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Variants in the gene NDP cause Norrie disease, a severe dual-sensory disorder characterized by congenital blindness due to disrupted retinal vascular development and progressive hearing loss accompanied by sensory hair cell death. NDP encodes the secreted signaling molecule norrin. The role of norrin in the cochlea is incompletely understood. We investigated whether the Norrie disease cochlear pathology can be ameliorated in an Ndp -knockout ( Ndp -KO) mouse model by conditional activation of stabilized β-catenin in vascular endothelial cells. We hypothesized that in the cochlea microvasculature, β-catenin is the primary downstream intracellular effector of norrin binding to endothelial cell surface receptors and that restoration of this signaling pathway is sufficient to prevent sensory hair cell death and hearing loss. We show that tamoxifen induction of Cdh5CreERT2;Ctnnb1 flex3/+ ;Ndp- KO mice stabilizing β-catenin in vascular endothelial cells alone rescued defects in cochlear vascular barrier function, restored dysregulated expression of endothelial cell disease biomarkers ( Cldn5, Abcb1a, Slc7a1, and Slc7a5 ), and prevented progressive outer hair cell death and hearing loss. Single-cell transcriptome profiling of human cochleas showed NDP expression by fibrocytes and glial cells while receptor gene expression ( FZD4, TSPAN12, LRP5, and LRP6 ) coincided in vascular endothelial cells. Our findings support the conclusion that vascular endothelial cells are a primary target of norrin signaling in the cochlea of mice and humans and restoration of β-catenin regulation of target gene expression within cochlear endothelial cells is sufficient to maintain a cochlear microenvironment critical for hair cell survival., Competing Interests: Competing interests statement:A patent application relating to this work has been filed by UCLB: application number 2214972.8. Authors work closely with the Norrie Disease Foundation Charity UK.

Purpose: To corroborate the vascular etiology of sudden sensorineural hearing loss (SNHL) utilizing magnetic resonance imaging (MRI)., Patient: A 24-year-old male with a history of sickle cell disease experienced sudden SNHL and right horizontal nystagmus, without accompanying vertigo., Intervention: Audiometric evaluation revealed left-sided SNHL, predominantly affecting high frequencies. Video head impulse testing demonstrated isolated dysfunction of the left posterior semicircular canal. An urgent brain MRI identified a recent punctiform ischemic stroke in the frontal region. A subsequent MRI, conducted with a 4-hour delay and post-contrast enhancement, highlighted a hyperintense signal within the left cochlear region and the left posterior semicircular canal., Conclusion: The investigative results substantiate an infarction in the territory of the cochlear artery, precipitated by a vaso-occlusive event, thereby reinforcing the vascular hypothesis of cochleovestibular artery syndrome. This case underscores the congruence between clinical observations and delayed post-contrast MRI findings., Competing Interests: Declarations Conflict of interest None., (© 2024. The Author(s).)

Idiopathic sudden sensorineural hearing loss (ISSNHL) is characterized by abruptly appearing hearing loss, sometimes accompanied by vertigo. Vascular pathologies (e.g., cochlear ischemia, or cochlear infarction) are one of the most likely causes of ISSNHL. This review aims to present current understanding of inner ear anatomy, clinical features of ISSNHL, and its treatment strategies. The labyrinthine artery is the only end artery supplying blood to the inner ear, and it has three branches: the anterior vestibular artery, the main cochlear artery, and the vestibulo-cochlear artery (VCA). Occlusion of the VCA can be caused by a variety of factors. The VCA courses through a narrow bone canal. ISSNHL is usually diagnosed after excluding retrocochlear pathologies of sudden sensorineural hearing loss (SSNHL), such as vestibular schwannoma. Therefore, a head MRI or assessing auditory brainstem responses are recommended for patients with SSNHL. Severe SSNHL patients with high CHADS 2 scores, an index of stroke risk, have a significantly lower rate of vestibular schwannoma than severe SSNHL patients with low CHADS 2 scores, suggesting that severe ISSNHL in individuals at high risk of stroke is caused by vascular impairments. Intralabyrinthine hemorrhage causes SSNHL or vertigo, as in ISSNHL. The diagnosis of intralabyrinthine hemorrhage requires careful interpretation of MRI, and a small percentage of patients diagnosed with ISSNHL may in fact have intralabyrinthine hemorrhage. Many studies have reported an association between ISSNHL and atherosclerosis or cardiovascular risk factors (e.g., diabetes mellitus, hypertension, dyslipidemia and cardiovascular disease), and subsequent risk of stroke in patients with ISSNHL may be elevated compared to controls. Increased hearing level on the healthy ear side, high Framingham risk score, high neutrophil-to-lymphocyte ratio, high platelet-to-lymphocyte ratio, and severe white matter lesions may be poor prognostic factors for patients with ISSNHL. The association between thrombosis-related genes and susceptibility to ISSNHL has been reported in many studies (e.g., coagulation factor 2, coagulation factor 5, plasminogen activator inhibitor-1, platelet-associated genes, a homocysteine metabolism-related enzyme gene, endothelin-1, nitric oxide 3, phosphodiesterase 4D, complement factor H, and protein kinase C-eta). Treatment of ISSNHL with the aim of mitigating the vascular impairment in the inner ear includes systemically administered steroids, intratympanic steroid injections, hyperbaric oxygen therapy, prostaglandin E1, defibrinogenation therapy, and hydrogen inhalation therapy, but there is currently no evidence-based treatment for ISSNHL. Breakthroughs in the unequivocal diagnosis and treatment of ISSNHL due to vascular impairment are crucial to improve quality of life., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)

Background and Aim: The cochlear aqueduct (CA) connects between the perilymphatic space of the cochlea and the subarachnoid space in the posterior cranial fossa. The study aimed to examine 1) whether cavitation of the CA occurs on the subarachnoid side or the cochlear side and 2) the growth and/or degeneration of the CA and its concomitant vein., Methods: We examined paraffin-embedded histological sections from human fetuses: 15 midterm fetuses (crown-rump length or CRL, 39-115 mm) and 12 near-term fetuses (CRL, 225-328 mm)., Results: A linear mesenchymal condensation, i.e., a likely candidate of the CA anlage, was observed without the accompanying vein at 9-10 weeks. The vein appeared until 15 weeks, but it was sometimes distant from the CA. At 10-12 weeks, the subarachnoid space (or the epidural space) near the glossopharyngeal nerve rapidly protruded into the CA anlage and reached the scala tympani, in which cavitation was gradually on-going but without epithelial lining. However, CA cavitation did not to occur in the anlage. At the opening to the scala, the epithelial-like lining of the CA lost its meningeal structure. At near-term, the CA was often narrowed and obliterated., Conclusion: The CA develops from meningeal tissues when the cavitation of the scala begins. The latter cavitation seemed to reduce tissue stiffness leading, to meningeal protrusion. The so-called anlage of CA might be a phylogenetic remnant of the glossopharyngeal nerve branch. A course of cochlear veins appears to be determined by a rule different from the CA development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

The three-dimensional stria vascularis (SV) and cochlear blood vessel structure is essential for inner ear function. Here, modified Sca/eS, a sorbitol-based optical-clearing method, was reported to visualize SV and vascular structure in the intact mouse cochlea. Cochlear macrophages as well as perivascular-resident macrophage-like melanocytes were detected as GFP-positive cells of the CX3CR1 +/GFP mice. This study's method was effective in elucidating inner ear function under both physiological and pathological conditions., (© 2023. The Author(s).)

