Melanie Cole, MS (Host): Welcome to UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole. And today, we're highlighting focused ultrasound. Joining me is Dr. Justin Hilliard. He's a neurosurgeon and an Associate Professor at the University of Florida College of Medicine, and he practices at UF Health Shands Hospital.

 Dr. Hilliard, it's a pleasure to have you join us today. And as we've heard a little more and more about focused ultrasound, it's generated pretty much excitement in neurosurgery. It represents something patients almost can't believe is possible, Doc, targeting these deep in the brain areas without making an incision. So for colleagues who may not yet fully understand where this technology fits in, can you start by explaining a little bit about what focused ultrasound actually is and why it's such a breakthrough in neuroscience?

Justin D. Hilliard, MD: Yeah, thanks, Melanie. You're right. Focused ultrasound is an incredible therapy. And it's being used for the treatment primarily of essential tremor. But in the future, also for perhaps aspects of Parkinson's disease. But for today, I'm going to focus on perhaps our conversation on essential tremor.

And essentially, it uses ultrasound technology. It uses 1,024 tiny ultrasound transducers that are lined on a special helmet that direct ultrasound waves at a very specific region of the brain in the thalamus that's implicated with tremor circuitry. And that ultrasound energy converts to heat in the brain. And the heat creates an ablation. It disrupts the tremor circuitry; thereby, reducing usually on the order of 70 to 80% the magnitude of an individual's tremor.

Melanie Cole, MS: Wow, isn't that amazing? It's really an exciting time in your field, Dr. Hilliard. So when people hear ultrasound, they usually think imaging, not treatment.

Justin D. Hilliard, MD: Yes.

Melanie Cole, MS: Walk us through a little bit of the science of how it works inside the brain.

Justin D. Hilliard, MD: Yeah. So, you're right. The ultrasound really just refers to a wavelength of emission. And so, the most common ultrasound that we're used to thinking about in the medical field might be an echocardiogram or maybe, you know, for obstetrics. So, this uses the same wavelength, but it uses, instead of just a single transducer that you might put on somebody's heart, it uses 1,024 transducers, like I said, lined on a helmet that are each sending a little bit of energy that at the focal point accumulates to a large amount of energy at the motor nucleus of the thalamus.

And where all of the ultrasound energy comes together at the focal point, thus the focused part of focused ultrasound, you create an increase in temperature to about the mid-50 degrees Celsius held for a few seconds. That creates a lesion, an ablation in the brain that completely disrupts the tremor circuitry there. And so, practically speaking, a candidate for focused ultrasound comes to the office. They undergo two imaging modalities to discern whether or not they're an appropriate candidate for this therapy, a CT scan and an MRI of their brain.

The MRI of the brain is what I use to identify the region in the thalamus that we want to target the ultrasound waves to. The CT scan is used to assess the geometry of the individual skulls. About 15% of people in North America will have a skull that absorbs or reflects so much of the ultrasound energy that I can't get enough to the brain to cause the temperature increase to cause the change that we're looking for. So, this is a screening tool that I'm able to use before the person goes into the scanner to know just the physics of the machine.

Will the physics of this person's skull, the geometry of their skull, allow enough energy to pass through to achieve the target temperature that we need in order to reduce their tremor? So when they come to clinic, we get those two images. I run the CT scan through a computational model, and this is true, this isn't specific to UF Health. This is anywhere in the country that you go for focused ultrasound, people are running the exact same computational model. It's part of the manufacturer's software package. And it basically calculates a number above which we can give the energy to a sufficient degree to raise the temperature, and below which the skull will absorb or reflect too much of the energy. So, that's sort of a little bit of nuts and bolts. But if you'd like, I can take you through the treatment day itself.

Melanie Cole, MS: Before you get into the day of, when we think of focused ultrasound and how it first gained national attention in the treatment of essential tremor as you're speaking about, what made tremor such an ideal early application for this technology?

Justin D. Hilliard, MD: That's a great question, Melanie. You know, one of the aspects of tremor that made this a good application early on is that it's something that is immediately noticeable. So, when I'm talking about giving energy first, it usually takes between four to eight doses of energy in order to reduce the tremor. Well, I'm not turning the machine on full blast to begin with. First, I'm starting off on real low doses of energy. And I can observe in real time between doses of energy whether their tremor is getting better or not, or whether the patient might be experiencing a side effect. And so, the immediacy of the patient's symptoms in someone with tremor is part of what made it a good first disease to be able to treat with ultrasound technology.

Melanie Cole, MS: So once you've done your patient selection and assumed that criteria, walk us through that day.

Justin D. Hilliard, MD: So, on the day of the procedure, the patient and I, we would meet in the preoperative area. And the first step that I have to do, or anyone who's doing focused ultrasound, I have to do a complete head shave. And it's not my preference again, this is universally done. But the reason is because the ultrasound waves can reflect off the hair in a manner that's unpredictable.

