#363 ‒ A new frontier in neurosurgery: restoring brain function with brain-computer interfaces, advancing glioblastoma care, and new hope for devastating brain diseases | Edward Chang, M.D.

26:27And one of the things that blew my mind was how it sounds silly, but when you look at textbooks and you study the homunculus and you look at all of the vasculature and then you actually look at the brain, it's just like any other organ, it's just kind of a blah. It's like looking at the pancreas for the first time. You're like, that's it. How do I know where everything is? I guess what makes it different is there's probably no part of a body where the real estate matters so much. When you're operating on other parts of the body, for example, if you're operating on the heart, you can really see what you're doing.

27:01You know where the left anterior descending artery is, you know where the occlusion is, and even though it's very technically complicated surgery, there is complete anatomic clarity of what is happening. I think the thing that struck me the most, the first time I saw neurosurgery was how the hell do they know what they're doing? Like, how many billion cells did we just lock off there? And obviously this speaks to what you're talking about from a functional standpoint, but a lot of times you're not doing that. So if a patient has a minigyoma or some other tumor, how do you bracket that trade off?

27:36So do you sort of say, look, there are places where you never want to have a tumor. For example, right above my left ear, that would be a really difficult place to have to resect because the real estate is so precious and that's where we're going to probably recommend doing an open awake procedure to help guide us. Is that how you're using that? That's exactly right. And so the real estate is critical. That's an understatement. But that being said, there are some really expensive real estate in there and there's also some cheaper real estate. But that's, I guess that's my point, Eddie. It's like, that's sort of like telling me about Manhattan.

28:10Yeah. Like, there's no cheap real estate in Manhattan. There happened to be areas that are $10 ,000 a square foot, but there's probably nothing less than 4 ,000 a square foot. So there's this popular idea that we only need 10 % of our brain. I'm sure you've heard this. I've heard this and I don't know what it means. It sounds like malarkey to me. That might mean to stay alive. To respire, you might only need 10 % of your brain. So what it really means is that there is maybe about 10 or 15 percent That is very critical for our basic functions are ability to move to talk to see etc It's actually a lot more than that But it's also referring to this point that there are parts of our brain actually that are extremely redundant With other parts of the brain so the frontal lobes for example We do surgeries there routinely and oftentimes people really have no effect even in terms of judgment even in terms of...

29:03Absolutely, yeah. Because we always think of the frontal lobe as where we have sort of executive function and where we have the ability. We always joke, like one of my friends in med school, we said he had no frontal lobe. Exactly. He just couldn't stop saying the most inappropriate things. And don't get me wrong. The frontal lobe actually has a lot of critical function for executive decision making and post -control, etc. But my point is that it's redundant, meaning that different parts of the frontal lobe actually have similar purposes and similar role. And so for the most part, a lot of our patients can accommodate a fairly large surgery.

29:36Sometimes even removing the entire frontal lobe. Both sides? No, not both sides. Really? Usually these pathologies are only at one side. If you took the entire frontal lobe from the left or right side, would it be a substantial difference? I've done that many times just so you know. And it really depends on the case and scenario. If someone's been having something that's slower growing there and there's been time for the brain to reorganize, we'll be called plasticity. A lot of those functions will essentially no longer be in that right frontal lobe, and they've moved to the left side. Wow. What is the mechanism by which that happens?

30:11Time and function, meaning these things don't happen overnight. They take sometimes weeks and years. But basically, what happens is some neurons get lost over time and then others will compensate in terms of that function. But how does that actually happen? So let's pause it there. We have a slow growing lesion in the left frontal lobe. What is the left frontal lobe doing to communicate with the right frontal lobe? To say, hey, these neurons are being compromised. Their function is deteriorating. You guys need to pick up the slack. How is that message being transmitted? Part of it is that both parts of the frontal lobe for people, most people are both doing the function most of the time.

30:55So it's not like it's just transferring the information. It's the both sides were originally involved in those functions. And then one side gets weaker and the other one has to pick up that slack. At a cellular level, this is what we call synaptic plasticity. The weights, you know, essentially make up who we are. These are just the weights that neurons use to communicate with one another. All of our learning is towards shaping that weighting of synapses that occur where neurons touch each other. And that can happen, that can change throughout our life. Every time we learn a new word, those are new synapses that have formed that were never there, new connections.

31:37Precisely from the left to the right side, there is this structure that we call the corpus colosum. It's an information highway that connects the left part of our brain from the right side. There was a Nobel Prize, Roger Sparrow, who done really incredible early experiments, describing patients who had surgeries, or you split that in certain instances. You have this phenomena where people essentially have two functioning brains, but they're not communicating to each other. So it does require that there is this connection between the two areas where they're being reorganized. Now, outside of epilepsy, why else would the corpus be severed?

32:13That's really the main one that we use it for. Can you describe how patients that undergo that procedure behave? It's very fascinating. So there's a phenomenon that we call a dissociation syndrome. The clinical indication, the medical indication for why someone would undergo this nowadays is that some patients with seizures have severe seizures where they fall down, what we call drop attacks. And usually what that means is that the seizure is spreading so quickly across the brain that people lose the tone in the body and then basically fall. And why that becomes a problem, the injury of the seizures, is that people actually injure themselves.

32:55So it's not uncommon for people who have these kind of seizures to actually be wearing helmets all the time because they're at such high risk of falling. These are just medically recalcitrant seizures that cannot be prevented with any degree of... That's right. That's absolutely right. I see. ...without any kind of medication. And these are particularly ones that... There's not one small spot that's causing this seizure. It's the whole half or quarter of the brain. But the problem is what a seizure is is basically when you have this very uncontrolled synchrony of a large mass of the brain cells.

33:30So normally, if you think about the brain and the neurons within the brain is like people in a stadium, they're having their individual conversations, that's the way the brain normally works. But let's say all of a sudden everyone's doing a wave and something hyper -acordinated. All of those normal conversations are now gone. The brain has now become hijacked by this other phenomenon where everything has become very coordinated. That's why people lose consciousness because all the normal function is basically shut down. And the way that it can become synchronized is through its conductivity. Every cell connecting to its adjacent cell and every cell connected to all the other cells in the brain through the things like the corpus colosum that connects the left to the right.

34:17And so when you get that hyper -synchrony, people can essentially lose consciousness almost instantaneously. So one of the reasons, historically, why the Corpus Gala Sanmea was invented in the very first place was to sever the connection between the left and right hemisphere. Which doesn't stop the seizure. It just limits the spread. That's exactly right. It doesn't stop the seizure, but what it does is stops the propagation, the very fast propagation of the seizure from one side to the other. And in order for someone to lose consciousness, You basically have to have both sides of the hemisphere or a deeper structure like the thalamus.

34:54That's basically in order to have consciousness you have to have both hemispheres out in order to lose consciousness or a deeper structure in the thalamus or something like that. And so these kind of drop attack seizures are once that people black out fall and one way you can actually dramatically stop a lot of that is disconnecting the left from the right hemisphere. And so how does that patient, how is their life different, aside from the fact that hopefully their pro seizures are gone, what's the change in the way that their left and right behave now disconnected? Most of the time when we do this nowadays, we disconnect about the anterior two -thirds of the corpus closeum.

35:35And the reason why we don't typically transect the whole corpus closeum is because of some of the side effects that people can have in which we'll recall the dissociation syndrome, where you can basically have a dissociation between what the left brain is doing in the right brain. So for example, someone essentially feeling something on the right hand which is processed by the left part of the brain and the right part of the brain really having no awareness of what's going on. People can get by with that but it does affect how they can get along. So nowadays we try to just do the front part of it and leave the back part that helps reduce some of those side effects.

