The Future of Focused Ultrasound: Movement Disorders and Beyond

Nir Lipsman, MD, PhD, of Sunnybrook Research Institute in Ontario, Canada

Nir Lipsman, MD, PhD

Focused ultrasound (FUS) technology is a highly promising treatment for tremors and Parkinson disease (PD), movement disorders that are currently managed via pharmacologic interventions and invasive surgery.¹ Surgery for PD includes deep brain stimulation (DBS) of the subthalamic nucleus and thalamotomy. However, DBS has several limitations, such as risks associated with device implantation and electrical stimulation. Additionally, it has relatively high maintenance costs and requires continual follow-up. Therefore, DBS is not suitable for immunocompromised patients or those for whom regular follow-up is difficult. Lesioning procedures may serve as a suitable substitute or complement to DBS in certain cases, but lesioning by radiofrequency techniques is associated with risks due to lack of control over lesion size, which can lead to irreversible adverse effects.²

Clinicians can use FUS to create lesions in the deep brain tissue in a noninvasive manner. Additionally, FUS can target specific regions of the brain. In this technique, thermal ablation is achieved by focusing high-frequency ultrasound on the target area, which leads to cell death through localized heat generation while causing minimal damage to surrounding tissue. Clinicians can monitor the ablation through magnetic resonance imaging (MRI). FUS-mediated ablation can treat multiple brain disorders, such as epilepsy, neuropathic pain, and movement disorders associated with PD.^3,4

Thermal ablation is not the only application of FUS in movement disorders. “FUS can currently be used in 2 ways, depending on the frequency of ultrasound applied,” explained Nir Lipsman, MD, PhD, of Sunnybrook Research Institute in Ontario, Canada. “High-frequency ultrasound can be used to generate noninvasive lesions in the brain for a wide variety of conditions [in which] making a lesion could be effective. Essential tremor is a good example, and FUS to generate a permanent lesion in the thalamus for essential tremor patients who are no longer responsive to medications is currently a standard of care.” He added that the second approach is to use low-frequency ultrasound, which can open the blood-brain barrier to improve drug delivery to the brain. This application is not approved by the FDA but is under clinical investigation.⁴

Current Applications

In July 2016, the FDA approved the MRI-guided FUS (MRgFUS) device Exablate Neuro from INSIGHTEC for the treatment of essential tremor in patients who are nonresponsive to medication.^5,6

“It’s too early to tell how the procedure will compare with current surgical approaches, but we hope it will one day provide a safe and effective option for patients. For essential tremor, FUS provides an alternative that is less invasive than standard surgical approaches but is just as effective,” said Lipsman. “FUS for essential tremor is well tolerated by patients, and they generally go home the same or next day after their procedure. Each FUS procedure involves a head shave and placement of a stereotactic frame under local anesthetic. The procedure itself takes about 3 hours in the MRI scanner. Because FUS is less invasive than standard surgical approaches for tremor, does not involve an implant, and is image guided, many patients are interested in finding out whether they would be eligible.”

Regarding the application of FUS in PD therapy, Lipsman said, “FUS for Parkinson is still in the experimental stages. We are determining its safety profile in phase 1 trials before expanding to larger, late-phase trials.”

Potential Applications of FUS

Investigators have conducted considerable research on applications of FUS beyond ablative treatment and thalamotomy. These therapeutic applications are under varying stages of development, ranging from early research to the clinical stage (FIGURE)⁷. Tim Meakem, MD, chief medical officer of the Focused Ultrasound Foundation (FUSF), told NeurologyLive^TM that “delivery of therapeutics facilitated by FUS-induced blood—brain barrier opening is a promising area of research with strong preclinical evidence that is being translated to the clinic. Neuromodulation and immunomodulation are other exciting areas of research, although more work is needed to fully understand how these biomechanisms can be tools for treating Parkinson disease.”

