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

Abstract

Background: 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. Objective: In this study, we sought to examine the involvement of peripheral auditory system activation from tFUS stimulation applied to elicit motor responses. The purpose was to determine to what extent ultrasound induced auditory artifact could be a factor in ultrasound motor neuromodulation. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflicts of interest No potential conflict of interest was reported by the authors. Declaration of interest We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property. We further confirm that any aspect of the work covered in this manuscript that has involved either experimental animals or human patients has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript.

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 .…”

“…This metric only included the 24 s following the onset of ultrasound in pulsed trials to keep the total amount of pressure cycles delivered comparable (250 kilocycles in continuous wave trials, 240 kilocycles in pulsed trials). The response rate is much lower than what is reported in in vivo murine models where motor responses > 80% were found for very similar US parameters (500 kHz 80 ms pulses at 300 kPa or 2.9 W/cm 2 I SPTA ) 42 . Factors inherent to our experimental design may have contributed to these low response rates.…”

“…Continuous and pulsed wave ultrasound have been shown to elicit a wide range of neuromodulatory effects in a variety of animal models (for reviews see Tufail et al 27 and Blackmore et al 13 ). The use of pulsed bursts in the kilohertz range generates acoustic waves capable of generating auditory brainstem response in mice, which can be mitigated by using smooth amplitude windows for the modulatory wave to reduce audible frequency components 42 . The inclusion of a pulsed wave compared to continuous ultrasound was not a strong indicator for modulation success in a mouse study measuring motor responses to modulation of the motor cortex 26 .…”

Neuronavigated Repetitive Transcranial Ultrasound Stimulation Induces Long-Lasting and Reversible Effects on Oculomotor Performance in Non-human Primates

“…With these latest developments, rTUS appears to be very promising and offers a novel and competitive neurostimulation technique. When compared to rTMS, rTUS offers a higher spatial resolution ( Pinton et al, 2012 ), a larger targeting envelope ( Krishna et al, 2018 ) and the absence of noise or mechanical vibration during stimulation ( Mohammadjavadi et al, 2019 ). This technique shows promise in the non-invasive exploration of cognition with non-human primate models.…”

Transcranial Ultrasound Innovations Ready for Broad Clinical Application

“…[36] Recent animal data have shown that these can be independently modulated by transcranial ultrasound and modulations cannot be explained by pure acoustic stimulation effects. [37,38] Ultrasound brain stimulation is typically performed with single channel systems equipped with neuronavigation for individualized targeting of the patient's brain. The novel technique has two major advantages compared to existing electromagnetic brain stimulation methods, for which several clinical trials exist [39] : 1) unprecedented precision for brain area targeting (independent of patho-logical conductivity changes) and 2) access to deep brain areas, which has not been possible previously.…”