36:15But does it solve the initial problem of the seizures? Yes. No. It doesn't cure the seizures, but it really just stops the propagation of the seizures so that people don't lose consciousness. Sorry, by leaving one third in the posterior still adjacent, it prevents the propagation across the hemispheres. In many, many cases. In some cases nowadays still we have to do a total calisotomy. It's a very delicate surgery because the corpus colosum that connects the left and the right, it's not sitting on the top of the brain. It's actually deep. It's very deep. So to get there, you actually have to physically separate the left and right hemisphere.

36:51We do that from the top. We do a craniotomy that's centered over the midline, but it can't be right over the midline because we have a large draining vein there called the superior sagittal sinus. So we have to either choose the left side or the right side, and then we have to very carefully separate the left from the right and through that narrow corridor, transect those connections. And what's directly underneath it that prevents you from just running that bow via a little too hot? Oh, well, there is a blood vessel that runs along the top of the corpus closeum, and that's actually the most critical part of the surgeries that we separate those two branches, those pericoloseal arteries.

37:29arteries are really important because they supply the part of the brain, the medial frontal cortex, and the part of that that is part of the motor cortex actually is what supplies and controls our legs. So if you have a stroke, let's say, as a side effect or a complication of that procedure, then someone would be paralyzed in the leg. So it's a fun, delicate surgery. It's amazing to see that exposure of the corpus chalosum. It's glistening white. That's how we can see it, and it's very distinct from the cortex because it's really clear white. That white comes from the myelin. It's a heavily, heavily myelinated structure because it's conveying information from the left side of our brain to the right side on the order of milliseconds, a super -fast connection.

38:15Do you ever think philosophically about what the implications are for human consciousness by the fact that you can do a complete transaction of the corpus and seemingly produce two people? That's right. Or potentially two consciousnesses. Yeah. What does that mean? Well, I think that goes back to a harder question of, how do you define what consciousness is in the first place? And this is where there's a lot of philosophical debate about that. Do you trouble yourself with such debates? Not really. I can't because I can't wrap my head around it. Yeah. It's above my pay grade. I do think about it from the practical clinical perspective, not so much the philosophical.

38:53The clinical one is like, is a patient in a coma or not, and why? And how do we get them out of that traumatic brain injury? Certain strokes, epilepsy, etc. We think about consciousness from that perspective, literally, all the time every day. But from the philosophical, I don't lose a lot of sleep over that one. I lose a little bit of sleep over it. Let's talk a little bit about brain computer interface. You've mentioned it already. I hope I'm not insulting people when I say this. But if we're going to be brutally honest, we should at least acknowledge that medicine to date has been pretty unimpressive when it comes to treating neurodegenerative disease.

39:32So whether we're talking about Alzheimer's disease or even other non -degenerative forms of dementia, whether we're talking about Parkinson's disease, Blue Gary's disease, I mean, we just don't seem to be able to treat these diseases. So whatever medications we throw at these things, maybe in the case of Parkinson's disease, we can delay progression a little bit. But would you agree with that assessment that the traditional approach to treating these diseases has been largely unsuccessful? I would largely agree with a caveat that I think a lot of progress is being made to understand what's going on, and from that I think there's a lot of promising therapies.

40:08I would generally agree that within neurology and neurosurgery traditionally, therapies really been designed to stop things from getting worse or slowing progression, replacing function has never really been possible until very recently. Yeah, I guess what I want to understand from you because I think this is something that you know more about than anyone, or certainly among the people who would know the most about it is, do we need to revisit our approach to these diseases more from an engineering perspective than from a peripherally administered medication perspective? So the traditional approach to treating disease would be medication.

40:51You take an injection, you take a pill, you take something, and you hope that enough of it gets across the blood brain barrier and it starts to treat the condition at hand. But it's hard to look at a patient with Parkinson's disease, which is a motor defect disease, admittedly, that stems from the CNS, and not at least think this is a functional condition. Why isn't there or is there an engineering approach that could be taken to this? It's a good question and let me put it this way. Medications are always going to be a really important goal not only to reduce symptoms but hopefully find cures.

41:31But there's this whole other class of therapies that are coming online that have to do with this other property of brain cells, which is very different than, let's say, the pancreas or the liver. It's the electrical side of the equation. So there's the chemical and biological side, but then there's this electrical side. And the brain is an electrical organ. Our thoughts are really dependent on these electrochemical kind of processes that happen at individual neurons and the collection of them. So, there's this large and growing field that we call neuroengineering that is really trying to use computers, sensors, chips in order to interpret eavesdrop on how the neurons are signaling to each other, regardless of their pathology or the biology.

42:28But just what are they saying to one another? Can we eavesdrop on that? Can we interpret it? Can we decode it? And then more importantly, can we use that information actually to guide more normal signaling? Why this is potentially important is that if the end of the day, the function is from that electrical activity. It's the propagation of those action potential by neurons, which give rise to our thoughts, or ability to communicate, or ability to walk, move our arm, without that it's not there. So I would say neuroengineering as a compliment to the biological or pharmaceutical approaches. Eddie, if you and I were mapped simultaneously together, this question might not even make sense.

43:10So please feel free to adjust the question to make it logical. But I think you'll understand what I'm trying to ask. All of the electrical activity of my brain could be mapped to a computer and the same could be done with yours. And we were thinking the same thing. So it was an experiment where we were both told to think the same thing. Peter, Eddie, we both want you to think about sitting on a beach with your feet in the sand. It's hot. It's descriptive as you want it to be. Would the outputs on the computer screen be similar? Would the computer be able to appreciate similar electrical output?

43:44Or could two people that are doing the best job they can to have the same thoughts not be able to produce that? In other words, is there a one -to -one map of thought to electrical activity? Short answer is actually both. both. So in that example that you gave, if both of us are looking at the same picture of a scene on the beach, yes, the same part of our brain is going to be processing those images in the very back of the brain that we call the sippetal lobe. The primary visual cortex is going to be parsing that space into what we call red and on topics based like essentially where those different pixels are located in the image.

44:22That part is going be highly conserved, not identical, but highly conserved between your brain and mine. It's where these computations go further upstream where they become much, much more differentiated, much more specific to our brain, much more dependent actually on our history, history of thoughts, our personality, everything that's interacting with the rest of the brain. I'll give you a great example. the way that you may hear Spanish or French or German is going to be very different than someone who is a native speaker of those languages. Your brain is going to process some of those sounds.

45:04You'll hear them, but you're not going to be able to pick out the words very easily. Or the way I hear an engine versus the way my wife hears an engine. I love the sound. She's mildly annoyed by the sound. We're hearing the same thing. Absolutely. Yeah. So there are parts that are going to be very similar, like how we process some of the sensory attributes. And then the further you go deep into the system, the more it becomes very, very tailored. Some of this is hardwired, the way that our visual system early on, a lot of it is hardwiring. It's heavily influenced by what we see. Seeing a snake should automatically produce a negative response that doesn't have to be learned in theory.

45:45I assume evolution probably hardwired us for that. There are some things that are instinctual. Certain odors would be hardwired not to like things that are going to smell rotten or something like that. Oh, yeah, absolutely. There's a lot of those things that are very intuitive. Now, going back to the, we're showing you the picture of the beach. How much do you change over time? So if we did that experiment when you were 10, 20, 30, 40, 50, would that also change? It will change, but less. I think over time, these things become refined and over time actually lose their refinement. So as we age some of those representations, I actually become less clear.

46:22If we talk about hearing, for example, there are a lot of people in the population over time. It's very hard for them to be in a crowded restaurant where there's a lot of background noise, competing conversations going on, and yet these individuals can have perfect hearing. So signal processing is becoming the problem? That's exactly right. It's not an ear problem per se. It's a perceptual problem. and largely in the brain, and that has to do with how that information, like the fidelity of the that a harbinger of something bad. independently know, but we do know that when people have that problem, they tend to be more socially isolated.

47:00So there's a lot of secondary things that happen. We do know that when people have hearing loss and it's unrecognized, a lot of people have unrecognized hearing loss. And what people don't fully appreciate is that if you don't have access to communication, to conversation, your brain is not getting those same signals, it's becoming deprived. And what we do know through many studies now is that the cognitive effects of that hearing loss actually can be quite profound. It accelerates age -related memory loss. We actually, internally in our practice, believe that that is causal to cognitive decline.

