Otolithic Membrane Research Articles

Residual Dizziness Characteristics of Idiopathic Sudden Sensorineural Hearing Loss Patients with Benign Paroxysmal Positional Vertigo.

ISSNHL, a common clinical condition, can be accompanied by vertigo. Initially, research on sudden deafness primarily focused on the hearing loss itself, with less emphasis on episodic vertigo. However, as vertigo research has advanced, it has been recognized that BPPV is a frequent accompaniment to ISSNHL-associated vertigo. Even after treatment, some patients may experience residual dizziness. This study investigates the characteristics of patients with ISSNHL accompanied by BPPV and the impact of residual dizziness on their lives. This study is being conducted on patients with ISSNHL accompanied by BPPV, analyzing the characteristics of such patients and the impact of residual dizziness on their lives. Overall, 54 adult inpatients with ISSNHL and BPPV were included in this study. All patients received 50 mg of intravenous prednisolone for 5 consecutive days and hemodilution agents for 10 days. At the same time, BPPV was treated with repositioning by the same therapist using the SRM-IV vertigo diagnostic and treatment system, and different repositioning methods were used for different types of otolithiasis. Patients were grouped according to the absence of residual dizziness when the nystagmus disappeared at the time of discharge. There were 24 cases in the group with residual symptoms, including 10 males and 14 females. The proportion of females was 58.33%, with an average age of 46.75 ± 13.80. The group without residual symptoms consisted of 30 cases, including 13 males and 17 females. The female proportion was 56.67%, with an average age of 45.77 ± 11.86. There is no statistical significance between the two groups in the pre-treatment hearing status and DHI scores. The HAMA (Hamilton Anxiety Rating Scale) scores before treatment were compared, revealing a significant statistical difference. ISSNHL-associated BPPV may be caused by vascular embolism or thrombosis in the cochlear or spiral modiolar artery. This disrupts blood flow, leading to ischemia in the otolithic membrane and subsequent detachment of otoconia. Because this detachment often occurs within 24 h of the initial event, patients experience positional vertigo early in the course of the disease.

A New Perspective to Interpret How the Vestibular Efferent System Correlates the Complexity of Routine Balance Maintenance with Management of Emergency Fall Prevention Strategies.

Bipedalism is unique among mammals. Until modern times, a fall and resulting leg fracture could be fatal. Balance maintenance after a destabilizing event requires instantaneous decision making. The vestibular system plays an essential role in this process, initiating an emergency response. The afferent otolithic neural response is the first directionally oriented information to reach the cortex, and it can then be used to initiate an appropriate protective response. Some vestibular efferent axons feed directly into type I vestibular hair cells. This allows for rapid vestibular feedback via the striated organelle (STO), which has been largely ignored in most texts. We propose that this structure is essential in emergency fall prevention, and also that the system of sensory detection and resultant motor response works by having efferent movement information simultaneously transmitted to the maculae with the movement commands. This results in the otolithic membrane positioning itself precisely for the planned movement, and any error is due to an unexpected external cause. Error is fed back via the vestibular afferent system. The efferent system causes macular otolithic membrane movement through the STO, which occurs simultaneously with the initiating motor command. As a result, no vestibular afferent activity occurs unless an error must be dealt with.

Blood Serum Levels of Magnesium in Patients with Benign Paroxysmal Positional Vertigo

Background and Aim: Magnesium is essential for the morphogenesis of otoconia. The imbalance in the chemical composition of otoconia can make people susceptible to Benign Paroxysmal Positional Vertigo (BPPV). The primary outcome was to compare serum magnesium levels in BPPV patients with controls. The Ca/Mg ratios in participants are also recorded and analyzed in the present study. Methods: In this case-control study, we measured the serum Mg, Ca, and vitamin D in BPPV patients and age-, sex-matched subjects without BPPV. The results were adjusted for Ca, vitamin D, hypertension, and body mass index. Results: A total of 123 BPPV patients participated in this study. The mean Mg value was higher in patients than controls (2.01 vs. 1.95 mg/dL, p=0.030). Condition logistic regression analyses showed a higher rate of BPPV among subjects with low Ca/Mg ratio (quartile 1), relative to subjects with medium ratio (quartiles 2 and 3) (adjusted OR: 3.92, p=0.003). Conclusion: The present study demonstrated an imbalance of Ca and Mg in the BPPV patients as significantly higher Mg levels and lower serum Ca/Mg ratio. Although it appears decreased Ca/Mg ratio to be a risk factor for BPPV, this result should be confirmed in confirmatory studies. Keywords: Magnesium; calcium; benign paroxysmal positional vertigo; otolithic membrane; matched-pair analysis

Otolith Membrane Herniation, not Semicircular Canal Duct Dilation, Is Associated with Decreased Caloric Responses in Ménière's Disease.

