A cell-type-specific atlas of the inner ear transcriptional response to acoustic trauma.

Noise-induced hearing loss (NIHL) results from a complex interplay of damage to the sensory cells of the inner ear, dysfunction of its lateral wall, axonal retraction of type 1C spiral ganglion neurons, and activation of the immune response. We use RiboTag and single-cell RNA sequencing to survey the cell-type-specific molecular landscape of the mouse inner ear before and after noise trauma. We identify induction of the transcription factors STAT3 and IRF7 and immune-related genes across all cell-types. Yet, cell-type-specific transcriptomic changes dominate the response. The ATF3/ATF4 stress-response pathway is robustly induced in the type 1A noise-resilient neurons, potassium transport genes are downregulated in the lateral wall, mRNA metabolism genes are downregulated in outer hair cells, and deafness-associated genes are downregulated in most cell types. This transcriptomic resource is available via the Gene Expression Analysis Resource (gEAR; https://umgear.org/NIHL) and provides a blueprint for the rational development of drugs to prevent and treat NIHL.

Evaluation of the blood-perilymph barrier in ears with endolymphatic hydrops.

BACKGROUND: Otological diseases including Meniere's disease (MD) involve endolymphatic hydrops (EH), which can be visualized by magnetic resonance imaging (MRI) with gadolinium contrast agents, but the temporal changes of contrast in the inner ear have not been evaluated. OBJECTIVES: We investigated the permeability of the blood-perilymph barrier (BPB) in ears with EH to evaluate the severity of the inner ear disturbances. MATERIALS AND METHODS: The study included 32 ears from 16 patients with EH or related diseases who underwent MRI. The permeability of the BPB was assessed by the signal-intensity ratio (SIR) at four-time points: before and at 10 min, 4 h, and 24 h after administration of gadolinium for assessing EH. RESULTS: Cochlear EH was found in 25 of the 32 ears, and vestibular EH in 11. The rate of EH was significantly higher in symptomatic ears; however, the existence of EH was not related to SIR values. Nevertheless, SIR values in the basal turn were significantly higher 4 and 24 h after injection of gadolinium in patients aged ≥50 years. CONCLUSION AND SIGNIFICANCE: Higher SIR values observed in older patients with EH indicate severe disturbances of the BPB in the cochlea, which may account for intractable inner ear disturbances in older patients.

Molecular Mechanisms of Sensorineural Hearing Loss and Development of Inner Ear Therapeutics.

The sense of hearing enables us to enjoy sounds and music and engage with other people [...].

Increased cochlear otic capsule thickness and intracortical canal porosity in the oim mouse model of osteogenesis imperfecta.

Osteogenesis imperfecta (OI or brittle bone disease) is a group of genetic disorders of the connective tissues caused mainly by mutations in the genes encoding collagen type I. Clinical manifestations of OI include skeletal fragility, bone deformities, and severe functional disabilities, such as hearing loss. Progressive hearing loss, usually beginning in childhood, affects approximately 70% of people with OI with more than half of the cases involving the inner ear. There is no cure for OI nor a treatment to ameliorate its corresponding hearing loss, and very little is known about the properties of OI ears. In this study, we investigate the morphology of the otic capsule and the cochlea in the inner ear of the oim mouse model of OI. High-resolution 3D images of 8-week old oim and WT inner ears were acquired using synchrotron microtomography. Volumetric morphometric measurements were conducted for the otic capsule, its intracortical canal network and osteocyte lacunae, and for the cochlear spiral ducts. Our results show that the morphology of the cochlea is preserved in the oim ears at 8 weeks of age but the otic capsule has a greater cortical thickness and altered intracortical bone porosity, with a larger number and volume density of highly branched canals in the oim otic capsule. These results portray a state of compromised bone quality in the otic capsule of the oim mice that may contribute to their hearing loss.

Melatonin reduces radiation damage in inner ear.

The purpose of this study was to use a murine model to determine if melatonin can protect the inner ear from radiation-induced damage. A total of 81 4-week-old Balb/c mice were randomly divided into five groups: control group; 50 mg/kg melatonin group; 5 mg/kg melatonin+radiotherapy group; 50 mg/kg melatonin+radiotherapy group; radiotherapy group. The radiotherapy groups received 16 Gy irradiation and melatonin was administered by intraperitoneal injection 30 min before radiotherapy. On days 3 and 7 after irradiation the function of outer hair cells was determined by auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAEs) testing, pathological changes of inner ear cells were observed by light microscopy, and the expression of prestin mRNA was determined. ABR thresholds were increased and wave I latencies were extended after radiotherapy; however, the increases were lower in the groups that received melatonin (P < 0.05). DPOAEs showed radiotherapy-induced hearing loss at 8-12 kHz, and hearing loss was greater on day 7 than day 3. However, hearing loss was less in the melatonin groups (P < 0.05). Histopathological examination showed irradiation resulted in breaks and distortion of the cochlear basement membrane, disruption of the stria vascularis, and swelling of outer hair cells. Melatonin reduced these changes. Radiotherapy upregulated prestin mRNA expression. Radiotherapy-induced upregulation of prestin was decreased in the melatonin groups (P < 0.05), and the decrease was greater in the 50 mg/kg melatonin group (P < 0.05). Melatonin protects against radiation-induced cochlear damage by reducing damage to outer hair cells.

