CIB2 function is distinct from Whirlin in the development of cochlear stereocilia staircase pattern.

Variations in genes coding for calcium and integrin binding protein 2 (CIB2) and whirlin cause deafness both in humans and mice. We previously reported that CIB2 binds to whirlin, and is essential for normal staircase architecture of auditory hair cells stereocilia. Here, we refine the interacting domains between these proteins and provide evidence that both proteins have distinct role in the development and organization of stereocilia bundles required for auditory transduction. Using a series of CIB2 and whirlin deletion constructs and nanoscale pulldown (NanoSPD) assays, we localized the regions of CIB2 that are critical for interaction with whirlin. AlphaFold 2 multimer, independently identified the same interacting regions between CIB2 and whirlin proteins, providing a detailed structural model of the interaction between the CIB2 EF2 domain and whirlin HHD2 domain. Next, we investigated genetic interaction between murine Cib2 and Whrn using genetic approaches. Hearing in mice double heterozygous for functionally null alleles (Cib2 KO/+ ;Whrn wi/+ ) was similar to age-matched wild type mice, indicating that partial deficiency for both Cib2 and Whrn does not impair hearing. Double homozygous mutant mice (Cib2 KO/KO ;Whrn wi/wi ) had profound hearing loss and cochlear stereocilia exhibited a predominant phenotype seen in single Whrn wi/wi mutants. Furthermore, over-expression of Whrn in Cib2 KO/KO mice did not rescue the stereocilia morphology. These data suggest that, CIB2 is multifunctional, with key independent functions in development and/or maintenance of stereocilia staircase pattern in auditory hair cells.

Sound-induced drug distribution in the cochlea, how close are we? A PRISMA scoping review.

OBJECTIVE: To 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. DESIGN: 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. STUDY SAMPLE: Thirteen studies met the inclusion criteria, providing insights into the mechanics of cochlear perilymphatic flow and its potential enhancement through sound stimulation. RESULTS: 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. CONCLUSIONS: 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.

From sound waves to molecular and cellular mechanisms: Understanding noise­induced hearing loss and pioneering preventive approaches (Review).

Noise-induced hearing loss (NIHL) is a significant and urgent global public health concern, arising from prolonged exposure to elevated levels of noise. This auditory impairment harms delicate inner ear structures, particularly the essential hair cells transmitting auditory signals to the brain. Recognized by the World Health Organization as a major contributor to worldwide hearing loss, NIHL requires a comprehensive examination of its molecular and cellular mechanisms. Animal models emerge as indispensable tools for unraveling these intricacies, allowing researchers to simulate and study the impact of noise exposure on auditory structures, shedding light on the interplay of oxidative stress, inflammation and immune responses-crucial factors in NIHL progression. The present review focuses on elucidating the molecular mechanisms of NIHL, with a specific emphasis on findings derived from animal models, alongside the exploration of thorough preventive strategies, including protective measures and probing potential interventions. Understanding the molecular underpinnings not only provides insight into targeted treatment approaches, but also unlocks pathways for exploring and implementing preventive actions. This approach not only deepens the current comprehension of NIHL, but also has the potential to influence the shaping of public health policies, offering a nuanced perspective on this prevalent auditory disorder.

Wnt7b acts in concert with Wnt5a to regulate tissue elongation and planar cell polarity via noncanonical Wnt signaling.

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, ß-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.

Developmental shaping of node of Ranvier geometry contributes to spike timing maturation in primary auditory afferents.

Sound is encoded by action potentials in spiral ganglion neurons (SGNs), the auditory afferents from the cochlea. Rapid action potential transmission along SGNs is crucial for quick reactions to sounds, and binaural differences in action potential arrival time at the SGN output synapses enable sound localization based on interaural time or phase differences. SGN myelination increases conduction speed but other cellular changes may contribute. We show that nodes of Ranvier along peripherally and centrally directed SGN neurites form around hearing onset, but peri-somatic nodes mature later. There follows an adjustment of nodal geometry, notably a decrease in length and increase in diameter. Computational modeling predicts this increases conduction speed by >4%, and that four additional myelin wraps would be required on internodes to achieve the same conduction speed increase. We propose that nodal geometry changes optimize signal conduction for mature sound coding and decrease the energy needed for myelination.