In addition to movement disorders, FUS may also be effective for various other neurological disorders. For example, FUS-mediated thermal ablation has been evaluated for the treatment of epilepsy and brain tumors. This method may be particularly effective for targeting deeply located tumors. For epilepsy, FUS has the potential to achieve ablation in the epileptogenic foci or to disrupt the epilepsy network. In addition, preclinical studies are evaluating nonthermal ablation using FUS for these conditions. To achieve nonthermal lesioning, FUS is used at a lower frequency of 250 KHz (as opposed to 650 KHz for thermal ablation), which induces excitation of gas bubbles that are trapped inside tissues and results in lesioning. This process is called histotripsy or cavitation.⁷

FUS can also be used to temporarily open the blood—brain barrier, through cavitation, at specific locations to improve the delivery of drugs to the brain. Clinical studies are evaluating this application in brain tumors and neurodegenerative disorders such as Alzheimer disease.⁷ Cavitation induced by FUS or FUS-mediated targeted drug delivery to the brain could also be utilized to induce thrombolysis in the treatment of stroke; this application is being evaluated in preclinical studies.^4,7

FUS ablation could further offer benefits for mental health conditions such as depression and obsessive-compulsive disorder (OCD).⁴ Indeed, in one clinical trial, FUS ablation of the anterior limb of the internal capsule showed an improvement in OCD symptoms without any complications. However, the sonication target needs to be further refined for this condition.⁷

FUS-mediated ablation in the thalamus may be used for the treatment of neuropathic pain. This application is under clinical evaluation in the United States.⁸ The use of FUS for the treatment of neuropathic pain has been approved in Europe, Russia, and Korea.⁶

FUS is also being evaluated in disorders of the consciousness, which include coma, vegetative state, and minimally conscious state. In an ongoing clinical study at the University of California, Los Angeles, application of low-intensity FUS pulsation to the thalamus improved the condition of a comatose patient through neuromodulation.⁹

FIGURE. Current and Future Clinical Applications of Focused Ultrasound (FUS) Technology

Improving Drug Delivery

After ablative therapy, facilitating drug delivery to the brain is the next application of FUS in the pipeline for movement disorders such as essential tremor and PD. A major challenge in the treatment of brain disorders is circumventing the blood—brain barrier

so that drugs can enter the brain and reach their targets. Over the years, clinicians have used various approaches to achieve this aim, including mannitol-mediated blood—brain barrier disruption, intranasal administration of drugs, and novel drug delivery vehicles such as liposomes and magnetic nanoparticles.¹⁰

FUS-mediated opening of the blood—brain barrier is one such novel approach. Significantly, the technique is a noninvasive, targeted approach, unlike other methods of disrupting the blood–brain barrier.³ “Low-frequency ultrasound can be used to open the blood— brain barrier, and we are interested in investigating whether this strategy can be used to enhance the delivery of compounds to the brain, including in Parkinson, which otherwise cannot pass through the blood–brain barrier,” Lipsman said.

With low-frequency focused ultrasound, pulses of sonication are directed in a controlled manner at gas-filled microbubbles in the blood. This leads to excitation of the microbubbles, stretching the endothelium, increasing the vascular permeability, and leading to the localized opening of the blood—brain barrier. This allows therapeutics to enter the brain.^3,10

Because this procedure uses pulses of low-frequency ultrasonic beams, it generates less localized heat compared with FUS-mediated ablation. This reduces the risk of adverse events at the focus site. Furthermore, because low-frequency FUS does not require an increase in localized temperature, clinicians can use it to target a wider range of regions compared with FUS for ablation.⁸

Results from studies have shown the procedure to be safe and reversible, with any disruption lasting approximately 24 hours. During this time, therapeutics with high molecular weight can enter the blood—brain barrier. Additionally, it improves the odds of treating the root cause of PD by improving the delivery of therapeutics that could restore damaged neurological function. Therapeutics of particular interest include gene therapies, neurotrophic factors, adeno-associated viral vectors, and antibodies against α-synuclein, the accumulation of which is known to contribute to neuronal death in PD.^{4,10, 11}

Additionally, practitioners can combine opening of the blood— brain barrier with the release of drugs from their delivery vehicle, speci cally at the target location, without affecting the nontarget regions of the brain. “You can use small microbubbles, encapsulating the required therapeutic, that can circulate through the body with no impact,” Meakem explained. “But in areas where they receive FUS stimulation, those bubbles will burst and release their payload in that local region, targeting the delivery of the drug right where you need it.”

