Complete Restoration of Hearing Loss and Cochlear Synaptopathy via Minimally Invasive, Single-Dose, and Controllable Middle Ear Delivery of Brain-Derived Neurotrophic Factor-Poly(dl-lactic acid-co-glycolic acid)-Loaded Hydrogel.

Noise-induced hearing loss (NIHL) often accompanies cochlear synaptopathy, which can be potentially reversed to restore hearing. However, there has been little success in achieving complete recovery of sensorineural deafness using nearly noninvasive middle ear drug delivery before. Here, we present a study demonstrating the efficacy of a middle ear delivery system employing brain-derived neurotrophic factor (BDNF)-poly-(dl-lactic acid-co-glycolic acid) (PLGA)-loaded hydrogel in reversing synaptopathy and restoring hearing function in a mouse model with NIHL. The mouse model achieved using the single noise exposure (NE, 115 dBL, 4 h) exhibited an average 20 dBL elevation of hearing thresholds with intact cochlear hair cells but a loss of ribbon synapses as the primary cause of hearing impairment. We developed a BDNF-PLGA-loaded thermosensitive hydrogel, which was administered via a single controllable injection into the tympanic cavity of noise-exposed mice, allowing its presence in the middle ear for a duration of 2 weeks. This intervention resulted in complete restoration of NIHL at frequencies of click, 4, 8, 16, and 32 kHz. Moreover, the cochlear ribbon synapses exhibited significant recovery, whereas other cochlear components (hair cells and auditory nerves) remained unchanged. Additionally, the cochlea of NE treated mice revealed activation of tropomyosin receptor kinase B (TRKB) signaling upon exposure to BDNF. These findings demonstrate a controllable and minimally invasive therapeutic approach that utilizes a BDNF-PLGA-loaded hydrogel to restore NIHL by specifically repairing cochlear synaptopathy. This tailored middle ear delivery system holds great promise for achieving ideal clinical outcomes in the treatment of NIHL and cochlear synaptopathy.

Multimodal quantitative magnetic resonance imaging of the thalamus in tinnitus patients with different outcomes after sound therapy.

AIMS: This study systematically investigated structural and functional alterations in the thalamus and its subregions using multimodal magnetic resonance imaging (MRI) and examined its clinical relevance in tinnitus patients with different outcomes after sound therapy (narrowband noise). METHODS: In total, 60 patients with persistent tinnitus and 57 healthy controls (HCs) were recruited. Based on treatment efficacy, 28 patients were categorized into the effective group and 32 into the ineffective group. Five MRI measurements of the thalamus and its seven subregions, including gray matter volume, fractional anisotropy, fractional amplitude of low-frequency fluctuation, and functional connectivity (FC), were obtained for each participant and compared between the groups. RESULTS: Patients in both the groups exhibited widespread functional and diffusion abnormalities in the whole thalamus and several subregions, with more obvious changes observed in the effective group. All tinnitus patients had abnormal FC compared with the HCs; FC differences between the two patient groups were only observed in the striatal network, auditory-related cortex, and the core area of the limbic system. We combined the multimodal quantitative thalamic alterations and used it as an imaging indicator to evaluate prognosis before sound therapy and achieved a sensitivity of 71.9% and a specificity of 85.7%. CONCLUSION: Similar patterns of thalamic alterations were identified in tinnitus patients with different outcomes, with more obvious changes observed in the effective group. Our findings support the tinnitus generation hypothesis of frontostriatal gating system dysfunction. A combination of multimodal quantitative thalamic properties may be used as indicators to predict tinnitus prognosis before sound therapy.

Clinical Analysis of Ear Congestion after Balloon Eustachian Tuboplasty (BET) with or without Tympanostomy Tube Insertion.

Objective: To explore the clinical analysis of ear congestion after balloon Eustachian tuboplasty (BET) with or without tympanostomy tube insertion. Methods: A total of 35patients (49 affected ears) with ear congestion following BET with or without tympanostomy tube insertion were recruited from the hospitalized patients from January 2015 to December 2017. The score of Eustachian Tube Dysfunction Questionnaire-7 (ETDQ-7) 15, visual analogue scale (VAS), and Valsalva scores were recorded before and after operation, and the influencing factors of prognosis were analyzed. The duration of follow-up was 1-4 years. Results: All patients showed significantly decreased average preoperative ETDQ-7 score, VAS, and Valsalva score after operation (p < 0.05). The significance of the surgery types, course of disease, severity of tympanic membrane retraction, and tympanogram tracings classification as influencing factors of prognosis did not come up to the statistical standard (p > 0.05). Conclusion: The patients showed relatively stable postoperative conditions after 3 years, and there were variations in the range of ETDQ-7 scores at 5 years postoperatively. Patients with levels I and II tympanic membrane retraction showed more favorable surgical effects. Surgical interventions are required for patients diagnosed with obstructive Eustachian tube dysfunction (ETD) after three months of conservative treatment without satisfactory results.

