Peter Attia MD363 ‒ A new frontier in neurosurgery: brain-computer interfaces, new hope for brain diseases, & more
EVERY SPOKEN WORD
110 min read · 21,739 words- 0:00 – 1:17
Intro
- PAPeter Attia
Whenever I think of the brain, I think of GBMs, right? I think of these awful tumors. Is there anything on the horizon to render them less lethal?
- ECEdward Chang
We are making progress, and specifically around understanding what causes.
- PAPeter Attia
I think that neurosurgery remains a little bit of a black box.
- ECEdward Chang
So we're starting to see things like stroke become more like heart attacks. These are really game-changing things when someone can go home the next day after such a huge thing.
- PAPeter Attia
Let's talk a little bit about brain-computer interface.
- ECEdward Chang
I think in a nutshell, what it means is a system that is recording from the brain and connecting those signals to a computer that analyzes the signal and then does something with it.
- PAPeter Attia
Have people understand how you even do awake surgery.
- ECEdward Chang
The brain itself doesn't have any pain receptors.
- PAPeter Attia
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?
- ECEdward Chang
[laughs]
- PAPeter Attia
Like, how, how many billion cells did we just lop off there?
- ECEdward Chang
There's this, like, popular idea that we only need ten percent of our brain. I'm sure you've heard this before.
- PAPeter Attia
I, I, I've heard this, and I don't know what it means.
- ECEdward Chang
Okay. Okay.
- PAPeter Attia
It sounds like malarkey to me.
- ECEdward Chang
Right.
- PAPeter Attia
What do you think the world looks like in twenty forty? Hey, everyone. Welcome to "The Drive" podcast. I'm your host, Peter Attia.
- 1:17 – 10:58
The evolution of neurosurgery and the shift toward minimally invasive techniques
- PAPeter Attia
Eddie, thank you so much for, uh, taking a, a, a time out of your, your very busy schedule to come to Austin. Really excited to talk with you today.
- ECEdward Chang
Oh, I'm thrilled to be here. Thanks, Peter.
- PAPeter Attia
So, um, there's so much I wanna talk about with respect to what your career is about today and, um, what the field of neurosurgery is, is, is in today and, you know, how, how the bounds are really being pushed. But as, as we were talking earlier, um, I think that neurosurgery remains a little bit of a black box.
- ECEdward Chang
Hmm.
- PAPeter Attia
And it might help orient our listeners if we give a little bit of a history lesson. Um, so can we orient ourselves back into the latter part of the nineteenth century? And, and what, what were the typical problems that would have presented to a neurosurgeon, and what were the tools that they had at their disposal? And let's, let's posit that we're speaking after the development of anesthesia at least, so we're not-
- ECEdward Chang
Okay
- PAPeter Attia
... in completely gruesome lands of-
- ECEdward Chang
[laughs]
- PAPeter Attia
... you know, holding people down.
- ECEdward Chang
Yeah. Um, well, that is a really interesting question, and one of the reasons neurosurgery is a little bit of black box is in many ways, people consider it sort of like extreme medicine, right? It's like a very small, uh, group of physicians that are taking care of patients with fairly severe kinda indications, a really rarefied field that takes a very long training in addition. Um, but let's say we go back a hundred years. Um, we're talking about the era of Harvey Cushing, who's considered really the father of modern neurosurgery. And, um, I think that was a clear inflection point in the history of medicine, in the hir- history of neuroscience, in the history of neurosurgery, really the beginning of what we would call the modern neurosurgery. And, um, why I think that Cushing was so powerful was, uh, his observation, uh, in addition to his ability to, uh, do extraordinary surgeries. So in addition to, um, being really an astute observer, um, in addition to being an incredibly technically skilled surgeon, um, I think he was also an incredible internist too, uh, diagnosing some of the first pituitary tumors and the effects of those on, you know, uh, endocrine function. Um, and then, um, really the era of, like, modern tools of craniotomy, you know, opening the skull to get access to brain tumors. Um, and everything followed since then. You know, the main categories of neurosurgery have to do with tumors, uh, the vascular system, which are aneurysms and strokes and blood clot, spine, and then probably the most recent one is the one we call functional, which actually has to do with, um, understanding the functions of brain circuit, but also intervening to change, um, how they work using deep brain stimulation or other ablation methods. And, um, those are the really exciting new developments.
- PAPeter Attia
And, and I think Harvey Cushing would be credited for the development of the electrocautery as well, wouldn't he?
- ECEdward Chang
Absolutely. I mean, there's like a huge list-
- PAPeter Attia
It's hard to imagine that you could operate without one of those things.
- ECEdward Chang
Yeah, and not just in the brain, but anywhere in the brain.
- PAPeter Attia
Anywhere in the body.
- ECEdward Chang
Yeah.
- PAPeter Attia
Yeah.
- ECEdward Chang
It's like the key of controlling bleeding in any surgery, but, but particularly in the brain.
- PAPeter Attia
Yeah.
- ECEdward Chang
It's a tricky thing. And so, um, Harvey Cushing was just, um, the starting point of modern neurosurgery. Then there's Wilder Penfield, who, uh, was an American, but really did some, uh, incredible work in creating the Montreal Neurological Institute. And, um, that was really the beginning of what we'd call, consider modern epilepsy surgery, so surgeries that are designed to stop people from having seizures. And he popularized this thing that we all learn in medical school, uh, called the homunculus. It's this picture, right, of, uh, the little man there and, um, essentially the part of our brain that controls every muscle in our body and how it's laid out in that particular part of the brain. It's something that we all learn. Um, he was also, um, a brilliant scientist who helped us understand, you know, some of the basic things that we know about language and from a technical perspective really popularized and developed, uh, the concept of awake brain surgery. Um, and that's really, um, something that's captivated me since medical school and what I now specialize in now.
- PAPeter Attia
So let's kinda fast-forward a little bit into, um, an era sort of before you and I were in medical school, um, but, you know, sort of call it the, the, the seventies and the eighties. What was the state of the art, call it forty, fifty years ago, with respect to The vascular management, the oncologic management of masses in the brain, uh, relative to today. So, uh, so, so exclusive of the interventional side of things, just in terms of being able to operate on the brain, when did it kind of-- like, where were the plateaus in, in technology?
- ECEdward Chang
Yeah. Well, um, what's interesting about it is some of the things that we do now are almost identical to the way that Cushing did it over a hundred years ago.
- PAPeter Attia
Mm.
