Vestibular-evoked Potentials Research Articles

TMC function, dysfunction, and restoration in mouse vestibular organs.

Tmc1 and Tmc2 are essential pore-forming subunits of mechanosensory transduction channels localized to the tips of stereovilli in auditory and vestibular hair cells of the inner ear. To investigate expression and function of Tmc1 and Tmc2 in vestibular organs, we used quantitative polymerase chain reaction (qPCR), fluorescence in situ hybridization - hairpin chain reaction (FISH-HCR), immunostaining, FM1-43 uptake and we measured vestibular evoked potentials (VsEPs) and vestibular ocular reflexes (VORs). We found that Tmc1 and Tmc2 showed dynamic developmental changes, differences in regional expression patterns, and overall expression levels which differed between the utricle and saccule. These underlying changes contributed to unanticipated phenotypic loss of VsEPs and VORs in Tmc1 KO mice. In contrast, Tmc2 KO mice retained VsEPs despite the loss of the calcium buffering protein calretinin, a characteristic biomarker of mature striolar calyx-only afferents. Lastly, we found that neonatal Tmc1 gene replacement therapy is sufficient to restore VsEP in Tmc1 KO mice for up to six months post-injection.

The Middle Ear Functions and Vestibular-Evoked Potentials in Springboard-Platform Diving Children

The Middle Ear Functions and Vestibular-Evoked Potentials in Springboard-Platform Diving Children

Is Skull-Vibration-Induced Nystagmus Modified with Aging?

Background: Despite clinical practice utilizing the Dumas test (SVINT), some questions remain unanswered, including the age-related changes in frequency (FN) and slow-phase angular velocity (SPAV). This study aims to retrospectively evaluate their variations in subjects affected by unilateral peripheral vestibular loss (UPVL). Methods: We evaluated the selected samples based on the results of the SVINT, the results of the vestibular-evoked potentials (C-VEMP and O-VEMP), and the results of the head impulse test (HIT) and we compared the results against the age of the patients. We calculated the timing between the onset of UPVL and clinical evaluation in days. The presence or absence of VEMP indicated the UPVL severity. UPVL and BPPV patients with spontaneous or pseudo-spontaneous nystagmus were compared. Results: Statistical analysis showed changes in the FN and SPAV depending on age and the side of the application of the stimulus. We also observed that, in the UPVL, the severity of the disease modifies the SPAV, but not the frequency. Conclusions: The SVINT is a simple, reliable, and straightforward test that, if evaluated instrumentally, can show significant differences with aging. Further studies need to be performed to refine the clinical significance of the test and clarify its physiological background.

Beneficial effects of time-restricted feeding on gentamicin cytotoxicity in mouse cochlea and vestibular organs.

ObjectiveTime restricted feeding (TRF), which is an intermittent fasting protocol, has been reported to decrease the toxicity and mortality rate associated with systemic gentamicin (GM) administration. The aim of this study is to evaluate the effect of TRF on GM‐induced vestibular and auditory function in mice.MethodsJapan Central Laboratory for Experimental Animals:Institute of Cancer Research (Jcl:ICR) mice were housed in a light–dark (LD) cycle (12:12) and were divided into three groups: (1) GM treatment at a dose of 220 mg/kg with TRF (feeding time: 8 h [9:00–17:00] during the light phase [7:00–19:00]) (GM + TRF group), (2) GM treatment at a dose of 220 mg/kg without TRF (GM group), and (3) saline injection with TRF (NS + TRF group). GM or saline was injected subcutaneously for 18 days (three courses of 5 days' injection + 2 days' rest, and an additional 3 days' injection). The auditory brainstem response (ABR) and vestibular evoked potential (VsEP) were tested after the treatments. The number of sensory hair cells in the cochlear organs and the vestibular organs were quantified using microscopic images.ResultsAll animals survived until the end of the experiment. One day after the last injection, GM + TRF mice showed significantly lower ABR thresholds at 4 kHz compared to GM mice, and there was no significant difference between the GM + TRF and NS + TRF groups. There was a significant difference of VsEP between GM and GM + TRF mice only in symmetric parabolic waves with linear acceleration and ramps waveform stimulation. GM + TRF mice showed significantly less outer and inner hair cell loss compared to GM mice. GM + TRF mice showed significantly less type II hair cell loss in the utricle and the ampulla compared to GM mice.ConclusionTRF with daytime feeding reduced GM cytotoxicity in the cochlea and vestibular organs of ICR mice.Level of EvidenceNA

