Neurotrophic treatment of the degenerating auditory nerve; cochlear implants in deafened guinea pigs

Abstract

To date, the cochlear implant is the most successful sensorineural prosthesis. The device consists of a small array with a number of electrodes implanted in the cochlea of profoundly hearing impaired people. Some people with an implant are able to use the telephone. Unfortunately, others hardly benefit from their cochlear implant. The large variability in the performance of cochlear implant recipients is an important motive for the research described in this thesis. A factor explaining the variability in the perceptual performance might be the degeneration of the auditory nerve that often occurs following the loss of the sensory cells in the cochlea: the hair cells. The principal aim of this thesis was to explore strategies that can prevent this degeneration. Guinea pigs were deafened with chemicals , which resulted in severe hair cell loss, a corresponding hearing loss of >55 dB, and a progressive degeneration of spiral ganglion cells (SGCs).We explored several strategies to prevent this degeneration of the auditory nerve. Chronic electrical stimulation (CES) of the cochlea was one of these strategies. CES did not affect the SGC density, nor the size and shape of the SGCs. This result indicates that frequent depolarization of SGCs as a result of electrical stimulation, does not by itself prevent degeneration of SGCs. Another strategy to prevent the degeneration of SGC was the continuous intracochlear infusion of brain derived neurotrophic factor (BDNF). This BDNF treatment was started two weeks after deafening, when degeneration of SGCs had set in. The SGC packing densities in the BDNF-treated cochleae were significantly larger than those in untreated cochleae. SGCs treated with BDNF were larger than SGCs in normal-hearing guinea pigs and the number of layers in the myelin sheath of BDNF-treated SGC was reduced as compared to the number of layers in the myelin sheath of SGCs in normal-hearing guinea pigs. These morphological changes of SGCs might be related to the rapid loss of SGCs that has been reported by others to occur after cessation of BDNF treatment. However, in contrast to these others, we demonstrated that the protective effect lasted at least two weeks after cessation of the neurotrophic treatment, and that the SGCs remained functional. This is a promising result for future clinical application of neurotrophic factors in implanted human cochleae. The cannula that was used to apply the BDNF in the experiments described above creates a possible route of access for bacteria and therefore we explored a new route of delivery. We demonstrated that when BDNF was delivered on the round window of the cochlea with an absorbable gelatin sponge, the rate of degeneration of SGCs in the basal turn of the cochlea was reduced. This result is promising because this mode of application of neurotrophins is clinically safer. In our last experiment we developed a behavioral model that can be used to demonstrate that deafened guinea pigs are able to detect electric pulse trains. Such a model is helpful to investigate whether preserving SGCs from degeneration affects the detection of electric pulse trains.