Jaro-Journal of the Association for Research in Otolaryngology最新文献

Purpose: The stria vascularis (SV) is a secretory epithelium that maintains fluid homeostasis and generates the endocochlear potential in the cochlear duct. Multiomic studies have identified genes in the SV that could contribute to the pathogenesis of Menière's Disease (MD), a disorder defined by episodic vertigo, sensorineural hearing loss, and tinnitus. This systematic review identified genes expressed in the SV cell types (marginal, intermediate, and basal) and gap junction proteins to evaluate their pathophysiological connections to MD.

Methods: We conducted a literature search on 1293 articles relevant to MD and SV that were screened for SV genes involved in MD. Following quality assessment, 130 studies met the inclusion criteria, comprising 26 human studies, 101 animal studies, and three human-animal studies.

Results: Seven immune-related and six auditory-related genes were identified: CACNA1D, ESRRB, HGF, KCNE1, MDH1, QSOX1, and SLC12A2 (marginal cells); ACTB, TMEM176A, and TMEM176B (intermediate cells); and ACTN1, COL11A2, and GSTM1 (basal cells). Gene-set-enrichment-analysis revealed pathways involving gap-junction assembly and electrical coupling. International Mouse Phenotyping Consortium data showed Gja1 and Kcne1 knockouts have immune system abnormalities. Single-cell RNA sequencing data of the lateral wall revealed high expression of Coch, Dtna, and Prkcb in fibrocytes, Reisner's cells, and immune cells. Furthermore, TWEAK released from intermediate cells and bound to its receptor (TNFRSF12A) in the marginal cells may upregulate NF-κB inflammatory response in MD patients.

Conclusion: We hypothesize that some SV genes may contribute to the audiovestibular phenotype in MD, but most of them play a role in the altered immune response found in Sporadic MD.

Purpose: The mammalian cochlea has two types of low abundance and highly specialized inner (IHC) and outer (OHC) mechanosensory hair cells. Their malfunction or death is a common cause of congenital and acquired deafness. IHCs and OHCs exhibit different transcriptomes during development. We wondered how differences in gene expression are regulated at the chromatin level in developing IHCs and OHCs, and whether there were also differences in mRNA splicing between IHCs and OHCs.

Methods: We separately collected developing mouse IHCs and OHCs to identify their mRNAs and chromatin states. We examined their transcriptomes by bulk (full coverage) RNA-seq from six biological replicates each to reveal differences in gene expression and in alternative mRNA splicing. We also examined their chromatin conformation by bulk ATAC-seq from two biological replicates each to reveal open vs. closed promoter and enhancer elements. We then compared ATAC-seq with RNA-seq datasets to determine if differential chromatin accessibility can account for differential gene expression. Each biological replicate consists of hair cells pooled from multiple neonatal mice of both sexes.

Results: We found that developing IHCs and OHCs have differentially accessible promoters in many differentially expressed genes. This includes functional genes whose expression is incipient in neonatal hair cells but will be maintained throughout life, and developmental genes which are only expressed transiently. We also found that different mRNA isoforms result from alternative mRNA splicing and transcription start sites. Finally, our data reveals that cochlear hair cells utilize unique promoters and mRNA isoforms absent in other cell types.

Conclusion: Differential transcriptomes between developing hair cell types result from pre- and post-transcriptional mechanisms. The unique promoters and mRNA isoforms in cochlear HCs highlight the importance of elucidating transcriptomes and epigenomes of rare cell types. We provide a comprehensive resource for the identification of promoters and mRNA isoforms of genes expressed by neonatal IHCs or OHCs, which is publicly-accessible for visualization of any gene of interest at  https://igvviewer.s3.us-east-2.amazonaws.com/index.html .