Ménière's disease (MD) is a debilitating disorder with unclear pathophysiology whose diagnosis often relies on clinical judgment rather than objective testing. To complicate matters further, a dissociation has emerged between two vestibular function tests commonly used in patients with MD to examine the same end-organ (the semicircular canals): the caloric test and video head impulse testing (vHIT). Caloric responses are often abnormal, while vHIT results remain normal. Explaining this dissociation could reveal novel insights into MD pathophysiology. Here, we conduct a histopathological study using temporal bone specimens (N = 58, 21 MD-affected ears and 37 age-matched controls) and their clinical testing data to examine current hypotheses aimed at this dissociation. We find otolith membrane herniation into the horizontal semicircular canal in 69% of MD ears, with 90% of these ears demonstrating a diminished caloric response. No ears with a normal response had this herniation. Moreover, we evaluated the semicircular canals for endolymphatic hydrops, which had been hypothesized to contribute to the dissociation, and found no evidence of duct dilation/hydrops. We did, however, note a potentially novel morphologic finding-smaller bony labyrinth cross-sectional diameters/areas in some MD ear canals compared to controls, suggesting relative size of the membranous duct to the bony canal rather than absolute size may be of importance. Taken together, this study refines hypotheses on the vestibular test dissociation in MD, holding diagnostic implications and expanding our understanding of the mechanisms underlying this enigmatic disease.

Vestibular Drop Attacks and Meniere’s Disease as Results of Otolithic Membrane Damage—A Numerical Model

Meniere’s disease (MD) is a condition of the inner ear with symptoms affecting both vestibular and hearing functions. Some patients with MD experience vestibular drop attacks (VDAs), which are violent falls caused by spurious vestibular signals from the utricle and/or saccule. Recent surgical work has shown that patients who experience VDAs also show disrupted utricular otolithic membranes. The objective of this study is to determine if otolithic membrane damage alone is sufficient to induce spurious vestibular signals, thus potentially eliciting VDAs and the vestibular dysfunction seen in patients with MD. We use a previously developed numerical model to describe the nonlinear dynamics of an array of active, elastically coupled hair cells. We then reduce the coupling strength of a selected region of the membrane to model the effects of tissue damage. As we reduce the coupling strength, we observe large and abrupt spikes in hair bundle position. As bundle displacements from the equilibrium position have been shown to lead to depolarization of the hair-cell soma and hence trigger neural activity, this spontaneous activity could elicit false detection of a vestibular signal. The results of this numerical model suggest that otolithic membrane damage alone may be sufficient to induce VDAs and the vestibular dysfunction seen in patients with MD. Future experimental work is needed to confirm these results in vitro.

Presence of chondroitin sulphate and requirement for heparan sulphate biosynthesis in the developing zebrafish inner ear.

Epithelial morphogenesis to form the semicircular canal ducts of the zebrafish inner ear depends on the production of the large glycosaminoglycan hyaluronan, which is thought to contribute to the driving force that pushes projections of epithelium into the lumen of the otic vesicle. Proteoglycans are also implicated in otic morphogenesis: several of the genes coding for proteoglycan core proteins, together with enzymes that synthesise and modify their polysaccharide chains, are expressed in the developing zebrafish inner ear. In this study, we demonstrate the highly specific localisation of chondroitin sulphate to the sites of epithelial projection outgrowth in the ear, present before any morphological deformation of the epithelium. Staining for chondroitin sulphate is also present in the otolithic membrane, whereas the otoliths are strongly positive for keratan sulphate. We show that heparan sulphate biosynthesis is critical for normal epithelial projection outgrowth, otolith growth and tethering. In the ext2 mutant ear, which has reduced heparan sulphate levels, but continues to produce hyaluronan, epithelial projections are rudimentary, and do not grow sufficiently to meet and fuse to form the pillars of tissue that normally span the otic lumen. Staining for chondroitin sulphate and expression of versican b, a chondroitin sulphate proteoglycan core protein gene, persist abnormally at high levels in the unfused projections of the ext2 mutant ear. We propose a model for wild-type epithelial projection outgrowth in which hyaluronan and proteoglycans are linked to form a hydrated gel that fills the projection core, with both classes of molecule playing essential roles in zebrafish semicircular canal morphogenesis.

