Focused ultrasound gaining proponents as breakthroughs are made

TORONTO – The blood-brain barrier – a selectively permeable capillary wall that bars circulating blood and extracellular fluid from entering the central nervous system – performs a critical function in preventing blood-borne pathogens from entering the central nervous system. But it also effectively resists the delivery of lifesaving drug therapies to the brain, requiring higher doses of dangerous chemotherapy drugs, for example, to treat conditions such as brain tumours.

Temporarily increasing the permeability of the blood-brain barrier to allow more efficient therapy delivery is one focus of research in the application of high-intensity focused ultrasound (HIFU).

This relatively new technology was the topic at a recent symposium in Toronto, presented by the Gairdner Foundation and Sunnybrook Research Foundation.

Focused Ultrasound: A New Frontier for Brain Therapy brought presenters from Canada, the U.S., Korea, France and Taiwan to Koerner Hall last November, along with keynote speakers Alan Alda, the iconic actor and science communicator, Brian Greene, a string theorist and author of The Elegant Universe, and Cori Bargmann, a neurobiologist and head of the Chan-Zuckerberg Foundation.

Kullervo Hynynen, director of physical sciences at Sunnybrook Research Institute (SRI), Canada Research Chair in Imaging Systems and Image-Guided Therapy and considered by many to be the “godfather” of the field, kicked off the clinical portion of the conference with a discussion of the blood-brain barrier issue. Many researchers previously thought the problem to be intractable.

“In all the papers, sometimes (using HIFU) worked, sometimes it did damage,” Hynynen says. “It wasn’t consistent.”

Hynynen found that microbubbles – pockets of air two to 10 micrometres in diameter – used for ultrasound imaging contrast, could be made to resonate and inflame the capillary walls temporarily, allowing the larger molecules of chemical therapies to pass through.

CT scans and computer modeling of resonation within the skull help focus and dial in the intensity of the ultrasound; the inflammation lasts only for the two minutes of sonification, and the increase in permeability is gone within six hours.

Surgery for brain tumours doesn’t always remove all the cancerous cells, so despite chemotherapeutic follow-up, recurrence is virtually inevitable, said Hao-Li Liu, a PhD electrical engineer and adjunct assistant researcher in the division of medical engineering research, National Health Research Institutes, Miaoli, Taiwan.

He said treating the blood-brain barrier improves the penetration of chemotherapy agents by two to three times, and as much as 60 times for larger molecule medications. He cited a 135 percent median survival rate increase in test animals.

SRI scientist and neurosurgeon Nir Lipsman extolled the effectiveness of HIFU in a number of treatment areas – including neurodegenerative disorders, cancer, and mental health – but called it “truly transformational” for treating tremor. HIFU is used to create a lesion on an area of the brain which “wipes out” tremor, he said.

“No patient leaves the scanner with a tremor,” Lipsman said. And patients are home the next day.

Moreover, it’s minimally invasive and safe. “They (patients) don’t want their skulls opened, and perhaps rightfully so.”

Lipsman said HIFU has great potential for treatment of mental illnesses such as obsessive compulsive disorder and depression, along with progressive diseases like Parkinson’s, Alzheimer’s and amyotrophic lateral sclerosis (ALS), which he called “relentless in its downward course.”

For Alzheimer’s, Phase 1 of clinical trials targeted the prefrontal cortex, demonstrating the blood-brain barrier dilation was safe and reversible – “not a trivial question,” Lipsman said. All patients asked to be included in the second phase of the trial which targeted amyloid deposits, the “plaque” that causes cognitive impairment, in other areas of the brain. Treatments at two-week intervals showed it could be used in all areas of the brain.

Jean-François Aubrey, MR-guided transcranial brain therapy expert and a director of research at France’s National Center for Scientific Research, said that at first “only a couple of teams believed” in ultrasound therapy for the brain.

“The first thing you’re taught in medical school is that ultrasound doesn’t go through bone,” he said. Breakthroughs led to increasingly complex and expensive systems to focus ultrasound beams within the skull. By 2010, focusing systems comprised as many as 512 elements. So there was skepticism when Aubrey’s team proposed going back to a single-element model. “It seems impossible,” Aubrey said.

Their solution was a patient-specific acoustic lens to recreate the wave pattern. It is cast from a polymer that slows sound and focuses it, much like a magnifying glass focuses light. The lens, with a 61-millimetre radius and 67-millimetre aperture, focuses a 914 KHz sound wave to a resolution on a single target with about 10 mm of play.

The previous evening at a public lecture, Alda and Greene had discussed the importance of communicating science. Alda, the former M*A*S*H star and longtime host of Scientific American Frontiers, who now owns a communications consultancy, said the most important element of communication is making sure an audience understands. In other words, he asked, “Are you getting it?”

The public “is on a blind date with science,” Alda said, and compared the journey of understanding to the phases of a relationship: attraction, infatuation, commitment.

Greene alluded to a cultural mindset that equates expertise with elitism, and disdains the latter. In an interview afterward, he explicitly called that suspicion a product of “inculcation that is for political gain.”

“It’s a real, devious plot,” he said.