At the SPIE Medical Imaging conference, held this week in San Diego, CA, Hynynen explained how focused ultrasound can achieve targeted ablation through the skull. "For many years, people believed it was not possible to use focused ultrasound in the brain," he told the assembled delegates. Problems arise when the ultrasound beam traverses the skull, as this defocuses the beam, as well as causing the skull to heat up. "So in early research, the skull bone was removed," he noted.
The heating problem has now been addressed with the introduction of multi-element hemispherical transducers. Meanwhile, CT scans of the skull can be used to calculate phase delays for each transducer and correct for skull-induced beam distortion. "We now know that we can treat the middle of the brain relatively precisely," Hynynen explained. "But some areas are still problematic, for example, tumours near the skull base."
One way to minimize skull-base heating is to reduce the total applied power. But this must be done whilst still achieving ablation at the focus. The answer, says Hynynen: "use microbubbles". Bubbles injected into the bloodstream will increase absorption at the acoustic focus, enabling equivalent biological effects with less acoustic pressure.
Tests in rabbit brains, for example, have shown that the presence of such microbubbles allowed a four-fold reduction in power. Hynynen and colleagues are currently developing models to simulate bubble-enhanced heating within the vasculature. "The use of microbubbles looks promising for being able to reduce the applied power and lower skull-base heating," he said.
BBB disruption
But focused ultrasound can do so much more than just ablate brain tumours. According to Hynynen, there are a host of other ultrasound-based applications that could prove valuable for treating diseases of the brain.
For example, over 95% of drugs used to treat central nervous system disorders don't penetrate the blood-brain barrier (BBB). Using a focused ultrasound beam to locally disrupt the barrier, without damaging the brain, could enable the use of a far greater range of drugs. It could also allow delivery of higher doses, as the non-targeted areas of the brain remain protected by the BBB.
Hynynen cited an example in which injection of microbubbles followed by 20 seconds of sonication opened the BBB, allowing the drug to enter the sonicated area only. Experiments in pigs have shown that focused ultrasound can also disrupt the BBB in large animals. "Local MRI-guided disruption of the blood-brain barrier is feasible and doesn't have an adverse effect on the animals," he said.
Most chemotherapy drugs are also incapable of penetrating the brain. Hynynen described a study looking at chemotherapy of a rat brain tumour. Rats were injected with doxorubicin and microbubbles, and sonication applied. While neither doxorubicin alone nor ultrasound alone had any impact upon the animals' survival, the combination of sonication plus drug halved the tumour doubling time and increased survival.
Hynynen also highlighted a preliminary study in which focused ultrasound was employed to treat Alzheimer's disease in a mouse model. Here, ultrasound-induced disruption of the BBB enabled delivery of antibodies that clear amyloid beta plaques in the brain. Mice were treated with the antibodies and ultrasound applied to one side of the brain. Four hours later, antibodies were detected only on the sonicated side. After four days, there were fewer plaques on the ultrasound-treated side.
Finally, Hynynen discussed the use of ultrasound as a potential treatment for stroke. In the CLOTBUST trial, for example, adding ultrasound exposure to patients receiving the clot-dissolving drug tPA was seen to enhance its effects. Elsewhere, an in vivo study of femoral arteries in rabbits showed that high-intensity focused ultrasound could eliminate clots in some animals and restore blood flow without the need for drugs.