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This article presents the possibility of controlling/managing the frequency selection ability of membrane-based broadband frequency sensors (MB2FS), exploiting systematic selection of membrane stiffness. MB2FS is a bio-inspired system mimicking the geometry and functionality of the basilar membrane (BM) in the mammalian cochlea. The actual BM is tapered in geometry (both length wise and thickness wise), which makes the stiffness of the membrane uniformly varied over its length. Because of varied stiffness, different locations of the BM show resonance deflection at different frequency inputs, which allow the BM to select/sense the entire sonic frequency band within its 35 mm length. While actual BM and conventional MB2FS possess homogeneous stiffness over the domain length, in this article, a comprehensive insight is provided of how the frequency selection ability of the sensors can be manipulated and controlled, predictively, using functionally graded structural stiffness. Therefore, this work is not intended to develop an artificial BM, rather is focused on developing frequency sensors inspired by the membrane stiffness of BM, which plays a vital role in the spatial selection of acoustic frequencies. The study is performed using a numerically validated predictive model developed in a semi-analytical interface to explain the effects of MB2FS stiffness variations. Based on biological occurrence of stiffness in natural BM, three functions (logarithmic, linear, and exponential) are assumed to predict the FSP. While a random sonic frequency band of 10–12 kHz is targeted in this study to demonstrate the stiffness grading principle of MB2FS, a similar process (e.g., choosing the appropriate stiffness distribution of the beam) can be used to develop both sonic and ultrasonic frequency sensors. This study presents a detailed framework of how the sensing parameters of a specific frequency band (e.g., sensing location of band start and end frequencies and membrane segment width necessary to sense the entire frequency band) are dependent on the function coefficients. Finally, a comprehensive guideline is provided to predictively determine the function coefficients for user-defined frequency selection parameters. While existing state-of-the-art only allows designing MB2FS for a specific frequency band, the work presented in this study will open the opportunity to select multiple frequency bands of an MB2FS without altering its geometric configuration. [ABSTRACT FROM AUTHOR]

Moderate noise exposure induces cochlear synaptopathy, the loss of afferent ribbon synapses between cochlear hair cells and spiral ganglion neurons, which is associated with functional hearing decline. Prior studies have demonstrated noise-induced changes in the distribution and number of synaptic components, but the dynamic changes that occur after noise exposure have not been directly visualized. Here, we describe a live imaging model using RIBEYE-tagRFP to enable direct observation of pre-synaptic ribbons in mature hearing mouse cochleae after synaptopathic noise exposure. Ribbon number does not change, but noise induces an increase in ribbon volume as well as movement suggesting unanchoring from synaptic tethers. A subgroup of basal ribbons displays concerted motion towards the cochlear nucleus with subsequent migration back to the cell membrane after noise cessation. Understanding the immediate dynamics of synaptic damage after noise exposure may facilitate identification of specific target pathways to treat cochlear synaptopathy.

Age-related hearing loss (ARHL) is a common sensory impairment with complex underlying mechanisms. In our previous study, we performed a meta-analysis of genome-wide association studies (GWAS) in mice and identified a novel locus on chromosome 18 associated with ARHL specifically linked to a 32 kHz tone burst stimulus. Consequently, we investigated the role of Formin Homology 2 Domain Containing 3 (Fhod3), a newly discovered candidate gene for ARHL based on the GWAS results. We observed Fhod3 expression in auditory hair cells (HCs) primarily localized at the cuticular plate (CP). To understand the functional implications of Fhod3 in the cochlea, we generated Fhod3 overexpression mice (Pax2-Cre+/-; Fhod3Tg/+) (TG) and HC-specific conditional knockout mice (Atoh1-Cre+/-; Fhod3fl/fl) (KO). Audiological assessments in TG mice demonstrated progressive high-frequency hearing loss, characterized by predominant loss of outer hair cells, and a decreased phalloidin intensities of CP. Ultrastructural analysis revealed loss of the shortest row of stereocilia in the basal turn of the cochlea, and alterations in the cuticular plate surrounding stereocilia rootlets. Importantly, the hearing and HC phenotype in TG mice phenocopied that of the KO mice. These findings suggest that balanced expression of Fhod3 is critical for proper CP and stereocilia structure and function. Further investigation of Fhod3 related hearing impairment mechanisms may lend new insight towards the myriad mechanisms underlying ARHL, which in turn could facilitate the development of therapeutic strategies for ARHL.

Our sense of hearing is mediated by cochlear hair cells, of which there are two types organized in one row of inner hair cells and three rows of outer hair cells. Each cochlea contains 5-15 thousand terminally differentiated hair cells, and their survival is essential for hearing as they do not regenerate after insult. It is often desirable in hearing research to quantify the number of hair cells within cochlear samples, in both pathological conditions, and in response to treatment. Machine learning can be used to automate the quantification process but requires a vast and diverse dataset for effective training. In this study, we present a large collection of annotated cochlear hair-cell datasets, labeled with commonly used hair-cell markers and imaged using various fluorescence microscopy techniques. The collection includes samples from mouse, rat, guinea pig, pig, primate, and human cochlear tissue, from normal conditions and following in-vivo and in-vitro ototoxic drug application. The dataset includes over 107,000 hair cells which have been identified and annotated as either inner or outer hair cells. This dataset is the result of a collaborative effort from multiple laboratories and has been carefully curated to represent a variety of imaging techniques. With suggested usage parameters and a well-described annotation procedure, this collection can facilitate the development of generalizable cochlear hair-cell detection models or serve as a starting point for fine-tuning models for other analysis tasks. By providing this dataset, we aim to give other hearing research groups the opportunity to develop their own tools with which to analyze cochlear imaging data more fully, accurately, and with greater ease.

Tinnitus is a heritable, highly prevalent auditory disorder treated by multiple medical specialties. Previous GWAS indicated high genetic correlations between tinnitus and hearing loss, with little indication of differentiating signals. We present a GWAS meta-analysis, triple previous sample sizes, and expand to non-European ancestries. GWAS in 596,905 Million Veteran Program subjects identified 39 tinnitus loci, and identified genes related to neuronal synapses and cochlear structural support. Applying state-of-the-art analytic tools, we confirm a large number of shared variants, but also a distinct genetic architecture of tinnitus, with higher polygenicity and large proportion of variants not shared with hearing difficulty. Tissue-expression analysis for tinnitus infers broad enrichment across most brain tissues, in contrast to hearing difficulty. Finally, tinnitus is not only correlated with hearing loss, but also with a spectrum of psychiatric disorders, providing potential new avenues for treatment. This study establishes tinnitus as a distinct disorder separate from hearing difficulties.

Introduction Auditory disabilities like tinnitus and hearing loss caused by exposure to blast overpressures are prevalent among military service members and veterans. The high-pressure fluctuations of blast waves induce hearing loss by injuring the tympanic membrane, ossicular chain, or sensory hair cells in the cochlea. The basilar membrane (BM) and organ of Corti (OC) behavior inside the cochlea during blast remain understudied. A computational finite element (FE) model of the full human ear was used by Bradshaw et al. (2023) to predict the motion of middle and inner ear tissues during blast exposure using a 3-chambered cochlea with Reissner's membrane and the BM. The inclusion of the OC in a blast transmission model would improve the model's anatomy and provide valuable insight into the inner ear response to blast exposure. Materials and Methods This study developed a microscale FE model of the OC, including the OC sensory hair cells, membranes, and structural cells, connected to a macroscale model of the ear to form a comprehensive multiscale model of the human peripheral auditory system. There are 5 rows of hair cells in the model, each row containing 3 outer hair cells (OHCs) and the corresponding Deiters' cells and stereociliary hair bundles. BM displacement 16.75 mm from the base induced by a 31 kPa blast overpressure waveform was derived from the macroscale human ear model reported by Bradshaw et al. (2023) and applied as input to the center of the BM in the OC. The simulation was run for 2 ms as a structural analysis in ANSYS Mechanical. Results The FE model results reported the displacement and principal strain of the OHCs, reticular lamina, and stereociliary hair bundles during blast transmission. The movement of the BM caused the rest of the OC to deform significantly. The reticular lamina displacement and strain amplitudes were highest where it connected to the OHCs, indicating that injury to this part of the OC may be likely due to blast exposure. Conclusions This microscale model is the first FE model of the OC to be connected to a macroscale model of the ear, forming a full multiscale ear model, and used to predict the OC's behavior under blast. Future work with this model will incorporate cochlear endolymphatic fluid, increase the number of OHC rows to 19 in total, and use the results of the model to reliably predict the sensorineural hearing loss resulting from blast exposure. [ABSTRACT FROM AUTHOR]

