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International Parkinson and Movement Disorder Society
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Hot Topic: Focused Ultrasound in Movement Disorders - Neuromodulation

March 04, 2024
Series:Hot Topics
Dr. Michele Matarazzo interviews Dr. Robert Chen about the rapidly expanding applications of focused ultrasound-based neuromodulation in neurology, particularly in movement disorders, from tremor to Parkinson's disease. Tune in to uncover the future and potential of non-invasive neurotherapies that are setting new standards in research and patient care.

[00:00:07] Dr. Michele Matarazzo: Hello and welcome to the MDS podcast, the podcast channel of the International Parkinson's and Movement Disorder Society. Today's episode is part of a Hot Topic series on the use of focused ultrasound in movement disorders. I have the pleasure of having with me a special guest, Dr. Robert Chen from the University of Toronto.

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Together, we will discuss a novel way to use ultrasound for brain disorder which is neuromodulation. First of all, welcome, Robert, it is great to have you here.

[00:00:34] Dr. Robert Chen: Well, it's good to be here. Thank you.

[00:00:37] Dr. Michele Matarazzo: Okay, let's start with a question to just familiarize with with basic terminology of this fascinating world of brain simulation. What do we mean by neuromodulation?

[00:00:48] Dr. Robert Chen: Well, neuromodulation usually refers to changes in brain activity using some means. Typical is like electrical stimulation. I think many of you are familiar [00:01:00] with deep brain stimulation, which is considered a form of neuromodulation. But we can also use other ways. For example, delivering stimulus more invasively, like electrical stimulation, magnetic stimulation, or ultrasound stimulation.

The idea is that we would want to change, bring activity, excitability, but usually without causing any permanent changes or permanent lesions.

[00:01:23] Dr. Michele Matarazzo: I understand, so there are different ways to modulate the brain somehow. Now, talking specifically about Focus Ultrasound, how does it work? I mean, how how does it simulate or modulate the brain,

[00:01:35] Dr. Robert Chen: Yeah, so I think that many of you are familiar with other ways of using ultrasound in movement disorder, but for example, using a thermal lesion is a topic of another discussion and then it's like opening a brain barrier, again, topic of another discussion. But what we, I think, want to talk about is using it to change brain excitability, possibly without producing a permanent lesion. [00:02:00] So exactly how this works is not completely known. There are several hypotheses. One is a called cavitation, which is involving bubble formation, which is involved in using ultrasound, for example, treating prostate cancer. But we don't think this is the mechanism, probably high intensity.

The other is a thermal effect, which of course the effect used for reduce lesioning. But again, we generally don't think this is the mechanism because it uses much higher intensity. So the most popular hypothesis is that it perturbs the membrane, but the membrane, there are enzymes that are linked to the membrane and it releases and it acts on ion channels.

So there are already several number of animal study have shown that there are different ion channels. One say, for example, called PEZO-1, some calcium channels, some are sodium channels and potassium channel that can be activated. Using ultrasound, and there's also an emerging [00:03:00] field of sonogenetics, which you can actually change the genes of some of these ion channels activated by ultrasound, and then to change the response to ultrasound.

So, it's probably, at least we think this is the most likely mechanism at this point.

[00:03:14] Dr. Michele Matarazzo: Okay. So there is a direct physical effect. It's likely to have a direct physical effect on the activity the membrane in the neurons, right?

[00:03:24] Dr. Robert Chen: Yes, so it will have a physical on the membrane and open up certain specific ion channels that are mechanosensitive,

[00:03:32] Dr. Michele Matarazzo: Interesting. Now, moving on to a related topic, you mentioned other techniques such as transcranial direct current stimulation or transcranial magnetic stimulation. What is the difference of this technique with focused ultrasound or maybe what's the advantage of using focused ultrasound as compared to these other techniques?

[00:03:49] Dr. Robert Chen: right? So you mentioned, like, transfer mechanism, or TMS, transfer, direct current, some of the TDCS. So these are actually currently fairly quite widely used methods [00:04:00] for, at least for non invasive neuromodulation. So ultrasound is another, I think, a newer method of, of non invasive, you know, neuromodulation.

So compared to the other two methods or the more commonly used methods, ultrasound, the main advantage is that it is much more focal. So transient directness is definitely not focal. Magnetic is more focal, but ultrasound is much more focal. So example TMS will the measured in like a few centimeters squares, whereas ultrasound would be in matching millimeters.

