Focused Ultrasound Emerges as Neuromodulation Tool

by James Cavuoto, editor

May 2021 issue

Neuromodulation researchers have looked at a number of noninvasive brain stimulation technologies as potential alternatives to DBS. The problem with approaches like TMS, tDCS, and tACS is the lack of specificity of brain targets. Recently, investigators at two U.S. institutions have reported novel ways of delivering ultrasound energy to the brain in a highly targeted manner.

A multidisciplinary team at Washington University in St. Louis has developed a new brain stimulation technique using focused ultrasound that is able to turn specific types of neurons in the brain on and off and precisely control motor activity without surgical device implantation. The team, led by Hong Chen, assistant professor of biomedical engineering in the McKelvey School of Engineering and of radiation oncology at the School of Medicine, demonstrated noninvasive, cell-type-specific activation of neurons in the brain of mammal by combining ultrasound-induced heating effect and genetics, which they call sonothermogenetics. Results of the three years of research, which was funded in part by the National Institutes of Health’s BRAIN Initiative, were published online in Brain Stimulation.

“Our work provided evidence that sonothermogenetics evokes behavioral responses in freely moving mice while targeting a deep brain site,” Chen said. “Sonothermogenetics has the potential to transform our approaches for neuroscience research and uncover new methods to understand and treat human brain disorders.”

Using a mouse model, Chen and the team delivered a viral construct containing TRPV1 ion channels to genetically-selected neurons. Then, they delivered small burst of heat via low-intensity focused ultrasound to the select neurons in the brain via a wearable device. The heat, only a few degrees warmer than body temperature, activated the TRPV1 ion channel, which acted as a switch to turn the neurons on or off.

“We can move the ultrasound device worn on the head of free-moving mice around to target different locations in the whole brain,” said Yaoheng Yang, first author of the paper and a graduate student in biomedical engineering. “Because it is noninvasive, this technique has the potential to be scaled up to large animals and potentially humans in the future.”

At Carnegie Mellon University’s He Lab, researchers have demonstrated that noninvasive neuromodulation via low-intensity ultrasound can have cell-type selectivity in manipulating neurons. Low-intensity transcranial focused ultrasound, or tFUS, is noninvasive, precise, and does not require surgery. During tFUS neuromodulation, pulsed mechanical energy is transmitted through the skull, with high spatial resolution and selectivity, at highly-targeted brain regions, which can be steered to elicit activation or inhibition through parameter tuning.

In work recently published in Nature Communications, He’s group demonstrated, for the first time, that specific cell types can be targeted through tFUS neuromodulation. Their study found that excitatory neurons showed high sensitivity to ultrasound pulse repetition frequency, while inhibitory neurons did not.

This finding is significant, because it demonstrates the first capability for a noninvasive neuromodulation technique to modulate a selected cell subpopulation, using a technique that can be directly translated for human use. With the demonstrated capability of tFUS to activate excitatory or inhibitory neurons, future applications may lead to precise targeting of brain circuits using focused ultrasound energy, and activate or inhibit selected sub-populations of neurons by tuning ultrasound parameters.

“As a result of our research, we obtained direct evidence that different neuron populations unequally respond to ultrasound stimulation in the brain,” said Kai Yu, co-first author of the paper and a research scientist in He’s lab at CMU. “We identified a critical stimulation parameter that is able to tune the balance between excitatory and inhibitory neuronal activities, and we conducted thorough control experiments to support these valuable neuroscience findings.”