AbstractObjectiveDesignStudy SampleResultsConclusionsTo evaluate the efficacy of sound stimulation for enhancing drug distribution in the cochlea’s perilymph, crucial for treating one of the most inaccessible organs and a major disability factor worldwide.A systematic scoping review following PRISMA guidelines was conducted, analysing studies on cochlear fluid dynamics influenced by sound stimulation. Data were collected from PubMed and Google Scholar using both MeSH and non-MeSH terms, with exclusions for unrelated topics.Thirteen studies met the inclusion criteria, providing insights into the mechanics of cochlear perilymphatic flow and its potential enhancement through sound stimulation.The review highlights two primary mechanisms capable of inducing significant perilymphatic flow from the base towards the apex: complex audible sound stimulation creating a "streaming channel" and low-frequency stimulation at high intensity. Despite the theoretical potential, the clinical applicability of these techniques remains unproven, and the safety of low-frequency, high-intensity stimulation for the cochlea and vestibular system should be demonstrated.Sound stimulation appears to be a viable method for inducing perilymphatic movements, potentially improving drug delivery to remote cochlear regions. Future research should focus on the clinical safety and efficacy of these stimulations to fully utilise this approach in therapeutic applications. [ABSTRACT FROM AUTHOR]

A spiral‐artificial basilar membrane (S‐ABM) sensor is reported that mimics the basilar membrane (BM) of the human cochlea and can detect sound by separating it into 24 sensing channels based on the frequency band. For this, an analytical function is proposed to design the width of the BM so that the frequency bands are linearly located along the length of the BM. To fabricate the S‐ABM sensor, a spiral‐shaped polyimide film is used as a vibrating membrane, with maximum displacement at locations corresponding to specific frequency bands of sound, and attach piezoelectric sensor modules made of poly(vinylidene fluoride‐trifluoroethylene) film on top of the polyimide film to measure the vibration amplitude at each channel location. As the result, the S‐ABM sensor implements a characteristic frequency band of 96‐12,821 Hz and 24‐independent critical bands. Using real‐time signals from discriminate channels, it is demonstrated that the sensor can rapidly identify the operational noises from equipment processes as well as vehicle sounds from environmental noises on the road. The sensor can be used in a variety of applications, including speech recognition, dangerous situation recognition, hearing aids, and cochlear implants, and more. [ABSTRACT FROM AUTHOR]

Sound vibrations generate electrical signals called cochlear potentials, which can reflect cochlear stereocilia movement and outer hair cells (OHC) mechanical activity. However, because the cochlear structure is delicate and complex, it is difficult for existing measurement techniques to pinpoint the origin of potentials. This limitation in measurement capability makes it difficult to fully understand the contribution of stereocilia and transduction channels to cochlear potentials. In view of this, firstly, this article obtains the stereocilia movement generated by basilar membrane (BM) vibration based on the positional relationship between the various structures of the organ Corti. Secondly, Kirchhoff's law is used to establish an electric field model of the cochlear cavity, and the stereocilia movement is embedded in the electric field by combining the gated spring model. Finally, a force-electric coupling mathematical model of the cochlea is established. The results indicated that the resistance variation between different cavities in the cochlea leads to a sharp tuning curve. As the displacement of the BM increased, the longitudinal potential along the cochlea continued to move toward the base. The decrease in stereocilia stiffness reduced the deflection angle, thereby reducing the transduction current and lymphatic potential. [ABSTRACT FROM AUTHOR]

Age‐related hearing loss (AHL) is the most common sensory disorder amongst the older population. Inflammaging is a ≈chronic low‐grade inflammation that worsens with age and is an early sign of AHL; however, the underlying mechanisms remain unclear. We used electrophysiological and genetic approaches to establish the importance of interleukin 6 (IL‐6)‐dependent inflammation in AHL. Elevated IL‐6 in the cochlea enhanced Cav1.3 calcium channel function in the inner hair cell (IHC) synapse in mice with AHL. IL‐6 upregulated the Cav1.3 channel via the Janus kinase‐mitogen activated kinase pathway, causing neurotransmitter excitotoxicity and synapse impairment; IL‐6 deficiency or the administration of a Cav1.3 channel blocker attenuated this age‐related damage, and rescued hearing loss. Thus, IL‐6‐dependent inflammaging upregulated the Cav1.3 channel in IHCs, contributing to AHL. Our findings could help the comprehensive understanding of inflammaging's effects on AHL, aiding in early intervention to protect against hearing decline. [ABSTRACT FROM AUTHOR]

In multicellular tissues, the size and shape of cells are intricately linked with their physiological functions. In the vertebrate auditory organ, the neurosensory epithelium develops as a mosaic of sensory hair cells (HCs), and their glial-like supporting cells, which have distinct morphologies and functional properties at different frequency positions along its tonotopic long axis. In the chick cochlea, the basilar papilla (BP), proximal (high-frequency) HCs, are larger than their distal (low-frequency) counterparts, a morphological feature essential for sound perception. Mitochondrial dynamics, which constitute the equilibrium between fusion and fission, regulate differentiation and functional refinement across a variety of cell types. We investigate this as a potential mechanism for regulating the shape of developing HCs. Using live imaging in intact BP explants, we identify distinct remodelling of mitochondrial networks in proximal compared with distal HCs. Manipulating mitochondrial dynamics in developing HCs alters their normal morphology along the proximal-distal (tonotopic) axis. Inhibition of the mitochondrial fusion machinery decreased proximal HC surface area, whereas promotion of fusion increased the distal HC surface area. We identify mitochondrial dynamics as a key regulator of HC morphology in developing inner ear epithelia. [ABSTRACT FROM AUTHOR]

Hair cell (HC) damage is a leading cause of sensorineural hearing loss, and in mammals supporting cells (SCs) are unable to divide and regenerate HCs after birth spontaneously. Procollagen C‐endopeptidase enhancer 2 (Pcolce2), which encodes a glycoprotein that acts as a functional procollagen C protease enhancer, was screened as a candidate regulator of SC plasticity in our previous study. In the current study, we used adeno‐associated virus (AAV)‐ie (a newly developed adeno‐associated virus that targets SCs) to overexpress Pcolce2 in SCs. AAV‐Pcolce2 facilitated SC re‐entry into the cell cycle both in cultured cochlear organoids and in the postnatal cochlea. In the neomycin‐damaged model, regenerated HCs were detected after overexpression of Pcolce2, and these were derived from SCs that had re‐entered the cell cycle. These findings reveal that Pcolce2 may serve as a therapeutic target for the regeneration of HCs to treat hearing loss. [ABSTRACT FROM AUTHOR]

Hearing loss is a health crisis that affects more than 60 million Americans. Currently, sodium thiosulfate is the only drug approved by the Food and Drug Administration (FDA) to counter hearing loss. Sirtuins were proposed as therapeutic targets in the search for new compounds or drugs to prevent or cure age-, noise-, or drug-induced hearing loss. Sirtuins are proteins involved in metabolic regulation with the potential to ameliorate sensorineural hearing loss. The mammalian sirtuin family includes seven members, SIRT1-7. This paper is a literature review on the sirtuins and their protective roles in sensorineural hearing loss. Literature search on the NCBI PubMed database and NUsearch included the keywords 'sirtuin' and 'hearing'. Studies on sirtuins without relevance to hearing and studies on hearing without relevance to sirtuins were excluded. Only primary research articles with data on sirtuin expression and physiologic auditory tests were considered. The literature review identified 183 records on sirtuins and hearing. After removing duplicates, eighty-one records remained. After screening for eligibility criteria, there were forty-eight primary research articles with statistically significant data relevant to sirtuins and hearing. Overall, SIRT1 (n = 29) was the most studied sirtuin paralog. Over the last two decades, research on sirtuins and hearing has largely focused on age-, noise-, and drug-induced hearing loss. Past and current studies highlight the role of sirtuins as a mediator of redox homeostasis. However, more studies need to be conducted on the involvement of SIRT2 and SIRT4-7 in hearing protection. [ABSTRACT FROM AUTHOR]

