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BackTable / MSK / Podcast / Transcript #16
Podcast Transcript: Transcranial Focused Ultrasound for Tremor: Next Generation Image-Guided Therapy for the Brain
with Dr. Bhavya Shah
In this episode, host Dr. Jacob Fleming interviews one of his attendings Dr. Bhavya Shah about the remarkable features of focused ultrasound technology and its applications. They discuss its dynamic nature, allowing for a wide range of applications. You can read the full transcript below and listen to this episode here on BackTable.com.
Table of Contents
(1) What is High-Intensity Focused Ultrasound?
(2) Who is HIFU indicated for?
(3) HIFU Procedural Considerations
(4) Potential Adverse Outcomes
(5) Intra-Procedural Safety Checks and When to Stop
(6) Post-Procedural Course
(7) Low-Intensity Focused Ultrasound?
(8) Focused Ultrasound for Bone Metastases
(9) Which clinicians will use focused ultrasound?
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[Dr. Jacob Fleming]
Hello, everyone, and welcome to the BackTable MSK Podcast, your source for all things musculoskeletal. You can find all previous episodes of our show on Spotify, Apple Podcasts, and on BackTable.com.
This is your host, Jacob Fleming. Today, we're going even further in our podcast. We're not just minimally invasive, but non-invasive today. I'm happy to have with us a very special guest, Bhavya Shah, neuroradiologist from UT Southwestern. He's also one of my attendings. We're going to try to keep the brown-nosing to a minimum, no promises. Dr. Shah, welcome to the show. Thanks for coming to share your time and expertise on HIFU.
[Dr. Bhavya Shah]
Thanks, Jacob. Thank you for having me. Looking forward to it.
(1) What is High-Intensity Focused Ultrasound?
[Dr. Jacob Fleming]
Absolutely. So am I. I think this is such a cool topic. Let's dive right in. What the heck is HIFU, first of all?
[Dr. Bhavya Shah]
HIFU, everybody calls it HIFU, it's a high-intensity focused ultrasound. It's important to note it's called focused ultrasound, and high-intensity and low-intensity, there's different applications depending on the duty cycle that you're using and things like that, so focused ultrasound, high-intensity applications, and low-intensity applications. It's the ability to focus ultrasound waves onto a single point and use it to change how neurons behave if you're using low-intensity and then ablate tissue or destroy tissue if you're using high-intensity with applications in the brain and outside of the brain, obviously.
[Dr. Jacob Fleming]
Very cool. Obviously, we immediately contrast this to the ultrasound that the rest of us radiologists or other interventional proceduralists are used to for diagnostic purposes. This is actually using the same underlying physics but for therapeutic purposes.
[Dr. Bhavya Shah]
Yes, therapeutic ultrasound is a great way to refer to it, too.
[Dr. Jacob Fleming]
Excellent. Let's start. Before we dive a little bit further, your training and your pathway in your career so far has really been wrapped up in this, and I always like to hear a little bit of the background from our guests first, so tell us a little bit about your life and your training and how everything has led up to where you are with this right now.
[Dr. Bhavya Shah]
Sure. When I was in Boston as a radiology resident, I was working on applications for nerve regeneration in a lab at the Brain and Cognitive Sciences at MIT. Now, how are we going to deliver these nanoparticles to the brain was always a question. Open surgery means you have to cut through tissue to get to your target, and then, vascular approaches aren't really going to work for what we're trying to do here. Focused ultrasound really stuck out to me as I was reviewing the literature and things.
Then I got accepted to the T32 fellowship at Stanford and was exposed to focused ultrasound. I think it really invigorated my passion for what we could do with this stuff. Especially as radiologists, people who are trained to use images to treat patients, I think this offers us an ability to use advanced imaging to target discrete tissues in the brain, either to ablate them thermally or with low-intensity focused ultrasound to deliver drugs or even do things such as liquid biopsies, which we'll talk about.
[Dr. Jacob Fleming]
That's really amazing. Can you tell us a little bit more about your experience with the T32 fellowship?
[Dr. Bhavya Shah]
Yes. The T32 fellowship is a two-year training program. 16 months of that is really dedicated to research and any subjects you really want to undertake. The reason there are so many options when you go into one of these T32 training programs, especially at a place as rich with resources as Stanford, the focused ultrasound, there was just something about it that was more than just diagnostic applications. I've always had an interventional bent to things and so it just seemed to make sense for me.
[Dr. Jacob Fleming]
Excellent. From there, building on your work with the T32 fellowship, how did you get started in your career and then work toward this?
[Dr. Bhavya Shah]
At Stanford, they were doing some of the original clinical trials to look at essential tremors. This idea that you could target a specific thalamic nucleus in the brain to treat essential tremor or tremor-dominant Parkinson's disease was really brought forth at the University of Virginia by Jeff Elias, who's a neurosurgeon there. They were doing a clinical trial multi-center and Stanford was one of the sites. I remember while I was training there, one of the questions that kept coming up is we can't see this target on high-resolution imaging. We can't see it on the best imaging that we have so we were resorting to indirect or landmark-based approaches.
