The multifaceted links between hearing loss and chronic kidney disease.

Hearing loss affects nearly 1.6 billion people and is the third-leading cause of disability worldwide. Chronic kidney disease (CKD) is also a common condition that is associated with adverse clinical outcomes and high health-care costs. From a developmental perspective, the structures responsible for hearing have a common morphogenetic origin with the kidney, and genetic abnormalities that cause familial forms of hearing loss can also lead to kidney disease. On a cellular level, normal kidney and cochlea function both depend on cilial activities at the apical surface, and kidney tubular cells and sensory epithelial cells of the inner ear use similar transport mechanisms to modify luminal fluid. The two organs also share the same collagen IV basement membrane network. Thus, strong developmental and physiological links exist between hearing and kidney function. These theoretical considerations are supported by epidemiological data demonstrating that CKD is associated with a graded and independent excess risk of sensorineural hearing loss. In addition to developmental and physiological links between kidney and cochlear function, hearing loss in patients with CKD may be driven by specific medications or treatments, including haemodialysis. The associations between these two common conditions are not commonly appreciated, yet have important implications for research and clinical practice.

Insight into postural control in unilateral sensorineural hearing loss and vestibular hypofunction.

This pilot study aimed to identify postural strategies in response to sensory perturbations (visual, auditory, somatosensory) in adults with and without sensory loss. We tested people with unilateral peripheral vestibular hypofunction (N = 12, mean age 62 range 23-78), or with Unilateral Sensorineural Hearing Loss (USNHL, N = 9, 48, 22-82), or healthy controls (N = 21, 52, 28-80). Postural sway and head kinematics parameters (Directional Path in the anterior-posterior and medio-lateral directions (sway & head); pitch, yaw and roll (head) were analyzed in response to 2 levels of auditory (none, rhythmic sounds via headphones), visual (static, dynamic) and somatosensory cues (floor, foam) within a simulated, virtual 3-wall display of stars. We found no differences with the rhythmic auditory cues. The effect of foam was magnified in the vestibular group compared with controls for anterior-posterior and medio-lateral postural sway, and all head direction except for medio-lateral. The vestibular group had significantly larger anterior-posterior and medio-lateral postural sway and head movement on the static scene compared with controls. Differences in pitch, yaw and roll emerged between vestibular and controls only with sensory perturbations. The USNHL group did not increase their postural sway and head movement with the increased visual load as much as controls did, particularly when standing on the foam. They did not increase their medio-lateral sway with the foam as much as controls did. These findings suggest that individuals with USNHL employ a compensatory strategy of conscious control of balance, the functional implications of which need to be tested in future research.

The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention.

Norrie disease is caused by mutation of the NDP gene, presenting as congenital blindness followed by later onset of hearing loss. Protecting patients from hearing loss is critical for maintaining their quality of life. This study aimed to understand the onset of pathology in cochlear structure and function. By investigating patients and juvenile Ndp-mutant mice, we elucidated the sequence of onset of physiological changes (in auditory brainstem responses, distortion product otoacoustic emissions, endocochlear potential, blood-labyrinth barrier integrity) and determined the cellular, histological, and ultrastructural events leading to hearing loss. We found that cochlear vascular pathology occurs earlier than previously reported and precedes sensorineural hearing loss. The work defines a disease mechanism whereby early malformation of the cochlear microvasculature precedes loss of vessel integrity and decline of endocochlear potential, leading to hearing loss and hair cell death while sparing spiral ganglion cells. This provides essential information on events defining the optimal therapeutic window and indicates that early intervention is needed. In an era of advancing gene therapy and small-molecule technologies, this study establishes Ndp-mutant mice as a platform to test such interventions and has important implications for understanding the progression of hearing loss in Norrie disease.

Effects of mild-to-moderate sensorineural hearing loss and signal amplification on vocal emotion recognition in middle-aged-older individuals.

