An Accurate and Individualized Preoperative Estimation Method for the Linear Insertion Depth of Cochlear Implant Electrode Arrays Based on Computed Tomography.

OBJECTIVES: Cochlear implantation or auditory brainstem implantation is currently the only accepted method for improving severe or profound sensorineural hearing loss. The length of the electrodes implanted during cochlear implantation is closely related to the degree of hearing improvement of hearing after the surgery. We aimed to explore new methods to accurately estimate the electrode array (EA) linear insertion depth based on computed tomography (CT) images prior surgery, which could help surgeons select the appropriate EA length for each patient. DESIGN: Previous studies estimated the linear insertion depth by measuring the length of the lateral wall of the cochlea rather than the electrode's path in the cochlea duct. Here, we determined the actual position of the EA on the CT image after cochlear surgery in order to predict the path of the EA, and the length of the predicted EA path was measured by the contouring technique (CoT) to estimate the linear insertion depth of the EA. Because CoT can only measure the length of the estimated EA path on a two-dimensional plane, we further modified the measurement by weighting the height of the cochlea and the length of the EA tail (the length of the last stimulating electrode to the end, which cannot be displayed on the CT image), which we termed the modified CoT + height + tail (MCHT) measurement. RESULTS: Based on our established method, MCHT could reduce the error to the submillimeter range (0.67 ± 0.37 mm) when estimating the linear insertion depth of various kinds of EAs compared with the actual implant length. The correlation coefficient between the linear insertion depth as predicted by MCHT and the actual was 0.958. The linear insertion depth estimated by this method was more accurate than that estimated using the classical CoT technique ( R = 0.442) and using the modified Escudé's method ( R = 0.585). CONCLUSIONS: MCHT is a method based on CT images that can accurately predict the linear insertion depth of cochlear implants preoperatively. This is the first report that we are aware of a method for predicting linear insertion depth before cochlear implantation with only submillimeter errors and that is tailored to different types of EAs.

Sox2 overexpression alleviates noise-induced hearing loss by inhibiting inflammation-related hair cell apoptosis.

BACKGROUND: The transcription factor Sox2 plays important roles in the developmental processes of multiple organs and tissues. However, whether Sox2 can protect mature or terminally differentiated cells against injury is still unknown. METHODS: We investigated the roles of Sox2 in cochlear hair cells, which are terminally differentiated cells, using conditional transgenic mice and several hearing loss models. RESULTS: Sox2 overexpression dramatically mitigated the degree of cochlear hair cell loss when exposed to ototoxic drugs. Noise-induced apoptosis of cochlear hair cells and hearing loss were also significantly alleviated by Sox2 overexpression. Notably, noise-induced upregulation of pro-inflammatory factors such as TNF-α and IL6 was inhibited by Sox2 overexpression. Then we used lipopolysaccharide to clarify the effect of Sox2 on cochlear inflammation, and Sox2 overexpression significantly inhibited lipopolysaccharide-induced upregulation of pro-inflammatory factors and alleviated inflammation-related cochlear hair cell death. CONCLUSIONS: These results demonstrate a novel protective role of Sox2 in mature and terminally differentiated cochlear hair cells by inhibiting inflammation.

Integration of Functional Human Auditory Neural Circuits Based on a 3D Carbon Nanotube System.

The physiological interactions between the peripheral and central auditory systems are crucial for auditory information transmission and perception, while reliable models for auditory neural circuits are currently lacking. To address this issue, mouse and human neural pathways are generated by utilizing a carbon nanotube nanofiber system. The super-aligned pattern of the scaffold renders the axons of the bipolar and multipolar neurons extending in a parallel direction. In addition, the electrical conductivity of the scaffold maintains the electrophysiological activity of the primary mouse auditory neurons. The mouse and human primary neurons from peripheral and central auditory units in the system are then co-cultured and showed that the two kinds of neurons form synaptic connections. Moreover, neural progenitor cells of the cochlea and auditory cortex are derived from human embryos to generate region-specific organoids and these organoids are assembled in the nanofiber-combined 3D system. Using optogenetic stimulation, calcium imaging, and electrophysiological recording, it is revealed that functional synaptic connections are formed between peripheral neurons and central neurons, as evidenced by calcium spiking and postsynaptic currents. The auditory circuit model will enable the study of the auditory neural pathway and advance the search for treatment strategies for disorders of neuronal connectivity in sensorineural hearing loss.

