Simulated auditory nerve axon demyelination alters sensitivity and response timing to extracellular stimulation

Since cochlear implant function involves direct depolarization of spiral ganglion neurons (SGNs) by applied current, SGN physiological health must be an important factor in cochlear implant (CI) outcomes. This expected relationship has, however, been difficult to confirm in implant recipients. Suggestively, animal studies have demonstrated both acute and progressive SGN ultrastructural changes (notably axon demyelination), even in the absence of soma death, and corresponding altered physiology following sensorineural deafening. Whether such demyelination occurs in humans and how such changes might impact CI function remains unknown. To approach this problem, we incorporated SGN demyelination into a biophysical model of extracellular stimulation of SGN fibers. Our approach enabled exploration of the entire parameter space corresponding to simulated myelin diameter and extent of fiber affected. All simulated fibers were stimulated distally with anodic monophasic, cathodic monophasic, anode-phase first (AF) biphasic, and cathode-phase-first (CF) biphasic pulses from an extracellular disc electrode and monitored for spikes centrally. Not surprisingly, axon sensitivity generally decreased with demyelination, resulting in elevated thresholds, however, this effect was strongly non-uniform. Fibers with severe demyelination affecting only the most peripheral nodes responded nearly identically to normally myelinated fibers. Additionally, partial demyelination (<50%) yielded only minimal increases in threshold even when the entire fiber was impacted. The temporal effects of demyelination were more unexpected. Both latency and jitter of responses demonstrated resilience to modest changes but exhibited strongly non-monotonic and stimulus-dependent relationships to more profound demyelination. Normal, and modestly demyelinated fibers, were more sensitive to cathodic than anodic monophasic pulses and to CF than AF biphasic pulses, however, when demyelination was more severe these relative sensitivities were reversed. Comparison of threshold crossing between nodal segments demonstrated stimulus-dependent shifts in action potential initiation with different fiber demyelination states. For some demyelination scenarios, both phases of biphasic pulses could initiate action potentials at threshold resulting in bimodal latency and initiation site distributions and dramatically increased jitter. In summary, simulated demyelination leads to complex changes in fiber sensitivity and spike timing, mediated by alterations in action potential initiation site and slowed action potential conduction due to non-uniformities in the electrical properties of axons. Such demyelination-induced changes, if present in implantees, would have profound implications for the detection of fine temporal cues but not disrupt cues on the time scale of speech envelopes. These simulation results highlight the importance of exploring the SGN ultrastructural changes caused by a given etiology of hearing loss to more accurately predict cochlear implantation outcomes. (C) 2018 Elsevier B.V. All rights reserved.