And we need to be able to precisely predict where those ultrasound waves are going to end up. So, shave the head. And then, we need a way to keep the patient's head still during the procedure. So, that's done by placing the patient in a frame. The frame is held in place with four pins. Prior to placing those pins, I give four injections of numbing medicine. It stings for a minute or two. We all know what that's like. It gets nice and numb, and then they have the frame in place.

As you mentioned, Melanie, it's called focused ultrasound. But it's done in conjunction with an MRI machine. So, we go to the room where we have the MRI machine, we have the focused ultrasound unit. We lay the patient down on the MRI table, get them padded under their knees, under their shoulders, under their neck. The head frame that I just placed attaches directly to the MRI table. And then, the ultrasound unit, it looks like a helmet, and it comes down and connects to the head frame that I placed. The patient goes into the MRI machine. I get an image, and then I start to deliver the energy. Again, four to eight doses, 20 seconds each generally, each dose a little bit higher than the last dose. And the patient typically will experience a headache or a spinning sensation as I'm giving that energy.

Between doses, I'm evaluating the patient, seeing their tremor improve, sometimes making minor adjustments to where I've targeted based on the MRI and based on the patient's feedback on how their symptoms are improving or whether they're experiencing any side effects before I turn the machine all the way up, so to speak, to deliver that final dose of energy that creates the permanent change.

Once that's completed, you're looking at about 60 to 90 minutes in total. We get the patient out of the head ring to the recovery area. They spend about 30 minutes there before they're ready to leave the hospital. The following day, I get an MRI to evaluate how their brain is reacting to what we just did, and that sort of dovetails into side effects and recovery that I can talk about if you'd like.

Melanie Cole, MS: Let's speak about recovery. And for patients with medication-refractory tremor, how do the outcomes compare, Dr. Hilliard, with more traditional interventions like deep brain stimulation?

Justin D. Hilliard, MD: I definitely want to get into that. For thoroughness, let me talk about recovery, and then I'll pivot and I'll make a comparison to deep brain stimulation or DBS. So, we're targeting a four-millimeter spot in the brain, in the thalamus. And the brain, that part's going to be permanently changed. It's going to be ablated. The surrounding brain tissue is going to be irritated. You're going to get some cerebral edema around the lesional site. And that edema impacts normal regions of the brain that affect other functions.

There are four domains that are commonly impacted: speech, dysarthria, and some word-finding difficulties; sensation, numbness, tingling, paresthesias, rarely a change in taste; coordination, clumsiness with the hand; and then balance, feeling like the person's leaning to one side or that they don't have quite as good power in their leg. The edema is at its worst within the first week, and then it begins to slowly dissipate. It takes about two to three months for the edema to resolve entirely. About 10% of patients will have a mild to moderate permanent side effect; 90%, no permanent side effect.

You can't get anyone through the procedure without a temporary side effect. If you're doing it right and you're creating a durable lesion, the surrounding brain, it's going to react to what you did. So, I tell patients I want them to have a cane, potentially even a walker available for their balance. I don't want to turn a good outcome of tremor relief into a new problem, a broken hip, you know, a subdural hematoma hitting their head, et cetera.

If you counsel patients correctly, which I try to do, I try to emphasize the recovery aspect, people know what to expect, and they're safe. And it's okay that there's a recovery. There are with most things in medicine, right? You have a knee replacement, it's no surprise that you're going to be using a walker for a couple weeks. You know, you have cataract surgery, it's no surprise that you might need to keep your eye covered or something like that for a period of time. So if people know what to expect, then the recovery is generally smooth.

Comparing outcomes to deep brain stimulation, I do both. I do focused ultrasound, and I do deep brain stimulation. And so whenever I'm seeing a patient, I'm thinking about which one should I do? Which one do I think would be best for this patient? And there are a number of considerations between that that we can get into, but focusing on outcomes.

Deep brain stimulation, it's the gold standard for treatment of essential tremor. Focused ultrasound, it's a great therapy, but DBS is the gold standard. Why? Because of the flexibility that it provides over time, being able to increase the stimulation and kind of keep up with the tremor. Generally speaking, you're looking at about an 80% to 90% reduction in tremor with DBS. With focused ultrasound, it's right there with it. It's about 70% to 80%, okay? So, about 10% less. When you look at durability five years out with focused ultrasound, it wanes to about a 45% reduction. With DBS, it hangs in there a little bit better. You're around 60% to 70% out at five years.

So, somebody who's relatively young, relatively healthy, I would steer them toward deep brain stimulation or DBS. For somebody who's older, maybe getting into their late 70s, 80s, even 90s, I've treated patients with focused ultrasound, that's the more ideal therapy. Less surgical risk, no risk of infection. You're not worried about wound healing, outpatient procedure, no general anesthesia. Somebody with a multitude of medical comorbidities, maybe they've had multiple heart attacks, maybe they have stents in place, maybe they're diabetic, that may be somebody that I'm less inclined to do DBS on because the risk of surgical complication.

