Baptist Health Miami Neuroscience Institute invited Dr. Mitchel S. Berger as the inaugural speaker for the Mitchel S. Berger Brain Tumor Lectureship. In his presentation, Dr. Berger presented his investigation of human language circuits from intraoperative mapping studies in patients with brain tumors.
Series of art invited lectureships. And um today, it gives me great pleasure to introduce uh my former chairman uh Mitch Berger from University of California San Francisco. And um last night, I thought about all the chairs that I in neurosurgery that I had experienced during my training uh from days of internship in Toronto, Alan Hudson, Gordon Thompson during residency, Felix dirty when I started it in practice. And then we did a lot bunch of flip flops at U CS F between Wilson and Wilson. And then Mitch came from University of Seattle, Washington in 1997. And uh that, that's my favorite picture of you. That last one, that one there, you were your suntanned. Yeah. And uh um I had the privilege of introducing Mitch when he was the president of the American Academy and went through his background learning that like Robert and Michael who are here that he was born and raised in Miami. He went to Coral Gables High School, played on the football team and was selected the outstanding high school football player of the year in Miami um during his final year 69. So he went to I just heard some of the story here about how he went to Harvard for undergraduate, then back to University of Miami for his MD. And he uh did his uh neurosurgery training at U CS F under Dr Charles Wilson. And then did two fellowships um research fellowships at U CS F. And then went to do a pediatric fellowship uh that sick kids with um Dr Hoffman. And then um went to University of Seattle, Washington where he was director of pediatric neurosurgery until he came to U CS F. He's held two endowed chairs, distinguished professorships in that time. He's been the director of the Brain Tum Research Center since he arrived until present, um continuous research funding at various levels, predominantly NIH since 2002 continuously and um is over. Um it should be 40 yes, 40 invited brain tumor lectureships. I couldn't count. It was from pages 1, 18 to 1 62. And I took a guess um 24 editorial boards, 766 papers, seven books, 100 you know, too much to, to count. So, a very distinguished and productive career and uh many of the things that Mitch did at U CS F over the years I tried to bring with me uh because he was my mentor and I had to start from scratch. So, um um but it's really been um uh honor privilege to work under Mitch's guidance and learn from him. And you can see some of the leadership positions that he had in organized neurosurgery. And I think his um he said that his favorite association is the American Academy of Neurologic Surgeons, which is primarily a little bit old school, but mainly program directors, chairmans of chairpeople of departments, men and women. Um and that's a very um I think very stimulating group to be with every year. So because of Mitch's long history in brain tumors and because of his um excellent contributions for low grade glioma inter operative tumor mapping and some of the work he's done with language that Eddie Chang has continued uh at U CS F. Eddie and at, in a large way, developed a human synthetic voice which I think Mitch is gonna give us a little. Do you have the, do you have the Pink Floyd thing on there? No. Anyway. But um uh because of his great contributions for brain tumor surgery, I wanted to name the brain tumor lectureship after him. So this is the first epi Michell Asperger, brain tumor lectureship. Mitch, please. Yes. Yeah. OK. Thanks Mike very, very much. It's obviously a great pleasure to be here. So when I was the uh chair at U CS F, I started in 1997 I inherited Mike mcdermott and we worked together for many, many years. Um And I remember when the search committee here, a Baptist called me about him. I said, here's the first thing I want to tell you, I don't want him to leave. I don't want him to leave. I'm gonna do everything I can to, you know, out recruit them or keep them here. Um, because he was a stalwart. I, I must say, you know, I've been in neurosurgery 39 years. I've been all over the world. I've operated with a number of people. Never ever in my life. Have I operated with anybody as technically superb as mcdermott who is really a, a pleasure. In fact, every time I had these weird complicated cases, I would say Michael, let's do this together. Uh And we did and uh he was just a joy to deal with. He ran our residency program director. He was a residency program director. So he kind of came up in an environment um that was really built around academic excellence, but it sort of had all the different bells and whistles of a great clinical program. Like I used to say it was the Nordstroms of neurosurgical care because when I lived in Seattle, I'll never forget. One day there was a knock on the door. You have Nordstrom here, don't you? Yeah, if you have, there was a, it started in Seattle. There was a knock on the door and this young woman was at the door and she had this box. I said, yes, she said uh is, is Mrs Burger here? I said, yeah, I said, Joan, somebody at the door for you said my name is so and so, and I'm bringing you this pair of shoes that you bought. And I said, what's this all about? She said, well, we're from Nordstroms. We provide service. This is our, you know, uh, our, for our business. Wow. So I said, ok, we're gonna be the Nordstrom of neurosurgery. We're gonna also really develop a strong research base. So we became the number one program for the last 15 years of NIH funding for neurosurgical programs. And then we did a lot of translational research as Mike said on, I've been NIH funded on P I of the Spore grant, which is a specialized program of research excellence in NeuroOncology. We were the first ones to get it. I just did my fifth renewal. It's probably the last time I'll do it my fifth year. It, it will be my fifth cycle and uh it was really great to do that. So he knows all he, he knows really how this whole thing was built and just in being here, I mean, again, uh going back a little bit, I grew up um north of Dixie Highway on 22nd Avenue. So on the other side of Coke, Peter Grove, um and when I grew up there was no day land and we used to come down here, there was a place called the Monkey Jungle. I don't know if the monkey jungle still. Well, you remember? Yeah. And parrot jungle, monkey June. So we used to come down here and I used to drive by this thing called Baptist. And I said, what is that? You know, it is this little tiny hospital, one building or so. And it is just exploded into clearly one of the premier um hospital systems, not only in the state, but in the south and probably in the country, it's