The other potential advantage of ultrasound is that it can stimulate a much deeper structures compared to TMS or, electrical stimulation. Because TM electric really can only stimulate surface structure of cortex. It is not possible just, for example, stimulate the basal ganglia without activating the cortex.

But it is possible with focused ultrasound.

[00:04:56] Dr. Michele Matarazzo: So you can really play with the location, the topography of the [00:05:00] simulation much more with focused ultrasound as compared to what you can do with the other techniques, right?

[00:05:06] Dr. Robert Chen: Yes, correct. Yes, it can. So, yeah, so it's much more focal and probably the main advantage or potential advantage in movement disorder is that it can reach deeper into the brain.

[00:05:16] Dr. Michele Matarazzo: Very interesting. Now what is the current evidence of the utility of focused ultrasound neuromodulation in movement disorders?

[00:05:23] Dr. Robert Chen: Yeah, so currently there is not a lot of studies in movement disorders. Many studies are in well, there's a lot of animal studies, many studies in normal subjects. So study have shown that for example, you can change. Bring excitability, we can measure functional MRI in normal subjects.

In terms of movement disorders there is some studies suggest that you can use it for treating tremors. I think there's an open label study recently published used targeting the VIN nucleus, which is the typical DBS [00:06:00] location for treating tremor. So that shows the transient effect.

There's also another group in Paris that have presented at conferences. I don't think the paper published again. They actually uses the high intensity device, but just before lesioning, they use a much lower intensity and showed a reduction in tremor. And our group has been doing some studies in Parkinson's disease.

We publish a study using the outside of the motor cortex which is a only 10 patients, but we showed a change in brain excitability associated with it. But using non invasive stimulation, usually one would need to use repeated sessions. It's not unlike DBS, which is implanted and simulated continuously.

So I think future studies will have to look at using repeated sessions of non invasive stimulation. To see if it will produce a lasting effect, which is what is TMS currently approved for depression. [00:07:00] Depression uses at least 40 sessions. I think the psychiatrist uses it for treatment, which is what is, for example, FDA approved, Health Canada, European Union approved 

[00:07:11] Dr. Michele Matarazzo: Great, now I'm just thinking, wouldn't it be an easy way to validate the focus ultrasound to just repeat what, has already been shown with TMS, for example?

[00:07:23] Dr. Robert Chen: That's true, correct. But I think that it is still in the very early stage compared to TMS or electrical simulation. So we still, I think, need to understand what different parameters ultrasound will do. For example, TMS, you can use low frequency simulation inhibit the area, high frequency to excite the area.

In ultrasound, we still have to work out the optimal parameters

[00:07:49] Dr. Michele Matarazzo: fine tuning part, right?

[00:07:50] Dr. Robert Chen: exactly. Yeah. We have effects on the cortex might be different from the basal ganglia, for example. So I think still a lot of work need to be done. [00:08:00] Also, although we can target. A deep brain structure, for example, the GPR, globus pallidus, for example, it is not simple because ultrasound is deflected and absorbed by the skull.

So we will have to do is. To individual MRI, sometimes even CT scan to model the skull and do kind of modeling to make sure that we can target a specific deep brain structure.

[00:08:30] Dr. Michele Matarazzo: Now, apart from what you just told me, the, the cortical excitability and maybe some effect on the VIM, which has already been shown by your group and others. What do you envisage for the future of this technique? How, how do you think it will impact both the research and our clinical practice in, in the future, in your opinion?

[00:08:50] Dr. Robert Chen: Right. I think still, as I mentioned, there's still a lot of work that needs to be done. So one, I think, is to look at how we apply it in a different frequency, [00:09:00] intensity, pattern, et cetera, to see what is the optimal parameter to change excitability if we want to, for example, increase area or decrease certain area.

That's one. The other one is, I think, is to look at different target areas. Trying to target what's a traditional DBS target, for example, the globus pallidus, the subthalamic nucleus, the thalamus. We also targeting the cerebellum, which may be involved, for example, in tremor or freezing of the gait in Parkinson's disease.

So I think we need to do further work to look at. You know, the optimal parameters as well as the different targets that we can potentially target and what symptoms it could potentially address. For example, cerebellum may be addressing tremor or freezing of gait in Parkinson's disease, whereas GPI may be addressing something different.

For example, motor symptoms or dyskinesia. For example, so these are [00:10:00] still a lot of, I think, work needs to be done in this area to try to sort out all these different parameters.