Previous research has shown deficits in vocal emotion recognition in sub-populations of individuals with hearing loss, making this a high priority research topic. However, previous research has only examined vocal emotion recognition using verbal material, in which emotions are expressed through emotional prosody. There is evidence that older individuals with hearing loss suffer from deficits in general prosody recognition, not specific to emotional prosody. No study has examined the recognition of non-verbal vocalization, which constitutes another important source for the vocal communication of emotions. It might be the case that individuals with hearing loss have specific difficulties in recognizing emotions expressed through prosody in speech, but not non-verbal vocalizations. We aim to examine whether vocal emotion recognition difficulties in middle- aged-to older individuals with sensorineural mild-moderate hearing loss are better explained by deficits in vocal emotion recognition specifically, or deficits in prosody recognition generally by including both sentences and non-verbal expressions. Furthermore a, some of the studies which have concluded that individuals with mild-moderate hearing loss have deficits in vocal emotion recognition ability have also found that the use of hearing aids does not improve recognition accuracy in this group. We aim to examine the effects of linear amplification and audibility on the recognition of different emotions expressed both verbally and non-verbally. Besides examining accuracy for different emotions we will also look at patterns of confusion (which specific emotions are mistaken for other specific emotion and at which rates) during both amplified and non-amplified listening, and we will analyze all material acoustically and relate the acoustic content to performance. Together these analyses will provide clues to effects of amplification on the perception of different emotions. For these purposes, a total of 70 middle-aged-older individuals, half with mild-moderate hearing loss and half with normal hearing will perform a computerized forced-choice vocal emotion recognition task with and without amplification.

Dynamic alterations of functional connectivity and amplitude of low-frequency fluctuations in patients with unilateral sudden sensorineural hearing loss.

Unilateral sudden sensorineural hearing loss (SSNHL) adversely affects the quality of life, leading to increased risk of depression and cognitive decline. Our previous studies have mainly focused on the static brain function abnormalities in SSNHL patients. However, the dynamic features of brain activity in SSNHL patients are not elucidated. To explore the dynamic brain functional alterations in SSNHL patients, age- and sex- matched SSNHL patients (n = 38) and healthy controls (HC, n = 44) were enrolled. The dynamic functional connectivity (dFC) and dynamic amplitude of low-frequency fluctuation (dALFF) methods were used to compare the temporal features and dynamic neural activity between the two groups. In dFC analyses, the multiple functional connectivities (FCs) were clustered into 2 different states; a greater proportion of FCs in SSNHL patients showed sparse state compared with HC. In dALFF analyses, SSNHL individuals exhibited decreased dALFF variability in bilateral inferior occipital gyrus, middle occipital gyrus, calcarine, right lingual gyrus, and right fusiform gyrus. dALFF variability showed a negative correlation with activated partial thromboplatin time. The dynamic characteristics of SSNHL patients were different from static functional connectivity and static amplitude of low-frequency fluctuation, especially within the visual cortices. These findings suggest that SSNHL patients experience cross-modal plasticity and visual compensation, which may be closely related to the pathophysiology of SSNHL.

The impairment of speech perception in noise following pure tone hearing recovery in patients with sudden sensorineural hearing loss.

To explore whether patients with unilateral idiopathic sudden sensorineural hearing loss (uISSNHL) have normal speech in noise (SIN) perception under different masking conditions after complete recovery of pure tone audiometry. Eight completely recovered uISSNHL patients were enrolled in ISSNHL group, while 8 normal-hearing adults matched with age, gender, and education experience were selected as the control group. Each group was tested SIN under four masking conditions, including noise and speech maskings with and without spatial separation cues. For both ISSNHL and control groups a two-way ANOVA showed a statistically significant effect of masking type (p = 0.007 vs p = 0.012). A significant effect of perceived spatial separation (p < 0.001 vs p < 0.001). A significant interaction between masking type and perceived spatial separation was found (p < 0.001 vs p < 0.001). A paired sample T-test showed that the SIN perception of the control group was statistically significant lower than that of ISSNHL patients only under speech masking without spatial separation cues (p = 0.011). There were still abnormalities in the auditory center shortly after complete recovery in the ISSNHL group (within 2 weeks). However, the auditory periphery and higher-level ability to use spatial cues was normal.

