Ultrasound may boost survival after a stroke by clearing brain debris

Pulsed ultrasound waves into the brain may improve survival after a type of stroke by helping clear away inflammatory dead blood cells, according to a study in mice. This approach, which enhances the effects of lymphatic drainage, could also treat Alzheimer’s disease, with a trial in people with the disease expected to begin next year.

Hemorrhagic strokes, which account for about 15 percent of all strokes, occur when a blood vessel in the brain ruptures, causing bleeding that disrupts the brain’s oxygen supply and damages its cells, often leading to problems with movement and cognition.

Treatment often involves sealing the broken vessel with a small metal clip, then removing dead red blood cells — via a catheter, for example — that would otherwise increase inflammation and cause further tissue damage. But this is very invasive, which can lead to brain damage and infections, says Raag Airan of Stanford University in California.

Airan wondered about the potential of ultrasound, delivered in pulses outside the head, after accidentally leaving such a device on too long while using it to activate drugs in the brains of mice. “What I saw was that the drug spots that I introduced into the brain were like they were spread out, like they were being transported further into the brain in one direction. [cerebrospinal] “It’s a liquid that generally removes dirt from the brain,” he says. “So I thought, ‘Can we actually use ultrasound to flush substances out of the brain?'”

To explore this, his team collected blood from the tails of mice and injected it into their brains, mimicking a hemorrhagic stroke. Over the next three days, the researchers sent ultrasound waves into the skulls of half of the mice, for 10 minutes per day. The remaining animals received no treatment.

Next, all mice completed a 3-minute test in which they were placed in a four-corner tank, which allowed them to turn left or right. Healthy mice, without movement or cognitive problems, typically turn in each direction 50% of the time.

The researchers found that mice in the ultrasound group turned left 39 percent of the time, compared to 27 percent of the time in the control group. They also found that early mice could grip a metal bar more tightly than control mice. This suggests that the treated animals had less brain damage, which the team later confirmed by analyzing slices of their brains after euthanasia.

A week after blood was injected into their brains, about half of the mice in the control group were dead, compared with a fifth of those in the ultrasound group. “We have increased survival by about 30 [percentage points] with just three 10-minute ultrasound sessions,” says Airan.

Further analysis revealed that the ultrasound pulses activated pressure-sensitive proteins on the animals’ microglia, the brain’s immune cells, making them less inflammatory and improving their ability to engulf and eliminate dead red blood cells. The pulses also increased the flow of cerebrospinal fluid through the brain, improving the removal of dead cells to the lymph nodes in the neck. As part of the lymphatic system, these help remove metabolic waste from the brain.

Although more research is needed, this approach could treat other brain conditions. “If ultrasound can remove red blood cells, which are quite large, from the brain, it should be able to remove toxic proteins that are much smaller, such as [misfolded] tau, which contribute to diseases like Parkinson’s and Alzheimer’s,” says Airan.

“This is a really impressive study with huge potential for future translation because it is non-invasive,” says Kathleen Caron of the University of North Carolina at Chapel Hill. The lymphatic systems of mice and humans appear to be quite similar, so the approach could work in humans, she says.

Ultrasound exposure is considered safe, so Airan is confident the treatment will not have any unexpected side effects, although research is needed to confirm this.

Researchers hope to eventually test this approach in people who have suffered a hemorrhagic stroke, but this requires urgent treatment. So they plan to collect more data on its safety and effectiveness in people with Alzheimer’s disease, a progressive disease, with a trial expected to start next year, Airan says.