2026
Neuromodulation: Technology at the Neural Interface 2026 Jul 3, doi: 10.1016/j.neurom.2026.06.469
Single-unit characterization of electrically evoked peripheral nerve entrainment failure
School of Biomedical Sciences, University of New South Wales, Sydney, NSW, Australia Neuroscience Research Australia, Sydney, NSW, Australia School of Biomedical Engineering, University of New South Wales, Sydney, NSW, Australia
Service type: Stock strains
Abstract
Objectives Evidence suggests that peripheral somatosensory nerves do not reliably entrain to electrical stimulation even at low frequencies (< 100 Hz). This is a concern for peripheral neuromodulation devices, as it may cause discrepancies between expected and actual stimulation outcomes. To study this, we investigated the relationship between single-unit peripheral nerve responses (spikes) and the duration, frequency, and amplitude of electrical stimulation. Materials and Methods Single-unit teased-fiber recordings of mechanosensitive units were obtained from Sprague Dawley rat sciatic nerves. To characterize spike entrainment failure, electrical stimulation was applied to the hindpaw at various durations, frequencies, and amplitudes. Additionally, interleaved trains of electrical and mechanical stimulus pulses were delivered to examine their interaction in generating responses. Spike response probability, spike latency, and spike amplitude were compared across stimulation conditions using linear mixed-effects regression models. To assess the ability of a standard nerve model to explain our findings, electrical stimulation was simulated in a COMSOL/NEURON McIntyre-Richardson-Grill model of myelinated fibers. Results Sustained electrical stimulation resulted in spike entrainment failure at frequencies as low as 50 Hz. Units were not uniformly affected; those with faster initial conduction velocity were more strongly affected by long-duration (5 min) electrical stimulation at 50 Hz, while slower units displayed more entrainment failure at high frequencies over shorter durations (3 s). Increased stimulation amplitude restored entrainment. Furthermore, electrical stimulation generated changes in both spike latency and amplitude and interfered with mechanically evoked activity. The standard nerve model also demonstrated entrainment failure, but the time course was dissimilar to our in vivo observations. Conclusions Our data support accounts of spike entrainment failure due to electrical stimulation in the peripheral somatosensory system. We hypothesize from our findings that initial failure of spike entrainment is related to previously reported slow axonal K+ channel activity, but progressive failure is better explained by the sodium-potassium pump conductance. This work provides important insight into mechanisms limiting the efficacy of clinical neuromodulation devices.
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