Stanford University School of Medicine scientists have developed a noninvasive way of delivering drugs to within a few millimeters of a desired point in the brain.

The method, tested in rats, uses focused ultrasound to jiggle drug molecules loose from nanoparticle “cages” that have been injected into the bloodstream.

In a proof-of-principle study, the researchers showed that pharmacologically active amounts of a fast-acting drug could be released from these cages in small areas of the rats’ brains targeted by a beam of focused ultrasound. The drug went to work immediately, reducing neural activity in the targeted area—but only while the ultrasound device was active and only where the ultrasound intensity exceeded a certain threshold. By modifying the strength and duration of the beam, the investigators could fine-tune the neural inhibition.

While the drug used in this study was propofol, an anesthetic commonly used in surgery, in principle the same approach could work for many drugs with widely differing pharmacological actions and psychiatric applications, and even for some chemotherapeutic drugs used to combat cancer.

By turning up the ultrasound intensity and monitoring brainwide metabolic activity, the researchers could also observe the drug’s secondary effects on distant downstream brain regions receiving input from the targeted area, said Raag Airan, MD, PhD, an assistant professor of neuroradiology. In this way, the researchers were able to noninvasively map out the connections among disparate circuits in the living brain.

A paper describing the study’s findings was published online Nov. 7 in Neuron. Airan is the senior author. Lead authorship is shared by Jeffrey Wang, a student in the MD-PhD program, and postdoctoral scholar Muna Aryal, PhD.

A kindred technology known as optogenetics, pioneered by Karl Deisseroth, MD, PhD, a Stanford professor of bioengineering and of psychiatry and behavioral sciences under whom Airan completed his PhD work a decade ago, uses invasive gene delivery to render specified classes of nerve cells vulnerable to precise experimental manipulation. Airan’s approach employs noninvasive pharmacological methods to achieve similar control of neural activity.

“This important work establishes that ultrasonic drug uncaging appears to have the required precision to tune the brain’s activity via targeted drug application,” said Deisseroth, who wasn’t involved in the study. “The powerful new technique could be used to test optogenetically inspired ideas, derived initially from rodent studies, in large animals—and perhaps soon in clinical trials.”