The ‘Enormous’ Promise of Focused Ultrasound Now Coming True

After several years of investigating focused ultrasound as a tool in treating Alzheimer’s, the field took a big leap forward this year.

Elisa Konofagou, PhD, a biomedical engineer who runs the Ultrasound and Elasticity Imaging Laboratory at Columbia University in the City of New York, published the results of her team’s groundbreaking research in July, demonstrating their noninvasive, fully portable system for delivering drugs and immunotherapy to patients with Alzheimer’s disease.

This after West Virginia University researchers established earlier this year how focused ultrasound can be used to sneak medication past the blood-brain barrier, reducing amyloid beta plaques.

But Konofagou’s study showed how this treatment can be done without MRIs, allowing them to “speed up the procedure while maintaining accuracy and ensuring affordability.” “Our system is also fully portable. The system can be moved to the patient, not the other way around,” Konofagou said.

It’s just one example of how focused ultrasound has, according to experts, surpassed the tipping point.

“The promise of ultrasound is enormous,” said Wynn Legon, PhD, assistant professor at the Fralin Biomedical Research Institute at VTC, Roanoke, Virginia, whose recent study looked at how focused ultrasound using low-intensity soundwaves aimed at the brain’s insula could dramatically reduce the perception of pain.

“It’s currently the only noninvasive method to transiently alter brain activity virtually anywhere in the brain,” Legon said, adding that it could soon be used in the treatment of everything from chronic pain to addiction to mental health disorders. “I think focused ultrasound has finally gained acceptance and critical mass.”

But the brain isn’t the only organ that can benefit from focused ultrasound. The technology is already helping doctors treat conditions that typically involve surgery or radiation, like prostate cancer and essential tremors.

Meanwhile, more than 170 diseases or clinical indications using focused ultrasound as a possible treatment are under investigation, said Neal F. Kassell, MD, a neurosurgeon at the University of Virginia and the founder and chairman of the Focused Ultrasound Foundation, Charlottesville, Virginia, which facilitates and funds research. “That’s how rapidly this field is growing.”

How We Got Here

Focused ultrasound is like diagnostic ultrasound, “but with some important differences,” said Kassell. Both use high-frequency sound waves undetectable to human ears. But instead of using these waves to look at babies in utero or check for blocked arteries or veins, the technique aims them at exact targets in the body.

It’s like focusing light with a magnifying glass to burn a hole in a leaf. “An acoustic lens is used to focus multiple beams of ultrasound energy with a high degree of precision and accuracy,” Kassell said.

Though ultrasound has been around since the late 19th century, the first focused ultrasound device was invented in 1942 by brothers William and Francis Fry, who used it to perform a partial ablation of the basal ganglia after a craniotomy in the mid-50s. “It was basically an alternative to the ice pick operation for frontal lobotomy,” said Kassell.

A focused ultrasound system designed to treat glaucoma was the first use of the tech approved by the US Food and Drug Administration (FDA) in 1988, and during the 1990s, experimental therapeutics utilized focused ultrasound for a variety of conditions, from brain tumors to prostatic hyperplasia.

But the biggest advances have come over the past 10-15 years, with the FDA approving focused ultrasound for a range of conditions, like bone cancer pain, essential tremor, and Parkinson’s disease.

And according to medical biophysicist Kullervo Hynynen, PhD, “We’re just scratching the surface of what’s possible.”

So what else is possible? Here are some of the most promising and exciting applications coming soon for focused ultrasound.

Improving Drug Delivery

Many researchers have paired focused ultrasound with microscopic bubbles, which are filled with drugs for whatever medical condition is being treated. The microbubbles are injected into the patient’s bloodstream and guided by focused ultrasound to an exact target in the body. Because the drugs are trapped within the nanoparticle, they can circulate through every tissue and organ without being activated.

“Only when it reaches the exact point where the ultrasound is focused, that’s when the microbubbles burst and release their pharmacological payload,” said Kassell. “It increases the effectiveness because we can deliver drugs in a much higher concentration than conventional means like intravenous or oral, and it also minimizes the systemic toxicity or side effects.”

Hynynen, who is vice president for research and innovation at Sunnybrook Research Institute in Toronto, Ontario, Canada, was one of the first to conduct a successful clinical trial using focused ultrasound in 2015 to deliver chemotherapy into a patient’s malignant brain tumor. He also developed a hemispheric helmet, with 1024 ultrasound transducers to deliver the ultrasound.

“It’s customized for each patient because every head is different, every brain is different,” Hynynen said. “It transmits and receives ultrasound and can control it very precisely. It allows us to see where the bubbles are activated and where they are in real time.”

Resetting the Brain

One of the most exciting fields of research is depressive disorders. At The University of Utah, researchers are testing a headphone-style device, called DIADEM, that uses noninvasive deep brain therapies with ultrasonic waves to treat depression.

