Research teams explore ultrasound for autonomic stim

by Victor Pikov, contributing editor

March 2022 issue, BioElectRx Business Report

Ultrasound has recently emerged as a viable method of stimulating autonomic nerves. Currently. Two major medtech manufacturers—GE Research and Medtronic—are testing the waters, as are several academic research groups.

Ultrasound’s advantages are readily apparent. It avoids a risky surgical procedure for implanting stimulating electrodes on delicate autonomic nerves and instead can deliver energy wirelessly from the skin surface. Studies in pigs and humans show that ultrasound can penetrate deep into tissue (at least 2 inches) while keeping a focused beam of energy (a few millimeters in diameter), allowing it to modulate the activity of autonomic nerves. This is in contrast to RF emitting devices used for powering medical implants that cannot penetrate more than 1 inch of tissue depth and are not focused well enough for producing any neural effects at that depth.

In order to prove ultrasound’s value as a bioelectronic therapy, researchers need to show that they can deliver ultrasonic energy in a reliable and safe fashion. To do that, they need to understand the mechanism of action of ultrasonic neuromodulation. Is it the nerve endings, the axon, the cell body, or some other indirect effect—such as heating of nearby tissue—that produces the therapeutic effect?

According to Chris Puleo at GE Research, ultrasound may activate mechano-sensitive ion channels within the neuronal cell membrane. However, according to Hubert Lim at the University of Minnesota, while activation of these ion channels can depolarize neurons, it does not create reliable action potentials, which is the dominant means of propagating information in myelinated nerves.

Lim believes that a more reliable way of using ultrasound is to depolarize the nerve endings, which triggers an immediate release of neurotransmitters and activation of end organs, such as the spleen, liver, and gut. Ultrasound may also be able to inhibit nerve activity by activating heat-sensitive receptors on the nerve endings, although such thermal mode of neuromodulation is potentially less safe.

Venturing even further, Lim suggests that ultrasound may bypass autonomic nerves altogether and activate other cells, such as chondrocytes in cartilage, for treating osteoarthritis. Determining whether ultrasound is in a mechanical or thermal mode of operation depends on many inter-related factors, such as its pulsing frequency, amplitude, pulse duration, and duty cycle.

Puleo thinks that development of ultrasound-based bioelectronic therapies can be greatly helped by directly monitoring nerve activity. Right now, optical monitoring approaches are readily available for rodents, but it would be challenging to apply them in large animals and humans. If such nerve-imaging tools can be developed for optimizing ultrasound delivery, it can bring us one step closer to a viable therapy.

Eventually, an ultrasonic neuromodulation device—perhaps a wearable—could be used for hours or even days when treating acute inflammatory diseases such as sepsis or COVID-induced cytokine storm. The device would probably need to be miniaturized even further to allow it to be implanted close to the target organ while treating chronic autoimmune and metabolic disorders, such as rheumatoid arthritis or diabetes.


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