- ECEdward Chang
And then some of it is radically different. So, um, you know, one of the workhorse surgeries that we do is called a craniotomy, and that basically means where you remove a piece of bone temporarily, you, you know, place it at the end of the procedure to access something like a brain tumor that's in the frontal or a temporal lobe. And, um, that's still being performed today and still really indicated. Um, but where we are now, um, there's ways of using laser probes through very small incisions to get to deep targets in the brain to ablate them. Um, there are ways of now even using focused ultrasound that can be targeted, you know, to specific nuclei in deep parts of the brain in order to control someone's tremor, for example. Uh, this is, um, what we'd consider a relatively non-invasive approach to, to do a neurosurgery. Um, so things have changed radically. I would say, um, one other area where we have seen, uh, tremendous, uh, disruption actually is in the vascular neurosurgery field. So, um, back in the '80s and '90s, uh, you'd have a large craniotomy, an incision probably about, you know, seven to nine inches long, uh, removal of a piece of bone, and then u-using an operative microscope to dissect down to the deepest parts where the blood vessels are coming and, uh, to fix, let's say, an aneurysm, which is es-essentially a ballooning of a, of a blood vessel that, um, when it ruptures, can be fatal. And so, um, that is a lot of what I trained on. Um, nowadays, ninety percent of those procedures are now done, you know, through a catheter in the groin that's visualized. Um, we put coils into the aneurysms to help secure them. We can now do stents. Um, a huge change actually now has been able to, um, now being able to retrieve and, uh, dissolve clots that are, you know, causing acute severe strokes. So, um, those are probably the most dramatic things that we've seen. Someone come in, uh, not able to talk, uh, paralyzed on half side of the body. Um, in the old days, we would just give some medications, keeping our fingers crossed that that would work. It rarely worked. It was really, uh, the minority of cases that it helped. But nowadays, there's a, a much bigger fraction of patients where you can put the device in, retrieve, uh, the stroke, and, um, these are really game-changing things when someone can go home the next day after such a huge thing. So we're starting to see things like stroke become more like heart attacks. The cath labs are not just treating heart attacks, but they're also treating, uh, what we call, um, uh, brain attacks or strokes. So, um, some things are relatively similar to a hundred years ago, and then some things have just been totally changed.
- PAPeter Attia
Yeah. So, so if thirty years ago a, a neurosurgeon was doing a craniotomy virtually every time-
- ECEdward Chang
Yeah
- PAPeter Attia
... they were addressing a pathology, today it might be less than half the time?
- ECEdward Chang
Yeah, that's right.
- PAPeter Attia
Yeah.
- ECEdward Chang
Yeah.
- 10:58 – 17:39
Glioblastomas: biology, current treatments, and emerging strategies to overcome its challenges
- ECEdward Chang
Yeah.
- PAPeter Attia
Now, I know this is not your field of interest, so feel free to say, "Yeah, I don't know enough about it." But w-whenever I think of the brain, I, I, I think of GBMs, right? I think of these awful tumors, uh, which I guess for the listener we can explain what that is. Um, so, so maybe tell folks what a GBM is, why a GBM is, um, truly one of the cancers that gives cancer a bad name. And, and I guess my real question for you is, given that traditional surgery has historically never worked for this tumor-
- ECEdward Chang
Mm-hmm
- PAPeter Attia
... you simply can't resolve it, and you think about the transition away from craniotomy, big open procedure, is there anything on the horizon for, for GBMs to, to render them less lethal?
- ECEdward Chang
Yeah, it's a great question. So GBM stands for glioblastoma multiforme, and it's a mouthful of a word. But, um, if you break it down, um, what it's referring to, the glial part of that word refers to the cell origin. Um, the brain has different types of cells, and if you look in the big buckets, there's neurons, which are the ones that primarily are the ones that allow us to do thinking and function, and then there's a large population of support cells. That we call glia, and that's that first part. Glioblastoma originates from those support cell population. Multiforme refers to, you know, these original descriptions histologically of the tumors that really showed, um, um, multiple form, multiple histology. Some of the key features of it are the necrosis. The tumor grows so quickly that it outstrips its blood supply, and in its wake, it leaves cell death, what we call necrosis. So like you alluded to, it really is, um, you know, a terrible kind of disease and condition. Um, we are making progress, and specifically around understanding what causes. So-
- PAPeter Attia
Mm-hmm
- ECEdward Chang
... you know, just ten years ago, uh, you would remove one of these tumors, and you send it to the lab, and you could get the diagnosis of that this is a glioblastoma. Now, uh, in most academic medical centers, you'll also get a genetic profile of the tumor. So nowadays, we actually know specifically what kind of mutations are involved in the tumor, and that's gonna be really critical for this next chapter, which is using those genetic alterations actually to, um, to tailor and personalize, you know, uh, chemotherapy and more. So, um, this has big implications because, um, we're now moving from an era where we use a visualization of the histology now to this molecular profiling, which is more mechanistic. Um, the new chemo agents are really gonna be targeting mechanisms as opposed to general things like cell cycle, um, and metabolism and things like that. So, um, these are the things that are changing, you know, and we need it to change faster. Um, there are also really exciting things that we're seeing around new ways to train the immune, immune cells to, to target things. It turns out that glioblastomas actually suppress parts of the immune system, so they, they're kind of like growing in stealth, and they activate, you know, molecules and cells in a, in a cloak way that can't be recognized by immune cells anymore. And so if we can basically allow the tumors to be recognized by the immune system, that could be something that really unlocks therapy in the future too. Um, but, um, the things that we do know that work pretty well right now, at least in terms of prolonging survival for patients and really meaningful survival actually still is around the surgery. We do know that the more extensive the resection, um, the longer the survival is, and that's been really well characterized now. But it's not curative, like you said. We can remove ninety-nine percent or even a hundred and beyond what we see on the MRI. Um, unfortunately, there's usually microscopic cells that go beyond what we can see on the MRI that are still there and over time will repopulate, you know, um, the tumor. And so it is a really complicated and, and, and tough disease, but we're working really hard on it.
- PAPeter Attia
Do we have any idea what predisposes an individual to this from a risk perspective?
- ECEdward Chang
Short answer is no. This is-
- PAPeter Attia
'Cause it afflicts young, it afflicts old.
- ECEdward Chang
Yeah.
- PAPeter Attia
I mean, I've watched children die of this, teenagers, people in midlife-
- ECEdward Chang
Right
- PAPeter Attia
... people at the end of life. It seems to have no apparent pattern.
- ECEdward Chang
Yeah, and part of that has to do with its mechanisms. It's not something that we consider as a heritable-
- PAPeter Attia
Mm-hmm
- ECEdward Chang
... kind of risk. Um, but what it does rely on is a set of mutations, and it's never-- it's rarely the same set, which is why this is-
- PAPeter Attia
Right. It's a very polygenic condition.
- ECEdward Chang
Exactly. And that's what makes it, you know, really tricky to treat. Um, when we talk about glioblastoma, we're actually not talking about one thing. We're talking about a system of genetic alterations that together have cascaded in-into the form that we see.
- PAPeter Attia
And I suspect we'll g-- we'll come back to this, Eddie, but you've alluded to chemotherapeutic agents that can be used, whether it's to treat glioblastoma or anything else, including mets of other epithelial cancers that spread to the brain. Um, the blood-brain barrier poses a challenge-
- ECEdward Chang
Yeah
- PAPeter Attia
... for treatment. Do you think the future lies in treatment within the CMS, uh, the C- the, the CSF, so treating directly inside, I don't know, intrathecally or directly into the central nervous system, uh, or do you think it's designing drugs that cross the blood-
- ECEdward Chang
Mm-hmm
- PAPeter Attia
... brain barrier? I mean, what do you think the future looks like?
