How combining ultrasound, gene therapy and drugs switches neurons on and off
Finding ways to activate or deactivate specific neurons in the brain could be the path to treating disorders like Parkinson's or epilepsy, but usually that requires surgery. Now, Caltech researchers have developed a three-part technique that's far less invasive, combining ultrasound waves, gene therapy and drugs that has been able to affect memory formation in mice.
If you're looking to interface with the brain, you've got a variety of options. There's transcranial magnetic stimulation, where magnetic coils against the skull trigger certain brain functions, or there's optogenetics, where shining light causes light-sensitive neurons to fire up. The problem with both of these is that often surgery is required to implant the receiving devices in the brain, while in other cases mice have to be genetically engineered to be receptive to the treatment.
The Caltech team set out to develop a new method that was only as invasive as an injection and an ultrasound. Given the technique involves ultrasound waves, drugs and genetics, the team calls it "acoustically targeted chemogenetics" (ATAC).
"By using sound waves and known genetic techniques, we can, for the first time, noninvasively control specific brain regions and cell types as well as the timing of when neurons are switched on or off," says Mikhail Shapiro, lead researcher on the study.
The first obstacle is the blood-brain barrier, that layer of fluid that protects the brain from foreign invaders. While it's crucially important for the wellbeing of the brain, that barrier is the bane of existence for scientists developing neural medicine, and getting past it is often one of the most challenging parts of that work.
In this case, the Caltech team overcame it by injecting tiny bubbles into the bloodstream, and then blasting them with ultrasound from outside the body. That works to temporarily open up the blood-brain barrier to let the drugs through.
"When the bubbles are hit with ultrasound waves, they vibrate, and this motion jostles the blood-brain barrier open for a brief period of time," says Jerzy Szablowski, lead author of the study.
With the Red Sea parted, the second phase of the treatment can get into the brain to do its work. The team has engineered viruses that carry genetic instructions to specific cells. Once there, they code for chemogenetic receptor proteins, which respond to a certain drug. Finally, that drug is administered, triggering the neurons to turn on or off.
The Caltech researchers tested the technique on mice. By switching off neurons in the hippocampus, the team was able to prevent the animals from forming new memories for a short while. And unlike the implant option, the ATAC method will naturally reverse itself over time.
"You can administer a drug to turn off neural cells of interest, but, with time, those cells will turn back on," says Szablowski. "You can also perform drug dosing to determine how completely you are shutting off that region of the brain."
While the current study was a proof of concept, in future the team hopes to test the ATAC technique as a possible treatment for conditions like epilepsy.
"Our method is a combination of technologies, each of which have been used in animals and are being advanced into the clinic," says Shapiro. "Because of this, we are further along in our development process than we would be if we started from scratch."
The research was published in the journal Nature Biomedical Engineering.