00:00We knew those patients inside out, for sure. We spent so much time with them. They were also part of the team to make this development because you also need the patients to be able to trust us to go into this pioneering surgery and spend so much time with us. It was like a miracle, you know. Left, right, and march. So, yes, I was so shocked and so amazed that I ran to get Pierre Pollack, who couldn't believe he was just a stimulation. He thought I'd given the patient medications. So it was quite an extraordinary moment, yes. Welcome to Stimulating Brains. Stimulating Brains Hello and welcome back, everybody, to Stimulating Brains, episode number 7. 01:13I'm really excited to talk with Professor Patricia Limousin today. Patricia is a consultant at the National Hospital for Neurology and Neurosurgery in London. She was the person to switch... on the first bilateral STN-DBS patient that we already heard about with Pierre Pollack in Grenoble. So she was really there when it all started. Patricia is one of the true giants of our field and has had tremendous impact on the history of DBS and continues to shape our field today. So I'm looking forward to an exciting episode with Patricia today. So Patricia, thank you so much for taking part in this. 02:00And to break the ice, first question would be, what do you do if you don't care for the patients and aren't involved in science? So what do you do in your free time? What do I do in my free time? Do you have free time at all? Well, I try to have some free times. I mean, I like outdoor activities. You know, I like... going to the park for walks. So I do horse riding as well. Oh, wow. When I have more time, like holidays, I like traveling. I mean, I've got two daughters. So for a long time that they occupied a lot of my time. And they are now at university. So I still enjoy spending time with them, but less time pressure. Makes sense. Do you have a horse? Like for real? No, I don't. I don't have mine. I have my own horse, but I go to a small stable where I pretty much 03:01have always the same one. So it nearly feel like I have one. Sounds good. Great. So let's dive into deep brain stimulation and neurology. So maybe weird question. What's your favorite brain stimulation target? Well, it's got to be the subthalamic nucleus, really. I mean, not only because a lot of my work has been focused on the brain, but also because of the brain stimulation. So I have a lot of work. I have a lot of work. It's also because it's the most interesting in the sense that it's the one that brings improvement in a broader range of symptoms. But it's also the one that's more challenging because there's more possible side effects and there's quite a lot of complexity with all the different connections and there's still a lot to understand there. So Marwan Hariz said, in the STNs, things happen. So why do you guys hate the GPI so much? 04:03Well, it's not that I don't hate GPI. I know, I know. Because it's used. But it's a bit more boring as a target, you know, because, you know, you turn it on and not much happens and then maybe a little bit builds up. It doesn't got the same acute effect. So, I mean, as I say, it does its use, but it's a less challenging, less exciting target. What I personally really like about the STN is that it seems to receive input from more or less the whole frontal cortex. And that, you know, makes it so interesting also from a neuroscience perspective that it is somehow maybe a miniature of the cortex because everything projects to the STN somehow. A lot of regions at least do. So I agree with you. That's really exciting. 05:01So maybe speaking a bit more about your career and, you know, the work in research, who were maybe defining role models and why? Did someone truly stick out? Who influenced and shaped the way you think about neurology and the brain? Well, it's, yes, it's definitely Pierre Pollack. You know, I went into neurology with him even as a medical student and then as a registrar. And we worked very closely many years. And he's the one who taught me both the, how to conduct rigorous assessments of patients, how to try and keep up with research and how to try and, you know, how to try and, you know, how to try and, you know, how to try and, you know, how to try and, you know, how to try and, you know, how to try and integrate all those things, keeping always the patient at the center of the care, 06:02but trying to make science progress. So, I mean, there has been many people, but he's certainly the main one, I would say. Would you have a story of, I mean, I'm sure you have a lot of stories of academic success, but maybe one that you want to share? I mean, I suppose it was still a surprise when we observed the impact of STN stimulation in patients because we were used to the effect of thalamic stimulation, which is, you know, quite striking on the tremor, but it's only the tremor. But when we realized in the early patient with STN stimulation 07:00that in some patients it could nearly have as much effect as levodopa, that was certainly a very striking moment that went above our expectations. So, Pierre Pollack, as you maybe know, was on the podcast before, and he told us that story when you turned on the first bilateral, STN-DBS patient, and he later said that maybe his whole career could be summarized by this event somehow, or, you know, it really is a summary or a great anecdote to describe what he did in his academic life. And I think it would be, you know, amazing to hear it one more time from you because, you know, you were there as well, obviously. So, what led to this event when, you know, the first bilateral STN-DBS patient was turned on, and then what happened? Yeah. Like I just mentioned before, it's because of the major impact it had. 08:00So, you