“It resets the deep brain regions,” focusing on the insular cortex, said Jan Kubanek, PhD, a biomedical engineering professor at The University of Utah, Salt Lake City, Utah, who’s leading the research.

They’ll soon begin phase 3 of their trials, with hopes of obtaining FDA approval within the next 1 or 2 years. And depression is just the beginning.

“We’ve also started clinical studies for PTSD, Alzheimer’s disease, and weight loss,” said Kubanek.

There’s also been promising research on how focused ultrasound could play a role in treating addiction.

“It’s a method we call neuromodulation,” said Kassell, “in which ultrasound is used to stimulate or block neural activity in areas of the brain related to addiction, to drugs, alcohol, tobacco, food, and so on. There’s fairly early-stage research, but it’s very encouraging.”

At West Virginia University’s Rockefeller Neuroscience Institute, focused ultrasound is being explored as a possible treatment option for opioid use disorder but could also expand to include addictions to cannabis, alcohol, methamphetamines, and more. The outpatient procedure involves MRI-guided focused ultrasound waves that target the nucleus accumbens, the brain’s “pleasure center” that plays a big role in reward and addiction.

At the neighboring University of Virginia campus, researchers at the UVA Center for Leading Edge Addiction Research are currently recruiting participants for a new clinical trial exploring how focused sound waves can target the dorsal anterior insular cortex — a distinct brain lobe linked to compulsive cocaine use in rats — which could potentially reduce cocaine cravings. Although their study is still very much in its infancy, it has already generated enough hopeful optimism that the National Institute on Drug Abuse has pledged $5 million in support.

The Future of Biopsies

Of course, treating diseases and disorders is only half the battle. What if focused ultrasound offered an alternative to traditional biopsies and wasn’t just less uncomfortable for the patient but could provide even more accurate and fast results? John Lewis, PhD, a professor of oncology at the University of Alberta, Edmonton, Alberta, Canada, has been studying the early detection and stratification of prostate cancer for several decades, and he said focused ultrasound can offer exactly that.

“A physical biopsy, particularly into a bone where metastatic prostate cancer might reside, is an extremely invasive procedure,” said Lewis. “But using high-intensity focused ultrasound to release extracellular vesicles is a completely noninvasive method to capture the same information, which would not be painful and would have a much lower chance of side effects.”

Lewis and his University of Alberta research team, which includes electrical engineering Professor Roger Zemp, MSc, PhD, began developing a new ultrasound technology called micro-histotripsy, which involves liquefying tiny volumes of tissue to release tiny biomarkers “that are present in the circulating tumor cells and released by ultrasound, but which are absent in the blood cells,” said Zemp. ” We’ve shown that this approach can release even more biomarkers than previous methods and that our approach is much more reliable than a fine-needle aspiration. We can detect even single tumor cells in several milliliters of blood.”

It has the potential to be a lifesaver for patients with cancer. “We can detect clinically significant prostate cancer with much improved detection performance compared to more conventional PSA tests,” said Zemp.

Although he believes that large core-needle biopsies will remain the standard of care, at least for now, Zemp and his colleagues are confident that focused ultrasound could be the future of biopsies. “With further work, we hope to show that we could confidently detect clinically significant prostate cancer with a blood test and avoid 30%-50% of biopsies,” Zemp said.

Challenges and What’s Next

Focused ultrasound has a few hurdles to pass before it becomes a medical standard. “We need more evidence of safety, efficacy, costs, and so on,” Kassell said. “It has to be developed through clinical trials, and then you have to get regulatory approval, which takes a long time because the clinical trials are complicated and expensive. Then there’s the issue of reimbursement, the insurance companies and what they will and won’t cover, which can be an agonizing process.”

As with any new technology, he said, there will be people within the medical field clinging to the old ways of doing things, who’ll push back against the doctors and researchers looking to innovate.

“There’s fairly vicious turf battles that develop between the different medical specialists because this is a highly disruptive technology that disrupts referral patterns and practice patterns,” said Kassell.

But despite the obstacles, Kassell believes the future is bright. Roughly 100,000 patients were treated with focused ultrasound in 2022, Kassell estimated. And in the next 5 years, that number could grow substantially — as costs come down and more hospitals and medical centers begin offering it for a wider range of conditions — with potentially up to a million patients being treated with focused ultrasound, at around 10,000 commercial treatment locations across the globe, every year, Kassell said.

The arguments for focused ultrasound far outweigh the arguments against it, said Kassell. “It improves the safety, increases the effectiveness, and decreases the side effects of therapy because it’s totally noninvasive,” he said. “There are no incisions, so there are no blood clots, and there are no infections. It’s shorter and more convenient. It’s an outpatient procedure.”

For Hynynen, the convenience may be the most remarkable thing about focused ultrasound and the reason he thinks patients will ultimately embrace it. “You can have a biopsy or fibroid treatment in the morning, and then go sailing and biking in the afternoon instead of staying in bed for 10 days,” Hynynen said. “What’s not to love about that?”