Modeling the response of small myelinated axons in a compound nerve to kilohertz frequency signals

Abstract

Objective There is growing interest in electrical neuromodulation of peripheral nerves, particularly autonomic nerves, to treat various diseases. Electrical signals in the kilohertz frequency (KHF) range can produce different responses, including conduction block. For example, EnteroMedics’ vBloc® therapy for obesity delivers 5 kHz stimulation to block the abdominal vagus nerves, but the mechanisms of action are unclear. Approach We developed a two-part computational model, coupling a three-dimensional finite element model of a cuff electrode around the human abdominal vagus nerve with biophysically-realistic electrical circuit equivalent (cable) model axons (1, 2, and 5.7 μm in diameter). We developed an automated algorithm to classify conduction responses as subthreshold (transmission), KHF-evoked activity (excitation), or block. We quantified neural responses across kilohertz frequencies (5 to 20 kHz), amplitudes (1 to 8 mA), and electrode designs. Main results We found heterogeneous conduction responses across the modeled nerve trunk, both for a given parameter set and across parameter sets, although most suprathreshold responses were excitation, rather than block. The firing patterns were irregular near transmission and block boundaries, but otherwise regular, and mean firing rates varied with electrode-fibre distance. Further, we identified excitation responses at amplitudes above block threshold, termed “re-excitation”, arising from action potentials initiated at virtual cathodes. Excitation and block thresholds decreased with smaller electrode-fibre distances, larger fibre diameters, and lower kilohertz frequencies. A point source model predicted a larger fraction of blocked fibres and greater change of threshold with distance as compared to the realistic cuff and nerve model. Significance Our findings of widespread asynchronous KHF-evoked activity suggest that conduction block in the abdominal vagus nerves is unlikely with current clinical parameters. Our results indicate that compound neural or downstream muscle force recordings may be unreliable as quantitative measures of neural activity for in vivo studies or as biomarkers in closed-loop clinical devices.

High-Resolution Multi-Scale Computational Model for Non-Invasive Cervical Vagus Nerve Stimulation

“…We developed an approach whereby we modeled rheobase thresholds, namely the response to a long duration pulse. This allowed us, as a first approximation, to remove considerations of neuron dynamics and stimulation train parameters such a number, pulse shape, frequency, and duty‐cycle which while important would incur a large set of additional fiber specific parameterizations —whereas our focus was to address the role of tissue modeling. The assumption also supports future efforts to optimize stimulation approaches leveraging linearity (see “Discussion” section).…”

Electrophysiology equipment for reliable study of kHz electrical stimulation

“…Yet, how neurons respond to kHz frequencies remains an open question (Pelot et al . ; Crosby et al . ; Dmochowski and Bikson, ; Li et al .…”

“…kHz fluctuations in membrane potential) are of interest (Pelot et al . ); and (4) when interactions between equipment and the body introduce complex distortions (Neuling et al . ; Noury and Siegel, ; Gebodh et al .…”

The cholinergic anti‐inflammatory pathway revisited

“…This seemingly trial and error approach to electrode placement and stimulation parameters highlight the need for robust models that integrates the type and site of electrode placement coupled with electrophysiological properties of the targeted neurons. This type of modeling has recently been applied to understanding the failure of kilohertz frequency blockade to achieve primary clinical endpoints as a therapy in obesity . Such analysis indicated that the selected parameters based on prior assumptions of electrophysiological properties of the nerve would appear to be ineffective, or could result in stimulation rather than blockade .…”

“…61 Such analysis indicated that the selected parameters based on prior assumptions of electrophysiological properties of the nerve would appear to be ineffective, or could result in stimulation rather than blockade. 61 With the use of unique electrodes, electrode placement, and stimulation parameters perhaps the variability in clinical outcomes should not be surprising. These issues remain unique challenges and opportunities for the continued development of therapeutic electroceutical device for practical application in the clinic.…”