Objectives: Objective measurements to predict the position of a cochlear electrode during cochlear implantation surgery may serve to improve the surgical technique and postoperative speech outcome. There is evidence that electrically evoked compound action potentials (ECAP) are a suitable approach to provide information about the site of stimulation. This study aims to contribute to the knowledge about the association between the intraoperative intracochlear ECAP characteristics and the site of stimulation. Methods: In a retrospective cohort study, patients undergoing cochlear implant surgery with flexible lateral wall electrode arrays (12 stimulating channels) between 2020 and 2022 were analyzed. The CDL was measured using a CT-based clinical planning software. ECAP were measured for all electrode contacts and associated to the CDL as well as to the site of stimulation in degree. Results: Significant differences among the amplitudes and slopes for the individual stimulated electrode contacts at the stimulation sites of 90°, 180°, 270°, 360°, 450° and 540° were found. The values showed a trend for linearity among the single electrodes. Conclusions: ECAP characteristics correlate with the electrode's position inside the cochlea. In the future, ECAP may be applied to assess the intracochlear position inside the cochlea and support anatomy-based fitting. [ABSTRACT FROM AUTHOR]

Objective: Blood-labyrinthine barrier leakage has been reported in sudden sensorineural hearing loss (SSNHL). We compared immediate post-contrast 3D heavily T2-weighted fluid-attenuated inversion recovery (FLAIR), T1 spin echo (SE), and 3D T1 gradient echo (GRE) sequences, and heavily T2-weighted FLAIR (hvT2F) with and without deep learning-based reconstruction (DLR) in detecting perilymphatic enhancement. Methods: Fifty-four patients with unilateral SSNHL who underwent ear MRI with three sequences were included. We compared asymmetry scores, confidence scores, and detection rates of perilymphatic enhancement among the three sequences and obtained 3D hvT2F with DLR from 35 patients. The above parameters and subjective image quality between 3D hvT2F with and without DLR were compared. Results: Asymmetry scores and detection rate of 3D hvT2F were significantly higher than 3D GRE T1 and SE T1 (respectively, 1.37, 0.11, 0.19; p < 0.001). Asymmetry scores significantly increased with DLR compared to 3D hvT2F for experienced and inexperienced readers (respectively, 1.77 vs. 1.40, p = 0.036; 1.49 vs. 1.03, p = 0.012). The detection rate significantly increased only for the latter (57.1% vs. 31.4%, p = 0.022). Patients with perilymphatic enhancement had significantly higher air conduction thresholds on initial (77.96 vs. 57.79, p = 0.002) and 5 days after presentation (63.38 vs. 41.85, p = 0.019). Conclusion: 3D hvT2F significantly increased the detectability of perilymphatic enhancement compared to 3D GRE T1 and SE T1. DLR further improved the conspicuity of perilymphatic enhancement in 3D hvT2F. 3D hvT2F and DLR are useful for evaluating blood-labyrinthine barrier leakage; furthermore, they might provide prognostic value in the early post-treatment period. Clinical relevance statement: Ten-minute post-contrast 3D heavily T2-weighed FLAIR imaging is a potentially efficacious sequence in demonstrating perilymphatic enhancement in patients with sudden sensorineural hearing loss and may be further improved by deep learning-based reconstruction. Key Points: • 3D heavily T2-weighted FLAIR (3D hvT2F) is a sequence sensitive in detecting low concentrations of contrast in the perilymphatic space. • 3D hvT2F sequences properly demonstrated perilymphatic enhancement in sudden sensorineural hearing loss compared to T1 sequences and were further improved by deep learning-based reconstruction (DLR). • 3D hvT2F and DLR are efficacious sequences in detecting blood-labyrinthine barrier leakage and with potential prognostic information. [ABSTRACT FROM AUTHOR]

Auditory sensitivity and frequency resolution depend on the optimal transfer of sound‐induced vibrations from the basilar membrane (BM) to the inner hair cells (IHCs), the principal auditory receptors. There remains a paucity of information on how this is accomplished along the frequency range in the human cochlea. Most of the current knowledge is derived either from animal experiments or human tissue processed after death, offering limited structural preservation and optical resolution. In our study, we analyzed the cytoarchitecture of the human cochlear partition at different frequency locations using high‐resolution microscopy of uniquely preserved normal human tissue. The results may have clinical implications and increase our understanding of how frequency‐dependent acoustic vibrations are carried to human IHCs. A 1‐micron‐thick plastic‐embedded section (mid‐modiolar) from a normal human cochlea uniquely preserved at lateral skull base surgery was analyzed using light and transmission electron microscopy (LM, TEM). Frequency locations were estimated using synchrotron radiation phase‐contrast imaging (SR‐PCI). Archival human tissue prepared for scanning electron microscopy (SEM) and super‐resolution structured illumination microscopy (SR‐SIM) were also used and compared in this study. Microscopy demonstrated great variations in the dimension and architecture of the human cochlear partition along the frequency range. Pillar cell geometry was closely regulated and depended on the reticular lamina slope and tympanic lip angle. A type II collagen‐expressing lamina extended medially from the tympanic lip under the inner sulcus, here named "accessory basilar membrane." It was linked to the tympanic lip and inner pillar foot, and it may contribute to the overall compliance of the cochlear partition. Based on the findings, we speculate on the remarkable microanatomic inflections and geometric relationships which relay different sound‐induced vibrations to the IHCs, including their relevance for the evolution of human speech reception and electric stimulation with auditory implants. The inner pillar transcellular microtubule/actin system's role of directly converting vibration energy to the IHC cuticular plate and ciliary bundle is highlighted. [ABSTRACT FROM AUTHOR]

The sensory epithelium of the cochlea, the organ of Corti, has complex cytoarchitecture consisting of mechanosensory hair cells intercalated by epithelial support cells. The support cells provide important trophic and structural support to the hair cells. Thus, the support cells must be stiff yet compliant enough to withstand and modulate vibrations to the hair cells. Once the sensory cells are properly patterned, the support cells undergo significant remodeling from a simple epithelium into a structurally rigid epithelium with fluid‐filled spaces in the murine cochlea. Cell adhesion molecules such as cadherins are necessary for sorting and connecting cells in an intact epithelium. To create the fluid‐filled spaces, cell adhesion properties of adjoining cell membranes between cells must change to allow the formation of spaces within an epithelium. However, the dynamic localization of cadherins has not been properly analyzed as these spaces are formed. There are three cadherins that are reported to be expressed during the first postnatal week of development when the tunnel of Corti forms in the cochlea. In this study, we characterize the dynamic localization of cadherins that are associated with cytoskeletal remodeling at the contacting membranes of the inner and outer pillar cells flanking the tunnel of Corti. Key Findings: F‐actin remodeling occurs between E18.5 to P7 in the cochlear sensory epithelium.Transient changes of F‐actin cytoskeleton drives epithelial morphogenesis.Fluid‐filled spaces in epithelium is driven by changes in cell adhesion. [ABSTRACT FROM AUTHOR]

