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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]

Signal transducer and activator of transcription 3 (Stat3) plays a role in various cellular processes such as differentiation, inflammation, cell survival and microtubule dynamics, depending on the cell type and the activated signaling pathway. Stat3 is highly expressed in the hair cells and supporting cells of the cochlea and is essential for the differentiation of mouse hair cells in the early embryonic stage. However, it is unclear how Stat3 contributes to the correct function of cells in the organ of Corti postnatally. To investigate this, an inducible Cre/loxp system was used to knock out Stat3 in either the outer hair cells or the supporting cells. The results showed that the absence of Stat3 in either the outer hair cells or the supporting cells resulted in hearing loss without altering the morphology of the organ of Corti. Molecular analysis of the outer hair cells revealed an inflammatory process with increased cytokine production and upregulation of the NF-kB pathway. However, the absence of Stat3 in the supporting cells resulted in reduced microtubule stability. In conclusion, Stat3 is a critical protein for the sensory epithelium of the cochlea and hearing and functions in a cell and function-specific manner. [ABSTRACT FROM AUTHOR]

Endolymphatic hydrops, increased endolymphatic fluid within the cochlea, is the key pathologic finding in patients with Meniere's disease, a disease of episodic vertigo, fluctuating hearing loss, tinnitus, and aural fullness. Endolymphatic hydrops also can occur after noise trauma and its presence correlates with cochlear synaptopathy, a form of hearing loss caused by reduced numbers of synapses between hair cells and auditory nerve fibers. Here we tested whether there is a mechanistic link between these two phenomena by using multimodal imaging techniques to analyze the cochleae of transgenic mice exposed to blast and osmotic challenge. In vivo cochlear imaging after blast exposure revealed dynamic increases in endolymph that involved hair cell mechanoelectrical transduction channel block but not the synaptic release of glutamate at the hair cell–auditory nerve synapse. In contrast, ex vivo and in vivo auditory nerve imaging revealed that synaptopathy requires glutamate release from hair cells but not endolymphatic hydrops. Thus, although endolymphatic hydrops and cochlear synaptopathy are both observed after noise exposure, one does not cause the other. They are simply co-existent sequelae that derive from the traumatic stimulation of hair cell stereociliary bundles. Importantly, these data argue that Meniere's disease derives from hair cell transduction channel blockade. [ABSTRACT FROM AUTHOR]

Type I spiral ganglion neurons are peripheral neurons essential for hearing perception. While they can be subdivided in mice based on characteristic gene expression patterns, detailed examinations of these subtypes in primates and humans are lacking. In this study, we investigated the developmental subtypes of spiral ganglion neurons in the common marmoset (Callithrix jacchus). We confirmed that Type I spiral ganglion can be divided based on the characteristic gene expression patterns of several marker genes. However, some combinations of these genes differ from those in rodents, suggesting common marmoset's suitability for advancing our understanding of human cochlear development. Additionally, identifying the essential time points for subtype specifications and subsequent maturation will aid in studying the primate-specific developmental biology of the inner ear. This could lead to new treatment strategies for hearing loss in humans and be valuable for studying age-related hearing loss, as well as designing regenerative therapies. [ABSTRACT FROM AUTHOR]

Sensorineural hearing loss (SNHL) is caused by damage to the mechanosensory hair cells and auditory neurons of the cochlea. The development of imaging tools that can directly visualize or provide functional information about a patient’s cochlear cells is critical to identify the pathobiological defect and determine the cells’ receptiveness to emerging SNHL treatments. However, the cochlea’s small size, embedded location within dense bone, and sensitivity to perturbation have historically precluded high-resolution clinical imaging. Previously, we developed micro-optical coherence tomography (μOCT) as a platform for otologic imaging in animal models and human cochleae. Here we report on advancing μOCT technology to obtain simultaneously acquired and co-localized images of cell viability/metabolic activity through dynamic μOCT (DμOCT) imaging of intracellular motion. DμOCT obtains cross-sectional images of ATP-dependent movement of intracellular organelles and cytoskeletal polymerization by acquiring sequential μOCT images and computing intensity fluctuation frequency metrics on a pixelwise basis. Using a customized benchtop DμOCT system, we demonstrate the detailed resolution of anatomical and metabolic features of cells within the organ of Corti, via an apical cochleostomy, in freshly-excised adult mouse cochleae. Further, we show that DμOCT is capable of capturing rapid changes in cochlear cell metabolism following an ototoxic insult to induce cell death and actin stabilization. Notably, as few as 6 frames can be used to reconstruct cochlear DμOCT images with sufficient detail to discern individual cells and their metabolic state. Taken together, these results motivate future development of a DμOCT imaging probe for cellular and metabolic diagnosis of SNHL in humans. [ABSTRACT FROM AUTHOR]