Comparison between postauricular steroid injection and intratympanic steroid perfusion for refractory severe and profound sudden sensorineural hearing loss.

BACKGROUND: To analyze the clinical efficacy of intratympanic steroid perfusion (ISP) and postauricular steroid injection (PSI) for refractory severe and profound sudden sensorineural hearing loss (SSNHL). METHODS: SSNHL patients who failed a conventional treatment with severe to profound hearing loss [pure tone average (PTA, 0.25-8 kHz) > 60 dB] were treated with ISP or PSI plus antioxidant and neurotrophin for 10 consecutive days. Antioxidant and neurotrophin were administrated either intravenously and/or orally. All patients were assigned into the ISP group or the PSI group and followed up for more than three months. The changes in PTA, effective rate and side effects were analyzed in the two groups. RESULTS: Similar hearing improvements and effective rates were observed in the two groups. However, a slightly better efficacy was observed in the PSI group compared to the ISP group. Patients with shorter intervals from onset to treatment had significantly more hearing improvements. The route of antioxidant and neurotrophin administration had no impact on treatment effects. CONCLUSION: Both ISP and PSI could be used as salvage treatments for refractory SSNHL. These salvage treatments should be started as soon as possible once SSNHL patients fail a conventional treatment.

Cochlear implantation of a patient with multiple sclerosis: case report and systematic review.

BACKGROUND: Cochlear implantation can be used when a patient's hearing cannot satisfactorily be improved after optimised hearing aid fitting. However, in patients with a cochlear nerve or brain disorder affecting hearing, the benefits of cochlear implants are not so straightforward. METHODS: This paper describes a 58-year-old patient suffering from multiple sclerosis and profound sensorineural hearing loss, rehabilitated with a cochlear implant. Literature concerning cochlear implantation in demyelinating conditions was systematically reviewed using PubMed/Medline and Web of Science databases. RESULTS: The patient's cochlear implantation was successful, with speech discrimination scores remaining above 90 per cent for eight years post-operatively. No previous cases of cochlear implantation with multiple sclerosis related hearing loss have been reported, despite the high incidence of hearing loss in multiple sclerosis patients. CONCLUSION: This paper demonstrates that multiple sclerosis lesions should not be an exclusion criterion in an otherwise suitable candidate for cochlear implantation.

The audiovestibular profile of Brown-Vialetto-Van Laere syndrome.

BACKGROUND: Brown-Vialetto-Van Laere syndrome, a rare disorder associated with motor, sensory and cranial nerve neuropathy, is caused by mutations in riboflavin transporter genes SLC52A2 and SLC52A3. Hearing loss is a characteristic feature of Brown-Vialetto-Van Laere syndrome and has been shown in recent studies to be characterised by auditory neuropathy spectrum disorder. METHOD: This study reports the detailed audiovestibular profiles of four cases of Brown-Vialetto-Van Laere syndrome with SLC52A2 and SLC52A3 mutations. All of these patients had auditory neuropathy spectrum disorder. RESULTS: There was significant heterogeneity in vestibular function and in the benefit gained from cochlear implantation. The audiological response to riboflavin therapy was also variable, in contrast to generalised improvement in motor function. CONCLUSION: We suggest that comprehensive testing of vestibular function should be conducted in Brown-Vialetto-Van Laere syndrome, in addition to serial behavioural audiometry as part of the systematic examination of the effects of riboflavin.

Ear fullness characteristics and prognosis in patients with all-frequency sudden sensorineural hearing loss.

OBJECTIVE: This study investigated the characteristics and prognosis of the feeling of ear fullness in patients with unilateral all-frequency sudden sensorineural hearing loss. METHODS: Our study included 56 patients with a diagnosis of unilateral all-frequency sudden sensorineural hearing loss accompanied by a feeling of ear fullness and 48 patients without a feeling of ear fullness. The condition of these patients was prospectively observed. RESULTS: Positive correlations were observed between grading of feeling of ear fullness and hearing loss in patients with a feeling of ear fullness (r = 0.599, p < 0.001). No significant differences were observed in the total effective rate of hearing recovery between patients with and without a feeling of ear fullness after one month of treatment (Z = -0.641, p = 0.521). Eighty-six per cent of patients (48 out of 56) showed complete recovery from the feeling of ear fullness. There was no correlation between feeling of ear fullness recovery and hearing recovery (r = 0.040, p = 0.769). CONCLUSION: The prognosis of feeling of ear fullness is good. There was no correlation between feeling of ear fullness recovery and hearing recovery for all-frequency sudden sensorineural hearing loss patients.