Does tympanic membrane perforation have a protective effect on the inner ear in blast-injured patients?

BACKGROUND: Blast-induced hearing loss is an acoustic trauma commonly caused by high-energy explosions of improvised explosive devices, and the auditory system may be affected by blast damage. This study aims to evaluate the protective effect of tympanic membrane perforation (TMP) on the inner ear against blast injury. METHODS: In this study, 43 adult patients who had suffered blast injury were divided into three subgroups: intact tympanic membranes in both ears, unilateral TMP, and bilateral TMP. Each patient underwent a comprehensive audiogram, including bone conduction, in the audiology department. RESULTS: Evaluation was performed on 43 (100%) males with a mean age of 31.44±8.01 years (range, 18-52 years). When the type of hearing loss was evaluated separately for each ear, sensorineural hearing loss (SNHL) was observed in 31 (36%), high-frequency SNHL in 26 (30.2%), conductive hearing loss in eight (9.3%), and mixed type hearing loss in 21 (24.4%) ears. TMP was detected in 21 (48.8%) of 43 blast-injured patients, on the right side in four (9.3%) patients, on the left side in seven (16.3%), and bilateral in 10 (23.3%). When the type of acoustic trauma was evaluated, 15 (34.9%) patients were observed to have suffered from the explosion of an IED, 12 (30.2%) from weapon explosion, six (14%) were a vehicle bomb explosion, three (7%) were projectile missile explosion, three (7%) were mortar explosion, two (4.7%) were mine explosion, and two (4.7%) were exposed to the explosion in an armored vehicle (Table 1). CONCLUSION: No significant difference was observed in the majority of the frequencies whether the tympanic membrane was perforated or not in the blast-injured patients and it was concluded that tympanic membrane perforation caused by blast injury had no protective effect on the inner ear.

Auditory impairment in H-ABC tubulinopathy.

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a neurodegenerative disease due to mutations in TUBB4A. Patients suffer from extrapyramidal movements, spasticity, ataxia, and cognitive deficits. Magnetic resonance imaging features are hypomyelination and atrophy of the striatum and cerebellum. A correlation between the mutations and their cellular, tissue and organic effects is largely missing. The effects of these mutations on sensory functions have not been described so far. We have previously reported a rat carrying a TUBB4A (A302T) mutation and sharing most of the clinical and radiological signs with H-ABC patients. Here, for the first time, we did a comparative study of the hearing function in an H-ABC patient and in this mutant model. By analyzing hearing function, we found that there are no significant differences in the auditory brainstem response (ABR) thresholds between mutant rats and WT controls. Nevertheless, ABRs show longer latencies in central waves (II-IV) that in some cases disappear when compared to WT. The patient also shows abnormal AEPs presenting only Waves I and II. Distortion product of otoacoustic emissions and immunohistochemistry in the rat show that the peripheral hearing function and morphology of the organ of Corti are normal. We conclude that the tubulin mutation severely impairs the central hearing pathway most probably by progressive central white matter degeneration. Hearing function might be affected in a significant fraction of patients with H-ABC; therefore, screening for auditory function should be done on patients with tubulinopathies to evaluate hearing support therapies.

Endoscopic-Assisted Drug Delivery for Inner Ear Regeneration.

Sensorineural hearing loss is caused by irreversible loss of auditory hair cells and/or neurons and is increasing in prevalence. Hair cells and neurons do not regenerate after damage, but novel regeneration therapies based on small molecule drugs, gene therapy, and cell replacement strategies offer promising therapeutic options. Endogenous and exogenous regeneration techniques are discussed in context of their feasibility for hair cell and neuron regeneration. Gene therapy and treatment of synaptopathy represent promising future therapies. Minimally invasive endoscopic ear surgery offers a viable approach to aid in delivery of pharmacologic compounds, cells, or viral vectors to the inner ear for all of these techniques.

Inner Ear Complications in Children and Adolescents with Sickle Cell Disease.