As a fellow and people are telling you, "Hey, this is a problem. Go find a solution," you're constantly, it's always running in the back of your head like, "How am I going to find this target?" and so I started working in tractography and things like that.
[Dr. Jacob Fleming]
Awesome. Let's just dive in and talk a little bit more about the specifics of it. You're, obviously, at UT Southwestern right now. You came in, as you started your early career, practicing as a neuroradiologist. Obviously, this was a particular interest to you and so I take it you knew that this is something that was going to be a major focus for you in your career, right?
[Dr. Bhavya Shah]
Yes, absolutely. Early on, when I went with Joe Maldjian and Neil Rofsky, they were really looking for somebody from our end to take us by the horns and really lead the program and make it what we could do it. That was really my whole reason for coming here or being hired to come here. Previously, I was working as a neuroradiologist at the VA. I just started a medical device company and I was spending three days a week reading spine MRI and routine brain MRIs and working on my company. As soon as that company took off on its own and didn't really need me so much for the chief scientific officer part of it, I spent all this time training. I always had passion for focused ultrasound, and to hear that Joe and Neil were looking for somebody to lead the program, it just fit.
[Dr. Jacob Fleming]
Right place at the right time.
[Dr. Bhavya Shah]
Exactly.
[Dr. Jacob Fleming]
That's great. You had that itch. You knew you needed to be doing something else. When I was a first-year resident, I think things were starting to get off the ground and so it's been cool to see this unfold and see the volume go up and the success. Tell us about the journey so far getting this program started.
[Dr. Bhavya Shah]
It's definitely been a journey. I think as most things, when we talk about medical technology, cost is a pretty significant burden. When this technology was getting FDA approved and other sites were picking it up and we wanted to purchase it, there's always limitations on how much money a hospital system can put into equipment. We got really lucky and Bill Dauer and Marc Diamond really spoke to me a little bit about focused ultrasound technology.
I was working with Marc on some preclinical experiments looking at Alzheimer's disease with focused ultrasound, and he introduced me to Bill. Bill's really been really instrumental in getting this technology here. He's the director of the O'Donnell Brain Institute at UT Southwestern. He really liked the idea. He supported the idea. Our movement disorder section also really supported the idea. We got the money from a donor to get the equipment, and then once we got the equipment, we just started rolling.
[Dr. Jacob Fleming]
Fantastic. I want to jump off from that. This is a predominantly IR podcast so there's a bunch of equipment nerds listening. Let's talk equipment. What all is involved in this operation?
[Dr. Bhavya Shah]
You either need a 1.5 Tesla or a 3 Tesla MRI scanner, and you need a 1024 array transcranial ultrasound transducer. That transducer has its own components, a water circulating tank, equipment that comes with the kit, and then, obviously, a stereotactic head frame that you have to place on the patient before you do the procedure to keep their head still. Those are the big components. Really big components is really that transducer. Right now there's only one company who makes a FDA approved transducer to do HIFU. The other is the 1.5T or 3T MRI. Those are the big pieces.
[Dr. Jacob Fleming]
Got you. This ultrasound unit is totally different than typical one we just got in the department using to do the DVT studies or for guided procedures.
[Dr. Bhavya Shah]
Yes. This doesn't even look like an ultrasound unit. It looks like those old school perm devices where you go and put that thing on your head. It looks exactly like that. It's a helmet. When you open that helmet up, you can find that there are 1024 phased array ultrasound transducers. That's what really makes it possible as a phased array technology.
Focused ultrasound in the brain isn't new, the Fry brothers at Springfield, Illinois. The problem was that we didn't really have the technology to image what we were doing and so they'd have to do a craniotomy and then use focused ultrasound. In fact, Lars Leksell even built a frame for it. He built a focused ultrasound stereotactic frame. It's been there. I think with the advent of technology imaging phased array ultrasound transducers, it really changed the game, allowed us to deliver ultrasound across an intact skull.
[Dr. Jacob Fleming]
That's really incredible. I love hearing that history that it was an open surgical technique, and now, like I said-- Would you consider this basically a non-invasive technology? Is that how you would describe this?
[Dr. Bhavya Shah]
A lot of people say it's non-invasive. I actually think it is pretty invasive because you are targeting deep structures of the brain. I think another way of maybe saying it is incisionless because you're not making any holes or making any incisions. I think that's more appropriate because deep thalamic nuclei is pretty invasive in my opinion.
(2) Who is HIFU indicated for?
[Dr. Jacob Fleming]
Yes, for sure. Trying to mitigate the risk of, obviously, the craniotomy and other things like this is really amazing that we've gotten to the point now with the technology doing this incisionless. Very, very cool. Talk about, you mentioned a couple of different clinical scenarios, essential tremor, Alzheimer's, are those the primary clinical issues we're seeing? What kind of clinical issues are you seeing in the clinic in treating these patients?
