Search Results (379)

The integrity of the blood–labyrinth barrier (BLB) is essential for inner ear homeostasis, regulating the ionic composition of endolymph and perilymph and preventing harmful substance entry. Endothelial hyperpermeability, central in inflammatory and immune responses, is managed through complex intercellular communication and molecular signaling pathways. Recent studies link BLB permeability dysregulation to auditory pathologies like acoustic trauma, autoimmune inner ear diseases, and presbycusis. Polymorphonuclear granulocytes (PMNs), or neutrophils, significantly modulate vascular permeability, impacting endothelial barrier properties. Neutrophil extracellular traps (NETs) are involved in diseases with autoimmune and autoinflammatory bases. The present study evaluated the impact of NETs on a BLB cellular model using a Transwell^® setup. Our findings revealed a concentration-dependent impact of NETs on human inner ear-derived endothelial cells. In particular, endothelial permeability markers increased, as indicated by reduced transepithelial electrical resistance, enhanced dextran permeability, and downregulated junctional gene expression (ZO1, OCL, and CDH5). Changes in cytoskeletal architecture were also observed. These preliminary results pave the way for further research into the potential involvement of NETs in BLB impairment and implications for auditory disorders. Full article

Conductive hearing loss caused by external or middle ear problems prevents the transmission of sound waves from the external auditory canal to the cochlea, and it is a common condition, especially in pediatric patients aged 1–5 years. The most common etiological factors are otitis media and cerumen during childhood. In some patients, external and middle ear functions and structures may be normal bilaterally despite the air-bone gap on the audiogram. This condition, which is often a missed diagnosis in children, is defined as a pseudo-conductive hearing loss (PCHL) caused by third window syndromes (TWSs) such as semicircular canal dehiscence, inner ear malformations with third window effect, and perilymphatic fistula. In this review of the literature, the authors emphasize the pitfalls of pediatric audio-vestibular evaluation on TWSs as well as the key aspects of this evaluation for the differential diagnosis of PCHL brought on by TWSs. This literature review will provide audiologists and otologists with early diagnostic guidance for TWSs in pediatric patients. Full article

Background: Cochlear implant (CI) electrode insertion can change the mechanical state of the ear whereby wideband tympanometry absorbance (WBTA) may serve as a sensitive tool to monitor these mechanical changes of the peripheral auditory pathway after CI surgery. In WBTA, the amount of acoustic energy reflected by the tympanic membrane is assessed over a wide frequency range from 226 Hz to 8000 Hz. The objective of this study was to monitor changes in WBTA in CI recipients before and after surgery. Methods: Following otoscopy, WBTA measurements were conducted twice in both ears of 38 standard CI recipients before and in the range of 4 to 15 weeks after CI implantation. Changes from pre- to postoperative absorbance patterns were compared for the implanted as well as the contralateral control ear for six different frequencies (500 Hz, 750 Hz, 1000 Hz, 2000 Hz, 3000 Hz, 4000 Hz). Furthermore, the influence of the time point of the measurement, surgical access, electrode type, sex and side of the implantation were assessed for the implanted and the control ear in a linear mixed model. Results: A significant decrease in WBTA could be observed in the implanted ear when compared with the contralateral control ear for 750 Hz (p < 0.01) and 1000 Hz (p < 0.05). The typical two-peak pattern of WBTA measurements was seen in both ears preoperatively but changed to a one-peak pattern in the newly implanted ear. The linear mixed model showed that not only the cochlear implantation in general but also the insertion through the round window compared to the cochleostomy leads to a decreased absorbance at 750 and 1000 Hz. Conclusions: With WBTA, we were able to detect mechanical changes of the acoustical pathway after CI surgery. The implantation of a CI led to decreased absorbance in the lower frequencies and the two-peak pattern was shifted to a one-peak pattern. The result of the linear mixed model indicates that WBTA can detect mechanical changes due to cochlear implantation not only in the middle ear but also in the inner ear. Full article