- ECEdward Chang
I think it's gonna look like all of the above-
- PAPeter Attia
Hmm
- ECEdward Chang
... actually. And this is a situation where we do need to look at all possible options. This is not like the kind of thing where we're thinking like, um, non-invasive or minimally invasive. Like, really something that will work is the first priority. Um, one of the technologies I'm, I'm, I'm really, um, interested in following how this develops, and we're doing research on this at UCSF, is using focused ultrasound. So most people know about ultrasound to diagnose, but if you change the energy profile of it, you can actually use acoustic energy through an ultrasound to, uh, actually open up the blood-brain barrier in targeted parts of the brain. And so there is a lot of development on using that as a way to do delivery as opposed to putting a catheter or something directly in the brain and then, um, with that, a set of new agents that can be really molecularly specific to get to targets once you open up that blood-brain barrier.
- 17:39 – 24:22
How brain mapping has advanced from preserving function during surgery to revealing how neurons encode language and cognition
- PAPeter Attia
So what attracted you to neurosurgery? Was it something you knew you wanted to do when you went to medical school, or did you figure it out while there?
- ECEdward Chang
I had a sense. It was probably latent. Uh, I always knew that I was really interested in neuroscience, so the general field. Um, it wasn't until I was in medical school, um, that I was actually exposed to it. And, um, I remember really clearly in my first year, I had this neuroanatomy professor, Diane Ralston, who was really, um, incredibly kind person who, uh, was patient with me as we were learning. You know, you, you probably remember med school, like learning hundreds of different parts of the brain anatomy.
- PAPeter Attia
All of which I've forgotten. [laughs] I know there's a brain stem somewhere in there that's-
- ECEdward Chang
There's somewhere, something like that.
- PAPeter Attia
Yeah.
- ECEdward Chang
Yeah. So, um That's part of our ritual, right, in medical school, to learn all of those terms and locations. Um, but as you know, you know, certain teachers, like, just make such a huge difference. And so, um, you know, she took me to the operating room one day and, um, you know, I saw, uh, one of my mentors, um, at the time I was just a student, but he ultimately became my mentor, uh, Dr. Berger, doing awake surgery on a patient with a glioblastoma.
- PAPeter Attia
Hmm.
- ECEdward Chang
And, um, you know, the surgery itself I thought was pretty interesting, but the part that left me awestruck and the part that basically made it very hard for me to sleep for a couple days was really just seeing, um, an exposed brain, what the cortex looks like. The cortex is the outermost part of the brain. Um, it pulsates, it moves, um, but those are not from the mechanics of the brain itself. Those are all just from the breathing and the heart rate, et cetera. You know, it's the blood flows coming through. So, um, you know, the thing that really struck awe for me was seeing a patient talking and not fully comprehending, but really being in awe of the kind of computations that must be happening in this part of the brain. And it's not like you're looking at a computer. It's you're looking at essentially an organ composed of biological cells, uh, eighty-six billion to be precise, you know, of how many neurons there are in the human brain. So that scene to me, um, was deeply inspiring, and I was basically hooked. Um, I was so, like, hooked that I didn't really understand what I was signing up for, um, because the training for it after that, you know, was, uh, pretty difficult. I have to say seven years and, um, uh, but it was worth it, and I love every minute of it, and I'm still learning, of course. Um, we're at the very beginning of, of a new inflection point in neurosurgery, which is understanding, you know, how the human brain works.
- PAPeter Attia
There was an epiphany you had at some point in residency, wasn't there?
- ECEdward Chang
Well, I think there was an epiphany about, um, well, we have this access, really privileged access, um, to use the information, uh, on what we call brain mapping, basically. And so, um, we do the brain mapping because we wanna be very precise about, um, how we're approaching, for example, a brain tumor or a spot of the brain that's causing seizures. And we do the brain mapping so that we can map out the areas that are really important for language or the ability, uh, to move your arm. Um, that's what we call the brain mapping, and we wanna identify those areas so we can protect them during the surgery. At the same time, do the maximal resection. Like we spoke about earlier, the more that we can remove the tumor, the longer the survival. The more that we can remove of the seizure zone, the more likely someone is gonna be cured of their epilepsy. Um, but in neurosurgery, there can always be a cost, right? And that cost would be paralysis or aphasia, which is a condition where you lose the ability to speak. And so we're always trying to balance, you know, sort of like is it worth it to go that extra couple of millimeters versus, versus not. And in many cases, these are really profoundly important decisions that have to be made right then and there in the operating room, and brain mapping is a way that we, um, figure this out. In the old days, Wilder Penfield, a hundred and fifty years ago, a hundred and twenty years ago, would use an electrical stimulator and would apply it to the cortex, um, and that will temporarily activate or disrupt the function of a specific part of the brain while someone is trying to speak or move, and that's traditionally how we've done mapping. And that's one of the s- the tools, the techniques we still use today, um, in order to make sure, you know, patients are safe during these procedures. Um, one of the revelations I had during residency, of course, is that I think we can do a lot more than just applying stimulators to do the mapping. Um, we've developed technologies to record from the brain that allows us to not only do the mapping, but also is really the first window that we have of, like, understanding, like, essentially how neurons work, how they, um, convey information about words, for example, like in the conversation we're having. There's a part of your brain in the temporal lobe, uh, which is right above your ear on both sides, but the one on the left in particular-- Uh, you're right-handed, right?
- PAPeter Attia
Yeah.
- ECEdward Chang
Yeah. So ninety-nine percent of right-handers are dominant for language on the left side, and there's this one spot in the temporal lobe, which is just about two centimeters above your left ear, that's processing all the words that I'm speaking to you right now. And so we've used this technology not only to map those critical functions, and that's sort of where the science was, I would say, about ten or fifteen years ago, figuring out where these functions are in the brain, and now we've moved the science to understanding how those areas work, um, by a progressive evolution of new technologies to get us, you know, to higher and higher resolution. And what I mean by that is, um, we can measure the neural activity of cells and cell populations and then link them to, for example, different consonants and vowels, and that's been really an ex- ex- like extremely exciting, uh, development in human neuroscience.
- 24:22 – 29:02
How awake brain surgery is performed
- PAPeter Attia
I wanna back up and just have people understand how you even do awake surgery because the traditional way that surgery is done Requires general anesthesia.
- ECEdward Chang
That's right.
- PAPeter Attia
And general anesthesia typically requires three things. Um, it requires one type of medication, uh, to s- to blunt pain.
- ECEdward Chang
Yeah.
- PAPeter Attia
Another type of medication to block memory [laughs] and another type of medication to paralyze you. Now, of course, if things go wrong, and things have gone wrong, sometimes patients are paralyzed, but they feel pain, but they can't communicate it, and these are these catastrophic, but fortunately very rare events that occur in anesthesia. But, but correct anesthesia is done where a patient has no sense of time or memory of anything. They can't feel anything, and they can't move, which means they're actually safe, right?
- ECEdward Chang
Right.
- PAPeter Attia
It's, it's to, it's to save them as well. So help us understand how it is that you can do surgery without all three of those conditions being present.
- ECEdward Chang
Like I said in the beginning, this is extreme form of medicine, extreme form of surgery. Um, and the way that, in a nutshell, it can be done is that the brain itself doesn't have any pain receptors. So the pain receptors are the ones that are in our nerves, that are in the scalp, that are throughout our body. These are actually the way that we perceive pain and touch. And, um, you know, I think it's paradoxical to many people at first, but the brain itself, which is processing that information in the body, actually doesn't have those receptors itself. So the way that we typically do this is to numb the, the scalp. We use things like when you go to the dentist office, like lidocaine. We can inject around the site of the incision. Um, the bone, by the way, doesn't have any pain receptors itself either. Um, the membrane on top of the brain that we call the dura does have some pain receptors, so sometimes we have to be sensitive around that and do some, uh, local anesthesia around the dura. And interestingly, the brain tissue itself doesn't. There are some other areas, like around the blood vessels, that can be sensitive. The membrane, the dura, is sensitive. So, um, there are areas, but they can be numbed. And so this is a really important fact that allows us to do these surgeries awake when it's necessary to do it.
