functional neurosurgeon. He said, what the hell are you doing? He mixed up the target. Did you say political stimulation? Why did you do so? So it took some years to convince people that this really works. And I just... I mean... Please... This is the same phenomenon than when we started posteroventral paludotomy for Parkinson disease in the mid 80s. 13:02And I was at two meetings in Paris and... ...Fried and... ...said to me, this is rubbish. This is obsolete. This is something that is abandoned. The paludon has been abandoned for... What are... What are you talking about? And... became a citation classic and the whole world then did post-seroventa pallidotomy. And the second thing I want to say is that Verle van der Walle, with all due respect, is wrong. It's not three papers in 1999, it's five papers. It's a paper about Tourette by van der Walle, it's Nuttin about OCD, it's Joachim Krauss about cervical dystonia, all three in Lancet. And then there is a paper in Vue neurologique from Bonpellier, Philippe Kube about DBS for generalized dystonia, also in 1999. And the fifth paper was from Kumar and Lozano in neurology about DBS and the PET study in generalized dystonia. And that 14:06paper is interesting because I asked Lozano, you are stimulating, I can send you the paper, I have it in front of me. They were stimulating with 10 volt on each side. And I used to say to Lozano, my car has 12 volt on one side. Are there electrodes in the brain? This was a paper that was also a pioneering paper, 10 volts in each pallidol. Wow. I have to defend Verle quickly because it was more me saying three papers, not her. And I know that from Joachim's point of view. Okay. It was her talk. So it was not her saying that. I just want to make her said that right. It was my fault. I blame you. It's five papers. Five papers. Good to learn. Always great to learn. Yeah. Thanks, Marvin. That's very interesting. 15:01And I agree. 10 volts. Yeah. That's a lot. On each side. We wanted to focus this episode on historical origins of the brain simulation and also functional neurosurgery. 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 The first one is Marwan and Joachim are authors on it, along other colleagues, and it entails the involvement of psychosurgery in the history of functional neurosurgery. So in a way, I think it makes the point that psychosurgery was a direct predecessor of the modern, more neurological, quote unquote, functional neurosurgery. And then the second is first authored by Marwan and has made strong waves this year about the impact of serendipity in functional neurosurgery. So maybe we can start with the first paper. And I would like to start asking Marwan, is it even possible to summarize in brief what people think now historically about the term psychosurgery? 16:09Who were the key players? What were the origins? And how did the key events unfold? The initiative for that paper. The initiative for that paper was from Joachim, together with Clara, what's her name? Ressi? Lara Ressi-Czech from Berlin. So the initiative was from Joachim and Lara. And this paper, actually, I learned a lot from this paper because, among other things, the picture about the first functional neurosurgery, stereotactic neurosurgery. What? The first functional neurosurgery was censored. So you find this picture everywhere with Spiegel and Weiss is operating and it's taken from Life magazine, I think, US magazine in the late 40s. And it is censored in the sense that that was a psychosurgical intervention. 17:05And one of my heroes, actually, my colleague who is dead now, who was student of Spiegel and Weiss, his name is Philip Gildenberg. He was the opponent in my PhD thesis here in Umeå. He always said that the first surgery was surgery for Huntington, while the paper demonstrated that the first surgery was the medial dorsal thalamotomy for for psychiatric illness. And the paper that we're talking about said that, as Mundiger said, that psychosurgery was progressing in the in the in the 60s and 70s in silence. So it was like under the radar. But then if I have to be co-author again on that paper, I would say maybe it's not so true because there have been a society called the International Society of Psychosurgery that had meeting the first meeting in Lisbon 1948, the second meeting in Copenhagen 1970, the third in Köln. 18:13And then the second meeting in Copenhagen 1970. The third in Köln. Cambridge 72, the fourth in Madrid 75. And the last was in Boston in 78. And this is there are pictures of everybody there. There were a lot of psychiatrists, neurologists, neurosurgeons, etc. And the key player on the neurosurgery side were Bill Sweet, Sixto Obrador from Madrid, Laurie Leithonen from Finland at that time and then Sweden, Björn Meijersson from Sweden. And many others. And they have proceedings. It's very interesting. These proceedings, you don't see them on PubMed. But I have all the books. And there were a lot of papers on ethics, a lot of papers on trials, a lot of papers on the involvement of psychiatrists, etc. 19:02So why I'm saying that is because there was a society of psychosurgery that had several big meetings that was multidisciplinary with many non-psychiatrists that were also psychiatrists. And they were also involved and wrote papers there. And this is contradictory to what we hear today that the neurosurgeons were alone, were like cowboys without multidisciplinarity, etc. This is wrong. This is a myth, a mantra that we hear all the time. Okay. Actually, when we started with this project, in the end, we had two papers and we published two papers with Laura and Marwan. The first paper was on the origin of functional stereotactic neurosurgery. And the second paper was on the hidden agenda, a little bit of hidden agenda of psychosurgery in the 60s and 70s. 20:01So it was two different papers. And I must say also, I wrote an article with Phil Gildenberg. Phil Gildenberg was also useful. I met him there. And so we wrote the chapter for the... Big textbook on functional stereotactic neurosurgery. And I do not know why Phil actually said that the first surgery was indeed for Huntington's disease. So that was also written in this chapter. And not only us, we made this meeting, actually everyone did. And as Marwan said, it was somehow censored, but so it was great. But I need to rediscover the history. So Marwan, me and Laura, we looked into the original data and it was clearly there. And initially, nobody tried to hide it. So stereotactic functional neurosurgery really was initiated to replace lobotomy and leukotomy. 21:02Yeah, absolutely. And the stereotactic technique, right? The stereotactic technique. And later, of course, there were all these troubles and traumas and negative breaths with psychosurgery. And then somehow people wanted to get rid of their past and history. And then it was the myth that ancient stereotactic neurosurgery was invented for movement disorders, which obviously is and was wrong. Well, one should, of course, not forget the pre-psychosurgical history in the realm of stereotaxis. So when Horsley initiated cortical surgery, right? There's many decades of cortical surgery. There's many decades of cortical and subcortical surgery. Before the surgeons really dared to touch upon subcortical structures, it took quite a while. And following Horsley's operations in 1890 and so on, quite a considerable amount of work had been carried out in surgery for movement disorders. 22:06And basically in parallel to psychosurgery developing. And but these were all mostly. Surgical interventions that were focused on the on this surface of the brain. So the surgeons were obviously hesitant to touch upon the deep structures. And that's the main issue, I think, about psychosurgery, because then the focus changed to the white matter tracks and to subcortical aspects. It became more the focused and still we take the same. Operative. And. Operative. Track from prefrontal and pre coronal areas of the bone. We still use this for movement disorder surgery today. But what I wanted to say is that we should, of course, not forget that following Horsley, Paul Bussey, 23:02Ottfried Förster and all these heroes of surgery who worked on in the domain of movement disorders were also very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. And they were very active. who just then remembered the stereotactic device that had been invented by Horsley and Clark and that he used this. But it didn't took very long that the subcortical structures and this method was then also applied to the field of movement disorders. And this, of course, then took over and became the primary focus of functional neurosurgery. 