Piezo proteins have been identified as mechanosensitive ion channels involved in mechanotransduction. Several ion channel dysfunctions may be associated with diseases (including deafness and pain); thus, studying them is critical to understand their role in mechanosensitive disorders and to establish new therapeutic strategies. The current study investigated for the first time the expression patterns of Piezo proteins in zebrafish octavolateralis mechanosensory organs. Piezo 1 and 2 were immunoreactive in the sensory epithelia of the lateral line system and the inner ear. Piezo 1 (28.7 ± 1.55 cells) and Piezo 2 (28.8 ± 3.31 cells) immunopositive neuromast cells were identified based on their ultrastructural features, and their overlapping immunoreactivity to the s100p specific marker (28.6 ± 1.62 cells), as sensory cells. These findings are in favor of Piezo proteins’ potential role in sensory cell activation, while their expression on mantle cells reflects their implication in the maintenance and regeneration of the neuromast during cell turnover. In the inner ear, Piezo proteins’ colocalization with BDNF introduces their potential implication in neuronal plasticity and regenerative events, typical of zebrafish mechanosensory epithelia. Assessing these proteins in zebrafish could open up new scenarios for the roles of these important ionic membrane channels, for example in treating impairments of sensory systems. Full article

The degeneration of spiral ganglion neurons (SGNs), which convey auditory signals from hair cells to the brain, can be a primary cause of sensorineural hearing loss (SNHL) or can occur secondary to hair cell loss. Emerging therapies for SNHL include the replacement of damaged SGNs using stem cell-derived otic neuronal progenitors (ONPs). However, the availability of renewable, accessible, and patient-matched sources of human stem cells is a prerequisite for successful replacement of the auditory nerve. In this study, we derived ONP and SGN-like cells by a reliable and reproducible stepwise guidance differentiation procedure of self-renewing human dental pulp stem cells (hDPSCs). This in vitro differentiation protocol relies on the modulation of BMP and TGFβ pathways using a free-floating 3D neurosphere method, followed by differentiation on a Geltrex-coated surface using two culture paradigms to modulate the major factors and pathways involved in early otic neurogenesis. Gene and protein expression analyses revealed efficient induction of a comprehensive panel of known ONP and SGN-like cell markers during the time course of hDPSCs differentiation. Atomic force microscopy revealed that hDPSC-derived SGN-like cells exhibit similar nanomechanical properties as their in vivo SGN counterparts. Furthermore, spiral ganglion neurons from newborn rats come in close contact with hDPSC-derived ONPs 5 days after co-culturing. Our data demonstrate the capability of hDPSCs to generate SGN-like neurons with specific lineage marker expression, bipolar morphology, and the nanomechanical characteristics of SGNs, suggesting that the neurons could be used for next-generation cochlear implants and/or inner ear cell-based strategies for SNHL. Full article

Cytomegalovirus infection contributes to 10–30% of congenital hearing loss in children. Vertebrate peripheral auditory organs include the outer, middle, and inner ear. Their development is regulated by multiple signaling pathways. However, most ear diseases due to viral infections are due to congenital infections and reactivation and affect healthy adults to a lesser extent. This may be due to the fact that viral infections affect signaling pathways that are important for the development of peripheral hearing organs. Therefore, an in-depth understanding of the relationship between viral infections and the signaling pathways involved in the development of peripheral hearing organs is important for the prevention and treatment of ear diseases. In this review, we summarize the effects of viruses on signaling pathways and signaling molecules in the development of peripheral auditory organs. Full article

