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Concept: Cochlea

170

To test the influence of multiple factors on cochlear implant (CI) speech performance in quiet and in noise for postlinguistically deaf adults, and to design a model of predicted auditory performance with a CI as a function of the significant factors.

Concepts: Cochlea, Hearing impairment, Cochlear implant, Implants, Otology, Models of deafness

170

Domestic dogs can suffer from hearing losses that can have profound impacts on working ability and quality of life. We have identified a type of adult-onset hearing loss in Border Collies that appears to have a genetic cause, with an earlier age of onset (3-5 years) than typically expected for aging dogs (8-10 years). Studying this complex trait within pure breeds of dog may greatly increase our ability to identify genomic regions associated with risk of hearing impairment in dogs and in humans. We performed a genome-wide association study (GWAS) to detect loci underlying adult-onset deafness in a sample of 20 affected and 28 control Border Collies. We identified a region on canine chromosome 6 that demonstrates extended support for association surrounding SNP Chr6.25819273 (p-value = 1.09×10(-13)). To further localize disease-associated variants, targeted next-generation sequencing (NGS) of one affected and two unaffected dogs was performed. Through additional validation based on targeted genotyping of additional cases (n = 23 total) and controls (n = 101 total) and an independent replication cohort of 16 cases and 265 controls, we identified variants in USP31 that were strongly associated with adult-onset deafness in Border Collies, suggesting the involvement of the NF-κB pathway. We found additional support for involvement of RBBP6, which is critical for cochlear development. These findings highlight the utility of GWAS-guided fine-mapping of genetic loci using targeted NGS to study hereditary disorders of the domestic dog that may be analogous to human disorders.

Concepts: Genetics, Cochlea, Hearing impairment, Genome-wide association study, Audiogram, Dog, Dog breed, Dog health

167

A topographical representation for frequency has been identified throughout the auditory brain in animals but with limited evidence in humans. Using a midbrain implant, we identified an ordering of pitch percepts for electrical stimulation of sites across the human inferior colliculus (IC) that was consistent with the IC tonotopy shown in animals. Low pitches were perceived by the subject for stimulation of superficial IC sites while higher pitches were perceived for stimulation of deeper sites. Interestingly, this pitch ordering was not initially observed for stimulation across the IC, possibly due to central changes caused by prior hearing loss. Daily implant stimulation for about 4 months altered the pitch percepts from being predominantly low to exhibiting the expected ordering across the stimulated IC. A presumably normal tonotopic representation may have been maintained within the IC or accessible through IC stimulation that helped form this pitch ordering perceived in higher centers.

Concepts: Nervous system, Psychology, Neuroanatomy, Brain, Human brain, Cerebral cortex, Cochlea, Sense

167

To evaluate the onset of vertigo, hearing loss and tinnitus in Ménière’s disease and the associated endolymphatic hydrops (EH) of the inner ear.

Concepts: Auditory system, Cochlea, Hearing impairment, Ear, Tinnitus, Ménière's disease, Inner ear, Endolymph

147

Background Rates of hearing preservation following surgery via middle fossa craniotomy in patients harboring tumors with unfavorable characteristics are significantly lower than for those patients with “favorable” tumors. Objectives We will present two cases both with unfavorable conditions, which underwent endoscopic-assisted middle fossa craniotomy (MFC) resection of intracanalicular vestibular schwannomas with preserved postoperative hearing. Methods Chart reviews were conducted on both patients. Their presentation, intraoperative details, and techniques, pre- and postoperative audiograms, and facial nerve outcomes are presented. Results Patient A had 5.6 × 6.8 × 13.2 mm intracanalicular tumor with unserviceable hearing (pure tone audiometry [PTA], 41; speech determination score [SDS], 47%; class D) but was blind so hearing preservation was attempted. Postoperative hearing was preserved (PTA, 47; SDS, 60%; class B). Patient B had a 5 mm round intracanalicular tumor immediately adjacent to the vestibule and cochlea without any fundal fluid present. Preoperative audiogram showed serviceable hearing (PTA, 48; SDS, 88%; class B). Postoperatively, aidable hearing was preserved (PTA, 51; SDS, 76%; class C). Conclusion Hearing preservation surgery via MFC can be enhanced with endoscopic-assisted dissection, especially in the lateral internal auditory canal. The superior optical view allows for preservation of cochlear nerve function and removal of residual tumor not otherwise seen on microscopy.

Concepts: Auditory system, Cochlea, Cranial nerves, Audiogram, Pure tone audiometry, Vestibular schwannoma, Schwannoma, Internal auditory meatus

145

To evaluate the factors that limit post-cochlear implantation (CI) speech perception in prelingually deaf children.