[Dr. Bhavya Shah]
The focused ultrasound technology or high-intensity focused ultrasound is currently FDA-approved for a couple of things, essential tremor, tremor-dominant Parkinson's disease. Those are patients who have a very specific type of Parkinson's disease in which their main symptom is tremor. Number three is also other motor symptoms in the setting of Parkinson's disease such as bradykinesia, rigidity, dyskinesias, things like that. Depending on what you're doing, the target is different. For essential tremor and tremor-dominant Parkinson's disease, the target has historically been considered the ventral intermediate nucleus of the thalamus, or some people, for the tremor-dominant Parkinson's disease, would consider even the ventral oralis posterior nucleus.
For Parkinson's disease, the target in the United States as FDA-approved is the globus pallidus internus, which is in contrast to some of the clinical trials that are coming out of Europe, in which they're targeting the subthalamic nucleus. Just, I think, last week there was a paper published in the New England Journal of Medicine looking at HIFU pallidotomy in the United States, multi-site clinical evaluation of how well it worked. Similarly, in the Journal of Neurology, maybe two or three weeks ago, the Europeans published their experience with the STN. I think without really getting into the nitty gritty, it's pretty obvious that the reductions in these motor symptoms are not as great as people had initially anticipated, although there is some effect and there is still a pretty significant adverse effect profile.
[Dr. Jacob Fleming]
Interesting. I understand that part of the reason that speaking to one of our colleagues, Fabricio Feltrin, shout-out to Fabricio. He's a great fellow, research fellow, and now attending at UT Southwestern. He's been very involved with this as well. He says part of the reason that your patients have such good improvement in a lot of cases has to do with the workup and using the MR tractography. Can you talk about that whole part of the pre-procedure aspect?
[Dr. Bhavya Shah]
Yes, absolutely. A shout-out to Fabricio as well. He's probably one of the best fellows I've ever worked with and he's a fantastic attending.
There's so many different ways to target the part of the brain that you're talking about. Let's talk about essential tremor because I think that's going to be the most straightforward way of thinking about this. The ventral intermediate nucleus is the target, but people can't see it on any kind of high-resolution imaging so they're relying on landmark or indirect-based methods. They identify key structures in their brain, like the anterior commissure and posterior commissure, and they make measurements from this and say, approximately, this is where they think the target is.
The great thing about focused ultrasound is before you treat, meaning, that before you ablate a part of the brain, you can use low-intensity focused ultrasound to stimulate what you think is the target. Then if you go and examine the patient in real-time, you can see that their tremor is getting better and you can also ask if they're having any side effects. If their tremor is getting better and they're not having side effects, it means you're in a great spot. You may not be in a great spot and patient's tremor might not have gotten better or they might have some side effects, in which case, you're going to have to move and search around looking for the target.
To get around this, we use this method called four-tract tractography that I developed here. Basically, we started in cadavers, maybe when I was recruited, so four or five years ago, that we obtained through the World Body Program. These people had passed, but they had donated their bodies to science. We were able to acquire them right after they'd passed so no fixation, no formaldehyde, nothing like that. We would get them on the scanner in the middle of the night and we'd run really high-resolution, 32, 64, 128 direction DTI, advanced structural imaging, such as this Fast Gray Acquisition T1 Inversion Recovery, and then we would process these different tractography things.
Meanwhile, we would take the patient's brain and we would put it in a 3D-printed slicing guide. The slicing guide, the whole purpose of it was to hold the brain like it is held anatomically, but in a specific plane known as the anterior commissure, posterior commissure plane. We would then slice through the brain at two-millimeter sections from the front to the back and then register these images of the MRI back to the path using block-face photography. Then we would dissect down in micron sections and identify white matter tracts so we're entering and leaving the thalamus.
We were looking at a couple of things. Number one, anytime you say DTI out loud, someone says distortion, huge gradients, lots of distortion. We're in the central part of the brain so we wanted to make sure that that wasn't going to be the case. Number two, people talk about biomarkers all the time. Imaging biomarkers are one of those things where just because you can identify it, is it really there? We wanted to show that, "Yes, it's really an anatomic structure that you can identify and it's pretty high likely what you're looking at.
The third thing we want to do, the reason we ran so many DTI scans, was because we wanted to use something that's clinically relevant. Radiology, sometimes we get really excited that we can make pretty pictures and then we have 256 directions, but no clinical protocol can support that. We wanted to drive it down to as little as possible so we were using 32 directions. At the same time this was going on, people in functional neurosurgery, neurosurgeons were reporting that the improvement of the patient's tremor, and essential tremor, didn't really matter how close you were to the VIM. What really mattered was how close you were to the white matter tract, the dentato-rubro-thalamic tract.
What tract they were looking at and what tract you should prospectively target, nobody really seemed to understand that. That's what we did. We came back and said, "Look, there are two components to the DRTT, a decassating and a non-decassating component. From histology and pathology and all the anatomic studies that have ever been done, we know that the decassating DRTT goes into two nuclei, the VOP and the VIM, and the non-decassating only goes into the VIM. If you're targeting at the posterior margin of those two, you're pretty much hitting VIM.
