Focused Ultrasound Has Widespread Potential to Treat Movement Disorders

Paul Fishman, MD, PhD, a professor of neurology and chief of the Neurology Service at the Maryland VA Health Care System

Paul Fishman, MD, PhD

Focused ultrasound, recently given the FDA go-ahead for use in tremor-dominant Parkinson disease, has sparked some excitement in the movement disorder community by providing patients with another option for treatment.

One such excited physician is Paul Fishman, MD, PhD, a professor of neurology and the chief of the neurology service at the Maryland VA Health Care System. Fishman has worked with the FDA-approved product, dubbed the Exablate Neuro, and has seen its ability to make an impact on patients with tremor-dominant Parkinson disease.

To find out more about who the ideal patient is for this method, and if it holds any promise for additional types of Parkinson and other disorders in general, NeurologyLive spoke with Fishman about his experience with focused ultrasound.

NeurologyLive: What does the ideal patient look like for focused ultrasound?

Paul Fishman, MD, PhD: The ideal patient is a patient who has functionally interfering tremor where that's their worst symptom of their Parkinson. What's interesting is, years ago, we really thought that these patients would later declare themselves as having many of the typical symptoms of Parkinson, but in a lot of ways they don't. For these tremor predominant patients, that will be their worst symptom for the entire duration of their disease. We know a lot more that tremor doesn't march in lockstep with the slowness and stiffness and postural problems that we see in typical Parkinson. The first thing is really to recognize that this separate group of patients really exists. I wrote something about this in a review article, probably more than a decade ago, and I'm surprised it still gets hits because—especially in the non-movement disorder community—the idea that this really, in a lot of ways, is a separate form of the disease is not appreciated.

Again, if somebody's had Parkinson for 2, 3, 4 years and in spite of levodopa and other medications, they still have an obvious functionally interfering tremor, and most Parkinson patients are asymmetrical, particularly where the worst tremor is involving the dominant side, they should at least consider it. Some of these patients say, “Well, it's just a tremor,” and do they want to go through DBS? This is still a rigorous procedure. You get your head shaved, you go into the frame—all the beginnings of it are very much like DBS, except that we never open the skin or the skull, and there's no physical probe. It does cause an ablation, and at this point in time, we're only doing 1 side. Obviously, if somebody has both sides involved, they’re clearly a candidate for DBS. If they have other aspects of Parkinson that are really bothersome to them, particularly those fluctuations or dyskinesias, they need a different type of surgery.

Right now, we're doing clinical trials for patients who have levodopa-induced involuntary movements or dyskinesias because we're targeting another brain area, not the VIM of the thalamus, but GPI and we're in a pivotal trial right now, but that's still experimental. There's experimental work moving forward in other types of Parkinson. The FDA approval applies to this 1 specific group—the tremor predominant ones.

What other types of Parkinson disease could this be used for, and could it possibly be utilized outside of Parkinson disease?

The nicest thing about this getting press is this is a very versatile technology. We talk about 3 forms of focused ultrasound. This usually goes by the funny acronym of HIFU—high intensity focused ultrasound—and this is capable of doing, essentially, stereotactic ablations without a probe. We use high-intensity energy and it all converges on a small spot of the brain, and we are doing an ablation without physically putting a probe in, to heat or destroy that area. That's in Parkinson, tremor, other things that DBS has been used for, other forms of surgery.

Right now, we have a trial of another thalamic region that's involved in chronic pain. It's been used mostly outside this country for severe depression, for OCD—the kinds of things that DBS has been looked at in. There are trials in epilepsy. Anything that has been looked at where, if you destroy a brain area you can improve symptoms, this is being looked at for.

For me, the most exciting aspect, not that this isn't usually exciting, is the future of how this medium-intensity ultrasound can be used. There's a trick that you can use with typical micro-bubbles that are used as ultrasound contrast agents, and when you excite them with medium levels of ultrasound, they vibrate so dramatically that they can open up the blood-brain barrier in a controlled way, in a targeted location. There's a huge amount of interest in this to improve brain delivery of things that you just have to put in the blood. My colleague, Dr. Graham Woodward, has a trial going on right now to improve chemotherapy for glioblastoma by taking that rim, where normal tissue and brain are intertwined—and it has a relatively normal blood-brain barrier—and opening that up to see if we can improve chemotherapy.

I should also credit that the chronic pain trial is led by Dr. Dheeraj Gandhi. He's taking the blood-brain barrier work we’ve already seen published in high-level publications, in Nature, that shows it's feasible to open the blood-brain barrier safely in patients with Alzheimer's disease. Their trial is going ahead and expanding on that to see if that will accelerate the clearance of the toxic amyloid protein on a brain.

We just got done last fall with a workshop to see if we can provide gene therapy for Parkinson disease without doing typical needle injections. Gene therapy for Parkinson has kind of a checkered track record—it goes ahead, it stalls—and one of the reasons for that is we're really not clear if that's the optimum way. Opening up and doing a craniotomy, doing a stereotactic multiple needle injection to try to spread the gene vector through the brain. There's plenty of animal evidence that says that if you open the blood-brain barrier and then you inject your vector directly into the blood, you can distribute that gene or trophic factor into the brain without doing a needle injection. That's the other part.

Finally, there's low-intensity focused ultrasound, LIFU, which is being used as a form of neuromodulation. There are trials at UVA to see if doing that repetitively can interrupt seizures for epilepsy. There are 3 different forms of use of it, with a wide array of potential applications.

Transcript edited for clarity.