The ototoxic mechanisms of cisplatin on the organ of Corti and spiral ganglion neurons have been extensively studied, while few studies have been focused on the stria vascularis (SV). Herein, we verified the functional and morphological impairment in SV induced by a single injection of cisplatin (12 mg/kg, I.P.), represented by a reduction in Endocochlear Potentials (EP) and strial atrophy, and explored underlying mechanisms. Our results revealed increased extravasation of chromatic tracers (Evans blue dye and FITC-dextran) around microvessels after cisplatin exposure. The increased vascular permeability could be attributed to changes of pericytes (PCs) and perivascular-resident macrophage-like melanocytes (PVM/Ms) in number or morphology, as well as the enhanced level of HIF-1α and downstream VEGF. This capillary leakage led to a high accumulation of cisplatin in the perivascular space in SV, and disrupted the integrity of blood-labyrinth barrier (BLB). Also, tight junction (ZO-1) loosening and Na + , K + -ATPase damage was considered to be other critical contributors of BLB breakdown, which resulted in EP drop and consequent hearing loss. This study explored the role of stria vascularis in cisplatin-induced ototoxicity in terms of BLB hyperpermeability and pointed to a novel therapeutic target for the prevention of cisplatin-related hearing loss., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Although previous studies continuously report an increased risk of hearing loss in diabetes patients, the impact of the disease on the inner ear remains unexplored. Herein, we examine the pathophysiology of diabetes-associated hearing impairment and cochlear synaptopathy in a mouse model of diabetes. Male B6.BKS(D)- Lepr db /J (db/db, diabetes) and heterozygote (db/+, control) mice were assigned into each experimental group (control vs. diabetes) based on the genotype and tested for hearing sensitivity every week from 6 weeks of age. Each cochlea was collected for histological and biological assays at 14 weeks of age. The diabetic mice exerted impaired hearing and a reduction in cochlear blood flow and C-terminal-binding protein 2 (CtBP2, a presynaptic ribbon marker) expression. Ultrastructural images revealed severely damaged mitochondria from diabetic cochlea accompanied by a reduction in Cytochrome c oxidase subunit 4 (COX4) and CR6-interacting factor 1 (CRIF1). The diabetic mice presented significantly decreased levels of platelet endothelial cell adhesion molecule (PECAM-1), B-cell lymphoma 2 (BCL-2), and procaspase-9, but not procaspase-8. Importantly, significant changes were not found in necroptotic programmed cell death markers (receptor-interacting serine/threonine-protein kinase 1, RIPK1; RIPK3; and mixed lineage kinase domain-like pseudokinase, MLKL) between the groups. Taken together, diabetic hearing loss is accompanied by synaptopathy, microangiopathy, damage to the mitochondrial structure/function, and activation of the intrinsic apoptosis pathway. Our results imply that mitochondrial dysfunction is deeply involved in diabetic hearing loss, and further suggests the potential benefits of therapeutic strategies targeting mitochondria.

As a general sensory disorder, hearing loss was a major concern worldwide. Autophagy is a common cellular reaction to stress that degrades cytoplasmic waste through the lysosome pathway. Autophagy not only plays major roles in maintaining intracellular homeostasis but is also involved in the development and pathogenesis of many diseases. In the auditory system, several studies revealed the link between autophagy and hearing protection. In this review, we aimed to establish the correlation between autophagy and hair cells (HCs) from the aspects of ototoxic drugs, aging, and acoustic trauma and discussed whether autophagy could serve as a potential measure in the protection of HCs., Competing Interests: The authors declare no competing financial interests., (Copyright © 2021 Chang Liu et al.)

Objective: To evaluate the effect of Lipopolysaccharide (LPS), a bacterial endotoxin on cochlear microcirculation, and its mode of action., Methods: Twenty-five Dunkin-Hartley guinea pigs were divided into five groups of five animals each. After surgical preparation, cochlear microcirculation was quantified by in vivo fluorescence microscopy. Placebo or LPS (1 mg, 10 µg, and 100 ng) was applied topically, and microcirculation was measured before and twice after application. A fifth group was pretreated with etanercept, a tumor necrosis factor (TNF) antagonist, and afterward the lowest LPS concentrations that yielded significant results (10 µg) were applied., Results: In the groups that had been treated with 1 mg and 10 µg LPS, a significant drop in cochlear microcirculation was observed after 30 (.791 ± .089 Arbitrary Units (AU), compared to baseline, and .888 ± .071AU) and 60 (.756 ± .101 AU and .817 ± .124 AU, respectively) minutes. The groups that had been treated with 100 ng LPS and that had been pretreated with etanercept showed no significant change in cochlear blood flow compared to placebo., Conclusion: Lipopolysaccharide shows a dose-dependent effect on cochlear microcirculation; this effect can already be observed after 30 min. Pretreatment with etanercept can abrogate this effect, indicating that TNF mediates the effect of LPS on cochlear microcirculation., (© 2021 The Authors. Microcirculation published by John Wiley & Sons Ltd.)

Millions of people are affected by hearing loss. Hearing loss is frequently caused by noise or aging and often associated with loss of pericytes. Pericytes populate the small vessels in the adult cochlea. However, their role in different types of hearing loss is largely unknown. Using an inducible and conditional pericyte depletion mouse model and noise-exposed mouse model, we show that loss of pericytes leads to marked changes in vascular structure, in turn leading to vascular degeneration and hearing loss. In vitro, using advanced tissue explants from pericyte fluorescence reporter models combined with exogenous donor pericytes, we show that pericytes, signaled by VEGF isoform A165 (VEGFA165), vigorously drive new vessel growth in both adult and neonatal mouse inner ear tissue. In vivo, the delivery of an adeno-associated virus serotype 1-mediated (AAV1-mediated) VEGFA165 viral vector to pericyte-depleted or noise-exposed animals prevented and regenerated lost pericytes, improved blood supply, and attenuated hearing loss. These studies provide the first clear-cut evidence that pericytes are critical for vascular regeneration, vascular stability, and hearing in adults. The restoration of vascular function in the damaged cochlea, including in noise-exposed animals, suggests that VEGFA165 gene therapy could be a new strategy for ameliorating vascular associated hearing disorders.

Objectives: Cochlear microcirculation disturbance caused by vasculopathy is a common cause of sudden deafness (SD). Reactive oxygen species (ROS) plays an important role in cochlear injury during ischemia-reperfusion. Butylphthalide can improve microcirculation, reduce ROS formation and inhibit apoptosis. The aim of this study was to investigate the therapeutic effect of butylphthalide on patients with SD., Patients and Methods: The hearing gains from 32 ears treated with butylphthalide were compared with that of 32 ears treated with non-butylphthalide. Butylphthalide capsules was administrated orally on an empty stomach for 10 continuous days. There were no significant differences in audiological and clinical data between butylphthalide and non-butylphthalide groups., Results: The hearing gain of butylphthalide group at 500, 1000, 2000, and 4000 Hz was significantly higher than that of non-butylphthalide group correspondingly (P<0.01). And, the hearing gain at PTA (pure-tone average of 500, 1000, 2000, and 4000 Hz) in butylphthalide group was significantly higher than that of non-butylphthalide group (P<0.01)., Conclusion: The recovery of hearing in butylphthalide group was significantly better than that of non-butylphthalide group. It is confirmed that butylphthalide has a definite therapeutic effect on SD., (Copyright © 2020. Published by Elsevier Inc.)

Adiponectin (APN) is an adipokine secreted from adipose tissue and exhibits biological functions such as microcirculation-regulating, hearing-protective, and antiapoptotic. However, the effect of APN on the apoptosis of spiral arterial smooth muscle cells (SMCs) under hypoxic conditions in vitro is not clear. We used cobalt chloride (CoCl 2 ) to simulate chemical hypoxia in vitro, and the SMCs were pretreated with APN and then stimulated with CoCl 2 . The viability of cells and apoptosis were assessed by CCK-8 and flow cytometry, respectively. Superoxide dismutase (SOD) activity, malondialdehyde (MDA) levels, cAMP level, and the activity of PKA were detected by ELISA. Protein expression and localization were studied by Western blot and immunofluorescence analysis. In the present study, we found that APN exhibits antiapoptosis effects. CoCl 2 exhibited decreased cell viability, increased apoptosis and MDA levels, and decreased SOD activity in a concentration-dependent manner, compared with the control group. Moreover, CoCl 2 upregulated the expression levels of Bax and cleaved caspase-3 and then downregulated Bcl-2 levels in a time-dependent manner. Compared with the CoCl 2 group, the group pretreated with APN had increased cell viability, SOD activity, PKA activity, cAMP level, and PKA expression, but decreased MDA levels and apoptosis. Lastly, the protective effect of APN was blocked by cAMP inhibitor SQ22536 and PKA inhibitor H 89. These results showed that APN protected SMCs against CoCl 2 -induced hypoxic injury via the cAMP/PKA signaling pathway., Competing Interests: The authors declared that they have no conflicts of interest to this work., (Copyright © 2020 Jingjie Xiao et al.)

