A Review on Ultrasonic Neuromodulation of the Peripheral Nervous System: Enhanced or Suppressed Activities?

Abstract

Ultrasonic (US) neuromodulation has emerged as a promising therapeutic means by delivering focused energy deep into the nervous tissue. Low-intensity ultrasound (US) directly activates and/or inhibits neurons in the central nervous system (CNS). US neuromodulation of the peripheral nervous system (PNS) is less developed and rarely used clinically. The literature on the neuromodulatory effects of US on the PNS is controversial, with some studies documenting enhanced neural activities, some showing suppressed activities, and others reporting mixed effects. US, with different ranges of intensity and strength, is likely to generate distinct physical effects in the stimulated neuronal tissues, which underlies different experimental outcomes in the literature. In this review, we summarize all the major reports that document the effects of US on peripheral nerve endings, axons, and/or somata in the dorsal root ganglion. In particular, we thoroughly discuss the potential impacts of the following key parameters on the study outcomes of PNS neuromodulation by US: frequency, pulse repetition frequency, duty cycle, intensity, metrics for peripheral neural activities, and type of biological preparations used in the studies. Potential mechanisms of peripheral US neuromodulation are summarized to provide a plausible interpretation of the seemly contradictory effects of enhanced and suppressed neural activities of US neuromodulation.

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

“…Ultrasound (US) is emerging as a promising modality to noninvasively stimulate brain circuits, as well as skin and deep receptor structures in animals and humans 1 – 7 , in which single element or phased array transducers can be designed to focus energy into different targets within the body 8 , 9 . However, direct excitation of peripheral nerves with US remains controversial with inconsistent findings across studies 10 – 12 . Previous in vivo noninvasive studies have reported that US can excite nerves through intact skin and muscle, particularly the rat abducens nerve or mouse sciatic nerve with low stimulus intensities (relative to levels recommended in the FDA guidance for diagnostic ultrasound 13 ; e.g., pressure of 0.53 or 2.6 MPa, respectively 11 , 12 , 14 ).…”

“…However, in mammalian experiments, US was either transcutaneously applied to the nerves 26 , 31 , 32 or was applied to nerves not being fully isolated from surrounding tissue 17 , 30 , which may have confounding effects of stimulation of muscle and skin. Additionally, there are discrepancies on the types of nerve modulation achievable with US stimulation (i.e., enhanced versus suppressed activity) 10 and the effective range of US parameters, such as related to duty cycle, stimulation time, intensity, and center frequency of the US transducer. While thermal and non-thermal effects have both been proposed as mechanisms for US modulation of nerve activity 17 , 18 , there remains a lack of in vivo studies with control experiments to elucidate the mechanism of modulation and its operating range of US parameters.…”

Blocking peripheral drive from colorectal afferents by subkilohertz dorsal root ganglion stimulation

“…41,57 Compound action potentials as temporal and spatial summations of neural activities from bulk nerve bundles are not sensitive enough to detect neuromodulatory effects on individual axons. 28 In particular, slow-conducting C and Ad fibers are underrepresented in the amplitudes of CAPs compared with Aa and Ab fibers, 16 rendering CAPs unsuitable for studying slow-conducting visceral afferents. Physiological functions allow convenient assessment of efferent nerve block, 13,57 but cannot be applied to studying sensory afferents.…”

Interfaces with the peripheral nervous system for the control of a neuroprosthetic limb: a review

“…High intensity focused ultrasound induces irreversible cell death [149], and low intensities are unable to evoke action potentials in peripheral nerves, unlike in the neurons of the brain. Thus, intermediate intensity range (1 -200 W/cm 2 ) should be employed for safety [150].…”