know, when patient had a unilateral stimulation, you know, you could see some unilateral effect, but there was no major effect on their axial function. But this patient who was very akinetic, rigid, and without medication, very, very limited ability to walk, could suddenly, you know, stand up and walk. So, yes, he was such a... And immediately, you know, that's another nice thing about STN stimulation. You can see most of the effect immediately. So, you know, it was like a miracle, you know. Lève-toi et marche. So, yes, I was so shocked and so amazed that I ran to get Pierre Pollack, who couldn't believe it was just a stimulation. He thought I'd given the patient medications to... So, it was quite an extraordinary moment, yes. 09:03And it was completely off medication, and then, you know, the patient could walk. Yes, that was just one of those, you know, marked effects. Do you think the most contribution to this general success back in the Grenoble time, and we'll come to that again, of course, anyways, but do you think the most contribution was on the surgical side or on the neurologist side? So, Benabit or Pollack or both? Or how... Looking back, what do you think? Well, it's really a teamwork. It's really a teamwork that also had inspiration within the basic scientist work, you know, all the work done in the subthalamic, the nucleus with Bergman and Tipo Aziz, et cetera. But then, you know, it was a combination 10:03of the surgeon daring to put electrodes there and the neurologist seeing the opportunity and then doing all the work of programming. And so, it's really a team. It's really a teamwork. Great. I once talked to Paul Krack about this, you know, about these years as well. And he once said that you could still somehow write books about these very first patients because the relationship with them was so intense. And also, Pierre Pollack said that he spent, you know, days with them testing different parameters and so on. And then, you know, in preparation, I asked just now Julian Neumann whether he also has... There's another question for you that I might ask. And he asked, do you still remember your first DBS patient? But I think probably the answer is yes, right? 11:01That you still remember these. Yes, yes. No, I mean, in particular, the first, at least five or six. Really, yes, it was very, it was very an intense, intense work. And yes, we knew those patients, we knew those patients inside out for sure. We spent so much time with them. You know, they were also part of the team to make this development because, you know, you also need the patients to be able to trust us to go into this pioneering surgery and spend so much time with us to try and make it work better. So they are also part of... They were part of the team. They were part of the team. I love that. That's great. How did you get into neurology in the first place? 12:00And then maybe, how did you get into DBS? Yes. Well, I wasn't expecting at all to go into neurology when I went into medicine. I'm from quite a rural part of France and nobody in my family had ever been a doctor. I mean, nobody had even gone to university. And because in that rural... rural area, there were not that many jobs if you're quite academic or, you know, if you're quite good at school. So I decided that I would do medicine to be the GP of my little village. Exactly. But during the medical study, you do rotation in the different departments. And when I did the rotation in neurology, I fell in love with neurology. I did find that so fascinating, you know, in particular, the clinical examination and the link with the physiology 13:03and the anatomy. And it was the early days of the brain stimulation in the thalamus. So I very early got involved into that. And that's what happened, really. The rest is history. Okay. Okay. And we have... We have talked about... Oh, I asked you the question about academic success or surprise. And maybe as a counter question, is there also, you know, a story where things went wrong or they just didn't work out as planned or, you know, a story where afterwards you said, this was a complete waste of my time? I don't know. I mean, obviously there has been... There has been things that... Didn't necessarily lead to... To a very interesting discovery or to papers or... 14:02But I think you learn from... You learn from all what you do. And I don't think there's anything I would say that was a waste of my time. And I shouldn't have done that, to be honest. Great. Super. Okay. So maybe diving a bit deeper, into these early days in preparation for this, I read your paper in The Lancet, 1995. And there you reported about the three first bilateral STN-DBS patients. And of course, needless to say, that was a big success. And we all know that, you know, a lot followed. But reading it from a modern perspective now, one patient was confused for two weeks after surgery. Another developed neuropsychologically, and then a physical impairment due to thalamic infarction, which then improved over three months. And one in one stimulation could induce ballism. 15:04So how did caring for these very initial patients feel like? Yes, well, those patients did spend a lot of time in hospital. And they spent a lot of time with us to try and, you know, adjust the parameters and all those things. And, you know, surgery at the time were very, very long. Sure. Surgery would last easily more than 12 hours with a patient awake. And there were, you know, this several trajectory on each side. So, of course, a number of patients were confused afterwards. Fortunately, many of them, I mean, most of them did recover. But they were certainly... You know, there were certainly a number of problems on the way. It wasn't always all straightforward. 