Objective: To study the surgical anatomy of the labyrinthine artery (LA) and the subarcuate artery (SA), their anatomic relationships, and clinical implications, as injury of the LA can result in hearing loss., Methods: Ten formalin-fixed, latex-colored specimens were studied (20 sides). After retrosigmoid craniotomy and neurovascular dissection under microscopic magnification, 4-mm 0° and 30° endoscopic lenses were used to improve visualization. Results were statistically analyzed., Results: The LA was a constant artery that followed the vestibulocochlear nerve into the internal auditory canal. The SA was an inconstant artery that ended in the dura mater around the subarcuate fossa in 35% of cases. The LA originated from the anterior inferior cerebellar artery in 89.3% of specimens and from the basilar artery in 10.7% of specimens. The SA branched off from the anterior inferior cerebellar artery when present. The origin of the LA was inferomedial to the vestibulocochlear nerve in most cases (71.4%), whereas the SA was usually lateral (70%). The distal portion of the LA was inferomedial to the vestibulocochlear nerve in 71.4% of cases. The distal portion of the SA was superolateral to the nerve in all cases (P < 0.00001)., Conclusions: Knowledge of the different trajectory and anatomic relationship of the LA and the SA with the vestibulocochlear nerve is of paramount importance to differentiate them during surgery. The LA is usually inferomedial to the vestibulocochlear nerve at its distal and proximal aspects, whereas the SA usually originates lateral and ends superolateral to the nerve., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Acoustic trauma disrupts cochlear blood flow and damages sensory hair cells. Damage and regression of capillaries after acoustic trauma have long been observed, but the underlying mechanism of pathology has not been understood. We show herein that loud sound causes change of phenotype from neural/glial antigen 2 positive/α-smooth muscle actin negative to neural/glial antigen 2 positive/α-smooth muscle actin positive in some pericytes (PCs) on strial capillaries that is strongly associated with up-regulation of transforming growth factor-β1. The acoustic trauma also reduced capillary density and increased deposition of matrix proteins, particularly in the vicinity of transformed PCs. In a newly established in vitro three-dimensional endothelial cell (EC) and PC co-culture model, transformed PCs induced thicker capillary-like branches in ECs and increased collagen IV and laminin expression. Transplantation of exogenous PCs derived from neonatal day 10 mouse cochleae to acoustic traumatized cochleae, however, significantly attenuated the decreased vascular density in the stria. Transplantation of PCs pretransfected with adeno-associated virus 1-vascular endothelial growth factor-A165 under control of a hypoxia-response element markedly promotes vascular volume and blood flow, increased proliferation of PCs and ECs, and attenuated loud sound-caused loss in endocochlear potential and hearing. Our results indicate that loud sound-triggered PC transformation contributes to capillary wall thickening and regression, and young PC transplantation effectively rehabilitates the vascular regression and improves hearing., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The mammalian cochlea possesses unique acoustic sensitivity due to a mechanoelectrical 'amplifier', which requires the metabolic support of the cochlear lateral wall. Loud sound exposure sufficient to induce permanent hearing damage causes cochlear blood flow reduction, which may contribute to hearing loss. However, sensory epithelium involvement in the cochlear blood flow regulation pathway is not fully described. We hypothesize that genetic manipulation of the mechanoelectrical transducer complex will abolish sound induced cochlear blood flow regulation. We used salsa mice, a Chd23 mutant with no mechanoelectrical transduction, and deafness before p56. Using optical coherence tomography angiography, we measured the cochlear blood flow of salsa and wild-type mice in response to loud sound (120 dB SPL, 30 minutes low-pass filtered noise). An expected sound induced decrease in cochlear blood flow occurred in CBA/CaJ mice, but surprisingly the same sound protocol induced cochlear blood flow increases in salsa mice. Blood flow did not change in the contralateral ear. Disruption of the sympathetic nervous system partially abolished the observed wild-type blood flow decrease but not the salsa increase. Therefore sympathetic activation contributes to sound induced reduction of cochlear blood flow. Additionally a local, non-sensory pathway, potentially therapeutically targetable, must exist for cochlear blood flow regulation.

Although cochlear venous insufficiency has been considered to cause sudden sensorineural hearing loss (SSHL), there is insufficient clinical evidence to support this hypothesis. We sought to determine whether there is a correlation between draining patterns of the dural venous sinuses and the side of the affected ear in SSHL, as well as hearing recovery. The medical records of 109 patients diagnosed with unilateral SSHL were retrospectively reviewed. Magnetic resonance images and pure tone audiometry were performed in all patients. We measured the dominance of the inferior petrosal sinus (IPS) and transverse-sigmoid sinus (TS/SS) ipsilateral to the affected ear. Most patients were characterized by asymmetric venous drainage (IPS, 53.2%; TS/SS, 81.7%). The dominant side of the IPS or TS/SS was independent of the side of the affected ear for all patients in this study. However, in 35 patients with early recovery within 2 weeks, the dominant side of TS/SS was significantly associated with the side of the affected ear (p = 0.011). Moreover, the dominance of both the IPS and TS/SS influenced hearing outcomes at 3 months. Dominant TS/SS ipsilateral to the affected ear, particularly in the presence of ipsilateral hypoplastic IPS, is associated with a favorable hearing prognosis of SSHL.

Age-related hearing loss (ARHL) is an irreversible, progressive neurodegenerative disorder and is presently untreatable. Previous studies using animal models have suggested mitochondrial damage and programmed cell death to be involved with ARHL. Thus, we further investigated the pathophysiologic role of mitochondria and necroptosis in aged C57BL/6J male mice. Aged mice (20 months old) exhibited a significant loss of hearing, number of hair cells, neuronal fibers, and synaptic ribbons compared to young mice. Ultrastructural analysis of aged cochleae revealed damaged mitochondria with absent or disorganized cristae. Aged mice also showed significant decrease in cochlear blood flow, and exhibited increase in gene expression of proinflammatory cytokines (IL-1β, IL-6, and TNF-α), receptor-interacting serine/threonine-protein kinase 1 and 3 (RIPK1 and RIPK3) and the pseudokinase mixed-lineage kinase domain-like (MLKL). Immunofluorescence (IF) assays of cytochrome C oxidase I (COX1) confirmed mitochondrial dysfunction in aged cochleae, which correlated with the degree of mitochondrial morphological damage. IF assays also revealed localization and increased expression of RIPK3 in sensorineural tissues that underwent significant necroptosis (inner and outer hair cells and stria vascularis). Together, our data shows that the aging cochlea exhibits damaged mitochondria, enhanced synthesis of proinflammatory cytokines, and provides new evidence of necroptosis in the aging cochlea in in vivo.

