Window In The Brain: A 256-channel ultrasound array (right) has been tested on a pig. The array could electronically steer ultrasound energy to open the blood-brain barrier and allow a substance (above, in red) to enter the brain.Images: Hao-Li Liu/Chang Gung University
There’s a barrier in your brain.
Composed of very densely packed cells in the capillary walls, it restricts the passage of substances of the wrong size or chemistry from the bloodstream. Like a locked fence around your home, the blood-brain barrier prevents intruders—such as infective bacteria—from entering.
But a locked fence can also keep out rescuers in an emergency, and the blood-brain barrier keeps out potentially helpful drugs that might be able to ease the suffering of the tens of millions of people with Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and other diseases of the central nervous system. Less than 5 percent of the roughly 7000 available drugs can get through. Basically, none of the large-molecule drugs can, severely limiting the options for new therapies.
But there’s hope. Blasts of ultrasound can temporarily open the barrier in tightly focused spots of the brain that are just millimeters in diameter. And engineers at Chang Gung University, in Taiwan, have recently come up with a much improved way of delivering that energy.
The prototype device they developed is a 256-channel ultrasound phased array. According to electrical engineering professor Hao-Li Liu, his team has developed a unique circuit design involving multiple microcontrollers and power-sensing feedback circuits that enable the system to deliver two frequencies at once instead of the single frequency that biomedical researchers have been working with. By altering the phase of individual channels, the array produces millimeters-wide spots of ultrasound energy that can be electronically steered to any point in the brain.
It’s been known for a while that ultrasound reversibly opens the blood-brain barrier, even if the exact workings haven’t quite been nailed down. The process relies on the acoustic cavitation effect, which is the growth and collapse of microbubbles in a liquid under the influence of an ultrasonic field. (Microbubbles are injected as a contrast agent to enhance ultrasound imaging.) This effect generates an acoustic shock wave, which causes the cells in the blood vessel walls—called endothelial cells—to deform.
“Like mimosa leaves, endothelial cells contract after being shocked, thereby generating gaps. The result increases the possibility of drug delivery,” Liu says, adding that other cells outside the ultrasound’s focal point are undisturbed. Doctors can deliver drugs for about 1 to 2 hours, after which the gaps close.
Therapeutic ultrasound machines available on the market today destroy benign tumors of the uterus and other tissue mostly using a single frequency to generate heat at the ultrasound array’s focal point.
Using two frequencies simultaneously instead can boost the power of these machines three- to fivefold, according to Liu. Greater cavitation “significantly enhances the blood-brain barrier opening,” he says.
In tests using pigs—which have a similar skull thickness to that of humans—the portion of the brain the researchers were aiming for took up 10 times as much of a test dye under the influence of ultrasound as it would have otherwise. They operated the array to produce either 400 kilohertz energy, 600 kHz (an “ultraharmonic” of 400 kHz), or both at once. The dual frequency produced the best results—nearly double what the single frequency delivered without causing damage. “Of course, the performance of different drugs vary,” Liu says.
Elisa Konofagou, associate professor of biomedical engineering and radiology at Columbia University, in New York City, who studies the mechanics of focused ultrasound’s effects, is concerned that the Chang Gung group might not be able to improve further on the results of their system. “The frequency range seems to be on the low end,” she says. “The frequencies would activate larger microbubbles—greater than 2 micrometers—when most microbubbles used are around 1 micrometer. So I’m not sure how they would enhance it.”
Liu counters that using multiple frequencies theoretically has a greater chance of exciting more bubbles. A bubble’s resonance frequency is primarily determined by its size, so more frequencies means more bubbles of different sizes are affected.
Liu hopes that a clinical trial involving the 256-channel ultrasound system could be launched within three years after gaining the support of neurologists. What might help to achieve that goal is a solution to the problem of real-time feedback. “After focused ultrasound energy is delivered to the target position, we can’t make sure if the blood-brain barrier is open. We can only have an answer postoperationally by using contrast-enhanced magnetic resonance imaging technology,” Liu says. His team and others have been looking for possible solutions to the problem.
According to research led by Kullervo Hynynen, senior scientist at Sunnybrook Health Sciences Centre, in Toronto, one way to determine if the blood-brain barrier has been breached is to listen for ultraharmonic frequencies emitted by the bubbles. “This signal can be used in a feedback system to control the exposures,” he says.
If researchers can prove that ultrasound can safely open a window into the brain, better drug therapies will likely step through it.
This article originally appeared in print as “Breaching the Blood-Brain Barrier.”