Concepts: Cochlea, Hearing impairment, Cochlear implant, Otology, Implantation, Deaf culture, Models of deafness, Prelingual deafness

143

A growing interest in cognitive effects associated with speech and hearing processes is spreading throughout the scientific community essentially guided by evidence that central and peripheral hearing loss is associated with cognitive decline. For the present research, 125 participants older than 65 years of age (105 with hearing impairment and 20 with normal hearing) were enrolled, divided into 6 groups according to their degree of hearing loss and assessed to determine the effects of the treatment applied. Patients in our research program routinely undergo an extensive audiological and cognitive evaluation protocol providing results from the Digit Span test, Stroop color-word test, Montreal Cognitive Assessment and Geriatric Depression Scale, before and after rehabilitation. Data analysis was performed for a cross-sectional and longitudinal study of the outcomes for the different treatment groups. Each group demonstrated improvement after auditory rehabilitation or training on short- and long-term memory tasks, level of depression and cognitive status scores. Auditory rehabilitation by cochlear implants or hearing aids is effective also among older adults (median age of 74 years) with different degrees of hearing loss, and enables positive improvements in terms of social isolation, depression and cognitive performance.

Concepts: Cognition, Gerontology, Cochlea, Hearing impairment, Cochlear implant, Otology, Audiogram, Models of deafness

130

Death of cochlear hair cells, which do not regenerate, is a cause of hearing loss in a high percentage of the population. Currently, no approach exists to obtain large numbers of cochlear hair cells. Here, using a small-molecule approach, we show significant expansion (>2,000-fold) of cochlear supporting cells expressing and maintaining Lgr5, an epithelial stem cell marker, in response to stimulation of Wnt signaling by a GSK3β inhibitor and transcriptional activation by a histone deacetylase inhibitor. The Lgr5-expressing cells differentiate into hair cells in high yield. From a single mouse cochlea, we obtained over 11,500 hair cells, compared to less than 200 in the absence of induction. The newly generated hair cells have bundles and molecular machinery for transduction, synapse formation, and specialized hair cell activity. Targeting supporting cells capable of proliferation and cochlear hair cell replacement could lead to the discovery of hearing loss treatments.

Concepts: DNA, Gene, Histone deacetylase, Stem cell, Auditory system, Cochlea, Hearing impairment, Hair cell

84

Mutation of the Gap Junction Beta 2 gene (GJB2) encoding connexin 26 (CX26) is the most frequent cause of hereditary deafness worldwide and accounts for up to 50% of non-syndromic sensorineural hearing loss cases in some populations. Therefore, cochlear CX26-gap junction plaque (GJP)-forming cells such as cochlear supporting cells are thought to be the most important therapeutic target for the treatment of hereditary deafness. The differentiation of pluripotent stem cells into cochlear CX26-GJP-forming cells has not been reported. Here, we detail the development of a novel strategy to differentiate induced pluripotent stem cells into functional CX26-GJP-forming cells that exhibit spontaneous ATP- and hemichannel-mediated Ca(2+) transients typical of the developing cochlea. Furthermore, these cells from CX26-deficient mice recapitulated the drastic disruption of GJPs, the primary pathology of GJB2-related hearing loss. These in vitro models should be useful for establishing inner-ear cell therapies and drug screening that target GJB2-related hearing loss.

Concepts: DNA, Developmental biology, Stem cell, Cochlea, Hearing impairment, Cochlear implant, Otology, Tinnitus

66

Efforts to develop gene therapies for hearing loss have been hampered by the lack of safe, efficient, and clinically relevant delivery modalities. Here we demonstrate the safety and efficiency of Anc80L65, a rationally designed synthetic vector, for transgene delivery to the mouse cochlea. Ex vivo transduction of mouse organotypic explants identified Anc80L65 from a set of other adeno-associated virus (AAV) vectors as a potent vector for the cochlear cell targets. Round window membrane injection resulted in highly efficient transduction of inner and outer hair cells in mice, a substantial improvement over conventional AAV vectors. Anc80L65 round window injection was well tolerated, as indicated by sensory cell function, hearing and vestibular function, and immunologic parameters. The ability of Anc80L65 to target outer hair cells at high rates, a requirement for restoration of complex auditory function, may enable future gene therapies for hearing and balance disorders.

Concepts: Gene, Genetics, Bacteria, Auditory system, Cochlea, Inner ear, Mouse, Organ of Corti