Purpose: Tone-pip-evoked otoacoustic emissions (PEOAEs) are transient-evoked otoacoustic emissions (OAEs) that are hypothesized to originate from reflection of energy near the best-frequency (BF) cochlear place of the stimulus frequency. However, individual PEOAEs have energy with a wide range of delays. We sought to determine whether some PEOAE energy is consistent with having been generated far from BF. Methods: PEOAEs from 35 and 47 dB SPL tone pips were obtained by removing pip-stimulus energy by subtracting the ear-canal sound pressure from scaled-down 59 dB SPL tone pips (which evoke relatively small OAEs). PEOAE delays were measured at each peak in the PEOAE absolute-value waveforms. While measuring PEOAEs and auditory-nerve compound action potentials (CAPs), amplification was blocked sequentially from apex to base by cochlear salicylate perfusion. The perfusion time when a CAP was reduced identified when the perfusion reached the tone-pip BF place. The perfusion times when each PEOAE peak was reduced identified where along the cochlea it received cochlear amplification. PEOAEs and CAPs were measured simultaneously using one pip frequency in each ear (1.4 to 4 kHz across 16 ears). Results: Most PEOAE peaks received amplification primarily between the BF place and 1–2 octaves basal of the BF place. PEOAE peaks with short delays received amplification basal of BF place. PEOAE peaks with longer delays sometimes received amplification apical of BF place, consistent with previous stimulus-frequency-OAE results. Conclusion: PEOAEs provide information about cochlear amplification primarily within ~ 1.5 octave of the tone-pip BF place, not about regions > 3 octaves basal of BF. [ABSTRACT FROM AUTHOR]

Presbycusis is a prevalent condition in older adults characterized by the progressive loss of hearing due to age‐related changes in the cochlea, the auditory portion of the inner ear. Many adults also struggle with understanding speech in noise despite having normal auditory thresholds, a condition termed “hidden” hearing loss because it evades standard audiological assessments. Examination of animal models and postmortem human tissue suggests that hidden hearing loss is also associated with age‐related changes in the cochlea and may, therefore, precede overt age‐related hearing loss. Nevertheless, the pathological mechanisms underlying hidden hearing loss are not understood, which hinders the development of diagnostic biomarkers and effective treatments for age‐related hearing loss. To fill these gaps in knowledge, we leveraged a combination of tools, including transcriptomic profiling and morphological and functional assessments, to identify these processes and examine the transition from hidden to overt hearing loss. As a novel approach, we took advantage of a recently characterized model of hidden hearing loss: Kcnt1/2 double knockout mice. Using this model, we find that even before observable morphological pathology, hidden hearing loss is associated with significant alteration in several processes, notably proteostasis, in the cochlear sensorineural structures, and increased susceptibility to overt hearing loss in response to noise exposure and aging. Our findings provide the first insight into the pathophysiology associated with the earliest and, therefore, most treatable stages of hearing loss and provide critical insight directing future investigation of pharmaceutical strategies to slow and possibly prevent overt age‐related hearing loss. [ABSTRACT FROM AUTHOR]

Background: Presbycusis, also referred to as age-related hearing loss (ARHL), is a condition that results from the cumulative effects of aging on an individual's auditory capabilities. Given the limited understanding of epigenetic mechanisms in ARHL, our research focuses on alterations in chromatin-accessible regions. Methods: We employed assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) in conjunction with unique identifier (UID) mRNA-seq between young and aging cochleae, and conducted integrated analysis as well as motif/TF-gene prediction. Additionally, the essential role of super-enhancers (SEs) in the development of ARHL was identified by comparative analysis to previous research. Meanwhile, an ARHL mouse model and an aging mimic hair cell (HC) model were established with a comprehensive identification of senescence phenotypes to access the role of SEs in ARHL progression. Results: The control cochlear tissue exhibited greater chromatin accessibility than cochlear tissue affected by ARHL. Furthermore, the levels of histone 3 lysine 27 acetylation were significantly depressed in both aging cochlea and aging mimic HEI-OC1 cells, highlighting the essential role of SEs in the development of ARHL. The potential senescence-associated super-enhancers (SASEs) of ARHL were identified, most of which exhibited decreased chromatin accessibility. The majority of genes related to the SASEs showed obvious decreases in mRNA expression level in aging HCs and was noticeably altered following treatment with JQ1 (a commonly used SE inhibitor). Conclusion: The chromatin accessibility in control cochlear tissue was higher than that in cochlear tissue affected by ARHL. Potential SEs involved in ARHL were identified, which might provide a basis for future therapeutics targeting SASEs related to ARHL. [ABSTRACT FROM AUTHOR]

Background: Ménière's disease is a chronic condition of the inner ear that causes vertigo, tinnitus and hearing loss. Its diagnosis relies on clinical criteria that are subjective and pure-tone audiometry results that are not specific. Its pathological substrate is endolymphatic hydrops. Its imaging was recently made possible by the late-enhanced 3D FLAIR sequence. This technique was primarily tested on 3 T. Our objective was to prove its feasibility using a 1.5 T magnet. Methods: We conducted a prospective study including 30 patients who fulfilled the Bárány society criteria for Ménière's disease. We performed the late-enhanced 3D FLAIR sequence on all patients. We used it to look for and grade endolymphatic hydrops in the utricle, the saccule and the cochlear canal using the Kahn method. Results: We found endolymphatic hydrops in all of the 30 patients who fulfilled the diagnostic criteria for Ménière's disease. We had no false positives and only one false negative with a patient presenting with bilateral disease clinically but having endolymphatic hydrops only on one side. Thus, our correspondence rate between clinical and imaging findings was 97%. Conclusions: It is possible to diagnose endolymphatic hydrops with the late-enhanced 3D FLAIR sequence using a 1.5 T MRI machine. Since Ménière's disease diagnosis is sometimes tricky, imaging endolymphatic hydrops can aid in the diagnosis when the clinical picture is incomplete. It also helps guide invasive treatment plans. Feasibility at 1.5 T ensures broader access to the late-enhanced 3D FLAIR sequence. Beyond the scope of Ménière's disease, this sequence offers the possibility to better understand pressure-related inner ear diseases. [ABSTRACT FROM AUTHOR]

Irreversible damage to hair cells (HCs) in the cochlea leads to hearing loss. Cochlear supporting cells (SCs) in the murine cochlea have the potential to differentiate into HCs. Neuron membrane glycoprotein M6B (Gpm6b) as a four‐transmembrane protein is a potential regulator of HC regeneration according to our previous research. In this study, we found that AAV‐ie‐mediated Gpm6b overexpression promoted SC‐derived organoid expansion. Enhanced Gpm6b prevented the normal decrease in SC plasticity as the cochlea develops by supporting cells re‐entry cell cycle and facilitating the SC‐to‐HC transformation. Also, overexpression of Gpm6b in the organ of Corti through the round window membrane injection facilitated the trans‐differentiation of Lgr5+ SCs into HCs. In conclusion, our results suggest that Gpm6b overexpression promotes HC regeneration and highlights a promising target for hearing repair using the inner ear stem cells combined with AAV. [ABSTRACT FROM AUTHOR]

The cells presented in this work are not classified as cells that make up the immune system. They, however, present functions and molecules, which are characteristic of immune cells. These characteristic functions are, for example, sensing threat, performing phagocytosis, presentation of foreign antigens, cytokine release or enhancing immune memory. The enlisted immune response mechanisms are carried out by the possession of molecules such as Toll‐like receptors, receptors for the Fc fragment of IgG, major histocompatibility complex class II molecules, costimulatory CD80/CD86 proteins and molecules needed for NLRP3 (NOD‐like family pyrin domain containing 3) inflammasome activation. Thanks to these properties, the described nonimmune cells play an important role in the local immune response and support of the entire body in the fight against pathogens. They constitute the first line of defense of tissues and organs against pathogens and molecules recognized as harmful. The cells described in this article are particularly important in immunologically privileged places (e.g. the Bowman's capsule in the kidney), where "typical" immune cells normally do not have access. In this paper, we present immune‐like functions and molecule suites of resident kidney cells (podocytes and mesangial cells), cochlear resident cells, fibrocytes and fibroblasts, as well as some stem cells (mesenchymal stem cells and umbilical cord Wharton's jelly–derived cells). [ABSTRACT FROM AUTHOR]

