Effective Temporal Envelopes for Transcranial Ultrasound Stimulation in the Absence of Auditory Peripheral Responses

Transcranial ultrasound (US) stimulation (TUS) has emerged as a promising technique for minimally invasive, localized, deep brain stimulation. However, indirect auditory effects during neuromodulation require careful consideration, particularly in experiments with rodents. One method to prevent auditory responses involves applying tapered envelopes to US bursts. However, the specific mechanisms by which these envelopes affect both auditory and nonauditory responses remain unclear. In this study, we aimed to elucidate the relationship between the temporal patterns of TUS and their effects on auditory responses.

We manipulated two key temporal parameters of the US stimulation envelope: the stimulus duration (0.05 or 1.0 ms) and the window rate of the rise/fall tapering (0%-45%); their effects were assessed using multiple experimental modalities and computational simulations. The simulations were conducted to analyze the energy spectrum of the acoustic pressure at the skull surface. Acoustic emission (AE) recordings were performed in vivo using piezoelectric sensors attached to the mouse skull. Auditory responses were evaluated in anesthetized mice by recording auditory brainstem responses (ABRs) to assess peripheral auditory activity, and local field potentials (LFPs) in the auditory cortex to assess central auditory activity. These complementary measurements enabled the differentiation between peripheral and central auditory effects based on response latencies and waveform characteristics.

We found that the energy within the audible frequency range at the skull decreased monotonically with increasing tapering window rates, as demonstrated by both simulations and AE measurements. Correspondingly, little to no peripheral auditory activity, as indicated by detectable auditory brainstem responses (ABRs), was observed within a specific range of tapering window rates and stimulation durations. Furthermore, we successfully evoked cortical activity without a detectable peripheral auditory response, using a shorter tapering window (<15%) than previously reported. Despite the absence or reduction of peripheral auditory responses, reliable cortical LFPs were still elicited, confirming that TUS can activate central auditory neurons while minimizing peripheral auditory input.

Frequency analyses from both simulation and AE recordings revealed a monotonic reduction of audible acoustic components with increased tapering. Importantly, we demonstrated that cortical activation could be achieved without substantial peripheral auditory activation.

Our findings provide a framework for optimizing temporal parameters of TUS to minimize confounding auditory effects in rodent neuromodulation studies.