Non-invasive in vivo acoustoelectric neuromodulation and its contribution to ultrasound stimulation

Non-invasive brain stimulation offers therapeutic potential without surgery, yet existing electrical approaches lack spatial precision due to the long wavelengths of electric fields. Here we demonstrate acoustoelectric neuromodulation, a nonlinear interaction between applied acoustic and electric fields that generates spatially localised, low-frequency electric fields at the ultrasound focus. Using in vitro and in vivo mouse electrophysiology, we show motor-evoked responses that depend on both the amplitude and frequency of the acoustoelectric field, with controls excluding purely acoustic or electrical origins. In vivo measurements show acoustoelectric potentials of ≈9 mV, corresponding to estimated focal electric fields of ~6 V/m at 500 kHz and 1 MPa acoustic pressure, with ~1.5 mm extrema spacing demonstrated in phantom experiments. Importantly, we identify an acoustoelectric contribution to conventional ultrasound stimulation, arising from interactions between ultrasound-induced electrical signals and propagating acoustic waves, establishing acoustoelectric neuromodulation as a distinct mechanism influencing ultrasound-based brain stimulation.