Benign paroxysmal positional vertigo in the older adults

Benign paroxysmal positional vertigo (BPPV) is one of the most common causes of vertigo. The prevalence of the disease increases with age. Course of the disease, clinical manifestations, and treatment approaches at older ages have their own characteristics. Frequent predominance of persistent instability over classic episodes of positional vertigo as well as tendency to chronicity are among the main clinical features of BPPV at advanced age. BPPV in the older adults has a higher frequency of relapses, which is explained by the continuing degenerative processes in the otolith membrane and concomitant diseases that limit physical activity of older patients. The BPPV treatment in the older can be difficult due to the technical problems during canalith repositioning procedures, concomitant diseases and insufficient mobility of patients. Nevertheless, in most cases, the treatment of BPPV in the older adults remains highly effective, which makes early-stage disease detection of great value, even with atypical clinical manifestations. Therefore, it is especially important to perform positional tests in any cases with complaints of dizziness and instability.

Ductus Reuniens and Its Possible Role in Menière's Disease.

After 160 years the true underlying cause of Meniere's disease remains enigmatic. The aim of our study is to discuss the possible implication of an obstruction of the ductus reuniens as a cause in Menière's disease. We first conducted an historical study of the description of the ductus reuniens. We then reviewed the literature regarding ductus reuniens obstruction in animal experiments, human post-mortem studies and living ear imaging. We completed its description by modern microCT imaging. Limited knowledge on the fate of dislodged saccular otoconia is summarized. The possible implications for Meniere's attacks are discussed. Victor Hensen was the first to describe the ductus reuniens in 1863. He described its length and width and predicted that saccular otoconia might enter the ductus and the cochlea. On microCT the narrowest width of the human ductus reuniens was 0.14 mm. The literature reports cochlear endolymphatic hydrops occurring after animal experimental obstruction of the duct. Human postmortem studies have confirmed saccular otoconial clumps entering the ductus and the cochlea. A postmortem study has shown sites of endolymphatic obstruction, and imaging speculates on blockages in ears with Meniere's disease. Dislodged utricular otoconia can be in clumps of otolithic membranes. Blockages of the ductus reuniens and at other endolymphatic system sites appear to be a feature in Meniere's disease ears. The blockages have been postulated to be saccular otoconia either causing or aggravating hydrops. This could be consistent with observed nystagmus reversals during attacks as the endolymphatic sac attempts to clear the hydrops and the otoconia.

Pathogenesis and pathophysiology of Meniere’s disease: An update

Meniere’s disease is known with certain clinical symptoms such as fluctuating hearing loss, episodic vertigo, and tinnitus and characterized by endolymphatic hydrops found on post-mortem examination. The pathophysiology of Meniere’s disease is still questionable, and it has not been fully understood despite almost a century of research. Many determinants are effective in the occurrence of endolymphatic hydrops and in the pathogenesis of relevant cochleovestibular dysfunction. This review discusses research studies conducted in recent years concerning the pathogenesis and pathophysiology of Meniere’s disease. Histopathological research studies conducted in recent years on patients with Meniere’s disease have often focused on certain subjects as follows: aquaporins, oxidative stress, genetics, cochlear lateral wall changes, longitudinal flow blockage, intraskeletal channels of the otic capsule, hydropic and cellular changes in Reissner’s membrane, cochlear hair cells and spiral ganglion cells, round window thickness, basement membrane pathology, and otolithic membrane damages. Recent studies conducted on pathogenesis mechanisms of Meniere’s disease would provide an insight for the improvement of diagnosis and treatment of this weakening disease.

Transversal Otolithic Membrane Deflections Evoked by the Linear Accelerations

Considered is the model of the transversal utricle membrane deflections evoked by the linear accelerations. The basic idea underlying this consideration is that the linear accelerations can cause both longitudinal and transversal deformations when acting along the membrane in the buckling way. The real 3D utricle membrane structure was simplified by considering its middle section and evaluating its elastic properties in 2D space. The steady state transversal deflections along the membrane are analytically evaluated and numerically simulated using the 2D elasticity theory. The transversal deflections are found to be more expressive and stronger as compared to the conventional longitudinal deformations. The maxima of longitudinal deformations and transversal deflections are observable in different regions of the utricle membrane. The revealed properties could be used for explanation of the transduction processes in the otolith organ. Based on the implemented modeling approach the new otolithic membrane mechanical properties are discussed and new explanations for the available experimental data are given.