Retinoic acid degradation shapes zonal development of vestibular organs and sensitivity to transient linear accelerations

Each vestibular sensory epithelium in the inner ear is divided morphologically and physiologically into two zones, called the striola and extrastriola in otolith organ maculae, and the central and peripheral zones in semicircular canal cristae. We found that formation of striolar/central zones during embryogenesis requires Cytochrome P450 26b1 (Cyp26b1)-mediated degradation of retinoic acid (RA). In Cyp26b1 conditional knockout mice, formation of striolar/central zones is compromised, such that they resemble extrastriolar/peripheral zones in multiple features. Mutants have deficient vestibular evoked potential (VsEP) responses to jerk stimuli, head tremor and deficits in balance beam tests that are consistent with abnormal vestibular input, but normal vestibulo-ocular reflexes and apparently normal motor performance during swimming. Thus, degradation of RA during embryogenesis is required for formation of highly specialized regions of the vestibular sensory epithelia with specific functions in detecting head motions.

Effects of Caffeine on Auditory- and Vestibular-Evoked Potentials in Healthy Individuals: A Double-Blind Placebo-Controlled Study.

Background and ObjectivesThe blockage of adenosine receptors by caffeine changes the levels of neurotransmitters. These receptors are present in all parts of the body, including the auditory and vestibular systems. This study aimed to evaluate the effect of caffeine on evoked potentials using auditory brainstem responses (ABRs) and cervical vestibular-evoked myogenic potentials (cVEMPs) in a double-blind placebo-controlled study.Subjects and MethodsForty individuals (20 females and 20 males; aged 18-25 years) were randomly assigned to two groups: the test group (consuming 3 mg/kg pure caffeine powder with little sugar and dry milk in 100 mL of water), and the placebo group (consuming only sugar and dry milk in 100 mL water as placebo). The cVEMPs and ABRs were recorded before and after caffeine or placebo intake.ResultsA significant difference was observed in the absolute latencies of I and III (p<0.010), and V (p<0.001) and in the inter-peak latencies of III–V and I–V (p<0.001) of ABRs wave. In contrast, no significant difference was found in cVEMP parameters (P13 and N23 latency, threshold, P13-N23 amplitude, and amplitude ratio). The mean amplitudes of P13-N23 showed an increase after caffeine ingestion. However, this was not significant compared with the placebo group (p>0.050).ConclusionsIt seems that the extent of caffeine’s effects varies for differently evoked potentials. Latency reduction in ABRs indicates that caffeine improves transmission in the central brain auditory pathways. However, different effects of caffeine on auditory- and vestibular-evoked potentials could be attributed to the differences in sensitivities of the ABR and cVEMP tests.

Synaptopathy as a Mechanism for Age-Related Vestibular Dysfunction in Mice

Age-related decline of inner ear function contributes to both hearing loss and balance disorders, which lead to impaired quality of life and falls that can result in injury and even death. The cellular mechanisms responsible for the ear’s functional decline have been controversial, but hair cell loss has been considered the key cause for a long time. However, recent studies showed that in the cochlea, loss of inner hair cell (IHC) synapses precedes hair cell or neuronal loss, and this synaptopathy is an early step in the functional decline. Whether a similar process occurs in the vestibular organ, its timing and its relationship to organ dysfunction remained unknown. We compared the time course of age-related deterioration in vestibular and cochlear functions in mice as well as characterized the age-associated changes in their utricles at the histological level. We found that in the mouse, as in humans, age-related decline in vestibular evoked potentials (VsEPs) occurs later than hearing loss. As in the cochlea, deterioration of VsEPs correlates with the loss of utricular ribbon synapses but not hair cells or neuronal cell bodies. Furthermore, the age-related synaptic loss is restricted to calyceal innervations in the utricular extrastriolar region. Hence, our findings suggest that loss of extrastriolar calyceal synapses has a key role in age-related vestibular dysfunction (ARVD).