24:11This is a great discussion. One second, just for the listeners. So what I wanted to make clear again, the central topic of the paper, I think we haven't summarized that yet, or the claim, if I might be able to summarize it, is that psychosurgery was there. It was there for a long time, but then it was no longer had a bad taste at some point and then was silently further developed into something and was then forced to become more neurologic. And I think in that concept, you now mentioned a few things. First of all, Huntington's disease apparently was the first case, not psychiatric illness. So let's say movement disorders cases were there from the beginning too. And then when Grenoble happened with essential tremor and so on, at that time, nobody dared, 25:06or not so many people probably dared to do psychiatric indications at that time. Is that still correct? That there was the reinvention of the same thing happening around the 90s? Yeah. Can I talk? Of course. Of course. It's at least in Sweden. Yeah. Yeah. In Sweden, I am brought up with capsulotomy, cingulotomy, thalamotomy, paludotomy, dentatotomy, osteomedial hypothalamotomy. So it was done, but it was done much less than movement disorder. And the reason is that the referrals were much less. Very few psychiatrists. They had or wanted to refer patients. 26:02But if I can just get back to one of the issues that why this fear, this panic of psychosurgery that Joachim mentioned, and this is a question to Joachim too, because in the chapter in the big textbook of functional and new serotactic neurosurgery. Yeah. The history of serotactic neurosurgery in Germany, Joachim. Yeah. You didn't mention at all the experience of Göttingen, of Voder and Ochner and the people who did surgery in Göttingen. That was mostly, but not only, mostly psychosurgery, sexual deviance, pedophilia. Yeah. And also pallidotomy. So how can you explain that? 27:06Well, I would say, you know, for some time, people just did not talk about it much. I would say in the early sixties, psychosurgery still was there, but by then in the, I would say mid sixties, in the end of the sixties, you just got a very bad reputation. That was because of new ideologies. Yeah. Yeah. New ideology, new politics. And then often people just didn't talk about it. So in the way that we can talk nowadays about psychosurgery, even use the word psychosurgery again, that is also something new. And the process of re-evaluation and also even if we're living in a cancel culture society, we still now can re-evaluate what happened with psychosurgery. Yeah. Yeah. And so this is kind of unique today because for example, when you give a lecture now, yeah, 28:01to students, you talk about psychiatric neurosurgery. People just listen. Nobody gets excited. If you would have done so 30 years ago, I think they would have escorted you out of the lecture hall. So I think it's also the sign of the times, different attitudes, different ideologies. And these changes to my opinion, do not happen in the same pace. Yeah. Yeah. And so I think it's also the same in each place in the world. So we also have different cultures where, for example, Japan where it's completely possible to do psychosurgery, even nowadays. And I think the world has become much more diverse now, even if we have new and more information. But it's always different attitudes. So always what we say, we talk from a European or European-American perspective. Yeah. And so to these people to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to 29:25of the stereotactic surgery that was done by this Göttingen team was also on movement disorders, right? So it's about 15 to 20% that was psychosurgery. And that is about perhaps Freiburg did a bit less psychosurgery because they performed movement disorder stereotactic surgery on an industrial scale throughout the 60s and 70s. That is perhaps a bit different. But overall, it's not that the Göttingen team did psychosurgery only, right? And this is just something that for me was important to say on this occasion here. I know, I know. We have published 30:05a paper together. Oh yeah, right. I remember. Yeah, yeah. I know. But they published the psychosurgical experience. Yes, yes. But can I tell you why? So why would they publish and why would they... Well, I think it's because they get this label of they are the prime, among the prime psychiatric surgeons in surgery because they developed this hypothalamotomy, right? And the ventromedial hypothalamotomy. And this was then kind of, this is the dream of every stereotactic neurosurgeon, right? So to have a label and a surgery that is your own, that is your baby, and then you publish it and then you follow the lines and then... So it's the most credit and the most, it's the most rewarding thing for a surgeon to invent this type of surgery, right? And this is how they tagged or this label became attached to the Göttingen team, right? 31:05And the first DBS in the more or less modern era, used a quadri-polar electrode, was done in Germany by Diekmann in Homburg-Saar. Yeah. For one patient and published in 1980, I think. Did you meet Diekmann, Joachim Enmermann? Was he present on the conferences when you... Well, if you ask me, Christian, you know, I said before there was one elderly gentleman at Tech. Okay. I wasn't... No. And talking about the pallium as a target. All right. So that actually was Diekmann. So I met him, yeah. Okay. That's interesting. That is very interesting. 32:02So that was 10 years before Grenoble then. And you say that that was with four electrodes and was chronically implanted as well? Yeah. I can send you the paper. I would love that. We can add it to the show notes as well. I think, Joachim, you have mentioned different cultures over the time. Of course, right? You would have been escorted out of the lecture hall if you even talk about psychosurgery 30 years ago. At that time, can... Because I was not... I mean, I was alive there, but I was not, you know, thinking much. Can you elaborate a bit? How do you guys think what led to that? You know, did the counterculture and LSD or the hippie movement play a role or was it really more the movies? Like... What? Like, one flew over the cuckoo's nest or Crichton's Terminal Man or... What led to that change of all of a sudden being so against this concept, in your opinion? 33:01I think... Question to everybody. I think a lot of different topics came together. First of all, people realized the misery sometimes of a lobotomy, leukotomy. That people just lost the interest, lost their will. And of course, also, it was a sign of the times, the 60s, when people revolutionized against older institutions. And they started to question things that were established before. And another strong impact, to my opinion, was psychoanalysis. Because the concept of psychoanalysis, of course, was in a way that you have the soul, there's a soul, there's a mind, and there's a brain. Yeah. So it was... Yeah. It was a different concept. It was a lot of biological concept, psychoanalysis. And so when you look at it from a psychoanalytic view, and really question how are you allowed to do such a terrible thing to modify somehow the basis of the mind, mind and soul. 34:13And I think that was one of the major things. And then what you said, like the film, I think that one flew over the cuckoo's nest. I think that had a big impact because then it became very popular. People went to the movie. It was a fantastic movie. And you saw Jack Nicholson. You saw the big Indian guy who was transformed into a will-less person. Before he was a sympathetic lady, he was just sitting there. And so I think it was different issues that came together. And then... People realized and suddenly the revolution in psychiatry, when they opened up the psychiatric wards and everything came together. And then it happened. 