Pretreatment intranetwork connectivity can predict the outcomes in idiopathic tinnitus patients treated with sound therapy.

Previous studies demonstrated that brain morphological differences and distinct patterns of neural activation exist in tinnitus patients with different prognoses after sound therapy. This study aimed to explore possible differences in intrinsic network-level functional connectivity (FC) in patients with different outcomes after sound therapy (narrow band noise). We examined intrinsic FC using resting-state functional magnetic resonance imaging in 78 idiopathic tinnitus patients (including 35 effectively treated and 43 ineffectively treated) and 52 healthy controls (HCs) via independent component analysis. We also investigated the associations between the differences in FC and clinical variables. Analyses revealed significantly altered intranetwork connectivity in the auditory network (AUN) and some nonauditory-related networks in the EG/IG patients compared to HCs; compared with EG patients, IG patients showed decreased intranetwork connectivity in the anterior default mode network (aDMN) and AUN. Meanwhile, robust differences were also evident in internetwork connectivity between some nonauditory-related networks (salience network and executive control network; posterior default mode network and dorsal attention network) in the EG relative to IG patients. We combined intranetwork connectivity in the aDMN and AUN as an imaging indicator to evaluate patient outcomes and screen patients before treatment; this approach reached a sensitivity of 94.3% and a specificity of 76.7%. Our study suggests that tinnitus patients with different outcomes show distinct network-level functional reorganization patterns. Intranetwork connectivity in the aDMN and AUN may be indicators that can be used to predict prognoses in patients with idiopathic tinnitus and screen patients before sound therapy.

Sound therapy can modulate the functional connectivity of the auditory network.

The functional connectivity of the auditory network is considered to be important in the development of tinnitus. We hypothesized that sound therapy, as a commonly used effective treatment for tinnitus, can modulate the functional connectivity of the auditory network. In this prospective observational study, we recruited 27 tinnitus patients who had undergone 12 weeks of sound therapy and 27 matched healthy controls. For the two groups of subjects, resting-state functional magnetic resonance imaging was acquired both at baseline and at the 12th week. We utilized independent component analysis and seed-based functional connectivity analysis to characterize the connectivity features of the auditory network. Interaction effects between the two groups and the two scans within the auditory network were observed, which were driven by increased functional connectivity in the left primary auditory cortex (PAC) and decreased values in the secondary auditory cortex (SAC) in tinnitus patients after treatment. Increased connections between the auditory network and limbic network, as well as decreased values with the bilateral thalami, were identified. The effects were mainly driven by the functional connectivity alterations of the SAC rather than that of the PAC. Significant positive correlations between the percent improvement in the Tinnitus Handicap Inventory (THI) score and the percentage change rates of functional connectivity between the SAC and bilateral thalami were observed. Our study contributes to the understanding of the mechanism of tinnitus and effective sound therapy, providing evidence to support the theory of a gain adaptation mechanism that quantifies the recovered gating function of the thalamus in tinnitus patients.

Outcomes at 6 months are related to brain structural and white matter microstructural reorganization in idiopathic tinnitus patients treated with sound therapy.