47:42Now there was a study that came out about two years ago that suggested it wasn't, although the study had a partial retraction, the methodology was a little flawed, but to my knowledge, I don't know if it's been repeated. The question being, of course, is if you correct hearing loss, let's say you randomize a group of people with early MCI and you correct hearing loss, do you correct or prevent or reverse it. And again, if there's causality there, you would expect that you would. What about with visual, as people get older and they develop cataracts or things of those nature, and their visual acuity goes down?

48:17Does it have the same effect on depriving them of enough neural stimulation to maintain her? Is it not as much? Because it's not a language issue. It's not as much, and I'm less aware in the prevalence of something that's age -related, just in the visual cortex, for example. So let's go back to brain computer interface. How would you explain this to somebody at a party if they said, that sounds pretty high tech, but what is it? Okay, let's just break apart the terms. Brain refers to really any kind of thing that interfaces with the cortex or the deeper structures. The computer is a digital device on the outside.

48:54A lot of people now call this BCI brain computer interface, for short. But it's a very messy term because it could mean a lot of different things. I think in a nutshell, what it means is for most people, a system that is recording from the brain, whether it's non -abasive from the scalp or something that's fully invasive within the brain itself and connecting those signals to a computer that analyzes the signal and then does something with it. In many cases of BCI research, the application is, for example, to remove a computer cursor, or the research that we've done is to replace speech words for someone who's severely paralyzed and unable to talk anymore.

49:40And so it's about interpreting brain signals and then using a computer to interpret those signals and then transform them into a form that's useful to us. So in that example, you gave, you're describing a patient with aphasia, who can't speak? Let me be very specific about that. So a lot of the work that we've done is on people that have severe form of paralysis. And aphasia we typically refer to as someone who's got, let's say, a stroke in the language centers of the brain, where we focus recently is on patients that have a severe form of prowess like ALS. So there the problem is they have largely normal language, but they can't get the motor signal out.

50:22Can't get the motor signal out to the vocal track, the lips, the tongue, the jaw, the larynx. Those descending fibers are severely affected by ALS, they degenerate, and that's why people progressively become paralyzed and lose ability to speak. An important part of that is that they lose ability to speak, but they still have full cognition. Yeah. And for that individual by attaching a computer to their brain, you're able to hopefully extract in written cursive text, whatever across the computer screen, what they're wishing to say. That's right. Okay. Let's talk about how that could possibly be done.

51:02You mentioned earlier, there are at least two broad ways to extract that information, a non -invasive way where presumably you're putting electrodes all over a head that says, Well, Shorn is mine. Alternatively, a very invasive way where you actually remove the scalp and you lay these things on the cortex itself, correct? Yeah. So, the range would be EEG, which is where sensors are placed on the scalp directly. Recording non -invasively, you can remove them at any time. And then the far other extreme is electrodes that are actually placed into the brain, the most invasive. ECOG would be electrodes that are on the brain service.

51:44That's short for electrocortychography, and that's where we've done the vast majority of our work in my lab. And that's just placed on the surface of the cortex, under the dura on the cortex. That's absolutely correct. So what's nice about that is that you don't have the injury to the brain itself from the insertion of the electrodes. It's a stable recording over time. We now use ECOG devices to essentially help people with seizures. For example, where you can basically have a pacemaker now that records from the brain service and then stimulates to help stop the seizures. And this is a fully implanted device?

52:19It's moving towards that. So, the work that we've done in our clinical trial is using an array that's surgically placed, but connected through a port. We call it a percutaneous port because it's actually physically attached and anchored to the skull. Then, in a ray on the brain, it comes out the dura and is anchored in the skull. Where does the port exit the body? Right on the top of the scalp. How do you prevent infection with such a close? Yeah, it's a really good question. And that's what the main problem with this early prototype BCI and it's our group. There's other groups around the world that are using similar things, primarily to show if it's possible actually to code brain activity for useful purposes.

53:03So, what's happening right now in the field is a lot of these technologies are now going to become wireless over time. But you're absolutely right. One of the main reasons is that we want to move away from the percutaneous. We want to move away from the ports which are infection risks on top of other problems and move to things that are fully implantable, fully wireless. How long do you feel you're away from that? Basically about a year. Okay. We've been working on it for quite some time. And so it's a really interesting time where we're seeing a convergence of like what's possible with electrical engineering, high bandwidth, wireless, pressure way beyond what we can do with Bluetooth, advanced electronics that now allows to print some of these sensors on a substrate that is thinner than a piece of paper, really, really small, and on a substrate that can conform to the convolutions, the different peaks and valleys of the human cortical surface, So what is the tradeoff between ECOG and sensors inserted directly in the brain?

54:07What's the resolution difference? Well, that's a very important question that we and many other people are trying to figure out right now. Most of the time when people are putting an electrode into the brain, there has to be some gain for that. And usually that's for recording a higher resolution, And usually trying to record the activity of single neurons, a single cell. How can you isolate a single cell? Really small electrodes, super small electrodes. We do a lot of work with this in our research. The challenge for the field is just been that it's very hard to stably record from single cells more than a couple of hours or days.

54:49So that's one challenge. The other challenge is that when you put the electrodes into the brain, it can create a reaction. Those glial cells, so we talked about the very beginning, those support cells, they actually have immune function as well. They detect that there is a foreign body, and they'll activate, and they'll react to it, create a scar around the electrodes. So, the advantage of having electrodes in the brain to do this very microscopic kind of is that you can get a finer signal from single cells. The disadvantage is that it can create a reaction that reduces the fidelity of those signals over time.

55:26One of the reasons we've been most interested in using these sensors on the brain cortex is that we've learned over time that if you don't have the electrodes penetrating through the peel surface of the cortex, that's the outermost, very thin membrane that's covering the cortex. If you don't have anything going through that, you can avoid a lot of those immune reactions, avoid a lot of that scarring, preserve the function that's underlying. But this is something that we're actively trying to understand. So, just to give me a sense of magnitude, if EEG on the surface is one, one unit of resolution, what would ECOGB and what would implant an electrode be?

56:05Is it 1 ,100? What's the scale at which you're thinking of that resolution? Well, I would say from the scalp, let's say we just arbitrarily they call that one. And then you think about what you could do with this ECOG. I think we're really talking about, let's say, a thousand times better resolution. We've been able to answer very fundamental questions actually about how the brain works using those kind of surface recordings in a way that's impossible with surface scalp electrodes. And then once you go take that further to single neurons and you've got another resolution, probably to 5 ,000. The big jump is just going from an EEG to an ECOG.

56:46Directly to the part. That's a three log change. Whereas you're a 5X change going over. And so one of the reasons for that is the skull and the scalp are major loss of signal. The signals are small to begin with. So once you're trying to interpret them through the skull of scalp, they're basically gone and very diffuse too. So, trying to understand like where they came from in any precise way is almost impossible. When you're recording directly on the surface, you're basically at the source itself. The cellular level, the single cell recordings are terrific for trying to understand that ultra -final resolution.

57:23Primarily, in the case that we use some force for research, primarily to understand what's happening at those units. But still to this day, there's really no way that you can chronically and stably record from the same cells. Because of the immune reaction? Also because of how fine of a problem it is, how precise it has to be. We're talking about a single cell, a couple of microns in diameter, and you've got an electrode, any micromotion at all, anything changes that. And so typically what we see with a lot of those systems, the record from those is there's a lot of turnover from day to day or hour to hour.

