Ultrasound does not activate but can inhibit in vivo mammalian nerves across a wide range of parameters

Abstract

Ultrasound (US) has been shown to stimulate brain circuits, however, the ability to excite peripheral nerves with US remains controversial. To the best of our knowledge, there is still no in vivo neural recording study that has applied US stimulation to a nerve isolated from surrounding tissue to confirm direct activation effects. Here, we show that US cannot excite an isolated mammalian sciatic nerve in an in vivo preparation, even at high pressures (relative to levels recommended in the FDA guidance for diagnostic ultrasound) and for a wide range of parameters, including different pulse patterns and center frequencies. US can, however, reliably inhibit nerve activity whereby greater suppression is correlated with increases in nerve temperature. By prohibiting the nerve temperature from increasing during US application, we did not observe suppressive effects. Overall, these findings demonstrate that US can reliably inhibit nerve activity through a thermal mechanism that has potential for various health disorders, though future studies are needed to evaluate the long-term safety of therapeutic ultrasound applications.

A review of the bioeffects of low-intensity focused ultrasound and the benefits of a cellular approach

“…In Collins et al (2021) , comparable intensities were insufficient to modulate the activity of the spontaneously-firing DE-3 neuron, nor evoke spikes from any of the other neurons whose axons pass through the DP nerve. This is consistent with others’ findings that peripheral nerves, in comparison to central neural tissues, require much more energy to achieve an effect ( Guo et al, 2022 ). Authors Wright et al (2017) averaged intensities used to modulate peripheral nerves across studies, and calculated a mean intensity of 59 W/cm 2 , versus 3 W/cm 2 in CNS studies.…”

“…In our studies of single identified leech motoneurons, we came to the conclusion that the bioeffects of FUS-mediated neuronal inhibition ( via action potential blockade) were thermally mediated. A parallel study to ours conducted in mammalian peripheral nerves came to the same conclusion that suppression of neural activity was mediated by FUS thermal effects ( Guo et al, 2022 ). In the following section we will outline the FUS stimulus parameters we used to arrive at our conclusions.…”

“…One group reported that FUS applied to the sciatic nerve evoked muscle activity in mice ( Downs et al, 2018 ), while another, also in mice, found that FUS was unable to evoke potentials, though it did increase the conduction velocity of single units (Ilham et al, 2018). Recently, guinea pig sciatic nerves, in vivo , were found to be inhibited via an FUS-induced thermal mechanism ( Guo et al, 2022 ).…”

Low-Intensity Focused Ultrasound Neuromodulation for Stroke Recovery: A Novel Deep Brain Stimulation Approach for Neurorehabilitation?

“…188,189 Due to the excellent focality and steering capacities of FUS-based neuromodulation, US-PNS has been successfully performed in numerous studies in animals and a few human studies showing inhibitory and exhibitory neuromodulation effects. 78,136,[190][191][192] Young and Henneman had already shown in 1961 that US could differentially modulate the activity of Aδ-and C-fibers, depending on the fiber diameter, US intensity, and US exposure time. 193 More recently, additional technical assistance via focal depth controller has been proposed to further improve peripheral nerves targeting for neurorehabilitation 194 , making FUS a very selective method for peripheral nerve stimulation.…”

Ultrasound neuromodulation of an anti-inflammatory pathway at the spleen produces sustained improvement of experimental pulmonary hypertension

“…Similarly, FUS of the hepatoportal nerve plexus in animal models of diabetes restores glucose homeostasis via activation of TRPA1-positive, afferent nerve fibers (35). Notably, the abovementioned mechanosensitive ion channels are expressed in peripheral ganglia, in the vagus nerve and in some spinal nerves (36); the same channels are not expressed in other peripheral nerves, such as sciatic nerve, in which FUS does not elicit nerve responses (37). Furthermore, we found no evidence of a direct hemodynamic effect of sFUS in the systemic or the pulmonary circulation (Suppl.…”