This study aimed to explore brain structural and white matter microstructural reorganization in the early stage of tinnitus and identify brain alterations that contribute to its relief after 6 months of sound therapy. We studied 64 patients with idiopathic tinnitus, including 29 patients who were categorized into an effective group (EG) and 35 who were categorized into an ineffective group (IG) according to the 6-month follow-up improvement of the Tinnitus Handicap Inventory score, along with 63 healthy controls (HCs). All participants underwent structural and diffusion tensor imaging scanning on a 3-T magnetic resonance system. Differences in brain gray/white matter volume and white matter microstructure were evaluated using voxel-based morphometry analysis and tract-based spatial statistics among the three groups. Associations between brain reorganization and the improvement of tinnitus symptoms were also investigated. Compared with EG patients, IG patients experienced a significant gray matter volume decrease in the right middle frontal gyrus (MFG)/right precentral gyrus (PreCG). Meanwhile, both EG and IG patients showed significant changes (decrease or increase) in brain white matter integrity in the auditory-related or nonauditory-related white matter fiber tracts compared with HCs, while EG patients showed decreased axial diffusivity in the bilateral middle cerebellar peduncle (MCP) compared with IG patients. We combined the gray matter change of the MFG/PreCG and the white matter integrity of the bilateral MCP as an imaging indicator to evaluate the patient's prognosis and screen patients before treatment; this approach reached a sensitivity of 77.1% and a specificity of 82.8%. Our study suggests that there was a close relationship between brain reorganization and tinnitus improvement. The right MFG/PreCG and bilateral MCP may be indicators that can be used to predict prognoses in patients with idiopathic tinnitus and may be used to screen patients before sound therapy. These findings may provide new useful information that can lead to a better understanding of the tinnitus mechanism.

Nicotinamide riboside protects noise-induced hearing loss by recovering the hair cell ribbon synapses.

OBJECTIVE: Nicotinamide riboside (NR) has been proved to protect the hearing. To achieve animal models of temporary threshold shift (TTS) and permanent threshold shift (PTS) respectively, evaluate the dynamic change of ribbon synapse before and after NR administration. METHODS: Mice were divided into control group, noise exposure (NE) group and NR group. The noise was exposed to NE and NR group, and NR was injected before noise exposure. Auditory brainstem response (ABR), ribbon synapse count and cochlear morphology were tested, as well as the concentration of hydrogen peroxide (H2O2) and ATP. RESULTS: Ribbon synapse count decrease with the intensity of noise exposure, and the cochlear morphology remains stable during TTS and was damaged during PTS. NR promotes the oxidation resistance to protect the synapse and the inner ear morphology. CONCLUSION: Our findings suggest that TTS mice are more vulnerable to noise, and NR can promote the recovery of the synapse count to protect the animals' hearing.

Altered functional connectivity of the thalamus in tinnitus patients is correlated with symptom alleviation after sound therapy.

Altered functional connectivity (FC) of the thalamus has been proven to be an important finding in tinnitus patients. Tinnitus can be effectively desensitized by sound therapy. However, it is still unclear whether and how sound therapy affects the FC of the thalamus. Resting-state functional magnetic resonance imaging data and anatomical data were longitudinally collected from 25 idiopathic tinnitus patients before and after 12 weeks of sound therapy by using adjusted narrow band noise and from 25 matched healthy controls at the same time interval without any intervention. The FC of bilateral thalami were analyzed by setting the left and right thalamus as the regions of interest. Significant main effect of group on the FC of the thalamus were found mainly in the key components of the default mode network, limbic network, salience network, cognitive control network, auditory network and occipital region. FC values between the thalamus, inferior frontal gyrus (IFG), and anterior cingulate cortex (ACC) featured higher values in the tinnitus group at baseline compared to the healthy controls and restoration in tinnitus patients after treatment. Decreased Tinnitus Handicap Inventory (THI) scores and decreased FC values between the right thalamus and right IFG were positively correlated (r = 0.476, P = 0.016). Abnormal FC of the thalamus is associated with multiple brain networks. Sound therapy has a normalizing effect on the enhanced FC of the thalamus-IFG and thalamus-ACC, representing decreased tinnitus attention control and less involvement of the noise-canceling system.

Dynamic Changes of Functional Neuronal Activities Between the Auditory Pathway and Limbic Systems Contribute to Noise-Induced Tinnitus with a Normal Audiogram.

Tinnitus is thought to be triggered by aberrant neural activity in the central auditory pathway and is often accompanied by comorbidities of emotional distress and anxiety, which imply maladaptive functional connectivity to limbic structures, such as the amygdala and hippocampus. Tinnitus patients with normal audiograms can also have accompanying anxiety and depression, clinically. To test the role of functional connectivity between the central auditory pathway and limbic structures in patients with tinnitus with normal audiograms, we developed a murine noise-induced tinnitus model with a temporary threshold shift (TTS). Tinnitus mice exhibited reduced auditory brainstem response wave I amplitude, and an enhanced wave IV amplitude and wave IV/I amplitude ratio, as compared with control and non-tinnitus mice. Resting-state functional magnetic resonance imaging (fMRI) was used to identify abnormal connectivity of the amygdala and hippocampus and to determine the relationship with tinnitus characteristics. We found increased fMRI responses with amplitude of low-frequency fluctuation (ALFF) in the auditory cortex and decreased ALFF in the amygdala and hippocampus at day 1, but decreased ALFF in the auditory cortex and increased ALFF in the amygdala at day 28 post-noise exposure in tinnitus mice. Decreased functional connectivity between auditory brain regions and limbic structures was demonstrated at day 28 in tinnitus mice. Therefore, aberrant neural activities in tinnitus mice with TTS involved not only the central auditory pathway, but also limbic structures, and there was maladaptive functional connectivity between the central auditory pathway and limbic structures, such as the amygdala and hippocampus.

