T35. Developing a mathematical model of the human peripheral myelinated axon: Effects of segmental demyelination and impaired sodium channel conductance

Abstract

Immune-mediated neuropathies affect myelinated nerve fibers, including Schwann cells, axons, and the complex array of ion-channels and other proteins in their membrane. The downstream events leading to damage or dysfunction of these structures in human neuropathies are often impossible to investigate because the available experimental methods cannot assess the consequences of a single pathophysiological mechanism and are only applicable to lower mammalian myelinated axons. Knowledge of these mechanisms is essential for the development of treatments aimed at prevention of irreversible nerve damage. The present study is a first step in the development of a complex forward mathematical model of the human peripheral myelinated axon which should incorporate all available functional knowledge on higher mammalian or human myelinated axons obtained, for instance, by patch-clamp studies. Here we assessed activation threshold for electrical stimulation and conduction behavior by focussing on segmental demyelination and sodium channel dysfunction in human motor and sensory axons. We applied an established peripheral myelinated axon model consisting of 40 nodes. To simulate human motor axons, we modified the nodal membrane dynamics to those used in human peripheral motor nerve excitability tests in the median nerve. Sensory axons were simulated by doubling the percentage of persistent sodium channels. Focal segmental demyelination was simultaneously applied on the paranodal, juxtaparanodal, and internodal regions surrounding the three middle nodes by gradually increasing myelin capacitance and conductance until conduction failure occurred. Subsequently, impaired nodal sodium channel function on the three middle nodes was simulated by gradually decreasing the nodal transient and persistent sodium conductance. Normal motor and sensory conduction velocity was approximately 53 m/s and 54 m/s. The activation threshold in the motor axon model was 2% higher than for the sensory axon model. At 70% demyelination, the motor and sensory conduction velocity dropped to 37 m/s. Conduction block occurred for both at 97% of segmental demyelination. With decreasing sodium channel conductance motor axons showed conduction block at a decrease of 94% and sensory axons at 95%. At the site of demyelination the activation threshold increased up to approximately 4-fold in motor and sensory axon model before conduction block occurred. For impaired sodium channel conductance the activation threshold increase was approximately a factor of 3. Using the longitudinal myelinated axon model, we successfully explored the increase in activation threshold and conduction slowing and block due to demyelination and decrease in sodium channel conductance.