Aims: Adiponectin (APN) is a protein hormone secreted mainly by adipose tissue that exhibits biological functions such as anti-inflammatory, anti-atherosclerotic, anti-apoptotic, hearing-protective and microcirculation-regulating functions. In this study, we explored whether APN could attenuate damage caused by CoCl 2 -induced hypoxic conditions in smooth muscle cells (SMCs) of the spiral modiolar artery (SMA)., Main Methods: We first cultured and identified primary SMCs of the SMA. Afterward, the SMCs were pre-treated with APN and then stimulated with CoCl 2 ., Key Findings: Compared with the control group, the group treated with CoCl 2 for 24 h exhibited significantly decreased cell viability, significantly increased apoptosis rates and Malondialdehyde (MDA) levels, and decreased Superoxide Dismutase (SOD) activity. In addition, the expression levels of Bax and cleaved caspase-3 were upregulated, while those of Bcl2 were downregulated evidently. Compared with the CoCl 2 group, the group pre-treated with APN before receiving CoCl 2 treatment had increased cell viability and SOD activity but decreased MDA levels and apoptosis rates. The expression levels of Bcl2, p-AMPKα and Cx43 were evidently increased, while those of Bax and cleaved caspase-3 were decreased, in the group pre-treated with APN compared to the CoCl 2 group. The protective effect of APN was blocked by the AMPK inhibitor Compound C and the Cx43 inhibitor Gap19., Significance: Our study demonstrated that APN protected SMCs against CoCl 2 -induced hypoxic injury via the AMPK signalling pathway and regulated the expression of Cx43 in cells. Therefore, APN might be a promising treatment for diseases related to circulation disturbances of the inner ear., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To determine the distribution of perivascularresident macrophages (PVMs) in BLB and their relationship with capillaries, and to explore the possible mechanisms responsible for lipopolysaccharide (LPS)-induced activation of PVMs and the breakdown of BLB., Methods: Adult Balb/c mice were either trans-tympanically injected with LPS, or mock-treated. Auditory brainstem response was tested before and 48 h after treatments. Distribution of pericytes, PVMs and capillaries was analyzed by immunohistochemical staining, and BLB permeability was estimated by FITC-dextran leakage assay. Ultrastructure of stria vascularis was examined by transmission electron microscope. Protein and mRNA level of matrix metallopeptidase 9 (MMP-9), zona occludens-1 (ZO-1), interleukin-33 (IL-33) and its receptor suppression of tumorigenicity 2 (ST2) was measured by IHC and qRT-PCR., Results: Unlike pericytes that surround one capillary, PVMs branched to connect with more than one capillary. LPS caused hearing loss in mice. Following LPS challenge, cochleae showed vascular leakage in stria vascularis, and PVMs presented morphological changes including reduced contact with capillaries. TEM revealed a reduced number of tight junction contact points between endothelial cells and a wider space between PVMs, pericytes and endothelial cells. The mRNA and protein levels of MMP-9 and ST2 in stria vascularis were up-regulated, while ZO-1 were down-regulated after exposure to LPS., Conclusions: Our results suggest that PVMs may play a more significant role than pericytes in maintaining the integrity of BLB. Our findings also reveal a possible mechanism contributing to LPS-induced activation of PVMs, breakdown of BLB and hearing loss., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Noise exposure affects the organ of Corti and the lateral wall of the cochlea, including the stria vascularis and spiral ligament. Although the inner ear vasculature and spiral ligament fibrocytes in the lateral wall consist of a significant proportion of cells in the cochlea, relatively little is known regarding their functional significance. In this study, 6-week-old male C57BL/6 mice were exposed to noise trauma to induce transient hearing threshold shift (TTS) or permanent hearing threshold shift (PTS). Compared to mice with TTS, mice with PTS exhibited lower cochlear blood flow and lower vessel diameter in the stria vascularis, accompanied by reduced expression levels of genes involved in vasodilation and increased expression levels of genes related to vasoconstriction. Ultrastructural analyses by transmission electron microscopy revealed that the stria vascularis and spiral ligament fibrocytes were more damaged by PTS than by TTS. Moreover, mice with PTS expressed significantly higher levels of proinflammatory cytokines in the cochlea (e.g., IL-1β, IL-6, and TNF-α). Overall, our findings suggest that cochlear microcirculation and lateral wall pathologies are differentially modulated by the severity of acoustic trauma and are associated with changes in vasoactive factors and inflammatory responses in the cochlea.

Objective: Tsumura Suzuki Obese Diabetes (TSOD) mice exhibit early age-associated hearing loss. Histopathological analysis of these mice shows narrowing of capillaries in the stria vascularis and chronic reduction of blood flow in the cochlea. In this study, we investigated the effect of oral administration of a herbal medicine or calorie restriction on hearing in TSOD mice., Methods: TSOD mice were divided into 4 groups: CR (calorie restriction), BF and DS (treated with the herbal medicines, Bofutsushosan and Daisaikoto, respectively), and the control group. Body weight, blood glucose levels, and auditory brainstem responses (ABRs) were measured. The cochleae were excised and evaluated histopathologically., Results: Blood glucose levels were suppressed in the CR, BF, and DS groups. In addition, the elevation of ABR thresholds was inhibited in the CR, BF, and DS groups. Cochlear blood vessels remained wide in the three treatment groups compared with the control group. These results suggested that the administration of these herbal medicines improved glucose tolerance and yielded results similar to those on calorie restriction., Conclusion: Oral administration of 2 herbal medicines can prevent hearing function disorder in a model mouse of diabetes. The results may clarify the possibility of clinical application., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Previous studies have confirmed the efficacy of acupuncture treatment for tinnitus. However, no relevant studies of the exact mechanism of acupuncture efficacy on tinnitus have been published. Enrolled participants with left-sided tinnitus received acupuncture treatment at TE3 and TE5. The acupuncture session lasted for 30 minutes. The infrared thermography (IRT) test of each participant's bilateral aural regions and visual analog scale scores were taken before and after the first acupuncture treatment session. Fifty-four participants accepted acupuncture treatment and the IRT test. The temperature differentials of both sides were reduced significantly, but the maximum, minimum, and average temperature of bilateral aural regions did not have a significant difference before and after acupuncture session. The acupuncture's effects for tinnitus were associated with the improvement of cochlear blood flow via the IRT test. We have planned a full-scale randomized controlled trial to find out more about the underlying mechanisms of acupuncture for tinnitus., (Copyright © 2019. Published by Elsevier B.V.)

Can damaged or degenerated vessels be regenerated in the ear? The question is clinically important, as disruption of cochlear blood flow is seen in a wide variety of hearing disorders, including in loud sound-induced hearing loss (endothelial injury), ageing-related hearing loss (lost vascular density), and genetic hearing loss (e.g., Norrie disease: strial avascularization). Progression in cochlear blood flow (CBF) pathology can parallel progression in hair cell and hearing loss. However, neither new vessel growth in the ear, nor the role of angiogenesis in hearing, have been investigated. In this study, we used an established ex vivo tissue explant model in conjunction with a matrigel matrix model to demonstrate for the first time that new vessels can be generated by activating a vascular endothelial growth factor (VEGF-A) signal. Most intriguingly, we found that the pattern of the newly formed vessels resembles the natural 'mesh pattern' of in situ strial vessels, with both lumen and expression of tight junctions. Sphigosine-1-phosphate (S1P) in synergy with VEGF-A control new vessel size and growth. Using transgenic neural/glial antigen 2 (NG2) fluorescent reporter mice, we have furthermore discovered that the progenitors of "de novo" strial vessels are NG2-derived cells. Taken together, our data demonstrates that damaged strial microvessels can be regenerated by reprogramming NG2-derived angiogenic cells. Restoration of the functional vasculature may be critical for recovery of vascular dysfunction related hearing loss., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

The blood-perilymph barrier serves a critical role by separating the components of blood from inner ear fluids, limiting traffic of cells, proteins and other solutes into the labyrinth, and allowing gas (O 2 -CO 2 ) exchange. Inflammation produces changes in the blood-perilymph barrier resulting in increased vascular permeability. It is commonly thought that compromise of the blood-inner ear barrier would lead to hearing impairment through loss of the endocochlear potential (EP). In fact, the effect of increasing cochlear vascular permeability on hearing function and EP is poorly understood. We used a novel method to measure the integrity of the blood-perilymph barrier and demonstrated the effects of barrier compromise on ABR threshold and EP. We also investigated the contribution of CX3CR1 cochlear macrophages and CCR2 inflammatory monocytes to barrier function after systemic exposure to lipopolysaccharide (LPS). We found that systemic LPS induced a profound change in vascular permeability, which correlated with minimal change in ABR threshold and EP. Macrophage depletion using CX3CR1-DTR mice did not alter the baseline permeability of cochlear vessels and resulted in preservation of barrier function in LPS-treated animals. We conclude that cochlear macrophages are not required to maintain the barrier in normal mice and activated macrophages are a critical factor in breakdown of the barrier after LPS. CCR2 null mice demonstrated that LPS induction of barrier leakiness occurs in the absence of CCR2 expression. Thus, enhanced aminoglycoside ototoxicity after LPS can be linked to the expression of CCR2 in inflammatory monocytes, and not to preservation of the blood-perilymph barrier in CCR2 knockout mice., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Permanent hearing loss affects more than 5% of the world's population, yet there are no nondevice therapies that can protect or restore hearing. Delivery of therapeutics to the cochlea and vestibular system of the inner ear is complicated by their inaccessible location. Drug delivery to the inner ear via the vasculature is an attractive noninvasive strategy, yet the blood-labyrinth barrier at the luminal surface of inner ear capillaries restricts entry of most blood-borne compounds into inner ear tissues. Here, we compare the blood-labyrinth barrier to the blood-brain barrier, discuss invasive intratympanic and intracochlear drug delivery methods, and evaluate noninvasive strategies for drug delivery to the inner ear., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Objectives/hypothesis: Pathologic involvement of the inferior cochlear vein is a mechanism of sensorineural hearing loss in patients with jugular foramen paraganglioma., Study Design: Retrospective case-control study., Methods: The presenting audiograms, magnetic resonance imaging, and computed tomography were reviewed in 46 subjects with jugular foramen paragangliomas. Four-frequency bone conduction average was compared between the tumor and nontumor ears in each subject to establish the presence of sensorineural hearing loss. Imaging findings for each subject were recorded. Univariate and multivariate statistical analyses were performed to determine which radiographic features were associated with sensorineural hearing loss. Hearing data were analyzed as a continuous variable and as a categorical variable., Results: Twenty subjects (43.4%) had a bone-conduction pure-tone asymmetry of greater than 15 dB. Inferior cochlear vein involvement was identified in 19 of the 20 (95%) subjects with sensorineural hearing loss. Inferior cochlear vein involvement was found to be a statistically significant predictor of sensorineural hearing loss using univariate and multivariate analyses. Other imaging findings that were statistically significant predictors of sensorineural hearing loss include Glasscock-Jackson stage, Fisch-Mattox stage, hypoglossal canal involvement, jugulo-carotid spin erosion, and petrous carotid canal erosion., Conclusions: Involvement of the inferior cochlear vein appears to be a plausible mechanism for sensorineural hearing loss in patients with jugular foramen paraganglioma., Level of Evidence: 4 Laryngoscope, 129:67-75, 2019., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