We did a lot of this preliminary work in cadavers. It really proved that what we were looking at was what we could see, and then it became translating into FDA-approved software for treatment. We started using Brainlab and processing this. Ever since then, we've been using this approach four-tract tractography to identify the targets, the decassating and the non-decassating DRTT, and also, identify tracts that we want to avoid, the medial lemniscus, which is primary sensory for the whole body, and also, the corticospinal tract, which is your primary motor tract. You want to stay away from those. That's how we've developed our protocols.
A lot of people tell me, "we've done tractography and it doesn't work." I think that that is a fair criticism because it depends on who's doing your tractography. One of my friends, he's a neurosurgeon, and he's like, "We gave the radiologist the protocol and they did it and they made the tracts." I would say to that, that's probably not going to work even without seeing the tracts because if you're the treatment physician, you should be making your tracts and looking at them yourself and making sure they make sense.
[Dr. Jacob Fleming]
It's definitely one of the advantages of you being the diagnostician and the treater.
[Dr. Bhavya Shah]
Yes, absolutely, and I think that's important. The other thing is, I think that protocols vary greatly and having a really good understanding of the anatomy is really essential. That being said, we've expanded. We've shared our approach with UCSF, Mayo Clinic in Rochester, University of Colorado, and Duke, and they seem to be getting the same tracts that we're getting, and the same responses so I think it's working out.
(3) HIFU Procedural Considerations
[Dr. Jacob Fleming]
Very cool. Just talk us through a patient gets referred to you, say a patient with an essential tremor, where are they usually in their treatment journey when they come to you? Then how does it go from you? What's your work up and then to getting them on to the procedure table and working on, actually, taking care of their issue?
[Dr. Bhavya Shah]
That's a great question. We get people referred to all stages in their journey. Essential tremor is one of those things where it is actually the most common movement disorder. People just say my dad used to shake or my grandpa shook and they never really did anything about it. I think for a long time, people have overlooked that this is actually a medical problem that they could do something about. A lot of these patients are managed by their primary care doctors, but when things get bad enough and none of the meds that they know seem to be working, they do get sent to movement disorders for a further evaluation.
When we're seeing them, they're usually at the point either where a primary care doctor has heard about us or the patient has heard about us and has called us directly and they haven't yet seen a movement disorder neurologist or they're being seen by a movement disorder neurologist who wants us to evaluate them. If it's the former, where they're being evaluated by a primary care doctor, we send them through our movement disorder group because we want to all be on the same page about what we're dealing with. If it's been a patient who's referred to us by movement disorder neurology, they'll come see us in the clinic and we'll evaluate them. We'll do an exam. We'll look at all the imaging with them and try to understand what kind of tremor they have, and if it is essential tremor or tremor-dominant Parkinson's disease.
This clinic visit and then after that clinic visit, we'll go over the risks and benefits of the procedure, the standard approach.
Then if a patient's interested in focused ultrasound on the same day of that clinic visit, we'll have them get a head CT. The head CT is done to calculate this thing called skull density ratio. We describe it to patients as, "Is your skull too thick for the ultrasound images to penetrate the skull?" but really, it's a ratio, cancellous bone in Hounsfield units versus cortical bone. Anything less than 0.40, we usually don't treat, and anything greater than 0.40, we treat. If they're greater than 0.40 skull density ratio, we then have an MRI that's ordered. It's an MRI that has our DTI protocol built into it, as well as our advanced structural imaging. The patient will get that and then I will process that and then burn that plan into the console. When the patient shows up for the treatment on a Monday, everything's already there and we're using it for real-time intraoperative guidance, and things like that.
[Dr. Jacob Fleming]
Awesome. Like you mentioned earlier, so you have them in the magnet and they're going to have the stereotactic frame and then the focused ultrasound perm machine?
[Dr. Bhavya Shah]
Yes.
[Dr. Jacob Fleming]
Is this procedure done under sedation or anesthesia or are the patients awake?
[Dr. Bhavya Shah]
The patient's awake through all of this and we don't give any sedation or anesthesia because it can affect their tremor. If you were to give them something like Versed, you could see that their tremor would be completely gone and that would eliminate our ability to do biofeedback. When we do these procedures, we just give them oral Tylenol, we give them 25 of fentanyl, we give them 4 of dexamethasone to prevent any swelling that may happen downstream after the procedure, and we give them Zofran because some patients complain they get nauseous during the procedure. That's all the medications that we give. Patients are awake and alert, interacting with us, and we're making sure their tremor is getting better and they're not having any side effects before we ablate.
[Dr. Jacob Fleming]
Very cool. You have that continuous feedback with the patient. About how long does the procedure go on for?
[Dr. Bhavya Shah]
The actual ultrasound portion of the procedure is probably 30 to 45 minutes, but there's other steps. When the patients come in on a Monday morning for the procedure, they've been off of their tremor medications for a week. If they're taking anti-coagulation, any kind of anti-coagulation, we also request they stop that seven days prior. We speak to their cardiologists and others to make sure that's okay. It's not really a hard no, but it's better because it prevents the likelihood of a hemorrhage. We basically have them off their tremor medications and so when they come in, their tremor is much worse than it was when you saw them in the clinic. A lot of patients will tell you in the clinic, "Oh, my meds don't work. They don't do anything." Then when you see them that morning, it's completely different. They're like--
[Dr. Jacob Fleming]
You see the difference.