16:02But, you know, we had a good team working closely together and helping each other. And we had also patients who were very motivated and who could see the broader picture in some ways. Yeah. One of the three patients developed stimulation-induced malism. And you have to correct me if I'm wrong, but based on my own limited clinical experience, this doesn't seem to happen that often anymore. At least, you know, not very frequently. Yes. But we know that, of course, surgeons shied away from targeting the STN exactly because of that, right? With lesioning already back way before that, out of fear of hemibilism. And as far as I understood, only with the... The Bergman paper in 1990 in Science that showed promising effects in non-human primates 17:00with MPTP-induced Parkinsonism. Only then we began carefully targeting the STN. And to me, there's somehow a little bit of disconnect. And I wanted to pick your brain. Why does DBS not frequent or more frequently induce malism? And maybe why did it do so in this one patient back in 1995? Was there something different back then? Different electrodes? Okay. Well, I think a lot of the difference is the way you program the stimulation. Okay. You know, we have learned that you can induce malism. And actually, you can quite easily induce this malism. At the time, we didn't know that you had to reduce medication. We didn't know that you had to increase the stimulation rapidly. So that particular patient, actually, which is also quite a slightly funny anecdote. 18:02So the other two patients didn't have very much levodopa-induced dyskinesia. So I think those were less sensitive to the malism effect. But for that particular patient, I had increased the amplitude. The day I turned on the stimulation, I had increased the amplitude to something like three volts, you know. And I left the patient in a room to go and get something. And when I came back, the patient was on the floor with malism, you know. I felt like he was having a seizure. And at the same time, he was laughing terribly. So we learned from that that, you know, there is a possibility of malism, in particular, if you increase the amplitude quickly and if you don't reduce medication. I mean, sometimes. Some patients are more sensitive than others. But I think if you really go to high amplitude, it's not so uncommon. 19:00But the interesting thing is later on, we realized as well that this patient, who's been published at some of the more psychological effect of the stimulation, he was actually laughing because of the stimulation. He wasn't just laughing because he was on the floor wiggling around. So, you know, there was so much to discuss. And I think that's something that we need to discover at the time. Of course. Yeah. But just to follow up, would that mean if we rapidly stimulate, so increase the voltage, then we can still, you know, often induce malism? And is frequency, does that also play a role, do you think? Because back then, the 130 hertz weren't established, right? So do you remember? Yes. I don't know. I don't think anybody has really studied. I don't know. I don't think anybody has really studied. So I think that's a good question. to get to these ideas to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to 20:23year 2020 uh the terrible covid year imagine you get to know an stn dbs patient out of your like out of your professional context maybe privately as the husband of you know a remote friend or something do you sometimes stand in awe of you know how much you together with the team in grenoble have changed the world for the better seeing dbs for parkinson's that had a tremendous impact on i think around 200 000 patients and that's the official numbers i think it's much more in in reality um and you played a major part in making that happen how how does it feel like 21:03i don't know i don't i don't really think about it like that you know i feel like i was just a little brick in a in a big building where lots of people have lots of people have have contributed um and you know things things don't just appear they they get transformed you know they are they are different things that get together to to gradually um evolve uh but it's you know it's it's certainly been a therapy that has benefited many patients and even in 2020 we don't have any surgical therapy superior to that you know even gene therapy or cell therapy nothing has been as reliable and as effective in in fact i i also um was briefly in contact with christian moeller just uh just today and 22:03asked him do you have another question for patricia patricia limousine and what what he said um was do you think the results got even better at all over the last 30 years so going in line with what you just said we have nothing that compares to sdn dbs um do you think it got better at all i don't know honestly i don't know i don't know i think um probably the there's a bit less morbidity you know surgery is shorter they tend to be less struck so patient might be a bit less commonly confused etc uh there's still a variability in outcome you know they are still patient who do a lot of things and they are still patient who do a lot of things and they are still patient who do less well um and you know we there has been some progress like you know we do have directional 23:02electrode we do a bigger range of parameters i'm not sure it's made a huge difference to be honest do you think closed loop dbs will make a big difference could that could could i i don't know i don't know i don't think the technology we have at the moment is necessarily going to make a huge difference i mean if it work it's already something i mean if it works as well as good already something but i think for it to really go to the next level we we might need much more complex system in terms of analysis of the