- PAPeter Attia
So the patient is rolled, and, and I've seen these and I, I just am blanking on exactly the procedure. So the patient is rolled into the OR. They're not intubated.
- ECEdward Chang
Right.
- PAPeter Attia
Correct?
- ECEdward Chang
They're never intubated during this, yeah.
- PAPeter Attia
Yeah. So they're, this is a patient-
- ECEdward Chang
Yeah
- PAPeter Attia
... who is laying there wide awake, no endotracheal tube.
- ECEdward Chang
Right.
- PAPeter Attia
Maybe a Foley catheter [laughs] for some comfort.
- ECEdward Chang
Yes, Foley catheter.
- PAPeter Attia
Okay.
- ECEdward Chang
Yeah, and usually Foleys are not that comfortable [laughs] .
- PAPeter Attia
Exactly.
- ECEdward Chang
But, but, uh, primarily so that we can monitor urine output-
- PAPeter Attia
Yeah
- ECEdward Chang
... during the surgery.
- PAPeter Attia
And you begin by, you know, making your incision, I mean, drawing where you wanna make your incision, and then literally just doing this as though it's a local, um-
- ECEdward Chang
Yeah
- PAPeter Attia
... you know, like you're having a lipoma removed or something.
- ECEdward Chang
[laughs]
- PAPeter Attia
You're literally just-
- ECEdward Chang
Right
- 29:02 – 43:46
How brain redundancy and plasticity allow some regions to be safely resected, the role of the corpus callosum in epilepsy surgery, and the clinical and philosophical implications of disconnecting the hemispheres
- ECEdward Chang
That's right.
- PAPeter Attia
Yeah.
- ECEdward Chang
Yeah.
- PAPeter Attia
Um, again, we were talking before the podcast how my second month of general surgery I did neurosurgery, uh, uh, meaning we rotated through it, and one of the things that blew my mind was how fr- [laughs] It sounds silly, but when you, 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?"
- ECEdward Chang
Yeah.
- PAPeter Attia
"How do I know where everything is?" Right? And, um, I guess what makes it different is there's probably no part of the body where the real estate matters so much.
- ECEdward Chang
Mm.
- PAPeter Attia
Right? Um, when you're operating on other parts of the body, y- for example, if you're operating on the heart, you can really see what you're doing.
- ECEdward Chang
Mm-hmm.
- PAPeter Attia
Right? You know where the left anterior descending artery is. You know where the occlusion is, and even though it's very technically, uh, complicated surgery, um, there is complete anatomic clarity of what is happening.
- ECEdward Chang
Yeah.
- PAPeter Attia
And 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?
- ECEdward Chang
[laughs]
- PAPeter Attia
Like, how, w- how many billion cells did we just lop off there?
- ECEdward Chang
Yeah.
- PAPeter Attia
And obviously, this speaks to what you're talking about from a functional standpoint. But, um, but a lot of times you're not doing that, right? So if a patient has a meningioma or, or some other tumor, um- How, how do you bracket that trade-off? So do you, do you sort of just sort of say, "Look, there are places where you never wanna 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 gonna probably recommend doing an open awake procedure to help guide us. I- is that kind of how you're using that?
- ECEdward Chang
That's exactly right. And so, um, the real estate is critical. That's an understatement. Um, but that being said, there is some really expensive real estate in there, and there's also some [chuckles] cheaper real estate in there. [laughs]
- PAPeter Attia
But, but that's-- I guess that's my point, Eddie. It's like that's sort of like telling me about Manhattan.
- ECEdward Chang
Yeah, yeah.
- PAPeter Attia
Like there's no cheap real estate in Manhattan.
- ECEdward Chang
[laughs] Right, right.
- PAPeter Attia
There happen to be areas that are-
- ECEdward Chang
Right
- PAPeter Attia
... ten thousand dollars a square foot.
- ECEdward Chang
Right.
- PAPeter Attia
But there's probably nothing less than-
- ECEdward Chang
Okay
- PAPeter Attia
... four thousand a square foot.
- ECEdward Chang
So, so there's this, like, popular idea that we only need ten percent of our brain. I'm sure you've heard this before.
- PAPeter Attia
I, I, I've heard this, and I don't know what it means.
- 43:46 – 54:40
How neural engineering may restore lost functions in neurodegenerative disease, how thought mapping varies across individuals, and how sensory decline contributes to cognitive aging
- ECEdward Chang
Yeah.
- PAPeter Attia
I lose a little bit of sleep over it.
- ECEdward Chang
[laughs]
- PAPeter Attia
Um, let's, let's talk a little bit about a brain computer interface. You, you've mentioned it already. Um, I hope I'm not insulting people when I say this, but if we're gonna be brutally honest, we should at least acknowledge that, that medicine to date has been pretty unimpressive when it comes to treating neurodegenerative disease. Um, so whether we're talking about Alzheimer's disease or even other non-degenerative forms of dementia, whether we're talking about Parkinson's disease, uh, Lou Gehrig's disease, I mean, we just don't seem to be able to treat these diseases. So whatever medications we throw at these things, they-- Maybe in the case of Parkinson's disease, we can, we can delay progression a little bit. But would, would you agree with that assessment that, that sort of the traditional approach to treating these diseases has been largely unsuccessful?
- ECEdward Chang
I, I would largely agree, um, with the 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. But I would generally agree that within neurology and neurosurgery, traditionally, um, therapy has really been designed to stop things from getting worse or slowing progression. Replacing function has never really been possible until very recently.
- PAPeter Attia
Yeah, and I guess what I w- want to understand from you, because I think this is something that you know more about than, than anyone, um, or certainly among the, 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, um, a peripherally administered medication perspective, right? So the traditional approach to treating disease, uh, would be medication, right? You, you, you 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, the, the condition at hand. But it's hard to look at a patient with Parkinson's disease, um, which is a motor defect disease-
- ECEdward Chang
Mm-hmm
- PAPeter Attia
... uh, admittedly that stems from the CNS, um, and not at least think h- you know, this is a functional condition, right?
- ECEdward Chang
Right.
- PAPeter Attia
Why isn't there, or is there an engineering approach that could be taken to this?
- ECEdward Chang
Yeah. Uh, it's a good question, and, um, I don't think that-- Well, let me put it this way. Um, medications are always gonna be a really important goal, um, not only to sort of reduce symptoms, but hopefully find cures. Um, but 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, um, at individual neurons and, uh, the collection of them. So, um, there's this large and growing field that we call neural engineering that is really trying to use computers, uh, sensors, chips in order to interpret, eavesdrop on how the neurons are signaling to each other, regardless of their, you know, pathology or the biology. But 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, you know, sort of m- more normal signaling? Uh, why this is potentially important is that at the end of the day, the function is from that electrical activity. It's the propagation of those action potential by neurons, which gives rise to our thoughts, our ability to communicate, our ability to walk, move our arm. Um, without that, it's not there. So, um, I would say neural engineering as a complement to the biological or pharmaceutical approaches.