Hearing impairment is a reported complication of sickle cell disease, yet inner ear pathology is not fully understood. The study purpose was to examine the patterns of inner ear involvement in patients with sickle cell disease by magnetic resonance imaging (MRI) and to assess its association with auditory functions. A cross-sectional study included 22 children with sickle cell disease examined for inner ear pathology by audiogram, MRI inner ear and transcranial Doppler (TCD) with revision of their hospital records for transfusion, chelation and hydroxyurea (HU) therapy. Abnormal MRI in the form of intrinsic T1 hyperintensity within the lumen of inner ear structures and cochlear neuropathy was found in five (22.7%) patients; left middle cerebral artery (MCA) flow velocity was higher in patients with abnormal MRI (83.4 ± 5.3 cm/sec) compared to normal MRI (68.2 ± 11.1 cm/sec) (p = 0.015), however, none of the patients had TCD of >170 cm/sec. There was no significant difference between patients with normal and abnormal MRI as regards hearing level and speech audiometry. Sensorineural hearing loss (SNHL) was present in two (9.1%) and conductive hearing loss (CHL) in two (9.1%) patients. There was a significant negative correlation between right ear mean hearing level and right MCA flow velocity and significant negative correlation between left ear mean hearing level and basilar artery (BA) flow velocity. We concluded that inner ear pathology is not uncommon in asymptomatic patients with sickle cell anemia, yet it did not correlate with hearing impairment and may occur with normal TCD results.

Modulation of hearing function following the downgrading or upgrading of endolymphatic hydrops in Meniere's disease patients with endolymphatic duct blockage.

The present study was to investigate the dynamics of endolymphatic hydrops (EH) and hearing function, and explore whether the hearing loss is caused by EH alone and whether the hearing function can be modulated by changes in the EH. The extent of EH visualized by gadolinium (Gd)-enhanced inner ear magnetic resonance imaging, hearing thresholds and the summating potential/action potential ratio (-SP/AP ratio) of electrocochleography (ECochG) were recorded prior to and following surgery in 22 patients with intractable Meniere's disease (MD) who underwent endolymphatic duct blockage (EDB). The difference value of the hearing threshold and -SP/AP ratio was significantly positively correlated with the difference value of the endolymph to vestibule-volume ratio (EVVR) and grading of cochlear hydrops between prior to and following surgery. Among patients with a decreased EVVR, the average hearing threshold and -SP/AP ratio was significantly decreased following surgery, as compared to that prior to surgery. Six out of seven patients with a hearing improvement (≥10-dB decline) and 4/5 patients with a negative conversion of EcochG showed downgrading of their hydrops in the cochlea and/or vestibule. By contrast, among patients with an increased EVVR, the average hearing threshold and -SP/AP ratio tended to increase following EDB, as compared with that prior to surgery. One out of two patients with a hearing deterioration (≥10-dB elevation) showed upgrading of her hydrops in both cochlea and vestibule. The present results showed the downgrading of cochlear and/or vestibular hydrops accompanied by the downregulation of the hearing threshold and -SP/AP ratio of EcochG, as well as the upgrading of cochlear and/or vestibular hydrops that tended to upregulate the hearing threshold and -SP/AP ratio of EcochG; this suggested that hearing loss is likely to be caused by hydrops and that the impaired hearing function be modulated by changes in the hydrops.

Application of Mesenchymal Stem Cell Therapy and Inner Ear Regeneration for Hearing Loss: A Review.

Inner and middle ear disorders are the leading cause of hearing loss, and are said to be among the greatest risk factors of dementia. The use of regenerative medicine for the treatment of inner ear disorders may offer a potential alternative to cochlear implants for hearing recovery. In this paper, we reviewed recent research and clinical applications in middle and inner ear regeneration and cell therapy. Recently, the mechanism of inner ear regeneration has gradually been elucidated. "Inner ear stem cells," which may be considered the precursors of various cells in the inner ear, have been discovered in the cochlea and vestibule. Research indicates that cells such as hair cells, neurons, and spiral ligaments may form promising targets for inner ear regenerative therapies by the transplantation of stem cells, including mesenchymal stem cells. In addition, it is necessary to develop tests for the clinical monitoring of cell transplantation. Real-time imaging techniques and hearing rehabilitation techniques are also being investigated, and cell therapy has found clinical application in cochlear implant techniques.

Trauma-induced vestibular dysfunction: Possible functional repair under α1-antitrypsin-rich conditions.