Although hearing loss is the most common sensory deficit in Western societies, there are no successful pharmacological treatments for this disorder. Recent experiments have demonstrated that manipulation of intracellular cyclic guanosine monophosphate (cGMP) concentrations can have both beneficial and harmful effects on hearing. In this review, we will examine the role of cGMP as a key second messenger involved in many aspects of cochlear function and discuss the known functions of downstream effectors of cGMP in sound processing. The nitric oxide-stimulated soluble guanylyl cyclase system (sGC) and the two natriuretic peptide-stimulated particulate GCs (pGCs) will be more extensively covered because they have been studied most thoroughly. The cochlear GC systems are attractive targets for medical interventions that improve hearing while simultaneously representing an under investigated source of sensorineural hearing loss.

Objectives: While an accurate placement in cochleostomy is critical to ensure appropriate insertion of the cochlear implant (CI) electrode into the scala tympani (ST), the choice of preferred cochleostomy sites widely varied among experienced surgeons. We present a novel technique for precise yet readily applicable localization of the optimum site for performing ST cochleostomy., Material and Methods: Twenty fresh frozen temporal bones were dissected using the mastoidectomy-posterior tympanotomy approach. Based on the facial nerve and the margins of the round window membrane (RWM), the cochleostomy site was chosen to insert the electrode into the ST while preserving the surrounding intracochlear structures., Results: There is a limited safe area suitable for the ST implantation in the area inferior and anterior to the RWM. There is a higher risk of scala vestibuli (SV) insertion anterior to that area. Posterior to that area, the cochlear aqueduct (CA) and inferior cochlear vein (ICV) are liable for the injury., Conclusion: For atraumatic CI, precise and easy localization of the site of cochleostomy play a pivotal role in preserving intracochlear structures. Accurate setting of the vertical and horizontal orientations is mandatory before choosing the site of cochleostomy. The facial nerve and the margins of the RWM offer a very helpful clue for such localization; meanwhile, it is readily identifiable in the surgical field.

Laser speckle contrast imaging (LSCI) enables continuous high-resolution assessment of microcirculation in real-time. We applied an endoscope to LSCI to measure cochlear blood-flow in an ischemia-reperfusion mouse model. We also explored whether using xenon light in combination with LSCI facilitates visualization of anatomical position. Based on a previous preliminary study, the appropriate wavelength for penetrating the thin bony cochlea was 830 nm. A 2.7-mm-diameter endoscope was used, as appropriate for the size of the mouse cochlea. Our endoscopic LSCI system was used to illuminate the right cochlea after dissection of the mouse. We observed changes in the speckle signals when we applied the endoscopic LSCI system to the ischemia-reperfusion mouse model. The anatomical structure of the mouse cochlea and surrounding structures were clearly visible using the xenon light. The speckle signal of the cochlea was scattered, with an intensity that varied between that of the stapes (with the lowest signal), the negative control, and the stapedial artery (with the highest signal), the positive control. In the cochlear ischemia-reperfusion mouse model, the speckle signal of the cochlea decreased during the ischemic phase, and increased during the reperfusion phase, clearly reflecting cochlear blood-flow. The endoscopic LSCI system generates high-resolution images in real-time, allowing visualization of blood-flow and its changes in the mouse cochlea. Anatomical structures were clearly matched using LSCI along with visible light.

Importance: The interruption of vascular supply to the cochlea has been proposed as a major etiological factor for sudden sensorineural hearing loss (SSNHL), and several risk factors for cardiocerebrovascular disease (CCVD) are associated with SSNHL, including heavy smoking, alcohol consumption, and thromboembolic events. However, the link between SSNHL and CCVD has not been fully evaluated., Objective: To investigate the association between SSNHL and CCVD., Design, Setting, and Participants: A retrospective propensity score-matched cohort study was conducted using a nationwide representative sample from the National Sample Cohort 2002 through 2013 data from the Korea National Health Insurance Service. The SSNHL group (n = 154) included certain patients who were diagnosed with SSNHL between January 2003 and December 2005. The comparison group was selected (4 patients for every 1 patient with SSNHL; n = 616) using propensity score matching, according to sociodemographic factors and the year of enrollment. Each patient was monitored until 2013., Main Outcomes and Measures: Survival analysis, the log-rank test, and Cox proportional hazards regression models were used to calculate the incidence, survival rate, and hazard ratio of CCVD for each group., Results: Among the 770 patients, 385 (50.0%) were female and 370 (48.1%) were aged between 45 and 64 years. Of the total study population, 66 patients developed CCVD, such as stroke and acute myocardial infarction, during the 11-year follow-up period: 18 patients in the SSNHL group (incidence, 13.5 cases per 1000 person-years) and 48 from the comparison group (incidence, 7.5 cases per 1000 person-years). After adjustment for other factors, the hazard ratio of CCVD during the 11-year follow-up period was 2.18 times (95% CI, 1.20-3.96) greater for patients with SSNHL. An increased risk of stroke was associated with SSNHL (HR, 2.02; 95% CI, 1.16-3.51); however, there was no relation between SSNHL and risk of myocardial infarction (HR, 1.18; 95% CI, 0.25-5.50)., Conclusions and Relevance: This observational study using nationwide data suggests that SSNHL is associated with an increased incidence of CCVD, specifically stroke. Therefore, patient surveillance for signs of CCVD should be considered for patients who receive a diagnosis of SSNHL.

In vestibular-schwannoma (VS) surgery, hearing-preservation rate remains low. Besides damage to the cochlear nerve, intraoperative cochlear ischemia is a potential cause of hearing loss. Here, we used non-invasive cochlear microphonic (CM) recordings to detect the cochlear vascular events of VS surgery. Continuous intraoperative CM monitoring, in response to 80-95 dB SPL, 1-kHz tone-bursts, was performed in two samples of patients undergoing retrosigmoid cerebellopontine-angle surgery: one for VS (n = 31) and one for vestibular neurectomy or vasculo-neural conflict causing intractable trigeminal neuralgia, harmless to hearing (n = 19, control group). Preoperative and postoperative hearings were compared as a function of intraoperative CM changes and their chronology. Monitoring was possible throughout except for a few tens of seconds when drilling or suction noises occurred. Four patterns of CM time course were identified, eventless, fluctuating, abrupt or progressive decrease. Only the VS group displayed the last two patterns, mainly during internal-auditory-canal drilling and the ensuing tumor dissection, always with postoperative loss of hearing as an end result. Conversely, eventless and fluctuating CM patterns could be associated with postoperative hearing loss when the cochlear nerve had been reportedly damaged, an event that CM is not meant to detect. Cochlear ischemia is a frequent event in VS surgery that leads to deafness. The findings that CM decrease raised no false alarm, and that CM fluctuations, insignificant in control cases, were easily spotted, suggest that CM intraoperative monitoring is a sensitive tool that could profitably guide VS surgery.

