Development and validation of a computational method to predict unintended auditory brainstem response during transcranial ultrasound neuromodulation in mice
Mi Hyun Choi, Ningrui Li, Gerald Popelka, Kim Butts Pauly
Brain Stimulation 2023, 16, 1362-1370 · 10.1016/j.brs.2023.09.004
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 (R 2 = 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.
Abstract via europepmc.
Exposures
Exposure 1: TUS parameter sweep to right sensorimotor cortex (ABR characterisation)
Target: sensorimotor cortex — “right sensorimotor cortical region”
Device: Olympus / Panametrics · Olympus · V301-SU ✓
| Waveform | continuous, pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | not reported | ⚑ |
| Pulse repetition frequency (Hz) | 130, 250, 500, 1,500, 8,000, 16,000swept | ✓✓✓ |
| Duty cycle (%) | 50, 100swept | ✓✓✓⚑ |
| Sonication duration (s) | 0.08 | ✓✓✓ |
| Free-field pressure (kPa) | 120, 180, 240, 310, 480, 560swept | ✓✓✓⚑ |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reported | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported |
All TUS signals were 80 ms long with 5 s intervals between sonications. Nineteen modulation conditions were tested in four groups: (1) rectangular-envelope continuous waves at four pressure amplitudes (prms 0.085-0.22 MPa); (2) continuous waves with a smoothed (Tukey-windowed) onset/offset ramp of 2-40 ms at constant prms=0.17 MPa; (3) pulsed rectangular waveforms at 50% duty cycle with PRF varied 0.5-16 kHz at constant prms=0.17 MPa; (4) pulsed sinusoidally-smoothed waveforms (100% duty cycle, double-sideband) with a 12 ms overall ramp and sinusoidal PRF varied 0.13-16 kHz at constant prms=0.17 MPa. Eight mice received 260 repetitions of 14 waveforms, and two further groups of four mice each received 260 repetitions of 4 other waveforms.
Flags from extraction
exposures[0].free_field.pressure_kpa— Paper lists 19 modulation conditions across 4 waveform categories (rectangular CW amplitude sweep, smoothed-ramp CW, pulsed rectangular PRF sweep, pulsed sinusoidal PRF sweep); only the rectangular-envelope amplitude sweep (4 values, quotable together) is recorded numerically here. Ramp durations, the smoothed-waveform amplitudes (Eq. 4), and the sinusoidal PRF sweep (0.13-16 kHz) are described only in protocol_description because no single contiguous sentence states them together.exposures[0].timing.duty_cycle_pct— Duty cycle differs by waveform sub-type: 50% for the pulsed rectangular condition (recorded) vs 100% for the pulsed sinusoidal condition (see protocol_description); no single quotable value covers both.exposures[0].timing.pulse_duration_ms— Individual pulse duration for the pulsed rectangular/sinusoidal waveforms could be derived from PRF and duty cycle but is not itself stated in the text; left not_reported per the burst rule rather than computed.auditory_control— This study is itself a characterisation of the TUS-evoked auditory confound (ABR); no masking or other auditory control condition was used, only parametric variation of the TUS waveform.