Zebrafish otolith biomineralization requires polyketide synthase

Deflecting biomineralized crystals attached to vestibular hair cells are necessary for maintaining balance. Zebrafish (Danio rerio) are useful organisms to study these biomineralized crystals called otoliths, as many required genes are homologous to human otoconial development. We sought to identify and characterize the causative gene in a trio of homozygous recessive mutants, no content (nco) and corkscrew (csr), and vanished (vns), which fail to develop otoliths during early ear development. We show that nco, csr, and vns have potentially deleterious mutations in polyketide synthase (pks1), a multi-modular protein that has been previously implicated in biomineralization events in chordates and echinoderms. We found that Otoconin-90 (Oc90) expression within the otocyst is diffuse in nco and csr; therefore, it is not sufficient for otolith biomineralization in zebrafish. Similarly, normal localization of Otogelin, a protein required for otolith tethering in the otolithic membrane, is not sufficient for Oc90 attachment. Furthermore, eNOS signaling and Endothelin-1 signaling were the most up- and down-regulated pathways during otolith agenesis in nco, respectively. Our results demonstrate distinct processes for otolith nucleation and biomineralization in vertebrates and will be a starting point for models that are independent of Oc90-mediated seeding. This study will serve as a basis for investigating the role of eNOS signaling and Endothelin-1 signaling during otolith formation.

Stereocilin gene variants associated with episodic vertigo: expansion of the DFNB16 phenotype

Vestibular disorders comprise a heterogeneous group of diseases with transient or permanent loss of vestibular function. Vestibulopathy is in most cases associated with migraine, Ménière disease, hereditary ataxias, or sensorineural hearing loss. We identified two brothers and their first cousin affected by hearing loss and episodic vertigo. The brothers were homozygous STRC nonsense variant [c.4027 C > T, p.(Q1343*)], whereas their first cousin was compound heterozygous for the STRC nonsense variant and a 97 kb deletion spanning the entire STRC gene. Clinical investigations confirmed pathological vestibular responses in addition to a characteristic DFNB16 hearing loss. The STRC gene encodes Stereocilin in the cochlea and in the vestibular organ where it ensheathes the kinocilium of the otolithic membranes. Stereocilin is associated with the gel overlaying the vestibular kinocilia, suggesting a role for the protein in sensing balance and spatial orientation. Our findings support such a function for Stereocilin in the vestibular organ and expand the phenotype associated with DFNB16.

Chapter 25 - Disorders of the inner-ear balance organs and their pathways

Disorders of the inner-ear balance organs can be grouped by their manner of presentation into acute, episodic, or chronic vestibular syndromes. A sudden unilateral vestibular injury produces severe vertigo, nausea, and imbalance lasting days, known as the acute vestibular syndrome (AVS). A bedside head impulse and oculomotor examination helps separate vestibular neuritis, the more common and innocuous cause of AVS, from stroke. Benign positional vertigo, a common cause of episodic positional vertigo, occurs when otoconia overlying the otolith membrane falls into the semicircular canals, producing brief spells of spinning vertigo triggered by head movement. Benign positional vertigo is diagnosed by a positional test, which triggers paroxysmal positional nystagmus in the plane of the affected semicircular canal. Episodic spontaneous vertigo caused by vestibular migraine and Ménière's disease can sometimes prove hard to separate. Typically, Ménière's disease is associated with spinning vertigo lasting hours, aural fullness, tinnitus, and fluctuating hearing loss while VM can produce spinning, rocking, or tilting sensations and light-headedness lasting minutes to days, sometimes but not always associated with migraine headaches or photophobia. Injury to both vestibular end-organs results in ataxia and oscillopsia rather than vertigo. Head impulse testing, dynamic visual acuity, and matted Romberg tests are abnormal while conventional neurologic assessments are normal. A defect in the bony roof overlying the superior semicircular canal produces vertigo and oscillopsia provoked by loud sound and pressure (when coughing or sneezing). Three-dimensional temporal bone computed tomography scan and vestibular evoked myogenic potential testing help confirm the diagnosis of superior canal dehiscence. Collectively, these clinical syndromes account for a large proportion of dizzy and unbalanced patients.

