Development and validation of a computational method to predict unintended auditory brainstem response during transcranial ultrasound neuromodulation in mice

Abstract

Background: Transcranial ultrasound stimulation (TUS) is a promising noninvasive neuromodulation modality. The inadvertent and unpredictable activation of the auditory system in response to TUS obfuscates the interpretation of non-auditory neuromodulatory responses. Objective: The objective was to develop and validate a computational metric to quantify the susceptibility to unintended auditory brainstem response (ABR) in mice premised on time frequency analyses of TUS signals and auditory sensitivity. Methods: Ultrasound pulses with varying amplitudes, pulse repetition frequencies (PRFs), envelope smoothing profiles, and sinusoidal modulation frequencies were selected. Each pulse's time-varying frequency spectrum was differentiated across time, weighted by the mouse hearing sensitivity, then summed across frequencies. The resulting time-varying function, computationally predicting the ABR, was validated against experimental ABR in mice during TUS with the corresponding pulse. Results: There was a significant correlation between experimental ABRs and the computational predictions for 19 TUS signals (R2 = 0.97). Conclusions: To reduce ABR in mice during in vivo TUS studies, 1) reduce the amplitude of a rectangular continuous wave envelope, 2) increase the rise/fall times of a smoothed continuous wave envelope, and/or 3) change the PRF and/or duty cycle of a rectangular or sinusoidal pulsed wave to reduce the gap between pulses and increase the rise/fall time of the overall envelope. This metric can aid researchers performing in vivo mouse studies in selecting TUS signal parameters that minimize unintended ABR. The methods for developing this metric can be adapted to other animal models.

Keywords

• Therapeutic ultrasound
• Transcranial ultrasound
• Neuromodulation
• Noninvasive
• Auditory confound
• Auditory brainstem response