Transient vestibular organ deafferentation, such that is caused by traumatic tissue injury, is presently addressed by corticosteroid therapy. However, restoration of neurophysiological properties is rarely achieved. Here, it was hypothesized that the tissue-protective attributes of α1-antityrpsin (AAT) may promote restoration of neuronal function. Inner ear injury was inflicted by unilateral labyrinthotomy in wild-type mice and in mice overexpressing human AAT. A 2-week-long assessment of vestibular signs followed. All animals responded with peak vestibular dysfunction scores within 4 h after local trauma. While wild-type animals displayed partial or no recovery across 7 days post-injury, AAT-rich group exhibited early recovery: from behavioral score 9-out-of-9 at peak to 4.8 ±â€¯0.44 (mean ±â€¯SD) within 8 h from injury, a time when wild-type mice scored 8.6 ±â€¯0.54 (p < 0.0001), and from vestibular score 15-out-of-15 to 7.8 ±â€¯2.2 within 24 h, when wild-type mice scored 13.0 ±â€¯2.0 (p < 0.01). Thus, recovery and functional normalisation of an injured vestibular compartment is achievable without corticosteroid therapy; expedited tissue repair processes appear to result from elevated circulating AAT levels. This study lays the foundation for exploring the molecular and cellular mediators of AAT within the repair processes of the delicate microscopic structures of the vestibular end organ.

Biomechanical analysis of the clinical characteristics of enlarged vestibular aqueduct syndrome with Mondini malformation.

BACKGROUND: numerous researches on the pathological mechanism of Enlarged Vestibular Aqueduct (EVA) syndrome mainly focuses on the genetic characteristics of SLC26A4 gene and the function of its encoding protein, Pendrin. One of the limitations with these explanations is that it does not explain why cerebrospinal fluid pressure can affect clinical manifestations. OBJECTIVES: To establish a new approach to explain the clinical manifestations of EVA syndrome with biomechanical method. MATERIAL AND METHODS: 108 cases of EVA syndrome who received cochlear implantation were analyzed retrospectively. A cochlear model was built to reflect the differences of the structure in EVA syndrome with or without Mondini malformation. The CFD software was used to simulate and display the differences in mechanical pathogenic factors to which the model was subjected. RESULTS: EVA syndrome patients with Mondini malformation suffer more mechanical damage from the cerebrospinal fluid pressure due to their structural reason and their symptoms appear earlier and progress faster. CONCLUSIONS: Biomechanics is an important aspect of pathological mechanism of EVA syndrome, and it provides a new angle for clinical decision-making.

The effect of middle ear effusion on the inner ear condition in children.

BACKGROUND: Otitis media with effusion (OME) is the most common cause of hearing impairment among children in developed nations. Middle ear (ME) fluid accumulation leads to progressive hearing impairment, usually of the conductive type. In some cases, mixed hearing loss associated with OME has been noted. It was reported that effusion in the ME has a negative impact on the vestibular system of the inner ear. OBJECTIVES: The aim of this random-sample cohort study was to evaluate postural stability and the influence of ME drainage on vestibulospinal reflexes in children with OME, and to determine whether disturbances in the vestibular organ correlate with a sensorineural component in OME-related hearing loss. MATERIAL AND METHODS: The study group consisted of 53 children with bilateral OME who were treated with bilateral ME drainage. The study group was divided into subgroups according to hearing loss. The control group consisted of 29 healthy children. Vestibular function and hearing evaluation were performed before and 4 weeks after drainage. RESULTS: A comparison of the stabilograms of the study group and the control group revealed elevated parameters in most of the tests. In the subgroup with mixed hearing loss, either before or after ME drainage, elevated stabilogram parameters were found in all tests. Posturography revealed vestibular system disturbances before and after ME drainage in the subgroup with mixed hearing loss, especially before ME drainage. The stabilogram parameters in the subgroup with conductive hearing loss after ME drainage were better in most tests in comparison to those before the procedure. CONCLUSIONS: The presence of effusion in the ME has a negative effect on the inner ear. We highlight the importance of monitoring the condition of the vestibular system in all children with OME, especially in cases with mixed hearing loss and more advanced clinical stages of the disease.

'Soft reinforcement' of the round window for superior semi-circular canal dehiscence syndrome.

BACKGROUND: Individuals with superior semi-circular canal syndrome often describe vestibular symptoms elicited by loud sounds, as well as other pressure-induced symptoms. They also often report other symptoms, including autophony, hyperacusis, cognitive dysfunction, spatial disorientation, anxiety and migraine headaches. Symptoms occur due to the presence of a 'third window' created by the dehiscence of the superior semi-circular canal. This case report describes a minimally invasive technique to provide soft reinforcement of the round window. CASE REPORT: Our patient underwent a permeatal procedure whereby the tympanic membrane was raised to allow inspection of the middle ear. The round window niche was identified and the round window membrane was reinforced with fat. The mucosa of the bony meatus leading to the round window was then disrupted before the application of a double layer of perichondrium to allow further reinforcement. CONCLUSION: The case provides support for the use of 'soft reinforcement' as a simple and effective technique to treat the symptoms of superior canal dehiscence syndrome.