Current knowledge in the diagnostics and treatment of benign paroxysmal positional vertigo

Benign Paroxysmal Positional Vertigo (BPPV) is the most common disorder of the peripheral part of the balance system. BPPV is caused by fragments of damaged utricular otolithic membrane which, when displaced into the membranous semicircular canals, or stuck to the cupula, are responsible for incorrect cupula movements due to gravity forces when the position of the head is being changed. The principles of diagnosis and treatment are focused on BPPV with canal pathology localized within the posterior semicircular canal; however, BPPV may also be due to a lateral and, less commonly, an anterior canal pathology which requires different diagnostic methods and treatment. The clinical presentation of BPPV may also be distorted due to its coexistence with other diseases of the balance system; this, however, does not exclude the treatment being targeted at BPPV. The treatment of BPPV is based on reposition maneuvers, selected and correctly applied in accordance to the canal location, so as to relocate otolithic debris back to the utriculus. As a complementary treatment of BPPV, vestibular rehabilitation, psychology support and rarely surgery are taken into consideration. Although the immediate efficacy of BPPV treatment is high, recurrences may occur quite often. BPPV may also be a self-limiting disease, making it difficult to evaluate the efficacy of treatment. The key issues in clinical practice include the correct criteria of BPPV definition, the extent of diagnostic methods required, and appropriate selection of treatment methods. The paper presents a review of current recommendations in this matter.

Location and phase effects for ocular and cervical vestibular-evoked myogenic potentials evoked by bone-conducted stimuli at midline skull sites.

Our object was to investigate the effect of location and phase on the properties of oVEMPs and cVEMPs evoked by two bone conducted (BC) stimuli, 500 Hz and an impulsive stimulus for midline skull sites from Nz to Iz, in normal volunteers. Compressive and rarefactive onset phases were used and the induced linear and rotational accelerations measured. We confirmed our previous finding of marked changes in the polarity of oVEMPs with location. For cVEMPs using the 500Hz stimulus there were few changes with location or phase, but the impulsive stimulus showed clear phase-related changes at several locations, with the shortest latencies occurring with compressive stimuli at AFz and Fz and the largest amplitudes at Iz. For oVEMPs, both stimuli showed clear effects of phase, with the shortest latencies with compressive stimuli at AFz and Fz and with the largest negativity at Oz or Iz. Whereas the effectiveness at Iz is consistent with a role in the linear VOR, the inversion of polarity and shorter latency around AFz and Fz is not and could not be explained by changes in acceleration of the head. The latency for BC 500Hz oVEMPs for AFz was the same as that for air-conducted (AC) stimuli. We suggest that whereas BC stimuli at most sites work through displacement of the otolith membrane, BC oVEMPs evoked at AFz and Fz may work through a direct action on utricular hair cells. Our findings have implications for clinical testing of VEMPs using midline BC stimuli. NEW & NOTEWORTHY We investigated VEMPs evoked from multiple midline skull sites. Large oVEMP responses were obtained with compressive stimuli at Iz, consistent with a role in the linear VOR, but we also showed inversion of polarity and the shortest latency for stimuli given at AFz and Fz. We propose that BC stimuli given at AFz and Fz may have a direct effect on otolith hair cells, whereas at other sites they work through displacement of the otolith membrane.

Residual Dizziness after Successful Repositioning Maneuver for Idiopathic Benign Paroxysmal Positional Vertigo: A Review.

The benign paroxysmal positional vertigo (BPPV) is a vestibular disorder cause of vertigo. The BPPV may be corrected mechanically by repositioning maneuvers but even after successful maneuvers, some patients report residual dizziness for a certain period afterward. Early recognition and treatment might decrease the incidence of residual dizziness in patients with BPPV, especially in those patients with psychiatric comorbidities and in the elderly, lowering the risk of falling. Many pathogenetic hypotheses for residual dizziness are under debate.The purpose of this review was to identify, evaluate and review recent researches about possible causal factors involved in residual dizziness and the implications on clinical practice. A literature search was performed using different databases such as Pubmed and Scopus. The following search terms were used: residual dizziness, otolithic membrane and BPPV. The search found a total of 1192 titles, which were reduced to 963 after a procedure of de-duplication of the found titles. The research was then restricted to an interval of time comprised between 2000 and 2016 for a total of 800 titles. Among these titles, only those including the terms benign paroxysmal positional vertigo were considered eligible for this review. Only publications in English language were taken into consideration and we excluded those with not available abstract. Finally, 90 abstracts were obtained and critically evaluated by two different Authors, and additional studies were identified by hand searching from the references of artiche of interest. Only 53 were included in this work.

The sense of balance in humans: Structural features of otoconia and their response to linear acceleration.

We explored the functional role of individual otoconia within the otolith system of mammalians responsible for the detection of linear accelerations and head tilts in relation to the gravity vector. Details of the inner structure and the shape of intact human and artificial otoconia were studied using environmental scanning electron microscopy (ESEM), including decalcification by ethylenediaminetetraacetic acid (EDTA) to discriminate local calcium carbonate density. Considerable differences between the rhombohedral faces of human and artificial otoconia already indicate that the inner architecture of otoconia is not consistent with the point group -3m. This is clearly confirmed by decalcified otoconia specimen which are characterized by a non-centrosymmetric volume distribution of the compact 3+3 branches. This structural evidence for asymmetric mass distribution was further supported by light microscopy in combination with a high speed camera showing the movement of single otoconia specimen (artificial specimen) under gravitational influence within a viscous medium (artificial endolymph). Moreover, the response of otoconia to linear acceleration forces was investigated by particle dynamics simulations. Both, time-resolved microscopy and computer simulations of otoconia acceleration show that the dislocation of otoconia include significant rotational movement stemming from density asymmetry. Based on these findings, we suggest an otolith membrane expansion/stiffening mechanism for enhanced response to linear acceleration transmitted to the vestibular hair cells.

Polyketide Synthase is Required for Zebrafish Otolith Biomineralization

ObjectiveDeflecting biomineralized crystals attached to vestibular hair cells is necessary for maintaining the body's balance. Zebrafish (Danio rerio) are useful organisms to study these biomineralized crystals called otoliths as many required genes are homologous to human otoconial development. We sought to identify and characterize the causative gene in a pair of genetically‐linked mutants, no content (nco) and corkscrew (csr), that fail to develop otoliths during early ear development.MethodsMutant nco embryos and wild‐type clutchmates (WT) were collected during the critical period of otolith nucleation (24 hours post fertilization, hpf) and submitted for RNA sequencing. Analysis was completed using MMAPPR (Mutation Mapping Analysis Pipeline for Pooled RNA‐seq). Whole genome sequencing of csr was performed and analyzed using MegaMapper. WT mRNA was synthesized using mMessage Machine from a clone provided by Dr. Hiroyuki Takeda (University of Tokyo), cleaned on an RNeasy column, and subsequently injected into single‐cell csr and nco embryos. For immunofluorescence (IF), csr embryos were collected during key stages in ear development, fixed with hydrogel and washed in CLARITY‐clearing solution. Embryos were decalcified with EDTA before blocking, incubating in primary and secondary antibodies, and imaging by confocal microscopy. To test the effects of exogenous calcium ions on otolith formation, embryos were kept in E3 Medium until early gastrulation. Embryos were washed and transferred to 1X Basic Solution (58 mM NaCl, 0.4 mM MgSO4 and 5 mM HEPES) supplemented with 0.7 mM potassium chloride [0 mM Ca2+], 0.6 mM calcium nitrate [0.15 mM Ca2+] or 0.6 mM calcium chloride [0.22 mM Ca2+]. Embryos were scored by the presence or absence of otoliths at 27 hpf. Statistical significance was calculated using Fisher's Exact Test and Chi‐Squared Distribution or by Linear Regression.ResultsTo positionally clone the gene responsible for nco and csr, we used complementary approaches for each strain. MMAPPR analysis of nco‐derived RNA sequencing and MegaMapper analysis of csr‐derived whole genome sequencing both identified a genomic region surrounding polyketide synthase 1 (pks1; current gene name wu:fc01d11), a candidate gene that was recently identified as a key factor of otolith biomineralization in Japanese medaka (Oryzias latipes, Ol). Microinjection of OI pks1 mRNA rescued otolith biomineralization in both csr (p<0.0001; χ2<0.0001) and nco (p=0.0032; χ2=0.0022) mutants. Using IF, an otoconial seeding protein, Otoconin‐90, and an otolith matrix protein, Starmaker, show diffuse expression inside the otocyst of csr mutant embryos. Expression of Otogelin, a primary component of the otolithic membrane, is localized near the apical surfaces of sensory hair cells in both csr and WT. Additionally, exogenous calcium concentrations correlate with penetrance of otolith formation in csr embryos (R2=0.9978); however, nco embryos were unaffected (R2=0.7802).ConclusionsOtolith nucleation is impaired in the genetically‐linked zebrafish mutants csr and nco. IF of csr embryos demonstrated that expression of a critical otoconial seeding protein, Otoconin‐90, within the otocyst is not sufficient for otolith biomineralization in the presence of the otolithic membrane. While WT Ol pks1 rescues otolith biomineralization in csr and nco, differences in penetrance of calcium ions on otolith formation suggest the nature of each mutation is fundamentally different.Support or Funding InformationThe work was supported by grants from the National Institutes of Health (8P20GM103471) and the Creighton Health Science Strategic Investment Fund.