To optimize the blood—brain barrier opening using FUS, clinicians must consider various factors, including frequency, pulse rate, characteristics of the microbubbles, and, most important, control of the cavitation process.⁴ Indeed, a major technical challenge of this approach is monitoring cavitation throughout the procedure. Another challenge is determining the power required to target specific brain regions, which depends on the skull, the target area, and tissue composition.⁴

This application might complement therapy using drugs currently under research for PD that are known to have beneficial effects but are limited by their inability to reach their target in the brain. One such example is the glial cell line—derived neurotrophic factor, which is hypothesized to improve the function of striatal dopaminergic neurons in PD. However, direct infusion of glial cell line–derived neurotrophic factor failed to achieve the expected outcome in a clinical trial, possibly due to ineffcient delivery.

Another application of using FUS to open the blood—brain barrier is in gene therapy. Currently, therapeutic genes are surgically implanted into the brain; however, surgery poses increased risk, and for patients whose cognition is impaired, intracerebral gene delivery is not an option. However, clinicians could make gene therapy available to these patients using FUS-mediated gene delivery because it is a noninvasive method.¹⁰

Current studies are focused on determining clinical safety and opti- mizing technical aspects of the procedure. One goal is to control pore size during blood—brain barrier disruption. Efforts are under way to measure and predict the dose of the drug delivered and the cavitation dose. Additionally, INSIGHTEC hopes to achieve automatic control of the acoustic parameters. The company is developing an Exablate system speciffically to open the blood–brain barrier, as the currently marketed device is intended for thermal ablation.⁴

FUS Pallidotomy

Clinicians have used radiofrequency pallidotomy for improving levodopa-associated dyskinesia in PD by lesioning the posteroventral portion of the globus pallidus.² Investigators are evaluating the safety and efficacy of pallidotomy via MRgFUS as a noninvasive alternative. Studies have demonstrated that the efficacy of unilateral pallidotomy in PD is comparable with that of DBS and radiofrequency lesions. A complication associated with this procedure is impairment of vision, speech, and motor skills; however, this is transient.⁴

Investigators have conducted pilot trials of FUS pallidotomy in multiple locations, including the United States and South Korea. The procedure has demonstrated a better safety profile compared with radiofrequency lesions as well as improvements in Unified Parkinson’s Disease Rating Scale scores.⁴ A large, international, prospective, 2-arm, randomized, multicenter pivotal study is also evaluating the safety and efficacy of unilateral FUS pallidotomy using the ExAblate 4000 MRgFUS system in advanced idiopathic PD.¹² Investigators anticipate the study will lead to FDA approval.

Once the safety and efficacy of this procedure have been more firmly established, the next logical step for FUS pallidotomy would be to evaluate bilateral pallidotomy, as most patients have bilateral disease. Furthermore, in addition to the subthalamic nucleus and the globus pallidus, investigators are also considering the substantia nigra and the striatum, among other targets, for ablative treatment.⁴

Immunostimulation

Studies have demonstrated that FUS activates the body’s immune response. For example, in Alzheimer disease models, FUS has been shown to activate microglia and increase phagocytosis of amyloid-β deposits in the brain by microglia and astrocytes.¹³ Investigators speculate that FUS also induces the entry of immune cells into the brain and an inflammatory response, which might facilitate the clearance of amyloid-β plaques.¹⁵ Similarly, this FUS-mediated immune response could aid in clearing the accumulation of α-synuclein in PD.¹³ Importantly, however, clinicians must control the activated immune response, instead of allowing it to proceed in a prolonged manner, to tap its beneficial effects.⁴

