Table 3.
Ultrasonic neuromodulation peripheral nervous system (PNS) studies
| Study | Organism & target | Key findings | Safety |
|---|---|---|---|
| Lee et al. (2014) | Human (Fingertip) | Induction of different peripheral sensations (thermal, vibrotactile and nociception) depending on US parameters. CW did not induce sensations. Thermal responses maximum over a band of intensities (Isppa = 10–30 Wcm−2), whereas for vibrotactile and nociception, response rate increased with intensity. Greater response rate at 350 kHz than 650 kHz. | No short-term or long-term tissue damage to insonified finger. |
| Legon et al. (2012) | Human (Fingertip) | US induced evoked potentials similar to other stimulus modalities. The waveform can be adjusted to preferentially stimulate different fibers (Aβ, Aδ and C) and the subsequent somatosensory neural circuits as confirmed by fMRI. | – |
| Dickey et al. (2012) | Human (Fingertip) | Sigmoidal response rate with increasing intensity. High specificity (participants ability to determine when US applied) indicates unique tactile sensations induced by US. Response correlates with density of mechanoreceptors. | No psychological or physiologic changes (assessed by questionnaire). |
| Gavrilov et al. (1977a) | Human (Hand, forearm) | Increasing intensity: Tactile, temperature and, finally, pain sensations. At deeper targets, only pain elicited. Longer stimuli (>100 ms), sensations present at start and end of waveform. Temperature sensations dependent on temperature of water bath that hand is immersed in. Cavitation detected before onset of pain sensations. | – |
| Downs et al. (2018) | Mouse (Sciatic nerve) | EMG activity and visible muscle activation for p > 3.2 MPa and BDC > 35%. A break period of 20–30 s improved the next stimulation success rate to 92%. Latencies similar to electrical stimulation. | Histology: no damage detected for successful US stimulation parameters or negative control groups. Damage observed for positive control (5.4 MPa, 90% BDC, 1 kHz PRF, 0.5 s BD) and for PL > 30 ms at 5.7 MPa. |
| Casella et al. (2017) | Rat (Posterior tibial nerve) | Inhibition of rhythmic bladder contractions. Longer latency and refractory periods compared with electrical stimulation. | – |
| Ni et al. (2016) | Rat (Sciatic nerve) | Improved regeneration and functional recovery following crush injury. BDNF levels increased for first 2 wk following treatment. | – |
| Juan et al. (2014) | Rat (Vagus nerve) | Decrease in electrically evoked CAPs; effect increased in magnitude with Ispta. Decrease in conduction velocities. | – |
| Tych et al. (2013) | Rat (Sciatic nerve) | US threshold for paw withdrawal reduced for neuropathic tissue compared with sham surgery tissue. | – |
| Kim et al. (2012) | Rat (Abducens nerve) | Eyeball movement. | Histology (H&E, trypan blue): no damage or BBB disruption. |
| Foley et al. (2008) | Rat (Sciatic nerve) | Increased reduction in CMAPs with intensity. CMAP amplitude recovered by 28 d in all but highest intensity, which showed no recovery. | Histology: increased levels of damage as intensity increased up to complete axonal degeneration and necrosis. |
| Ellisman et al. (1987) | Rat (Dorsal nerve roots) | Electron microscope: morphologic changes in rats at myelination development stage (3–5 d old)—enlargement of periaxonal space, abnormal morphology of nodes of Ranvier and demyelination. | See results. |
| Gavrilov (1984) | Various | Human: skin receptors, threshold value dependent on density of receptors distributed on skin surface. Perception of 400 ms pulse the same as two spaced 10 ms pulses. Use of US for diagnosis of neurologic diseases based on tactile sensation response. Skate fish: stimulation of electroreceptors only achieved with pulsed US and not CW. | – |
| Gavrilov et al. (1977b) | Cat (Pacinian corpuscle), Frog (Ear labyrinth) | APs induced in Pacinian corpuscle for intensities in range 0.1–4.2 Wcm−2. Amplitude of receptor potentials increased with intensity. Evoked potentials in frog auditory brain at intensities as low as 0.01 W cm−2 similar in shape to sonic stimuli. | – |
| Lele (1963) | Cat, Monkey, Human, Earthworm. | Progressive US dose leads to initial AP amplitude enhancement, then reversible and finally irreversible depression. Conduction velocities increase with dose. Physiologic effects reproduced by heat application. | Enhancement/reversible depression: undistinguishable from unirradiated nerves. Irreversible depression: nodularity, fragmentation of axis cylinders restricted to irradiated section of nerve (indistinguishable from heat damage). Prolonged, intense US irradiation without rise in nerve surface temperature without apparent physiologic and anatomic effects. |
| Young and Henneman (1961) | Cat (Saphenous nerve) | Differential blocking of mammalian nerves. C-fibers most responsive. A-a least sensitive. Reversible and then permanent block with increasing US dose. | – |
| Wahab et al. (2012) | Earthworm (Giant Axon) | Cumulative ARF negatively correlated to reduction in conduction velocity and AP amplitude. At low impulses, enhancement in amplitude before dropping at longer exposure times. Final changes semi-permanent: no recovery within 15 min. | Semi-permanent effects in reduction of AP amplitudes following repeated single pulse sonications 100 times a second for over 200 s. |
| Wright et al., 2017, Wright et al., 2015) | ex vivo: Crab (Leg nerve axon) | Unpredictable responses with slight preference for first stimulus. Lowest intensity for successful stimulation was 100 Wcm−2 (1.8 MPa) at 0.67 MHz. No responses at 1.1 or 2 MHz. Cavitation signals detected for all successful stimuli; afterdischarge at 230 Wcm−2 resulting in reduced CAPs – probably due to cavitation-induced membrane rupture. | |
| Colucci et al. (2009) | ex vivo: Bullfrog (Sciatic nerve) | 1.986 MHz: reduction in CAP amplitude, thermal effect matched by experiments varying water bath temperature. 0.661 MHz: discrepancy with thermal effects. Pulsed US: initial small increase in CAP then reduction. | Histology (H&E): 1.986 MHz, little or no damage consistent with thermal effects. 0.661 MHz, varying levels of damage depending on intensity. At higher intensities evidence of cavitation. |
| Tsui et al. (2005) | ex vivo: Bullfrog (Sciatic nerve) | Increased conduction velocity with power. Amplitude increased by 9% at 1 W but then decreased at higher powers. | – |
| Schelling et al. (1994)* | ex vivo: Frog (Sciatic nerve) | CAPs generated similar in shape but lower in amplitude than electrically induced CAPs. Movement away from the focus prevented CAP generation until air bubbles where added. | – |
| Mihran et al. (1990) | ex vivo: Frog (Sciatic nerve) | Latency of applied US results in different responses: enhancement or suppression of electrically induced CAP. Required BD to induce response reduced as intensity increases. | – |
| Fry et al. (1950) | ex vivo: Crayfish (Ventral nerve) | Increased spiking and then reversible depression of spontaneous activity. | – |
⁎
Shock wave source.
AP = action potential; ARF = acoustic radiation force; BBB= blood–brain barrier; BD = burst duration; BDC = burst duty cycle; BDNF = brain-derived neurotrophic factor; CAP = compound action potential; CMAP = compound muscle action potential; CW = continuous wave; EMG = electromyography; fMRI = functional magnetic resonance imaging; Ispta= spatial-peak, temporal-averaged intensity; H&E = hematoxylin and eosin (staining); p = pressure (peak instantaneous); PL = pulse length; PRF = pulse repetition frequency.