Clinical correlation research of 3D reconstruction of retrolabyrinthine space based on HRCT of temporal bone.

Background: The retrolabyrinthine approach helps clinicians perform complex surgeries such as vestibular neurectomy, resection of petrous apex cholesteatoma, or use this space to complete endoscopic combined with microscope surgical operations in a relatively safe buffer space. Some of our current studies using 3D reconstruction in the clinic have also helped us perform some complex surgical procedures.Objective: This study aims to reveal the relationship between important structures in retrolabyrinthine space through objective parameters. These measurement data help clinicians locate intraoperatively and provide a reference for clinical surgery. Also, we are intended to help improve surgical techniques and expand the operating space to increase reachable anatomic structure.Material and Methods: The inner structures of the temporal bone from HRCT (High-resolution computed tomography) images which were taken at the Eye & ENT Hospital of Fudan University were reconstructed. Precise measurement of the structures was accomplished by using the software 3D-Slicer (3D Slicer, https://www.slicer.org/; version 4.8.0, Massachusetts, USA).Results: 3D model of temporal bone structures, including the cochlea, semicircular canals (SCCs), the internal auditory canal (IAC), facial nerve (FN), jugular bulb(JB), and carotid artery was reconstructed. The combination of HRCT and 3D models is utilized to analyze the Quantitative data of the retrolabyrinthine space and its adjacent structures.Conclusions and Significance: 3D reconstruction of CT images clearly displayed the detailed structures of the temporal bone. Surgical adaptability of the retrolabyrinthine approach can be assessed preoperatively by image and other methods, and anatomical parameters play an important role in the retrolabyrinthine space. Therefore, this study helps to skeleton the bone as much as possible to expand the surgical space, so that the surgeon can contact the anatomical structure more diversified to expand the surgical indications.

Generation of p27icreER transgenic mice: A tool for inducible gene expression in supporting cells in the cochlea.

The loss of cochlear hair cells (HCs) is an important cause of sensorineural hearing loss, and finding ways to regenerate HCs would be the ideal way forward for restoring hearing. In this research field, tamoxifen-inducible Cre recombinase (iCreER) transgenic mice and the Cre-loxp system are widely used to manipulate gene expression in supporting cells (SCs), which lie beneath the sensory HCs and are a natural source for HC regeneration. However, many iCreER transgenic lines are of limited utility because they cannot target all subtypes of SCs or they cannot be used in the adult stage. In this study, a new line of iCreER transgenic mice, the p27-P2A-iCreERT2 knock-in mouse strain, was generated by inserting the P2A-iCreERT2 cassette immediately in front of the stop codon of p27, which kept the endogenous expression and function of p27 intact. Using a reporter mouse line with tdTomato fluorescence, we showed that the p27iCreER transgenic line can target all subtypes of cochlear SCs, including Claudius cells. p27-CreER activity in SCs was observed in both the postnatal and the adult stage, suggesting that this mouse strain can be useful for research work in adult cochlear HC regeneration. We then overexpressed Gfi1, Pou4f3, and Atoh1 in p27+ SCs of P6/7 mice using this strain and successfully induced many new Myo7a/tdTomato double-positive cells, further confirming that the p27-P2A-iCreERT2 mouse strain is a new and reliable tool for cochlear HC regeneration and hearing restoration.

Dynamic change of vestibular function and the long-term prognosis of vestibular neuritis.

AIM: To comprehensively evaluate the dynamic change of vestibular function during long-term follow-up of vestibular neuritis, as well as the co-relationship with the outcomes of vestibular neuritis (VN), which provides the recommendations for vestibular function tests during the course of VN. METHODS: A prospective cohort study was conducted on 16 patients with acute VN. Caloric test, vHIT, rotatory chair tests, VEMP, dizziness handicap inventory (DHI) score, and dynamic dizzy scales (VAS-DD) was first performed within 7 days of neuritis onset, which were further re-evaluated during the 6-12 months of follow-up. The dynamic changes on multiple objective vestibular examinations were analyzed during the acute and recovery stage of VN. We further evaluated the co-relationship between the vestibular dysfunction scales and the prognosis of VN. RESULTS: In more than 6 months of follow-up, 44% of the ultralow frequency, 94% of the low-to-mid frequency, and 44% of the high-frequency function of the horizontal semicircular canal returned to normal (p < 0.05). The change degree in symmetry of the rotatory chair test was correlated with the gain of the horizontal semicircular canal on the vHIT and the unilateral weakness (UW) value on the caloric test (p < 0.05). The change in DHI score was correlated with the phase; change in VAS-DD level correlated with the symmetry and TC of the rotatory chair test at VN recovery stage (p < 0.05). There was no significant correlation between the change in DHI score or change in VAS-DD and the degree of vestibular function recovery (p > 0.05). CONCLUSION: In general, vestibular function improved during the course of VN. The rotatory chair test can be used to evaluate the overall function of the vestibular system and the compensatory state in patients with VN.

Reduced BDNF expression in the auditory cortex contributed to neonatal pain-induced hearing impairment and dendritic pruning deficiency in mice.

INTRODUCTION: Procedural pain in neonates is associated with impaired neurodevelopment. Whether hearing development is impaired, however, remains unknown. This study examined potential cause-and-effect relationship between neonatal pain and subsequent hearing loss in mice. METHODS: Male C57BL/6J mouse pups received an intra-plantar injection of complete Freund's adjuvant on postnatal day 7 or repetitive needle prick stimuli from postnatal days 0-7. Mechanical and thermal pain thresholds were tested between postnatal days 14 and 49. The auditory brainstem response test was used to determine hearing thresholds. The inner ear structures and dendritic morphology in auditory cortex were assessed using immunofluorescence and Golgi-staining. The effects of oxycodone, tropomyosin receptor kinase B agonists and antagonists were tested. RESULTS: Neonatal pain resulted in impaired hearing in adulthood of both pain models No damage or synapse loss was found in the cochlea but increased dendritic spine density and reduced brain-derived neurotrophic factor level were found in auditory cortex in neonatal pain group. Oxycodone attenuated hearing loss and the associated changes in dendritic spine density and brain-derived neurotrophic factor changes in auditory cortex. A tropomyosin receptor kinase B agonist reversed neonatal pain-induced hearing impairment and decreased caspase 3 expression in auditory cortex. Administration of tropomyosin receptor kinase B antagonist in naïve mouse pups impaired hearing development suppressed phosphorylated-AKT, and increased caspase 3 expression. CONCLUSION: Chronic pain during the neonatal period resulted in impaired hearing in adulthood in mice, possibly via the brain-derived neurotrophic factor signaling pathway and dendritic spine pruning deficiency in auditory cortex.

Varying mechanical forces drive sensory epithelium formation.

The mechanical cues of the external microenvironment have been recognized as essential clues driving cell behavior. Although intracellular signals modulating cell fate during sensory epithelium development is well understood, the driving force of sensory epithelium formation remains elusive. Here, we manufactured a hybrid hydrogel with tunable mechanical properties for the cochlear organoids culture and revealed that the extracellular matrix (ECM) drives sensory epithelium formation through shifting stiffness in a stage-dependent pattern. As the driving force, moderate ECM stiffness activated the expansion of cochlear progenitor cell (CPC)-derived epithelial organoids by modulating the integrin α3 (ITGA3)/F-actin cytoskeleton/YAP signaling. Higher stiffness induced the transition of CPCs into sensory hair cells (HCs) through increasing the intracellular Ca2+ signaling mediated by PIEZO2 and then activating KLF2 to accomplish the cell specification . Our results identify the molecular mechanism of sensory epithelium formation guided by ECM mechanical force and contribute to developing therapeutic approaches for HC regeneration.