Hearing Loss and Tinnitus.

A focused history, otoscopic and tuning fork examination and formal hearing testing are the diagnostic pillars for the workup of hearing loss and tinnitus. The causes of hearing loss and tinnitus are varied and range from relatively common age-related hearing loss to rare tumors of the brain and skull base. In this chapter, the authors explain the diagnostic workup of hearing loss and tinnitus, review the pathophysiology of the most common causes, and describe the treatments available.

Calculated versus measured pure tone bone conduction 3 kHz thresholds in sudden sensorineural hearing loss.

OBJECTIVE: To compare the measured bone conduction threshold at 3 kHz with the calculated threshold in newly diagnosed sudden sensorineural hearing loss. METHODS: A retrospective chart review was conducted of pure tone audiograms in confirmed sudden sensorineural hearing loss cases. RESULTS: Of 157 patients with sudden sensorineural hearing loss, 144 had idiopathic hearing loss, 8 had vestibular schwannoma and 5 had Ménière's disease. The r value for the correlation between the two methods of 3 kHz assessment for all patients was 0.887 (p < 0.001). The mean difference between the measured and calculated 3 kHz thresholds was 0.76 ± 7.96 dB, 0.4 ± 8.08 dB and 1.5 ± 1.8 dB in the sudden sensorineural hearing loss, idiopathic and Ménière's disease groups, respectively. The mean difference between the measured and calculated 3 kHz thresholds was significantly greater in the vestibular schwannoma group (6.86 ± 4.38 dB) than in the idiopathic group (p = 0.013). CONCLUSION: The 3 kHz frequency may encompass important audiometric information. A discrepancy between the measured and calculated bone conduction 3 kHz thresholds raises suspicion of an underlying vestibular schwannoma as an aetiology for sudden sensorineural hearing loss, and these thresholds should therefore be measured independently and routinely.

Distribution and Afferent Effects of Transplanted mESCs on Cochlea in Acute and Chronic Neural Hearing Loss Models.

Hearing loss is a sensory deprivation that can affect the quality of life. Currently, only rehabilitation devices such as hearing aids and cochlear implants are used, without a definitive cure. However, in chronic hearing-deprived patients, in whom secondary auditory neural degeneration is expected, a relatively poor rehabilitation prognosis is projected. Stem cell therapy for cochlear neural structures would be an easier and feasible strategy compared with cochlear sensory cells. Considering the highly developed cochlear implantation technology, improving cochlear neural health has significant medical and social effects. Stem cell delivery to Rosenthal's canal in an acutely damaged mouse model has been performed and showed cell survival and the possibility of differentiation. The results of stem cell transplantation in chronic auditory neural hearing loss should be evaluated because neural stem cell replacement therapy for chronic (long-term) sensorineural hearing loss is a major target in clinics. In the present study, we established a mouse model that mimicked chronic auditory neural hearing loss (secondary degeneration of auditory neurons after loss of sensory input). Then, mouse embryonic stem cells (mESCs) were transplanted into the scala tympani and survival and distribution of transplanted cells were compared between the acute and chronic auditory neural hearing loss models induced by ouabain or kanamycin (KM), respectively. The mESC survival was similar to the acute model, and perilymphatic distribution of cell aggregates was more predominant in the chronic model. Lastly, the effects of mESC transplantation on neural signal transduction observed in the cochlear nucleus (CN) were compared and a statistical increase was observed in the chronic model compared with other models. These results indicated that after transplantation, mESCs survived in the cochlea and increased the neural signaling toward the central auditory pathway, even in the chronic (secondary) hearing loss mouse model.

Intracochlear distortion products are broadly generated by outer hair cells but their contributions to otoacoustic emissions are spatially restricted.

Detection of low-level sounds by the mammalian cochlea requires electromechanical feedback from outer hair cells (OHCs). This feedback arises due to the electromotile response of OHCs, which is driven by the modulation of their receptor potential caused by the stimulation of mechano-sensitive ion channels. Nonlinearity in these channels distorts impinging sounds, creating distortion-products that are detectable in the ear canal as distortion-product otoacoustic emissions (DPOAEs). Ongoing efforts aim to develop DPOAEs, which reflects the ear's health, into diagnostic tools for sensory hearing loss. These efforts are hampered by limited knowledge on the cochlear extent contributing to DPOAEs. Here, we report on intracochlear distortion products (IDPs) in OHC electrical responses and intracochlear fluid pressures. Experiments and simulations with a physiologically motivated cochlear model show that widely generated electrical IDPs lead to mechanical vibrations in a frequency-dependent manner. The local cochlear impedance restricts the region from which IDPs contribute to DPOAEs at low to moderate intensity, which suggests that DPOAEs may be used clinically to provide location-specific information about cochlear damage.

Glial-Specific Deletion of Med12 Results in Rapid Hearing Loss via Degradation of the Stria Vascularis.

Mediator protein complex subunit 12 (Med12) is a core component of the basal transcriptional apparatus and plays a critical role in the development of many tissues. Mutations in Med12 are associated with X-linked intellectual disability syndromes and hearing loss; however, its role in nervous system function remains undefined. Here, we show that temporal conditional deletion of Med12 in astrocytes in the adult CNS results in region-specific alterations in astrocyte morphology. Surprisingly, behavioral studies revealed rapid hearing loss after adult deletion of Med12 that was confirmed by a complete abrogation of auditory brainstem responses. Cellular analysis of the cochlea revealed degeneration of the stria vascularis, in conjunction with disorganization of basal cells adjacent to the spiral ligament and downregulation of key cell adhesion proteins. Physiologic analysis revealed early changes in endocochlear potential, consistent with strial-specific defects. Together, our studies reveal that Med12 regulates auditory function in the adult by preserving the structural integrity of the stria vascularis.SIGNIFICANCE STATEMENT Mutations in Mediator protein complex subunit 12 (Med12) are associated with X-linked intellectual disability syndromes and hearing loss. Using temporal-conditional genetic approaches in CNS glia, we found that loss of Med12 results in severe hearing loss in adult animals through rapid degeneration of the stria vascularis. Our study describes the first animal model that recapitulates hearing loss identified in Med12-related disorders and provides a new system in which to examine the underlying cellular and molecular mechanisms of Med12 function in the adult nervous system.

Paraneoplastic cochleovestibulopathy: clinical presentations, oncological and serological associations.

OBJECTIVE: Cochleovestibulopathy is a distinguishable paraneoplastic phenotype. In this study, we evaluate clinical presentation, serological/cancer associations and outcomes of paraneoplastic cochleovestibulopathy. METHODS: Retrospective chart review of patients with hearing impairment and/or vestibulopathy who underwent serological evaluations for paraneoplastic antibodies between January 2007 and February 2021 was performed. RESULTS: Twenty-six patients were identified (men, n=23; median age, 45 years, range: 28-70). Biomarkers detected included: KLHL11-IgG| |(n=20,| |77% (coexisting LUZP4-IgG, n=8)),| ||ANNA1-IgG| | |(n=3,| |12%),| |amphiphysin-IgG|| |(n=2,| |8%)| |and| |LUZP4-IgG|| |(n=1,| |4%). Most common neoplastic association was |testicular|/|extra-testicular| |seminoma| | (n=13,| |50%).|| Hearing| impairment (bilateral, 62%) was |present| |in| |all| |patients.| |Fifteen patients (58%) had cochleovestibular dysfunction as their initial presentation before rhombencephalitis/encephalomyelitis manifestations (hearing loss, four; acute vertigo, eight; both, three). |Brain| |MRI| |demonstrated| |internal| |auditory| |canal| |enhancement| |in| |four |patients.| Audiometry commonly revealed severe-profound bilateral sensorineural hearing loss. Most patients |had| a refractory course |despite| |immunotherapy| |and/or| |cancer| |treatment|. CONCLUSION: Cochleovestibulopathy commonly presents with rapidly progressive bilateral hearing loss and/or acute vertigo. However, in some patients, these symptoms present along with or following brainstem/cerebellar manifestations. KLHL11-IgG and seminoma are the most common serological and cancer associations, respectively. Recognition of this phenotype may aid in earlier diagnosis of paraneoplastic autoimmunity and associated cancer.