35:01And if you still would try to defend psychosurgery, you would be a bad guy and a culprit affecting the past. Would you think some of these concepts apply today as well? Or is it really the more very devastating effect sometimes of flubbering? I think it's a very different thing than what we're doing right now, I would say. But, you know, could... Yeah, sorry. No, the criticism still lingers around, right? I mean, the times have changed. And so the mind has opened and the public has participated in the discussion. The politics had strong impacts and authorities were questioned. And... Yeah. So this, of course, is something from the past. So we are now in... So this is perhaps not the... 36:00Something to ask to criticize now. So the authorities, so the relationship between the physician and the surgeon to the patient has completely changed. Also due to this development, right? Due to the 60s. But still this discussion and this very... Intuitive reflexes are still lingering around in terms of criticism. So and I can understand that from a point of view that, of course, psychosurgery, you know, it touches upon the core self of people and people can really connect to this. And it's much, you know, it's... You think like, okay, it's what would happen to me if I woke up the next day? And I wouldn't be able to do that. I wouldn't be the same person. So this core fear that everyone can connect to. 37:00I think there are different levels that intermix still today when it's about the criticism. So it's very difficult, in other words, to dissociate these levels of criticism and to just talk about psychosurgery. Just to talk about it. Just to talk about it. Just to talk about it. Just to talk about it. Just to talk about it. Just on the very, say, objective and factual based medicine side. That is very, very difficult to convey. I think. And the... It's a critical issue. Right. To make people understand that they learned from history. And that the psychosurgeons are no more, you know, let alone. And can do what they want. And so on. And so forth. And. then it's very important to transfer the knowledge and the progress that has been made throughout the last 50 or 60 years in the domain of functional neurosurgery and network neuroscience 38:02to convince and to stand these very understandable reflectors. I think when you mentioned, Christian, that surgeons are not let alone anymore, I think Marwan always brings up a very good point about that, that even also in the past, it was not just surgeons acting alone. It was sometimes even neurologists being left by their surgeons. Marwan, maybe you've mentioned that quite often. So I think that's a valid point here. Have you seen this book? So Marwan is showing a book, Studies in Lobotomy by Milton Greenblatt, Robert Arnott, and Harry Solomon. I have not seen it. Okay. This book. It is a book authored by neurologists, neurosurgeons, psychiatrists, psychologists, occupational therapists, physiotherapists, rehab doctors, students, et cetera. 39:00A huge thing. Everything. Sexual issue after lobotomy, urination after lobotomy, rehabilitation of everything. A truly multidisciplinary book from 1950. 1950. So when. People say today that it was the neurosurgeons alone. This is a myth. If you go on the street and you ask somebody who is responsible for lobotomy, they will tell you the neurosurgeon. This is wrong. The most, the most fundamentalist for lobotomy have been neurologists, psychiatrists, even operating themselves in Norway, in Sweden, in many places. Don't forget that James удa surgeon Adam Fremont. that it was Freeman who popularized this. He learned this lobotomy with the ice peak from an Italian psychiatrist in Varese in northern Italy. 40:05Agas Moniz, he went around in the world and instructed psychiatrists how to do this. Neurosurgeons were very reluctant. And I will mention here just one thing. So I cannot show you, but I will read it. It is the first Congress of Psychosurgery in Lisbon. That was the first Congress in Lisbon in 1948. 26 countries were represented, none from Germany at that time. That was after the war, etc. But the interesting thing there is that, and I will read from the book now, one of those who were at that meeting in 1948 wrote a memoir, and I will read. At that meeting there was Scoville, who was a neurosurgeon, who described a method of just opening here and sucking in the section. 41:03It was called section of part of the frontal lobe instead of the big lobotomy from here or from here. And Walter Freeman, not very kindly, said of the technique used that it was like putting a vacuum cleaner into a bath of spaghetti. And trying to make a clean incision. I will send you the slide that is in front of me from that book. So Freeman was criticizing a neurosurgeon who tried to develop a technique that is less traumatic, less invasive than lobotomy, saying that it was like sucking a bath of spaghetti. So this was the attitude of some psychiatrists. And neurosurgeons, if you look at the proceeding of the psychiatry, the different meeting I was mentioned, they urged Laurie Leighton to propose a trial of psychosurgery, 42:02which was capsulotomy and singulotomy, versus best psychiatric treatment. The same as Deutschel has done for STN-DBS, right? Best medical treatment versus DBS for STN. That was proposed several times by Leighton, but the psychiatrists were not interested. And that was in the 19... early 1970s. So the neurosurgeons were not alone. It was the psychiatrists and the neurologists who were alone. May I make a side remark, Andy? Of course. Just bear with me that I have... I suffer from Germany-centric myopia in this respect. But Marwan, if you look at the photograph from 1948, where all the participants of the symposium and Lisabon came together, from a German perspective, it's actually very interesting to note that although it's shortly after the Second World War, 43:00and obviously German physicians had difficulties to attend international symposia at that time, you find some of the German... you find some German participants, and in particular, it's Traugott Richard from Freiburg, who participated in the symposium, not with a stereotactic contribution, but it is most... likely that he learned here about Spiegel and Weiss's, because Weiss's was also participating in the symposium, and took these ideas then to Freiburg. That was 1948, and just shortly before he started with his own career to construct a stereotactic apparatus and so on. That's just a side remark, and has nothing to do with the whole story. Thank you. But for a German perspective, it may be of some importance. Thank you. Thank you for this clarification. But were there any psychiatrists from... 44:00Yes, yes, there were two. At least I could identify two of them. Köpke from Tübingen, and Sud, I think he was... Was he in Frankfurt or Berlin at that time? I don't know. But yeah, there were some psychiatrists as well. Well, he's not very well known, but after we had attended that conference, he performed some necrotomies in Freiburg as well. It's not a big experience, but some cases, and that was before they started to do function stereotactic music. But then somehow in Freiburg, the focus shifted very soon. Yeah, yeah, yeah. As elsewhere, as elsewhere, as elsewhere, right. So how... Sophie? So moving to the more modern time after DBS was reinvented in the 90s in Grenoble, we did briefly talk about the first case 45:01by Wehrle-Wiss-Wandewalle in 1999, which was Tourette's. And I think Wehrle quoted you, Marwan, indeed, in this case that you said this was maybe the first neuropsychiatric indication in the modern era with DBS. And then of course, the same year, also 1919, also 1999 OCD by Bart Nutter with the first cases. So how did the feeling shift and why did we start then DBS for psychiatric diseases again? Shall I start? I think it was omitted again that if you don't mention lesions, not even stereotactic lesions, that would appeal more to the psychiatrist. And this has been going on since 1999. So it's like 24 years, which is still in gestation. 