- PAPeter Attia
Eddie, if you and I were mapped simultaneously together, and, uh, and I-- This question might not even make sense, so please feel free to adjust the question to make it logical, but I think you'll understand what I'm trying to ask. Um- Somehow 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. Uh, "Peter, Eddie, we both want you to think about sitting on a beach with your feet in the sand. It's hot." Like, what, as descriptive as you want it to be. Would the output, would the outputs on the computer screen be similar? Would the computer be, um, able to appreciate similar electrical output, or 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?
- ECEdward Chang
Short answer is actually both. Okay, so in that example that you gave, um, if both of us are looking at the same picture of a scene on the beach, um, yes, the same part of our brain is gonna be processing those images in the very back of the brain that we call the occipital lobe. The primary, uh, visual cortex is gonna be parsing that space into what we call retinotopic space, like essentially, you know, where those different pixels are located in, in the image. Um, that part is gonna 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-
- PAPeter Attia
Mm.
- ECEdward Chang
-and our thought, um, you know, um, history of thoughts, uh, our personality, you know, everything that's interacting with the rest of the brain. I'll give you a great example. Um, the way that you may hear Spanish or French or German is gonna be very different than someone who is a native speaker of those languages, right? Your brain is gonna process some of those sounds. You'll hear them, but you're not gonna be able to pick out the words very easily.
- PAPeter Attia
Or the way I hear an engine versus the way my wife hears an engine.
- ECEdward Chang
[chuckles] Absolutely.
- PAPeter Attia
I, I love the sound. She's mildly annoyed by the sound.
- ECEdward Chang
Right.
- PAPeter Attia
We're hearing the same thing.
- ECEdward Chang
Absolutely, yeah. So, um, so there are parts that are gonna 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's becomes, like, very, very tailored. Uh, some of this is hardwired, right? Like the way that our visual system early on is, um, a lot of it is hardwiring. It's heavily influenced by what we see, is, you know, if a child-
- PAPeter Attia
So seeing a snake should automatically produce a negative response that doesn't have to be learned in theory, I assume. Evolution-
- ECEdward Chang
Yeah, right
- PAPeter Attia
... has probably hardwired us for that.
- ECEdward Chang
There are some things that are instinctual. Um-
- PAPeter Attia
Certain odors would be, we'd hard- be hardwired not to like-
- ECEdward Chang
Yeah
- PAPeter Attia
... things that are gonna smell rotten or something like that.
- ECEdward Chang
Oh, yeah, absolutely. There's a lot of those things that are very intuitive and in-instinctive.
- PAPeter Attia
Now, going back to the, 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 ten, twenty, thirty, forty, fifty-
- 54:40 – 1:09:02
Brain–computer interfaces explained: EEG vs. ECoG vs. single-cell electrodes and their trade-offs
- PAPeter Attia
So let's go back to, to, to brain computer interface. What would be-- H-how would you explain this to somebody at a party if they said, "But it would, you know, that, that, that sounds pretty high-tech, but what is it?"
- ECEdward Chang
[chuckles] Okay. Um, well, um, okay, so let's just break apart the terms. A brain refers to really any kind of thing that interfaces with the cortex or the deeper structures. Uh, the computer is a digital device on the outside. Um, a lot of people now call this BCI, brain computer interface for short. Um, it's a very messy term, um, because it could mean a lot of different things. But I think in a nutshell, what it means is for most people, a system that is recording from the brain, whether it's non-invasive from the scalp or something that's fully invasive, like 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, uh, BCI research, the application is, uh, for example, to remove a computer cursor or, uh, in the research that we've done is to replace speech words for someone who's severely paralyzed and unable to talk anymore. And so, uh, it's about interpreting brain signals-
- PAPeter Attia
Mm.
- ECEdward Chang
And then using a computer to, um, interpret those signals and then, um, transform them into a form that's useful to us.
- PAPeter Attia
So in that example you gave, you're describing a patient with aphasia who can't speak?
- ECEdward Chang
Let me be very specific about that. So a lot of the work that we've done is on people that have a severe form of paralysis. And aphasia, we typically-
- PAPeter Attia
I see. Yep
- ECEdward Chang
... refer to as someone who's got, let's say, a stroke-
- PAPeter Attia
Yep
- ECEdward Chang
... um, in the language centers of the brain. Um, where we've focused recently is on patients that have a f- severe form of paralysis like ALS. So there the problem is they have largely normal language, but they can't get those-
- PAPeter Attia
Can't get the motor signal out.
- ECEdward Chang
Can't get the motor signal out to the vocal tract, the lips, the tongue, the jaw, the larynx. Those descending fibers are severely affected by ALS. They degenerate.
- PAPeter Attia
Yep.
- ECEdward Chang
And that's why people progressively become paralyzed and lose ability to speak.
- PAPeter Attia
And for-
- ECEdward Chang
Uh, and an important part of that is that they lose ability to speak, but they still have full cognition.
- PAPeter Attia
Yeah. And for that individual, by attaching a computer to their brain, you're able to hopefully extract in written cursive text, you know, whatever across the computer screen, what they're wishing to say?
- ECEdward Chang
That's right.
- PAPeter Attia
Okay. Let's talk about how that could possibly be done. Um, you mentioned earlier there are t- at, at least two broadly, you know, two broad ways to extract that information. A, a non-invasive way where presumably you're putting electrodes all over a head that's as well shorn as mine. Um, alternatively, a very invasive way where you actually remove the scalp and you lay these things on the cortex itself, correct?
- ECEdward Chang
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 s- extreme is, uh, electrodes that are actually placed into the brain, the most invasive.
- PAPeter Attia
ECoG.
- ECEdward Chang
Um, ECoG would be electrodes that are on the brain surface. That's short for electrocorticography, and that's where we've done the vast majority of our work in my lab.
- PAPeter Attia
And that's just placed on the surface of the cortex, under the dura on the cortex.
- ECEdward Chang
That's absolutely correct. Yeah.
- PAPeter Attia
Okay.
- ECEdward Chang
So what's nice about that is that you don't have, um, the injury to the brain itself-
- PAPeter Attia
Mm-hmm
- ECEdward Chang
... from the insertion of the electrodes. Um, 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 surface and then stimulates to help stop the seizures. Um, and there's various forms-
- PAPeter Attia
And this is a fully implanted device?
- ECEdward Chang
Um, it's moving towards that. So m- the work that we've done in our clinical trial is using an array that's surgically placed but connected through, uh, a port. We call it a percutaneous port because it's actually physically attached, uh, and anchored to the skull.
- 1:09:02 – 1:20:41
Edward’s clinical trial using ECoG to restore speech to a stroke patient
- PAPeter Attia
So with ECoG, tell me how many words per minute you could capture from a patient with ALS.
- ECEdward Chang
Okay. So, um, what we did in our clinical trial at UCSF-
- PAPeter Attia
Was this the twenty twenty-three paper?
- ECEdward Chang
Yes.
- PAPeter Attia
Okay. This is the Nature paper.
- ECEdward Chang
That's right.
- PAPeter Attia
Yep.
- ECEdward Chang
So we published a paper in twenty twenty-three. Uh, we worked with an, uh, participant named Anne. Um, she had a very severe brainstem stroke about, uh, twenty years ago.