Melanie Cole, MS: Well, thank you for explaining that. Now, Dr. Hilliard, as exciting as this is, we're seeing these applications expanding into Parkinson's disease, other movement disorders, even possibly over the next several years, psychiatric disease, epilepsy. I mean, they're talking about this for so many indications. Where's the field headed? What are the most promising indications that you would be most excited about?

Justin D. Hilliard, MD: Absolutely right, Melanie. The future is quite bright for the utility of focused ultrasound in a host of diseases beyond movement disorders, like you mentioned, including epilepsy. And I'm going to pivot for a minute and make a distinction between something called high-intensity focused ultrasound, which is what you and I have been talking about, and low-intensity focused ultrasound.

So, some of the most exciting research that's on the horizon and that UF is participating in is the use of low-intensity focused ultrasound to disrupt what's called the blood-brain barrier. That's a protective mechanism that our body has to shield our brain from chemicals and substances that might get into our blood.

But with certain diseases, we want to disrupt the blood-brain barrier so that we can preferentially deliver an immunologic therapy or a pharmaceutical therapy and deposit a high concentration of that drug in a specific brain region. For example, in Alzheimer's disease, there are several exciting immunologic therapies right now that have shown some promise, but it's hard to get the concentration of that medicine in the particular areas of the brain that you need to create a big effect.

You can take a patient, potentially, this is the research that's being done, the hypothesis, you could take a patient to low-intensity focused ultrasound. It's a different frequency of ultrasound waves. It disrupts the blood-brain barrier temporarily for about 24 hours. As soon as you disrupt it, you co-administer an immunologic, and it has the potential to preferentially deposit in the region of the brain that you just disrupted the blood-brain barrier. This is the area that I am perhaps most excited about in terms of evolving indications, but I think we're a couple years out from things like that.

Melanie Cole, MS: Wow. So Dr. Hilliard, this really changes the concept of what surgery can look like. And for other neurosurgeons and even referring physicians, how has this technology altered the way you're thinking about interventions in the brain, and where do you see this headed in the next five to 10 years?

Justin D. Hilliard, MD: Some of the things that I'm excited about, other areas of research that might be, you know, within the timeline of five to 10 years out are things like incisionless biopsies. So for a neurosurgeon, some of the most treacherous biopsies that we have to do are deep-seated lesions in the brain that are relatively inaccessible and high risk, where we have to drill a hole, insert a cannula several inches through normal brain before we get to the brain tumor or the lesion that we're worried about is a brain tumor. And inserting that cannula, that little piece of metal to get a biopsy, we can cause a hemorrhage and can cause somebody who has a bad problem and make it even worse.

With low-intensity focused ultrasound, there's potential to disrupt the blood-brain barrier around these tumor cells or this, you know, deep-seated lesion in the brain, which would hypothetically allow some of the DNA of that tumor to leak into the bloodstream that you could then do a peripheral blood draw, analyze fragments of the tumor DNA from that blood work, and be able to tell the patient, "This is the type of tumor you have. Here are its mutations. Here's how we're going to treat it," without ever having to make an incision. That's probably the area that I would be most excited about in terms of changing how we're treating people currently.

I don't think focused ultrasound is going to replace things like deep brain stimulation. Again, I think DBS, it's the gold standard for the treatment of many movement disorders and so forth. But for the right patient, focused ultrasound is a phenomenal therapy.

Melanie Cole, MS: Well, it certainly sounds like that. And Dr. Hilliard, as we wrap up, for referring physicians, what's most important for them to understand about when to consider referral for focused ultrasound evaluation?

Justin D. Hilliard, MD: So right now, I am using focused ultrasound for the treatment of essential tremor. So, we've talked about some exciting things, Melanie. But I think it is best suited for essential tremor, and that's what its FDA labeled for right now. It also has an FDA label for Parkinson's disease. But the vast, vast majority of patients, I think, are still better served with DBS who have Parkinson's disease.

So for referring physicians who have essential tremor patients, it's important that they've failed medical management. That is defined as failure of two first-line medical agents like primidone or propranolol who are having a tremor that is significantly impairing their quality of life, their ability to feed themselves, to drink from a cup, to write.

I don't expect my primary care colleagues to understand the nuances of, you know, movement disorders, neurology. So if you have a patient that you've tried a couple of medications on and they failed, I'm happy to review the referral and to evaluate the patient here at UF and help, you know, partner with you to see if the patient would be a reasonable focused ultrasound candidate or potentially a deep brain stimulation candidate.

A lot of people are afraid of brain surgery, Melanie, and when they have an opportunity to come and meet our team here under the headline of focused ultrasound, they realize, "Hey, actually, when I've heard some of the relative advantages of DBS, maybe that's not such a bad way to go." And so, anyone that I'm receiving in the office, I'm trying to think about what is the modality that's best to treat this patient.

Melanie Cole, MS: Great information. Dr. Hilliard, thank you so much for joining us today and really sharing your incredible expertise on this amazing technology. Thank you again. And to learn more about this and other healthcare topics at UF Health Shands Hospital, please visit innovation.ufhealth.org. And to listen to more podcasts from our experts, please visit ufhealth.org/medmatters. That concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole.