Thesis (Ed.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / 2031-01-01

Indiana University-Purdue University Indianapolis (IUPUI) / Age-related hearing loss is an acute health problem affecting people worldwide, often arising due to defects in the proper functioning of sensory hair cells in the inner ear. The apical surface of sensory hair cells contains actin-based protrusions known as stereocilia, which detect sound and head movements. Since hair cells are not regenerated in mammals, it is important to maintain the functioning of stereocilia for the life of an organism to maintain hearing ability. The actin filaments within a stereocilium are extensively crosslinked by various actin crosslinking proteins, which are important for stereocilia development and maintenance. Multiple studies have shown that the stereocilia actin core is exceptionally stable whereas actin is dynamic only at the tips of stereocilia. However, whether the actin crosslinking proteins, which are nearly as abundant as actin itself, are similarly stable or can freely move in and out of the core remains unknown. Loss or mutation of crosslinkers like plastin-1, fascin-2, and XIRP2 causes progressive hearing loss along with stereocilia degeneration while loss of espin prevents stereocilia from even developing properly. Do these phenotypes stem from an unstable stereocilia core? Does crosslinking confer stability to the core? To address these questions, we generated novel transgenic reporter lines to monitor the dynamics of actin in mice carrying fascin-2R109H mutation and espin null mice and also to study the dynamics of actin crosslinkers, in vivo and ex-vivo. We established that actin crosslinkers readily exchange within the highly stable F-actin structure of the stereocilia core. In addition, we determined that stereocilia degeneration in mice carrying fascin-2R109H mutation and espin null mice could possibly occur due to a less stable actin core. These studies suggest that dynamic crosslinks stabilize the core to maintain proper stereocilia functioning. Future work warrants understanding the reason behind the importance of dynamic crosslinks within a stable stereocilia core. Actin stability not only depends on actin crosslinkers, but also on actin filament composition as evident from distinct stereocilia degeneration and progressive hearing loss patterns in hair-cell specific knockout of actin isoforms. Although beta- and gamma- actin polypeptide sequences differ by only 14 four amino acids, whether the latter determine the unique function of each cytoplasmic actin isoform was previously unknown. Here we determined that these four critical amino acids determine the unique functional importance of beta-actin isoform in sensory hair cells. Taken together, our study demonstrates that actin cytoskeletal proteins are important for the morphogenesis and maintenance of stereocilia.

<p>Age-related hearing loss is an acute health problem affecting people worldwide, often arising due to defects in the proper functioning of sensory hair cells in the inner ear. The apical surface of sensory hair cells contains actin-based protrusions known as stereocilia, which detect sound and head movements. Since hair cells are not regenerated in mammals, it is important to maintain the functioning of stereocilia for the life of an organism to maintain hearing ability. The actin filaments within a stereocilium are extensively crosslinked by various actin crosslinking proteins, which are important for stereocilia development and maintenance. Multiple studies have shown that the stereocilia actin core is exceptionally stable whereas actin is dynamic only at the tips of stereocilia. However, whether the actin crosslinking proteins, which are nearly as abundant as actin itself, are similarly stable or can freely move in and out of the core remains unknown. Loss or mutation of crosslinkers like plastin-1, fascin-2, and XIRP2 causes progressive hearing loss along with stereocilia degeneration while loss of espin prevents stereocilia from even developing properly. Do these phenotypes stem from an unstable stereocilia core? Does crosslinking confer stability to the core? To address these questions, we generated novel transgenic reporter lines to monitor the dynamics of actin in mice carrying fascin-2R109H mutation and espin null mice and also to study the dynamics of actin crosslinkers, in vivo and ex-vivo. We established that actin crosslinkers readily exchange within the highly stable F-actin structure of the stereocilia core. In addition, we determined that stereocilia degeneration in mice carrying fascin-2R109H mutation and espin null mice could possibly occur due to a less stable actin core. These studies suggest that dynamic crosslinks stabilize the core to maintain proper stereocilia functioning. Future work warrants understanding the reason behind the importance of dynamic crosslinks within a stable stereocilia core. Actin stability not only depends on actin crosslinkers, but also on actin filament composition as evident from distinct stereocilia degeneration and progressive hearing loss patterns in hair-cell specific knockout of actin isoforms. Although beta- and gamma- actin polypeptide sequences differ by only 14 four amino acids, whether the latter determine the unique function of each cytoplasmic actin isoform was previously unknown. Here we determined that these four critical amino acids determine the unique functional importance of beta-actin isoform in sensory hair cells. Taken together, our study demonstrates that actin cytoskeletal proteins are important for the morphogenesis and</p> <p>maintenance of stereocilia.</p>

Word recognition is based on the complex interplay of bottom up processing of acoustic input and corresponding top-down processing based on linguistic redundancies (i.e., contextual cues). Friedrich and Kotz (2007) investigated the timeline of integrating top-down and bottom-up processes among young adults with normal hearing using sentences presented in quiet. As a follow-up study, also with young adults with normal hearing (Experiment 1 of this dissertation), we used sentences embedded in multi-talker background noise and found similar results to Friedrich and Kotz (2007); but, with the use of principal component analysis (PCA) unveiled additional effects of phonological and semantic integration of spoken sentences presented in background noise. These past studies provide evidence of the time course of bottom-up and top-down mechanisms among young adult listeners in quiet and in noise; however, it is unknown if a similar pattern would be present among older adult listeners, which was the primary goal of the dissertation. In Experiment 2, we aimed to elucidate the time-course, and behavioral and neural correlates of word recognition primed by speech-in-noise in older adults with near normal hearing (i.e., thresholds ≤ 25 dB-HL through 3000 Hz and minimal high frequency hearing loss). Older adults often report difficulty understanding speech in the presence of background noise. Degradation in peripheral and central auditory processing along with age-related cognitive decline has been hypothesized as reasons why older adults struggle in the presence of noise.

Age-related declines in hearing abilities are common and can be attributed to changes in the peripheral and central levels of the auditory system. Although central auditory processing is enhanced in younger musicians, the influence of lifelong musicianship on age-related decline in central auditory processing has not yet been investigated. Therefore, the purpose of this dissertation was to investigate whether lifelong musicianship can mitigate age-related decline in central auditory processing. In the first experiment, age-related declines on four hearing assessments were compared between musicians and non-musicians. Speech-in-noise and gap-detection thresholds were found to decline at a slower rate in musicians, providing an increasing advantage with age. Furthermore, musicians had a lifelong advantage in detecting a mistuned harmonic, although the rate of age-related decline was similar for both musicians and non-musicians. Importantly, there was no significant effect of musicianship on pure-tone thresholds, suggesting that lifelong musicianship can mitigate age-related decline in central but not peripheral auditory processing. To test this hypothesis, a second experiment compared auditory evoked responses (AERs) between groups of older and younger musicians and non-musicians. Results indicated that exogenous neural activity was enhanced in musicians, but that age-related changes were similar between musicians and nonmusicians. Furthermore, endogenous, attention-dependent neural activity was enhanced in older adults, suggesting a compensatory cognitive strategy. Importantly, endogenous activity was preferentially enhanced in older musicians, suggesting that lifelong musicianship enhanced cognitive processes related to auditory perception. In the final experiment, the ability to segregate simultaneous sounds was tested in older and younger musicians and non-musicians by using a mistuned harmonic paradigm, where AERs to harmonic complexes were compared to AERs when one of the harmonics was mistuned. Results indicated that musical training in older adults has little effect on early automatic registration of the mistuned harmonic. In contrast, late attention-dependent activity, associated with the perception of the mistuned harmonic as a separate sound, was influenced by musical training in older adults, suggesting that lifelong musicianship preserves or enhances cognitive components of concurrent sound segregation. In summary, musical training was found to reduce age-related decline in hearing abilities due to enhanced central processing of auditory information.

Age-related declines in hearing abilities are common and can be attributed to changes in the peripheral and central levels of the auditory system. Although central auditory processing is enhanced in younger musicians, the influence of lifelong musicianship on age-related decline in central auditory processing has not yet been investigated. Therefore, the purpose of this dissertation was to investigate whether lifelong musicianship can mitigate age-related decline in central auditory processing. In the first experiment, age-related declines on four hearing assessments were compared between musicians and non-musicians. Speech-in-noise and gap-detection thresholds were found to decline at a slower rate in musicians, providing an increasing advantage with age. Furthermore, musicians had a lifelong advantage in detecting a mistuned harmonic, although the rate of age-related decline was similar for both musicians and non-musicians. Importantly, there was no significant effect of musicianship on pure-tone thresholds, suggesting that lifelong musicianship can mitigate age-related decline in central but not peripheral auditory processing. To test this hypothesis, a second experiment compared auditory evoked responses (AERs) between groups of older and younger musicians and non-musicians. Results indicated that exogenous neural activity was enhanced in musicians, but that age-related changes were similar between musicians and nonmusicians. Furthermore, endogenous, attention-dependent neural activity was enhanced in older adults, suggesting a compensatory cognitive strategy. Importantly, endogenous activity was preferentially enhanced in older musicians, suggesting that lifelong musicianship enhanced cognitive processes related to auditory perception. In the final experiment, the ability to segregate simultaneous sounds was tested in older and younger musicians and non-musicians by using a mistuned harmonic paradigm, where AERs to harmonic complexes were compared to AERs when one of the harmonics was mistuned. Results indicated that musical training in older adults has little effect on early automatic registration of the mistuned harmonic. In contrast, late attention-dependent activity, associated with the perception of the mistuned harmonic as a separate sound, was influenced by musical training in older adults, suggesting that lifelong musicianship preserves or enhances cognitive components of concurrent sound segregation. In summary, musical training was found to reduce age-related decline in hearing abilities due to enhanced central processing of auditory information.

People with presbyacusis commonly report difficulties in conversation in everyday settings. Although previous research has focused on self-report inventories concerning conversation difficulties in age related hearing difficulties, there is a lack of published work describing the interactions between people with presbyacusis and their conversational partners. The aim of this study is to describe conversational interactions between people with presbyacusis and their main everyday conversational partner and to determine whether there is evidence of change in interaction before and after the fitting of hearing aids. Ten participants recruited from a larger cohort were included in this study, consisting of 5 participants with diagnosed presbyacusis and 5 frequent conversation partners. A battery of audiological assessments was completed for each participant with presbyacusis. Each participant with presbyacusis was videotaped in conversation at home with their main everyday conversational partner: once before hearing aid fitting and once two months following hearing aid fitting. The conversational interactions before and after hearing aid fitting were analysed using Conversation Analysis. The results of the study revealed that both the people with presbyacusis and the conversation partners used patterns of interaction in instances of mishearings in conversation. The person with presbyacusis shifted gaze direction to show a need for repair. In addition, the conversation partner used physical prompting to gain gaze directed attention from the person with presbyacusis. The person with presbyacusis also made verbal requests for a repair as a result of mishearings. These patterns in interaction showed co-ordination and timing of the repair recognition, initiation and completion by both parties. The phenomena uncovered in this study indicate that the responsibility to monitor and maintain conversation was increasingly placed on the conversation partner of the person with presbyacusis. This could explain why people with presbyacusis and their conversation partners frequently complain of frustration in conversation activities. In the postamplification conversations, no mishearings occurred, suggesting a trend towards fewer mishearings on conversation as a result of amplification of hearing. The research findings contribute to the evidence base concerning the real benefit of digital hearing aids to these elderly clients. The findings of this study can be used to design assessment and intervention tools in the future. / Dissertation (M (Communication Pathology))--University of Pretoria, 2007. / Speech-Language Pathology and Audiology / M (Communication Pathology) / Unrestricted

A hearing impairment is primarily diagnosed by measuring the hearing thresholds at a range of auditory frequencies (air-conduction audiometry). Although this clinical procedure is simple, affordable, reliable and fast, it does not offer differential information about origins of the hearing impairment. The main goal of this thesis is to quantitatively link specific cochlear pathologies to certain changes in the spectral and temporal characteristics of the auditory system. This can help better understand the underlying mechanisms associated with sensorineural hearing impairments, beyond what is shown in the audiogram. Here, an electromechanical signal-transmission model is devised in MATLAB where the parameters of the model convey biological interpretations of mammalian cochlear structures. The model is exploited to simulate the cell-level cochlear pathologies associated with two common types of sensorineural hearing impairments, 1: presbyacusis (age-related hearing impairment) and, 2: noise-induced hearing impairment. Furthermore, a clinical study, consisting of different psychoacoustic and physiological tests, was performed to trace and validate the model predictions in human. The results of the clinical tests were collated and compared with the model predictions, showing a reasonable agreement. In summary, the present model provides a biophysical foundation for simulating the effect of specific cellular lesions, due to different inner-ear diseases and external insults, on the entire cochlear mechanism and thereby on the whole auditory system. This is a multidisciplinary work in the sense that it connects the ‘biological processes’ with ‘acoustic modelling’ and ‘clinical audiology’ in a translational context.