- PAPeter Attia
How old was Anne?
- ECEdward Chang
She was in her twenties. Um, it wasn't long after she had gotten married. Actually, um, just a couple months after her second daughter was born. She was playing volleyball with her friends, collapsed, uh, taken to the hospital. Uh, she survived the injury. She woke up-
- PAPeter Attia
Was it a, was it a verte- vertebral artery-
- ECEdward Chang
Yes, that's exactly right
- PAPeter Attia
... dissection?
- ECEdward Chang
Yeah.
- PAPeter Attia
Okay.
- ECEdward Chang
Peter, you're, you're-
- PAPeter Attia
They're very-- This is just such a memory thing
- ECEdward Chang
Your, your memory from medical school is actually pretty good. You're-- This is impressive. Um, but back to Anne. Yeah, absolutely devastating. Okay, so just so people understand, vertebral artery-- Everyone's heard of the carotid arteries. Okay, the carotid 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 brainstem, which connects the brain to the spinal cord, uh, in the back of the brain. So we have these two pairs of really important blood vessels that come to our brain, the carotid and then the vertebral arteries. And Anne had an injury, uh, while she was playing, um, and it was really just unfortunate that she had this stroke in the vertebral artery that blocked the blood supply to the brainstem. So functionally, what this means-
- PAPeter Attia
Can I ask a naive question?
- ECEdward Chang
Mm-hmm.
- PAPeter Attia
Um, does it have to be bilateral to cause the injury, or if it happens on one side, can the other side not perfuse around the circle of Willis? H- Why-
- ECEdward Chang
Yeah
- PAPeter Attia
... why does that injury happen?
- ECEdward Chang
Yeah. Um, just to be even more precise about this, unlike the carotid artery, the vertebral arteries, you have a left and right vertebral artery. They come up through your neck, and then they go through the, um, the base of the skull through the foramen magnum. It's essentially where the spinal cord is coming through the base of the skull. Um, when they enter the skull, they become one artery.
- PAPeter Attia
Ah.
- ECEdward Chang
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. Probably-
- PAPeter Attia
So it depends where the dissection occurs.
- ECEdward Chang
Exactly.
- PAPeter Attia
If it occurs before the bifurcation, you're probably fine. If it occurs above the bifurcation or the, the-- where they join. It's not the bifurcation-
- ECEdward Chang
Yeah
- 1:20:41 – 1:41:10
How a stroke patient regained speech through brain–computer interfaces: training, AI decoding, and the path to scalable technology
- ECEdward Chang
syllables, for example.
- PAPeter Attia
How big a dataset was required to create that knowledge?
- ECEdward Chang
Probably about 36-
- PAPeter Attia
That's incredible
- ECEdward Chang
... participants' data, you know, to just get the basic idea of the neural-
- PAPeter Attia
And is this something where if that were 36,000, it would be how much better?
- ECEdward Chang
Almost hopefully perfect, like near perfect. What we're talking about, um, let's, let's get to that.
- PAPeter Attia
We'll-- Yeah. Okay.
- ECEdward Chang
We'll get to that because, um, that's where things are going.
- PAPeter Attia
Okay.
- ECEdward Chang
Right? Like, how does this scale-- How do we use the information from other individuals to help N of one, for example? Um, but in Anne's 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.
- PAPeter Attia
Yeah.
- ECEdward Chang
Okay, so all of these tools that we now are using every day, just transcribing our voice right now into text, um, we use that technology. We can actually use those same technologies that generate voices called, um, uh, speech synthesis. And so we've used a lot of the same tools, machine learning tools, that are in modern-day AIs, and we're now applying them on the brain activity and trying to use them to not translate, for example, text and synthesized speech, but now the equation is different. It's translating from brain activity into synthesized speech. The input is not text. The input is the ECoG activity across these two hundred and fifty-three sensors.
- PAPeter Attia
Which, of course, is the logical extension. Um, but just if you ignore the cost of compute, is there an advantage to doing it that way because you take out an intermediary step?
- ECEdward Chang
Yes. Yeah. Um, it's because we know that the ballpark is there, but we know that everyone's brain at that detail level, like if you're gonna reconstruct their words, you can't just be in the ballpark. You have to know basically like what each leaf of grass on that ballpark is doing, and that's highly variable across individuals.
- PAPeter Attia
So what is AI-- I'm just trying to think about what the machine has to do. What is its training set? How does it know? Yeah, walk me through.
- ECEdward Chang
I'll walk you through. So the way that we train the algorithm, um, 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. So the value of that is we know-
- PAPeter Attia
Can she move her lips?
- ECEdward Chang
She can move a little bit, but she can't speak. So she can move her jaw, her lips, but none of it is intelligible. She has what we call anarthria. Basically, she can vocalize a little bit, but none of it is intelligible in any form.
- PAPeter Attia
I see. But if her inner monologue-- If you, 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.
- ECEdward Chang
Yeah.
- PAPeter Attia
At that point, you have infinite training data. You would basically just have her read War and Peace.
- ECEdward Chang
Right. So let me just clarify. The, the area that we are decoding from is not the part of the brain that is processing either inner monologue or reading. Uh, it really is this part that is about this volitional intent-
- PAPeter Attia
Oh, that's such a good point
- ECEdward Chang
... to speak, right?
- PAPeter Attia
Yes.
- ECEdward Chang
So it's not about her-
- PAPeter Attia
It's not reading
- ECEdward Chang
... like perception. It's not the reading.
- PAPeter Attia
It's-- 'Cause so, so, so when I'm reading the cow jumped over the fence, but I'm not-- Or if I just go, what part of my brain is-
- 1:41:10 – 1:47:56
Using brain-computer interfaces to restore breathing, movement, and broader function in ALS patients
- PAPeter Attia
it, right? So you've, you've, you have the proof of concept for the engineering problem that says brain works, motor system doesn't work, we can extract speech. What about these other problems that we talked about at the outset? What about ALS, right? Not for speech, but for respiratory function, right?
- ECEdward Chang
Yeah.
- PAPeter Attia
So a patient with ALS is, I assume, pr- uh, it's, I, I don't actually, believe it or not, know much about it, but I assume that they ultimately succumb to respiratory complications-
- ECEdward Chang
That's right
- PAPeter Attia
... and, and whether it be aspirations-
- ECEdward Chang
Infections. Mm-hmm
- PAPeter Attia
... or things like that.
- ECEdward Chang
Yeah.
- PAPeter Attia
So, so if we could, 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?
- ECEdward Chang
When we say solution, I mean to preserve communication for someone, to preserve-
- PAPeter Attia
Well, I would say let's go even beyond the ability to talk, but the ability to breathe normally, for example.
- ECEdward Chang
Right.
- PAPeter Attia
Like the ability-
- ECEdward Chang
Yeah
- PAPeter Attia
... and ultimately the ability to not lose motor function outside of-
- ECEdward Chang
Right
- PAPeter Attia
... the CNS.
- ECEdward Chang
Yeah. So to do that basically is another couple of step functions in engineering-
- PAPeter Attia
Okay
- ECEdward Chang
... where you basically are talking about bypassing a pretty significant s- like 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 like, as you know, um, is, um, is wired. We're not thinking about it, certainly.