Spiral ganglion neurons (SGNs) are primary sensory afferent neurons that relay acoustic information from the cochlear inner hair cells (IHCs) to the brainstem. The response properties of different SGNs diverge to represent a wide range of sound intensities in an action‐potential code. This biophysical heterogeneity is established during pre‐hearing stages of development, a time when IHCs fire spontaneous Ca2+ action potentials that drive glutamate release from their ribbon synapses onto the SGN terminals. The role of spontaneous IHC activity in the refinement of SGN characteristics is still largely unknown. Using pre‐hearing otoferlin knockout mice (Otof−/−), in which Ca2+‐dependent exocytosis in IHCs is abolished, we found that developing SGNs fail to upregulate low‐voltage‐activated K+‐channels and hyperpolarisation‐activated cyclic‐nucleotide‐gated channels. This delayed maturation resulted in hyperexcitable SGNs with immature firing characteristics. We have also shown that SGNs that synapse with the pillar side of the IHCs selectively express a resurgent K+ current, highlighting a novel biophysical marker for these neurons. RNA‐sequencing showed that several K+ channels are downregulated in Otof−/− mice, further supporting the electrophysiological recordings. Our data demonstrate that spontaneous Ca2+‐dependent activity in pre‐hearing IHCs regulates some of the key biophysical and molecular features of the developing SGNs. Key points: Ca2+‐dependent exocytosis in inner hair cells (IHCs) is otoferlin‐dependent as early as postnatal day 1.A lack of otoferlin in IHCs affects potassium channel expression in SGNs.The absence of otoferlin is associated with SGN hyperexcitability.We propose that type I spiral ganglion neuron functional maturation depends on IHC exocytosis. [ABSTRACT FROM AUTHOR]

Mechanical force controls the opening and closing of mechanosensitive ion channels atop the hair bundles of the inner ear. The filamentous tip link connecting transduction channels to the tallest neighboring stereocilium modulates the force transmitted to the channels and thus changes their probability of opening. Each tip link comprises four molecules: a dimer of protocadherin 15 (PCDH15) and a dimer of cadherin 23, all of which are stabilized by Ca2+ binding. Using a high-speed optical trap to examine dimeric PCDH15, we find that the protein's mechanical properties are sensitive to Ca2+ and that the molecule exhibits limited unfolding at a physiological Ca2+ concentration. PCDH15 can therefore modulate its stiffness without undergoing large unfolding events under physiological conditions. The experimentally determined stiffness of PCDH15 accords with published values for the stiffness of the gating spring, the mechanical element that controls the opening of mechanotransduction channels. When PCDH15 exhibits a point mutation, V507D, associated with nonsyndromic hearing loss, unfolding events occur more frequently under tension and refolding events occur less often than for the wild-type protein. Our results suggest that the maintenance of appropriate tension in the gating spring is critical to the appropriate transmission of force to transduction channels, and hence to hearing. [ABSTRACT FROM AUTHOR]

Background: A number of drugs are toxic to the cochlear sensory cells known as hair cells (HCs), resulting in hearing loss. Treatment with survival-promoting growth factors, antioxidants, and inhibitors of cell death pathways or proteinases have been shown to reduce HC damage in in vivo and/or in vitro animal models. Conversely, translation to humans has often been disappointing. This may be due to the complexity of intracellular damage processes. We hypothesized that combining treatments targeting different cellular processes would be more effective. Methods: Using an in vitro model of gentamicin ototoxicity for murine cochlear hair cells, we screened all 56 possible combinations of inhibitors targeting five different cell damage mechanisms, plus the activator of one cell survival pathway, each of which have been shown to be singly effective in preventing HC loss in experimental studies. A high dose of gentamicin (200 µM) was used over three days in culture. All compounds were added at a dosage below that required for significant protection in the assay, and only this single dose was then employed. This was done so that we could more easily detect interactive, as opposed to additive, effects. Results: Increasing protection of hair cells was observed as combinations of compounds were increased from two to four factors, although not all combinations were equally protective. The optimal combination of four compounds consisted of an anti-oxidant, an apoptosis inhibitor, an autophagy inhibitor and a protective growth factor. Increasing the number of factors to five or six resulted in decreased protection. Conclusion: The results support the hypothesis that targeting multiple cellular damage or survival pathways provides more an effective hair cell protection approach. The results help to identify critical interactions among the cellular processes that operate in gentamicin ototoxicity. They also suggest that inhibiting too many biological processes impairs functions critical to HC survival, resulting in decreased protection. [ABSTRACT FROM AUTHOR]

