Effective Ultrasonic Stimulation in Human Peripheral Nervous System

Abstract

Low-intensity ultrasound can stimulate excitable cells in a noninvasive and targeted manner, but which parameters are effective has remained elusive. This question has been difficult to answer because differences in transducers and parameters-frequency in particular-lead to profound differences in the stimulated tissue volumes. The objective of this study is to control for these differences and evaluate which ultrasound parameters are effective in stimulating excitable cells. Methods: Here, we stimulated the human peripheral nervous system using a single transducer operating in a range of frequencies, and matched the stimulated volumes with an acoustic aperture. Results: We found that low frequencies (300 kHz) are substantially more effective in generating tactile and nociceptive responses in humans compared to high frequencies (900 kHz). The strong effect of ultrasound frequency was observed for all pressures tested, for continuous and pulsed stimuli, and for tactile and nociceptive responses. Conclusion: This prominent effect may be explained by a mechanical force associated with ultrasound. The effect is not due to heating, which would be weaker at the low frequency. Significance: This controlled study reveals that ultrasonic stimulation of excitable cells is stronger at lower frequencies, which guides the choice of transducer hardware for effective ultrasonic stimulation of the peripheral nervous system in humans.

Effects of transcranial ultrasound stimulation pulsed at 40 Hz on Aβ plaques and brain rhythms in 5×FAD mice

“…Here, ultrasound stimulation with pulse repetition frequency of ~ 300 kHz was selected due to its higher efficacy in human and animal brain neuromodulation compared with other higher frequencies. Previous studies [ 32 , 33 ] have shown that neuromodulation in vivo is more effective at frequencies less than 1 MHz, especially 300 kHz, than at 1 MHz. In addition, here the tUS stimulation pulsed at 40 Hz resulted in a strong response, similar to the auditory steady-state response to the click sounds at 40 Hz [ 34 ].…”

Focused ultrasound excites action potentials in mammalian peripheral neurons in part through the mechanically gated ion channel PIEZO2

“…Ultrasound has been reported to both suppress and augment electrically evoked activity in the mammalian and invertebrate PNS ( 14 – 20 ). Notably, human psychophysical studies revealed that transdermal sonication induced somatic sensations such as touch, thermoreception, and pain, suggesting that ultrasound activates sensory neurons ( 15 , 21 – 23 ). In addition, noninvasive sonication of the mouse sciatic nerve elicited muscle activity, indicating that FUS excites motor neurons ( 24 , 25 ).…”

Controlled delivery of ultrasound through the head for effective and safe therapies of the brain

“…The successful stimulation of nerves following the RTT compensation provides a physiologically-relevant validation of the method and thus serves as a proof of concept. Notably, however, the stimulation of peripheral nerves differs significantly from stimulation of neurons in the brain 60 . Therefore, these findings should be interpreted as a physiological readout of the compensated intensity rather than a direct evidence of stimulation of neurons.…”

“…The ability of RTT and the associated hardware to stimulate nerves at depth is therefore critical for effective future treatments. Ultrasonic stimulation of neurons generally requires lower ultrasound intensities than stimulation of nerves 5,52,62 . Moreover, ultrasonic stimulation of nerves in the brain also appears to require lower stimulation intensities compared to nerves in the periphery 62 .…”

“…1,2 . The approaches have included transient 3–5 and durable 6–11 modulation of neural circuits, and the delivery of specific drugs across the intact 12–15 and transiently opened 16,17 blood-brain barrier. Unlike other noninvasive approaches, ultrasound-based approaches reach millimeter-level precision deep in the brain 18 .…”