Visual and vestibular functioning, and age and surgery effects on postural control in healthy children with vertical strabismus.

Purpose:To describe visual and vestibular functioning and the effects of age and surgery effects on postural control in healthy children with vertical strabismus.Design:This is a comparative case series.Methods:We evaluated participants at the Scientific Institute Eugenio Medea during routine clinical activities. We enrolled 30 consecutive children/adolescents (age range 4–13 years) with isolated vertical strabismus, with and without corrective surgery. Participants were split into four subgroups according to age (4–8 years versus 9–13 years) and ocular surgery (surgery versus no surgery). The clinical protocol included ophthalmological, orthoptic, neurological, physiatrical, otolaryngological, and vestibular evaluations, and the instrumental protocol included ocular cyclotorsions assessment, posturography, and vestibular myogenic-evoked potentials. Main outcome measures of the study were the prevalence of study-relevant orthopedic, ocular, vestibular, and posturographic abnormalities.Results:Among the overall largely variable findings across patients’ groups, we found some interesting trends: larger binocular vision and convergence disorders in younger children, smaller prevalence of asymmetric vestibular-evoked potentials in operated children, less posturographic abnormalities in younger children. No clear-cut beneficial effect of surgery was found on all clinical and instrumental parameters considered, despite good re-alignment of the eyes.Conclusion:The pathophysiology of postural control in vertical strabismus is extremely complex and above the potential of this study design and should be specifically addressed in deeper experimental studies.

92. Myogenic vestibular-evoked potentials: An extension of the assessment protocol

Vestibular-Evoked-Myogenic-Potentials (VEMPs) represent a muscular response following an intense acoustic stimulation. The cVEMPs explore a reflex arc (from saccule to the neck musculature) and usually are only recorded from sternocleidomastoideus (SCM). 1 They are non-invasive, well-tolerated, simple-to-perform and very useful in several diseases. The normal response is a biphasic complex P13/N23. We propose a more extensive protocol. We recruited 31 subjects (mean age ± SD:50.8 ± 19.0). VEMPs were recorded symmetrically and simultaneously through surface electromyography from SCM, splenius (SPL), trapezius (TRP) and orbicularis oculi (OO). The sensitivity was 20 μ V, band pass filter 20–2000 Hz, tone acoustic stimulus was monaural and binaural at 500 Hz, rate at 5.3 Hz. Three runs of 150 sweeps were averaged. The patients remained in clinostatic position with anterior neck flexion. Like the SCM cVEMP, the SPL and TRP cVEMP was characterized by a biphasic wave of muscle activity that began at ∼13 ms. Responses were consistent and repeatable. VEMPs latencies and amplitude showed a higher inter-reliability for the four muscles. The protocol offer a complementary target for cVEMP assessments. The simultaneous recording of oVEMPs and cVEMPs provide the evaluation of the ascending and descending vestibular pathways, allowing an extensive overview of brainstem function.

Auditory- and Vestibular-Evoked Potentials Correlate with Motor and Non-Motor Features of Parkinson's Disease.

