Abstract
Reversible block of nerve conduction using kilohertz frequency electrical signals has substantial potential for treatment of disease. However, the ability to block nerve fibers selectively is limited by poor understanding of the relationship between waveform parameters and the nerve fibers that are blocked. Previous in vivo studies reported non-monotonic relationships between block signal frequency and block threshold, suggesting the potential for fiber-selective block. However, the mechanisms of non-monotonic block thresholds were unclear, and these findings were not replicated in a subsequent in vivo study. We used high-fidelity computational models and in vivo experiments in anesthetized rats to show that non-monotonic threshold-frequency relationships do occur, that they result from amplitude- and frequency-dependent charge imbalances that cause a shift between kilohertz frequency and direct current block regimes, and that these relationships can differ across fiber diameters such that smaller fibers can be blocked at lower thresholds than larger fibers. These results reconcile previous contradictory studies, clarify the mechanisms of interaction between kilohertz frequency and direct current block, and demonstrate the potential for selective block of small fiber diameters.
Highlights
Implanted neural stimulation devices for the treatment of disease are widespread and typically deliver electrical signals at tens to hundreds of hertz to evoke neural activity[1,2]
Quantifying the effects of direct current (DC) offsets on block thresholds in a computational model of 5.7 μm myelinated fibers from 10 to 100 kHz revealed that non-monotonic effects of frequency on block threshold resulted from amplitude- and frequency-dependent charge imbalances (Fig. 3)
Using high-fidelity computational models and in vivo experiments, we quantified the effects of kilohertz frequency (KHF) signals with a range of charge imbalances on KHF nerve block to clarify the mechanisms of non-monotonic threshold-frequency relationships
Summary
Implanted neural stimulation devices for the treatment of disease are widespread and typically deliver electrical signals at tens to hundreds of hertz to evoke neural activity[1,2]. Generated by the instrumentation[20] which modulated the threshold-frequency relationships; this explanation is consistent with computational modeling studies of charge-imbalanced asymmetric waveforms which produced non-monotonic block t hresholds[21,22]. Those modeling results did not clarify the relative roles of charge imbalance and waveform asymmetry in determining block thresholds, and the lack of experimental data limits the relevance to in vivo applications. We conducted a comprehensive study to quantify the effects of charge imbalance, frequency, and asymmetry of KHF signals on block thresholds using computational models and in vivo experiments. Our data provide the first experimental evidence of nonmonotonic effects of frequency with charge-imbalanced waveforms, harmonize previous contradictory findings, and clarify the mechanisms of interaction between KHF and DC that can be leveraged for fiber-selective block
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