46:03It's a chronic pregnancy. It still has not delivered because they tried to fool the psychiatrist to be more approachable, more keen on referring patients by saying that this is not a lesion. This is deep brain stimulation, reversible. We can shut it down, et cetera. And many psychiatrists, they don't care. As long as you enter the brain, it's for them, it's surgery. And I think that this is the main issue because they are replacing a cheap, efficient therapy called singulotomy or capsulotomy with a very expensive one that is DBS that can help. Of course, I have done it. And we know it helps. But this has been something that the companies have reacted to because now in Europe it's not approved for OCD. 47:02Even in Germany, you have to seek approval. And the reason is that it was approved for a while. I mean, for OCD, DBS was approved. And now again, you have to seek approval. Yeah. And the reason is not. It's not. It's not profitable enough for the industry. But the issue is that the main issue is that and I was at the first meeting. That was, I think, in Ex-Lebanon in 2001 after that Nutan started in 99. And they thought that this will be the second chance for psychosurgery to come back. And if we look at the result 23 years later, it's still very, very, very few patients who are referred to OCD or Tourette or depression. May I say something? 48:00I think why Tourette? Why did we first see DBS in Tourette? I think that's because somehow Tourette is on the border zone between movement disorders and psychiatry. So to my opinion, it was. Yeah. It was to my opinion to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to rooted in psychological issues, then let's say dystonia or Parkinson's disease, pre-monitory urge, then the storm of ticks, when you suppress it and so on. 49:01But it's just the way to accept it easier in a movement disorder than in a psychiatric disorder. With OCD, I don't fully understand why OCD became that readily accepted. But one reason might be that OCD might be seen, like many other movement disorders, like a circuitopathy. Like we can say, okay, we have the adenocleus, we have the amygdala, we have the internal capsule, and below the circuitry. Which is not the case for that simply for schizophrenia or depression, which is much more complex, it's more of the whole of the brain. But I still don't understand why OCD smunks. It's more important, as you say, in Germany, which is regularly accepted by most. The question is as to how far this theoretic background with a circuit being involved, providing a rationale for surgery, as to how far this really played a role 50:01when Barton Norton started his work on OCD patients, right? I think with OCD, it's like there had been a lot of experience with OCD also during the stereotactic lesional area. And this is certainly different from Tourette's. I mean, Tourette's, with Tourette's, there have been, I think, very few patients with Tourette's had been treated also during the lesioning area of stereotaxy. But this was different with OCD. So OCD became one of the mainstays of psychosurgery actually after the open psychosurgery had been abandoned. Yeah. So, yeah. So, yeah. So, yeah. So, yeah. So, yeah. So, yeah. So, yeah. So, yeah. So, yeah. So, yeah. So, yeah. So, yeah. So, yeah. So, yeah. So, yeah. So, yeah. So, yeah. So, yeah. So, yeah. So, yeah. So, yeah. OCD and aggressive behavior, that was, I think, these three were the cardinal, the three main indications of stereotactic Psychosurgery, if I'm right in this respect. 51:00And perhaps it may also be interesting to think about the lastly mentioned behavioral disorder abnormality that had been widely treated and had been at least in the domain of functional psychosurgery, and it was an accepted indication, so to speak, in parallel to OCD and to schizophrenia. What happened to these patients? Maybe interesting to think about that. I'm not suggesting this is a new hot topic. It should be treated, but it's interesting, and it also confirms what Joachim mentions, is that the hesitancy to talk about this topic. So, okay, with Tourette's, it's closer to neurology. With OCD, well, yeah, there is some behavioral output, but it gets more and more difficult and more complicated 52:01and even more black the box. And when it comes about these aggressive, autoaggressive behavior, then it may have been very difficult to tackle this subject at that time. But it had been one of the main indications. One of the best papers on lesions for Gilles de la Tourette is from Freiberg. I have it in front of me. By Babel, Warnke, and Osterdout. Published in 2001. But this is an experience from a long time ago. It's a fantastic paper about lesion in the thalamus and infratalamic area. And there is a quality of life. There is activity of daily living. There is a lot in this lesion paper. And now, I know that in some places, 53:01lesional surgery is coming back for Gilles de la Tourette, especially in the capsule. And one of the papers was Mark Hallett, who was on that paper, is from China. Mark Hallett is co-author of Pallidotomy for Gilles de la Tourette. The other thing I want to say is that when it comes to DBS, the STN accepted. If you accept the STN from this, all the targets that have been lesioned, somebody come and put an electrode. So why the capsule for Bart Nuttin? That was actually the idea of Björn Mertz, who was on the paper. Although the patients of Björn Mertz were never reported in that paper, the Newtown paper in 1999, it should have been six patients. It was only four patients in the Lancet paper. But this is another story. So I'll tell later. What happened is that Van der Walle put an electrode 54:05where Hassler did the lesion. Ben and Abid put an electrode where the thalamotomy. Jean Siegfried put an electrode where lightened palidop. All of them, except the STN in movement disorder, were lesion targets. And the same in psychiatry. The posterior medial hypothalamus, the cingulum, the arterial capsule, the bed nucleus of stria terminalis. The bed nucleus of stria terminalis was lesioned by Bursaco, neurosurgeon in Spain, a psychosurgeon in Spain. And they put Nutan. They put an electrode there. So my opinion is that all this is mimicking the lesion. And why? Because the circuitry that some people are rediscovering today, thanks to tractography and functional imaging, etc., they knew the circuitry. Spiegel himself, he explained in a nice paper 55:02why he chose the dorsal medial thalamus. Well, he chose the dorsal medial thalamus because after lobotomy, the valerian degeneration was passed down to the dorsal medial thalamus. And he said, if you have a dorsal medial thalamus, you can't do this. So he said, if you have a dorsal medial thalamus, you can't do this. So he said, if you have a dorsal medial thalamus, you can't do this. So Spiegel published the same year from the orbit of frontal cortex was back to the thalamus. So Spiegel chose, based on this circuitry, the medial dorsal thalamus as a target. While Tallerac, instead of the thalamus, he chose the fibers doing the anterior capsulotomy, the fibers from the thalamus to the orbit of frontal cortex. And don't forget that the circuitry of Papes was published in 1937. And he said, if you have a dorsal medial thalamus, you can't do this. So Spiegel published the same year from the orbit of frontal cortex. And don't forget that the circuitry of Papes was published in 1937. And most of the targets for both lesion and later for stimulation are on different nodes, different points in the circuitry of Papes, the circuitry of emotion. That was tracing studies, not imaging studies. Absolutely. And I personally, even though I use tractography, often look at the Hasler books and so on to get the information that I can get. And I think that's a very good point. And I think that's a very good point. And I think that's a very good point. And I think that's a very good point. I use tractography, 56:00often look at the Hasler books and so on to get the actual knowledge. And so I totally agree with you. A lot was, much more was known back then, I would even say. This is the perfect segue into the second paper that was authored by Ma Wan, I think his first author, and with several co-authors as