Debating on Neural Cell Regeneration Success on Improving Hearing

Published: 2021-06-25 22:20:04
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Statement of the Problem: Recent advances in cell and neural regeneration research may soon lead to a biological cure for hearing loss. Advanced diagnostic tools will be essential for accurate application of these groundbreaking advancements in patient care. For example, the auditory brainstem response (ABR), which is generated by neural activity in response to sound, is now the primary diagnostic tool for newborn hearing screenings[3,5]. Such electrophysiological measures play a critical role in the objective assessment of hearing loss. Several studies have highlighted the significance of stimulus type in electrophysiological testing. A more frequency specific response ultimately benefits hearing aid fitting techniques. However, few of these studies have focused on the compound action potential (CAP) that is generated by portions of the auditory nerve that are below the brainstem. Also, it is still unclear whether the chirp stimulus or the traditional tone burst provides greater specificity in finding the region of inner ear activation for different frequencies. The purpose of this study is to compare the CAP activation patterns for these two types of stimuli using a specialized technique involving different bandwidths of simultaneous masking noise. The implications of this study will be critical in assessing which stimulus is most useful in identifying regions of inner ear (cochlea) damage in a clinical setting.
Background: Currently, clinical ABR testing most widely uses a transient click stimulus, which triggers neural activation across a broad range of frequencies. Several studies have compared the click ABR to the chirp ABR to identify which stimulus elicits the most prominent response[1,4,5].The chirp is thought to produce a larger response than the click stimulus because of its quick rise from low to high frequency energy. This unique design is thought to allow for simultaneous neural activation across nearly the entire cochlea.The tone burst is also used in ABR testing to obtain a more frequency-specific nerve response. However, most previous studies have only used the ABR to compare the timing and size of the neural response to clicks or tones and narrowband chirps. Rodrigues et al. (2013) found that narrowband chirps with center frequencies at .5, 1, 2, and 4 kHz exhibited higher ABR amplitudes than did tone bursts at the same frequencies, except at higher intensities. Yet, no masking paradigm was used in order to determine the pattern of neural firing.
The compound action potential (CAP), the primary component of the electrocochleography (EcoG), may be a more precise method of analyzing auditory nerve activation patterns. The CAP is a summed response of peripheral auditory neurons to acoustic stimuli[2]. Earl & Chertoff (2012) found that CAP amplitude growth (i.e., CAP activation patterns) seemed to be affected for moderate-level chirps but not for high-level chirps. Therefore, high-level stimuli could be independent of cochlear outer hair cell function, suggesting a combination of peripheral and neural pathology in patients with hearing loss. The overall goal of this study is to determine if analyzing CAP amplitude growth patterns can reveal the extent and cochlear location of auditory nerve activation of two different acoustic stimuli in animals with normal-hearing and those with noise-induced hearing loss (NIHL). The objectives of the proposed research are to determine by what means the CAP can best provide a location-specific estimate of neural activation patterns within the cochlea and if the masking noise technique can aid in identifying regions of cochlear hair cell and neural degeneration in animals with NIHL. There are two central hypotheses for this project. These hypotheses will be tested using a gerbil model in two specific aims:
Specific Aim #1 – Investigate the effects of two different stimulus types on the magnitude of the CAP response across multiple frequencies.
Amplitude growth patterns (i.e., activation patterns) of the CAP will be mapped for each stimulus at low to high levels with high-pass noise of multiple bandwidths in a group of animals with normal hearing. The first derivative of the normalized amplitude growth function yields a neural density function that is assumed to represent the distribution of nerve fibers throughout the cochlea that synchronously discharge to generate a CAP. My working hypothesis is that the narrowband chirp will elicit a higher peak neural firing density in the CAP response than will the traditional tone burst stimulus.
Specific Aim #2 – Investigate the relationship between CAPs at both low (speech-centered) and high frequencies in an animal model of NIHL.
Peak location and peak density of neural density functions for animals with NIHL will be compared to those functions for normal-hearing animals for low to high frequencies (e.g, 500-8000 Hz). My working hypothesis is that animals with NIHL will exhibit decreased peak densities, especially at low stimulus frequency locations, in comparison to normal-hearing animals.
Methods & Outcome Measures: Mongolian gerbils will be used for both specific aims. Gerbils are ideal for translational auditory research due to the overlap between their range of hearing sensitivity and that of humans. Noise exposure and CAP recording will be conducted with animals under anesthesia. The masking technique will be used to map out neural activation patterns for eight different stimulus conditions (tone bursts and narrowband chirps with center frequencies at 0.5, 2, 4, and 8 kHz) at a moderate intensity level of 60 dB pSPL. Peak location, peak density, and width of the activation patterns will be the outcome variables. The differences between these variables will be analyzed using one-way multivariate analysis of variance (MANOVA).
Anticipated Results:
A one-way MANOVA will indicate higher peak neural firing density, increased width of response, and more excitation across all frequencies in the CAP response to chirp stimuli compared to traditional tone bursts. Implications: Using narrowband chirps in conjunction with a masking technique will allow clinicians to gain more insight into sensorineural pathology in those with frequency-specific hearing loss. Furthermore, this will provide a more objective measure of the region of hearing loss during clinical assessments for hearing aid fittings.

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