Objective: The aim of this work was to evaluate the effect of tumor necrosis factor (TNF) and its neutralization with etanercept on the capability of cochlear pericytes to alter capillary diameter in the stria vascularis., Methods: Twelve Dunkin-Hartley guinea pigs were randomly assigned to one of three groups. Each group was treated either with placebo and then placebo, TNF and then placebo, or TNF and then etanercept. Cochlear pericytes were visualized using diaminofluorescein-2-diacetate and intravasal blood flow by fluorescein-dextrane. Vessel diameter at sites of pericyte somas and downstream controls were quantified by specialized software. Values were obtained before treatment, after first treatment with tumor necrosis factor or placebo and after second treatment with etanercept or placebo., Results: Overall, 199 pericytes in 12 animals were visualized. After initial treatment with TNF, a significant decrease in vessel diameter at sites of pericyte somas (3.6 ±4.3%, n = 141) compared with placebo and downstream controls was observed. After initial treatment with TNF, the application of etanercept caused a significant increase (3.3 ±5.5%, n = 59) in vessel diameter at the sites of pericyte somata compared with placebo and downstream controls., Conclusion: We have been able to show that cochlear pericytes are capable of reducing capillary diameter after exposition to TNF. Moreover, the reduction in capillary diameter observed after the application of TNF is revertible after neutralization of tumor necrosis factor by the application of etanercept. It seems that contraction of cochlear pericytes contributes to the regulation of cochlear blood flow.

Tinnitus is recognized as a refractory disease, which is common in clinic, and always treated from the liver and kidney. We treat tinnitus mainly by heart based on syndrome differentiation. It often works well when the left cukou pulse is abnormal. Referring to ancient literature, we find that the heart is related to ears by meridians, and the kidney and heart govern ears. The normal function of heart and kidney means normal hearing. The heart secretes atrial natriuretic polypeptins (ANP), whose receptor is widely distributed in ears and can increase the cochlear blood flow. In this paper we explore the relationship between the heart and the ears so as to provide theories of treatment by heart for tinnitus.

Hypothesis: The potential of Fingolimod (FTY-720), a sphingosine-1-phosphate analogue, to revoke the changes in cochlear blood flow induced by tumor necrosis factor (TNF) was investigated., Background: Impairment of cochlear blood flow has often been considered as the common final pathway of various inner ear pathologies. TNF, an ubiquitous cytokine, plays a major role in these pathologies, reducing cochlear blood flow via sphingosine-1-phosphate-signaling., Methods: Fifteen Dunkin-Hartley guinea pigs were randomly assigned to one of three groups (placebo/placebo, TNF/placebo, TNF/FTY-720). Cochlear microcirculation was quantified over 60 minutes by in vivo fluorescence microscopy before and after topical application of placebo or TNF (5 ng/ml) and after subsequent application of placebo or FTY-720 (200 μg/ml)., Results: Treatment with TNF led to a significant decrease of cochlear blood flow.Following this, application of placebo caused no significant changes while application of FTY-720 caused a significant rise in cochlear blood flow., Conclusions: FTY-720 is capable of reversing changes in cochlear blood flow induced by application of TNF. This makes FTY-720 a valid candidate for potential treatment of numerous inner ear pathologies.

Objective: Disturbance of cochlear microcirculation is considered to be the final common pathway of various inner ear diseases. Hyperfibrinogenemia causing increased plasma viscosity is a known risk factor for sudden sensorineural hearing loss and may lead to a critical reduction of cochlear blood flow. The aim of this study was to evaluate the effect of a substantial reduction of plasma fibrinogen levels by drug-induced defibrinogenation for the treatment of acute hearing loss in vivo., Methods: Acute hearing loss was induced by hyperfibrinogenemia (i.v. injection of 330 mg/kg BW fibrinogen), using a guinea pig animal model. Parameters of cochlear microcirculation and hearing thresholds were quantified by intravital microscopy and evoked response audiometry. After obtaining baseline values, the course of hearing loss and disturbances of microcirculation were investigated under influence of intravenous defibrinogenation therapy (ancrod), corticosteroid, or placebo treatment, using 5 animals/group., Results: Acute hyperfibrinogenemia caused hearing loss from 10 ± 7 to 26 ± 10 dB SPL at baseline. Drug-induced reduction of fibrinogen levels showed a significant increase of cochlear microcirculation (1.6-fold) and recovered hearing threshold (11 ± 6 dB SPL). Placebo or corticosteroid treatment had no effect on hearing loss (35 ± 7 dB SPL and 32 ± 18 dB SPL, respectively)., Conclusion: Acute hyperfibrinogenemia resulted in hearing loss. Drug-induced reduction of elevated fibrinogen levels caused an increase in cochlear blood flow and a decrease in hearing thresholds. Placebo or corticosteroid treatment had no effect. Reduction of plasma fibrinogen levels could serve as a clinical treatment option for acute hearing loss.

Cytomegalovirus (CMV) infection is one of the most common causes of congenital hearing loss in children. We have used a murine model of CMV infection to reveal functional and structural cochlear pathogenesis. The cerebral cortex of Balb/c mice (Mus musculus) was inoculated with 2000 pfu (plaque forming units) of murine CMV on postnatal day 3. At 6 weeks of age, cochlear function was monitored using auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) measures. Histological assessment of cochlear vasculature using a corrosion cast technique was made at 8 weeks. Vascular casts of mCMV-damaged cochleas, and those of untreated control animals, were examined using scanning electron microscopy. We find very large variations in the degree of vascular damage in animals given identical viral injections (2000 pfu). The primary lesion caused by CMV infection is to the stria vascularis and to the adjacent spiral limbus capillary network. Capillary beds of the spiral ligament are generally less affected. The initial vascular damage is found in the mid-apical turn and appears to progress to more basal cochlear regions. After viral migration to the inner ear, the stria vascularis is the primary affected structure. We suggest that initial auditory threshold losses may relate to the poor development or maintenance of the endocochlear potential caused by strial dysfunction. Our increased understanding of the pathogenesis of CMV-related hearing loss is important for defining methods for early detection and treatment.

Purpose: Iatrogenic noise produced by mastoid or craniotomy drills may cause hearing damage, which is induced by the generation of reactive oxygen species (ROS) and the reduction of cochlear blood flow (CoBF). This study investigated whether propofol could reduce noise-induced hearing loss (NIHL) in a guinea pig model., Methods: Sixty-four male pigmented guinea pigs were randomly and equally divided into 4 groups: control, noise, propofol and propofol+noise. Propofol was infused intravenously for 20min prior to noise exposure with a loading dose of 5mg·kg -1 for 5min and a maintenance infusion of 20mg·kg -1 ·h -1 for 135min. For noise exposure, an octave band noise at a 124dB sound pressure level (SPL) was administered to animals for 2h. The mean arterial pressure (MAP) and CoBF were monitored continuously. Auditory function was measured by the level of distortion product otoacoustic emission (DPOAE) before and at 1h, 72h and 240h after noise exposure. Cochlear levels of 8-iso-Prostaglandin F 2alpha (8-iso-PGF2α) were measured immediately after the termination of noise exposure. Cochlear silver nitrate staining and outer hair cell (OHC) counting were performed after the final functional test., Results: Noise exposure caused decreases in the CoBF and DPOAE amplitudes, over-generation of 8-iso-PGF2α and the loss of OHCs. Pre-treatment with propofol significantly increased the CoBF and DPOAE amplitudes, decreased 8-iso-PGF2α and the loss of OHCs., Conclusions: Propofol exerted protective effects against NIHL in this animal model by suppressing a lipid peroxidation reaction and improving CoBF., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The objective was to design in gerbils a model of reversible decrease in cochlear blood flow (CBF) and analyze its influence on cochlear function. In Mongolian gerbils injected with ferromagnetic microbeads, a magnet placed near the porus acusticus allowed CBF to be manipulated. The cochlear microphonic potential (CM) from the basal cochlea was monitored by a round-window electrode. In 13 of the 20 successfully injected gerbils, stable CBF reduction was obtained for 11.5 min on average. The CM was affected only when CBF fell to less than 60% of its baseline, yet remained >40% of its initial level in about 2/3 of such cases. After CBF restoration, CM recovery was fast and usually complete. Reduced CM came with a 35- to 45-dB threshold elevation of neural responses determined by compound action potentials. This method allowing reversible changes of CBF confirms the robustness of cochlear function to decreased CBF. It can be used to study whether a hypovascularized cochlea is abnormally sensitive to stress., (© 2017 S. Karger AG, Basel.)