Degeneration of several brainstem nuclei has been long related to motor and non-motor symptoms (NMSs) of Parkinson’s disease (PD). Nevertheless, due to technical issues, there are only a few studies that correlate that association. Brainstem auditory-evoked potential (BAEP) and vestibular-evoked myogenic potential (VEMP) responses represent a valuable tool for brainstem assessment. Here, we investigated the abnormalities of BAEPs, ocular VEMPs (oVEMPs), and cervical VEMPs (cVEMPs) in patients with PD and its correlation to the motor and NMSs. Fifteen patients diagnosed as idiopathic PD were evaluated by Unified Parkinson’s Disease Rating Scale and its subscores, Hoehn and Yahr scale, Schwab and England scale, and Non-Motor Symptoms Scale. PD patients underwent pure-tone, speech audiometry, tympanometry, BAEP, oVEMPs, and cVEMPs, and compared to 15 age-matched control subjects. PD subjects showed abnormal BAEP wave morphology, prolonged absolute latencies of wave V and I–V interpeak latencies. Absent responses were the marked abnormality seen in oVEMP. Prolonged latencies with reduced amplitudes were seen in cVEMP responses. Rigidity and bradykinesia were correlated to the BAEP and cVEMP responses contralateral to the clinically more affected side. Contralateral and ipsilateral cVEMPs were significantly correlated to sleep (p = 0.03 and 0.001), perception (p = 0.03), memory/cognition (p = 0.025), and urinary scores (p = 0.03). The oVEMP responses showed significant correlations to cardiovascular (p = 0.01) and sexual dysfunctions (p = 0.013). PD is associated with BAEP and VEMP abnormalities that are correlated to the motor and some non-motor clinical characteristics. These abnormalities could be considered as potential electrophysiological biomarkers for brainstem dysfunction and its associated motor and non-motor features.

The inion response revisited: evidence for a possible cerebellar contribution to vestibular-evoked potentials produced by air-conducted sound stimulation.

This study investigated the effect of eye gaze and head position on vestibular-evoked potentials (VsEPs). Head position would be expected to affect myogenic sources, and eye position is known to affect ocular myogenic responses (ocular vestibular-evoked myogenic potentials), whereas a neurogenic source should behave otherwise. Eleven healthy subjects were recruited, and VsEPs, using 72-channel EEG, were recorded at a fixed intensity above the vestibular threshold. Three eye gaze and three head positions were tested (-20°, 0°, and +20° to the horizontal). Short-latency potentials showed that in addition to the expected effect of gaze on infraocular (IO') leads, where up-gaze gives a maximum response, significant changes in amplitude were also observed in electrodes remote from the eyes and in particular, from contralateral parietal-occipital (PO) and neck (CB') leads. Short-latency potentials of similar latency were observed (p10/n17 and n10/p17, respectively). The pattern of change with gaze in the PO leads was distinct from that observed for the IO' leads. For the PO leads, the maximum response was obtained with neutral gaze, and this was also distinct from that observed for CB' electrodes, where a maximal response was observed with head flexion in the second wave but not the first. Evidence of modulation of N42 and N1 potentials with both eye and head position was also observed. Head- and eye-position manipulation thus suggests that the inion response consists of an early neurogenic component, as well as myogenic responses. The p10/n17 at PO, in particular, may be an indicator of vestibulocerebellar projections.NEW & NOTEWORTHY Loud sounds were used to activate vestibular receptors in human volunteers and the effects of head and eye position studied for short-latency responses. A potential (p10/n17) recorded in the parieto-occipital leads showed behavior not expected for a response with a myogenic origin. Source modeling suggested a possible origin from the cerebellum. It may represent a new indicator of human vestibulocerebellar function.

International clinical protocol of vestibular disorders (dizziness)

Vertigo - a common symptom, which traditionally presents the results of vestibular dysfunction and non vestibular dysfunction. Vertigo refers to violations of orientation in space. The main symptoms, which produce the patients in the survey: dizziness, subjective vertigo, dizziness objective, pseudo vertigo, imbalance, kinetosis. In many cases, dizziness is functional, rather than an organic nature. Diagnosis of the causes of vertigo arises from the concept of the structure of the vestibular apparatus, the main idea of which is the formation of vertigo in the vestibular system. Morpho-physiological, vestibular system consists of four main projections: vestibular-cortical (sensory), vestibular-motor, vestibular-autonomic and vestibular-limbic. One of the main methods of research of a condition the vestibular apparatus and projections are vestibular evoked potentials (VEP). Owing to this method, have been established objective limits to the sensitivity of the movement. Research of vestibular-spinal responses are based on Romberg test, Unterberger-Fukuda test and Uemura test. Evaluation and treatment of patients with dizziness will differ significantly once the category of dizziness has been determined

Vestibular dysfunction, altered macular structure and trait localization in A/J inbred mice.