Predicting ecology and hearing sensitivities in Parapontoporia-An extinct long-snouted dolphin.

Analyses of the cetacean (whale and dolphin) inner ear provide glimpses into the ecology and evolution of extinct and extant groups. The paleoecology of the long-snouted odontocete (toothed whale) group, Parapontoporia, is primarily marine with its depositional context also suggesting freshwater tolerance. As an extinct relative of the exclusively riverine Lipotes vexillifer, Parapontoporia provides insight into a transition from marine to freshwater environments. High-resolution X-ray CT scans (~3 microns or less) of three individual specimens from two species, P. sternbergi and P. pacifica, were acquired. Digital endocasts of the inner ear labyrinths were extracted non-destructively. Nine measurements of the inner ear were compared with an existing dataset covering 125 terrestrial and aquatic artiodactyls. These measurements were then subjected to a principal component analysis to interpret hearing sensitivities among other artiodactyls. Based on our analyses, Parapontoporia was likely to have been able to hear within narrow-band high frequency (NBHF) ranges. This finding indicates another convergence of NBHF-style hearing, or, more intriguingly, suggests that it may be an ancestral characteristic present among the longirostrine dolphins that dominated in the Miocene prior to the evolution of more modern lineages.

Relationship Between Cochlear Lateral Wall Changes and Endolymphatic Hydrops in Otitis Media.

OBJECTIVES: Despite otitis media and various disease processes being associated with endolymphatic hydrops (EH), an exact explanation of the pathophysiology has yet to be reported. This study aimed to investigate the changes in the cochlear lateral wall structures and their potential correlation with the presence and severity of cochlear EH in acute and chronic otitis media cases. The investigations were conducted in both chinchilla animal model and human temporal bone specimens. METHODS: We studied a total of 15 chinchilla and 25 human temporal bones from our collection, which were categorized into acute otitis media, chronic otitis media (COM), and control groups. Through quantitative analysis, we measured the area of cochlear lateral wall structures and observed the presence and the degree of EH using light microscopy. RESULTS: No significant changes were determined in the area of the spiral ligament (p > 0.05) across the species. However, a significant (p < 0.05) decrease in the mean area of the stria vascularis in the basal turn was identified in COM groups compared to controls of both species. Chinchilla model additionally exhibited pathology extending to the lower mid turn. A negative correlation was found between the mean strial area and the severity of EH in both the animal model and human samples. CONCLUSIONS: COM associated with significant changes in the stria vascularis that may lead to significant increase in the degree of EH. The presented animal model exhibited parallel findings with human samples, suggesting its viability as a valuable model for future studies. LEVEL OF EVIDENCE: N/A Laryngoscope, 2024.

Hyperosmotic sisomicin infusion: a mouse model for hearing loss.

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.

Pathophysiological processes underlying hidden hearing loss revealed in Kcnt1/2 double knockout mice.

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.

On the Design, Fabrication, and Characterization of a Novel Thin-Film Electrode Array for Use in Cochlear Implants.

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.

Pulsed DPOAEs in serial measurements : Combined analysis paradigm of simultaneously occurring changes in hearing thresholds and DPOAEs.

BACKGROUND: To date, there is no consensus on how to standardize the assessment of ototoxicity in serial measurements. For the diagnosis of damage to the cochlear amplifier, measurement methods are required that have the highest possible test-retest reliability and validity for detecting persistent damage. Estimated distortion-product thresholds (LEDPT) based on short-pulse distortion-product otoacoustic emission (DPOAE) level maps use individually optimal DPOAE stimulus levels and allow reliable quantitative estimation of cochlea-related hearing loss. MATERIALS AND METHODS: Hearing thresholds were estimated objectively using LEDPT and subjectively using modified Békésy tracking audiometry (LTA). Recordings were performed seven times within three months at 14 frequencies (f2 = 1-14 kHz) in 20 ears (PTA4 (0.5-4 kHz) < 20 dB HL). Reconstruction of the DPOAE growth behavior as a function of the stimulus levels L1, L2 was performed on the basis of 21 DPOAE amplitudes. A numerical fit of a nonlinear mathematical function to the three-dimensional DPOAE growth function yielded LEDPT for each stimulus frequency. For the combined analysis, probability distributions of hearing thresholds (LTA, LEDPT), DPOAE levels (LDP), and combinations thereof were determined. RESULTS: LTA and LEDPT each exhibited a test-retest reliability with a median of absolute differences (AD) of 3.2 dB and 3.3 dB, respectively. Combining LEDPT, LDP, and LTA into a single parameter yielded a significantly smaller median AD of 2.0 dB. CONCLUSION: It is expected that an analysis paradigm based on a combination of LEDPT, suprathreshold LDP, and fine-structure-reduced LTA would achieve higher test performance (sensitivity and specificity), allowing reliable detection of pathological or regenerative changes in the outer hair cells.

Intra-Cochlear Electrode Position Impacts the Preservation of Residual Hearing in an Animal Model of Cochlear Implant Surgery.

INTRODUCTION: Preservation of residual hearing after cochlear implantation remains challenging. There are several approaches to preserve residual hearing, but the configuration of the implant electrode array seems to play a major role. Lateral wall electrode arrays are seemingly more favorable in this context. To date, there are no experimental data available which correlate the spatial electrode position in the scala tympani with the extent of hearing preservation. METHODS: Based on micro-computed tomography (µCT) imaging data, this study analyses the exact position of a pure silicone electrode array inserted into the cochlea of four guinea pigs. Array position data were correlated with the extent of hearing loss after implantation, measured using auditory brainstem measurements in the frequency range of the area occupied by the electrode array area as well as apical to the array. RESULTS: The use of pure silicone arrays without electrodes resulted in artifact-free, high-resolution µCT images that allowed precise determination of the arrays' positions within the scala tympani. The electrode arrays' locations ranged from peri-modiolar to an anti-modiolar. These revealed a correlation of a lower postoperative hearing loss with a higher spatial proximity to the lateral wall. This correlation was found in the low-frequency range only. A significant correlation between the inter-individual differences in the diameter of the scala tympani and the postoperative hearing loss could not be observed. CONCLUSION: This study demonstrates the importance of the intra-cochlear electrode array's position for the preservation of residual hearing. The advantage of such an electrode array's position approximated to the lateral wall suggests, at least for this type of electrode array applied in the guinea pig, it would be advantageous in the preservation of residual hearing for the apical part of the cochlea, beyond the area occupied by the electrode array.

Nanodelivery of antioxidant Agents: A promising strategy for preventing sensorineural hearing loss.

Sensorineural hearing loss (SNHL), often stemming from reactive oxygen species (ROS) generation due to various factors such as ototoxic drugs, acoustic trauma, and aging, remains a significant health concern. Oxidative stress-induced damage to the sensory cells of the inner ear, particularly the non-regenerating hair cells, is a critical pathologic mechanism leading to SNHL. Despite the proven efficacy of antioxidants in mitigating oxidative stress, their clinical application for otoprotection is hindered by the limitations of conventional drug delivery methods. This review highlights the challenges associated with systemic and intratympanic administration of antioxidants, including the blood-labyrinthine barrier, restricted permeability of the round window membrane, and inadequate blood flow to the inner ear. To overcome these hurdles, the application of nanoparticles as a delivery platform for antioxidants emerges as a promising solution. Nanocarriers facilitate indirect drug delivery to the cochlea through the round and oval window membrane, optimising drug absorption while reducing dosage, Eustachian tube clearance, and associated side effects. Furthermore, the development of nanoparticles carrying antioxidants tailored to the intracochlear environment holds immense potential. This literature research aimed to critically examine the root causes of SNHL and ROS overproduction in the inner ear, offering insights into the application of nanoparticle-based drug delivery systems for safeguarding sensorineural hair cells. By focusing on the intricate interplay between oxidative stress and hearing loss, this research aims to contribute to the advancement of innovative therapeutic strategies for the prevention of SNHL.