Objective: The ability to discriminate natural soundscapes recorded in a temperate terrestrial biome was measured in 15 hearing-impaired (HI) listeners with bilateral, mild to severe sensorineural hearing loss and 15 normal-hearing (NH) controls. Design: Soundscape discrimination was measured using a three-interval oddity paradigm and the method of constant stimuli. On each trial, sequences of 2-second recordings varying the habitat, season and period of the day were presented diotically at a nominal SPL of 60 or 80 dB. Results: Discrimination scores were above chance level for both groups, but they were poorer for HI than NH listeners. On average, the scores of HI listeners were relatively well accounted for by those of NH listeners tested with stimuli spectrally-shaped to match the frequency-dependent reduction in audibility of individual HI listeners. However, the scores of HI listeners were not significantly correlated with pure-tone audiometric thresholds and age. Conclusions: These results indicate that the ability to discriminate natural soundscapes associated with changes in habitat, season and period of the day is disrupted but it is not abolished. The deficits of the HI listeners are partly accounted for by reduced audibility. Supra-threshold auditory deficits and individual listening strategies may also explain differences between NH and HI listeners. [ABSTRACT FROM AUTHOR]

Age-related hearing loss (ARHL) or presbycusis is associated with irreversible progressive damage in the inner ear, where the sound is transduced into electrical signal; but the detailed mechanism remains unclear. Here, we sought to determine the potential molecular mechanism involved in the pathogeneses of ARHL with bioinformatics methods. A single-cell transcriptome sequencing study was performed on the cochlear samples from young and aged mice. Detection of identified cell type marker allowed us to screen 18 transcriptional clusters, including myeloid cells, epithelial cells, B cells, endothelial cells, fibroblasts, T cells, inner pillar cells, neurons, inner phalangeal cells, and red blood cells. Cell-cell communications were analyzed between young and aged cochlear tissue samples by using the latest integration algorithms Cellchat. A total of 56 differentially expressed genes were screened between the two groups. Functional enrichment analysis showed these genes were mainly involved in immune, oxidative stress, apoptosis, and metabolic processes. The expression levels of crucial genes in cochlear tissues were further verified by immunohistochemistry. Overall, this study provides new theoretical support for the development of clinical therapeutic drugs. [ABSTRACT FROM AUTHOR]

Noise-induced hidden hearing loss (HHL) is a newly uncovered form of hearing impairment that causes hidden damage to the cochlea. Patients with HHL do not have significant abnormalities in their hearing thresholds, but they experience impaired speech recognition in noisy environments. However, the mechanisms underlying HHL remain unclear. In this study, we developed single-cell transcriptome profiles of the cochlea of mice with HHL, detailing changes in individual cell types. Our study revealed a transient threshold shift, reduced auditory brainstem response wave I amplitude, and decreased number of ribbon synapses in HHL mice. Our findings suggest elevated oxidative stress and GDF15 expression in cochlear hair cells of HHL mice. Notably, the upregulation of GDF15 attenuated oxidative stress and auditory impairment in the cochlea of HHL mice. This suggests that a therapeutic strategy targeting GDF15 may be efficacious against HHL. HHL mice had a transient threshold shift, reduced ABR wave I amplitude, and decreased number of ribbon synapses. HHL mice's cochlear hair cells exhibited increased oxidative stress and elevated GDF15 expression. Upregulation of GDF15 attenuated oxidative stress and auditory damage in the cochlea of HHL mice, implying that GDF15-targeted treatment techniques may be useful for HHL. [ABSTRACT FROM AUTHOR]

Background: Several studies have demonstrated the presence of resident immune cells in the healthy inner ear. Aim: This scoping review aimed to systematize this knowledge by collecting the data on resident immune cells in the inner ear of different species under steady-state conditions. Methods: The databases PubMed, MEDLINE (Ovid), CINAHL (EBSCO), and LIVIVO were used to identify articles. Systematic reviews, experimental studies, and clinical data in English and German were included without time limitations. Results: The search yielded 49 eligible articles published between 1979 and 2022. Resident immune cells, including macrophages, lymphocytes, leukocytes, and mast cells, have been observed in various mammalian inner ear structures under steady-state conditions. However, the physiological function of these cells in the healthy cochlea remains unclear, providing an opportunity for basic research in inner ear biology. Conclusions: This review highlights the need for further investigation into the role of these cells, which is crucial for advancing the development of therapeutic methods for treating inner ear disorders, potentially transforming the field of otolaryngology and immunology. [ABSTRACT FROM AUTHOR]