58:02Meaning you're drifting between which neuron you're recording in. That's exactly. Yes. Does that imply then that, I mean, just taking a step back, you said 82 billion neurons in our brain. So you put the probe into one and it moves over to the next one and the next one and the next one. One like me would naively assume they're all the same. Those are like three row homes that are basically all identical on the upper west side. We're not talking about Tribeca here. Does it really matter if the probe moves between those three? Sounds like the answer is yes, but I'm curious as to why. The answer is yes, because we now know that cells that are right next to each other can have some very different information.

58:46Now that being said, when you go through a column of the cortex, a column is this vertical organization. Typically, what we're thinking about when we look at is the two dimension of the surface. But there's a third dimension of information processing, which is the different layers of the cortex we call the lamina and Typically in some of the sensory areas for example if you put on electrode It's primarily going to be tuned to the same information across those different neurons across that depth So you're right in certain areas you may have neurons that are tuned to the exact identical thing and for decoding purposes is that may actually not be a big deal to have it not very stationary over time.

59:28In other instances where you're trying to code from areas where it's a lot more intermix, it could have really profound implications where you have to recalibrate the algorithms that the machine is doing to interpret the signals every couple of hours or days. So when you do ECOG, how do you direct the sensor at the part of the brain you want to to because I assume it has to be far more nuanced than just where you slap it on the cortex. Yeah. We're definitely getting into details and I love that Peter about you. You're not afraid of getting into the details. This alludes to one of the things we were talking about earlier.

1:00:05The part of my brain and the part of your brain that is responsible for speaking, especially in the motor control part, is largely the same. It's in the same ballpark. There's a lot of variation when we come down to the details. the microgeography, but it's in the same, largely in the same city, if we're talking about geography, where your house is, first my house, et cetera, that's going to be a little bit varied within that. One of the nice features about using ECOG or electrocortigraphy is that you can put an array over that entire area safely, and you can sample very, very densely across the entire city, let's say.

1:00:42And so it doesn't really matter actually at the end of the day if one person's there and the others Basically, you're gonna cover it. That seems to actually be a feature not a bug, right? I mean the bug is you give up the resolution at what's happening in the kitchen of that house But you now get to look at all the houses Exactly and you get to do it in a way that's very safe and scalable. I mean the biggest thing you give up is 80 % of the resolution roughly Yeah, so with ECOG Tell me how many words per minute you could capture from a patient with ALS. What we did in our clinical trial at UCSF was this the 2023 paper?

1:01:25Yes. Okay. This is the Nature Paper. That's right. We published a paper in 2023. We worked with an participant named Anne. She had a very severe brainstem stroke about 20 years ago. How old was in? She was in her 20s. It wasn't long after she had gotten married. Just a couple months after her second daughter was born. She was playing volleyball with her friends, collapsed, taken to the hospital. She survived the injury. Was it a for team, her team of arteries? Yes, that's exactly right. Yeah. Okay. This is just such a scary thing. You're in your memory from medical school is actually pretty good.

1:02:03This is impressive, but back to end, absolutely devastating. Just so people understand, retieble artery, everyone's heard of the crotted arteries. Okay, the crotted arteries come up through our neck and they primarily give the blood flow to the front part of the brain. The vertebral artery is an equally, if not more important, set of arteries that supply the brain stem, which connects the brain to the spinal cord and the back of the brain. So we have these two pairs of really important blood vessels that come to our brain, the crotted, and then the vertebral arteries. And Anne had an injury while she was playing.

1:02:42And it was really just unfortunate that she had this stroke and the vertebral artery that blocked the blood supply to the brain stem. So functionally, what this means. Can I ask you a naive question? Does it have to be bilateral to cause the injury? or if it happens on one side, can the other side not profuse around the circle of Willis? Why does that injury happen? Just to be even more precise about this, unlike the crotted artery, the vertebral arteries, you have a left and right vertebral artery. They come up through your neck and then they go through the base of the skull through the frame and magnum.

1:03:17Essentially where the spinal cord is coming through the base of the skull. When they enter the skull, they become one artery. It's called the basilar artery. And the basilar artery and the small perforating arteries that come off that supply the brainstem are absolutely critical. So, it depends where the dissection occurs. If it occurs before the bifurcation, you're probably fine if it occurs above the bifurcation or where they join. It's not the bifurcation, but yes. Yeah, yeah, yeah, yeah. Actually, you're right. There are many cases. In fact, sometimes we, for various reasons, actually have to occlude a vertebral artery and then the other one, just collateral, gives the collateral flow.

1:03:57The basilar, however, doesn't have that kind of... Yeah, it's mission critical. Doesn't have that insurance policy. No backup. It's such a critical structure, and when there's a problem there, it's usually actually like terminal. Answer vived this stroke. She was left quadruplegic, meaning she couldn't move her arms and legs, but in addition to that she couldn't speak because the nerves that come through the brain down through the brain stem and go to the cranial nerves, which supply the vocal track, those were also directly affected. And yet, just again, you'll have to pardon my profound ignorance.

1:04:36Those would be lower cranial nerves. That's right. Three, four, five, the ones for the diaphragm were intact so she could still breathe on her own, but what is 7, 8, 9 would have been compromised, which is why she couldn't speak or something in that neighborhood. Yeah, so it's the cranial nerves in particular around the lower ones and those distributions that allow the control of the tongue. That's a hypoglossal nerve. That's number 12. It's number 10, the vagus. But it's not precisely the nerves. It's actually the brainstem nuclei. Where the nerves originate. That's exactly right. And that's not something one predicts from any type of stroke.

1:05:15It's simply the nature of what part of the brainstem was affected. That's exactly right. And was the paralysis a result of her cerebellum also having infarcts? No. No, it was all brainstem, right? Just brainstem. Good for God. Yeah, precisely the part that we call the ponds. Devastating. Devastating. So this for 20 years and is now in her 40s in a wheelchair unable to speak. Right. So I think some important things about this are that it was actually about 18 years after her stroke That she decided to participate in our trial and we had talked actually a year earlier She said I really want to wait to participate in this trial because I want to wait until my daughter Graduates and then I can do this with you guys and I assume she said that because the risk of something catastrophic Happening was high enough that she felt she needed to wait Well, she's a mom.

1:06:08She wanted to be there for a daughter and she had a year before the graduation and she reached out to us because we had an earlier participant also with a brainstorm stroke that we treated, that we did this trial that I'm about to describe and she read about it and so she reached out to us. How did she communicate at that point in time? So the main way that she communicates is through devices that can track our eye movements. those are translated to a pointer that can point on a screen to individual letters or words. And so it's a very painstaking way of communicating. One thing I've learned about Anne is she's just a tremendous person, positive person.

1:06:46She's just a force of nature. She recently actually used that same system to write a book chapter. Just incredible. Okay, so we started this trial called the bravo trial is something that we worked with FDA very closely to get approved because it requires a brain surgery. It requires this percutaneous port that we talked about. The reason we were able to get it approved in this form was that a lot of the components that we were using were actually existing medical materials. So the safety of it was largely already known in terms of its bio -compactability, its biosatability. What was not known is that if someone is not spoken for a decade or two, whether or not those parts of the brain actually would still work.

1:07:35Yeah, it's really interesting because we know that if a person loses their sight for X number of years, I'm guessing that the occipital lobe doesn't work the same way. It's not processing the information. So it I don't know that it actually physically atrophies, but I'm guessing that the neurons aren't firing the same way, right? That's right. So what would be interesting is we just don't know if Anne's inner monologue is still happening the same way, right? That's a very interesting question. And I think that ultimately that was the biggest risk actually. There's a lot of emphasis on the technology, but the basic biology of how the brain works and and whether that information is still being processed, I think are really the more important ones actually.

1:08:27And so what we did was we did a surgery where we implanted an array of 253 ECOG sensors. These are the sensors that are densely spaced. How many? 253. So we're talking about something about the surface area of a credit card and it's filled with electrode sensors that are spaced about three millimeters apart. Each sensor is about a millimeter, diameter, and so basically you've got this credit card sized array that was placed on the part of a brain that processes words, in particular the motor, production of the words. The parts I control the lips, the jaw, the larynx, the tongue. Areas that were functionally disconnected from her vocal tract because of this stroke and the brain stem, which connects the brain to those muscles.