[Dr. Bhavya Shah]
You see the difference. You see the difference. We want a really good baseline because we're trying to see how they're doing after that. We have a movement disorder neurologist who's with us during this part. We're both doing a neuro exam, two attending physicians doing their independent neuro exam, and then concurring on what they're finding. This is really important when you talk about the side effects and things like that. We do that. We do a full neuro exam immediately before the procedure. We give them, the patient, the meds, we bring them back to the focused ultrasound suite, and then we put the stereotactic frame on them, which isn't super challenging. The biggest thing is you want to keep the frame as low as possible so your ultrasound helmet can give you the maximum ultrasound coverage of the skull.
We do that, and then we get the patient on the table. An interesting thing is this cold water bag that sits on the patient's head. The reason it does that is because the skull wants to absorb as much ultrasound energy as it can, and so we want to keep their skull cool and prevent any burns. This water bag is just circulating ice water on their scalp throughout the entire procedure.
(4) Potential Adverse Outcomes
[Dr. Jacob Fleming]
Got you. Just from that, before I forget, I think this is important to talk about, it's that this technique, like you described earlier, incisionless, probably a good way to think about it, and definitely not without risk, and like you've described, the whole point is using the ultrasound waves, which we normally think of as innocuous, to ablate tissue. What are the worst theoretical sort of things that can happen? Then you described about the burns and things like that, and potential for hemorrhage, is that something that's been reported, and obviously, using an abundance of caution, but what are the kind of things that may actually show up as a result of the focused ultrasound?
[Dr. Bhavya Shah]
The burns, interestingly enough, they haven't really been reported in the literature. Early on, people just know that bone is such a great conductor of ultrasound energy and so that's always been a concern, but I would say nothing in the commercial treatments that's ever been reported, to my knowledge. Then the other thing that I would say, when you're talking about delivering energy into the brain to a specific target, like most things, it's really important to know your boundaries.
Your more posterior boundary is the medial lemniscus, and the medial lemniscus is important for sensation. If you get edema there, or if the focused ultrasound beam, even the low-intensity focused ultrasound beam grazes the medial lemniscus, the patient's going to tell you they're having numbness and tingling around the mouth or in the fingertips. It's very common. Same kind of issue with the corticospinal tract. If the ultrasound beam hits the corticospinal tract, the patient's, obviously, going to have some kind of motor weakness, depending on where you've hit it. I think those are the two biggest side effects.
I haven't heard so much about thalamic hemorrhages or things like that in recent years, maybe initially. Same thing with the scalp burns, I haven't really seen of that or heard that. We've treated people with low skull density ratios, we're not seeing that with them either. I think the biggest thing is knowing where your focused ultrasound lesion is when you're doing the treatment and making sure you're in a safe space. My understanding, after talking to people that were involved in those trials was; they wanted to be sure that they were going to hit the part of the brain causing the tremor. They would keep going posterior until they hit medial lemniscus, and they had some sensory side effects at low-intensity ultrasound. They were just validating their target because they knew that those transient side effects would go away because they were at a lower intensity, but they just wanted to make sure that they were close to actually hitting the target that they were considering.
The other thing is that when they did the initial trial, the approach and the technique had changed. Back then, they were going straight at the indirect coordinate, so right at the anterior commissure, posterior commissure plane, at ACPC. During that trial, a lot of people felt that just by changing that to going just two millimeters superior to ACPC, you could prevent a lot of side effects because you see the focused ultrasound lesion is shaped like a football. It's not a perfect circle. It extends in the superior-inferior plane so it could go below ACPC and hit something else. Most practices, most groups across the world just migrated to going two millimeters above ACPC, and they were hoping that that in itself would limit the side effects. The largest retrospective study in focused ultrasound really didn't support that, so we don't think that that's the answer completely.
[Dr. Jacob Fleming]
Got you. Part of the reason I wanted to make a side tour on that is because interventional radiology is all about planning, planning, planning, and just complication avoidance above complication management, but then handling that when it does arise. I think this is very similar in that. I mean, the treatment is entirely dependent on the pre-procedural imaging and having a very, very precise plan. Sorry for that little sidebar on that. I just wanted to make sure we did talk about the reality that focused ultrasound can have sort of off-target effects. The thing that it just made me think of is like non-target embolization in radiology, in trying to embolize a target, you may get something, or same with any of the thermal ablation technologies we use.
(5) Intra-Procedural Safety Checks and When to Stop
[Dr. Jacob Fleming]
Back to talking about the day of the procedure, so the patient is on the table, and you're delivering the ultrasound beams, and you said that this is going to be about 30, 45 minutes for that part of the process, and you're getting the continual feedback with a neuro exam. What is the end point for you?