well. The central, that's a serendipity paper. So the central take there is that serendipitous discoveries, for example, with a stroke leading to death or leading to a symptom improvement or symptom worsening, have been driving the fields of neuromodulation and functional surgery and not so much in contrast maybe what we would think, which could be translating things from animals to humans, which is the mainly funded model. That's what everybody thinks. So your paper, I think that did a great job and opened the eyes of many people actually to see, no, if we just look back there are not so many wins 57:00for that classic model from animals to humans, but it's usually really from humans to humans. Do you want to say a bit more broadly about this topic Ma Wan? I think the best one to say more broadly about the topic is Joachim, because I think he reviewed the paper and accepted it eventually. Okay. Well, I cannot see anything new, of course, but I know that you reviewed the paper. I always like to read the paper, Ma Wan, of course. Thank you for accepting of the modification. Did you have doubts that it would be accepted, Ma Wan? He wanted me to change the title. He wanted me to say Serendipity and Observation. That is the title. As if serendipity didn't include observation. Anyway. Of course, I cannot say anything about it 58:00because I should know. Okay. Andy, you are in this field better known than anybody else. Tell me which targets have been implemented in humans based on animal model except the STL. Exactly. So I very much agree with you, but it still opened my eyes. That's why I think it's such an important paper. So Mike Fox, my mentor in Boston, is also a great fan of it. And we've been discussing it really a lot and thought about can we find different counter examples. And I would even say even the one with Hagai Bergman's STN lesion paper, you could still say that the MPTP model, which is a great Parkinsonian animal model, still came from humans, right? From serendipitous discovery with the frozen addicts and so on. So even, you know, you could say that came from humans 59:00to monkeys and then back to humans, which I think is maybe a better model to find serendipity, then go to the animal to study it better. That makes a lot of sense to me. But I think we talked, we keep actually now challenging also sometimes basic scientists to give us good wins and good examples. And I think some have come up with some stories in MS for drug discovery where I think there are a few wins, but it's very scarce. There's not much that we can really say, oh, this was an animal discovery. It worked in the animal and then it worked in the human, especially really nothing in functional. Do you have examples? Yes, there are two. To my knowledge, there is the STN, which was a lesion, not a stimulation to start with. And there is the PTSD. I published a review paper of animals and human work with the PTSD. The stimulation of the amygdala is based on hundreds of animal models 01:00:02of post-traumatic stress disorders. And there is a huge literature on animal models before Langevin was the first to put electrode for PTSD. And this paper was rejected actually from a brain simulation and eventually published in Pseudotactic and Movement Disorder. And you know why it was rejected from Brain Box, because it was not a good simulation? Because our conclusion in the paper, me and my fellow who is a psychologist from London, we said that post-traumatic stress disorder, which is very common in war veterans, you know, in the US, in people coming from Afghanistan and Iraq, soldiers, we said in that paper, as conclusion that PTSD is probably the only psychiatric disease that can be prevented, preventable. Don't send them to war. Don't send them to war. Yeah. And you don't have it. And it was rejected flatly by the reviewer 01:01:03because it was politics, which is rubbish, of course. Anyway, so PTSD with amygdala and SCN with Hagai Bergman and Tipo Aziz, don't forget the year after, Tipo Aziz confirmed the same model, the same, well, with the same model. So apart from these, animal work is done after human work. I mean, Lozano, he publishes mice and rats swimming around after he discovered by serendipity that the electrode was in the, close to the phoenix. So functional neurosurgery with the patient awake, not like today everybody is asleep, is a fantastic laboratory. You learn a lot. I have seen orgasm during surgery. I have seen sexual fantasy. I have seen many, many things. People crying, people laughing, people, you know, during intraoperative stimulation, 01:02:02just by, by, and this sometimes can lead to too much serendipity. Yacine Temel, my friend from Maastricht, he thought he discovered the center for erection because in the Tourette patient, the three Tourette patients, they had one who had hypersexuality, one who had hypo, and one who was normal. And I told to Temel and Verli, who was on the paper, this is everyday life. Sometimes more, sometimes less, sometimes nothing. So this is nothing special, but they put three papers, three papers on erection by a so-called serendipitous discovery. So sometimes it's too much serendipity. And the same with the experience of Oxford, where they have for urination, blood pressure, respiration, et cetera, because they were stimulating in the periaqueductal gray, where many things happen there. Blood pressure can go up or can go down. And then we discover where to, 01:03:00for high blood pressure or... So I think it's important to look at the patient and the functional neurosurgeon are the best place, and the neurologist, if they are in the operating room, to observe what happened and try to correlate to the location of the electrode. Yeah. And if you say too much serendipity, you mean that's because it was already known, right? But then maybe it wasn't reported enough. And that's another point, right? How can we make sure these serendipitous discoveries, even if they might be known to some, get better venues and published better or incentivize this more? Because that's maybe another question that we had, that we feel like if this is where everything came from, how can we double down on the strategy? How can we make it more systematic? How can we... I know you can't force serendipity, 01:04:00but is there a way to better, you know, better observe or better report or find better journals even just, you know, to publish case reports? Or do you have any thoughts, all of you, how we could use this more systematically? It depends also on the consistency of the observation. For example, Shakespeare wrote somewhere that once is nothing, twice is a coincidence, three times is a damn reality. So if you have the same thing three times, so it's a reality. Otherwise, it's a coincidence. And if you see, for example, Viagra, how did Viagra come about? It was tried for the heart and the patients were lying on their stomach in the ward, the trial patients, because they were afraid to show the erection. And it was not only one or two, it was several patients. So that's how Viagra, which was designed for heart issues, became for erection issues. It's serendipity too. You have many serendipity in medicine also. 01:05:02Carbamazepine discovered for tick-doodle-do by a Swedish neurophysiologist who worked in Uppsala and published in the 60s and 70s was also serendipity. So you have to be open-minded and observant and it has to be systematic. And the second thing when it comes to DBS is to have to check where is it coming from and see what circuitry, what are you activating or inhibiting. But, Marwan, in an optimal world, following the accepted indication, your electrodes are always going to the very same place. And if the community agrees and Andy finds out the sweet spot for every disease that is accepted, in an optimal world, all the electrodes go perfectly to the anticipated sweet spot. So how many serendipitous discoveries 01:06:04can be made in the optimal world than in the future if everyone is as a precise neurosurgeon as you both are? So that's my provoking question. We are not that precise, as you know. Despite micro-recording, despite everything, we are not that precise, number one. Number two, there may be different parts in the brain of the basal ganglia that react differently for some reason. We have one case that is published of a patient having a severe depression, crying in pallid DBS. Pallid DBS, and we have video of him, you know, completely crying. And the patient didn't know where we were stimulating, but the electrode was in the very posterior and medial GPI. And it was not too ventrally located? 