Purpose: The basic principle of sensorimotor gating (SMG) relies on the ability of a weak lead stimulus (such as a pre-pulse) to inhibit a startling effect of a following, more intense, abrupt stimulus-the so-called pre-pulse inhibition (PPI) paradigm. PPI has been used for near half a century as a means to investigate psychiatric disorders in which its disruption is a surrogate for altered SMG in schizophrenia. However, the blinking response is very variable, making it a poor outcome measure at the individual level. Unlike PPI, which is regulated in the lateral globus pallidus from the basal ganglia, inhibition of the startle reflex by preceding silent gaps embedded in continuous background noise is processed in the auditory cortex, making it particularly suitable for measuring cortical responses.

Methods: Here, based on the behavioral gap-pre-pulse inhibition of acoustic startle (GPIAS) stemming from animal research in tinnitus research, we present a new sensory gating (SG) paradigm using source-localized magnetoencephalography (MEG) in 26 normal hearing healthy participants (13 females, 12 males, 1 other) with a mean age of 28.4 (SD $\pm 5.8$ ), where we expose them to various levels of sound pulses in presence or absence of preceding silent gaps embedded in broadband carrier noises of either 60 or 70 dB SPL, using various interstimulus intervals (ISI: 0, 60, 120, 240 ms).

Results: We evidence a near 72.5% (SD $\pm 15.9$ ) suppression of N1 evoked response to a pulse as high as 90 dB(A) sound pressure level (SPL) when preceded by a 50 ms long silent gap in a 60 dB(A) SPL broadband carrier noise. Cortical inhibition was greatest with 240 ms ISI between gap and pulses, and about 1.5 times larger in the right transverse temporal gyrus when compared to the left hemisphere. While merely 68% of the individuals blinked at the highest pulse levels, cortical evoked responses were found in all participants.

Conclusion: Overall, we provide evidence that SG, measured by N1 cortical response to sound pulses, is reliably inhibited by preceding gaps. We propose this paradigm as an effective method to assess auditory SG through development and aging, and potentially as a method for the diagnosis of hearing disorders like tinnitus or hyperacusis.

Tinnitus, a common auditory phenomenon, often presents with considerable between-person heterogeneity and within-person fluctuations. To understand the pathophysiological mechanisms and advance patient-centred care, it is essential to recognise these variations. Ecological Momentary Assessment (EMA) is a (close-to) real-time data collection method that offers insights into short- and long-term fluctuations of subjective symptoms and their interaction with psychological, environmental, and physiological factors. EMA applied in tinnitus research has shown promise in capturing the nuances of tinnitus experience in naturalistic settings, minimizing recall bias inherent in traditional retrospective methods. This narrative literature review aims to provide a comprehensive up-to-date picture of EMA in tinnitus research by describing previous and current applications, summarising scientific findings, and identifying research gaps by drawing lessons from adjacent mental health fields. 28 publications were identified and assigned to six different topics based on thematic and methodological matters. We highlight contributions of EMA methodology for tinnitus research such as findings on momentary and longitudinal symptom interactions, circadian rhythms, individual differences in symptom patterns and its contributions to treatment evaluation. Emerging technologies, including machine learning, are opening new avenues for personalised tinnitus understanding and management. Despite promising advances, challenges such as data reliability, participant compliance, and integration with sensor-based passive data collection remain areas for further exploration. Drawing lessons from adjacent mental health fields, we propose future directions for EMA in tinnitus research, emphasizing the integration of multimodal data, advanced analytics, and ecological validity to enhance the understanding and management of chronic tinnitus.

Purpose: Permanent hearing loss primarily results from the inability of the mammalian cochlea to replace lost inner ear hair cells. However, neonatal mice exhibit a unique capacity: isolated cochlear floor cells can efficiently proliferate in vitro and form organoids that harbor new hair cells and supporting cell populations. In this study, we isolated extracellular vesicles (EVs) from organoids and analyzed the miRNAs derived from them to identify gene regulatory elements that coordinate proliferation and regeneration.

