## 3 Ultrasonic Neuromodulation of the Peripheral Nervous System  
The effect of US stimulation to alter tissue activities was reported as early as in 1929 by a study on frogs and turtles [71]. The ability of low-frequency low-intensity US to modulate the CNS neural activities is elegantly demonstrated both in vivo in whole animals and in vitro in reduced systems of brain tissue slices (see reference [9] for a review). Recent studies indicate that US neuromodulation of the CNS might take an indirect route through the auditory cochlear pathway [29; 30]. In stark contrast, the mechanisms of US neuromodulation of the PNS are still under debate, partly because of the contradictory experimental outcomes, which are systematically summarized and discussed below. As summarized in Table 1, US appears to directly activate peripheral sensory nerve endings, as evidenced by studies of US stimulation of human hand, skin, soft tissues, bones, joints, ears, acupuncture points [53; 72; 73; 74; 75], as well as of cat ear [76] and frog Pacinian corpuscles [77]. CAP activities are evoked by US stimulation in animal preparations. More convincing evidence has been found by clinical studies in which direct verbal reports show that US stimulation is able to evoke virtually all the somatosensory modalities: tactile, warm, cold, itch, deqi, hearing, and pain. Unlike in the CNS, low-intensity US (\(<\)1 W/cm\({}^{2}\)) is unable to activate mammalian nerve endings. In non-mammals, dissociated frog Pacinian corpuscles can be activated by US with intensity as low as 0.4 W/cm\({}^{2}\). US with intermediate intensity (1-200 W/cm\({}^{2}\)) activates only low-threshold mechanoreceptors, e.g., tactile receptors and auditory nerve endings. Activation of other sensory modalities like temperature and pain generally requires high-intensity US stimulation (\(>\)1000 W/cm\({}^{2}\)). However, it remains unclear whether US inhibits sensory nerve endings, which unlike neurons in the CNS, generally do not fire spontaneously. Further experimental studies are required to investigate whether US application to sensory nerve endings could lead to the loss of sensation. \begin{table}
\begin{tabular}{l l l l l l l l l l} \hline \hline
**PNS Endings (Research)** & **Effect** & \begin{tabular}{c} **Freq** \\ **(MHz)** \\ \end{tabular} & \begin{tabular}{c} **PRF** \\ **(Hz)** \\ \end{tabular} & \begin{tabular}{c} **DC (\%)** \\ **(Hz)** \\ \end{tabular} & \begin{tabular}{c} **Intensity** \\ **(W/cm\({}^{2}\))** \\ \end{tabular} & \begin{tabular}{c} **Duration** \\ **(mSec)** \\ \end{tabular} & \
\begin{tabular}{c} **Metric for** \\ **Modulation** \\ \end{tabular} &
\begin{tabular}{c} **Preparation** \\ **Type** \\ \end{tabular} \\ \hline Human hand nerve & Tactile, warm, & 0.48 & & & & & & \\ endings [72] & cold, itch, and & 0.887 & & & & & & & \\ ([PERSON] et al., 1977) & pain sensation & 2.67 & & & & & & & \\ \hline Human skin, soft tissue, bone, & & & & & & & & & \\ joint [73] & Pain sensation & 0.48–2.67 & & & & & & & & \\ (ab [PERSON] et al., 1996) & & & & & & & & & \\ \hline Human fingers and upper forearm [74] & Tactile sensation & 2.2 & 50–1000 & 50\% & 150 & 0.1 to 100 & Verbal report & Clinical study \\ ([PERSON] et al., 1995) & & & & & & & & \\ \hline Human ear [75] & Activation of & & & & & & & \\ ([PERSON] et al., 1988) & acoustic nerve & 2.5 & 125–8000 & 50\% & 1–5 & 0.05–0.1 & Verbal report & Clinical study \\ \hline Human acupuncture point [53] & Deqj sensation & 0.65 & 50 & 10\% & 1–3 (SPPA) & 1000 & Verbal report & Clinical study \\ ([PERSON] et al., 2014) & & & & & & & \\ \hline Cat ear [76] & Activation of & & & & & & & \\ ([PERSON] and [PERSON], 1978) & auditory nerve & 5 & & & & & & \\ \hline Frog Pacinian corpuscle [77] & & & & & & & & \\ ([PERSON] et al., 1977) & & & & & & & & \\ \hline \hline \end{tabular}
\end{table} 
Table 1: US neuromodulation of peripheral nerve endings. PNS: peripheral nervous system; PRF: pulse repetition frequency; DC: direct current.