01:07:02Yeah, it is partly too ventrally located, just going into the capsular. But it was not a bull-burn reaction. It was like the Bejani patient who was crying, the same. And I don't know why. We don't know why. Some comments on serendipity. So I think it was very important that you brought up this paper, Marwan, because it showed people that there's more than only systematic research. But I would say serendipity is actually a very common phenomenon. And for example, the place you are sitting now, Andy, it was discovered by serendipity. And so I think many great discoveries in history, in art, just anywhere, it's serendipity. But the issue is that serendipity only will be fruitful 01:08:01when you have a prepared mind. So if you are prepared, then maybe serendipity will come and will enlighten you. So if you're not prepared, you can see a lot of things, but you just don't know what it means. And if it will be important or not. And to come back to the second topic we discussed about animal research and as a tactic function of research, I think that's great. Going back and forth from the lab to the clinic. And that, of course, will not happen anymore in the future. Because when we look at the discovery, that was not... It was not in rats or in mice. It was actually primates. And this is not possible anymore in these times. And I think we don't need to discuss about this. But I think we just enter a new state here. 01:09:02And we have to see how we... This will develop further. With the prepared mind, what you mentioned, I really liked the talk by Benavid. He talked in Charleston at the Brain Simulation Conference last year. And he said that Newton... Many people had seen the apple falling down the tree, but Newton was the prepared mind to then think about why does the apple fall down the tree? And I think he made... Compared himself to Newton in a way, also in that case, because many people had seen in the operation room that high frequency stimulation did lead to cessation of tremor. That is, you all know this, but I don't think everybody knows this. So it wasn't a real discovery by him. It was more than to act upon it, to make it a chronic treatment outside of the operation room. That is the real maybe invention that he with Pierre Pollack, I think that's how Pierre Pollack at least told me. 01:10:00That was the real contribution in Grenoble, not so much the discovery that high frequency stimulation works, but to make it possible to do it outside of the operation room. So this is a very interesting and this is a very good point, the prepared mind. Again, maybe we can double down on that. Maybe we can teach people better to be prepared minds, or to have better venues of how to... Because I think a lot of serendipity can be lost if it happens and nobody watches in a way. So maybe to now combine the two topics we had, I think in your paper, Marwan, you described that one of the six patients reported, even by James Parkinson, in the beginning had a stroke, which led to cessation of tremor. And there I'm not knowledgeable enough, but I think that led to all, like many of the historical attempts to lesion M1 and maybe capsule. Can you try to replicate that same effect? 01:11:02Is that true? Can you enlighten me a bit on why did people start lesioning primary motor cortex, for example, for tremor? My grandson. This is... Ivan. Hi, Ivan. Good to see you. How is it going? Very good. I'm coming, sir. Bye. We are babysitting here, my grandson. Anyway, yes. What did you say, Andy? So, why did, like, the one case that had a stroke and then that led to cessation of tremor from the reports by James Parkinson, did that lead to ablational studies in M1 at the time? That's what the scholarly literature should say, 01:12:01that why did they start the operation on the pyramidal tract, from the cortex to the spine, on different level. And I have read several old papers by Bussey, by others. There are two reasons. One was mentioned by... Shall I say Dr. Mohn or shall I say Christian? Christian, please. Okay. It was that Walter Dandy had said for a long time that the basal ganglia is a no man's land. Don't touch it. Because it has to do with the consciousness, etc. So people didn't dare to touch the basal ganglia. And they started with operation with removing parts of M1 and all the way down. And the reason... They justified this, that patients who had a severe tremor would rather have a half-paralyzed arm 01:13:00than shake. The problem is that later on they developed spasticity. You know, you get spasticity. So it was not... But for many years it was the only operations. And they tried to have as small vision as possible in the peduncle and down to the spinal roots. René Lériche, a French neurosurgeon, he tried to remove the spinal roots to diminish the tremor. And it is said that this is based on that observation that a stroke took away the shaking, which was the main... the most observable sign of Parkinson's disease at that time. You see, this is the only explanation. Yeah. And that is such a great example. Sorry. 01:14:00Yeah. I think it's not at the heart of the start of corticotomies for movement disorders, right? If I... I just remember Horsley talking about this observation. I mean, he didn't start with Parkinson's disease or didn't operate on Parkinson's disease. But when he started to operate on this boy with athertosis in 1890, he was just... He was familiar with the state-of-the-art neuroscience. He was a neuroscientist and a neurosurgeon at the same time. And he had the electrical stimulation at hand to delineate motor cortex, the excitable part of the cortex. And then he had the technical skills and surgical skills to take the arm region out and to alleviate the symptoms. And that was the main start then for movement disorder surgery and corticotomies, all alike, that followed then in different indications and so on and so forth. I think the discovery 01:15:00or it was just a rediscovery that Parkinson had mentioned this in his essay. I doubt it very much that this was one of the driving forces that led to the origin of movement disorder surgery or Parkinson's surgery, even on a cortical or lower level. Yeah. Mostly operated on a patient with athertosis, not with Parkinson's. Yeah, yeah, yeah. That's what I said. That's what I said, yeah. That's what I said. I'm not that old to be there. So I just read the literature. I wasn't around when this happened in the 30s and 40s. So I just read one. I was not suggesting that, Marwan. Bear with me. Of course not. It probably is hard to make a direct causal link here between the report by Parkinson and then the many cortical surgeries. Yeah, but from a nowadays perspective, 01:16:02it's still very striking that first of all, the surgeons really were hesitant to touch the deep structures and all these superficial structures were cut with a scalpel first. Motor cortex, the peduncle, the spinal cord and whatever. So that's pretty interesting to follow this line of evolution of movement disorder surgery before also by chance it was discovered that the striatum and the depth part of the brain was actually not the seat of consciousness as proposed by Dandy that should not be touched. But it was also a random observation that led Russell Myers then to dare to put the scalpel deeper than cortex and to cut down into the fibers and eventually following, you know, under visual inspection to cut the paraparameter axis 01:17:03and the interparameter pathways then. So would you say that was the first subcortical surgery? It's certainly among the first. I think it has to be mentioned to be the first subcortical. So not on the surface of the brain, a subcortical surgery for Parkinson's disease by Russell Myers. And actually he describes it. Why did he dare to do so? Although it was against the surgical mainstream and this very influential dogma that you should not touch upon the depth structures because he had seen a patient when being a resident that had an accident and his frontal lobe was cut by a propeller of an airplane. 