The operating room demands well-functioning workflows and optimized communication. Based on the formalization of specific surgical interventions via BPMN, intraoperative checklists can automatically be generated to support the surgical team by the provision of relevant clinical information and situation-dependent assistive functions. While focusing on the surgeon, other actors have not yet been considered. The aim of this work is therefore the extension of the intraoperative checklist to enable role-specific support and improved communication between the actors. The BPMN approach is adapted to depict role-specific surgical steps and clinical information to realize the collaborative, multi-role usage of the checklist. The proof of concept demonstrates the automatic generation of intraoperative checklists which provide relevant information depending on the role. An initial evaluation of the checklist based on the cochlea implantation use case shows promising results. [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]

The complex fluid–solid coupling movement of macro–micro structures and lymphatic fluid in the cochlea plays a crucial role in the mechanism of sound perception in the human ear. However, previous studies have primarily focused on the macrostructure and overlooked the microstructure of the Organ of Corti (OC). In reality, the microstructure of the OC can regulate the vibration of the basilar membrane, which is important for sound perception. To address this, a three-dimensional spiral passive cochlear model containing a complete OC that conforms to the real physiology of the human ear was developed, but the significant amplification of its motion by the action of outer hair cells (OHC) in the living cochlea was not considered. The fluid–solid coupling calculations were conducted on this model, specifically examining the mechanical response of the OC microstructure and the pressure changes in the lymphatic fluid. The results showed that the lower stiffness structure in the OC has a lower stress level, which contributes to the realization of sound perception. As the frequencies increases, the region of peak stress and displacement in the OHC moves from the apex to the base of the cochlea, reflecting frequency-selective characteristics. The tunnel of the OC amplifies pressure waves at specific locations, enabling more accurate frequency recognition. Furthermore, the presence of the OC not only causes significant radial differences in lymphatic fluid pressure in the scala vestibule, but also enhances internal cochlear vibration, playing an undeniable regulatory role in the sound perception.Kindly check and verify edit made in article title.We have checked and verified the editing in the article title. [ABSTRACT FROM AUTHOR]

Background: Correct individual tonotopic frequency stimulation of the cochlea plays an important role in the further development of anatomy-based cochlear implantation. In this context, frequency-specific fitting of the basal electrode contact with a normal insertion depth can be difficult since it is often placed in a frequency range higher than 10 kHz, and current audio processors only stimulate for frequencies up to 8.5 kHz due to microphone characteristics. This results in a mismatch of the high frequencies. Therefore, this study represents a proof of concept for a tonotopic correct insertion and aims to develop an algorithm for a placement of the basal electrode below 8.5 kHz in an experimental setting. Methods: Pre- and postoperative flat-panel volume CT scans with secondary reconstructions were performed on 10 human temporal bone specimens. The desired frequency location for the most basal electrode contact was set at 8.25 kHz. The distance from the round window to the position where the basal electrode contact was intended to be located was calculated preoperatively using 3D-curved multiplanar reconstruction and a newly developed mathematical approach. A specially designed cochlear implant electrode array with customized markers imprinted on the silicone of the electrode array was inserted in all specimens based on the individually calculated insertion depths. All postoperative measurements were additionally validated using otological planning software. Results: Positioning of the basal electrode contact was reached with only a small mean deviation of 37 ± 399 Hz and 0.06 ± 0.37 mm from the planned frequency of 8.25 kHz. The mean rotation angle up to the basal electrode contact was 51 ± 5°. In addition, the inserted electrode array adequately covered the apical regions of the cochleae. Conclusion: Using this algorithm, it was possible to position the basal electrode array contact in an area of the cochlea that could be correctly stimulated by the existing speech processors in the context of tonotopic correct fitting. Plain Language Summary: Tonotopic-matched stimulation of the cochlea is important in the context of anatomy-based cochlear implantation. The basal cochlear implant electrode contact is often placed in a frequency range higher than 10 kHz – when a normal insertion depth is reached – and can therefore be difficult to fit since current audio processors only stimulate for frequencies up to 8.5 kHz. This leads to a mismatch of high frequencies. This study represents a proof of concept for a tonotopic correct insertion and aims to develop an algorithm for a placement of the basal electrode below 8.5 kHz in an experimental setting. Therefore, pre- and postoperative CT scans were performed on 10 human temporal bone specimens. Tonotopic information about the aimed position of basal electrode contact was extracted from the imaging dataset by using 3D-curved multiplanar reconstruction and a newly developed mathematical approach. A specially designed cochlear implant electrode array was inserted in all specimens based on the individually calculated insertion depths. Positioning of the basal electrode contact was reached with only a small mean deviation of 37 ± 399 Hz and 0.06 ± 0.37 mm from the planned frequency of 8.25 kHz. In addition, the inserted electrode array adequately covered the apical regions of the cochleae. Using this algorithm, it was possible to position the basal electrode array contact in an area of the cochlea that can be correctly stimulated by the existing speech processors in the context of tonotopic correct fitting. [ABSTRACT FROM AUTHOR]

