Physical mechanisms of ultrasonic neurostimulation of the retina

Focused ultrasound has been shown to be effective at stimulating neurons in vivo, ex vivo and in vitro preparations. Ultrasonic neuromodulation is the only non-invasive method of stimulation that could reach deep in the brain with high spatial-temporal resolution, and thus has potential for use in clinical applications and basic studies of the nervous system. Understanding the physical mechanism by which energy in a high acoustic frequency wave is delivered to stimulate neurons will be important to optimize this technology. Two primary candidates for a physical mechanism are radiation force, the delivery of momentum by the acoustic wave, and cavitation, oscillating gas bubbles. We imaged the isolated salamander retina during ultrasonic stimuli that drive ganglion cell activity and observed micron scale displacements consistent with radiation force. We recorded ganglion cell spiking activity with a planar multielectrode array and changed the acoustic carrier frequency across a broad range (0.5 - 43 MHz), finding that increased stimulation occurs at higher acoustic frequencies, a result that is consistent with radiation force but not cavitation. A quantitative radiation force model can explain retinal responses, and could potentially explain previous in vivo results in the mouse, suggesting a new hypothesis to be tested in vivo. Finally, we found that neural activity was strongly modulated by the distance between the transducer and the electrode array showing the influence of standing waves on the response. We conclude that radiation force is the physical mechanism underlying ultrasonic neurostimulation in the ex vivo retina, and that the control of standing waves is a new potential method to modulate these effects.