signal and and and the of the stimulation um i think the current closed loop are still quite basic if you compare to the to the function of the circuitry makes sense there was there was i don't know if you attended but 24:03there was this dbs conference today and it's also tomorrow um organized by the team in düsseldorf i think um and they had these battle talks and one was closed loop are we ready yet um with mike oaken saying yes we are and Sergio Groppa was the contrahand defending that not yet option so you would also think and I think the question was ready for clinical routine so hearing from what you just said you probably also would think you know it's it might work but it's probably not going to supersede continuous DBS but there might be promising results in the future or what's your position on that yes I think it's an interesting area of research we still have to demonstrate that it's at least as good 25:01um on with the further with longer follow-ups yeah but then to to be better really I think it's it's still a good idea to do that I think it's a good idea to do that I think it's a good idea to it's still too simple in a moment yeah okay there was a second um maybe since we added there was a second um battle uh between asleep versus awake DBS and asleep was um I think uh the talk was was was held by Patrick Blomstedt and awake was by Christian Moll what's your opinion in that well uh we do um we do asleep in London I've done awake for many years um both in Grenoble and for a number of years in London we were doing um awake as well I mean I think sleep is obviously a lot more comfortable for the patients and for the majority of patients the the outcome is is not that different um 26:07at this point in time so I think if a surgeon is um is used to doing sleep is used to doing it this way and does all the good means of localization um it is a very um valuable method yeah um but you know I think different uh surgeons have different different experience use different methods so I think it's uh it's important to to be able to to analyze um the the outcome and see and be able to do that um so I think it's uh it's important to to to assess its own its own methods I don't think everybody's got to do the same thing that's a good take yeah and maybe that the last uh battle talk they had was for OCD DBS the question was STN versus ALIC and you're probably biased because of the STN already but even more so because 27:04um Paul Krack gave the STN lecture and uh Damian Deniz the ALIC lecture so any any thoughts about STN? In our center, we did a small trial where we implanted two systems. We implanted the subthalamic nucleus and the anterior limb of the internal capsule. And patients were randomized, one target, the other target, or both targets. It was only six patients. It was a small trial. And it was quite heterogeneous. You know, some patients had really very good effect with the anterior limb of the internal capsule. And some patients had good effect with the subthalamic nucleus. I'm not sure I would be ready to say which target is better. 28:03I mean, the anterior limb of the internal capsule needed a lot of electricity, which is a downside. But some patients had quite remarkable results. Some patients had quite remarkable effect. And I would say after the first patient with bilateral STN stimulation I mentioned earlier, the second amazement of my career is one OCD patient. Because as the neurologist, we were programming the stimulator and the psychiatrists were doing the assessment. And there was this young lady who had been... She had been living in institution for years because OCD was so severe. And she would normally take several hours in the morning to get ready. And I had turned her stimulator on one afternoon and I went to see her the following morning. And she was already dressed and ready. 29:02Overnight, she had improved tremendously. So that was also quite... Quite impressive. Amazing. Was that in the STN as well? No, that was in the anterior limb. In the anterior limb. Okay. Would have been funny to have the same... And for her, actually, the STN didn't do that much. But we had other patients who did well with the STN. So I don't know. My experience is too limited to choose between the two. But it can certainly have also a very dramatic effect. But in general... So that sounds like you're convinced OCD-DBS makes sense. Yes. Yeah. And why do you think that at least sometimes the same target, such as the STN, works for both diseases? And it seems to also work for dystonia. And there are even people using it for Tourette's disease. 30:02Why do you think that is? How can we use the same target to treat so many diseases? Well, as you know... All those diseases involve the basal ganglia circuitry and the STN is quite one of the centerpiece of the basal ganglia circuitry. So that probably explains it, although of course we still need a lot more understanding of which circuit we really influence. So you moved from Grenoble to London in 1997 and then I think you defended your PhD with the topic STN-DBS for Parkinson's disease 1998 in Lyon still. Why London? Why England even? Yes, yes. 31:02Well, I actually first came to London in 1995 for a year to do research. To do a fellowship where I worked with John Roswell in what was Human Movement and Balance Unit and also David Marsden was around there. So I spent a year in London and came back to Grenoble for a while and then I finally came back mostly for personal reasons at the time. Was DBS already established back then? Back then in London and who was the team? Yes, not very much in London. Tipo Aziz was one of and Steve Gill were the two main surgeons at the time, one in Bristol, one was in Charing Cross and then moved to Oxford. 