OBJECTIVE: Evaluation of the Slim Modiolar (SM) electrode in temporal bones (TB) will elucidate the electrode\'s insertion outcomes.
BACKGROUND: The SM electrode was designed for atraumatic insertion into the scala tympani, for ideal perimodiolar positioning and with a smaller caliber to minimize interference with cochlear biological processes.
METHODS: The SM electrode was inserted into TBs via a cochleostomy. First, the axial force of insertion was measured. Next, TBs were inserted under fluoroscopy to study insertion dynamics, followed by histologic evaluation of electrode placement and cochlear trauma. A subset of TBs were inserted with the Contour Advance (CA) electrode for comparison.
RESULTS: Sixteen of 22 insertions performed to measure the axial force of insertion had flat or near zero insertion force profiles. Six insertions had increased insertion forces, which were attributed to improper sheath depth before electrode insertion. Under real-time fluoroscopy, 23 of 25 TBs had uneventful insertion and good perimodiolar placement. There was 1 scala vestibuli insertion due to suboptimal cochleostomy position and 1 tip roll over related to premature electrode deployment. When compared with the CA electrode, 14 of 15 insertions with the SM electrode resulted in a more perimodiolar electrode position. No evidence of trauma was found in histologic evaluation of the 24 TBs with scala tympani insertions.
CONCLUSIONS: TB evaluation revealed that the SM electrode exerts minimal insertion forces on cochlear structures, produces no histologic evidence of trauma, and reliably assumes the perimodiolar position. Nonstandard cochleostomy location, improper sheath insertion depth, or premature deployment of the electrode may lead to suboptimal outcomes.

In order to improve the prediction accuracy of the sound quality of vehicle interior noise, a novel sound quality prediction model was proposed based on the physiological response predicted metrics, i.e., loudness, sharpness, and roughness. First, a human-ear sound transmission model was constructed by combining the outer and middle ear finite element model with the cochlear transmission line model. This model converted external input noise into cochlear basilar membrane response. Second, the physiological perception models of loudness, sharpness, and roughness were constructed by transforming the basilar membrane response into sound perception related to neuronal firing. Finally, taking the calculated loudness, sharpness, and roughness of the physiological model and the subjective evaluation values of vehicle interior noise as the parameters, a sound quality prediction model was constructed by TabNet model. The results demonstrate that the loudness, sharpness, and roughness computed by the human-ear physiological model exhibit a stronger correlation with the subjective evaluation of sound quality annoyance compared to traditional psychoacoustic parameters. Furthermore, the average error percentage of sound quality prediction based on the physiological model is only 3.81%, which is lower than that based on traditional psychoacoustic parameters.

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.

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.

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.

The discovery and development of electrocochleography (ECochG) in animal models has been fundamental for its implementation in clinical audiology and neurotology. In our laboratory, the use of round-window ECochG recordings in chinchillas has allowed a better understanding of auditory efferent functioning. In previous works, we gave evidence of the corticofugal modulation of auditory-nerve and cochlear responses during visual attention and working memory. However, whether these cognitive top-down mechanisms to the most peripheral structures of the auditory pathway are also active during audiovisual crossmodal stimulation is unknown. Here, we introduce a new technique, wireless ECochG to record compound-action potentials of the auditory nerve (CAP), cochlear microphonics (CM), and round-window noise (RWN) in awake chinchillas during a paradigm of crossmodal (visual and auditory) stimulation. We compared ECochG data obtained from four awake chinchillas recorded with a wireless ECochG system with wired ECochG recordings from six anesthetized animals. Although ECochG experiments with the wireless system had a lower signal-to-noise ratio than wired recordings, their quality was sufficient to compare ECochG potentials in awake crossmodal conditions. We found non-significant differences in CAP and CM amplitudes in response to audiovisual stimulation compared to auditory stimulation alone (clicks and tones). On the other hand, spontaneous auditory-nerve activity (RWN) was modulated by visual crossmodal stimulation, suggesting that visual crossmodal simulation can modulate spontaneous but not evoked auditory-nerve activity. However, given the limited sample of 10 animals (4 wireless and 6 wired), these results should be interpreted cautiously. Future experiments are required to substantiate these conclusions. In addition, we introduce the use of wireless ECochG in animal models as a useful tool for translational research.

