Precision Sound Measurement
It’s been a
decade since high-frequency focused ultrasound was first FDA-approved
for thermal ablation therapies, with prostate tissue ablation leading
the way, and later followed by therapies for essential tremor, Parkinson’s disease, epilepsy, and chronic pain.
Now,
low-frequency focused ultrasound for brain therapeutics is poised for
its last stretch of research before FDA approval consideration.
The parameters discussed in the newly published Device paper
for reliably opening the BBB address elements such as pulse length,
frequency, and acoustic power that “are variable, depending on what
company’s device you have or what technology you’re using. That’s why
standardization is really important,” said co-author Ali Rezai, MD,
executive chair of the Rockefeller Neuroscience Institute at West
Virginia University in Morgantown, West Virginia, whose team has studied focused ultrasound BBB opening to deliver aducanumab antibodies in patients with Alzheimer’s disease.
Focused ultrasound frequencies are so low that they’re just out of
the range of the best-hearing mammals (bats). The low frequencies are
needed to make microbubbles oscillate to create the temporary opening
used to deliver drugs or take a liquid biopsy in the brain.
The
new paper provides dose parameters for reliable expansion and
contraction — called stable cavitation — of the microbubbles. The
opening typically lasts 48 hours, Rezai said. Early indications,
Woodworth added, are that the opening starts immediately and then
quickly diminishes, meaning during the first few minutes is “when you
want your agent to be at peak plasma concentration.”
The new
standards rely on acoustic emissions signals. The monitoring method was
necessary because high-frequency ultrasound for ablation measured
temperature change, but for low frequency, you are monitoring the
microbubbles’ motion via sound.
“The ultrasound is 220 kilohertz,
so by listening at harmonic frequencies of 220k [physicists have
determined how to] hear the bubbles oscillating and quantify it, which
is amazing to me,” said senior author Alexandra J. Golby, MD,
of the Departments of Neurosurgery and Radiology at Brigham and Women’s
Hospital in Boston. “They put these little microphones, which are
called hydrophones, inside the helmet with water, and they listen for
those frequencies and how much is coming out. The application of the
focused ultrasound is actually many, many, many applications — it’s
happening very quickly, multiple times — and they can kind of listen to
each one, and it actually moves through our prescribed area one dot at a
time.”
“We did over 40 treatments,” she added. “And I think that gave us a
real opportunity to not just run people through a clinical trial but to
use this as a real opportunity to try to understand where we could do
better.”
The newly published parameters are expected to supercharge the technology’s scientific, clinical, and regulatory trajectory.
“It
is still early days for this technology, but the more it is tested in
the clinic and for a variety of diseases, such measurements will be
critical for accelerating its clinical adoption, while ensuring safe and
effective application,” said co-author and biomedical acoustics expert Costas D. Arvanitis, PhD,
associate professor at Georgia Institute of Technology in Atlanta,
whose team is studying how ultrasound frequency can be used to change
BBB signaling to accumulate immune cells in brain tumors.
The framework in the Device paper is important because “it
will allow comparisons among different hospitals as well as among
different vendors,” Arvanitis said. “Ultimately, it will allow us to
identify optimal settings for treating different diseases.”
What’s Next
An FDA application for liquid biopsy will likely be made by the end of the year, Woodworth said.
What he’s also watching, he cautiously admits, is how some of the patients in the 2023 temozolomide trial are doing.
“It is quite remarkable to see this number of patients still alive
with what were very bad looking brain tumors and MRI scans,” he said,
adding that “there’s no causal inference that you can necessarily draw
from that. But what gets me excited about this is we know what we’re
doing. We’re targeting specific areas of the brain with acoustic fields
that we control. We know the dose of energy delivered to those regions.
We know the therapies that patients are receiving at the same time. We
know the diagnosis that patients have from very rigorous molecular and
histopathological analysis, and we know those patients are still alive.”
It
reminds him of why he started down this research path in the first
place — because no matter how well a surgery goes, his ultimate goal is
to find a better treatment for residual invasive disease.
“It is
the beginning of something, and that’s very exciting to me,” he said.
“So I’m going to continue to wake up every day and remember that and
just keep pushing because these patients deserve better than two decades
of the same thing.”