Sensorineural hearing loss (SNHL), characterized by damage to the inner ear or auditory nerve, is a prevalent auditory disorder. This study explores the potential of Castanopsis echinocarpa (CAE) as a therapeutic agent for SNHL. In vivo experiments were conducted using zebrafish and mouse models. Zebrafish with neomycin-induced ototoxicity were treated with CAE, resulting in otic hair cell protection with an EC₅₀ of 0.49 µg/mL and a therapeutic index of 1020. CAE treatment improved auditory function and protected cochlear sensory cells in a mouse model after noise-induced hearing loss (NIHL). RNA sequencing of NIHL mouse cochleae revealed that CAE up-regulates genes involved in neurotransmitter synthesis, secretion, transport, and neuronal survival. Real-time qPCR validation showed that NIHL decreased the mRNA expression of genes related to neuronal function, such as Gabra1, Gad1, Slc32a1, CaMK2b, CaMKIV, and Slc17a7, while the CAE treatment significantly elevated these levels. In conclusion, our findings provide strong evidence that CAE protects against hearing loss by promoting sensory cell protection and enhancing the expression of genes critical for neuronal function and survival. Full article

Previous studies have suggested a role for selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac^®) in the treatment of dizziness and inner ear vestibular dysfunction. The potential mechanism of action within the vestibular system remains unclear; however, fluoxetine has been reported to block certain types of K⁺ channel in other systems. Here, we investigated the direct actions of fluoxetine on membrane currents in presynaptic hair cells and postsynaptic calyx afferents of the gerbil peripheral vestibular system using whole cell patch clamp recordings in crista slices. We explored differences in K⁺ currents in peripheral zone (PZ) and central zone (CZ) calyces of the crista and their response to fluoxetine application. Outward K⁺ currents in PZ calyces showed greater inactivation at depolarized membrane potentials compared to CZ calyces. The application of 100 μM fluoxetine notably reduced K⁺ currents in calyx terminals within both zones of the crista, and the remaining currents exhibited distinct traits. In PZ cells, fluoxetine inhibited a non-inactivating K⁺ current and revealed a rapidly activating and inactivating K⁺ current, which was sensitive to blocking by 4-aminopyridine. This was in contrast to CZ calyces, where low-voltage-activated and non-inactivating K⁺ currents persisted following application of 100 μM fluoxetine. Additionally, marked inhibition of transient inward Na⁺ currents by fluoxetine was observed in calyces from both crista zones. Different concentrations of fluoxetine were tested, and the EC₅₀ values were found to be 40 µM and 32 µM for K⁺ and Na⁺ currents, respectively. In contrast, 100 μM fluoxetine had no impact on voltage-dependent K⁺ currents in mechanosensory type I and type II vestibular hair cells. In summary, micromolar concentrations of fluoxetine are expected to strongly reduce both Na⁺ and K⁺ conductance in afferent neurons of the peripheral vestibular system in vivo. This would lead to inhibition of action potential firing in vestibular sensory neurons and has therapeutic implications for disorders of balance. Full article

Objective: The electrically evoked compound action potential (ECAP) is an objective measure to indirectly assess spiral ganglion neurons. The ECAP provides inputs about the prognoses of cochlear implant (CI) recipients. Several factors such as cochlear morphology can affect ECAP measurements. This study aims to investigate the variation effect of cochlear parameters on intraoperative ECAP thresholds. Methods: This is a retrospective study on patients who underwent CI surgery with normal inner ear morphology at our center between 2017 and 2023. Cochlear anatomical parameters, including diameter (A value), width (B value), and height (H value), as well as cochlear duct length (CDL), were measured pre-operatively using OTOPLAN software (Version 3.0). Cochlear implant intraoperative objective measures were also collected. The correlation between the cochlear parameters and intraoperative objective measures was studied. Results: A total of 45 patients underwent cochlear implantation. The mean age was 2.4 ± 0.9 years. The mean CDL and cochlear coverage values were 33.2 ± 2.0 mm and 76.0 ± 5.7%, respectively. The ECAP threshold increased toward basal electrodes, with ECAP values as follows: apical 13.1 ± 3.8; middle 14.3 ± 3.7; and basal 15.6 ± 4.8. Additionally, the A, B, and H values showed a positive correlation with ECAP thresholds in different cochlear regions. The B value showed a significant moderate correlation with ECAP thresholds in the middle and basal electrodes but not in the apical electrodes. Conclusions: Cochlear anatomical parameters correlate with intraoperative ECAP thresholds. The B value showed a significant association with ECAP thresholds in the middle and basal electrodes. These findings could delineate the impact of the B value in CI and optimize electrode selection. Further research is required to study this correlation and its impact on postoperative outcomes. Full article