Neuromodulation

Results from other studies have shown that FUS at a lower intensity than that used for opening the blood—brain barrier safely modulates neuronal activity in animals and healthy humans.¹⁴ This application of FUS can induce reversible stimulation and inhibition of neurons in multiple regions of the brain, including the thalamus. Animal trials have demonstrated that ultrasound delivery parameters such as sonication duration determine the neuromodulation effect; short sonication times appear to increase neural activity in the motor pathway, whereas long durations suppress it.¹⁵

Investigators are evaluating FUS-mediated neuromodula- tion by administering weekly stimulations in animal models, with the observed effects of a single sonication lasting 2 hours.⁴ Investigations are under way to determine the mechanism underlying this effect. In vitro and in vivo studies have hypothesized various mechanisms, such as presence of mechanosensitive ion channels within the neural membrane, dissolved gas bubbles oscillating within the lipid bilayer of neurons, and radiation forces.¹⁵

Investigators are unsure of how the topology and density of the skull affect ultrasound focusing on the target region, so studies are needed to improve the understanding of this effect and to determine the long-term effects of FUS on neuronal tissue. Further studies are also required to determine the individual effects of frequency, pulse timing, intensity, and total sonication time on neuromodulation.¹⁵

Other Applications

In addition to the discussed applications of FUS for treating tremors and PD, investigators are exploring several other therapeutic effects. “There are a lot of interesting ways that we can use FUS, and there is research going forward in every one of these applications,” said Meakem. “Other possibilities include sonodynamic therapy, where you can administer medications that are not active in their native state but turn from inactive to active when targeted with FUS.”

Meakem added that histotripsy is another potential application of FUS, as “it damages cells more from a mechanical impact of the ultrasound energy in a very short burst.” This is different from thermal ablation, in which cell damage occurs through localized generation of heat.

Challenges of FUS

Despite its advantages and treatment possibilities, FUS has its share of challenges. Although improved penetration of the blood— brain barrier is a boon for drug delivery, it increases the risk of unwanted substances, including foreign matter and inflammatory agents, entering the brain. Importantly, clinicians must understand the significance of tissue responses that have been observed following FUS, including localized edema, hemorrhage, ischemia, and glial activation. A greater understanding of the risks associated with administration of microbubbles and cavitation is also needed.^3,10 As with every new treatment approach, extensive research is critical to further improving the therapy, expanding its applications, and determining its long-term effects. However, lack of funds for clinical trials is a roadblock. “As with other areas in the biomedical field, funding for clinical trials is a challenge, particularly once trials move past phase 1. Many of our trials are funded by the foundation, whose support for our work has allowed us to significantly accelerate FUS research over the past 5 to 10 years,” Lipsman said.

Meakem also cited a lack of awareness of FUS. “Even in the medical community, people are generally unaware of FUS,” he said, “but we are trying to work against that.” In this regard, a need exists to educate patients, clinicians, and scientists about this technology.¹⁵

What Does the Future Hold?

“FUS is a standard treatment for patients with severe, treatment-resistant essential tremor, and our hope is to provide this option to as many eligible patients as possible,” Lipsman said. “In Parkinson disease, we are hoping to demonstrate that opening the blood—brain barrier is safe, technically feasible, and ultimately effective at delivering therapeutics to the brain that would otherwise not be possible to deliver. In this way, we hope to move the dial on this and other challenging and disabling conditions where delivering therapeutics to the brain is a major challenge.”

Because FUS is a noninvasive approach that can target specific brain regions, it has been a source of hope for clinicians and patients alike. Although further research is required, particularly long-term studies on optimizing the technical aspects of the procedure, this technology looks set to make its mark in movement disorders and beyond.

