High-frequency amplitude-modulated sinusoidal stimulation desynchronizes neural activity and enhances naturalness of evoked sensations

Abstract

Regaining sensory feedback is critical for people living with limb amputation. Electrical stimulation of sensory fibers in peripheral nerves has been shown to restore focal percepts in the missing limb. However, conventional rectangular current pulses induce sensations often described as unnatural, likely due to the synchronous and periodic nature of activity they evoke. Here we introduce a fast-oscillating amplitude-modulated sinusoidal (FAMS) stimulation waveform that desynchronizes neural activity. Using computational modeling, we show that sinusoidal waveforms evoke asynchronous and irregular firing patterns, with frequency-dependent effects. Leveraging both low- and high-frequency mechanisms, FAMS exploits membrane nonlinearities to enhance neuron-specific differences. In a feline model of peripheral nerve stimulation, FAMS evoked activity that was more asynchronous than conventional rectangular pulses, while remaining easily controllable with simple stimulation parameters. Importantly, in human experiments using noninvasive stimulation of the median nerve, participants reported that FAMS evoked more natural sensations compared to rectangular biphasic pulses in a two-alternative forced-choice task. The preference for FAMS increased at higher intensities above sensory threshold, despite intensity-matched stimulation across waveform types. These findings provide evidence that reduced synchrony in afferent recruitment translates into more naturalistic and comfortable sensory percepts. Together, our results establish FAMS as a promising biomimetic stimulation strategy with potential for clinical applications in sensory feedback restoration. One Sentence SummaryA new electrical stimulation waveform allows for evoking and controlling more naturalistic neural activity than can be achieved with traditional stimulation waveforms.