Key Signaling Pathways Regulate the Development and Survival of Auditory Hair Cells.

The loss of auditory sensory hair cells (HCs) is the most common cause of sensorineural hearing loss (SNHL). As the main sound transmission structure in the cochlea, it is necessary to maintain the normal shape and survival of HCs. In this review, we described and summarized the signaling pathways that regulate the development and survival of auditory HCs in SNHL. The role of the mitogen-activated protein kinase (MAPK), phosphoinositide-3 kinase/protein kinase B (PI3K/Akt), Notch/Wnt/Atoh1, calcium channels, and oxidative stress/reactive oxygen species (ROS) signaling pathways are the most relevant. The molecular interactions of these signaling pathways play an important role in the survival of HCs, which may provide a theoretical basis and possible therapeutic interventions for the treatment of hearing loss.

Effects of Androgen Receptor Inhibition on Kanamycin-Induced Hearing Loss in Rats.

Megalin has been proposed as an endocytic receptor for aminoglycosides as well as estrogen and androgen. We aimed to investigate the otoprotective effects of antiandrogens (flutamide, FM) on kanamycin (KM)-induced hearing loss in rats. Rats were divided into four groups. The KM group was administered KM (20 mg/kg/day) for 5 days, while the FM group received FM (15 mg/kg/day) for 10 days. In the KM + FM group, KM and FM (15 mg/kg/day) were simultaneously injected for 5 days and then FM was injected for 5 days. Auditory brainstem responses were measured. Western blotting and/or quantitative reverse transcriptase-polymerase chain reaction were performed for megalin, cytochrome P450 1A1 (Cyp1a1), Cyp1b1, metallothionein 1A (MT1A), MT2A, tumor necrosis factor (TNF)-α, caspase 3, and cleaved caspase 3. The FM + KM group showed attenuated auditory thresholds when compared with the KM group at 4, 8, 16, and 32 kHz (all p < 0.05). The KM + FM group showed lower megalin and Cyp1b1 levels than the KM group (all p < 0.05). The KM + FM group revealed lower MT1A, TNFα, and caspase 3 protein levels, compared with those in the KM group (all p < 0.05). Androgen receptor inhibition protects against cochlear injuries in KM-induced hearing loss rats by attenuating megalin expression, revealing anti-inflammatory and anti-apoptotic effects.

Altered resting-state functional network connectivity in profound sensorineural hearing loss infants within an early sensitive period: A group ICA study.

Data from both animal models and deaf children provide evidence for that the maturation of auditory cortex has a sensitive period during the first 2-4 years of life. During this period, the auditory stimulation can affect the development of cortical function to the greatest extent. Thus far, little is known about the brain development trajectory after early auditory deprivation within this period. In this study, independent component analysis (ICA) technique was used to detect the characteristics of brain network development in children with bilateral profound sensorineural hearing loss (SNHL) before 3 years old. Seven resting-state networks (RSN) were identified in 50 SNHL and 36 healthy controls using ICA method, and further their intra-and inter-network functional connectivity (FC) were compared between two groups. Compared with the control group, SNHL group showed decreased FC within default mode network, while enhanced FC within auditory network (AUN) and salience network. No significant changes in FC were found in the visual network (VN) and sensorimotor network (SMN). Furthermore, the inter-network FC between SMN and AUN, frontal network and AUN, SMN and VN, frontal network and VN were significantly increased in SNHL group. The results implicate that the loss and the compensatory reorganization of brain network FC coexist in SNHL infants. It provides a network basis for understanding the brain development trajectory after hearing loss within early sensitive period.