01:18:01So and but the patient survived. And he did not. And he could then directly see by this massive accident to the skull. He could see the basal ganglia directly. So the stratum. So he was he. This was not in accordance what Dandy had taught. So that this was the center of consciousness. You should never touch it. This depth structures. And he this at least he describes it as one of the main main experiences that he had in order that that that made him to to dare to put the scalpel deeper to through during one of his cortical surgeries on a patient with Parkinson's disease in 1939. That was even before the Second World War started. Okay. And I ask all of you maybe Joachim first. Why do you think animal research 01:19:00has not led to many treatments in surgery or neuromodulation? Is the brain just too complex or are the model diseases too far off from the actual diseases? So why do we have little wins in that classical? Well, I think that. The basic. So we should when you think about it, we should know more about the basic ganglia when we look at animal research. But somehow it is still difficult, despite the nature of it. The real function of basal ganglia. So I think I mean still in the age where we can see the effects of malfunction of the basal ganglia, but we still not fully understand the function of the basal ganglia. Okay, we know much more than like 20 years ago, 40 years ago. But still when we see sometimes people can live still without some part of the basic ganglia. And so it's still questionable. 01:20:01Why does it cause a disease in some patients and others not? And so the models we have are very simple, I think. For example, like six hydroxy dopamine model, alpha-synogreen model. It's just too simple. And we look into always certain aspects. So we don't just don't understand the whole picture. And maybe if you look at the future, we can use other models. And we can use artificial intelligence also to understand more of the functions. But often we have one thesis, we want to prove that thesis. And the trial will be negative if that thesis has not been proven. And in a clinical trial. Yeah, clinical trial. But also when we go to end-on-end research, we want to show this or that. And I think we should come to a point where we are able to understand 01:21:01more the complex issues we see. And I think we are not there yet. So basically animal models are too simple in many aspects. And then this revelation, right, that again, it was eye-opening to read your paper, Marwan, and to me. This revelation that most wins come from human observations and serendipity should have strong implications for funding and also how we publish, right? So I've heard the quote that there's always a Nature article each year about a cure in Alzheimer's disease in mice, right? But not in humans. And animal research gets published higher, gets more funding and so on. And I pitched this concept to the director of the National Institute of Mental Health, Josh Gordon, who I interviewed in episode 27, who is an optogenetics researcher, which again already is a bit telling, right? 01:22:00The director for mental health, of course, is a basic science researcher. And he was not readily convinced. I think he saw certainly very much value in serendipity and also said it's very hard to, of course, systematically exploit that. But do you think that there should be potentially a shift in the things that have the wins in treating the brain? Being more, you know, better funded, better published or so? What are your thoughts on that? I think that two things. Number one, that as you said, in my university here in Umeå and even in London before and everywhere, basic science and animal basic science weighs a lot more in terms of grants and prestige and Nobel Prize and all you want. So clinical trials, it's like audits, more or less. 01:23:00And it is a little bit soft science. So one of the latest Nobel Prize who worked and discovered in this university, who is now in Max Planck Institute, is the French lady, Charles Pantier, who discovered the CRISPR scissor, you know, the scissor of the genetic curve. She worked here in Umeå and she discovered here in Umeå and then she moved to Max Planck and she is the most renowned. And they have put a lot of, of energy and of funding and of prestige in basic science. Now, when it comes to our field, which is actually functional neurosurgery, functional neurosurgery is not only tremor. It's the personality, it's the so-called now non-motor symptoms in Parkinson's disease. It's psychiatry, it's dystonia, it's body image. It's all these things. These cannot be replicated properly in animal model. 01:24:02I remember Ted Hitchcock, who is one of the pioneers, a great neurosurgeon in the UK, is dead now. I'm sure Joachim knows him. You remember Ted Hitchcock, right? When fetal cell transplants were proven to be very good in mice, he had a talk and he said, fetal transplant can cure Parkinson's disease. This is very good news for the mice. That was his comment. So this is very good news for Alzheimer rats or mice. But in terms of functional neurosurgery that deals with not only tremor again, even in Parkinson's disease, you have to, why do you investigate patients with Parkinson's disease regarding cognition, behavior, your comorbidities, etc. 01:25:00You cannot replicate these in an animal model. You can do animal model for glioma to test a new therapy, a new medication, a new whatever. You can do animal models especially to check the side effect and complication of drug therapy. Not only that effect, but the side effect. And the dosage. But especially in psychiatry, but even in movement disorder, it's very difficult to have an animal model that is immediate disease. Remember the MPTP is an immediate Parkinson's disease overnight. Andy, are you there? Right? I'm there. Yes. So it's MPTP patients who in California, they got Parkinson's disease overnight. They didn't get the slowly progressive disease. So in my opinion, our source of knowledge is to see and observe 01:26:03and be prepared as Joachim said, and also to try to understand why an electrode in that, where is the electrode? What goes there? What happens if you simulate high or low frequency? Your tractography, functional imaging, all these things can help us to understand in the patient. My only regret now is that, most of our patients are operated nowadays asleep, not only here, but also, and we lose this during surgery. We may have it after surgery when we program the patient, but it's too late then to change or to test extra or to, you understand. It is interesting, Marwan, because you were... That's so true. Sorry. Sorry, Andy, I have to make that point. That is so true, Marwan. Thank you. Thank you. But you were always pushing for image guided and no microelectrode recordings and so on, Marwan, right? 01:27:00But you were not pushing for... You're wrong. You're wrong. Okay. Everybody does image guided. What I was pushing was for image verified. In London, we always did an MRI immediately during surgery on the awake or asleep patient to see the electrode on 50 shades of gray MRI, not technically called MRI. You know, where you see the HTN and you see if the electrode is there. Or the pallidome, where in the pallidome it is. So it is image guided. Everybody has image guided. Everybody does an MRI before or CTE. We have image verified before removing the frame, before you remove the frame. Because once you remove the frame and you're wrong, you have a new operation. If we were wrong, we could replace it half an hour in the same session. So image verified. And this is to understand the correlation anatomy to... Now, it was not physiology. Unless you think that physiology is only micro recording. Actually, it was physiology. 