The objectives of the present work were the overview of the results of the modern investigations concerning etiology of idiopathic sensorineural impairment of hearing as well as the analysis of the theory of microthrombus formation and its role in pathogenesis of hearing impairment.

Background and Objective: Propofol is the most commonly used intravenous (IV) anesthetic agent and is associated with hypotension upon induction of anesthesia. Intravenous propofol infusion has several properties that may be beneficial to patients undergoing middle ear surgery. Topical application of concentrated epinephrine is a valuable tool for achieving hemostasis in the middle ear and during mastoid surgery. The purpose of the present study was to determine the effects of propofol infusion with topical epinephrine on cochlear blood flow (CBF) and hearing in rats., Materials and Methods: Twenty one male Sprague-Dawley rats were divided into three groups. The rate of intravenous infusion of propofol was 4-6 ml/kg/hour. The first group (control group, n = 7) was given IV infusion of phosphate buffered saline (PBS) with topical application of PBS in the round window. In study group A (n = 7), the effect of topical phosphate buffered saline with IV infusion of propofol on CBF and hearing was evaluated. In study group B (n = 7), additional effects of topical epinephrine with IV infusion of propofol on CBF and hearing were evaluated. The laser Doppler blood flowmeter, CBF, and the mean arterial blood pressure (MAP) were measured and analyzed. Additionally, hearing test using auditory brainstem response (ABR) was performed in both groups., Results: In both groups, infusion of propofol induced a time-dependent decrease in MAP. Approximately 30 min after the start of the propofol infusion, the CBF started to decrease slowly. The decrease in CBF was significantly greater in the study group compared to the control group. The threshold was elevated in the study group relative to the control group., Conclusion: During middle ear surgery, use of IV infusion of propofol with topical epinephrine cotton ball or cottonoid application is not recommended., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: In many vascular smooth muscle cells (SMCs), ryanodine receptor-mediated Ca 2+ sparks activate large-conductance Ca 2+ -activated K + (BK) channels leading to lowered SMC [Ca 2+ ] i and vasodilation. Here we investigated whether Ca 2+ sparks regulate SMC global [Ca 2+ ] i and diameter in the spiral modiolar artery (SMA) by activating BK channels., Methods: SMAs were isolated from adult female gerbils, loaded with the Ca 2+ -sensitive flourescent dye fluo-4 and pressurized using a concentric double-pipette system. Ca 2+ signals and vascular diameter changes were recorded using a laser-scanning confocal imaging system. Effects of various pharmacological agents on Ca 2+ signals and vascular diameter were analyzed., Results: Ca 2+ sparks and waves were observed in pressurized SMAs. Inhibition of Ca 2+ sparks with ryanodine increased global Ca 2+ and constricted SMA at 40 cmH 2 O but inhibition of Ca 2+ sparks with tetracaine or inhibition of BK channels with iberiotoxin at 40 cmH 2 O did not produce a similar effect. The ryanodine-induced vasoconstriction observed at 40 cmH 2 O was abolished at 60 cmH 2 O, consistent with a greater Ca 2+ -sensitivity of constriction at 40 cmH 2 O than at 60 cmH 2 O. When the Ca 2+ -sensitivity of the SMA was increased by prior application of 1 nM endothelin-1, ryanodine induced a robust vasoconstriction at 60 cmH 2 O., Conclusions: The results suggest that Ca 2+ sparks, while present, do not regulate vascular diameter in the SMA by activating BK channels and that the regulation of vascular diameter in the SMA is determined by the Ca 2+ -sensitivity of constriction.

Objectives: Presence of aberrant internal carotid artery (ICA) in the tympanic cavity is a very rare case and therefore the diagnosis is a challenge. Here, the authors aimed to address the importance of the diagnosis since the intervention to the middle ear and implants is increasing in number and this condition may lead to life-threatening bleeding., Methods: Between 2012 and 2016, among the patients referred to the authors' Radiology Department from the Department of Otolaringology for the evaluation of the temporal region for various indications, the authors reported this anomaly in 6 patients and multidetector computerized tomography of these 6 patients and magnetic resonance imaging of 2 were assessed in detail., Results: The mean age of the 6 patients was 28.8 and aberrant ICA abnormality was observed in 2 patients bilaterally and 4 patients unilaterally on the right side. In 1 patient ICA was not totally regressed and observed as hypoplastic. In one of the patients, dehiscence was evident between ICA and the cochlea. Moreover, in 1 patient the contralateral ICA was not observed., Conclusion: Although rare, aberrant ICA is an abnormality that should be kept in mind by the clinicians and the radiologists, since it leads to abundant bleeding when undiagnosed before the surgical interventions.

The blood-labyrinth barrier (BLB) in the stria vascularis is a highly specialized capillary network that controls exchanges between blood and the intrastitial space in the cochlea. The barrier shields the inner ear from blood-born toxic substances and selectively passes ions, fluids, and nutrients to the cochlea, playing an essential role in the maintenance of cochlear homeostasis. Anatomically, the BLB is comprised of endothelial cells (ECs) in the strial microvasculature, elaborated tight and adherens junctions, pericytes (PCs), basement membrane (BM), and perivascular resident macrophage-like melanocytes (PVM/Ms), which together form a complex "cochlear-vascular unit" in the stria vascularis. Physical interactions between the ECs, PCs, and PVM/Ms, as well as signaling between the cells, is critical for controlling vascular permeability and providing a proper environment for hearing function. Breakdown of normal interactions between components of the BLB is seen in a wide range of pathological conditions, including genetic defects and conditions engendered by inflammation, loud sound trauma, and ageing. In this review, we will discuss prevailing views of the structure and function of the strial cochlear-vascular unit (also referred to as the "intrastrial fluid-blood barrier"). We will also discuss the disrupted homeostasis seen in a variety of hearing disorders. Therapeutic targeting of the strial barrier may offer opportunities for improvement of hearing health and amelioration of auditory disorders. This article is part of a Special Issue entitled ., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Hypothesis: This study aimed to quantify the effects of tumor necrosis factor (TNF) inhibitor Etanercept and sphingosine-1-phosphate receptor 2 antagonist JTE-013 on cochlear blood flow in guinea pigs after TNF-induced decrease., Background: Sudden sensorineural hearing loss is a common cause for disability and reduced quality of life. Good understanding of the pathophysiology and strong evidence-based therapy concepts are still missing. In various inner ear disorders, inflammation and impairment of cochlear blood flow (CBF) have been considered factors in the pathophysiology. A central mediator of inflammation and microcirculation in the cochlea is TNF. S1P acts downstream in one TNF pathway., Methods: Cochlea lateral wall vessels were exposed surgically and assessed by intravital microscopy in guinea pigs in vivo. Twenty-eight animals were randomly distributed into four groups of seven each. Exposed vessels were superfused by TNF (5.0 ng/ml) and afterward repeatedly either by Etanercept (1.0 μg/ml), JTE-013 (10 μmol/L), or vehicle (0.9 % NaCl solution or ethanol: phosphate-buffered saline buffer, respectively)., Results: After decreasing CBF with TNF (p <0.001, two-way RM ANOVA), both treatments reversed CBF, compared with vehicle (p <0.001, two-way RM ANOVA). The comparison of the vehicle groups showed no difference (p = 0.969, two-way RM ANOVA), while there was also no difference between the treatment groups (p = 0.850, two-way RM ANOVA)., Conclusion: Both Etanercept and JTE-013 reverse the decreasing effect of TNF on cochlear blood flow and, therefore, TNF and the S1P-signalling pathway might be targets for treatment of microcirculation-related hearing loss.

p66(shc), a member of the ShcA protein family, is essential for cellular response to oxidative stress, and elicits the formation of mitochondrial Reactive Oxygen Species (ROS), thus promoting vasomotor dysfunction and inflammation. Accordingly, mice lacking the p66 isoform display increased resistance to oxidative tissue damage and to cardiovascular disorders. Oxidative stress also contributes to noise-induced hearing loss (NIHL); we found that p66(shc) expression and serine phosphorylation were induced following noise exposure in the rat cochlea, together with markers of oxidative stress, inflammation and ischemia as indicated by the levels of the hypoxic inducible factor (HIF) and the vascular endothelial growth factor (VEGF) in the highly vascularised cochlear lateral region and spiral ganglion. Importantly, p66(shc) knock-out (p66 KO) 126 SvEv adult mice were less vulnerable to acoustic trauma with respect to wild type controls, as shown by preserved auditory function and by remarkably lower levels of oxidative stress and ischemia markers. Of note, decline of auditory function observed in 12 month old WT controls was markedly attenuated in p66KO mice consistent with delayed inner ear senescence. Collectively, we have identified a pivotal role for p66(shc) -induced vascular dysfunction in a common pathogenic cascade shared by noise-induced and age-related hearing loss.