[Dr. Bhavya Shah]
We start first by using the low-intensity focused ultrasound, and we're just delivering into the target with a thermal dose of around 44 to 45 degrees, so not a permanent lesion, just a purely mechanical, maybe early, minimal heating effect. We have to do these things called alignments on occasions first, and what that means is where you think your transducer is focusing the ultrasound energy is where the ultrasound energy is actually going. We use very low energy because we want to make sure that things lined up. We do, obviously, anterior-posterior, superior-inferior, and medial-lateral, make sure it's lined up where you think it is.
After you do that, we pause and we all go examine the patient. Reduction in tremor already. They don't have any side effects. Once we get to that, once we're seeing that, we come back out and we turn the energy up and ablate. We'll do two targets. The rationale for that is really from the prior ablation literature in which they describe what they call a snowman lesion, where there's two stacked lesions on top of each other. There's been some discussion recently about whether that's necessary with focused ultrasound, but it seems to be the current norm and the trend and the practice and we stick with that. We'll do two lesions. The target temperature dose of 57 degrees Celsius and we'll stop.
We also are evaluating the patient for other kinds of tremor symptoms. A lot of these patients will have a voice tremor or head tremor. We have successfully treated patients with voice tremor and head tremor even though they might have required an additional lesion, more medial and more anterior. These are the kinds of things that we're doing. We're constantly monitoring the patient, constantly examining them after every focused ultrasound delivery, and then we're done. I think 30 to 45 minutes is where we're at in terms of treatment times.
(6) Post-Procedural Course
[Dr. Jacob Fleming]
Beautiful. After the procedure, they come out, I guess they're sitting in recovery for a little bit. Are they going to be going home the same day or are they staying in the hospital for a little bit?
[Dr. Bhavya Shah]
They're going to be going home the same day. We keep them two hours after the procedure. The first hour, we want them to recover, obviously. We take the frame off, the water bag off. They're just going to go back to prep and recovery. The second hour, we're repeating that initial planning MRI that we'd done with the tractography just to see the relationship of where the lesion that we created is compared to those tracts and the other structures on Fast Gray Acquisition T1 Inversion Recovery sequences, and things like that. Then the patient goes home two hours later. I usually give them a call that night to check out and make sure they're doing okay, and then I see them in the clinic two days after on Wednesday afternoon, just to see how they're doing.
Now 30% of these patients, they're going to complain of a transient imbalance that starts the night of or the day after the treatment and just goes away on its own three to four weeks after the procedure. We've prepared the patients for that and coach them, making sure they have help or a walker or something else.
[Dr. Jacob Fleming]
Nice. One question I had is about the timeline for both the improvement, as well as any side effects that may show up. Are you pretty much going to see the maximal effect size pretty immediately or within a few days of the procedure?
[Dr. Bhavya Shah]
For essential tremor, you're going to see it immediately. It's like one of those things. It's like doing a joint injection where you do a joint injection and the patient jumps off the table and it's just like ready to go dancing or something. It's the same thing.
[Dr. Jacob Fleming]
Very satisfying.
[Dr. Bhavya Shah]
Very satisfying. It's also really emotional for the patients because as you can imagine, people have been dealing with their tremor for so long, right? Yes, it's pretty rewarding. I would say for Parkinson's disease and dystonia and other things, that the time frame for improvement is a little bit longer. I don't know if that's reflective of the target or the circuit that needs to change its behavioral patterns for things to show up clinically.
[Dr. Jacob Fleming]
That's really interesting. Then, similarly, with the side effects like the gait or any of these like dysesthesias and stuff like that, those are going to be showing up pretty much at that time or within a couple of days?
[Dr. Bhavya Shah]
If you're right on the medial lemniscus or if you're right on something that you shouldn't be on, you'll see the side effect right away. Sometimes what we see is that when we get to the higher energies, we create more edema in the brain. Even though the patient's not having any kind of numbness or tingling the day of the procedure, when they come in on Wednesday, they might say, "Oh, I just developed some numbness and tingling in my finger." It's the edema. As the edema goes away, they're going to get fine.
[Dr. Jacob Fleming]
It's always the edema. The edema is always causing problems.
[Dr. Bhavya Shah]
Yes, that's right. Always in the brain at least.
[Dr. Jacob Fleming]
Yes.
(7) Low-Intensity Focused Ultrasound?
[Dr. Jacob Fleming]
That is just really incredible to hear about and it's been so cool to see this program blossom at UT Southwestern to the point that now you're definitely being an example to other places getting this off the ground. I did want to talk about the low-intensity focused ultrasound, which you just brought to my attention.
We got HIFU. We got LIFU. Who knows what else? Tell us about disrupting the blood-brain barrier intentionally. This is some science fiction stuff and just really exciting to hear about. Tell us about that.
[Dr. Bhavya Shah]
The greatest thing about focused ultrasound is it's such a dynamic technology. If you're using high intensity and you're destroying tissue, you can turn that intensity all the way down and you can do things like transiently open the blood-brain barrier, but it's even cooler than that because with this mechanical wave stimulation, you can change how neurons are firing. You can actually do neuromodulation with low-intensity focused ultrasound. That's really being looked at for neuropsychiatric illnesses like depression, addiction, things like that. I think it's a really promising technology and it also begs the question like, does it need to be done in an MRI scanner or can this be like a wearable thing that the patient can have based on biofeedback, some constant stimulation parameters, and things like that?