[00:10:07] Dr. Michele Matarazzo: Thank you. As you were talking, I was also thinking that. possible challenges of this technique. Well, you mentioned one of them is where you have a higher spatial resolution, but when you go to deeper parts of the brain it's more complicated still. We have to have some technical improvement because we, before we are sure where we are stimulating exactly and in which way we are stimulating.

Right? But apart from that Also one other thing that is already a problem for other types of brain simulation is the portability of the technique because, well, with deep brain simulation, obviously that's implanted. But what happens with focused ultrasound is that, is it something that you can do just in the clinics or like TMS, or is there any way you can you can do it more easily or how complicated is it?

[00:10:57] Dr. Robert Chen: Yeah, so currently, I, I think it [00:11:00] is complicated in the sense that it's actually a little more complicated than TMS, in the sense that TMS, you can put the coil. Many studies do use neural navigation. For example, subjects can do MRI and and use neuro navigation protocol. So I think to target a deep brain area, one will have to do neuro navigation and also do individual modeling.

So I think that currently it is, in terms of the processing and technology, it is a little bit more complicated than TMS. Having said that I think it's not insurmountable because I think if it becomes more wisely used. I think the pipeline would like to do this would become simpler. And so potentially it can be outpatient procedure like TMS.

So you can set up the clinic and effective subject can come in for a few sessions maybe over a week. And that could have the effects for several months. For example, we [00:12:00] see with TMS. I, I read, I don't see that as a permanent change because that's the intensity. Doing it, we're not trying to induce a lesion or some permanent change.

So it probably will not be a permanent kind of neuromodulation. But as we know, for example, TMS, we can apply for a number of sessions, say for a week, we potentially could have effect for like three to six months, for example. So I think it is potentially a Adjunctive treatment for like movement disorder, Parkinson's disease, or you could call it maybe a kind of non-invasive DBS potentially.

[00:12:37] Dr. Michele Matarazzo: Well, and the good part of it is that some is, is much less invasive than other techniques. So, and it's reversible and all of this makes it a very appealing technique , to study in a deeper way. Now to end up, what are your future plans to keep studying the use of the for neuromodulation in movement disorders?

[00:12:58] Dr. Robert Chen: Yeah. We have actually quite a, [00:13:00] a lot of studies in our, our lab, you know, using focus ultrasound in movement disorder. So we have some studies targeting the cerebellum we. Wanted to see what's really going on, see if we can improve freezing of gait and also tremor. We have a study used in patients with orthostatic tremor, which is at least thought to partly originate from the cerebellum and other study we're pursuing is actually stimulating the like the typical deep brain targets, the globus pallidus and the cephalonucleus.

We actually have some study going on with patients for implanted DBS lead attached to a device you may look at the Percept device, which can actually record the local field potential. So we're trying to look at targeting area what happened to the local field potential. Can we reduce the pathological oscillation?

We're trying to see if we can establish optimal parameters. Then we can use it maybe repeatedly over the long term.

[00:13:58] Dr. Michele Matarazzo: And this is feasible, right? It's, [00:14:00] those are compatible like having deep brain stimulation implanted and doing foggy ultrasound.

[00:14:06] Dr. Robert Chen: Yeah, this is a very good question. Yes, it is compatible. And so we actually did some safety study first. We have to do it like ex vivo study in the water tank to show that it's safe, no heating or no move of the electro et cetera. So we do have our Research ethics approval to do it. I mean, it's that's such a few patients.

I don't have any too soon to share the results. But yeah, but I think it is at least feasible in the way that it do it.

[00:14:34] Dr. Michele Matarazzo: Well, and that's a great opportunity to look at the effects more directly than what you can normally do. Just looking at TMS metrics, for example, right?

[00:14:43] Dr. Robert Chen: Yes. Yes. I think that this is one of the unique opportunity, right? In someone with implanted electrode that we can record from and we can try to see what's happening to, for example, pathological brain signals in those [00:15:00] conditions.

[00:15:01] Dr. Michele Matarazzo: Well, thank you very much, Robert. I believe we have provided a very comprehensive overview of the current state of this very promising and exciting technique. We'll be awaiting for more interesting results from your group and others. So thank you very much for joining the MDS Podcast.

[00:15:17] Dr. Robert Chen: Well, thank you for having me. 

Special thank you to:

Dr. Robert Chen
University of Toronto

Michele Matarazzo, MD 

Neurologist and clinical researcher HM CINAC

Madrid, Spain

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