Sensorineural hearing loss can be caused by lesions to the inner ear during development. Understanding the events and signaling pathways that drive inner ear formation is crucial for determining the possible causes of congenital hearing loss. We have analyzed the innervation and expression of SOX2, JAGGED1, β-catenin (CTNNB1), and vitamin D receptor (VDR) in the inner ears of human conceptuses aged 5 to 10 weeks after fertilization (W) using immunohistochemistry. The prosensory domains of the human inner ear displayed SOX2 and JAGGED1 expression throughout the analyzed period, with SOX2 expression being more extensive in all the analyzed timepoints. Innervation of vestibular prosensory domains was present at 6 W and extensive at 10 W, while nerve fibers reached the base of the cochlear prosensory domain at 7–8 W. CTNNB1 and VDR expression was mostly membranous and present during all analyzed timepoints in the inner ear, being the strongest in the non-sensory epithelium. Their expression was stronger in the vestibular region compared to the cochlear duct. CTNNB1 and VDR expression displayed opposite expression trends during the analyzed period, but additional studies are needed to elucidate whether they interact during inner ear development. Full article

Ménière’s disease (MD) has an unclear cause. The microvascular dysregulation of the inner ear has been increasingly pointed out as a potential contributor. This study investigates the prevalence of cardiovascular risk factors (CVRFs) in MD patients compared to those with posterior circulation cerebral infarction (POCI). CVRFs like hypertension, diabetes, dyslipidemia, obesity, coronary heart disease, and smoking were assessed in both MD and POCI patients. Brain MRI identified POCI etiology as “small vessel occlusion” (SVO) or “other etiology” (OE). This study included 64 MD and 84 POCI patients. Compared to MD, POCI OE showed a higher prevalence of CVRFs across various age groups, including hypertension, diabetes, dyslipidemia, and smoking. Notably, the odds of having POCI OE were significantly higher for individuals with hypertension and smoking. On the other hand, POCI SVO showed a similar prevalence of CVRFs compared to MD. This study revealed no significant differences in CVRF prevalence between MD and smaller vessel POCI. However, a clear distinction emerged when comparing MD to POCI with the involvement of larger blood vessels. Further research is needed to confirm these findings and explore potential shared risk factors between POCI (SVO) and MD. Full article

Objectives: To study the correlation between positive cochlin tomoprotein testing (CTP), magnetic resonance (MR) imaging, and the auditory and vestibular function amongst patients with sudden hearing loss. Study Design: Prospective case series. Methods: We prospectively examined eight patients who presented with sudden hearing loss (>60 dB) with or without vertigo or tinnitus. We performed an ELISA-based CTP detection test using middle ear lavage samples. In addition to the CTP examination, a magnetic resonance imaging (MRI) examination was performed using different sequences (T1 and a T1 sequence with a contrast medium (CM), a T2 sequence, 4 h delayed intravenous gadolinium-enhanced three-dimensional fluid-attenuated inversion recovery (3D FLAIR)). Results: All patients with sudden hearing loss (>60 dB) presented a non-specific contrast enhancement in the cochlea and vestibulum on the affected side on delayed 3D-FLAIR MRI. Four patients had a positive CTP test, suggesting a perilymphatic fistula (PLF). However, no specific MRI signal for a PLF was observed. Conclusions: Using multimodal diagnostic measures, such as CTP testing and different MRI sequences, no correlation could be found in patients with a PLF. Full article