32:01At the National Hospital for Neurology, there was little brain stimulation activity. There was a surgeon. There was a surgeon, David Thomas, who did a few, but his interest was more in another area of neurosurgery and then he was close to retirement age. So we did have quite a difficult phase over a few years, not having very much surgery and then we managed to recruit Marwan Harris and we were very fortunate to develop. To develop our team, which has been a great team to work with, where we've managed to integrate even more closely in neurology, neurosurgery, specialist nurse, speech therapist. So that's... So you basically built that up. I think Marwan joined in 2002, if I remember correctly. 33:03Yes, that's correct. And did Ludwig Srinzo come much later, right? Yes, I mean, he was still quite young then. So he came first as a registrar and then eventually was able to join us as consultant. But yes, he grew up with the team like many people. Yeah, great. And if I understand correctly, you co-lead movement disorders with Tom Foltzinger, is that correct currently? Well, Tom... Well, I wouldn't say we lead the whole movement disorders. I mean, Tom Foltzinger and I are the two neurologists in the D-Brain stimulation team. So what we call the unit of functional neurosurgery. Yeah. But we do have, you know, we do have also other colleagues, specialists in movement disorder who refer patients but are not directly involved with... 34:09with our program. Makes sense. Great. So maybe let's talk a bit now about the present and later a bit about the future. So what are you currently involved in? I, of course, looked a bit at your publications and there were so many alone in 2020. And you've been so productive throughout your whole career. Is there something that you like currently, you know, that fascinates you most in terms of a research question or clinical question? Or is it very diverse these days? Yes. I mean, it's still quite diverse, you know. I mean, there are still questions to be answered in, you know, in terms of, as I mentioned earlier, there's still some heterogeneity of outcome. 35:00We are both in Parkinson and in Dystonia as well. We are currently looking at our large series of... Dystonia to try also to understand a bit better what are the factors influencing their outcome. We are also preparing a new trial for DBS for Tourette's because we did one a few years ago, but it's not approved in UK. So patients with Tourette's cannot routinely have the brain stimulation. Great. So we are looking at the 36:03And the NHS has asked for more evidence before deciding on commissioning. So... Okay. Which target? With the pallidum. With the pallidum. Since 30 years. Any ideas? I mean, as we... As we discussed earlier, I think... I think for... Close-loop system to... To really... Have... An important impact, I think... We would need... A lot of progress with the technology, you know... Ideally, we would need... we would need multiple small wires in different places that record the signal and having computers able to interpret all these signals and generate, trying to reproduce more physiological activity in all those circuitry and then possibly address those 37:04that are refractory to the current technique. As you know, the main problem in Parkinson's is the problem that are not responsive to Libodopa, false cognitive problem. So, whether we will be able to do that or not, or whether there will be progress in disease modifying medication, which will mean that those techniques become unnecessary. We will see. How about MR-gated focused ultrasound? If you were a patient or if your close relative would be a patient, what would you prefer, DBS or focused ultrasound? Well, we do not have access to focused ultrasound in the UK. So, 38:02I have to say I haven't really got any personal experience of it. But you do lesioning, right? We do thermocoagulation. Yeah. We, in particular in the thalamus, we don't really do in other target, we do in the thalamus. I don't know, I would probably be more inclined towards the stimulation. But I haven't got much experience at all with focus addressing. Maybe one follow-up question about the lesioning versus TBS in tremor. How do you decide usually whether which one you would do, patient age or like what are the factors whether to put a lesion or a TBS? 39:00The consideration is only in the thalamus so it's only patients who are candidate to a thalamic procedure. You mean VIM right? For tremor. Yeah. I mean sometimes it's I think for VIM in particular if it's predominant on one side we often discuss both options with the patients. So sometimes it's the patient who is the most likely to have a lesion and then the patient who is the most likely to have a lesion. So that's the reference. We've had a few patients who escaped the effect of VIM-DBS for which we then suggested a lesion. I mean it's still a relatively small number. We've probably done about 20 thalamotomies in the last 20 years. 40:00So it's a little bit more complicated. So you're saying that the patient who has a lesion fails or not failed but maybe afterwards the patient escapes the effect due to maybe plasticity and then pull the lead out make a lesion and now it works again. Is it even more disrupting information flow there or what's your do you have an explanation for that? Probably in the sense that you know I think I mean there's still a lot of debate around those patients who escape the control of the lesion. It's very likely that some pathways develop an abnormal activity and lesions sometimes no activity is better than bad activity. Yeah yeah true. But that subsequent lesion would not be done via the DBS lead right? Probably you pull it out. 41:00So we yes the problem I mean it has been done in some centers. The problem of using the DBS lead is that you cannot control the temperature. Okay. Makes sense yeah. So it might be bigger than intended and of course that we don't know. Yes exactly. Okay. Is there something you think is important for our field but that is often neglected or forgotten? You know maybe something that you thought about back in the time when you were in the hospital. 