Sustained and Transient Vestibular Systems: A Physiological Basis for Interpreting Vestibular Function.

Otolithic afferents with regular resting discharge respond to gravity or low-frequency linear accelerations, and we term these the static or sustained otolithic system. However, in the otolithic sense organs, there is anatomical differentiation across the maculae and corresponding physiological differentiation. A specialized band of receptors called the striola consists of mainly type I receptors whose hair bundles are weakly tethered to the overlying otolithic membrane. The afferent neurons, which form calyx synapses on type I striolar receptors, have irregular resting discharge and have low thresholds to high frequency (e.g., 500 Hz) bone-conducted vibration and air-conducted sound. High-frequency sound and vibration likely causes fluid displacement which deflects the weakly tethered hair bundles of the very fast type I receptors. Irregular vestibular afferents show phase locking, similar to cochlear afferents, up to stimulus frequencies of kilohertz. We term these irregular afferents the transient system signaling dynamic otolithic stimulation. A 500-Hz vibration preferentially activates the otolith irregular afferents, since regular afferents are not activated at intensities used in clinical testing, whereas irregular afferents have low thresholds. We show how this sustained and transient distinction applies at the vestibular nuclei. The two systems have differential responses to vibration and sound, to ototoxic antibiotics, to galvanic stimulation, and to natural linear acceleration, and such differential sensitivity allows probing of the two systems. A 500-Hz vibration that selectively activates irregular otolithic afferents results in stimulus-locked eye movements in animals and humans. The preparatory myogenic potentials for these eye movements are measured in the new clinical test of otolith function—ocular vestibular-evoked myogenic potentials. We suggest 500-Hz vibration may identify the contribution of the transient system to vestibular controlled responses, such as vestibulo-ocular, vestibulo-spinal, and vestibulo-sympathetic responses. The prospect of particular treatments targeting one or the other of the transient or sustained systems is now being realized in the clinic by the use of intratympanic gentamicin which preferentially attacks type I receptors. We suggest that it is valuable to view vestibular responses by this sustained-transient distinction.

Do patients with Ménière's disease have attacks of syncope?

The aim of the present study was to evaluate the prevalence and associated factors for syncope among patients with Ménière's disease (MD). An attack of syncope was defined as a sudden and transient loss of consciousness, which subsides spontaneously and without a localizing neurological deficit. The study used an across-sectional survey design. Information from a database consisting of 961 individuals was collected from the Finnish Ménière Association. The data contained case histories, general health-related quality of life (HRQoL), and impact measurements of the complaints. In the current study sample, syncope occurred in 12.3% of the patients with MD. It was more prevalent among elderly persons and among those with a longer duration of MD. Syncope was significantly associated with disturbances of otolith function reflected as Tumarkin attacks, gait and balance problems, environmental change of pressure, and physical strain. It was also associated with visual blurring; in fact, patients with otolith dysfunction in MD often experience visual field changes. It was also associated with headache, but not with migraine. Syncope was experienced as frightening and HRQoL was significantly worsened. The patient had higher anxiety scores, and suffered more from fatigue. The results demonstrate that neurally mediated syncope occurs in patients with an advanced form of MD who suffer from Tumarkin attacks due to failure in otolith function. The mechanism seems to be triggered through the vestibular sympathetic reflex when the otolith system fails due to disrupted utricular otolithic membrane mediate erroneous positional information from the otolith organ to the vasomotor centres in the brain stem and medulla.