- PAPeter Attia
Yeah.
- ECEdward Chang
Um, central pattern generators in the brainstem, for example, are really important for that breathing pattern.
- PAPeter Attia
Like this might sound naive, Eddie, but like why is it that we couldn't wire into all of the cranial nerves outside of the cranium-
- ECEdward Chang
Yeah
- PAPeter Attia
... and create a respiratory system that is fully automated? Like, like almost think of an AICD-
- ECEdward Chang
Right
- PAPeter Attia
... for the diaphragm and chest wall.
- ECEdward Chang
Yeah. 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, um, the cervical nerves that go to the diaphragm. Um, but you bypass those two, and you go directly to the muscles.
- PAPeter Attia
Go to the muscle. Yeah.
- ECEdward Chang
Exactly. And so, um, there is a field, we're not directly doing this research ourselves, but it's highly related. It's where the future is. It's called, uh, FES, functional electrical stimulation. So 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, um, uh, electrodes that are in the muscles themselves and, and, and doing that coordinated movement. Breathing actually is a really interesting one because it's not as complex as like, let's say using our-
- 1:47:56 – 1:52:35
The 2030 outlook for brain–computer interfaces
- PAPeter Attia
What is your stretch goal for the field, uh, in twenty thirty? So stretch goal meaning the, I define that as things have to go well, but it's, we're not talking science fiction.
- ECEdward Chang
By twenty thirty, 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. Um, the proof of concept. What really needs to be done is a lot of hard engineering to make this practical, usable, useful for people like with a variety of different neurological conditions, not just ALS, but spinal cord injury, stroke, multiple sclerosis. Um, and that's a challenge, right? Like everyone 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 twenty thirty. Like just let's get a couple of these across the finish line so that they're actually out in the world helping people.
- PAPeter Attia
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 be, you know, that, that have to become capitalized and do this de novo? Like, uh-
- ECEdward Chang
Yeah. It's-
- PAPeter Attia
Who, who would be the natural owner of this?
- ECEdward Chang
Well, I think it's both. So, um, the most famous probably is Neuralink, Elon Musk's-
- PAPeter Attia
Mm-hmm
- ECEdward Chang
... uh, company that, uh, has a very specific approach where you have a robot that is surgically inserting and sewing electrodes into the brain. Um, and trying to record from that, you know, very finest resolution, and 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 at that scale. Um, there's a variety of other companies in that vein. Uh, one of the things that we're working on is a, 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, um, and make it much safer with a fully implantable system. Um, and then we're gonna see more and more over time that this is gonna become less and less invasive. Just like we were talking at the very beginning of our conversation, surgeries have become less invasive over time. Brain computer interfaces will become less an-less invasive. Um, we're at the very beginning of this story, so, like, getting the most amount of data right now is the most important with highly invasive approaches. But I think as time goes on, we're gonna back out from that invasiveness. That's always how things evolve to make it more generalizable, easier and safer for people to do.
- PAPeter Attia
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 gonna bore a single hole in there, we're gonna put a small tiny chip in through the dura, implant it on there, and we're done?
- ECEdward Chang
I think that there's some-- I, I-- The, the latter.
- PAPeter Attia
Okay.
- ECEdward Chang
Okay, and the reason-
- PAPeter Attia
In other words, the resolution at the outside of the skull is probably never going to be good enough.
- ECEdward Chang
We're, we're talking about a physics problem-
- PAPeter Attia
Yep
- ECEdward Chang
... that I think a lot of people have tried to solve a lot.
- PAPeter Attia
Batteries will never store-
- ECEdward Chang
[laughs]
- PAPeter Attia
... energy nearly as well as hydrocarbons, full stop.
- ECEdward Chang
That level of resolution that we have from the scalp, like y-you know, in theory, I think, um, but in practice, no one has been able to crack that. A lot of smart people have worked on that problem.
- PAPeter Attia
Yeah, interesting.
- ECEdward Chang
Um, I do know that devices can continue to be miniaturized. I know that surgery can continue to be safer. So we will see this point in history where, you know, devices, um, at some point are not gonna just be about medical applications. They'll be essentially, you know, enhancement level. There's huge ethical questions that we're gonna have to deal with when that time comes. We're not there right now. Um, but I would bet on the technology, you know, because that-- we're not talking about breaking any rules and laws of physics in order to get there. We're just talking about scaling, uh, electronic or miniaturizing it in a way that is just a smaller form factor. But over time, everything becomes
- 1:52:35 – 1:57:54
The potential of stem cell and cell-based therapies for regenerating lost brain function
- ECEdward Chang
less invasive.
- PAPeter Attia
So I'm sure you get asked this question all the time, but going back to the origin of Anne's story, um, so many people suffer brain injuries, and if you could wave a magic wand, you would just hope for some regeneration of the injured 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, you know, half the size of your thumb, right?
- ECEdward Chang
Mm-hmm.
- PAPeter Attia
I mean, it's a relatively small, but it just happened to be in the most precious part of real estate in 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, uh, re-regeneration, specifically in the CNS?
- ECEdward Chang
Yeah, I mean, this is an area that I think got a lot of focus and attention maybe about ten or fifteen years ago, and I would say largely the results were pretty modest.
- PAPeter Attia
Uh, yeah, at best.
- ECEdward Chang
Um, yeah, at best. Um, it's coming back now because of a lot of cell-based therapies, organoids, um, building miniature models of brains, um, on cell cultures, basically. Um, I think the first things that we're gonna see and where I am seeing some promise is, uh, very focal delivery in replacing cells that have been lost in small targets of the brain. So back to Parkinson's disease-
- PAPeter Attia
Mm
- ECEdward Chang
... where you've got degeneration of dopaminergic neurons in the substantia nigra, the goal is can you replace and basically transplant some stem cells into that part of the brain, um, or, or-
- PAPeter Attia
And remind me why the cells in the substantia nigra go-- Is it an autoimmune-- Like, what-- Do we know what's killing them?
- ECEdward Chang
I think there's a lot of, um, a lot of inform-- It could be multiple fault. It's partly genetic.
- PAPeter Attia
Mm.
- ECEdward Chang
Um, there are certain genes that predispose to degeneration there. Um, there's certain environmental toxins that can cause the degeneration, and then there's, like, a huge bucket. Like, we still don't know, you know, what's causing that. Um, but at the end of the day, there is a degeneration of those very specialized cells. Most of the treatments are around dopamine replacement-
- PAPeter Attia
Yeah
- ECEdward Chang
... right, medications.
- PAPeter Attia
And how close do you think we are towards, um, transplant?
- ECEdward Chang
Well, um, it's already been done actually like twenty, thirty years ago.
- PAPeter Attia
Oh, really? I wasn't aware of that.
- ECEdward Chang
Yeah, using fetal, uh, grafts and-
- PAPeter Attia
They just didn't take?
- ECEdward Chang
Um, some of them took. In fact, um, patients, some patients got benefit from it. The side effects were also fairly severe. Um, there were a variety of different reasons that-
- PAPeter Attia
What kind of side effects?
- ECEdward Chang
Um, like if you have too much dopamine, you can actually get dyskinesias, so hyper movement. So Parkinson-- One of the cardinal symptoms-
- PAPeter Attia
Yeah
- ECEdward Chang
... of Parkinson's-
- PAPeter Attia
Hypo movement.
