There is evidence that ultrasound neuromodulation can become both a new therapeutic tool for the nervous system and a research technique for investigating aspects of brain function. The question of whether ultrasound could be more usefully and safely applied to treat neurological and psychological disease requires pre-clinical research in the laboratory animals which has been under considerable investigation in our group over the past years.

We have studied ultrasound neuromodulation in mice using electromyography (EMG). We first investigated the optimal ultrasound stimulation parameters, with the conclusion that continuous wave can be more effective than pulsed ultrasound, and that higher frequencies require more intensity (King et al. 2013).

We further demonstrated localization of the response by differences in EMG responses in the neck and tail when the transducer was cranially placed vs. caudally placed (King et al., 2015).

We later confirmed the frequency dependence over a wider range of frequencies and multiple transducers (Ye et al. 2016). We found that the intensity threshold for stimulation varies with the square of frequency. There are several hypothesized ultrasound physical mechanisms that could explain ultrasound neuromodulation, and the trend we observed best correlates with cavitation index as opposed to radiation force or mechanical index.

In the absence of a clear understanding of US neurostimulation mechanisms, there remains a critical need to consider alternative explanations that may undermine the possibility of a direct interaction between ultrasound stimulation and nervous system function. We have shown that the source of the auditory activation is a portion of the rectangular envelope of the US stimulus waveform that generates vibratory signals in the auditory range that propagate to the sensory cells in the cochlea. We did this, in part, by modifying the ultrasound envelope in such a way as to eliminate most if not all peripheral auditory activation yet while still maintaining the motor response. As further evidence, we took two different strains of genetically deaf mice and confirmed that they exhibited no auditory responses to sound stimuli, yet they maintained the same kind of motor responses as those seen in normal hearing mice. These points, taken together, strongly suggest that the motor response to ultrasound stimuli previously reported in rodents does not rely on activation of the auditory system and is not simply an auditory startle reflex.