A/J mice develop progressive hearing loss that begins before 1month of age and is attributed to cochlear hair cell degeneration. Screening tests indicated that this strain also develops early onset vestibular dysfunction and has otoconial deficits. The purpose of this study was to characterize the vestibular dysfunction and macular structural pathology over the lifespan of A/J mice. Vestibular function was measured using linear vestibular evoked potentials (VsEPs). Macular structural pathology was evaluated using light microscopy, scanning electron microscopy, transmission electron microscopy, confocal microscopy and Western blotting. Individually, vestibular functional deficits in mice ranged from mild to profound. On average, A/J mice had significantly reduced vestibular sensitivity (elevated VsEP response thresholds and smaller amplitudes), whereas VsEP onset latency was prolonged compared to age-matched controls (C57BL/6). A limited age-related vestibular functional loss was also present. Structural analysis identified marked age-independent otoconial abnormalities in concert with some stereociliary bundle defects. Macular epithelia were incompletely covered by otoconial membranes with significantly reduced opacity and often contained abnormally large or giant otoconia as well as normal-appearing otoconia. Elevated expression of key otoconins (i.e., otoconin 90, otolin and keratin sulfate proteoglycan) ruled out the possibility of reduced levels contributing to otoconial dysgenesis. The phenotype of A/J was partially replicated in a consomic mouse strain (C57BL/6J-Chr 17(A/J)/NaJ), thus indicating that Chr 17(A/J) contained a trait locus for a new gene variant responsible to some extent for the A/J vestibular phenotype. Quantitative trait locus analysis identified additional epistatic influences associated with chromosomes 1, 4, 9 and X. Results indicate that the A/J phenotype represents a complex trait, and the A/J mouse strain presents a new model for the study of mechanisms underlying otoconial formation and maintenance.

Linear Acceleration Response Variation in Inbred Strains of Mice: The Requisite for Gene Discovery

Objectives: (1) Evaluate gravity receptor function using vestibular evoked potentials (VsEPs) recordings in different strains of mice. (2) Indicate functional variation in VsEPs response parameters across strains for the Genome-Wide Association Study (GWAS) mapping of the vestibular system. Methods: Mice (6 weeks old) were anesthetized with ketamine 100 mg/kg and xylazine 10 mg/kg and were positioned supine with the head mount coupled and the cranium securely fastened to a mechanical shaker. Stimuli consisted of linear acceleration (17 pulses/s) applied to the cranium in the naso-occipital axis. The first (P1) and second (P2) positive and negative response peaks were measured as phenotypes. Mice were selected based on a combined set of classic inbred (CI) and recombinant inbred (RI) strains from the Hybrid Mouse Diversity Panel (HMDP). A total of 13 CI (C57BL/6J, FVB/NJ, Balb/cJ, C3H/HeJ, Balb/cByJ, AKR/J, 129x1/SvJ, A/J, DBA/2J, SJL/J, CBA/J, SEA/GnJ, and NOD/ShiLtJ) and 10 RI (BXA14/PgnJ, BXD84/RwwJ, BXH19/TyJ, BXH22/KccJ, BXH9/TyJ, BXH10/TyJ, BXA14/PgnJ, BXA4/PgnJ, BXA16/PgnJ, and CXB9/HiAJ) were evaluated with an average of 2.7 mice/strain. Results: A wide range of phenotypic responses was observed. The mean threshold (–8.73 ± 5.1 dB re: 1 g/ms) and P2-N2 amplitude at +6 dB re: 1 g/ms (0.682 ± 0.51 mV) both demonstrated statistical significant variation (analysis of variance) in VsEP thresholds ( P = .008) and P2-N2 amplitude ( P = .001). Conclusions: These data demonstrate significant variation in VsEP response parameters across strains, strongly suggesting the hypothesis that there exists functional variation of vestibular function among strains of mice and the genetic determinants of such variation can be mapped using GWAS.