1:09:16We did the surgery about three weeks later. We started our research sessions with her. We connected the cable. It's basically an HDMI cable that is attached to a head stage. The head stage transforms the analog signals from her brain. These are a small voltage recordings. I know I get into the weeds a bit much, but I think it's kind of interesting in signal processing. Can you explain why the brain is analog and why you have to convert that to digital? Well, to some degree, there's a level that it is digital. Like, when we talk about... Action potentials are digital. Single neurons. Action potentials, like firing, yes or no, like a digital form.

1:09:59But when we're recording a lot of these, especially at the ECOG, it's an analog. It's looking at the average of these from a population of, let's say, a couple thousand of those neurons activating. And the work that we've done actually over the last decade and a half, which led up to this, using methods like ECOG, we've learned from that there's a map what we would do in the very beginning, like the homonculus, but a mini homonculus that is corresponding to those parts of the vocal track, the larynx, the tongue, the jaw. We figured out essentially how those signals correspond to every consonant and vowel in English about a decade ago.

1:10:38that was the impetus for actually starting this clinical trial was that we essentially had identified What the neural code was like what part of the brain and how that neural activity corresponds to all the movements that create syllables for example how big a data set was required to create that knowledge probably about 36 that's incredible participants data to just get the basic idea of the world and is this something where if that were 36 ,000, it would be how much better. Hopefully, perfect, like near perfect. We'll get to that because that's where things are going. How does this scale? How do we use the information from other individuals to help end of one, for example?

1:11:24But in Ants particular case, we started from the beginning. We actually didn't use that data. We knew that it was possible. We knew what the nature of that data and that code would look like. And then at the same time that we're doing all of this research, Peter, AI is developing in parallel. All of these tools that we now are using every day, transcribing our voice right now into text. We use that technology. We can actually use those same technologies that generate voices, called speech synthesis. We've used a lot of the same tools, machine learning tools, that are in modern day AIs, we're now applying them on the brain activity and trying to use them to not translate, for example, text and synthesize speech.

1:12:13But now the equation is different. It's translating it from brain activity to synthesize speech. The input is not text. The input is the ECOG activity across these 253 sensors. which of course is the logical extension. If you ignore the cost of compute, is there an advantage to doing it that way because you take out an intermediary step? Yes, it's because we know that the ballpark is there but we know that everyone's brain at that detail level, if you're going to reconstruct their words, you can't just be in the ballpark. You have to know basically like what each leave of class on that ballpark is doing and that's highly variable across individuals.

1:12:58So what is AI just trying to think about what the machine has to do? What is its training set? I'll walk you through. So the way that we train the algorithm, the way that we started this was we would give Anne prompts on a screen in text and basically we would ask her to try to say it. Can she move her lips? She can move a little bit, she can't speak. So she can move her jaw or her lips, but none of it is intelligible. She has what we call an R3A. Basically, she can vocalize a little bit, but none of it is intelligible in any form. I see. But if her inner monologue, if you put up the word, the cow jumped over the fence, and she says, and in her mind, the signal is the cow jumped over the fence, then I totally see how it works.

1:13:46Yeah. At that point, you have infinite training data. You would basically just have her read, war and peace. Right. So let me just clarify. The area that we are decoding from is not the part of the brain that is processing either inner monologue or reading. It really is this part that is about this volitional intent. Oh, that's such a good point. Right. So it's not about her like perception. It's not the reading. So when I'm reading the cow jumped over the fence, If I just go, what part of my brain is internalizing the cow, jumped over the... Well, your visual cortex. Yeah. And then as it goes further, it's going into some of the language areas.

1:14:24But it's not necessarily activating the lips, John, the larynx, the areas that are paralyzed. And so we're tapping into a part of the brain that is really... So this is a hard exercise. This takes a lot of effort on her part. A lot. So let me describe actually what that was. So for days, what we would do is have a sentence on a screen and we'd give her the start time and the end time and during that she would just look at the sentence, she'd give her an go cue and then try to say it. Nothing intelligible comes out, she may or may not be moving the lips job, but just try to say it. And that turns out to be very important.

1:15:02Oh my God. Like, you can't just think about it, you can't just hold it. You have to actually try to say it. And that's what she did. So we started with a very simple vocabulary of about 27 words. The words that we chose are the NATO code words, alpha, bravo, charlie, delta, echo. We did that because we could measure basically the accuracy of the decoder that was analyzing those brain signals and translating them into those 26 different code words. And on the first day, we were able to train the algorithm on a data set of maybe about an hour and a half to get to about 50 % accuracy. Does 50 % accuracy mean she could get half of them right or any time you showed her one, there is a 50 % chance it would be correct.

1:15:55Both. Well, you just said in our sense, identical. But there wasn't a bias towards a subset of them that she was always getting right and others that she was always getting wrong. Actually, there actually was a bias. Yeah. Actually, if I get into details, yes. Some of them were more discriminable than other. And was it based on the number of syllables? Yes. Actually, it was based on that in some of the phonetic properties. But one of the reasons why NATO code words for us was a really useful training task for us is because NATO code words were developed in the first place by the military to improve communication accuracy.

1:16:32The reason why we actually use those code words is because sometimes if you just say A, B, D, Z, there's a lot of confusion. So that's why we actually use those code words. It increases the discriminability and intelligibility. Where a lot of those settings, you just can't make those errors. For example, pilots in the call numbers, for example. So we use that because it has high discrimability and on that first day, I think we got about 50%. This is going straight to voice. This is going to text. This is straight to text. Okay. Yeah. And so we're just trying to figure out, could we decode which word it was and it was displayed in text?

1:17:10That's the first day. That's the first day. Yeah. And then over the next, I would say about six days, the performance just got better and better and then buy about like a week into this, she was up into the 95, 100 % range. So that was unexpected. It was incredible to see the performance increase so quickly, but that did take a full week. I ask you a question now, and I'm sure that the NATO code is not designed for this purpose, but presumably one could concoct a series of words that contain within them the full range of tones of phonetics, of syllable juxtapositions that would allow you to use the smallest possible training data to get the largest possible outcome.

1:18:02Does that make sense? Absolutely. How would one even develop such a thing? This is a novel problem. Right. It's actually a really important and more profound actually than you may realize. What you're referring to is the generative property of speech in language. And what I mean by generative is that you can take these individual elements like consonants and vowels which by themselves have no meaning at all and give rise to all possible meaning from just different combinations of them. Just like DNA. DNA we've got for base pairs essentially is a code for all of life. except DNA is so much easier because it's finite and the rules are always the same.

1:18:45You can define all the rules. Here you have, there's only four base pairs and they can only combine in two ways and everyone has a one -to -one mapping with what it's going to become. Here you have 26 letters, they can combine in a near infinite ways and then there are all these dumb exceptions. Right. Right. So that's where the AI comes in. Let me just explain a little bit about how the algorithm works because what you asked about actually is very, very much at the heart of the way that we do this. So we don't go from the brain activity directly to speech and words and sentences. In the very beginning with the NATO, that's what we do.

1:19:24You can use an algorithm called a classifier. It's going to look at the pattern activity and then just say, okay, it looks mostly like beta. another one looks mostly like echo, another one looks like Charlie. Okay, but to get to expressive normal speech you need something that actually can open up much more commonatorial potential to generate sequences of syllables, words, and sentences. So what we did was we built a decoder that translates the brain activity patterns in very small segments 10 to 20 millisecond little chunks of brain data, really small signals, small windows of signals. And the machine learning is looking at those small windows and making an educated guess, how does the mapping of that brain activity relate to a given consonant or vowel?