The effect of premature ovarian failure on inner ear function.

The aim of this study was to test whether hearing function is impaired in women with premature ovarian failure. Thirty (30) women with premature ovarian failure (POF), 30 women in menopause and 30 healthy controls were recruited in this study. Pure tone audiometric (PTA), transiently evoked otoacoustic emissions (TEOAEs) and distortion product otoacoustic emissions (DPOAEs) of the study participants were analysed. At PTA, 6 and 8 kHz were lower in menopause group compared with both women with POF and controls. At TEOAE 3 and 4 kHz and at DPOAE 1, 2, 4 and 6 kHz were lower in menopause group compared with the controls. At DPOAE 6 kHz was lower in the POF group compared with the controls. Women with POF comparing to menopause group at TEOAE 3, 4 kHz and at DPOAE 4 and 6 kHz were lower in the menopause group. Inner ear function of both women in menopause and women with POF was declined compared to the healthy controls. Clinically, evaluation of hearing status may be considered in women with POF.Impact statementWhat is already known on this subject: Premature ovarian failure (POF) affects 1%-2% of women, and it adversely effects on health status (such as cardiovascular, psychological and cognitive disorders). Previous studies suggested that a lack of oestrogen might play a role in hearing disorders in women. However, we do not know POF's adversely effect on cochlea and hearing.What the results of this study add: The present study demonstrates that lower serum oestrogen has a negative effect hearing in women with POF at DPOAE 6 kHz.What the implications are of these findings for clinical practice and/or further research: The women with POF must be evaluated for hearing status.

Results in caloric test, video head impulse test and inner ear MRI in patients with Ménière's disease.

OBJECTIVE: Our aim was to elucidate relationships between results from the caloric test (c-test), video Head Impulse Test (vHIT) and inner ear gadolinium-enhanced MRI (ieMRI) in patients with endolymphatic hydrops (EH), especially patients with Ménière's disease (MD). METHODS: We managed 1789 successive patients at the Vertigo/Dizziness Center in Nara Medical University from May 2014 to December 2018. After providing informed consent for vertigo/dizziness examinations, 281 patients were hospitalized to check their inner ear function for proper diagnosis and treatment. Then 76 participants underwent the c-test, vHIT and ieMRI. Among these 76 cases, 20 were diagnosed with MD (20/76; 26.3%) and 56 were non-MD (56/76; 73.7%) according to the 2015 diagnostic guideline of the International Classification of Vestibular Disorders. The MD group included 15 unilateral and 5 bilateral cases. The non-MD group included 22 benign paroxysmal positional vertigo, 10 vestibular neuritis, 8 sudden deafness with vertigo, 6 orthostatic dysregulation, 4 vestibular neuropathy and 6 others. Results in these examinations in the side of an active lesioned inner ear were representative in each peripheral case. RESULTS: Twenty-nine of the 76 patients (38.1%) showed discrepant results between the c-test (outside of normal range) and vHIT (within normal range). Twenty-two of 76 patients (28.9%) had a positive EH sign on ieMRI. The c-test/vHIT discrepancy percentage in MD (14/20; 70.0%) was significantly higher than that in non-MD (15/56; 26.8%) (p=0.00179). The positive EH sign in ieMRI percentage in MD (15/20; 75.0%) was significantly higher than that in non-MD (7/56; 12.5%) (p=0.0015). There was a significant positive relationship between the c-test/vHIT discrepancy and the positive EH sign (p=0.00058) in all 76 cases combined. However, there was no significant relationship between c-test/vHIT discrepancy and positive EH sign (p=0.13) in the 20 MD cases. Considering the 15 unilateral and 5 bilateral MD cases, the c-test/vHIT discrepancy was observed in 14 of the 25 affected ears. Positive signs of vestibular EH herniation into the cupula in the lateral semicircular canal was seen in 14 of the 25 MD ears. There was significant relationship between the c-test/vHIT discrepancy and EH herniation (p=0.0012) in MD ears. CONCLUSION: The present results suggest that patients with MD could have inner ear EH significantly more often than those with non-MD. In cases with MD, a positive EH sign on ieMRI did not always indicate a c-test/vHIT discrepancy; both findings may occur due to herniation of vestibular EH adjacent to the lateral semicircular canal.