The motor protein prestin, found in the inner ear’s outer hair cells (OHCs), is responsible for high sensitivity and sharp frequency selectivity in mammalian hearing. Some studies have suggested that prestin could be a serological biomarker for cochlear damage, as OHCs are highly vulnerable to damage from various sources. However, the reported data are inconsistent and lack appropriate negative controls. To investigate whether prestin can be used as a serological biomarker for cochlear damage or stress, we measured prestin quantities in the bloodstreams of mice using ELISA kits from different companies. Wildtype (WT) mice were exposed to different ototoxic treatments, including noise exposure and ototoxic reagents that rapidly kill OHCs. Prestin-knockout (KO) mice were used as a negative control. Our data show that some ELISA kits were not able to detect prestin specifically. The ELISA kit that could detect the prestin protein from cochlear homogenates failed to detect prestin in the bloodstream, despite there being significant damage to OHCs in the cochleae. Furthermore, the optical densities of the serum samples, which correlate to prestin quantities, were significantly influenced by hemolysis in the samples. In conclusion, Prestin from OHCs is not a sensitive and reliable serological biomarker for detecting cochlear damage in mice using ELISA. Full article

Background: Enlarged vestibular aqueduct (EVA) syndrome can mimic otosclerosis in adults, presenting with an air–bone gap (ABG) and even absent stapedial reflexes. The ABG in inner-ear disorders is currently the object of several authors’ studies and seems to be related to a third mobile window (TMW) phenomenon. This can lead to misdiagnosis and inappropriate treatment. Given that it would be inappropriate and harmful to perform CT scans in all patients with a clinical diagnosis of otosclerosis, this study aims to highlight some clinical features useful for the differential diagnosis between otosclerosis and these rare cases of EVA presenting with an ABG, thus enabling the identification of suspected cases to be tested with CT scans. Methods: Between April and May 2024, a narrative review was conducted focusing on the differential diagnosis between some rare cases of EVA and otosclerosis. Clinical, audiological, and radiologic features of both conditions were investigated. Results: This review demonstrates the diagnostic challenge in differentiating atypical cases of EVA from otosclerosis in a subset of patients. Clinical and audiological features are important for differential diagnosis, but may not always be sufficient. Therefore, high-resolution computed tomography (HRCT) of the temporal bone plays a pivotal role in definitive diagnosis. Conclusions: In some specific cases, pre-operative imaging assessment using HRCT emerges as an essential tool for differentiating these two conditions and avoiding unnecessary stapes surgery. Full article

Deafness in vertebrates is associated with variants of hundreds of genes. Yet, many mutant genes causing rare forms of deafness remain to be discovered. A consanguineous Pakistani family segregating nonsyndromic deafness in two sibships were studied using microarrays and exome sequencing. A 1.2 Mb locus (DFNB128) on chromosome 5q11.2 encompassing six genes was identified. In one of the two sibships of this family, a novel homozygous recessive variant NM_005921.2:c.4460G>A p.(Arg1487His) in the kinase domain of MAP3K1 co-segregated with nonsyndromic deafness. There are two previously reported Map3k1-kinase-deficient mouse models that are associated with recessively inherited syndromic deafness. MAP3K1 phosphorylates serine and threonine and functions in a signaling pathway where pathogenic variants of HGF, MET, and GAB1 were previously reported to be associated with human deafness DFNB39, DFNB97, and DFNB26, respectively. Our single-cell transcriptome data of mouse cochlea mRNA show expression of Map3k1 and its signaling partners in several inner ear cell types suggesting a requirement of wild-type MAP3K1 for normal hearing. In contrast to dominant variants of MAP3K1 associated with Disorders of Sex Development 46,XY sex-reversal, our computational modeling of the recessive substitution p.(Arg1487His) predicts a subtle structural alteration in MAP3K1, consistent with the limited phenotype of nonsyndromic deafness. Full article