Auditorische Synaptopathien verursachen sensorineurale Schwerhörigkeit unterschiedlicher Ausprägung. Dabei sind sowohl erworbene, als auch angeborene Formen bekannt. Eine häufige Form ist die rezessive, nichtsyndromale Taubheitsform DFNB9, die auf einer Mutation des für Otoferlin kodierenden Gens beruht. Otoferlin ist ein Transmembranprotein, das essentiell für die stimulusabhängige Transmitterausschüttung an der Bändersynapse der Haarzellen ist . Um die Prognose von Patienten mit auditorischen Synaptopathien einschätzen zu können, ist es wichtig, den zeitlichen Verlauf der neuronalen Degeneration zu kennen. Aufgrund des Fehlens von protektiven Mittelohr und olivocochleären Reflexen könnte zusätzlich eine erhöhte Lärmempfindlichkeit bestehen, die einen frühen Verlust der Funktion der äußeren Haarzellen begünstigen wurde. Wir haben Otoferlin-Knockout-Mäuse im Alter von 6 Tagen bis 12 Monaten untersucht und die Funktion des Corti-Organs mittels Hirnstammaudiometrie und Messung der otoakustischen Emissionen getestet. In immunhistochemischen Färbungen von Corti-Organ Präparaten wurde die Degeneration von inneren und äußeren Haarzellen, Bändersynapsen und Spiralganglienneuronen beobachtet. Weiterhin wurden bei 2 Monate alten Otoferlin-Knockout-Mäusen die Auswirkungen eines leichten oder schweren Lärmtraumas quantifiziert. Wir beobachteten bei den Mutanten eine frühere und schnellere Degeneration der inneren und äußeren Haarzellen, insbesondere in der basalen Windung der Kochlea. Die Lärmtraumaversuche zeigten keinen Unterschied in der Empfindlichkeit von Otoferlin-Knockout-Mäusen und Wildtyp-Kontrollen, so dass die Ursache des Haarzellverlustes ungeklärt bleibt. Die Zahl der Bändersynapsen war ab Beginn des Hörens auf die Hälfte reduziert und blieb dann konstant, dennoch waren Spiralganglienneurone auch bei 12 Monate alten Tieren kaum reduziert. Das lässt auf einen relativ langen Erhalt des Hörnerven schließen Wir beschrieben hier zum ersten Mal die Degeneration des Corti-Organs in Otoferlin-Knockout-Mäusen. Gleichzeitig erfolgte die systematische Quantifizierung der synaptischen Degeneration von C57BL/6-Mäusen im Zusammenhang mit deren Altersschwerhörigkeit.

Despite the preventability of noise-induced hearing loss (NIHL) a high prevalence is still reported in South African mines. The study aimed to describe the hearing of gold miners pertaining to the prevalence and degree of NIHL and effectiveness of current RSA impairment criteria to identify NIHL. The audiological data, collected between 2001 and 2008, of 57 714 mine workers were investigated in this retrospective cohort study. Data was accessed through the mine’s electronic database and exported to Microsoft Excel 2007 worksheets. Participants were categorised in terms of noise exposure (level and working years), age, race and gender. Noise exposure levels were described in terms of a specific occupation and categorized into four groups based on dosimeter data received from the mine’s noise hygienist, namely: 1) Below surface (underground) noise exposure, ≥85 dB A, classified according to the South African regulations on the daily permissible dose of noise exposure8, named Noise Group 1; 2) Surface noise exposure, ≥85 dB A, named Noise Group 2; 3) No known occupational noise exposure, named control group; and 4) Uncertain levels of noise exposure, e.g. students and trainees, named Noise Group 4. The control group was matched with participants of noise group 1 and 2 based on gender, race and age at the most recent audiogram test. Descriptive and inferential statistics were employed. Measures of central tendency and variability were used with analysis of covariance (ANCOVA) and pairwise comparisons according to Fisher’s Least Squares Differences Approach (F test). Results indicated that noise exposed groups had significantly higher prevalence of high and low frequency hearing loss than the control group. High-frequency hearing loss was also present in the control group. The greatest differences in prevalence of hearing loss were observed at 3, 4 kHz and age group 36 to 45 years. Thresholds at 8 kHz were worse than expected and decline slowed down with age. High-frequency thresholds showed a non-linear growth pattern with age with a greater decline at 2 kHz with age in the noise-exposed population compared to the control group. Hearing deteriorated more across age groups with more noise-exposed years, and this deterioration was most visible after 10 to 15 working years and at 3 kHz. Females had better hearing than males across the frequency spectrum. Black males had significantly better high-frequency hearing than white males but significantly worse low-frequency hearing than white male counterparts. PLH values showed poor correlation (through statistical analyses) with other well-accepted hearing impairment criteria. To date this was the largest study conducted on the hearing of gold miners and the sample included a very large number of black males exposed to occupational noise (N=17 933). Values supplied in distribution table format are therefore unique and contribute greatly to the knowledge base. / Thesis (PhD)--University of Pretoria, 2012. / Speech-Language Pathology and Audiology / unrestricted