Theoretical principles underlying optical stimulation of myelinated axons expressing channelrhodopsin-2

Numerous clinical conditions can be treated by neuromodulation of the peripheral nervous system (PNS). Typical electrical PNS therapies activate large diameter axons at lower electrical stimulus thresholds than small diameter axons. However, recent animal experiments with peripheral optogenetic neural stimulation (PONS) of myelinated axons expressing channelrhodopsin-2 (ChR2) have shown that this technique activates small diameter axons at lower irradiances than large diameter axons. We hypothesized that the small-to-large diameter recruitment order primarily arises from the internodal spacing relationship of myelinated axons. Small diameter axons have shorter distances between their nodes of Ranvier, which increases the number of nodes of Ranvier directly illuminated relative to larger diameter axons. We constructed "light-axon" PONS models that included multi-compartment, double cable, myelinated axon models embedded with ChR2 membrane dynamics, coupled with a model of blue light dynamics in the tissue medium from a range of different light sources. The light-axon models enabled direct calculation of threshold irradiance for different diameter axons. Our simulations demonstrate that illumination of multiple nodal sections reduces the threshold irradiance and enhances the small-to-large diameter recruitment order. In addition to addressing biophysical questions, our light-axon model system could also be useful in guiding the engineering design of optical stimulation technology that could maximize the efficiency and selectivity of PONS.