1:20:17Now, I'm using consonant vowel just because it's easy to understand. The reality is we used a speech unit. Like a phone number or something like that? A phoneme, yeah. But actually something that was statistically derived from a speech recognition algorithm. It was statistically derived. It was not something that was linguistically or that you read about. It's really a computational unit that we know if you can decode 100 of these units, you can generate fluent, comprehensible speech. So we used AI actually to derive what those units would be in the first place. we took a speech recognition system that Meta had made open source about five years ago.

1:20:54It's one of the leading speech recognition algorithms. We took essentially the neurons and what they do in that neural network. And then we tried to map those actually to the brain activity patterns. That's on the very front end. The first step of the decoding, it's translating the neural activity patterns to these individual speech units that are just 10 to 20 milliseconds long. And then it of course, knows the sequence of these units over time because it's part of the algorithm calculation And we use something called a language model Which is something that all of us are now familiar with when you're texting it out of corrects Your speech why because it has got a model of English in there and that it knows what the particular sequence of the things should be like and so Even if a lot of the data is kind of fuzzy as more data accumulates you get a sequence and then it can basically use a best guess over time.

1:21:45What we call probabilistic inference of what was the most likely word or phoneme at any given time point. And ultimately we could construct sentences. Did you get a sense from Anne as to how her level of fatigue with this progressed? In other words, what becomes the bottleneck? Does it get easier and easier for her to go through this talking motion as she practices more? Is it just like any other muscle that we think of that has sort of atrophied and now she's sort of getting her talking back in shape? It is a bit of that. We're trying to make that easier over time. I think in the beginning days, we're trying everything to get it to work.

1:22:29And a lot of it again has to do with this volitional intent to speak. That turns out to be the most critical thing. One of the things that I thought was really interesting also was we were doing so much decoding through these tests that over time actually a couple months into this and it reported to us actually the strength of our our official muscles or jaw tongue. They were actually getting stronger through this constant therapy, constant rehabilitation. And so I think right now everything is about just decoding the brain activity to an artificial digital thing. But I do think that in the future BCIs are also going to be a way that we can do rehabilitation.

1:23:12It's a way that we have this direct readout of what the brain is trying to do. You can essentially build a prosthetic that helps people speak. But in the process, someone who has been spoken for a while, what regains some of that natural strength over time. So that's a new indication that we're thinking about in the future. How do you technology actually to augment and accelerate rehabilitation. If Anne had that stroke today, how different if at all would this process look if you were working with a person who hadn't spent 20 years or 18 years without speaking? There's no question that I think it would work faster.

1:23:53There's less to learn. For her not speaking for 18 years basically meant that she basically had to relearn how to speak and we had to keep up with her relearning. Her brain was probably reorganizing, relearning actually some of those fundamental things and she could see the feedback of essentially whether or not what she was trying to say was right or wrong. And it was very intense work. So we're trying to make that easier over time. but I think certainly the more preserved, the more recent that activity is, those memories, the synapses we talked earlier, the more stable, the more functional they are, the easier it is to actually decode them.

1:24:35So what will be this ceiling for the current technology? How many words per minute and at what resolution or accuracy do you think the current technology? Because this Where do you think it's gonna go? Where will this asymptote? We're seeing a lot of progress in this field. At the same time or soon after, what we were doing, there were other groups that basically could see similar effects. ours was primarily from the brain service. Other groups, close colleagues of mine. We're able to now do this with electrodes that were inside the brain, you know, seeing these inter -cortical arrays. So it seems that it's possible with different approaches.

1:25:18I think what is going to be a key question is what's going to be the right form moving, moving in the future for many patients With Anne we were able to get about 80 words per minute on average So sometimes much faster than that comparison how many words can you and I speak comfortably? You and I are probably doing about 150 160 words per minute right now. Wow, so she could speak at half the rate you could speak at That's pretty amazing Yeah, and it's not like the speech was coming out super slow. It's just that there's this built -in latency time that We used to translate the brain activity into those words and sentences and what we published in 23 You had a very short latency and you're more recent paper didn't you?

1:26:01That's exactly right in the 23 paper Our decoding strategy was to take this sequence of decoded phonetic elements and And we could look at that sequence and then apply the decoding algorithm in the language model to reconstruct full sentences. And then we could even synthesize them. In fact, I'm personalized, I'm actually to her pre -entry voice. In a more recent study that we just published this year, we were able to do this in a streaming way with less than a second latency between each phonetic element. So it's not like we're waiting for the whole sentence to occur, but we're doing decoding on the fly and it's intelligible and fast.

1:26:41And that will get the words up to what you think. It's quickly as she can try to say them basically. And this is all with the same hardware. This is with the same hardware, totally different algorithm. On the intracranial hardware, obviously there's a big material science push to come up with the most immunologically inert substance possible. That's your challenge there. But with the ECOG, is there another hardware step function you're waiting for? Not really. I mean, I think the thing that's most exciting about this is that we have the technology now. We got to optimize it in the right form factor.

1:27:16I mean, I guess it's just moving to a fully implantable device. That's right. So you don't have to deal with the infection risk. So we need to have the array that will have a lot more channels actually. So last time I talked about a credit card size with 253, we'd like to have something that has 4x, that amount of sensors. This seems completely achievable when you think about what Nvidia is doing or TSMC. I mean, that strikes me as very solvable. It is, and we are doing it right now. With any medical device, you've got to put it all together and improve it. So we've taken these components that have very high bandwidth wireless connected to this array.

1:27:54And I think in many ways we've done the hard part already. like what Andit, what Pancho did, he was one of our early participants, what Walter are doing. These are incredible people that really the first people in the world actually to be able to achieve this real pioneers. That was the hard part. The hard part is always the first time. Yeah, for sure. It's the proof of concept. It's the proof of concept. Everything now is actually just about optimization to be honest with you. Do you think of this more as an engineering problem now? It is. Yes. Let's now expand it. So you have the proof of concept for the engineering problem that says brain works motor system doesn't work we can extract speech.

1:28:36What about these other problems that we talked about at the outset? What about ALS? Not for speech but for respiratory function. A patient with ALS is I assume I don't actually believe it or not know much about it but I assume that they ultimately succumb to respiratory complications and whether it be aspirations or things like that. So if we could overcome that problem and bypass the degenerative motor neurons, is there an engineering solution to ALS based on the type of technology we're seeing today? When we say solution, I mean to preserve communication for someone. Well, I would say let's go even beyond the ability to talk, but the ability to breathe normally, for example.

1:29:20and ultimately the ability to not lose motor function outside of the CNS. Yeah, so to do that basically is another couple of step functions in engineering where we basically are talking about bypassing pretty significant section of the nervous system. So you're going to tap into the brain to get some of the control signals. Some of this you don't even need to tap in the brain for breathing. A lot of it is, as you know, is wired. We're not thinking about it certainly. Central pattern generators in the brainstem, for example, are really important for that breathing pattern. This might sound naive, Eddie, but why is it that we couldn't wire into all of the cranial nerves outside of the cranium and create a respiratory system that is fully automated?

1:30:05Like almost think of an AICD for the diaphragm and chest wall. So we've spent almost all of our time really talking about the brain side, but then you can imagine another whole new enterprise and endeavor of building the electronics that not necessarily even tap into the nerves, the cranial nerves, let's say, or the cervical nerves that go to the diaphragm. But you bypass those too and you go directly to the muscles. Yeah. Exactly. And so there is a field we're not directly doing this research ourselves, but it's highly related to where the future is. It's called FES functional electrical stimulation.

1:30:43So coupling the brain computer interface, the device that's decoding the brain activity, translating into the control signals, and then actually acting on the muscles through stimulating electrodes that are in the muscles themselves and doing that coordinated movement. Breathing actually is a really interesting one because it's not as complex, it's like restoring our hand. It's interesting. Everybody assumes today, if you really want to be in the CS side, but the truth of the matter is you need just as much horsepower on the bioengineering side here. Electrical engineering, biomedical engineering, mechanical engineering.

1:31:19I mean, these are material science. I mean, these are this type of problem is the intersection of everything that is high tech from AI to computer science to all disciplines of engineering, coupled with medicine. I mean, you have to have the surgeon too. That's exactly right. I think that you're the nail in the head because in many ways, That's the challenge, actually. More than the technology itself is really how do you get the engineer in the room with a neurosurgeon, with a neurologist, the neuroscientist all thinking in a really conservative way about solving this problem. And then what you're going to see in the future, actually, is that this is going to evolve more and more as a biological problem.

1:31:57Thinking about biology is the next technology solution. Engineering itself that are interfacing with the brain as opposed to metal electrodes. new ways of doing computing that are through biology, that are not through semiconductors. That, I think, ultimately is where things are going to go in the future. Well, let's say more about that. I mean, this is, there are some people that are already talking about this, but I'd like people to understand more what you mean by that, because it's complicated. It is complicated. What I'm talking about really is, I think, the next couple of steps. But one of the reasons why this comes up is that you actually said it really precisely before.

1:32:34or okay, you've got this electrode system. Let's say you're recording from one cell. Best case scenario, you'd be the electronic system that can maybe do 10, maybe 40 in the future, 1000 channels. But the denominator is 86 billion. We're not in the scale, not in the same regime of scale. Biology has done that all along. Biology has solved a lot of these scaling problems. Cells that have the same genetic programming multiply because of their environment, other factors, it becomes specialized for a specific function. That's how our brain is. Each individual cell has the same genetic program, but because of its local maleew, ends up having a different identity, different purpose.

1:33:17And so I think that is really thinking outside of the electronical engineering, really moving into the realm of bioengineering. And this field is moving pretty fast. There's a whole field that we call organoids. This is creating mini brains from cell cultures or stem cells, building miniature brains, primarily being used as models of disease right now, but also as ways to test new drugs. But we're going to see these now interfacing with the world of brain computer interfaces. And so I think that that's part of the future for sure. It's very exciting. It's not near -term, but there certainly is something about the future of technologies actually in biology.

1:34:02What is your stretch goal for the field in 2030? So stretch goal meaning I define that as things have to go well but we're not talking science fiction. By 2030 I hope that we have these systems actually available to a much broader market. Like we have shown in a research setting, very controlled setting that this can be done, the proof of concept. What really needs to be done is a lot of hard engineering to make this practical, usable, useful for people with a variety of different neurological conditions, not just ALS, but spinal cord injury, stroke, multiple sclerosis. And that's a challenge.

1:34:44Everyone may have a very specific need. We need to be able to solve that. It is an optimization. It can be solved. That's what I'd love to see by 2030. Let's get a couple of these across the finish line So that they're actually out in the world helping people Is there a current Company or set of companies that are the natural owner to solving this problem based on their existing expertise? or is what you're talking about basically new companies that have to become capitalized and do this Denova. Who would be the natural owner of this? I think it's both. So the most famous probably is Neurlink, Elon Musk's company that has a very specific approach where you have a robot that is surgically inserting and sewing electrodes into the brain and trying to record from that very finest resolution.

1:35:35And I think there's a lot of progress with that, but also we've seen a lot of challenges. It's a really hard technical problem to solve it that scale. There's a variety of other companies in that vein. One of the things that we're working on is a highly customized ECOG approach because basically we already know that it works from a lot of the work that we've done and we can make it a lot higher resolution than we've done before and make it much safer with a fully implantable system. And then we're going to see more and more over time that this is going to become less and less invasive. Just like we were talking at the very beginning of our conversation.

1:36:10Surgery have become less invasive over time. Brain, computer, and faces will become less invasive. We're at the very beginning of this story, getting the most amount of data right now is the most important with highly invasive approaches. But I think it's time goes on. We're going to back out from that invasiveness. That's always how things evolve to make it more generalizable, easier and safer for people to do. Now, when you say less invasive, do you think there will ever be a day when you can do this off an EEG on the surface, or do you think, no, it will be more like minimally invasive surgery to open surgery, where instead of a craniotomy, we're going to bore a single hole in there.

1:36:49We're going to put a small tiny chip in through the dura implanted on there and we're done. The latter. The resolution at the outside of the skull is probably never going to be good enough. We're talking about a physics problem. I think a lot of people have tried to solve. Batteries will never store energy nearly as well as hydrocarbons full stop. That level of resolution that we have from the scalp, in theory, I think, but in practice, no one has been able to crack that. A lot of smart people have worked on that. Yeah, interesting. I do know that devices can continue to be miniaturized. I know that surgery can continue to be safer.

1:37:27So we will see this point in history where devices at some point are not going to just be about medical applications. There will be essentially enhancement level. There's huge ethical questions that we're going to have to deal with when that time comes. We're not there right now. But I would bet on the technology. We're not talking about breaking any rules and laws of physics. In order to get there, we're just talking about scaling, electronic, or miniaturizing it in a way that is just a smaller form factor. but over time everything becomes less invasive. So I'm sure you get asked this question all the time, but going back to the origin of Anne's story, so many people suffer brain injuries.

1:38:08If you could wave a magic wand, you would just hope for some regeneration of the injury portion of her brain. And my guess is in the case of Anne, the actual total volume of cells that are damaged is quite small. It could be this half the size of your thumb, right? I mean, it's a relatively small, but it just happened to be in the most precious part of real estate and her entire body. So do we know or do you have any point of view on the potential future of stem cell like interventions for the purpose of regeneration specifically in the CNS? Yeah, I mean, this is an area that I think got a lot of focus and attention maybe about 10 or 15 years ago.

1:38:50And I would say largely the results were pretty modest. Yeah, it best. Yeah, it best. It's coming back now because of a lot of cell -based therapies, organoids, building miniature models of brains on cell cultures, basically. I think the first things that we're going to see and where I am seeing some promise is very focal delivery in replacing cells that have been lost in small targets of the brain. So back to Parkinson's disease where you've got the generation of dopaminergic neurons and the substantial nigra, the goal is, can you replace and basically transplant some stem cells into that part of the brain?

1:39:32Remind me why the cells in the substantial nigra, do we know what's killing them? It could be multiple fault. It's partly genetic. There are certain genes that pre -just postage generation there. There's certain environmental toxins that can cause the degeneration and then there's like a huge bucket. We still don't know what's causing that. But at the end of the day, there is a degeneration of those very specialized cells. Most of the treatments are around dopamine replacement medications. And how close do you think we are towards transplant? It's already been done, actually like 23 or 30 years ago.

1:40:06Oh really? I was wondering. Yeah, using fetal grafts. They just didn't take. Some of them took, in fact, some patients got benefit from it. The side effects were also fairly severe. What kind of side effects? If you have too much dopamine, you can actually get dyskinesias. So hyper movement. So one of the current symptoms of Parkinson's. Hyper movement. Yeah. Brady Kinesha, specifically, where you have slowed movements, slowed initiate movements as well. But if you have cells that are just pumping out, don't mean they can also be putting out too much and you get the opposite effect. So it's not as simple as just putting them in there.

1:40:40They actually have to be tuned in the right way to put out the right levels. cells. So there's a new generation of new therapies that we're really interested in trialling UCSF that are much better cell models, much better control that don't mean that's involved. We have much better delivery systems. Could you imagine that? Could you imagine engineering your way out of Parkinson's disease? We're working on it. What about synthetic cells where you completely get to control it? So again, you have the substrate problem, but if it's truly a synthetic excel, then presumably it can make dopamine as well as opposed to an implantable, slow -leaked dopamine that you've come up with some slick way to refill.

1:41:18But what do you think is more likely, the more pure engineering approach or the more biologic transplant approach where you just try to tune it? The near term, of course, is taking some cell cultures that are not purely synthesized. That's still, I think, is a huge goal outside of just brain like, can you generate a cell de novo without some origins? And does that require immune modulation? Oh, absolutely. So it's a full transplant. Yeah. So a lot of these patients initially will be on immunosuppression for that. But that's also improved a lot. As immunosuppressive as if they had a kidney transplant or a liver heart transplant?

1:41:55Yes. Wow. Yeah. I think that's primarily right now the level of precaution. There is progress being made in trying to make these things as least immunogenic as possible. That's where a lot of the engineering actually is focused on. is just make it the least immunogenic to avoid a rejection scenario. So I am excited about that. And that's some of the biological engineering that I was talking about, biotechnology or the future of technology, we really coming back to the biology, moving a little bit away from the electrical engineering. So in 15 years in 2040, you're still going to be operating. You'll probably be in the final decade or 15 years of your career.

1:42:35So by a surgeon's standards plenty of work to do What do you think the world looks like in 2040 which made your problems that stand in front of you today? Do you expect to fall and what will be the implications? I think that the course that things are changing and how many things are being unlocked right now We're close. I think we're really getting close some of these things are not standard because of the side effect profiles or two severe but they can have therapeutic efficacy. We need to do that tuning this optimization. There's a lot of proof of concept out there, but like I alluded to earlier before, 99 % of the work is in the optimization in that engineering.

1:43:17I do think that now that we understand what are the molecular and genetic drivers of a disease devastating as glioplastoma, we will have way more powerful tools that will hopefully make it a chronic condition as opposed to a life of death sentence in 18 months on average. That being said, with surgeries, we can get out to years, many years. But a goal would be to make a chronic, potentially cure, by essentially attacking the mechanisms. We now know the genes that are altered. We need to be able to turn on the immune system, to recognize huge amount of effort and trying to figure this out. I do think, and I'm very optimistic around neurodegenerative disorders.

1:43:58There's just so many promising things. Including the cognitive ones like Alzheimer's. I think earlier diagnosis and earlier treatment is going to be the first thing where we're going to have the best effects. That is a really difficult one, but around Parkinson's where there's a focal problem, you can regenerate those cells. So you're more optimistic on the movement disorders than you are the cognitive disorders. That's right. Partly it's because the target in the cell loss is very focal. we can get cells through a surgery. When we're talking about Alzheimer's, it's a bit trickier because it involves multiple systems in the brain simultaneously.

1:44:36There are studies even using electrical stimulation in parts of the brain that are really important for encoding memory. These things are promising, but I think for these really step functions at what everyone wants is either stall disease or reverse it, it's gonna take more time. But I do think that early detection is gonna be a game changer. A little off topic, but it's come up through the story of Anne. Do you have a point of view on things that place people at risk for vestibular artery dissections? For example, for whatever reason, whether it's just a wives tale or not, I've always been afraid of having anybody ever adjust my neck for fear of having a vestibular artery dissection.

1:45:14Is there any truth to that? Is there other things that people should be aware of given the low probability but very, very high severity of such an injury? It's not a lifestyle. It's actually statistically proven that certain kind of chiropractic movements around the neck can cause an injury to the wall of the vertebral artery. That term dissection means that the wall of the artery has dissected. There's usually multiple different layers to that vessel wall. What happens with the dissection is the vessel is injured and then blood actually starts splitting the wall of the artery more up until the point where it becomes occluded.

1:45:53And so it's a very, very dangerous situation, and like you said, a critical part of the brainstem. So generally, we recommend not severe aggressive movements, but sometimes you can't see it actually around sports. You have a very high velocity movement around imposter around the neck. And so those are the other cases where you can see it. That being said, this is very low incidence. Yeah, low probability of happening. It's not at the level that you could really tell people to avoid certain sports or anything like that. If we could bring Harvey Cushing back from the dead, then you could have dinner with him tonight.

1:46:33What do you think he would say if he saw what was going on in the field that he created? I think that there would be one part of him that is looking at some of the surgeries that we do, or we're still doing cranium and we've seen you would say, that looks pretty similar to what we did 150 years ago. I think that's part of his genius. The fact that we still do it means that it still works and it's still safe, gets people through. A lot of that credit goes to Dr. Cushing. But there will be things that I don't think he could have ever conceived, the way that where retrieving blood clots that are reversing strokes.

1:47:12What we're doing with brain computer interfaces, decoding brain activity, the substrate of thought, to replace communication for people who are paralyzed, I think that that would have been very hard to really imagine back then. Primarily because our knowledge was so limited and electronics was nowhere even close to being able to imagine what could be done now. So a lot of what we're seeing actually relies on technology that has evolved like artificial intelligence. A lot of the work that we did on decoding the brain just couldn't work even though we had a hardware maybe 10 or 20 years ago probably even earlier than that.

1:47:50The decoding was not possible until this modern machine learning. These things are just accelerating very, very fast right now. When I was a resident I used to have this very famous picture on my wall of the five physicians who were sort of the founding physicians at Hopkins. So of course you had Hallstead insurgery and Osler and medicine and I think Kelly was gynecology and then there was a pathologist and of course, Cushing was the understeady of Hallstead before he left for Harvard. I honestly think if you could bring all of them back to life today to see how much each of their fields had progressed, I think that cushing would be the one most blown away because, and maybe I'm wrong in some historian will correct me, but I really think that what we've talked about today is to your point unimaginable.

1:48:43So, of course, Osler would see medications that he never could have conceived him, right? He could never conceive of a GLP1 agonist and the profound effect it could have on weight loss. He could never conceive at the time that there would be a medication that could eradicate cholesterol, let alone an injection once every six months that could do it. He might have not even conceived obesity back then. That's a good point. Although he was tasting urine, so he's serving the old diabetes. But yeah, I think the mental leap to where we are, although look, maybe the pathologist would have never imagined the genomic sequencing that we could do with tumors today.

1:49:20Of course, back then, it was all histology. So So it is amazing to me how much medicine has changed in 100 years. Of course, it doesn't take a leap to imagine that if we're still around as a species in 100 years, the next 100 years is going to offer far bigger changes. Absolutely. I mean, the pace of acceleration now is unprecedented. The underlying reason why I think cushing would be the one that would be the hardest to understand what's happening now is because we are talking about the brain. We are talking about an organ system that we're just starting to fathom and put our heads around sort of the complexity.

1:49:59For the last 150 years, neurosurgery has really actually been about how do you avoid injuring the brain? How do you take a tumor out of it? How do you deal with the plumbing, which is the vascular system, the blood supply? But if you think about it, the biggest open -ended questions are really being addressed right now in the coming decades. How does the brain itself work? And then how do we tap into that to address a large Friday of neurological and psychiatric conditions? The history of neurosurgery was actually primarily about trying to avoid injury, stay outside of the brain, etc. Now it's much more inward looking, trying to understand actually how the system works, how the organ works.

1:50:44And it's a super exciting time because every time we unlock essentially a function of a certain part of the brain There's a very high probability that there's gonna be a therapy either through a brain computer interface or through a Neobiological approach every time we unlock a new mechanism There'll be something that we can do to treat it and that's what the future is gonna look like One of my hidden agendas of this podcast is to encourage as many young people as possible to go into medicine And I understand that today medicine is not nearly as attractive a career as it was 20 years ago, 30 years ago, 50 years ago, and that the best and the brightest are typically going elsewhere.

1:51:22But I think a podcast like this, as many of the podcasts I do with doctors, I really hope it showcases that we need the best and the brightest to go into this. And again, this is not saying we don't need another brilliant person doing AI or investment banking or law or wherever else the top people go. but there is really an opportunity to bend the arc of civilization by choosing a career in medicine and what you're doing Eddie is really on the forefront of that especially the way it combines all disciplines of science medicine and technology is just it's super exciting. Thanks Peter Yeah, I'm really excited for that too.

1:52:02Thanks for coming. I really appreciate this discussion. Thanks for having me Thank you for listening to this week's episode of the drive. Head over to peteratia -md .com forward slash show notes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram and Twitter all with the handle peteratia -md. You can also leave us review on Apple podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional health care services, including the giving of medical advice.

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