Direct delivery of modulated kilohertz frequency waveforms enable simultaneous electrical stimulation and recording with minimal-artifact

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Abstract Objective. Kilohertz frequency waveforms have received increasing attention in the field of neuromodulation in recent years. These waveforms are frequently used to develop transcutaneous stimulation therapies, although they have also been used with implanted electrodes. While the goal is non- or minimally-invasive stimulation, an underappreciated aspect of modulated waveforms with kilohertz frequencies is the ability to remove the stimulation artifact with simple linear filters. These modulated sinusoids can be made using kilohertz frequency signals that do not overlap with the neural signal spectrum. In this work we deliver amplitude modulated kilohertz frequency waveforms directly into the brain via implanted electrodes. We refer to these waveforms as premodulated TI as they are created directly by the stimulator hardware. Approach. We performed both benchtop and in vivo experiments to study premodulated TI. Benchtop measurements investigated the role of intermodulation, a phenomenon that can generate phantom artifacts. In vivo experiments with parameter sweeps compared the evoked responses between premodulated TI and square pulses. Simulations in the NEURON environment were performed on an MRG axon model. Main results. We demonstrate that hardware-based intermodulation can be significantly reduced by using parallel stimulators and separate electrodes. We further identified another source of intermodulation, the neural amplifier. We showed that premodulated TI evokes similar neural response as conventional pulses in the single tested neural pathway. Simulation results mirrored the threshold results found in vivo. Significance. Together we present a method to stimulate neural tissue with significantly reduced hardware-based artifacts as compared to conventional pulse waveforms. This technique could open possibilities for studying direct neural responses during electrical stimulation in closed loop applications.

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