Auditory processing in mammals begins in the peripheral inner ear and extends to the auditory cortex. Sound is transduced from mechanical stimuli into electrochemical signals of hair cells, which relay auditory information via the primary auditory neurons to cochlear nuclei. Information is subsequently processed in the superior olivary complex, lateral lemniscus, and inferior colliculus and projects to the auditory cortex via the medial geniculate body in the thalamus. Recent advances have provided valuable insights into the development and functioning of auditory structures, complementing our understanding of the physiological mechanisms underlying auditory processing. This comprehensive review explores the genetic mechanisms required for auditory system development from the peripheral cochlea to the auditory cortex. We highlight transcription factors and other genes with key recurring and interacting roles in guiding auditory system development and organization. Understanding these gene regulatory networks holds promise for developing novel therapeutic strategies for hearing disorders, benefiting millions globally. [ABSTRACT FROM AUTHOR]

Purpose: While cochlea is adult size at birth, etiologies and bone density may differ between children and adults. Differences in neural response thresholds (tNRT) and the spread of excitation (SOE) width may impact the use of artificial intelligence algorithms in speech processor fitting. Aim: To identify whether neural response telemetry threshold and spread of excitation width are similar in adults and children. Methods: Retrospective cross-sectional study approved by the Ethical Board. Intraoperative tNRT and SOE recordings of consecutive cochlear implant surgeries in adults and children implanted with Cochlear devices (Cochlear™, Australia) were selected. SOE was recorded on electrode 11 (or adjacent, corresponding to the medial region of the cochlea) through the standard forward-masking technique in Custom Sound EP software, which provides SOE width in millimeters. Statistical comparison between adults and children was performed using the Mann–Whitney test (p ≤ 0.05). Results: Of 1282 recordings of intraoperative evaluations, 414 measurements were selected from children and adults. Despite the tNRT being similar between adults and children, SOE width was significantly different, with lower values in children with perimodiolar arrays. Besides, it was observed that there is a difference in the electrode where the SOE function peak occurred, more frequently shifted to electrode 12 in adults implanted. In straight arrays, there was no difference in any of the parameters analyzed on electrode 11. Conclusion: Although eCAP thresholds are similar, SOE measurements differ between adults and children in perimodiolar electrodes. [ABSTRACT FROM AUTHOR]

Spontaneous bursts of neural activity in the developing auditory system prior to hearing onset are generated by inner supporting cells (ISCs), which depolarize adjacent inner hair cells (IHCs) by locally increasing extracellular potassium. Restricted spatiotemporal IHC activation in the cochlea induces correlated firing of neurons aligned to isofrequency lamina within central auditory centers. Astrocyte calcium transients are induced by engagement of metabotropic glutamate receptors following glutamate spillover from active synapses during neuronal burst firing. Disruption of spontaneous activity in the cochlea leads to increased gain, impaired synaptic refinement, and altered tonotopic maps in auditory centers of the CNS. Spontaneous activity is preserved in many models of congenital deafness, which may enable initial circuit maturation, increasing the efficacy of later restorative interventions. Sensory systems experience a period of intrinsically generated neural activity before maturation is complete and sensory transduction occurs. Here we review evidence describing the mechanisms and functions of this 'spontaneous' activity in the auditory system. Both ex vivo and in vivo studies indicate that this correlated activity is initiated by non-sensory supporting cells within the developing cochlea, which induce depolarization and burst firing of groups of nearby hair cells in the sensory epithelium, activity that is conveyed to auditory neurons that will later process similar sound features. This stereotyped neural burst firing promotes cellular maturation, synaptic refinement, acoustic sensitivity, and establishment of sound-responsive domains in the brain. While sensitive to perturbation, the developing auditory system exhibits remarkable homeostatic mechanisms to preserve periodic burst firing in deaf mice. Preservation of this early spontaneous activity in the context of deafness may enhance the efficacy of later interventions to restore hearing. [ABSTRACT FROM AUTHOR]

The peaked cochlear tonotopic response does not show the typical phenomenology of a resonant system. Simulations of a 2 D viscous model show that the position of the peak is determined by the competition between a sharp pressure boost due to the increase in the real part of the wavenumber as the forward wave enters the short-wave region, and a sudden increase in the viscous losses, partly counteracted by the input power provided by the outer hair cells. This viewpoint also explains the peculiar experimental behavior of the cochlear admittance (broadly tuned and almost level-independent) in the peak region. [ABSTRACT FROM AUTHOR]

Thin-film electrode arrays (TFEAs) have been developed as an alternative to conventional electrode arrays (CEAs) used in cochlear implants. However, TFEAs produced by microfabrication techniques have not yet been used clinically because their structural and mechanical properties are far from those of CEAs. The aim of this study is to design, fabricate, and investigate the mechanical and tribological behavior and evaluate the performance of different TFEA designs. Finite Element Analysis (FEA) is performed to determine the elastic properties of several designs. A custom-build experimental setup is designed to observe the tribological behavior in different speeds and environments where frictional (lateral) and vertical force (normal force) are measured on a flat surface and within artificial cochlea. According to the FEA results, the maximum stiffness of the CEA is 37.93 mN/mm and 0.363 mN/mm and TFEA-4 has a maximum stiffness of 39.08 mN/mm and 0.306 mN/mm in the longitudinal and transverse axes, respectively. It is shown experimentally that adding a dummy wire to the carrier of the EA enhances both its longitudinal and transverse stiffness, thereby postponing the initiation of dynamic sliding due to the elevated buckling limit. It is also revealed that the type of TFEA support structure affects both normal and frictional forces, as well as the coefficient of friction. [ABSTRACT FROM AUTHOR]

Transmembrane and tetratricopeptide repeat 4 (Tmtc4) is a deafness gene in mice. Tmtc4-KO mice have rapidly progressive postnatal hearing loss due to overactivation of the unfolded protein response (UPR); however, the cellular basis and human relevance of Tmtc4-associated hearing loss in the cochlea was not heretofore appreciated. We created a hair cell-specific conditional KO mouse that phenocopies the constitutive KO with postnatal onset deafness, demonstrating that Tmtc4 is a hair cell-specific deafness gene. Furthermore, we identified a human family in which Tmtc4 variants segregate with adult-onset progressive hearing loss. Lymphoblastoid cells derived from multiple affected and unaffected family members, as well as human embryonic kidney cells engineered to harbor each of the variants, demonstrated that the human Tmtc4 variants confer hypersensitivity of the UPR toward apoptosis. These findings provide evidence that TMTC4 is a deafness gene in humans and further implicate the UPR in progressive hearing loss.

Abstract Losing either type of cochlear sensory hair cells leads to hearing impairment. Inner hair cells act as primary mechanoelectrical transducers, while outer hair cells enhance sound-induced vibrations within the organ of Corti. Established inner ear damage models, such as systemic administration of ototoxic aminoglycosides, yield inconsistent and variable hair cell death in mice. Overcoming this limitation, we developed a method involving surgical delivery of a hyperosmotic sisomicin solution into the posterior semicircular canal of adult mice. This procedure induced rapid and synchronous apoptotic demise of outer hair cells within 14 h, leading to irreversible hearing loss. The combination of sisomicin and hyperosmotic stress caused consistent and synergistic ototoxic damage. Inner hair cells remained until three days post-treatment, after which deterioration in structure and number was observed, culminating in a complete hair cell loss by day seven. This robust animal model provides a valuable tool for otoregenerative research, facilitating single-cell and omics-based studies toward exploring preclinical therapeutic strategies.