I know there's TMS. I know there's other stimulation technologies out there. The great thing about focused ultrasound though is it is so precise in terms of the target area. The other really great thing about the low-intensity focused ultrasound is something that we've been working on in our lab and we're doing several studies on campus in humans. You can inject these microbubbles, like Definity microbubbles. We hear that all the time in cardiac imaging, other kinds of things.
[Dr. Jacob Fleming]
Love the microbubbles.
[Dr. Bhavya Shah]
Love the microbubbles, right? You inject these microbubbles into a peripheral vein, they circulate, and then you expose them to focused ultrasound. When you expose these microbubbles to low-intensity focused ultrasound, they start to vibrate. They oscillate. When they oscillate in the brain-- Let's say you want to target the hippocampus, so you aim your focused ultrasound transducer at the hippocampus, you start this Definity infusion, you administer low-intensity focused ultrasound waves to the hippocampus, these microbubbles start to vibrate. When they vibrate, they transiently open the blood-brain barrier. Then you inject gadolinium, and you can see gadolinium leaking out because it's too large to leak out. Now you have opened the BBB in a very discrete part of the brain.
There's so many applications to this, Jacob. I think that the biggest one is, obviously, therapeutic delivery. That is so obvious. People will have gliomas or lung cancer metastases or other kinds of metastases of the brain. There's also other things that are really, really cool. The idea that you're disrupting the blood-brain barrier in a very targeted fashion also opens you up to things like liquid biopsies.
What do I mean by that? When someone has a glioma, right now all of their treatment is really guided by the mutations that these patients have. They had to put a needle in, get some tissue, and we all know about tissue sampling, bias, and things like that. With focused ultrasound, you can expose the whole tumor volume to focused ultrasound, open the blood-brain barrier, it'll close transiently in six hours, but you'll open it up temporarily, and all the circulating tumor DNA will be excreted into the blood. You'll do a peripheral blood test. They'll pull the circulating tumor DNA and find out what mutations that brain tumor has. Obviously, the applications are endless, but it's just so cool.
[Dr. Jacob Fleming]
That is so freaking cool. Obviously, in radiology we deal with biopsies every day and it's a misnomer that, "Oh, it's just the biopsy." It's like, "Well, yes," I mean, certain biopsies can be quite risky, actually. Then talk about the brain, the one biopsy that radiologists don't really do. I know our amazing neurosurgeons, to them, that's a pretty minor thing, but it still carries a substantial risk profile so then if you can do this incisionless and then get a liquid biopsy, that just blows my mind. I think that's really exciting. I can't wait to hear more about it. I'm sure we'll be hearing more in the near future.
[Dr. Bhavya Shah]
Yes, we're doing the clinical trial at UT for delivering therapies to lung cancer metastases and also this liquid biopsy. Dr. Toral Patel is the co-PI on that study. We're just really, really enthused to have the opportunity to do this here. I think it's going to change how we think about things. I think what's really cool about it is we're always sitting there looking at MRI scans saying, "Hey, is this radiation necrosis or is this a recurrent tumor?" I mean, what an awesome application for something like that. I think that's really cool.
We're also doing stuff in neurodegenerative diseases and Alzheimer's disease, specifically. Depending on the type of tau isoform that you have in the brain, you can have a different type of neurodegenerative disease. If you're looking at the patient clinically, it might be really hard to tell which dementia does this patient have. We're doing a trial right now on patients who have Alzheimer's disease to get an amyloid PET scan and a tau PET scan before the procedure. We use that advanced imaging, pair it up with the procedure to target that part in that patient specifically. It's very precise to that individual.
Then we target the blood-brain barrier opening in those regions, then they get all their neurocognitive testing, assessments done, and then we see on a repeat amyloid PET tau three months down the road like has the amyloid and tau decreased or not? I don't think anybody thinks that this focused ultrasound by itself is going to cure neurodegenerative diseases, but I think it definitely gives us a way, a theranostic approach, if you will, to diagnose and treat things in a targeted way.
(8) Focused Ultrasound for Bone Metastases
[Dr. Jacob Fleming]
Oh, man, it's just so cool. I'm just going to keep repeating exciting and cool over and over again but, seriously, my mind is just blown hearing about this. I'm sure you're just scratching the surface in terms of the potential applications. Speaking of that, I did want to talk about one other potential application which is of particular interest to me for HIFU, which is bone metastases, which sounds just amazing. Can you tell us a little bit about that? Is that something you're working with yet?
[Dr. Bhavya Shah]
I would expand it from just bone metastases though, to also talk about, and painful bone metastases to be more accurate, and to, also, to facet disease, neurodegenerative spine disease things like that. The way this works is as we were talking about with the skull and how bone really likes to absorb ultrasound energy. When someone has a painful bony metastasis, destroying the periosteal nerve is a great palliative treatment because you are getting rid of the sensory input that's causing that pain. There is a clinically available system that can be used to target bone lesions. It heats the bone up and it destroys the periosteal nerve and the patient's pain goes away. Now, in terms of are we actually able to destroy the tumor and things like that, I think there's some possibility of that. People have looked at that for some benign bone tumors.
