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HIFU vs LIFU in Neurodegenerative Disorders

Author Caleb Solivio covers HIFU vs LIFU in Neurodegenerative Disorders on BackTable MSK

Caleb Solivio • Oct 9, 2023 • 36 hits

As the field of medicine continues to evolve with new discoveries and improvements in research, so too do the tools and therapeutics that clinicians use. Ultrasound, widely known as a convenient diagnostic imaging tool, is a perfect example of such an evolution through the development of High-Intensity Focused Ultrasound and Low-Intensity Focused Ultrasound. Through Dr. Bhavya Shah’s journey with the technology, this article overviews the development of focused ultrasound therapies and explores their current and potential uses in the world of neurodegenerative diseases and oncologic therapeutics.

This article features excerpts from the BackTable MSK Podcast. We’ve provided the highlight reel in this article, but you can listen to the full podcast below.

The BackTable MSK Brief

• Depending on the frequency of ultrasound waves, focused ultrasound therapies can achieve different goals. In general, high-frequencies can ablate or destroy targets while low-frequencies can modulate target activity.

• The development of focused ultrasound techniques has been difficult due to poor target visualization and exorbitant costs, but new developments and improvements in efficiency make focused ultrasound techniques more viable clinical tools.

• Focused ultrasound techniques in neurodegenerative disorders have the potential to achieve what could only be done with a craniotomy, less invasively, making it a viable option for patients who may not be able to tolerate brain surgery.

High Intensity-Focused Ultrasound (HIFU) vs Low Intensity-Focused Ultrasound (LIFU) in Neurodegenerative Disorders

Table of Contents

(1) What is High-Intensity Focused Ultrasound (HIFU)? Applications in Neurodegenerative Disorders

(2) What is Low-Intensity Focused Ultrasound (LIFU)? Applications in Neurodegenerative Disorders

What is High-Intensity Focused Ultrasound (HIFU)? Applications in Neurodegenerative Disorders

High-Intensity Focused Ultrasound (HIFU) is an advanced non-invasive medical procedure that focuses ultrasound ultrasound waves onto specific purposes for therapeutic purposes. Specifically, HIFU has the potential to target subcortical and deep brain structures noninvasively, in other words, without necessitating a craniotomy. In its development, HIFU faced challenges such as inadequate visualization of certain brain targets and high equipment costs. However, now, HIFU has evolved to be more efficient and precise. HIFU has a role in treating essential tremors and tremor-dominant Parkinson’s Disease and may augment management of other conditions such as Alzheimer’s Disease. Further development of HIFU will underscore its growing clinical significance and role in treating difficult conditions.

[Dr. Jacob Fleming]
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]

[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.

Listen to the Full Podcast

Transcranial Focused Ultrasound for Tremor: Next Generation Image-Guided Therapy for the Brain with Dr. Bhavya Shah on the BackTable MSK Podcast)
Ep 16 Transcranial Focused Ultrasound for Tremor: Next Generation Image-Guided Therapy for the Brain with Dr. Bhavya Shah
00:00 / 01:04

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What is Low-Intensity Focused Ultrasound (LIFU)? Applications in Neurodegenerative Disorders

Similar to HIFU, Low-Intensity Focused Ultrasound (LIFU) is also a therapeutic treatment that uses ultrasound, which is typically used by many providers as a diagnostic tool. However, in contrast to HIFU, which uses higher frequency ultrasound waves to ablate tissue, LIFU uses lower frequency ultrasound waves to modulate or disrupt specific targets. While it can be used on its own, it can also be used in conjunction with other diagnostics or therapies to improve resolution or improve delivery, respectively. Currently, the utility of LIFU is being investigated in delivering therapies to lung cancer metastases, neuromodulation in Alzheimer’s Disease, and enabling liquid biopsies.

[Dr. Jacob Fleming]
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.

Podcast Contributors

Dr. Bhavya Shah discusses Transcranial Focused Ultrasound for Tremor: Next Generation Image-Guided Therapy for the Brain on the BackTable 16 Podcast

Dr. Bhavya Shah

Dr. Bhavya Shah is a practicing neuroradiologist with UT Southwestern in Dallas, Texas.

Dr. Jacob Fleming discusses Transcranial Focused Ultrasound for Tremor: Next Generation Image-Guided Therapy for the Brain on the BackTable 16 Podcast

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

Disclaimer: The Materials available on 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.



Transcranial Focused Ultrasound for Tremor: Next Generation Image-Guided Therapy for the Brain with Dr. Bhavya Shah on the BackTable MSK Podcast)



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