really incredibly impressive. I think of all the things I'll take back with me growing up in Florida is the knowledge that this has really exploded into a premier health care system with superb individuals who are here. So I'm sorry, Mike left. But on the other hand, I'm actually, I was telling Rachel, I'm actually happy that I came to this visit because I was always worried about Mike. I didn't want him to be unhappy and he's happy as a clam. So he'll never come back to San Francisco. And why would you, because you know, things there have gone like this and things here have gone like this and we won't get into the issues of San Francisco. Ok. So, you know, I'm from Miami. I was born and reared here. I was born on first baby, born in Mount Si a hospital in 1953. So I'm 70 oh, we lived near the Grove and uh Coral Gables High School and then I came back to medical school at the University of Miami because I was tired of the cold icy, cold of Boston where it would snow in May. I never saw snow until I went to Boston. Never, first time in my life because I never was on a plane. I lived here anyway. That's, that's as much as I need to say. But it's, it's a pleasure to be here and I'm, I'm thrilled to meet all of you, many new friends and to see that Mike is happy as a clam. So I'll take that information back with me. OK. So, um I wanna to this lecture in the form of well, kind of telling a story and it's a story about and you'll see on one of the last slides, it's a story about melding, um the best of both worlds for me. So, number one, I am a surgical neuro Ecologist. That's my belief in life. And that's what I have always uh tried to do is to really be an aggressive surgeon safely and try to extend life, not just quantity but quality of life. It's been really critically important to me as a neurosurgeon to do that. But I learned early on in my career that it's a dangerous thing to be an aggressive surgeon. And in the beginning of my career, I was criticized dramatically for taking an aggressive approach in an era that was really um locked into the concept of biopsy, only her gliomas, too dangerous to take him out. And I would see one person after another die and I just said, you know, enough is enough, we're gonna try to do something different along the way. I realized I had to learn a few tricks. And so this is a story about one of those tricks that I learned. And it's, it's, it's an interesting story and it's based on functional localization of language in the brain and how I use that information to dictate what I do in surgery. So that the history of of language is kind of uh it's kind of interesting in the neuroscience field. And we all have heard of, bro. And in that day and age, there was this concept that language was all over the brain. It was um in both hemispheres. And then Broca reported this injury to the posterior inferior frontal lobe and started to talk about the lateralization or the local, the local view of function. And this was um a very difficult concept at the time. And then came, we, I don't know if I can get this top thing off, do you think? Probably not? That's OK. So then came uh wary and what Warneke was really interested in had to do with the area of comprehension in the brain, which was separate. So this is kind of the first concept if you will of the difference between speech and language, what is speech? It's speech is what I'm doing. I'm opening my mouth, I'm moving my phx and my tongue and comprehension is really about understanding that we're in a room that I have a code on that, that's a dog when I see that dog and that I could read dog and know its dog. And then the idea evolved that there were connections, subcortical connections in the brain. And this turns out to be very important as you'll see. And then the French neurologist Jules Dear came along and was the first one that showed that there was a connection. So language function starts on the surface of the brain. But in order for you to be able to develop syntax, so syntax just means you're using a word or in a phrase to create a sentence that you understand. In order to do that, there's gotta be a connection in different areas of the brain. So this was the first connection and and mind you, this was before language or MRI scans were ever identified using functional imaging on MRI scans for language localization. Well, there was Pierre Marie, this was another French neurologist and I'm not gonna get much more into the history. But this had to do with the concept that there was really only one brain region and not a separate one that was connected. And so there were lots of debates at this point in time and this is basically all we knew about language uh at this point in time before the turn of the century, nothing really happened until and it was very fortuitous until um a neurologist by the name of Shwin, um who was at Harvard. And when I was an undergraduate at Harvard, and I was interested in medicine, I would go audit because at Harvard playing football, unlike the University of Miami, they have spring practice. We never had spring practice so I could go to the medical school in the spring and audit the course and I audited his course and it was really quite amazing. And what Shwin did was he confirm based on postmortem studies in stroke patients that there was connectivity between say this broker area and area. And it resulted in if parts of it were injured, different forms of inability to comprehend language which you know, of is a word called aphasia or if it's partial, it's dysphagia and there's all sorts of different terminologies that we won't go into. But the other thing that's important and you'll see the practical aspect of it is the idea of plasticity. And Gein was really the first neuroscientists, neurologists. If you will, who said that the brain is plastic? What it means is if somebody sustains a gunshot wound to the head and they lose their language, they will never recover it because it's an acute injury. And what he didn't realize at the time is that if you put something into the cranium, that's a, a compressive lesion over time that will result in reorganization. Oh, you didn't. Thank you. Reorganization just means that certain areas of the brain that are not functional can become functional, but it can't happen quickly. Um And so this and I'll come back to this because I was really one of the first ones that ever showed in a series of cases that I operated on at one time. And then I came back because the tumor recurred and had to do the map the brain mapping as you'll see again, that I was able to prove that this actually does take place. OK. So after this period, in time, neurosurgeons were beginning to experiment with stimulation of the human brain. And in the most part, it was very crude and it was very simple and it was pretty much driven by some neurop physiologists who were working with neurosurgeons until the famous Canadian. I put this in for Mike because he's Canadian Wilder Penfield was one of the first ones to actually directly stimulate the brain and create brain mapping. And when I was a resident, there was one of his students by the name of Ed Baldry, who was one of my attendings who would tell me about this. And little did I know that I would get into this as time went on and I thought you might enjoy this. Look at that phone. Have some of you never seen that kind of phone? They will. And mhm OK. OK. So this was just a classic and then um he went on to really sort of um compartmentalize if you will, different areas of the brain that had different functions. And again, this is at a time before CT scans, let alone MRI scans. So when I was uh finishing up my residency committed to being a surgical neur oncologist. But seeing the devastation of doing intracranial surgery on patients where they would wake up and they couldn't talk, I couldn't move. I, I knew there had to be a better way. So as I looked at jobs around the country, I gravitated towards the University of Washington because there was an epilepsy surgeon there. Now, the difference between epilepsy and what I do is epilepsy is more of a surface gray matter problem. But I have to go deep to the gray matter to deal with tumors, not only in the gray matter but in the white matter. So he really didn't have any experience on the tumor side, but we work together and he taught me how to map patients awake. It was a very, I had never seen a case as a resident. And uh when I started doing this, there was only one paper in the entire literature and actually Mike, it was written by Peter Black. Hm started this, he did one small series and then that was the end of it. And then he went on to intraoperative MRI as you know, but there was only one article in the paper in the field at that point in time about um cortical mapping. So I show this paper because I think when you get to my stage in life as an academician, having done this 39 years, you always ask yourself, what are the five most important manuscripts you've ever written in your life? And this is one of them because this represented a series of cases. In fact, it was the largest series ever published in, in the history of medicine on language localization in the brain. And basically what it showed was that if you stimulate the brain in a given area, like here, it simulated say 69 times, but only 19% of the time, would you find a stimulation induced deficit in language? Will that was totally counter to what Wernicke taught us that that was an area called Wernicke's area that always had comprehension in it, but it didn't. And what it started getting me to think about at that point in time. Although I didn't, I was blinded, I didn't see it then. But I realized that many years later, as you'll see is that if you put a tumor in the brain that takes time to grow, you can move, things can be reorganized, language systems, motor systems. And it explains why in that area, every time you stimulate it, you don't see a deficit because the brain can rewire itself if it's under the appropriate conditions. Now, we learned a lot of things from this study. And I think one of the most, the probably the most important thing that I learned. And that to this day, 39 years later I can say is that I've, I've mapped, as you'll see, over 1500 awake surgical cases on 1500 patients, some repeats from reoperations. And I've never found in one patient the same language localization as I found in another patient. And that's very different than the fact that your motor system is hardwired. Everybody's motor pathway is in one area. Everybody's sensory system is in one area. In fact, everybody's visual pathways are wired the same way. But everybody in this room has different language localization. And there is no preoperative test to show you where your language is located. These preoperative imaging studies only give you an approximation of where language is. That was one thing I learned. The other thing I learned from this study is that you have to do a big exposure and you have to map many different areas of the brain. And you have to find one positive site to convince yourself that your mapping is working before you commit yourself to taking any part of the brain out, to know that you're not gonna hurt that patient. So that's what we call positive mapping. And that doing it entirely in which you don't find any sites at that point. In my training said that I couldn't do the reception. So I had to have big exposures. But I realized as a tumor surgeon, unlike as an epilepsy surgeon, where you're doing one case a day is a tumor surgeon. I learned early on as Mike did, we were doing two or three cases a day. So we couldn't spend eight hours times three doing these cases. So we needed to do more focus exposure. So that began um sort of a, a very novel, innovative strategy and I'll show you the end result of that just to skip ahead about variability. Because when I first wrote that article, there was a lot of uh contradictory reports and letters to the editor from a number of individuals. And I said, well, it's gonna take me a whole career to prove that language is variable and it's not the same in everybody. And this is the article that proved it. And basically what it showed when I published this in 2016 with Eddie Chang, who's now the chair of the department and also somebody interested in language mapping that you can see like in red on the left, the probability of finding stimulation, induced arrest of speech on the right, in red, the probability of finding stimulation induced lack of ability to name objects, anomia. But in green, you find the variability, you can find speech arrest in areas, you never would think you could find it. And same thing with naming, so you just can't go into the operating room and assume you're gonna find something. So this is what's evolved and what's evolved is the technique of brain mapping to do this. And I'm gonna show you a little glimpse of it. Um So that you understand how we do this with some cases. Now, going back to my oncology roots, I wanna just go back and emphasize why we were doing this, we were doing this for safety. And so what I showed in this article where we publish it with colleagues from around the world is that if you're going to take out a glioma, the only way to do it is to use stimulation mapping because you can reduce the risk profile by 50%. If you map function, why do surgeons? Why does every neurosurgeon not do mapping? It's very simple. It takes a lot of time to do it. So you have to be willing to devote time to do the mapping before you take the tumor out. So it has really become the standard of care. And that's a dicey term in this day and age because it's a legal term. Is it the standard of care? And so it is for glioma surgery? OK. Now, the other piece of this again before I go back to the language is I just wanna spend a few minutes talking about extent of reception and outcome because I think it's critically important if you're saying now, well, OK, he's doing this mapping technique. It's taking more time. I know it's safer for patients. But is it making a difference in outcome. And so I'm gonna just show you two papers that I've published recently that are what we call in our business. Paradigm shifting. You know, that's a term we often use in the NIH when we're on study sections. Is it paradigm shifting? This is an article I published in gem oncology with my colleagues including Mike, um in which we looked at in the modern era of glioblastoma, we don't call it glioblastoma anymore. We call it I DH wild type diffuse leoma. That's really the term for glioblastoma. Now, and when we looked at all of these patients who were homogeneously treated with the standard of care, which is Temodar and, and um six months of Temodar typically and using Temodar concomitant with radiation. Um and knowing their I DH status and the M GMT status which predicts response to Temodar, you can stratify these patients in a way that all you got to take home from this chart here is that the upper lines are creating a median survival for glioblastoma of about 37 months. Now, when I started my training mean in survival was eight months. But if and how did we get there? Basically, we got there in this group of patients who had a complete removal of the enhancing tissue and we went out into the nonenhancing tissue and left less than five cubic centimeters. And so when we did that, that group there, that was ID type we pushed the survival curve way up very significant. So now if that patient's M GMT methylated and they get Temodar in standard of care and we can do that kind of a resection based on mapping, then we can get that kind of survival. So that was paradigm shifting, especially for patients under 65 we then repeated this study published it this year in the journal of Clinical Oncology on low grade gliomas showing basically the same kind of strategy. And here we had an external validation cohort from Europe and from the Boston group that we work with at Brigham Mike, that's Nino and his group. And so we looked at our cohort, they looked at theirs and we were primarily looking at what we used to call low grade gliomas. Now we call them I DH mutated, diffuse gliomas, co deleted or I DH mutant tumors that um there isn't a co deletion that they have a TRX mutations. P 53 mutations, what we used to call astrocytoma. And when we look at these curves again, all you got to take home, don't worry about the numbers. But what you want to take home here is the upper curve. So this is our data on this side and this is the data from the external cohort. And basically what it shows is that when we leave um less than 4.5 cubic centimeters on a post operative scan for these low grade gliomas that we can shift their survival curves up to the point where we now show that we can get median survivals beyond 20 years. That's not progression free survival. We know that a certain percent of those patients will progress. But the first paper I ever wrote in my career, I showed a difference in five years survival. Then I wrote a compendium paper showing how extensive resection affects 10 years survival. Now, at the end of my career, with enough follow up, I now have shown that I haven't hit median survival 20 years for either type of low grade glioma. To me, that is a massive victory in the field. And with the recent data that's come out in the New England journal using the new third generation I DH inhibitor. I think there's hope now for patients who have these low grade gliomas that we can get them into a chronic state with surgery with the I DH inhibitor for maybe 34 decades. I mean, this, that's where we are right now because that data is very, very impressive. Just came out in the New England journal earlier this month. OK. And then the other point I wanted to make is in red, that little red bar up there. Those are the patients who had a gross total resection plus, meaning with mapping, I could go beyond the tumor get out into the margin because of course, that's where infiltrating cells are. So if we can take that out, that would be even better. We can shift those curves up even higher. So the bottom line is that for the low grade tumors, we can really affect the hazard of death. If you will, you see these hazard ratios change, if you could increase your extent of resection to 100%. And if you go beyond that, it gets even better. So again, we have a paradigm shift and what that means for us and for Mike and all the neurosurgeons that work with you is it's their responsibility now to get a great reception and to get that patient out of the or intact or as close to being intact as they can get, that's where we are in neurosurgery in 2023. Ok. So how did we do this or how did I do this? I did this through a wake surgery and I've done, as I said, over 1500 of these cases where most of the patients I operate on now are awake. Um And you have to develop a mindset to do this kind of thing. I'm not gonna go through the technical nuances of it. That's not what we're here to discuss. I would just say that it's not a trivial procedure for either me or the patient. We have to use a lot of psychology to get patients through this. We have to use the right kind of medications that don't obscure the mapping findings. And we have to have the right team of anesthesiologists to work with. So it's, it's multifactorial, it's complicated and we go through all these different triage processes of. Do we put in a general anesthesia with a laryngeal mask? Do we take it out? When do we do that? What do we do if the patient becomes anxious during surgery? What happens if they don't tolerate the medication? I remember one of the first young males that ever operated on. Um, we put him on this drug Propofol, you know, Propofol, great drug. But it can make people disinhibited and he swore that we sexually manipulated him. Now, what that was, it was the foley going in. But the only thing he could remember was this and it required a lot of discussions and psychiatric help. But I realized then that propofol is sometimes a dangerous drug in this situation. So I've now used a lot of dex meat tomate, which doesn't cause that disinhibition. And I only see the disinhibition in young muscular males. And I don't know what the relationship is. My anesthesia colleagues don't know either but it is what it is. So I'm very, very careful about that now. And so I've written again a lot about this, but as complicated as it seems, the chart on the right, the lower chart which you don't have to read. It just basically says that you can do everything you need to do with three or four or five basic tests, you can do naming, you can do reading, OK. You can look at syntax depending on as I'll show you where the location is. Um But basically the motor aspects of speech are located close to the back of the frontal lobe. And the comprehension areas can be located anywhere around that frontal lobe, bottom of the parietal lobe, temporal lobe. And you have to understand as I'll show you how to map those connections. So this is kind of the operating room set up again, we're not gonna go through that. These are the kinds of simple pictures I will show people. And these are kind of the tests that will go through from basic counting to reading to word repetition, syntax, et cetera. And if I want to get fancy, depending on, and I always say to a patient, what is the most important function in your life when I'm in the clinic with him? And so I remember one patient said to me play, playing my guitar. So I said, well, bring the guitar in the or you'll play it because I was gonna operate on the right part of lobe. And that can cause what's called an a praxia or an inability to do something that you've learned to do, like buttoning your shirt, can't do it anymore. So he said, I don't really care about my language. I just want to play the guitar. So we went in the room and he played the guitar and we kept doing it until it was clear to me that he was losing that function as I was stimulating. So we stopped, got 80% of the tumor out, but that was basically it. So we have to do that. And as I said, there are a number of things I'm not gonna go through. We deal with like um when patients are overweight, it can be very difficult because they retain co2, they snore. You have to put nasal trumpets in and you have to just work your way through it and that's fine. But in all these locations in the brain, we can pretty much interrogate function depending on where it is. So you just, it's like a menu. I look at a scan and II, I study it. I think I was saying to Mike earlier that, you know, he and I are similar because the night before we go up there and we rehearse it in our mind. I close the door. I open up my computer the night before I look at the scan, I turn it upside down three dimensions. And I just try to understand how I'm gonna go through this whole thing and what tests I'm gonna use. And so basically, the way it works, as you'll see is I will stimulate the brain, the the electrical stimulation temporarily stops the function of the brain. If you stimulate the motor system, it will activate it and things will move or they'll, patients will say I feel a tingling. But if they're trying to speak, you can interrupt that function, but you have to stimulate it before the picture or the word drops into their view. Otherwise you have to call into memory circuits and that's more complicated. So when it's all said and done, this is, and you look at the literature, my morbidity rate is about 2% using these techniques. So like this week when I operated, where I came out, patients said to me, what's the risk? And I said, I know as I'll show you a slide, I know things are not gonna look great for the first few days. But if I do the map and I know where your function is or I know it's not there. And I take that area out, there's only a 2% risk of a permanent deficit. You could say that another way, right? You could say, well, there's a 98% chance it's gonna go great and you're gonna be OK. OK. So this is another one of those top five papers for me. It took me three years to get this in the New England Journal. I had a fight with the editor. I finally had to say something that I never said to an editor before I said with all due respect, I know more about this topic than your reviewers and they're wrong and they kept asking me for data and I kept giving them data and long story short, got it published. And so this is one of those, you know, for me personally, one of those landmark articles, but what it showed was I was right. I'm glad I made the right decision, right? It was 50 50. So I, I was either gonna go on in my career and do these big exposures where I was going to do very focal exposures and get negative maps. Hold my breath for a few years. Make sure it was going OK, and then go from there and it turned out that that was the right approach. So the paradigm shift in neurosurgery now is negative map after I wrote the original article on pos what that means is you can go into the RR do a very limited exposure over the tumor, get a negative stimulation map and go for it, take the tumor out. So that was a very important part of this. And what I learned here is that essentially if there's gonna be a deficit in a patient, it's gonna go away by three months. So when they say to me, OK, I'm gonna have a temporary deficit. How long is it gonna last? Well, it shouldn't ever go beyond three months because if it does then it's permanent and that's what got me to the 2%. It'll never be zero, it's never gonna be risk free, but it's pretty darn good. But here's what happens when you look at these curves of these different functions. Well, in the first few days, patients look horrible when you make rounds the next day. And the resident calls you and says, hey, Mr Brown's not speaking, he's not moving. Can't understand what I'm saying. We know it's gonna get better. And certainly by a month you see those curves drift back to baseline and then by three months you're at your final step. What about right side? How many of you are right handed? OK. 99.9% of you have language over here. I don't know where somewhere if you're left handed, who's left-handed? OK. One left hander, you have a 75% chance of having language on your left brain, 20% on your right brain and 5% bilateral. So we do tests now preoperatively with it with MRI and we can look at activation patterns and basically, I can tell you whether it's left or right. And that tells me whether I need to do it awake or sleep. So if I see somebody left handed and they have a right sided tumor, I do this test because I don't always do it awake right sided. But when I have done awake cases on the right side, the take home message here is that the language maps are the same as left side. There's no difference. OK. What about in Children? I've done a lot of stimulation mapping in Children. I still do it to this day, the youngest person I've ever a child I've ever operated on awake was a little 10 year old boy. And I remember describing this to him and his parents. And he said, you know, I'm ok with it, it sounds ok. And I said it won't hurt or anything like that. And he said, well, I just, I don't want to be frightened. So I said to the mother, I said, do you want to come in the operating room? And she said, yeah. So I said, you won't be on my side of the