In the brain, FUS has mostly been applied to treat essential tremor. The ExAblate Neuro system from InSightec, for example, is approved in Europe for treatment of essential and Parkinsonian tremor and neuropathic pain. But with continuing advances in FUS apparatus and expertise, can this promising modality be applied to treat other brain disorders? And what are the associated technical requirements?

Speaking at the recent AAPM Annual Meeting, Kullervo Hynynen from Sunnybrook Research Institute and the University of Toronto took a look at the wide range of brain therapies that may be enabled by FUS.

Clot busting

For treatment of embolic stroke, it may be possible to use FUS to fragment blood clots in the brain. In a study of rabbits with injected blood clots, Hynynen and colleagues demonstrated that FUS could restore blood flow. Applying 415 W of acoustic power led to reperfusion in two of four treated animals, while 550 W proved effective for five of seven animals tested.

"We were able to open up flow in the blood vessel at fairly high acoustic powers, and needed even higher power to produce consistent results," Hynynen told the AAPM delegates. "We could do this without damaging surrounding tissue. The next question is can this be performed through the skull?"

Simulations revealed that through-skull clot lysis using a FUS transducer array may be technically feasible, though high surface acoustic powers and intensities are required to achieve target pressures. Increasing the number of transducer elements lowers these requirements, but the element count needed (9–10,000 at 1.5 MHz) is an order of magnitude higher than currently available. New transducer arrays will need to be developed for this approach to be realised as a clinical stroke treatment.

Hynynen noted that it may also be possible to reduce the acoustic power requirements by introducing submicron perfluorocarbon droplets. Such droplets can be vaporized in situ to locally create microbubbles and induce inertial cavitation. In vivo animal studies revealed that with intravascular droplets, an average power of about 100 W was needed to break down clots in the brain, compared with 550 W without droplets. "This factor of five reduction in required power is promising, and something that we can potentially do clinically," he said.

Through the BBB

Focused ultrasound pulses, combined with microbubble-based contrast agents, can also be used to temporarily open the blood-brain barrier (BBB) – potentially enabling delivery of chemotherapy drugs, antibodies, cells and other therapeutic agents into the brain. Hynynen noted that over 100 animal-based studies have been published describing FUS-enabled delivery of such agents.

He described an animal study using targeted natural killer (NK) cells to selectively destroy metastatic tumour cells. "If we can open the BBB and get the NK cells into the brain, they will target and kill tumour cells. This is an ideal way to treat brain tumours with immunotherapy," he explained.

Hynynen and colleagues used FUS to deliver NK-92 immune cells, which target HER2-expressing tumour cells, to brain metastases in mice. Opening the BBB with ultrasound allowed effective delivery of the NK-92 cells. The average ratio of NK-92 to tumour cells was 1:100 when NK cells were injected before sonication, versus 2:1000 and 1:1000 when delivered after sonication and without BBB disruption, respectively.

The researchers treated the mice with NK-92 cells and FUS once per day for five days, followed by two treatments in the next week and one treatment in week three. This regime significantly reduced tumour growth compared with that seen in mice receiving either NK-92 cells or ultrasound alone. The combined treatment also doubled survival times from 50 to 100 days.

"This approach looks extremely promising and, if we can translate it to the clinic, should provide a very gentle way of treating brain tumours," Hynynen said.

Applications in Alzheimer's

Finally, Hynynen discussed FUS treatments of Alzheimer's disease, a progressive neurodegenerative disorder characterized by the presence of β-amyloid plaques in the brain. In animals, immunotherapies have proved successful in removing these plaques. But this approach has failed in human trials, due to the BBB preventing large molecules penetrating into the brain.

Tests combining FUS with antibodies, however, demonstrated successful delivery of antibodies to sonicated regions of the brain and subsequent reduction of plaque. Interestingly, such studies revealed that FUS opening of the BBB can, by itself, reduce Alzheimer's pathology. So is FUS alone effective for treating Alzheimer's disease?

To answer this, Hynynen and colleagues treated diseased and non-diseased mice weekly with FUS to open the BBB at the hippocampus. After one month, the working memory of each mouse was tested in a Y-maze. The test revealed vastly improved memory performance in FUS-treated mice, which exhibited similar behaviour to non-diseased controls. "Somehow, we were able to restore memory in these animals," said Hynynen.

Pathology revealed that FUS had reduced the plaque load in the mice's brains, as well as stimulated growth of new neurons. So could this approach be translated to the clinic? Hynynen described the challenges involved. For starters, the human skull is highly variable, necessitating careful monitoring and control of bubble activity: too low exposure levels will not create BBB opening, while too high may cause vascular and neuronal damage.

He noted that large-volume, high-precision treatments require large ultrasound arrays with fast electronic scanning. Full-scale arrays can be complex and costly, but it may be possible to use sparse arrays instead. "Sparse arrays don't work well for thermal ablation therapies through the skull, because they cause too much skull heating," he explained. "But they may work for bubble-based therapies that have lower power requirements."

"There are many new treatments that may be possible in the future," Hynynen concluded. "These have been demonstrated in animals and now need to be taken into the clinic. Provided that we have the technologies, FUS could have a huge impact."

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