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 non-invasively 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. Methods 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. Results 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. Conclusion These results support the concept that tFUS-evoked motor responses are not a result of stimulation of the peripheral auditory system.

Abstract via europepmc.

Flags from extraction

• exposures[0].timing.pulse_duration_ms — Individual tone-burst width for the pulsed envelopes (PW1.5re, PW8.0re) is not stated directly; only PRF (1.5/8.0 kHz) and duty cycle (80%) are given, and pulse width was not computed per extraction rules. For the continuous-wave envelopes (CWre, CWse) pulse_duration_ms would be null by convention, but cannot be represented separately from the pulsed envelopes' value within a single list-valued field for this single target x frequency exposure.
• exposures[0].timing.pulse_repetition_frequency_hz — The 8.0 kHz PRF value (list) is sourced from the sentence describing PW8.0re ('This signal is the same as in number 2 above except with a PRF of 8.0 kHz'), not reproduced in source_quotes; the quoted sentence covers the 1.5 kHz value.
• exposures[0].free_field.isppa_w_cm2 — Pressure was measured with a hydrophone in a degassed water tank (~2 mm from the waveguide tip), but ISPPA/ISPTA were computed using brain-tissue acoustic impedance (density 1040 kg/m3, speed of sound 1560 m/s) because 'the mouse skull has negligible attenuation for ultrasound at 500 kHz... attenuation due to the skull was ignored.' Values are recorded under free_field since they were physically measured in water; the paper's stated assumption implies these approximate in-brain values too, but no explicit in-situ number is separately restated, so in_situ is left not_reported.
• conditions — TRIOBP and Samba LOXHD1 knockout mice are genetically deaf strains used as a mechanistic control to eliminate peripheral auditory input, not a disease model of translational relevance; conditions is recorded as healthy.
• sham_type — Sham sonications used 0 W/cm2 output (transducer present, no acoustic energy delivered); classified as inactive_transducer.