A macaque monkey sat in front of a computer. A yellow square—the target—appeared in the periphery on the left side of the screen. After a few seconds delay, a second target appeared on the right. The question was: Which target would the monkey look at first? So far so routine as neuroscience experiments go, but the next step was unusual. By non-invasively directing bursts of inaudible acoustic energy at a specific visual area of the brain, a team of scientists steered the animal’s responses. If they focused on the left side of the brain, the monkey looked to the right more often. If they focused on the right side, the monkey looked to the left more often.
The results of the experiment, which were presented last week at the annual Society for Neuroscience meeting, marked the first time that focused ultrasound was safely and effectively used in a nonhuman primate to alter brain activity rather than destroy tissue. A second study, in sheep, had similar results. “The finding paves the way to noninvasive stimulation of specific brain regions in humans,” says Jan Kubanek, a neural engineer at Stanford University School of Medicine and lead author of the macaque study. The technology might ultimately be used to diagnose or treat neurological diseases and disorders like Parkinson’s disease, epilepsy, addiction, and depression. Other scientists are optimistic. “The idea that, with a very carefully designed dose, you could actually deliver [focused ultrasound] and stimulate the brain in the place you want and modulate a circuit rather than damage it, is a really important proof of principle,” said Helen Mayberg, MD, of Emory University School of Medicine, who was not involved with the study.
Ultrasound has long been used for imaging. When sound waves above the level that humans can hear (more than 20,000 hertz) are aimed at the body, some of the energy bounces back creating a picture of internal bodily structures. Focused ultrasound, or FUS, raises the energy level to accomplish other ends. Like using a magnifying glass to focus beams of light on a single point and burn a leaf, FUS concentrates as many as 1,000 sound waves on a specific target with precision and accuracy.
First approved by the Federal Drug Administration in 2004 as a treatment for uterine fibroids, focused ultrasound has gained an increasing variety of potential uses, generating excitement among many doctors. “There are 18 ways, or mechanisms of action, by which focused ultrasound affects tissue. That fact creates the opportunity to treat a whole variety of medical disorders,” says Neal Kassell, MD, former co-chair of neurosurgery at the University of Virginia and founder and chairman of the Focused Ultrasound Foundation, which seeks to speed the development and adoption of the technology.
A decade ago, FUS was being investigated as a treatment for three diseases or disorders. Today that number stands at more than 90. Thus far, however, it has only been used in humans to target and destroy tissue with heat. In addition to uterine fibroids, it is approved for four other therapeutic uses in the United States. Prostate cancer was added to the list in 2015, although some urologists have been lukewarm about its use, emphasizing in the Journal of the American Medical Association in 2016 that the long-term efficacy is not yet proven. In the brain, the FDA approved its use as an ablation treatment (removing tissue) for essential tremor in 2016. (In Europe, it’s more widely used.)
Howard Eisenberg, professor and chief of neurosurgery at the University of Maryland School of Medicine, participated in the clinical studies of FUS as an ablative treatment for essential tremor and Parkinson’s disease, targeting different brain areas for each disorder. He has found that patients like the technology because it’s less invasive than deep brain stimulation, which requires surgery to implant an electrode. “It’s not surgery really,” says Eisenberg. In addition, because FUS is so precise, says Eisenberg, “you can sculpt the lesion, you might make three ablations all close to each other.”
Comparatively speaking, neuromodulation, which entails altering electrical and chemical signaling in brain circuits, requires lower doses of energy that are delivered as intermittent pulses and is relatively far down the list of possible uses for FUS in the brain. “It’s a frontier approach,” says Eisenberg, who is more excited about using FUS to open the blood-brain barrier for drug delivery But if the technique can be perfected as a method of brain stimulation it will open a new range of possibilities. It can be aimed more precisely—on the order of millimeters rather than centimeters—than transcranial magnetic stimulation (TMS). And it can go deeper into the brain. “I think the first opportunity is on the diagnostic side,” said Kubanek. “Disease circuitry might be variable across patients. If we can specifically stimulate regions deep in the brain and measure the reduction of tremor, that would [tell us that region is] involved in that behavior.” The next step would be to apply focused ultrasound as a method of brain stimulation for a variety of mental health and neurodegenerative disorders like Alzheimer’s.
Like Kubanek, Seung-Schik Yoo, professor of radiology at Harvard Medical School and director of the neuromodulation lab at Brigham and Women’s Hospital, demonstrated successful brain stimulation using FUS at the Society for Neuroscience meeting. In sheep, Yoo and his colleagues showed that FUS could both excite and inhibit brain activity without apparent harm. But Yoo’s primary aim was to develop a wearable transcranial FUS system. His team created a small apparatus weighing only a quarter of a pound that could be worn by the sheep, whose cranial structure is similar to humans. The system consisted of a focused ultrasound transducer to generate the signal, an optical tracker, and an applicator to hold the transducer over the head via an implanted pedestal. (In humans, they plan to do away with the need for implantation.) The group also developed a computer algorithm capable of predicting the intensity and location of the acoustic focus, which Yoo likened to an area the size of a large piece of orzo pasta.
“The tools themselves are really changing the face of what’s possible,” Mayberg says. “Wouldn’t it be great if we could tune [brain circuitry] with ultrasound and don’t have to open the brain?” she says. That would avoid surgery and the need for periodically changing batteries. “You could wear a device like the sheep,” she adds. “We can start to dream about some innovations that are based on exquisite neuroscience.”
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