Apigenin alleviates neomycin-induced oxidative damage via the Nrf2 signaling pathway in cochlear hair cells.

Oxidative stress plays an important role in the pathogenesis of aminoglycoside-induced hearing loss and represents a promising target for treatment. We tested the potential effect of apigenin, a natural flavonoid with anticancer, anti-inflammatory, and antioxidant activities, on neomycin-induced ototoxicity in cochlear hair cells in vitro. Results showed that apigenin significantly ameliorated the loss of hair cells and the accumulation of reactive oxygen species upon neomycin injury. Further evidence suggested that the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway was activated by apigenin treatment. Disruption of the Nrf2 axis abolished the effects of apigenin on the alleviation of oxidative stress and subsequent apoptosis of hair cells. This study provided evidence of the protective effect of apigenin on cochlear hair cells and its underlying mechanism.

Long-Term Hearing Stability at Different Frequencies after Lower Intact Bridge Tympanomastoidectomy and Possible Theoretical Basis.

Objective: We aimed to review the long-term hearing outcomes of intact bridge tympanomastoidectomy (IBM) to discuss hearing preservation and combine the theory of "modified miniature lung," middle ear ventilation, and gas pressure balance theory to explore the possible reasons for long-term stable hearing. Study Design: We designed a collection of patients with chronic suppurative otitis media (CSOM) who underwent IBM and divided them into 2 groups to compare long-term and short-term hearing level. Setting: From April 2007 to July 2017, 102 patients received IBM for CSOM treatment in Eye & ENT Hospital of Fudan University. Methods: We divided the patients into 2 groups according to whether the follow-up period was longer than 6 months. We used the numerical value of the air-bone gap difference as an index to evaluate the degree of hearing recovery. Results: We found that 99/102 (97.1%) of the hearings were improved to more than 3 frequencies. There was no significant difference between long-term hearing level and short-term hearing level, which means IBM could get long-term hearing stability. Conclusion: Intact bridge tympanomastoidectomy could provide significant hearing recovery and long-term hearing stability.

The Role of Anti-Endothelial Cell Autoantibodies and Immune Response in Acute Low-Tone Hearing Loss.

OBJECTIVE: Immunity is associated with acute low tone hearing loss. However, the exact pathophysiology of immunity-mediated acute low tone hearing loss remains unknown. In this study, we evaluated the presence, therapeutic effectiveness, and immunopathological mechanisms of anti-endothelial cell autoantibodies (AECEs) in patients with acute low-frequency hearing loss. MATERIAL AND METHODS: Forty-nine patients who were treated as inpatients having acute low-frequency hearing loss and additional symptoms, such as ear fullness, tinnitus, dizziness, or hyperacusis, were enrolled in this study. Serum samples from these patients were collected for laboratory serum autoimmunity detection, including AECAs, antinuclear antibodies, immunoglobulin, and circular immune complex. Therapeutic responses to combination therapy in short-term outcome and serum cytokine levels were compared between AECA-positive and AECA-negative patients. RESULTS: Anti-endothelial cell autoantibodies-positive patients tended to show significantly less response to standard therapy compared with AECAs controls (P < .05). Moreover, some serum cytokine levels elevated in both AECAs- and AECAs+ groups. Positive ratio of interleukin-8 and concentrations of macrophage inflammatory protein-1α were found higher in AECAs+ groups (P < .05). CONCLUSION: The results supported that AECAs might wield influence on the short-term outcome of acute low-tone hearing loss (ALHL) treatment. Furthermore, AECA-mediated acute low-frequency hearing loss possibly involved dysregulation of inflammation process and release of cytokines.