01:28:01Because as soon as you have a probe in the brain and you stimulate, you're doing physiology. Right, Christian? You're right. So DBS is applied neurophysiology in the hands of a stereotactic neurosurgeon. And in an optimal world, it's applied neurophysiology in the hands of an interdisciplinary team consisting of neurologists, surgeons and perhaps psychiatrists. Yes, you're right. All right. So that's what I want to say. I want to slowly wrap up to be mindful of your time as well. So we've talked a lot about history today. But I wanted to ask each one of you maybe after another about the future of the field as well. So maybe if you have the time, each one of you could tell us where we will be in five to ten years and maybe also touch upon the future of the field. And maybe also touch upon missed opportunities. So things we should be doing to get there faster but are not doing right now. 01:29:02Can we start with, I don't know, Christian maybe? Yeah. Well, it's difficult to tell where we are in five years from now on. So I feel we are not much farther than we have progressed throughout the last five years. But leaving the skepticism apart, I think what is important for the future is one of the most important lessons to learn from history as we have discussed. So my take is that it's about interdisciplinary teamwork and the conjunction. So, therapeutic and functional neurosurgery is really at the heart of multiple disciplines. And we can learn this from history. So we talked about Spiegel. He worked together with the neurosurgeon Weiss. We talked about Hasler. He worked together with Richard. We talked about Spiegel. Richard and Munninger, the neurosurgeons. And so he talked about Bina a bit. He worked with the neurologist Pollack and so on. 01:30:00This list is endless. And I think it's about one of the most important things that we should never forget. That it's about the, if you want to further develop this discipline and make further progress, that this interdisciplinary effort is not lost and is even intensified although I understand that you need to fight the gravitational forces of the ever more specialized disciplines like neurology is getting more specialized, neurosurgery and so on and so forth. And I think we have to fight these gravitational forces and bring back this interdisciplinary effort to the core of our work and to develop this interdisciplinary curriculum where basically, all the disciplines are equally contributing. And then I think this would be the best thing for the future. 01:31:00Great. Joachim? Well, I think the future will be great and open and we always in a way go forward and backward at the same time. So what we saw during the last few years, we had the rediscovery of lesioning surgery. We had rediscovery of surgery. We had rediscovery of psychiatry surgery. I think this will be ongoing. I'm certain we will rediscover peripheral denervation and other methods that have been abandoned. Somebody will think we just discovered something great and new. On the other hand, I think maybe DBS will not be the main topic forever. We've been living in the realm of the brain simulation now for 25, 30 years. And many people think that, many people think that actually the brain simulation, or I should say the other way, many people think that functional neural surgery is the same like the brain simulation, which of course is not the case. It's just one aspect. 01:32:01And as I said before, I think we should use more and think about artificial intelligence. We recently started to analyze brain signals with convolution neural networks. I think this is completely underused nowadays. And this will help certainly to understand, because very complex situations, which we cannot decipher very easily when we look only at single aspects. But if you also have some practical use, for example, you could have more of automated programming. Because nowadays, for example, with DBS, machinery is getting more and more complex. So every one of us is spending, so much time on programming. And we're very happy to have 12 contacts, maybe 16 contacts, maybe 100 contacts in the end. But it's beyond our capabilities to take care of that. So I think we will, 01:33:00in the future, we will have many algorithms which will be helpful. In Europe, I must say we have one special problem that is not the case in the United States. And that is the medical device regulation. So the medical device regulation when it was installed, it was for good reasons. But in the meantime, I think it hinders progress in many different aspects. Development of new instruments, development of specific ways to perform new indications. Also the OCD issue we talked about is related with the medical device regulation, that it has not a CE mark any longer. And that is not because the companies do not see the data, they don't see the data. They don't see that they can make money. Because the other way, it has become too expensive for them, for often indications to establish these systems. And there's some sign that this mellows down the roots for the medical device regulation. 01:34:06And I hope we will have much more allowance again in the future. Great. Now Juan. I have been fortunate to be invited to talk when DBS had the 10 years anniversary in 97 in Amsterdam, 20 years anniversary in Madrid, 2007, and 30 years anniversary, it was in London actually in 2017. And each time it was, what is the future? And I used to say what I would say now, the next five to 10 years, it will be Parkinson's disease, dystonia, essential tremor. I said that every time. I said that every time, even when the psychiatry was coming up in 99 after that, I said the future will be of DBS will be mainly in movement disorder in five to 10 years. 01:35:00I have said that now three times over the last 35 years. And I will say it again today. It will be with new technology products, new technology technologies, it will be with new technology, probably with better imaging, with the electrodes, with the 18 contacts or whatever they do, or directional technological advances that by the way, will complicate our life much more without making a dent into the results. And I asked Falkman, are your results better now than in Kiel? Oh, he said, we need thousands of patients to prove that. So, we need more and more complicated tools, more and more expensive tools. Precept now with sensing and sensing is a tool of research. Mainly it drains the battery like hell if you use sensing too much. But you have nice papers. You have papers like the last one from Andrea Kuhn about what happened at Christmas with your beta activity that goes down. 01:36:07You've seen that paper, Andy, and one in here. Yeah. So, what happened now is that it will be new tools, new imaging, new maybe artificial intelligence to see better the STN for those who are blind. And I cannot look at the MRI T2. But the future, and I say today, and let's meet in five years if I'm still alive, it will be movement disorders mainly. Not tinnitus, not Alzheimer, not anything else. They will be there. They will be there, but it will be mainly a movement disorder. So you have a bright future as a neurologist, Andy. Okay, great. That is, I mean, I wouldn't even say this is pessimistic. This is very much, it's still marvelous how well it works for these indications. And we don't need to broaden the indications if they don't, 01:37:02if it doesn't work as well for the other diseases. So I'm totally with you. We have to prove that there is, we can make a dent in other indications before they will, of course, become relevant. So yeah, thank you everyone. This was really amazing for me. You three are really the heroes when it comes to knowledge, especially in the history field, but also your knowledge, of course, very much goes beyond that. And it was, you know, even just when you talk, sometimes very impressive how much you can just pull out of your hat and knowledge. did you want to add anything? Did you want to say something? No, no, no, no, no. So thanks again for taking the time. I know how busy you all are. It was hard to find a date where everybody could make it. So it is very much appreciated. And I think I learned a lot. So I hope the listeners will learn a lot too. Thanks again. Yeah, thanks, Andy. 01:38:00It was great fun. Thank you, Andy. That was great fun to talk to you all guys. 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