- ECEdward Chang
Yeah. Um, bradykinesia specifically, uh, where you have slowed movements, slow to initiate movements as well. Um, but if you have cells that are just pumping out dopamine, 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. They actually have to be tuned-
- PAPeter Attia
Yeah
- ECEdward Chang
... in the right way to put out the right levels. And so there's a new generation Of new therapies that we're really interested in trialing at UCSF that are much better cell models, much better control of the dopamine that's involved. We have much better delivery systems to make sure that the distribution and-
- PAPeter Attia
Could you imagine that? Could you imagine engineering your way out of Parkinson's disease?
- 1:57:54 – 2:00:43
Edward’s vision for how neurosurgery and treatments for glioblastoma, Parkinson’s disease, and Alzheimer’s disease may evolve by 2040
- PAPeter Attia
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, so by a surgeon's standards, plenty of work to do. What do you think the world looks like in 2040?
- ECEdward Chang
[sighs]
- PAPeter Attia
Which major problems that stand in front of you today do you expect to fall, and what will be the implications?
- ECEdward Chang
I think that at 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 are too 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. I do think that now that we understand what are the molecular and genetic drivers of a disease as devastating as glioblastoma, we will have way more powerful tools that will hopefully make it a chronic condition as opposed to a life, a death sentence and 18 months on average. That being said, with surgeries, we can get out to years, many years. But a goal would be to make it 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 in trying to figure this out. I do think, and I'm very optimistic around neurodegenerative disorders. There's just so many promising things between cell-
- PAPeter Attia
Including the cognitive ones like Alzheimer's?
- ECEdward Chang
I think earlier diagnosis and earlier treatment is going to be the first thing where we're going to have the best effects. But that is a really difficult one. But around Parkinson's where there's a focal-
- PAPeter Attia
Yes
- ECEdward Chang
... problem, you can regenerate those cells.
- PAPeter Attia
So you're more optimistic on the movement disorders than you are the cognitive disorders.
- ECEdward Chang
That's right. And partly it's because the target and the cell loss is very focal. We can get cells through a surgery.
- PAPeter Attia
Yeah.
- ECEdward Chang
When we're talking about Alzheimer's, it's a bit trickier because it involves multiple systems in the brain simultaneously. There 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 and what everyone wants is to either stall the disease or reverse it. It's going to take more time. But I do think that early detection's going to be a game changer.
- 2:00:43 – 2:02:31
The rare but dangerous risk of vertebral artery dissections from chiropractic neck adjustments and high-velocity movements
- PAPeter Attia
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. Is there any truth to that as a risk? Are there other things that people should be aware of given the low probability but very, very high severity of such an injury?
- ECEdward Chang
It's not a wives' tale. 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. And that term dissection means that the wall of the artery has dissected. There's usually multiple different layers to that vessel wall. And what happens with the dissection is that the vessel's injured, and then blood actually starts splitting the wall of the artery more up until the point where it becomes occluded. And so it's a very, very dangerous situation and, like you said, a critical Part of the brainstem. So, um, generally we recommend, you know, like not severe aggressive movements, you know. But sometimes you can see it actually around sports, um, where you have a very high velocity, uh, movement around and posture around the neck, you know. And so those are the other cases where you can see it. That being said, this is very low incidence.
- PAPeter Attia
Yeah, low probability of it.
- ECEdward Chang
Low probability of, of happening.
- PAPeter Attia
Yeah.
- ECEdward Chang
So, um, it's not at the level that you could really tell people to avoid certain sports or anything like that.
- 2:02:31 – 2:09:13
How Harvey Cushing might view modern neurosurgery, and how the field has shifted from damage avoidance to unlocking the brain’s functions
- PAPeter Attia
Yeah. If, um, if we could bring Harvey Cushing back from the dead, and you could have dinner with him tonight, what do you think he would say if he was, you know, if he saw what was going on in the field that he created?
- ECEdward Chang
I think that there would be one part of him that is looking at some of the surgeries that we do where we're still doing craniotomies and he would say, um, "That looks pretty similar to what [laughs] we did one hundred fifty years ago." Um, 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. Um, and a lot of that credit goes to Dr. Cushing. Um, but there will be things that I don't think he could have ever conceived. The way that we're retrieving blood clots that are reversing strokes. What we're doing with brain computer interfaces, um, you know, decoding brain activity, the substrate of thought to replace communication for people who are paralyzed. Um, I think that that would've been very hard to really imagine back then, um, 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 the hardware, you know, like maybe ten or twenty years ago, um, probably even earlier than that. The decoding was not possible until this modern machine learning. And so these, these things are just, um, accelerating very, very fast right now.
- PAPeter Attia
When I was, um, a resident, I used to have this, uh, very famous picture on my wall of the sort of, um, the five physicians who were sort of the founding physicians at Hopkins. So of course you had, um, Halsted in surgery and Osler in medicine and Kelly, I think so-- I, I think Kelly was gynecology, and then there was a pathologist, and of course Cushing was the understudy of Halsted before he left for Harvard. And 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 and some historian will correct me, but I, I really think that what we've talked about today is, to your point, unimaginable, right? So of course, Osler would see medications that he never could have conceived of, right?
- ECEdward Chang
Mm-hmm.
- PAPeter Attia
He could never conceive of a GLP-1 agonist-
- ECEdward Chang
Yeah
- PAPeter Attia
... 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, um, let alone an injection once every six months that could do it.
- ECEdward Chang
He, he might have not even conceived obesity back then [laughs] .
- PAPeter Attia
That's a good point [laughs] . Um, although he was tasting urine, so he certainly knew about diabetes.
- ECEdward Chang
Yeah, sure. Sure.
- PAPeter Attia
Um, but yeah. I think, I think the mental leap to where we are-- Although, look, maybe, maybe the pathologist would've never imagined the genomic sequencing that we could do of tumors today, right? Of course, back then it was all histology. So, um, it is amazing to me how much medicine has changed in a hundred years, and of course it doesn't take a leap to imagine that if we're still around as a species in a hundred years, the next hundred years is gonna offer far bigger changes.
- ECEdward Chang
Absolutely. I mean, the pace of acceleration now is unprecedented. Um, the underlying reason why I think Cushing would be the one that would be the hardest, uh, 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 around our heads around sort of the complexity. And for the last one hundred and fifty 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, the vascular system, the blood supply? Um, but if you think about it, like 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 variety of neurological and psychiatric conditions? The history of neurosurgery was actually primarily about trying to avoid injury, stay outside of the brain, et cetera. Now it's much more inward-looking, trying to understand actually how the system works, how the organ works, and 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 new biological approach. Every time we unlock a new mechanism, there'll be something that we can do to treat it, and, um, that's what, you know, the future's gonna look like.
- PAPeter Attia
You know, 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 twenty years ago, thirty years ago, fifty years ago, and that the best and the brightest are typically going elsewhere. But, but I think a podcast like this, as, as are many of the podcasts I do with doctors, I think it-- 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. It's just, it's super exciting.
- ECEdward Chang
Thanks, Peter. Yeah, I'm really excited for that too.
- PAPeter Attia
Thanks for coming. I really appreciate this discussion.
- ECEdward Chang
Yeah. Thanks for having me. [outro music]
Episode duration: 2:09:13
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