During embryonic development, Wnt signaling influences both proliferation and sensory formation in the cochlea. How this dual nature of Wnt signaling is coordinated is unknown. In this study, we define a novel role for a Wnt-regulated gene, Mybl2, which was already known to be important for proliferation, in determining the size and patterning of the sensory epithelium in the murine cochlea. Using a quantitative spatial analysis approach and analyzing Mybl2 loss-of-function, we show that Mybl2 promoted proliferation in the inner sulcus domain but limited the size of the sensory domain by influencing their adjoining boundary position via Jag1 regulation during development. Mybl2 loss-of-function simultaneously decreased proliferation in the inner sulcus and increased the size of the sensory domain, resulting in a wider sensory epithelium with ectopic inner hair cell formation during late embryonic stages. These data suggest that progenitor cells in the inner sulcus determine boundary formation and pattern the sensory epithelium via MYBL2. [ABSTRACT FROM AUTHOR]

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Intercellular signaling mediated by evolutionarily conserved planar cell polarity (PCP) proteins aligns cell polarity along the tissue plane and drives polarized cell behaviors during tissue morphogenesis. Accumulating evidence indicates that the vertebrate PCP pathway is regulated by noncanonical, β-catenin-independent Wnt signaling; however, the signaling components and mechanisms are incompletely understood. In the mouse hearing organ, both PCP and noncanonical Wnt (ncWnt) signaling are required in the developing auditory sensory epithelium to control cochlear duct elongation and planar polarity of resident sensory hair cells (HCs), including the shape and orientation of the stereociliary hair bundle essential for sound detection. We have recently discovered a Wnt/G-protein/PI3K pathway that coordinates HC planar polarity and intercellular PCP signaling. Here, we identify Wnt7b as a ncWnt ligand acting in concert with Wnt5a to promote tissue elongation in diverse developmental processes. In the cochlea, Wnt5a and Wnt7b are redundantly required for cochlear duct coiling and elongation, HC planar polarity, and asymmetric localization of core PCP proteins Fzd6 and Dvl2. Mechanistically, Wnt5a/Wnt7b-mediated ncWnt signaling promotes membrane recruitment of Daple, a nonreceptor guanine nucleotide exchange factor for Gαi, and activates PI3K/AKT and ERK signaling, which promote asymmetric Fzd6 localization. Thus, ncWnt and PCP signaling pathways have distinct mutant phenotypes and signaling components, suggesting that they act as separate, parallel pathways with nonoverlapping functions in cochlear morphogenesis. NcWnt signaling drives tissue elongation and reinforces intercellular PCP signaling by regulating the trafficking of PCP-specific Frizzled receptors. [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]

Background: Using Otoplan software, it is possible to measure the cochlea before cochlear implant surgery. Until now, computed tomography (CT) of the cochlea has been necessary for this purpose. The aim of this study was to find out whether measuring the cochlea with magnetic resonance imaging (MRI) using Otoplan is possible with the same accuracy. Methods: The cochlea of 44 patients of the local cochlear implant centre was measured by Otoplan using high-resolution CT-bone and MRI images, and the determined lengths were compared. Results: No significant difference was found between the cochlear lengths measured, regardless of whether the length measurement was based on a CT or an MRI data set. Conclusion: For the determination of cochlear length prior to cochlear implant surgery, MRI images are just as suitable as CT images, therefore CT is not mandatory for length measurement by Otoplan, which could reduce the patient's radiation exposure. [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]

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]

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]

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]

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]

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]

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]

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]

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]

Copyright of Acta Oto-Laryngologica is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Acta Oto-Laryngologica is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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 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]

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]

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]

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]

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]

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 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]

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]

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]

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]

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]