REFERENCES

1. Focused ultrasound for Parkinson’s disease. Focused Ultrasound Foundation website. fusfoundation.org/images/pdf/FUS_Parkinsons_flyer_MegaDocument_20190307_Approved_Electronic.pdf. Accessed June 10, 2019.

2. Jung NY, Park CK, Kim M, Lee PH, Sohn YH, Chang JW. The efficacy and limits of magnetic resonance—guided focused ultrasound pallidotomy for Parkinson’s disease: a phase I clinical trial. J Neurosurg. 2018;130(6):1853-1861. doi: 10.3171/2018.2.JNS172514.

3. Bretsztajn L, Gedroyc W. Brain-focussed ultrasound: what’s the “FUS” all about? A review of current and emerging neurological applications. Br J Radiol. 2018;91(1087):20170481. doi: 10.1259/bjr.20170481.

4. Focused Ultrasound Foundation. Focused ultrasound opening of the blood-brain barrier for the treatment of Parkinson’s disease. fusfoundation.org/images/pdf/Focused-Ultrasound-Foundation-Parkinsons-Disease-BBB-Workshop-2018-Report.pdf. Published October 21, 2018. Accessed June 10, 2019.

5. FDA approves first MRI-guided focused ultrasound device to treat essential tremor [news release]. Silver Spring, MD: FDA; July 11, 2016. fda.gov/news-events/press-announcements/fda-approves-first-mri-guided-focused-ultrasound-device-treat-essential-tremor. Accessed June 15, 2019.

6. INSIGHTEC for neurosurgery. INSIGHTEC website. insightec.com/clinical/neurosurgery. Accessed June 15, 2019.

7. Krishna V, Sammartino F, Rezai A. A review of the current therapies, challenges, and future directions of transcranial focused ultrasound technology: advances in diagnosis and treatment. JAMA Neurol.2018;75(2):246—254. doi:10.1001/jamaneurol.2017.3129

8. Global Registry: ExAblate Neuro MR Guided Focused Ultrasound (MRgFUS) of Neurological Disorders. https://clinicaltrials.gov/ct2/show/NCT03100474. Updated June 2019. Accessed July 10, 2019.

9. Thalamic Low Intensity Focused Ultrasound in Acute Brain Injury (LIFUP). https://clinicaltrials.gov/ct2/show/NCT02522429. Updated March 2018. Accessed July 10, 2019.

10. LeWitt PA, Lipsman N, Kordower JH. Focused ultrasound opening of the blood—brain barrier for treatment of Parkinson’s disease [published online May 28, 2019]. Mov Disord. doi: 10.1002/mds.27722.

11. Rocha EM, De Miranda B, Sanders, LH. Alpha-synuclein: pathology, mitochondrial dysfunction and neuroinflammation in Parkinson’s disease. Neurobiol Dis. 2018;109(pt B):249-257. doi: 10.1016/j.nbd.2017.04.004.

12. ExAblate Pallidotomy for Medically-Refractory Dyskinesia Symptoms or Motor Fluctuations of Advanced Parkinson’s Disease. clinicaltrials.gov/ct2/show/NCT03319485. Updated June 2019. Accessed June 15, 2019.

13. Poon CT, Shah K, Lin C, et al. Time course of focused ultrasound effects on β-amyloid plaque pathology in the TgCRND8 mouse model of Alzheimer’s disease. Sci Rep. 2018;8(1):14061. doi: 10.1038/s41598-018-32250-3.

14. Fomenko A, Lozano AM. Neuromodulation and ablation with focused ultrasound—toward the future of noninvasive brain therapy. Neural Regen Res. 2019;14(9):1509. doi: 10.4103/1673-5374.255961.

15. Overview. Focused Ultrasound Foundation website. fusfoundation.org/the-foundation/overview. Accessed June 20, 2019.