drape, you'll be on that side. We'll bring you in after the saw cut. She went in, held his hand. He got through it beautifully. No problem. That kid. Now he sent me a card a while. He's 26 years old. He had a lower grade tumor talks, went to college. Everything was great. So that was wonderful. So Children bottom line is they have the same language systems that we do and that starts at around age four or five. But the younger Children need different stimulation parameters. Let's just leave it at that. But we can do that. What about uh I'm sure this relates to everybody here. How many people here speak more than one language? I don't. Um But if you do, here's the, here's the take home message there is that if you learn that second language early in life, say before adolescence, then in that setting, you have two areas for the same language function. If you learned it like in college. And this is why these Rosetta Stone things work because it's mostly memorization of sounds and syllables. And so that's why in those patients, the language systems overlap. So if I showed that person, a dog, I would stimulate in one language, in another language, it would be in the same location. But if they learn their second language at four or 56, then they have different areas. So we have to do, I always ask the question to patients. Are you bilingual? We like in San Francisco, we have a very um extensive Spanish community, Latino community. And so uh it's not unusual, we have to do mapping in each language. And sometimes if there are three languages, what I'll say to the patient is you have to make a decision what language you're willing to give up if it's gonna mean what I'm gonna do with the tumor resection. So they all declare which language they want to give up. And then we often will take that if it means a better reception. OK. So I'm gonna show you a case and I wanna be careful about the time. How much time do we have? Because you carried on for too long. Hm. OK. So that's fine. And I'm gonna just, this is seven minutes, but I'm gonna just take you through it real quickly. Bits and pieces I just wanted to just show you. So I just want to show an example of how this await case plays out. Ok. So that's, yeah, so I'm in the operating room and I'm just lining this up with my navigation system. I'm gonna skip that part for a moment and I'm gonna do the injection. They should be, there's a lot of Southern, right? Ok. Then I'm gonna just get you through this stuff. So we see. Oh, very good. So basically, and my, my arm will go out of the way in a minute. But you see, I'm stimulating and he's moving his arm. So this is motor mapping. I'm activating. OK? But then I'm gonna start mapping his language function. So I'm recording off the brain because it's a very fine line. When you stimulate that, you don't evoke a seizure and if they have a seizure, they can come out of the pin. So you have to be careful. So I'm, I'm just doing that. So bird. OK. So I'm stimulating the picture appears. He tells me it's OK. I tell my person the or 28 they write it down. No problem. And we just go through this until we make this brain map and then there's the tumor there. And again, since we're not here to talk about tumor resection, I'm just gonna kind of take you through it and I'll speed it up and you know, I'm stimulating now those connections. So I So I get through the surface and you see this, this is a little electron that's constantly monitoring motor function. So he's talking to me, he's awake while I'm doing this reception and I'm stimulating and I'm going through that. And basically that pretty much takes us to the end. So we're able to take a tumor like this, create a brain map. Keep the patient awake during surgery, clean it out. Get it to this point where in the post opera scan looks fine. That's what we want to achieve. We wanna get that out. Plus we wanna do a super total beyond the flare resection if at all possible. OK. So this is taught me some interesting things along the way. And one of the things that's taught me is that you have to challenge dogma. So when we were all in medical school, we learned that you could not resect Broca's area. So let's go back to that case of bro. In the posterior part of the left frontal lobe, there's an area called Broca's area. It's otherwise known as Broad Man's area 44 45. If you take that out, it was always taught to us that you get a broker's aphasia. What does that mean? That just means that you can't speak very well. So you're dis Arthur but you comprehension remains largely intact. Well, it turns out I had published the paper and I went back and one of the curious things was that I realized that the there was only one patient that I caused the language deficit. And if I took out, broke his area, and that was in a patient who had a positive little tiny infarct that I found on DW I imaging deep in the cavity that I caused from the surgical manipulation. It was very, very tiny, but it happened to be right in that white matter pathway. And that patient had a deficit. But everybody else I took broke his area out, didn't have the deficit. So we went on recently to publish this paper, which it completely has refuted dogma. And basically what it says is that Broca's area, if you remove, it does not cause Broca's aphasia. And basically, in order to get Broca's aphasia, you have to take out an area tier and that's when you see this inability to speak, but you can comprehend it. It's very different. But if you pick up both those areas, you have a very transient issue with motor speech and then it goes away. So we now routinely take that out. But we did find along the way that there are components of syntax in this area. So now and again, not to belabor it. But now when I do this testing and mapping, I will get into the weeds. If you will of mapping, and I'll start showing them different types of phrases of activity, which helps me to understand whether if I took this area out. It would cause deficits in syntax, meaning the ability to take words and phrases and put them together in the sentences. So this is very, very helpful, but it comes back to the basic tenet that broken never understood. And that is that it wasn't the cortical injury in the surface. It was the white matter, those connections that dear talked to us about that was really important for causing Broca's aphasia. So another thing we've learned with language localization is how do we determine connections between the two areas? So I started working with, I was confused about this and I contacted one of the cognitive neuroscientists at University of California Berkeley, which if you know San Francisco, San Francisco is on a little peninsula, then you have the Bay and then you have Berkeley. So it's not far, but it takes about two hours to drive across the bridge, the Bay Bridge. But we had an idea that we were gonna put electrodes down on the brain and we were gonna record different speeds of activity from the cortex to try to see if we could understand how these regions are connected. And to make a very, very long story short, we found that if we looked at very low frequency, what we call the activity versus higher frequency gamma activity, that it was the connection between beta and gamma that defined a connection. So let me, let me show you what I mean by that if I asked you to look at that object over there and you say it's a ball and I say to you, what would you do with the ball? You might kick it, you might throw it, you might hit it. So with this electrode grid in place, this defines how the circuit works. The first thing that happens is you hear in your auditory cortex that you're saying, you're thinking about what to do about it is, is activated, it shuts down and then the motor cortex is activated and says, kick the ball. So in order for you to understand what to do with an object, in terms of the relationship between noun and verb generation, there's a circuit where you hear it, you think about it, you activate the area in the frontal lobe and that's broke his area and then it sends a signal to the motor cortex which fires and you say, kick it or you put your foot up and kick it and all that happens in what 2000 milliseconds. And that's how you think and that's how you put things together. And this just shows you how things are active before they're active in the motor cortex. So it was another translational part of language. And so we wrote a paper on it and I wrote a paper because I, I would ask my resident what they knew about language and they didn't know very much about it. And then we'd go to meetings and people ask me the same questions over and over. So I said, ok, I'm gonna write an article on the contemporary model of language organization and we wrote that and especially as it related to the subcortical system. So now we're talking about the highways underneath the surface that connect different regions of the brain. They have names like DEJ called it the arch. There are other pathways that we know of, but how do we interrogate those pathways? Well, basically, there are two main systems in the brain that connect that provide connections. One is what we call the ventral stream, which comes from the frontal lobe and is communicated through something called inferior frontal occipital fasciculus. It's a white matter bundle underneath the surface. And if you stimulate that you can produce semantic paraphasia when you talk. So you can either stimulate and look for semantic paraphrases or you can show this kind of a picture, word interference where you say in either situation to the patient. I want you to look at the related image when I'm stimulating your brain. And I want you to tell me which one of those is related versus which one isn't. So let's just concentrate on the related one. Well, of course, there are two animals over there and there's an animal and a fruit there. So I could have done it with unrelated, it doesn't really matter, but I train them to do it. Then we show them different pictures. And while I'm stimulating, if I can interfere with this picture, word recognition, I'm in the ventral stream and I know to get out of there. And likewise, I can show them pictures like this. I could stimulate the white matter in the back in the arch fasciculus and identify the dorsal stream or I can stimulate and look for phonological paraphasias instead of saying a plane, they say it's a pair. Uh I mean, it's a plane phonological paraphasia. So these are all the nuances of mapping. And of course, these are the connections, the archaic physic in part. And this just shows you an example of a case that I map, you see it falling into place where that pathway is in the brain under the surface that causes a phonological paraphasia. And how in this, in that setting, I had to leave a little bit so as to not injure that. And now we have ways postoperatively if I have a patient that's having problem talking, I can interrogate that with postoperative diffusion tensor imaging to look at the tracks to make sure I didn't interrupt them. And this is a study that we published not that long ago showing that based on the postoperative diffusion tensor imaging, I can determine and predict whether a patient's gonna recover based upon whether I've interrupted the track or as I'm doing now in a study that we're looking at the percentage of that track that's interrupted in relationship to the recovery. And when we go down underneath the surface, we look, we have different forms of mapping. I won't bore you with that. But it's generally a very high frequency stimulation with a tiny little probe, a monopolar probe or a low frequency with a, a bipolar. And this is what it looks like with the low frequency bipolar probe that's in my left hand. And then this instrument that takes the tumor out in my right hand. And I'll show you a one minute video of a case where you would use this. So I'm going to, I've identified the tumor. I've done the brain map, this is the motor cortex here. So you're gonna take yourself to the motor cortex. And as I'm doing this, um I'm gonna stimulate from time to time and I'm going to look for motor responses as well as I'm gonna be showing the, the pictures to the patient. And because of where I'm located, I'm going to be looking for the uh semantic paraphasias in that ventral stream and make sure I don't get into that. So all of that's going on and the patients awake very, very important. So that's basically that OK, I'm almost done. So I wanna come back to this, this thing that came into my mind years ago about plasticity. I learned it from shin, but I didn't understand it. And then I learned it from that first paper we published why the map why there were certain areas that didn't stimulate when all of our textbooks told us it should be there. But I didn't get it. I only got it after I started talking to one of my former fellows who came to me from France to learn the technique who's gone back. And he does it. He maps patients in France. And he said to me, you ought to look at some of your patients you've remapped. So I did that because he said, I think I'm seeing this happen. And so for example, I mapped the patient took the or photo on the upper left hand corner, right then reoperated. 