Method: We utilized cochlear floor cells from postnatal day two mice and optimized the culture conditions to efficiently grow organoids that exhibit progenitor properties. Next, we isolated EVs from the culture media of organoids in their proliferative state. We analyzed miRNAs contained in these EVs to identify potential regulators that drive or modulate organoid cell proliferation. The miRNA sequencing data from organoid EVs were compared with miRNAs identified in EVs obtained from the culture supernatant of P2 mouse cochlear ducts.

Results: We identified 184 miRNAs in organoid EVs and 176 miRNAs in cochlear duct EVs. A total of 122 miRNAs differed more than twofold between these groups, with 12 miRNAs (10 upregulated and 2 downregulated in organoid EVs) exhibiting statistically significant differences. The target genes of these twelve differentially expressed miRNAs are associated with pathways related to pluripotent stem cell regulation, cell proliferation, ear development, and cell fate modulation. This indicates that the miRNAs in organoid-derived EVs may impact processes associated with cell proliferation and the generation of inner ear cell types.

Conclusion: Our study comprehensively inventoried miRNAs contained in EVs released by growing inner ear organoids. Our differential miRNA expression analysis provides insight into regulatory mechanisms that promote cochlear floor cell proliferation and organoid formation, which could be leveraged in miRNA-based therapeutic approaches.

Purpose: The efficacy of the Cochlear Implant (CI) in listeners with single-sided deafness (SSD) was evaluated by comparing single-ear speech perception in SSD listeners and bilateral cochlear implant listeners (BCI).

Methods: Consonant-nucleus-consonant (CNC) speech perception scores for the CI-only ear in SSD listeners (N = 55; 36 female, 19 male) were compared to single-ear performance in age and device experience-matched BCI listeners (N = 55; 29 female, 26 male). Separate analyses examined: (1) a matched ear from the BCI listeners (for sequentially implanted BCI listeners, the first-implanted ear in sequential BCI listeners, or, for simultaneously implanted BCI listeners, the ear on the same side as the CI in the matching SSD listener), and (2) the lower-performing ear across BCI listeners. Additional models included moderators such as age, time since activation, CI usage, and etiology. A final analysis compared first and second implants for sequential BCI listeners.

Results: SSD listeners showed significantly lower CNC performance after controlling for age, time since activation, CI usage, and etiology. Sequential BCI listeners exhibited significantly lower CNC performance on their second ear, compared to their first ear.

Conclusion: Speech perception with CIs is reduced in SSD listeners compared to BCI users, likely due to blocking, where the normal-hearing ear diminishes reliance on the CI. Lower performance in the second implanted ear of sequential BCI listeners also suggests greater reliance on the more experienced ear. These findings highlight the need for additional training, resources, and support to optimize CI performance in SSD listeners, despite prior evidence of positive CNC outcomes.

Purpose: The human cochlear partition (CP) at the high-frequency region features a radially wide, layered osseous spiral lamina (OSL) and a soft-tissue bridge connecting it to the basilar membrane (BM). The OSL consists of two thin bony plates separated by a cavernous space that serves as a conduit for auditory nerve fibers. We used a finite element model with two fluid chambers, incorporating novel implementations of the CP features, to study the human cochlea. Model results were compared with experimental measurements of CP motion.

Methods: Model geometrical and material properties either came from the literature or were tuned to produce a frequency-place map for the passive human cochlea and measurements of the CP velocity normalized to the stapes velocity in human cadaver temporal bones. The best frequency (BF) for the experimental measurements' seven specimens ranged from 9.5 to 14.4 kHz.

Results: The model motion results of the basal CP had similar trends to the experimentally measured results in both magnitude and phase. Sensitivity analysis studies changing material-property parameters of the nerve-fiber layer between the OSL plates produced small changes and showed negligible stress along a neutral axis compared to the outer OSL plates.

