Elimination of peripheral auditory pathway activation does not affect motor responses from ultrasound neuromodulation

Abstract

Recent studies in a variety of animal models including rodents, monkeys, and humans suggest that transcranial focused ultrasound (tFUS) has considerable promise for noninvasively modulating neural activity with the ability to target deep brain structures. However, concerns have been raised that motor responses evoked by tFUS may be due to indirect activation of the auditory pathway rather than direct activation of motor circuits. In this study, tFUS-induced electromyography (EMG) signals were recorded and analyzed in wild-type (WT) normal hearing mice and two strains of genetically deaf mice to examine the involvement of the peripheral auditory system in tFUS-stimulated motor responses. In addition, auditory brainstem responses (ABRs) were measured to elucidate the effect of the tFUS stimulus envelope on auditory and motor responses. We also varied the tFUS stimulation duration to measure its effect on motor response duration. We show, first, that the sharp edges in a tFUS rectangular envelope stimulus activate the peripheral afferent auditory pathway and, second, that smoothing these edges eliminates the auditory responses without affecting the motor responses in normal hearing WT mice. We further show that by eliminating peripheral auditory activity using two different strains of deaf knockout mice, motor responses are the same as in normal hearing WT mice. Finally, we demonstrate a high correlation between tFUS pulse duration and EMG response duration. These results support the concept that tFUS-evoked motor responses are not a result of stimulation of the peripheral auditory system.

Ultrasound neuromodulation depends on pulse repetition frequency and can modulate inhibitory effects of TTX

“…We hypothesize that Sato et al observed a combined effect of direct USN and auditory effects but the direct effects were below the detection threshold of the in vivo optical system, which would primarily be sensitive to cortical activation in the living animal. This interpretation is consistent with in vivo studies in genetically deafened mice that demonstrate motor responses from transcranial ultrasound 42 . www.nature.com/scientificreports/ Role of pRf.…”

Optoacoustic brain stimulation at submillimeter spatial precision

“…Modulation of motor activity by FOC stimulation. Since ultrasound is known to modulate motor activities in vivo 5,6,17 , we next turned to the motor cortex to investigate the functional outcome of the FOC mediated neural modulation. The FOC was placed on the motor cortex based on stereotaxic coordinates and an electromyography (EMG) electrode was inserted subcutaneously and parallel to the triceps brachii muscle (Fig.…”

“…Two recent papers by the Shapiro group 12 and Lim group 13 argued that these responses could be a consequence of indirect auditory stimulation through the cochlear pathway. On the other hand, Tyler, Baccus, Shoham, Pauly, and their coworkers reported direct activation of neurons in brain slices 14 , isolated retina 15,16 , and deaf mice 17 , where no auditory circuitry is involved. A major challenge facing ultrasound neural modulation, which contributes to the mentioned controversies, is that delivery of transcranial ultrasound would inevitably go through the skull, and eventually reach the cochlea through bone transduction.…”

Radiation Force as a Physical Mechanism for Ultrasonic Neurostimulation of the Ex Vivo Retina

“…One can view stimulation of auditory or vestibular organs as being an off-focus activated brain region where low frequencies will be more effective due to their larger focal volumes as demonstrated in Figure 8. Recent research has demonstrated how to avoid auditory stimulation by smoothing the sharp edges on an 80 ms CW pulse of ultrasound, thereby eliminating the auditory brainstem response without affecting motor responses in normal hearing mice (Mohammadjavadi et al, 2019).…”

“…The direct conversion of the envelope of the stimulus to a mechanical stimulus through radiation force could explain why pulse repetition frequencies in the audible range are chosen as being more effective. In vivo researchers should address this potential confound, such as by using deafened animals, using continuous stimuli (King et al, 2014;Ye et al, 2016), or smoothing the edges of ultrasound pulses to reduce audible frequency components (Wattiez et al, 2017;Mohammadjavadi et al, 2019). Other potential confounds to direct brain stimulation in addition to the auditory system are activation of the vestibular and somatosensory systems.…”