32 months later, did the same map, took the same photo myself compared all that painstakingly and found the changes in those patients and basically created this paradigm where in 40% of the patients, you can see loss of function, you don't see function move into the tumor, it moves away from the tumor. I can't tell you what causes it to happen. And I can't tell you how to predict it. And I can't tell you what the time course is. But all I know now is if I do an operation tomorrow and I have to leave a piece of tumor because it's functional, I will leave the piece of tumor and I will come back if it recurs or when it recurs and hoping that in 40% of those situations, function moves away OK. So I got three slides left and this is my philosophical component of the lecture, Mike. And I used to philosophize a lot over a scotch or two in the car when we were doing concussion assessments for the 49ers, um which I still do, but he doesn't do that. Ok. For the Dolphins. Anyway, these were the two worlds I was entering when I started my residency. You see the young doctor Berger on the left, my mentor, Doctor Wilson or who Expo who mentored both me and Mike. And you know, I wanted to maximize extent of resection, but I wanted to minimize morbidity. That was it. That was the key. And in fact, when I was president of the American Association of Neurosurgeons, my keynote address to every neurosurgeon in the country, all 2600 of them was patient safety. It was all in the patient safety movement that we needed to embrace as a neurosurgical culture. You know, to stop doing things that were hurting people. We need to pay attention to all those details. So this is the road I took. I would tell you that there's a learning curve as it relates to extent of resection. But as I learned more about mapping, my extent of resection went up and you know, as Mike and I were talking about this earlier, I said, gee at the age of seven, I said to him, when do you quit? When do you stop doing this stuff, but at the age of 70 I do it as good as I ever could do it. I don't have a tremor. I'm compas mentalist. So I'd like to keep doing it. But obviously I have to be careful about that. But I, I assess my morbidity constantly and I know that it's ok. And then I'm doing, I'm doing fine. But this is really our goal now. Like why Mike's here, why I'm where I am. This is my young partner, Sean Jumper, who I stole at the University of Michigan and train him as a fellow. Now he's taking, he'll take over my Glioma practice. But, you know, our goal is to impart knowledge to all of our residents and fellows continue to develop innovative techniques and um really translate, you know, try to keep pushing the boundaries forward and make an impact on this disease. Um The other thing, Mike didn't mention, I'll just mention this is the other hat I wear is several years ago. Um I was called on, I was in the operating room, I was called on one day and my secretary, my assistant said, hey, there's a call from the White House, the White House physician wants to speak with you. And I said, yeah, OK, just tell him I'm operating. I thought she was kidding me. And so I went up to the office, I called back and it was um President Obama's uh you know, physician and he said we have a situation here. The vice President's son has a brain tumor and we need your help. Tell us what to do. This is like Friday night at 6 p.m. And he said tomorrow at 7 a.m. the vice president wants to talk with you. I said, where is he? He says he's in Delaware with his son. And I said, seven o'clock my time. He said, no, seven o'clock, Philadelphia time. So I got up at 3:34 a.m. and I had this zoom visit where you organize a visit. I think it was Skype back then. Anyway, I got to know the vice president then and his wife Jill and um helped him through that journey. Um Unfortunately, his son succumbed like all of our patients with glioblastoma. But last year, he asked me to be on his presence cancer panel and there are three of us who do this and we're now trying to help um advise the president. I report directly to the president when we have these meetings every week about um where we think the whole national cancer agenda and plan should go. And, and interestingly enough, the first thing I thought about and we all agreed as a committee, I didn't talk to Mike about it was, you know, I've had so many patients and families tell me over the years that no matter what, where they're from, no matter what socioeconomic background, no matter what culture they all feel lost in the process and that they don't have appropriate navigation. So we chose navigation as our first topic to write an annual report for the President. It's due next uh April and it's all about trying to harness um technology like A I platforms to reach into the rural communities or to disadvantaged areas in our cities. For example, where patients have no access, they don't know how to get to the clinical trial, They don't know even how to get to their appointments. So we're trying to build an AI based platform in navigation so that when anybody gets a diagnosis through their cell phone or we give them an ipad, they can go on there, they can talk to this system and the, the system, the A I platform can navigate for the patient and tell them, OK, you're located, I have your whereabouts. I know where you are, you're located here, here's where you have to go. Here's what you should do. Here are the resources for you. So navigation is our first strategy, which we think is very, very important for patients and their caregivers. So that's, that's another journey um for another time. But anyway, that's how that began. So that's what's happening and it just shows you serendipity sometimes works out, right? Because it was serendipitous that I saw some of these horrible complications early in my career that said it gotta be a better way. And there was, and this is one of the outputs of that. So, thanks very, very much. The first thing I said was, that's normal. I wasn't this depressed before. I said, well, there's a reason for that part of it. I just, when I questioned her, she did have a little history of, but this induced it and I said you have PTSD, she was awake and so she did great. But the PTSD is a phenomenon that induces some of the neuropsychological issues. And that's why we sit down in the visit before and say here's what's gonna happen. I now talk about the poly cat that goes back 26 years. So I now I'm talking about the are gonna put the cat or you may think of something going on in the history. So I, I think this the neuropsychological aspect of it's a whole different option. It is. And you got, uh reminds me of something you're talking about. This kind of work requires the 80 80 80% effort, 80% clinically, 80% research, 80% teaching, which sounds funny. It's over 100%. But that means that it's, you know, a continuous effort. So, congratulations to Mitch for establishing mapping is a very important part of it. So I think you'd like establishing lecture. You know, fighting, associated our, our pleasure and honor. If you have a reception and you have to exit the side doors here to the left, you can't go out that door in the back because there's another group. So please join us for some wine and cheese. Thank you.