Assessment and Preservation of Auditory Nerve Integrity in the Deafened Guinea Pig

Abstract

Profound hearing loss is often caused by cochlear hair cell loss. Cochlear implants (CIs) essentially replace hair cells by encoding sound and conveying the signal by means of pulsatile electrical stimulation to the spiral ganglion cells (SGCs) which form the auditory nerve. SGCs progressively degenerate following hair cell loss, as a result of lost neurotrophic signaling from the hair cells. Degeneration of the auditory nerve may compromise the ability to hear with a CI. Therefore, the first goal of this thesis was to extend the current knowledge on this degeneration process, with emphasis on changes in functionality. To this end, normal hearing and deafened guinea pigs received a CI, and the responses of the auditory nerve to electrical stimulation (electrically evoked compound action potentials; eCAPs) were recorded. Several characteristics of the eCAP correlated well with SGC survival, suggesting that eCAP recordings in human CI users, too, may be indicative of the extent of degeneration of the auditory nerve. The ability to estimate the extent of neural loss in CI users may greatly advance current research into the effect of auditory nerve degeneration on sound perception with a CI. In animal models of severe hair cell loss, treatment with exogenous neurotrophic factors such as brain-derived neurotrophic factor (BDNF) has been shown to prevent secondary SGC degeneration. However, the functionality of the SGCs rescued by the treatment has not been properly evaluated. In order to provide a comprehensive assessment of SGC functionality after neurotrophic treatment, deafened guinea pigs were chronically implanted with an intracochlear electrode array combined with a cannula, through which BDNF was slowly infused into the cochlea over a period of four weeks. Histological analysis at the end of the treatment showed almost complete survival of SGCs; eCAP recordings indicated that SGC responsiveness to electrical stimulation was often similar to that in normal-hearing controls. In order to assess clinical practicability of BDNF treatment, the long-term effects of the four-week treatment were evaluated both at the histological and at the functional level. Sustained survival of SGCs was observed both four and eight weeks after cessation of the BDNF treatment. Moreover, near-normal SGC functionality was preserved during this eight week period as well. These findings are important for translation to clinical application, since continuous administration is impractical, and may even bring risk of tumorigenesis on the long term. In summary, the experimental work described in this thesis has led to the identification of useful electrophysiological measures with which the extent of auditory nerve degeneration can be estimated. It has additionally demonstrated that, in case of auditory nerve degeneration, treatment with neurotrophic factors prevent further degeneration, preserves the nerve’s functionality, and is clinically feasible.