The Cochleural Alternating Acoustic Beam Therapy (CAABT): A pre-clinical trial.

PURPOSE: We intend to assess the effectiveness of a novel tinnitus treatment therapy, the Cochleural Alternating Acoustic Beam Therapy (CAABT) using the psychoacoustic measures, the questionnaires and rs-fMRI. MATERIALS AND METHODS: In this study, we enrolled 11 older than 18 years old Chinese patients with normal hearing who had unilateral, chronic (longer than 6 months), sensorineural tinnitus, of frequencies between 125-8000 Hz, and an average loudness of 31 dB. The patients underwent the treatment with the CAABT method for 12 weeks and the outcomes were evaluated with tinnitus questionnaire scores, a set of psychoacoustic measures, and rs-fMRI testing before treatment and at 3 months. This was an earlier study of the controlled randomized clinical trial which was registered with ClinicalTrials.gov, number NCT02774122. RESULTS: Almost all the patients reported reduced tinnitus annoyance after the three-month treatment. The THI and VAS scores showed decreased tinnitus severity. The rs-fMRI results indicated that the right middle frontal gyrus and the right superior temporal gyrus displayed noticeable decreases of the ReHo values for the subjects between the before and after treatment, supporting the clinical evidence of significant tinnitus reduction. CONCLUSION: The therapy seemed effective in patients of varying severities, and no side effects were observed in this trial. The CAABT can be an alternative for those who are suitable for sound therapy once a large scale of and better controlled clinical studies have validated the findings of this experiment.

Development and evaluation of the Nurotron 26-electrode cochlear implant system.

Although the cochlear implant has been widely acknowledged as the most successful neural prosthesis, only a fraction of hearing-impaired people who can potentially benefit from a cochlear implant have actually received one due to its limited awareness, accessibility, and affordability. To help overcome these limitations, a 26-electrode cochlear implant has been developed to receive China's Food and Drug Administration (CFDA) approval in 2011 and Conformité Européenne (CE) Marking in 2012. The present article describes design philosophy, system specification, and technical verification of the Nurotron device, which includes advanced digital signal processing and 4 current sources with multiple amplitude resolutions that not only are compatible with perceptual capability but also allow interleaved or simultaneous stimulation. The article also presents 3-year longitudinal evaluation data from 60 human subjects who have received the Nurotron device. The objective measures show that electrode impedance decreased within the first month of device use, but was stable until a slight increase at the end of two years. The subjective loudness measures show that electric stimulation threshold was stable while the maximal comfort level increased over the 3 years. Mandarin sentence recognition increased from the pre-surgical 0%-correct score to a plateau of about 80% correct with 6-month use of the device. Both indirect and direct comparisons indicate indistinguishable performance differences between the Nurotron system and other commercially available devices. The present 26-electrode cochlear implant has already helped to lower the price of cochlear implantation in China and will likely contribute to increased cochlear implant access and success in the rest of the world. This article is part of a Special Issue entitled .

[Clinical application of bone-anchored hearing aid implantation].

OBJECTIVE: To discuss the indications, surgery methods and effects of the BAHA implantation by analyzing the patients' medical records of bone-anchored hearing aids(BAHA). METHODS: Retrospective analyzed the records of 16 patients of BAHA implantation, including nine males and seven females. Their average age was 31 years old (8-53ys). Nine of them were congenital ear malformation, two were chronic suppurative otitis media, two were otosclerosis and three were unilateral severe sensorineural deafness. We evaluated their pure tone audiometry (PTA), speech audiometry and temporal CT before the surgery, and evaluated the aided PTA in soundfield and speech audiometry in sound field. RESULTS: These patients received BAHA implantation and installed the speech processor their months later. The average preoperative PTA measurements (PTA at 0.5, 1, 2, 4 kHz) was (63.2 ± 19.0) dB HL and postoperative aided PTA in sound field was (35.5 ± 10.9)dB HL. The average improvement in Hearing In Noise Test (HINT) was 37.0% ± 31.7%. The average improvement in Mandarin Speech Test was 76.0% ± 19.7%. After 4-16 months' follow-up, no significant complications were recorded. CONCLUSION: BAHA is a safe and effective bone implantable hearing device.