Association of audiovestibular findings with fluid-attenuated inversion recovery magnetic resonance imaging in patients with vestibular schwannoma.

BACKGROUND: Vestibular schwannoma (VS) is a benign tumor of the vestibular nerve. Flair-attenuated inversion recovery (FLAIR) of magnetic resonance imaging (MRI) images are sensitive in detecting high protein contents of fluids. OBJECTIVES: To investigate the association between signal intensity (SI) on FLAIR images and audiovestibular findings in patients with VS. METHODS: Medical records of twenty-five patients with VS were retrospectively analyzed. RESULTS: Larger tumors were associated with increased FLAIR SI of the cochlea, vestibule, and semicircular canal (SCC) on the affected side compared to those of the unaffected side. Pure-tone audiometry (PTA), and speech audiometry were associated with the SI of the affected cochlea. There was no significant correlation between the SI of the vestibule and vestibular evoked myogenic potential, SI of the SCC, and caloric test or video head impulse test results. CONCLUSION: Our study suggests that tumor size was significantly associated with high SI on FLAIR imaging, and audiological findings were associated with the SI of the affected cochlea. Further studies with larger cohorts are required to confirm the association between vestibular function and FLAIR imaging in VS.

Age-related changes in olivocochlear efferent innervation in gerbils.

Introduction: Age-related hearing difficulties have a complex etiology that includes degenerative processes in the sensory cochlea. The cochlea comprises the start of the afferent, ascending auditory pathway, but also receives efferent feedback innervation by two separate populations of brainstem neurons: the medial olivocochlear and lateral olivocochlear pathways, innervating the outer hair cells and auditory-nerve fibers synapsing on inner hair cells, respectively. Efferents are believed to improve hearing under difficult conditions, such as high background noise. Here, we compare olivocochlear efferent innervation density along the tonotopic axis in young-adult and aged gerbils (at ~50% of their maximum lifespan potential), a classic animal model for age-related hearing loss. Methods: Efferent synaptic terminals and sensory hair cells were labeled immunohistochemically with anti-synaptotagmin and anti-myosin VIIa, respectively. Numbers of hair cells, numbers of efferent terminals, and the efferent innervation area were quantified at seven tonotopic locations along the organ of Corti. Results: The tonotopic distribution of olivocochlear innervation in the gerbil was similar to that previously shown for other species, with a slight apical cochlear bias in presumed lateral olivocochlear innervation (inner-hair-cell region), and a broad mid-cochlear peak for presumed medial olivocochlear innervation (outer-hair-cell region). We found significant, age-related declines in overall efferent innervation to both the inner-hair-cell and the outer-hair-cell region. However, when accounting for the age-related losses in efferent target structures, the innervation density of surviving elements proved unchanged in the inner-hair-cell region. For outer hair cells, a pronounced increase of orphaned outer hair cells, i.e., lacking efferent innervation, was observed. Surviving outer hair cells that were still efferently innervated retained a nearly normal innervation. Discussion: A comparison across species suggests a basic aging scenario where outer hair cells, type-I afferents, and the efferents associated with them, steadily die away with advancing age, but leave the surviving cochlear circuitry largely intact until an advanced age, beyond 50% of a species' maximum lifespan potential. In the outer-hair-cell region, MOC degeneration may precede outer-hair-cell death, leaving a putatively transient population of orphaned outer hair cells that are no longer under efferent control.

On the design of a macro-micro parallel manipulator for cochlear microrobot operations.

