Tapered-window ultrasound stimulation directly evokes characteristic laminar responses in the mouse auditory cortex while minimizing peripheral auditory responses.

Transcranial ultrasound stimulation (TUS) is a minimally invasive technique used to modulate neuronal activity and target deep brain regions in small animal models and humans. However, TUS in small animals induces cortical responses that may be indirectly mediated via the peripheral auditory pathway rather than through direct cortical activation. Thus, this study presents a TUS method using tapered temporal envelopes to directly stimulate the auditory cortex (AC) and minimize peripheral auditory activation in small animals. We aimed to provide the minimal temporal parameters of continuous ultrasound stimuli that reduce auditory artifacts while reliably evoking localized responses in the mouse AC. We simultaneously recorded auditory brainstem responses (ABRs) and AC neural activity in normal hearing and ototoxically deafened mice. We evaluated the effects of varying the temporal envelope of continuous TUS on ABRs and cortical laminar responses. Rectangular waveforms with abrupt onset and offset edges elicited strong peripheral auditory responses in normal mice. By contrast, gradual tapering of the envelope suppressed ABRs while preserving AC activation. Notably, in ototoxically deafened mice, tapered envelope stimuli continued to evoke direct responses in the AC, indicating minimal peripheral involvement. These results demonstrate that appropriately shaping the temporal pattern of TUS enables direct stimulation of the AC with reduced peripheral activation. This approach highlights the potential of ultrasound-based neuromodulation to deliver stimulation signals directly to the cortex and influence plasticity within auditory neural circuits.