Conclusion: Our model, which incorporated human cochlear structures like the wide OSL with a layer sandwiched between the plates for auditory nerve fibers, successfully simulated CP motion, exhibiting trends that closely resembled experimental data. The relatively wide three-layered OSL structure's neutral axis may serve as a stress-free conduit for the passage of auditory nerve fibers.

Purpose: Birth cohort differences capture secular trends in population health. We aimed to determine birth cohort differences, defined by generation, in hearing-related outcomes.

Methods: Participants were from a community-based cohort study. Generation was classified according to birth year: Greatest (1901-1924), Silent (1925-1945), Baby Boom (1946-1964), Generation X (1965-1980), or Millennial (1981-1996) and Gen Z (1997-2012). Primary outcomes were audiometric hearing loss, defined as a worse ear pure-tone average (PTA) of thresholds at frequencies 0.5, 1.0, 2.0, and 4.0 kHz > 25 dB HL, and self-reported hearing difficulty, defined as a score ≥ 6 on the Revised Hearing Handicap Inventory (RHHI). Analyses focused on hearing aid use included only participants with audiometric hearing loss. We used multivariable adjusted logistic regression models to evaluate associations between generation and each outcome. Models were stratified to sex when there was evidence of effect modification.

Results: This cross-sectional study included 1554 participants (mean age 63.7 [SD 14.4] years; 56.8% female, 20.0% racial Minority). The prevalence of audiometric hearing loss, self-reported hearing difficulty, and hearing aid use (among participants with audiometric hearing loss) was 48.9%, 48.8%, and 22.0%, respectively. Generation was associated with audiometric hearing loss in the entire sample and males only. Generation was not consistently associated with self-reported hearing difficulty or hearing aid use.

Conclusion: More recent generations had lower prevalence of audiometric hearing loss. There were no generational differences in self-reported hearing difficulty or hearing aid use. Secular hearing-related trends can inform accurate projections of the burden of hearing loss and health care utilization.

Purpose: Age-related hearing loss (ARHL) is one of the most prevalent conditions affecting the elderly. ARHL is influenced by a combination of environmental and genetic factors; the identification of the genes that confer risk will aid in the prevention and treatment of ARHL. The mouse and human inner ears are functionally and genetically homologous. We used Carworth Farms White (CFW) mice to study the genetic basis of ARHL because they are genetically diverse and exhibit variability in the age of onset and severity of ARHL.

Methods: Hearing at a range of frequencies was measured using auditory brainstem response (ABR) thresholds in 946 male and female CFW mice at the age of 1, 6, and 10 months. We genotyped the mice using low-coverage (mean coverage 0.27 ×) whole-genome sequencing (lcWGS) followed by imputation using STITCH. To determine the accuracy of the genotypes, we sequenced 8 samples at > 30 × coverage and used those data to estimate the accuracy of lcWGS genotyping, which was > 99.5%. We performed a genome-wide association study (GWAS) for the ABR thresholds for each frequency at each age, and we also performed a GWAS for age at deafness.

Results: We obtained genotypes at 4.18 million single nucleotide polymorphisms (SNP). The SNP heritability for traits ranged from 0 to 42%. GWAS identified 10 significant associations with ARHL that contained potential candidate genes, including Dnah11, Rapgef5, Cpne4, Prkag2, and Nek11. Genetic ablation of Prkag2 caused ARHL at high frequencies, strongly suggesting that Prkag2 is the causal gene for one of the associations.

Conclusions: GWAS for ARHL in CFW outbred mice identified genetic risk factors for ARHL, including Prkag2. Our results will help to define novel therapeutic targets for the treatment and prevention of this common disorder.

This article reviews basic and clinical research on the human middle ear. The topics include the use of temporal bones as models of the human middle ear; the integration of mechanical measurements, clinical results and middle-ear models to direct lines of inquiry; hearing with no tympanic membrane or ossicular chain; hearing after tympanic membrane replacement; the function of the tympanic membrane; and sound conduction through the ossicular chain.