Histotripsy through the skull

28:34fourth paper in 2021. Transcranial magnetic resonance guided hystootripsy for brain surgery. We are not just done with cancer. We're going to go to brain surgery. This is a preclinical investigation by Zu and her colleagues. They tested whether they could make controlled lesions behind pig brains inside pig brains while transmitting through an excised human skull. This is a human skull that has been donated for medical research. So this is a preclinical experiment and the geometry is worth explaining. So you've got the pig skull which is the model organism and there's a human skull around it. So we want to test whether this ultrasound can go through the human skull and

29:16actually do brain surgery on neural tissue inside. The skull is notoriously a terrible interface. Okay, I dealt with this as a PhD student, right? Like if you do if you do um just ECOG, ECOG data is terrible. Okay, look, I'm sorry. It's not terrible. It's not terrible, but like I'm a Ephys guy, which means like it's invasive. But I had to do it on rodents obviously because I wanted highfidelity 40 kHz data. I want 40,000 data points per second so that I can localize single neurons and things like that right? >> You wanted 4K, you're getting 480p. >> Yeah. like no it's like uh 20

29:56>> 20 >> and and really like ECOG data like the stuff that you see of like the um you know patients with electrodes on their skull even if you had even even if you put that ECOG wires on a data acquisition system that was taking data at 40,000 hertz like 40,000 data points a second it would be a total waste because all frequencies higher than like 40 hertz don't pass through the brain. So you would just see giant waves like this, right? Any blip that is like a millisecond long, which is about the size of an action potential, is not going to make it through the skull. So there's no point in like taking data at

30:38that fast of a rate. And I think part of the so what I'm understanding the part of the point here is is ultimately if we want to take this from the experimental environment to being functional for humans anything that's passing through a skull matters and the human skull specifically is is the barrier that we need to make sure that this actually gets through. >> Yeah. I mean there's a very good reason right the the brain is a nice thing that we have evolved over the last 10 million years and uh the skull has been evolved to take care of that brain. Okay. So like I'm not saying the skull is a bad thing. I'm just saying it's a little bit annoying for basic science research and for basic medical procedures. So the

31:18skull is a difficult electronic device as I just told you, but it's also difficult acoustically for the same reason. So like ultrasound is there's going to be impedance >> from the skull and so and so there's going to be problems, right? It attenuates sound and the thickness and the internal structure vary across the beam. like there's the skulls can be thick here and and thinner on other parts. So different paths through the bone delay the wave by different amounts. You're going to get like weird defraction signatures when the ultrasound goes through the brain. So all of that has to um has to be dealt with. These are engineering problems as much as biological ones if you want to use ultrasound >> and precision matters as we've

31:58discussed. >> Exactly. So what they what these guys did was they used a 128 element 700 kHz array. >> Okay, >> compatible with a three Tesla MRI scanner. So they've got an MRI scanner at the same time that they're administering ultrasound. Why? Because the ultrasound, they're trying to mess with the brain that's on the inside. The MRI scanner is their read cuz they want to see how what what it was like before and then they mess with it with the ultrasound. What's it like after? Can I localize my pulses? Right? Turns out they can. Um, they had successful treatment in eight pig brains and the MRI treatment regions show that they actually also did hisystologology which is the real ground truth. I think

32:40hisystologology meaning you take out the brain, you put it into slices, you stain it and then you can really see what's happening in the tissue, right? And this is a slice of that brain and there's clear demarcation. Okay, the D is the disrupted debris from my target. >> Oh my goodness. The eye is the intact neurons. And you can see just how sharp >> the interface is. >> Yeah. >> Right between the part of the brain that you wanted to ablate and sort of disrupt and the part that you wanted to keep intact. The scale bar there is 100 microns. >> This is unbelievable. >> Incredible. I mean the the thickness of that black line there, I would say tops is 10 microns. I'd even say maybe one to

33:21one to five. That's the size of large neurons. Okay. maybe groups of small neurons. >> And so we're we're now getting confirmational data that our the level of precision when going through a human skull of this ultra ultrasound approach has micron level thick. >> Mhm. >> Precision. >> Precision. >> That's right. >> And and we built this, right? Because in the beginning we were just doing bubbles and then we built, okay, how do we how do we make sure that >> the the the precision is there? Well, we can actually tune the amplitude of the pressure wave and now we can actually do it within the skull. We can deal with all of the defraction and all of the

34:02weird wave stuff that's happening on the skull. >> And it seems like the skull is a region because obviously we've targeted different parts of the body over the course of this discussion. The heart uh we obviously we're going to get to other places but the brain now is another >> and the uh the uh the TSA of the brain is pretty tough to get through. >> Yes. Exactly. And um the one one other thing I want to just touch on here before we move on to our fifth paper. Why use hystootripsy um rather than just heating for this job? >> Well, it's in the name itself. You don't want to heat the brain. >> Mhm. >> The brain is incredibly conductive.

34:42>> There's fluid everywhere. And so >> if you heat part of the brain, that heat is going to travel. Thanks to the Navier Stokes >> which we which we tune in to our last episode for that one four hour. >> There's gonna be a lot more Navier Stokes in the last when when we talk about Sydney. Yeah. Um and his physics stuff but for now >> because fluid can sort of transport energy very well. That's a really bad thing. On the other hand histori the pulses can have a very low duty cycle. A duty cycle is imagine you've got a sine wave right? A sine wave is exactly half duty cycle. It's one up one down. just up and down. Um, but you can imagine

35:22that's a really small duty cycle because the amount of time that something is on is very short compared to the amount of time something is off. The frequency can still be the same. >> Mhm. >> But the the part of the wave that is above threshold and the part of the wave that is below threshold, that ratio is called the duty cycle. And for these cavitation experiments, the duty cycle can be very low, which means that you're only actively sending this high-pressure ultrasound not that long. >> Yeah. >> Right. >> Yeah. >> And so you're not heating up the skull that much. It it circumnavigates the skull heating problem. >> Um and you can you can really target that mechanical disruption that you're talking about without really heating up

36:03the brain tissue in the first place. The idea is a longer duty cycle would mean we're doing too much. We're causing too much chaos. That chaos creates heat, creates more destruction than intended. So the the fact that we do have a short duty cycle is actually uh a benefit to the functionality that we're trying to accomplish. >> Yeah, exactly. Um and so there there's still something that is that is lacking here, which is fully like now we're trying to do it on straight up human beings. >> Yeah. >> Okay. >> Yeah. Yeah, like we've we've proven it in all these um model organisms. We've proven it with sort of a half model organism and a donated human skull. But

36:44now, can we actually do this very precisely? Can we compensate for the variable acoustic medium? The brain, you know, once you get past the skull, the brain is kind of same same, >> but other parts of the body, there's organs everywhere. >> Y >> right. So, there's going to be variable acoustic medium. Can you maintain a useful pressure focus and generate bubbles? exactly where you intend. >> That's actually a really good point. The all these environments have very different variables you're dealing with. >> Yeah. Yeah. And that's why the last paper that I'm going to focus on is the one in the liver. This is in 2024. It's a clinical paper. So this is, you know, um now we're getting into like human clinical trials.