New insights into glutamate ototoxicity in cochlear hair cells and spiral ganglion neurons.

CONCLUSION: Excess glutamate (Glu) exposure (20 mM) in the cochlear perilymph affects the physiological function of outer hair cells (OHCs) within a 2 h period and induces apoptosis in the modiolus spiral ganglion neurons (SGNs) in an apoptosis-inducing factor (AIF)-dependent manner. OBJECTIVES: To determine whether high-dose Glu affects the function of OHCs and whether it induces AIF- and caspase-3-dependent apoptosis in the cochlear SGNs. METHODS: Perilymphatic perfusions of Glu (20 mM) and artificial perilymph (AP) solutions were performed in adult guinea pig cochleae. Both cochlear microphonics (CM) and electrical auditory brainstem response (eABR) were measured before and 2 h after perfusions. The hair cell morphologies were examined using transmission electron microscopy. The expression of two apoptotic indicators, AIF and caspase-3, was examined 8 h after perfusions. RESULTS: In contrast to AP perfusions, the perfusion of 20 mM Glu caused significant reduction in the CM and eABR amplitudes. Inner hair cells (IHCs) after Glu perfusion were deformed and exhibited vacuolization in the postsynaptic region, whereas the OHC system appeared unaffected. AIF expression was detected in the nuclei of SGNs 8 h after Glu exposure, but the expression of caspase-3 was not shown in any cochlear tissues.

[Chronic tinnitus: a grading management mode study].

OBJECTIVE: To probe into grading management mode for chronic tinnitus victims, so as to improve the cost-effectiveness rate of tinnitus treatment. METHODS: According to the severity of patient's own feeling and the therapy demand, the authors managed 587 of chronic tinnitus victims using a progressive methods: Level 1 was primary evaluation, counseling and treatment for tinnitus victims, then determined if the victim require further clinical intervention. Level 2 was educational counseling about the knowledge of tinnitus. Level 3 was further evaluation for hearing function and the severity of tinnitus. Than the authors made and put in practice an individual integrative treatment project for every victim according to the assessment results. RESULTS: 75% (441/587) of the chronic tinnitus victims needed only educational counseling which can free them from the mystification and dread of tinnitus, the counseling helped them get habituation of tinnitus; the rest 25% (146/587) needed long-term integrative clinical treatment. CONCLUSION: Effective grading management can hold the tinnitus severity level and the treatment desirability from the victims rapidly and exactly, then provided them multiple modalities treatment from counseling to long-term integrative therapy. The grading management mode improved the cost-effectiveness rate of tinnitus treatment.

Effect of DRB on the biological characteristics of human laryngeal carcinoma Hep-2 cell line.

In order to study the effect of 5, 6-Dichloro-1-beta-D-ribofuranosyl-benzimidazole (DRB) on the biological characteristics of human laryngeal carcinoma Hep-2 cell line in vitro, Hep-2 cells cultured in vitro were treated with different concentrations of DRB. Changes in cell proliferation, apoptotic rate and invasiveness were detected by MTT assay, flow cytometry (FCM) and matrigel in vitro invasion assay, respectively. It was found that DRB inhibited the proliferation of Hep-2 cells in a dose-and time-dependent manner. After being treated with 0, 10, 20, 40, 80 microm mol/L DRB for 24 h, the apoptotic rate in Hep-2 cells was (0.68+/-0.19)%, (1.95+/-0.12)%, (8.51+/-0.26)%, (11.26+/-0.17)% and (14.99+/-0.32)%, respectively. The matrigel in vitro invasion assay revealed that DRB began to inhibit the invasion of Hep-2 cells at the concentration of 5 microm mol/L, and with the increase of DRB concentration, the inhibitory effect was enhanced. It was suggested that DRB could influence the essential biological characteristics of Hep-2 cells, inhibit Hep-2 cells proliferation, reduce invasive ability and induce apoptosis of Hep-2 cells.