Sounds are temporal stimuli decomposed into numerous elementary components by the auditory nervous system. For instance, a temporal to spectro-temporal transformation modelling the frequency decomposition performed by the cochlea is a widely adopted first processing step in today\'s computational models of auditory neural responses. Similarly, increments and decrements in sound intensity (i.e., of the raw waveform itself or of its spectral bands) constitute critical features of the neural code, with high behavioural significance. However, despite the growing attention of the scientific community on auditory OFF responses, their relationship with transient ON, sustained responses and adaptation remains unclear. In this context, we propose a new general model, based on a pair of linear filters, named AdapTrans, that captures both sustained and transient ON and OFF responses into a unifying and easy to expand framework. We demonstrate that filtering audio cochleagrams with AdapTrans permits to accurately render known properties of neural responses measured in different mammal species such as the dependence of OFF responses on the stimulus fall time and on the preceding sound duration. Furthermore, by integrating our framework into gold standard and state-of-the-art machine learning models that predict neural responses from audio stimuli, following a supervised training on a large compilation of electrophysiology datasets (ready-to-deploy PyTorch models and pre-processed datasets shared publicly), we show that AdapTrans systematically improves the prediction accuracy of estimated responses within different cortical areas of the rat and ferret auditory brain. Together, these results motivate the use of our framework for computational and systems neuroscientists willing to increase the plausibility and performances of their models of audition.

UNASSIGNED: Diabetes is closely linked to hearing loss, yet the exact mechanisms remain unclear. Cochlear stria vascularis and pericytes (PCs) are crucial for hearing. This study investigates whether high glucose induces apoptosis in the cochlear stria vascularis and pericytes via elevated ROS levels due to oxidative stress, impacting hearing loss.
UNASSIGNED: We established a type II diabetes model in C57BL/6J mice and used auditory brainstem response (ABR), Evans blue staining, HE staining, immunohistochemistry, and immunofluorescence to observe changes in hearing, blood-labyrinth barrier (BLB) permeability, stria vascularis morphology, and apoptosis protein expression. Primary cultured stria vascularis pericytes were subjected to high glucose, and apoptosis levels were assessed using flow cytometry, Annexin V-FITC, Hoechst 33342 staining, Western blot, Mitosox, and JC-1 probes.
UNASSIGNED: Diabetic mice showed decreased hearing thresholds, reduced stria vascularis density, increased oxidative stress, cell apoptosis, and decreased antioxidant levels. High glucose exposure increased apoptosis and ROS content in pericytes, while mitochondrial membrane potential decreased, with AIF and cytochrome C (CytC) released from mitochondria to the cytoplasm. Adding oxidative scavengers reduced AIF and CytC release, decreasing pericyte apoptosis.
UNASSIGNED: Hyperglycemia may induce mitochondrial apoptosis of cochlear stria vascularis pericytes through oxidative stress.

Sgms1 encodes sphingomyelin synthase 1, an enzyme in the sphingosine-1-phosphate signalling pathway, and was previously reported to underlie hearing impairment in the mouse. A new mouse allele, Sgms1tm1a, unexpectedly showed normal Auditory Brainstem Response thresholds. We found that the Sgms1tm1a mutation led to incomplete knockdown of transcript to 20 % of normal values, which was enough to support normal hearing. The Sgms1tm1b allele was generated by knocking out exon 7, leading to a complete lack of detectable transcript in the inner ear. Sgms1tm1b homozygotes showed largely normal auditory brainstem response thresholds at first, followed by progressive loss of sensitivity until they showed severe impairment at 6 months old. The endocochlear potential was consistently reduced in Sgms1tm1b mutants at 3, 4 and 8 weeks old, to around 80 mV compared with around 120 mV in control littermates. The stria vascularis showed a characteristic irregularity of marginal cell surfaces and patchy loss of Kcnq1 expression at their apical membrane, and expression analysis of the lateral wall suggested that marginal cells were the most likely initial site of dysfunction in the mutants. Finally, significant association of auditory thresholds with DNA markers within and close to the human SGMS1 gene were found in the 1958 Birth Cohort, suggesting that SGMS1 variants may play a role in the range of hearing abilities in the human population.

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.