Introduction: Even with recent research advances, effective delivery of a compound to its target cells inside the inner ear remains a challenging endeavor due to anatomical and physiological barriers. Direct intracochlear drug administration with an inner ear catheter (IEC) aims to overcome this obstacle and strives to provide a safe and efficient way for inner ear pharmacotherapy. The goal of this study was to histologically and audiologically evaluate the traumatic properties of a novel IEC for intracochlear drug delivery in a large animal model. Methods: Seven inner ears of piglets that had undergone intracochlear fluorescein isothiocyanate dextran application via an IEC (n = 4) or round window membrane (RWM) puncture with a needle (n = 3) followed by sequential apical perilymph sampling were histologically analyzed. Additionally, obtained objective auditory compound action potential and cochlear microphonic measurements were compared. Cochlear cryosections were stained using hematoxylin and eosin, and preservation of inner ear structures was investigated. Moreover, one cochlea was methylmethacrylate-embedded and analyzed with the IEC in situ. Results: Histological evaluation revealed an atraumatic insertion and subsequent compound application in a majority of IEC-inserted inner ears. Click cochlear compound action potential (CAP) shifts in the IEC groups reached a maximum of 5 dB (1.25 ± 2.5 dB) post administration and prior to perilymph sampling. In comparison, application by RWM puncture generated a maximum click CAP hearing threshold shift of 50 dB (23.3 ± 23.1 dB) coinciding with coagulated blood in the basal cochlear turn in one specimen of the latter group. Furthermore, in situ histology showed an atraumatic insertion of the IEC demonstrating preserved intracochlear structures. Conclusion: The IEC appears to be a promising and efficient way for inner ear drug delivery. The similarities between the porcine and human inner ear enhance the clinical translation of our findings and increase confidence regarding the safe applicability of the IEC in human subjects. [ABSTRACT FROM AUTHOR]

Simple Summary: Cisplatin-based chemoradiation is the standard of care for patients with squamous cell carcinomas of the head and neck area. Recent data from randomized phase 3 studies showed that weekly cisplatin has the same oncological outcomes as high-dose triweekly cisplatin when combined with definitive radiation. In this study, audiologic data were prospectively collected before, during, and after treatment completion. Standard audiogram evaluation was used in all cases. The primary endpoint was a hearing change grade of ≥3 (CTCAE v5.0) after completion of chemoradiation. The high-dose cisplatin regimen significantly increased the ≥grade 3 severe irreversible ototoxicity risk compared to the low-dose weekly regimen, irrespective of cumulative cisplatin dose, even with the use of cochlear-sparing intensity-modulated radiation therapy. No significant difference in oncologic outcomes was observed between the two schedules. These findings should be validated in a larger prospective multi-institutional study. Cisplatin, one of the most ototoxic anti-neoplastic agents, causes permanent hearing loss in up to 90% of patients. We assessed ototoxicity rates and prospectively collected audiologic outcomes of patients receiving low-dose or high-dose cisplatin with concurrent cochlear-sparing intensity-modulated radiation therapy (IMRT). Patients with head and neck squamous cell carcinoma (HNSCC) receiving definitive or adjuvant cisplatin-based chemoradiotherapy (CRT) were analyzed. Cisplatin was administered either in low doses weekly (40 mg/m2) for up to seven doses or in high doses triweekly (100 mg/m2) for up to three doses. Cochlear-sparing IMRT was delivered in all cases. Audiologic data were prospectively collected before, during, and after treatment completion. The primary endpoint was a hearing change grade of ≥3 after CRT completion. Of the 96 HNSCC patients evaluated, 69 received weekly cisplatin and 58 received definitive CRT. Of patients receiving weekly cisplatin, 13% developed ≥G3 ototoxicity vs. 56% of patients who received triweekly cisplatin (p < 0.001). In multivariable modeling, the cisplatin dose schedule remained significant (OR: 8.4, 95%CI: 2.8–27.8, p < 0.001) for risk of severe irreversible ototoxicity. Triweekly cisplatin CRT significantly increased the ≥G3 severe irreversible ototoxicity risk compared to low-dose weekly cisplatin, irrespective of the cumulative cisplatin dose, even with the use of cochlear-sparing IMRT. No significant difference in oncologic outcomes was observed between the two schedules. [ABSTRACT FROM AUTHOR]

The mouse auditory organ cochlea contains two types of sound receptors: inner hair cells (IHCs) and outer hair cells (OHCs). Tbx2 is expressed in IHCs but repressed in OHCs, and neonatal OHCs that misexpress Tbx2 transdifferentiate into IHC-like cells. However, the extent of this switch from OHCs to IHC-like cells and the underlying molecular mechanism remain poorly understood. Furthermore, whether Tbx2 can transform fully mature adult OHCs into IHC-like cells is unknown. Here, our single-cell transcriptomic analysis revealed that in neonatal OHCs misexpressing Tbx2, 85.6% of IHC genes, including Slc17a8, are upregulated, but only 38.6% of OHC genes, including Ikzf2 and Slc26a5, are downregulated. This suggests that Tbx2 cannot fully reprogram neonatal OHCs into IHCs. Moreover, Tbx2 also failed to completely reprogram cochlear progenitors into IHCs. Lastly, restoring Ikzf2 expression alleviated the abnormalities detected in Tbx2+ OHCs, which supports the notion that Ikzf2 repression by Tbx2 contributes to the transdifferentiation of OHCs into IHC-like cells. Our study evaluates the effects of ectopic Tbx2 expression on OHC lineage development at distinct stages of either male or female mice and provides molecular insights into how Tbx2 disrupts the gene expression profile of OHCs. This research also lays the groundwork for future studies on OHC regeneration. [ABSTRACT FROM AUTHOR]

The inner ear is a complex sensory organ responsible for hearing and balance. It is deeply embedded in the temporal bone with challenging access for diagnostic and therapeutic purposes. Stress and injury to the peripheral hearing organ (cochlea) lead to temporary or permanent sensorineural hearing loss (SNHL), which is the most common form of hearing loss resulting from cellular and molecular damage to the sensory hair cells and primary auditory neurons in the spiral ganglion. These cells cannot regenerate, and their loss leads to hearing disability. Hearing aids can amplify sound and improve residual hearing ability but cannot restore function; therefore, alternative therapies are urgently needed. The pharmacological approach to treating SNHL has been our mainstream research over the past two decades. This review describes our studies investigating the purinergic signalling system in the cochlea and its implications for inner ear therapies. Using animal models of SNHL, we have established that purinergic P1 (adenosine) and P2 (ATP) receptors can prevent or mitigate cochlear injury by reducing cochlear sensitivity to loud sound and improving the survival of sensorineural tissues. Here, we highlight our research investigating the therapeutic potential of P1 and P2 receptor agonists and antagonists in inner ear disorders. [ABSTRACT FROM AUTHOR]

The optimal placement of a cochlear implant (CI) electrode inside the scala tympani compartment to create an effective electrode--neural interface is the base for a successful CI treatment. The characteristics of an effective electrode design include (a) electrode matching every possible variation in the inner ear size, shape, and anatomy, (b) electrically covering most of the neuronal elements, and (c) preserving intra-cochlear structures, even in non-hearing preservation surgeries. Flexible electrode arrays of various lengths are required to reach an angular insertion depth of 680° to which neuronal cell bodies are angularly distributed and to minimize the rate of electrode scalar deviation. At the time of writing this article, the current scientific evidence indicates that straight lateral wall electrode outperforms perimodiolar electrode by preventing electrode tip fold-over and scalar deviation. Most of the available literature on electrode insertion depth and hearing outcomes supports the practice of physically placing an electrode to cover both the basal and middle turns of the cochlea. This is only achievable with longer straight lateral wall electrodes as single-sized and preshaped perimodiolar electrodes have limitations in reaching beyond the basal turn of the cochlea and in offering consistent modiolar hugging placement in every cochlea. For malformed inner ear anatomies that lack a central modiolar trunk, the perimodiolar electrode is not an effective electrode choice. Most of the literature has failed to demonstrate superiority in hearing outcomes when comparing perimodiolar electrodes with straight lateral wall electrodes from single CI manufacturers. In summary, flexible and straight lateral wall electrode type is reported to be gentle to intra-cochlear structures and has the potential to electrically stimulate most of the neuronal elements, which are necessary in bringing full benefit of the CI device to recipients. [ABSTRACT FROM AUTHOR]