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. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. I don't know. I mean, one thing we were looking at at the beginning, you know, with thalamic stimulation, we would ask patients to switch off the stimulation at night to try and limit this tolerance phenomenon in the long term. So at the beginning of the STN stimulation, we try to switch it off at night, similarly thinking that it might work less well with time. 42:07But clearly, that was quite difficult because they had this marked rebound of symptoms when they would stop the stimulation. So then we try to program cyclic modes, but that didn't really work either because however short was the off, the symptoms gradually came back for that brief period of time. But for quite many years now, STN stimulation has been using. Continuously, we've never really, although I suppose one could argue that the closed loop might allow to not have a continuous stimulation, which maybe would have some potential advantage. And the frequency domain. So Pierre Pollack, when I asked him a similar question, he basically said that, you know, especially for new indications such as, I don't know, depression or OCD. 43:06It seems like people. Just adopt the 130 hertz without even thinking about it. But back then, you know, he went through all or not he, but you all went through all these frequencies and tested and in the Lancet 1991 paper, we see this beautiful graph of the, you know, tremor effect, depending on frequency. Do you think there's a missed opportunity, for example, in OCD to test different frequencies? Yes, it's, it's possible. It's possible. Nevertheless, it's not as straightforward because, I mean, the effect in OCD takes a little bit more time than, than the effect on tremor or bradykinesia, which means that for the motor symptoms of Parkinson, you can test several frequency during the same half day. 44:02Yeah. Um, but for. For some conditions such as OCD, um, it's not, it's, it's not so straightforward. Um, I think that would probably happen as, as there are more patients and then you can do some longer period of time with, with different, with different parameters. Great. And then similar question, but, um, directed at the young and wild listeners of this show. 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. Great. And then similar question, but, um, directed at the young and wild listeners of this show. Um, is there any advice that you would like to pass on to the, you know, next generation, um, advice to survive in academia or just, you know, thoughts about what we should think about when we pursue research? Yes. I mean, uh, academia, uh, in particular, clinical research. Um, clinical academia is, is certainly, is certainly challenging. 45:03And I think it's also becoming more challenging because they are, um, more and more, um, bureaucracy on the research, I would say, you know, there's a lot of things we, we were doing 20 years ago that now would take us several months of paperwork to be able to, to be able to do. Um, so, and getting grants and, um, you know, I think papers as well, it's getting more, more difficult to, to have interesting original ideas. Um, so the, I mean, the, the academic field is certainly, is certainly, is certainly challenging. And one, there, there are a lot of competing, um, interest as well. Yeah. 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 46:05to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to 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 I think one shouldn't forget why the research is done and clinical research should aim at improving patients' outcome or improving science for the long term. And I think it's a bit sad sometimes to see research just for the sake of writing papers or getting grants losing a bit what should be the ultimate aim. Any advice for women in academia? Well, that's... 47:01That's putting an extra obstacle, but... Yeah, of course. Yes. Well, I think it's certainly important to have women in academia. I think there are more as time goes. I think in this field you need to try and be organized. Organized and set times for different priorities and maybe not expect to be perfect at everything. Is there something that you think we missed that you would have liked to talk about now, talking about the old times, but the present and the future? Something that you wished I would have asked? No. 48:01I don't know. You have covered so many activities and made me think of aspects of the past I hadn't thought for a long time. I can imagine. One gets caught up in the daily routine, I guess, especially in London, maybe, very easily, right? I could imagine. I've once met you very briefly when I visited Vladimir Litvak, and I remembered that you had a very... It seemed like you had a very busy schedule, so with patience and I can imagine that thinking about Grenoble 1995 is not on your daily routine. No, but it's an enjoyable memory. Yeah. Okay. Great. So thank you so much, Patricia. This was amazing. It's always, especially for us young people, I think, but I think for everybody, really enlightening. 49:00I just hear someone talk who was at the forefront when it all started, at least for movement disorders. And yeah, so thank you so much for taking the time. And yeah, have a great day. Thank you. Thank you for asking and for the memory trip. 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