BACKGROUND: The method of stem cell transfer to narrow cochlear canals in vivo to generate hair cells is still an unclear operation. Thus, the development of any possible method that will ensure the usage of medical microrobots in small cochlear workspaces is a challenging procedure. METHODS: The current study tries to introduce a macro-micro manipulator system composed of a 6-DoF industrial serial manipulator as a macro manipulator and a proposed 5-DoF parallel manipulator with dual end effectors as a micro manipulator carrying permanent magnets for tetherless microrobot actuation inside the cochlea. RESULTS: Throughout the study, structural synthesis and kinematic analysis of the proposed micro manipulator were introduced. A prototype of the manipulator was manufactured and its hardware verification procedures were carried out using motion capture cameras and surgical navigation registration methodologies. CONCLUSIONS: Following motion training, the assembled macro-micro manipulator was successfully utilised to actuate a microrobot placed inside a manufactured cochlea mockup model.

Associations between diabetes mellitus and sensorineural hearing loss from humans and animal studies.

There is controversy regarding the association and etiopathogenesis of diabetes mellitus (DM) and sensorineural hearing loss (SNHL). Some studies support that SNHL develops because of angiopathy and/or neuropathy caused by DM, but many of the findings have been inconsistent. This review aims to highlight a select number of studies that effectively describe the relationship between DM and SNHL, thus bringing more attention and awareness to this area of research. This review also describes animal models to understand better the mechanisms of DM contributing to SNHL in the inner ear. The goal of this narrative review is for researchers and healthcare professionals to further their understanding and investigation of the etiopathogenesis of both DM and SNHL, therefore leading to the development of effective treatments for diabetic patients displaying symptoms of SNHL.

Spiral ganglion neuron degeneration in aminoglycoside-deafened rats involves innate and adaptive immune responses not requiring complement.

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 aminoglycoside-induced 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 kanamycin-induced 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.

Cochlear Implantation: Long-Term Effect of Early Activation on Electrode Impedance.

Objectives: The growing adoption of cochlear implants (CIs) necessitates understanding the factors influencing long-term performance and improved outcomes. This work investigated the long-term effect of early activation of CIs on electrode impedance in a large sample of CI users at different time points. Methods: A retrospective study on 915 ears from CI patients who were implanted between 2015 and 2020. According to their CI audio processor activation time, the patients were categorized into early activation (activated 1 day after surgery, n = 481) and classical activation (activated 4 weeks after surgery, n = 434) groups. Then, the impact of the activation times on the electrode impedance values, along the electrode array contacts, at different time points up to two years was studied and analyzed. Results: The early activation group demonstrated lower impedance values across all the electrode array sections compared to the classical activation at 1 month, 1 year, and 2 years post-implantation. At 1 month, early activation was associated with a reduction of 0.34 kΩ, 0.46 kΩ, and 0.37 kΩ in the apical, middle, and basal sections, respectively. These differences persisted at subsequent intervals. Conclusions: Early activation leads to sustained reductions in the electrode impedance compared to classical activation (CA), suggesting that earlier activation might positively affect long-term CI outcomes.

Electron Microscopic Mapping of Mitochondrial Morphology in the Cochlear Nerve Fibers.

To enable nervous system function, neurons are powered in a use-dependent manner by mitochondria undergoing morphological-functional adaptation. In a well-studied model system-the mammalian cochlea, auditory nerve fibers (ANFs) display distinct electrophysiological properties, which is essential for collectively sampling acoustic information of a large dynamic range. How exactly the associated mitochondrial networks are deployed in functionally differentiated ANFs remains scarcely interrogated. Here, we leverage volume electron microscopy and machine-learning-assisted image analysis to phenotype mitochondrial morphology and distribution along ANFs of full-length in the mouse cochlea inner spiral bundle. This reveals greater variance in mitochondrial size with increased ANF habenula to terminal path length. Particularly, we analyzed the ANF terminal-residing mitochondria, which are critical for local calcium uptake during sustained afferent activities. Our results suggest that terminal-specific enrichment of mitochondria, in addition to terminal size and overall mitochondrial abundance of the ANF, correlates with heterogenous mitochondrial contents of the terminal.