Spiral ganglion neurons (SGNs) transmit auditory information from cochlear hair cells to the brain. SGNs are thus not only important for normal hearing, but also for effective functioning of cochlear implants, which stimulate SGNs when hair cells are missing. SGNs slowly degenerate following aminoglycosideinduced hair cell loss, a process thought to involve an immune response. However, the specific immune response pathways involved remain unknown. We used RNAseq to gain a deeper understanding immune-related and other transcriptomic changes that occur in the rat spiral ganglion after kanamycininduced deafening. Among the immune and inflammatory genes that were selectively upregulated in deafened spiral ganglia, the complement cascade genes were prominent. We then assessed SGN survival, as well as immune cell numbers and activation, in the spiral ganglia of rats with a CRISPR-Cas9-mediated knockout of complement component 3 (C3). Similar to previous findings in our lab and other deafened rodent models, we observed an increase in macrophage number and increased expression of CD68, a marker of phagocytic activity and cell activation, in macrophages in the deafened ganglia. Moreover, we found an increase in MHCII expression on spiral ganglion macrophages and an increase in lymphocyte number in the deafened ganglia, suggestive of an adaptive immune response. However, C3 knockout did not affect SGN survival or increase in macrophage number/activation, implying that complement activation does not play a role in SGN death after deafening. Together, these data suggest that both innate and adaptive immune responses are activated in the deafened spiral ganglion, with the adaptive response directly contributing to cochlear neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: In most cases, intralabyrinthine schwannoma (ILS) occurs in patients with unilateral hearing deterioration or neurofibromatosis type II (NF II). The pattern of localization of these tumors varies but mostly affects the cochlea. Extirpation of the cochlear schwannoma, if hidden by the cochlea modiolus, is difficult under the aspect of complete removal. Therefore, a tissue removal device (TRD) was designed and tested in temporal bones. The principle of handling the new device is a pushing and pipe cleaner handling inside the cochlea. This present study aimed to describe the first in vivo experience with the newly developed TRD for removing cochlear intralabyrinthine schwannomas. Methods: In three patients, the TRD was used for the tumor removal of cochlear schwannomas. In two patients with a cochlear schwannoma in combination with a cochlea implantation and one patient suffering from NF II, a cochlear schwannoma was removed with the TRD. The access was performed with a posterior tympanotomy, an enlarged round window approach and an additional second turn access. The device was inserted and extracted gradually from the second turn access until the rings were visible in the second turn access. By pushing and pipe cleaner handling, the tumors were removed. An MRI control was performed on the day postoperatively with a T1 GAD sequence. Results: Tumor removal with the TRD was performed in a 15-min procedure without any complications. An MRI control confirmed complete removal on the postoperative day in all cases. Conclusions: In vivo handling of the device confirmed straightforward handling for the tumor removal. MRI scanning showed complete removal of the tumor by the TRD. [ABSTRACT FROM AUTHOR]

This study describes the clinical profile, operative findings, surgical technique, type of implant and complications encountered in implantation of abnormal cochlea by the transcanal (veria) technique in a tertiary care centre. This is a retrospective study done amongst 337 patients who underwent cochlear implantation by veria technique between January 2013 to August 2023. Based on pre-operative imaging with high-resolution computed tomography and magnetic resonance imaging the cochleovestibular malformations in this study were classified according to Sennaroglu classification and the cochlear ossification was graded from I to IV. Amongst the 337 patients who underwent cochlear implantation during the study period there were 79 cases (23.4%) with abnormalities of cochlea. This included 45 patients (13.4%) with congenital malformations, 20 patients (5.9%) with cochlear fibrosis and 14 patients (4.2%) with cochlear ossification. The commonest cochlear malformation was Incomplete Partition 2 which was present in 21 patients (46.7%). The other common malformations were cochlear hypoplasia (31.1%), Incomplete Partition 1(13.3%) and common cavity (8.9%). Out of the 20 patients with cochlear fibrosis, 17 patients had fibrosis only in the basal turn. Out of the 14 patients with cochlear ossification 8 patients (57.1%) had a grade 1 ossification, 2 patients (14.3%) had a grade 2 ossification and 4 patients (28.6%) had a grade 3 ossification. One of the patients required re-exploration for correcting the placement of electrode. The type of implant were chosen depending on individual malformation or length of ossification and fibrosis. In the past, inner ear anomalies were considered as a contraindication for cochlear implantation however it is now possible to implant most of these abnormal cochlea by careful planning, a modification of the surgical technique and the type of electrode used. [ABSTRACT FROM AUTHOR]

Background: Subtotal petrosectomy (STP) has attracted massive interest over last two decades. The aim is to present our experience of this uncommon surgery. The indications, outcomes, and our variation in surgical technique would be presented and literature reviewed. Methods: A retrospective observational study of all patients who underwent STP at a tertiary care center in India was analyzed. Results: A total of 9 ears (in 8 patients) underwent STP over last 5 years at our center. The pathological conditions for which STP was done included chronic otitis media squamous (four ears), middle ear tumors (three ears), petrous apicitis (one ear), and traumatic cerebrospinal fluid (CSF) otorhinorrhea (one ear). The indication of STP included disease clearance (eight ears), unserviceable hearing (seven ears), hearing rehabilitation with otological implants (six ears), and intraoperative CSF gusher (one ear). Intraoperative indications included CSF gusher, large tegmen defect with erosion of apical turn of cochlea, and erosion of anterior bony wall of external auditory canal. The mean follow-up period was 36 months (range of 6 months to 60 months). None of the patients had any dehiscence of blind sac closure or secondary acquired cholesteatoma on imaging. Conclusions: STP facilitates disease clearance by providing unmatchable exposure in difficult otological scenarios and additionally isolates middle ear cleft from external environment, thereby eliminating problems of mastoid cavity. Furthermore, it also prepares ear for second stage otological implants. It is a safe surgery with minimal complications. [ABSTRACT FROM AUTHOR]

Auditory research aims in general to lead to understanding of physiological processes. By contrast, the state of the art in automatic speech processing (notably recognition) is dominated by large pre-trained models that are meant to be used as black-boxes. In this work, we integrate a physiologically plausible (albeit simple filter-based) model of the cochlea into a much larger pre-trained acoustic model for speech recognition. We show that the hybrid system can be trained and evaluated with various combinations of fine-tuning and self-supervision. The results broadly show that the system automatically yields structures that are known to work well. Moreover, these structures lack artifacts that were apparent in (our) previous work using less sophisticated neural models. We conclude that the hybrid structure is an appropriate way to proceed in auditory research, more generally allowing the work to take advantage of larger models and databases from which it would not otherwise benefit. [ABSTRACT FROM AUTHOR]

Purpose: This study sought to evaluate the feasibility and efficacy of the Halcyon Ring Delivery System (RDS) for delivering stereotactic radiotherapy (SRT) treatments for intracranial tumors beds. Methods: Ten previously treated brain SRT patients for 30 Gy in five fractions with non‐coplanar HyperArc plans on TrueBeam (6MV‐FFF) were replanned on Halcyon (6MV‐FFF) using the same number of arcs and Eclipse's AcurosXB dose engine. Plan quality evaluation metrics per SRT protocol included: PTV coverage, GTV dose (minimum and mean), target conformity indices (CI), heterogeneity index (HI), gradient index (GI), maximum dose 2 cm away from the PTV (D2cm), and doses to organs‐at‐risk (OAR). Additionally, patient‐specific quality assurance (QA) results and beam‐on‐time (BOT) were analyzed. Results: The Halcyon RDS provided highly conformal SRT plans for intracranial tumor beds with similar dose to target. When benchmarked against clinically delivered HyperArc plans, target coverage, CI(s) and HI were statistically similar. The Halcyon plans saw no statistical difference in maximum OAR doses to the brainstem, spinal cord, and cochlea. Due to the machine's coplanar geometry, the Halcyon plans showed a decrease in optic pathway dose (0.75 Gy vs. 2.08 Gy, p = 0.029). Overall, Halcyon's coplanar geometry resulted in a larger GI (3.33 vs. 2.72, p = 0.008) and a larger D2cm (39.59% vs. 29.07%, p < 0.001). In this cohort, multiple cases had the PTV and the optic pathway in the same axial plane. In one such instance, the PTV was <2 cm away from the optic pathway but even at this close proximity OAR, Halcyon still adequately spared the optic pathway. Additionally, the Halcyon's geometry provided slightly larger amount of normal brain dose receiving 24.4 Gy (8.99 cc vs. 7.36 cc) and 28.8 Gy (2.9 cc vs. 2.5 cc), although statistically insignificant. The Halcyon plans achieved similar delivery accuracy, quantified by patient‐specific QA results evaluated with a 2%/2 mm gamma criteria (99.42% vs. 99.70%). For both plans, independent Monte Carlo second checks calculation agreed within 1%. Average Halcyon BOT was slightly higher by 0.35 min (p = 0.045), however, due to the one‐step patient set‐up and verification overall estimated treatment times on Halcyon were lower compared to HyperArc treatments (7.61 min vs. 10.26 min, p < 0.001). Conclusions: When benchmarked against clinically delivered HyperArc treatments, the Halcyon brain SRT plans provided similar plan quality and delivery accuracy but achieved faster overall treatment times. We have started treating select brain SRT patients on the Halcyon RDS for patients having tumor beds greater than 1 cm in diameter with the closest OAR distance of greater than 2 cm away from the target. We recommend other clinics to consider commissioning SRT treatments on their Halcyon systems–allowing including remote Halcyon‐only clinics to provide exceptionally high‐quality therapeutic brain SRT treatments to an otherwise underserved patient cohort. [ABSTRACT FROM AUTHOR]