(9) Which clinicians will use focused ultrasound?
[Dr. Jacob Fleming]
Oh man, that is really exciting. You've just really opened my mind to the possibilities of focused ultrasound and it's clear that this is going to be really big over the next few years. There's going to be a lot of interest in this from a lot of different specialties. My question to you is, how do you see radiologists best staying at the forefront of this treatment and being not just involved with the basic science and the imaging but actually as the treating physicians? How do you see that?
[Dr. Bhavya Shah]
Well, I think that's really important. I think radiology has changed over the years and we've learned some hard lessons. I think number one is patient engagement. We have to be willing to engage patients and the patients are the most important thing. They're the reason we are doing any of the things that we're doing. That's the reason that any of us took the jobs that we took. We have to remember that. We have to work to understanding that whatever we do, we're trying to do it to improve the standard of care for patients.
Number two, we have to realize that we are a key component of a multidisciplinary team. In the brain, that is so critical. It is important to have people with different perspectives, different experiences. Even though they clash, even when they say, "Hey, Bhavya, I've done tractography. It doesn't work," or, "I've looked at perfusion imaging. It doesn't work," really understand why it hasn't worked for them and what they have done or they haven't done. I think having that multidisciplinary team is really important because--
The O'Donnell Brain Institute, one of its core principles is to get people out of boxes. "I'm a neurosurgeon. I'm a neuroradiologist. I'm a neurologist." Well, we think that going forward, the most evolved way of thinking about this is who's doing what that's in the best interest of the patient and letting them do that. Then I would say that for radiologists who are interested in this technology, I think, it is very imaging-heavy. I just gave grand rounds at University of Colorado and that was a question that came up. "Hey, Bhavya, I'm really interested in this. What can we do? How how can I be involved?"
Well, all of this technology is image-based therapy. I think there's a very strong argument to be made that when you're doing precise lesioning of the brain or other parts, having really advanced, not cursory knowledge, but really deep knowledge of what advanced imaging can offer you, what its limitations are, what you can do with it, is critical.
[Dr. Jacob Fleming]
Yes, absolutely. Especially in your applications, the people you are working very closely with, the other physicians, neurosurgeons, and neurologists, they're extremely adept at imaging. Especially at UT Southwestern world-class physicians we're working with. You, actually, I remember you impressed this upon me when I was a first year resident, is don't settle for fuzzy descriptions of things. If it's Broca's the area where you're seeing a lesion, describe it there. The neurosurgeon may see a report with a vague description, they have the benefit of the patient in front of them, and they say, "Oh, I think this may be actually affecting Broca's area," for example.
I think about that a lot because when we're just looking at from the diagnostic aspect, we can sometimes be a little bit hamstrung and it's easy to describe things, we can easily be way too specific sometimes. It's of debatable utility but I think it's really important in our training that we have the most in-depth, eloquent descriptions of the anatomy. Then that becomes second nature to us. I couldn't agree anymore with what you said. I think that, clearly, this is going to be a multidisciplinary and interdisciplinary effort going forward. I think that's one of the many values that radiology brings is just having that extremely specific understanding of the anatomy and also how the imaging, especially the tractography, like you talked about, is being used for this.
[Dr. Bhavya Shah]
I think that's critical. I think that the training is an important and a critically important part of that.
[Dr. Jacob Fleming]
I couldn't agree anymore. Well, Dr. Shah, that's all the questions I had. I want to ask any final thoughts or topics you'd like to discuss, any projects you want people to know about?
[Dr. Bhavya Shah]
No, this has been great, Jacob. Thank you so much for inviting me and I really enjoyed it.
[Dr. Jacob Fleming]
Thank you so much. I really enjoyed this too. I think a lot of people are going to be really excited to hear about some of this stuff for the first time. Others, probably going to be excited to hear about it in a different avenue than before beyond very neuro-focused meetings so really, really excited to get people to hear this. Thanks again for your time.
To our listeners, thanks for tuning in. We'll catch you next time.
[Dr. Bhavya Shah]
All right. Thank you.
[Dr. Jacob Fleming]
Thank you. That was a lot of fun.
Podcast Contributors
Dr. Bhavya Shah
Dr. Bhavya Shah is a practicing neuroradiologist with UT Southwestern in Dallas, Texas.
Dr. Jacob Fleming
Dr. Jacob Fleming is a diagnostic radiology resident and future MSK interventional radiologist in Dallas, Texas.
Cite This Podcast
BackTable, LLC (Producer). (2023, June 21). Ep. 16 – Transcranial Focused Ultrasound for Tremor: Next Generation Image-Guided Therapy for the Brain [Audio podcast]. Retrieved from https://www.backtable.com
Disclaimer: The Materials available on BackTable.com are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.
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