The patency of the inferior cochlear vein (ICV) may be challenged in cochlear implantation (CI) due to its location near the round window (RW). This may be essential to consider during selection of different trajectories for electrode insertion aiming at preserving residual hearing. Venous blood from the human cochlea is drained through the ICV. The vein also drains blood from the modiolus containing the spiral ganglion neurons. Surgical interference with this vein could cause neural damage influencing CI outcome. We analyzed the topographical relationship between the RW and ICV bony channel and cochlear aqueduct (CA) from a surgical standpoint. Archival human temporal bones were further microdissected to visualize the CA and its accessory canals (AC1 and AC2). This was combined with examinations of plastic and silicone molds of the human labyrinth. Metric analyses were made using photo stereomicroscopy documenting the proximal portion of the AC1, the internal aperture of the CA and the RW. The mean distance between the AC1 and the anterior rim of the RW was 0.81 mm in bone specimens and 0.67 mm assessed in corrosion casts. The AC1 runs from the floor of the scala tympani through the otic capsule passing parallel to the CA to the posterior cranial fossa. The mean distance between the CA and AC1 canal was 0.31 and 0.25 mm, respectively.

Importance: Age-related changes in cochlear vessel wall thickness in human temporal bones have not been described previously., Objectives: To compare thickness of the spiral modiolar artery and strial capillaries and to investigate strial atrophy and vessel loss in temporal bones with and without presbycusis., Design, Setting, and Participants: This retrospective case-control study examined the autopsy reports of 1024 patients in the temporal bone collection at the University of Minnesota. Inclusion criteria consisted of being 60 years or older with sensorineural hearing loss and progression of hearing loss with age (presbycusis group). Age-matched controls had no record of hearing loss. All patients underwent pure-tone audiometry. Exclusion criteria included a history of otologic disease, ototoxic drug use, head or acoustic trauma, or systemic disease. Data were collected from October 1, 2013, to October 1, 2014., Main Outcomes and Measures: Vessel wall thickness in the modiolar artery and strial vessels, the strial area, and number of strial vessels were measured under light microscopy., Results: Among the 1024 autopsy reports examined, 11 patients (19 temporal bones) with presbycusis (7 men and 4 women; age range, 67-88 years; mean [SD] age, 78 [7] years]) and 15 controls (24 temporal bones) (7 men and 8 women; age range, 67-94 years; mean [SD] age, 79 [8] years) met the inclusion criteria. Compared with the control group, the presbycusis group had significantly increased mean (SD) thickness of vessel walls in the modiolar arteries (6.73 [2.39] vs 5.55 [0.86] μm; P = .02) and the strial capillaries in the lower basal (1.57 [0.21] vs 1.39 [0.15] μm; P = .005), upper basal (1.62 [0.28] vs 1.40 [0.13] μm; P < .001), lower middle (1.68 [0.22] vs 1.39 [0.20] μm; P < .001), upper middle (1.74 [0.39] vs 1.40 [0.19] μm; P = .01), and apical (1.70 [0.36] vs 1.47 [0.21] μm; P = .04) turns of the cochlea. Compared with the control group, the presbycusis group had significant loss of strial area in the lower basal (6614 [1559] vs 8790 [1893] μm2; P = .002), upper basal (6387 [2211] vs 9105 [2700] μm2; P < .001), lower middle (5140 [1471] vs 7269 [2181] μm2; P = .003), upper middle, (5583 [1742] vs 7206 [2258] μm2; P = .02), and apical (4286 [1604] vs 6535 [2454] μm2; P < .001) turns of the cochlea; in the vessel area in the lower basal turn (74.65 [127.74] vs 124.92 [89.04] μm2; P = .01); and in the number of vessels in the lower basal (1.00 [0.78] vs 1.94 [0.93]; P = .008) and lower middle (1.00 [0.78] vs 1.94 [0.93]; P = .04) turns of the cochlea., Conclusions and Relevance: The histopathologic findings of increased thickness of the vascular walls of the modiolar arteries and stria vascularis, increased strial atrophy, and decreased number of strial vessels may have led to decreased cochlear microcirculation. Deficiency in the circulation and perfusion of the cochlea may be a factor in presbycusis.

Some forms of sensorineural hearing loss involve damage or degenerative changes to the stria vascularis and/or other vascular structures in the cochlea. In animal models, many methods for anatomical assessment of cochlear vasculature exist, each with advantages and limitations. One methodology, corrosion casting, has proved useful in some species, however in the mouse model this technique is difficult to achieve because digestion of non vascular tissue results in collapse of the delicate cast specimen. We have developed a partial corrosion cast method that allows visualization of vasculature along much of the cochlear length but maintains some structural integrity of the specimen. We provide a detailed step-by-step description of this novel technique. We give some illustrative examples of the use of the method in mouse models of presbycusis and cytomegalovirus (CMV) infection., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Purpose: The purpose of this investigation was to evaluate the topographic relations of cochlea with vital neurovascular structures and their implications for cochlear implantation (CI)., Methods: Sixty cadaveric human temporal bones were microdissected to expose the basal turn (BT) of cochlea, the carotid canal, the facial canal (FC) and the jugular fossa (JF). The minimum distances of BT of the cochlea from the carotid canal, the FC and roof of the JF were measured., Results: The mean minimum distances of BT of the cochlea from the carotid canal, the FC and roof of the JF were found to be 1.38 ± 0.82, 1.06 ± 0.46 and 4.68 ± 2.21 mm, respectively. The abutment and impingement of carotid canal on anterior cochlear wall was found in three (5 %) and six (10 %) cases, respectively. Thin bone separation was observed between cochlea and FC (0.1 mm) in one case (1.67 %)., Conclusions: The preoperative knowledge of the variant anatomy of BT of cochlea in relation to adjacent vital structures like abutment and impingement of carotid canal and thin bone separation of the BT of cochlea from FC and JF is of immense importance in CI, which may otherwise lead to disastrous consequences during surgery.

Obesity-related complications are associated with the development of age-related hearing impairment. β-Conglycinin (β-CG), one of the main storage proteins in soy, offers multiple health benefits, including anti-obesity and anti-atherosclerotic effects. Here, to elucidate the potential therapeutic application of β-CG, we investigated the effect of β-CG on age-related hearing impairment. Male wild-type mice (age 6 months) were randomly divided into β-CG-fed and control groups. Six months later, the body weight was significantly lower in β-CG-fed mice than in the controls. Consumption of β-CG rescued the hearing impairment observed in control mice. Cochlear blood flow also increased in β-CG-fed mice, as did the expression of eNOS in the stria vascularis (SV), which protects vasculature. β-CG consumption also ameliorated oxidative status as assessed by 4-HNE staining. In the SV, lipofuscin granules of marginal cells and vacuolar degeneration of microvascular pericytes were decreased in β-CG-fed mice, as shown by transmission electron microscopy. β-CG consumption prevented loss of spiral ganglion cells and reduced the frequencies of lipofuscin granules, nuclear invaginations, and myelin vacuolation. Our observations indicate that β-CG ameliorates age-related hearing impairment by preserving cochlear blood flow and suppressing oxidative stress.