Objective:Methods:Results:Conclusion:This study emphasizes the role of preoperative high-resolution computed tomography (HRCT) temporal bone in evaluating the variation in cochlear orientation and proposes a grading system to determine the level of intraoperative difficulties encountered.Preoperative correlation of middle ear and inner ear structures along with the basal turn angle (BTA) was done to assess the orientation. Patients were divided into three groups depending on BTA and radiology findings.Group A (BTA = 55°-60°) had statistically significant (p < 0.05) correlation between middle ear to inner ear structures on HRCT, whereas group B (BTA >60°) and C (BTA <55°) had variations in the alignment of middle ear structures to their corresponding inner ear structures.The association of BTA to the correlation between middle ear and inner ear structures can determine the orientation of the cochlea. This evaluation makes the surgeon aware of intraoperative challenges and helps in surgical planning. [ABSTRACT FROM AUTHOR]

Background: Despite its location near infection-prone areas, the human inner ear demonstrates remarkable resilience. This suggests that there are inherent instruments deterring the invasion and spread of pathogens into the inner ear. Here, we combined high-resolution light microscopy, super-resolution immunohistochemistry (SR-SIM) and synchrotron phase contrast imaging (SRPCI) to identify the protection and barrier systems in the various parts of the human inner ear, focusing on the lateral wall, spiral ganglion, and endolymphatic sac. Materials and methods: Light microscopy was conducted on mid-modiolar, semi-thin sections, after direct glutaraldehyde/osmium tetroxide fixation. The tonotopic locations were estimated using SR-PCI and 3D reconstruction in cadaveric specimens. The sections were analyzed for leucocyte and macrophage activity, and the results were correlated with immunohistochemistry using confocal microscopy and SR-SIM. Results: Light microscopy revealed unprecedented preservation of cell anatomy and several macrophage-like cells that were localized in the cochlea. Immunohistochemistry demonstrated IBA1 cells frequently co-expressing MHC II in the spiral ganglion, nerve fibers, lateral wall, spiral limbus, and tympanic covering layer at all cochlear turns as well as in the endolymphatic sac. RNAscope assays revealed extensive expression of fractalkine gene transcripts in type I spiral ganglion cells. CD4 and CD8 cells occasionally surrounded blood vessels in the modiolus and lateral wall. TMEM119 and P2Y12 were not expressed, indicating that the cells labeled with IBA1 were not microglia. The round window niche, compact basilar membrane, and secondary spiral lamina may form protective shields in the cochlear base. Discussion: The results suggest that the human cochlea is surveilled by dwelling and circulating immune cells. Resident and blood-borne macrophages may initiate protective immune responses via chemokine signaling in the lateral wall, spiral lamina, and spiral ganglion at different frequency locations. Synchrotron imaging revealed intriguing protective barriers in the base of the cochlea. The role of the endolymphatic sac in human inner ear innate and adaptive immunity is discussed. [ABSTRACT FROM AUTHOR]

Pending questions regarding cochlear amplification and tuning are hinged upon the organ of Corti (OoC) active mechanics: how outer hair cells modulate OoC vibrations. Our knowledge regarding OoC mechanics has advanced over the past decade thanks to the application of tomographic vibrometry. However, recent data from live cochlea experiments often led to diverging interpretations due to complicated interaction between passive and active responses, lack of image resolution in vibrometry, and ambiguous measurement angles. We present motion measurements and analyses of the OoC sub-components at the close-to-true cross-section, measured from acutely excised gerbil cochleae. Specifically, we focused on the vibrating patterns of the reticular lamina, the outer pillar cell, and the basilar membrane because they form a structural frame encasing active outer hair cells. For passive transmission, the OoC frame serves as a rigid truss. In contrast, motile outer hair cells exploit their frame structures to deflect the upper compartment of the OoC while minimally disturbing its bottom side (basilar membrane). Such asymmetric OoC vibrations due to outer hair cell motility explain how recent observations deviate from the classical cochlear amplification theory. We analyzed the organ of Corti motions, component by component. Outer hair cells exploit their supporting cells to boost vibrations of the upper part of the organ of Corti while minimally disturbing the basilar membrane. [ABSTRACT FROM AUTHOR]

Age-related hearing loss (HL), or presbycusis, is a complex and heterogeneous condition, affecting a significant portion of older adults and involving various interacting mechanisms. Metabolic presbycusis, a type of age-related HL, is characterized by the dysfunction of the stria vascularis, which is crucial for maintaining the endocochlear potential necessary for hearing. Although attention on metabolic presbycusis has waned in recent years, research continues to identify strial pathology as a key factor in age-related HL. This narrative review integrates past and recent research, bridging findings from animal models and human studies, to examine the contributions of the stria vascularis to age-related HL. It provides a brief overview of the structure and function of the stria vascularis and then examines mechanisms contributing to age-related strial dysfunction, including altered ion transport, changes in pigmentation, inflammatory responses, and vascular atrophy. Importantly, this review outlines the contribution of metabolic mechanisms to age-related HL, highlighting areas for future research. It emphasizes the complex interdependence of metabolic and sensorineural mechanisms in the pathology of age-related HL and highlights the importance of animal models in understanding the underlying mechanisms. The comprehensive and mechanistic investigation of all factors contributing to age-related HL, including cochlear metabolic dysfunction, remains crucial to identifying the underlying mechanisms and developing personalized, protective, and restorative treatments. [ABSTRACT FROM AUTHOR]

The synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) are the most vulnerable structures in the noise-exposed cochlea. Cochlear synaptopathy results from the disruption of these synapses following noise exposure and is considered the main cause of poor speech understanding in noisy environments, even when audiogram results are normal. Cochlear synaptopathy leads to the degeneration of SGNs if damaged IHC-SGN synapses are not promptly recovered. Oxidative stress plays a central role in the pathogenesis of cochlear synaptopathy. C-Phycocyanin (C-PC) has antioxidant and anti-inflammatory activities and is widely utilized in the food and drug industry. However, the effect of the C-PC on noise-induced cochlear damage is unknown. We first investigated the therapeutic effect of C-PC on noise-induced cochlear synaptopathy. In vitro experiments revealed that C-PC reduced the H2O2-induced generation of reactive oxygen species in HEI-OC1 auditory cells. H2O2-induced cytotoxicity in HEI-OC1 cells was reduced with C-PC treatment. After white noise exposure for 3 h at a sound pressure of 118 dB, the guinea pigs intratympanically administered 5 μg/mL C-PC exhibited greater wave I amplitudes in the auditory brainstem response, more IHC synaptic ribbons and more IHC-SGN synapses according to microscopic analysis than the saline-treated guinea pigs. Furthermore, the group treated with C-PC had less intense 4-hydroxynonenal and intercellular adhesion molecule-1 staining in the cochlea compared with the saline group. Our results suggest that C-PC improves cochlear synaptopathy by inhibiting noise-induced oxidative stress and the inflammatory response in the cochlea. [ABSTRACT FROM AUTHOR]