Vestibular evoked potentials (VsEPs) of cortical origin produced by impulsive acceleration applied at the nasion.

We report the results of a study to record vestibular evoked potentials (VsEPs) of cortical origin produced by impulsive acceleration (IA). In a sample of 12 healthy participants, evoked potentials recorded by 70 channel electroencephalography were obtained by IA stimulation at the nasion and compared with evoked potentials from the same stimulus applied to the forefingers. The nasion stimulation gave rise to a series of positive and negative deflections in the latency range of 26–72 ms, which were dependent on the polarity of the applied IA. In contrast, evoked potentials from the fingers were characterised by a single N50/P50 deflection at about 50 ms and were polarity invariant. Source analysis confirmed that the finger evoked potentials were somatosensory in origin, i.e. were somatosensory evoked potentials, and suggested that the nasion evoked potentials plausibly included vestibular midline and frontal sources, as well as contributions from the eyes, and thus were likely VsEPs. These results show considerable promise as a new method for assessment of the central vestibular system by means of VsEPs produced by IA applied to the head.

A vestibular prosthesis with highly-isolated parallel multichannel stimulation.

This paper presents an implantable vestibular stimulation system capable of providing high flexibility independent parallel stimulation to the semicircular canals in the inner ear for restoring three-dimensional sensation of head movements. To minimize channel interaction during parallel stimulation, the system is implemented with a power isolation method for crosstalk reduction. Experimental results demonstrate that, with this method, electrodes for different stimulation channels located in close proximity ( mm) can deliver current pulses simultaneously with minimum inter-channel crosstalk. The design features a memory-based scheme that manages stimulation to the three canals in parallel. A vestibular evoked potential (VEP) recording unit is included for closed-loop adaptive stimulation control. The main components of the prototype vestibular prosthesis are three ASICs, all implemented in a 0.6- μm high-voltage CMOS technology. The measured performance was verified using vestibular electrodes in vitro.

Source analysis of short and long latency vestibular-evoked potentials (VsEPs) produced by left vs. right ear air-conducted 500 Hz tone pips

Todd et al. (2014) have recently demonstrated the presence of vestibular dependent changes both in the morphology and in the intensity dependence of auditory evoked potentials (AEPs) when passing through the vestibular threshold as determined by vestibular evoked myogenic potentials (VEMPs). In this paper we extend this work by comparing left vs. right ear stimulation and by conducting a source analysis of the resulting evoked potentials of short and long latency. Ten healthy, right-handed subjects were recruited and evoked potentials were recorded to both left- and right-ear sound stimulation, above and below vestibular threshold. Below VEMP threshold, typical AEPs were recorded, consisting of mid-latency (MLR) waves Na and Pa followed by long latency AEPs (LAEPs) N1 and P2. In the supra-threshold condition, the expected changes in morphology were observed, consisting of: (1) short-latency vestibular evoked potentials (VsEPs) which have no auditory correlate, i.e. the ocular VEMP (OVEMP) and inion response related potentials; (2) a later deflection, labelled N42/P52, followed by the LAEPs N1 and P2. Statistical analysis of the vestibular dependent responses indicated a contralateral effect for inion related short-latency responses and a left-ear/right-hemisphere advantage for the long-latency responses. Source analysis indicated that the short-latency effects may be mediated by a contralateral projection to left cerebellum, while the long-latency effects were mediated by a contralateral projection to right cingulate cortex. In addition we found evidence of a possible vestibular contribution to the auditory T-complex in radial temporal lobe sources. These last results raise the possibility that acoustic activation of the otolith organs could potentially contribute to auditory processing.

A null mutation of mouse Kcna10 causes significant vestibular and mild hearing dysfunction

KCNA10 is a voltage gated potassium channel that is expressed in the inner ear. The localization and function of KCNA10 was studied in a mutant mouse, B6-Kcna10TM45, in which the single protein coding exon of Kcna10 was replaced with a beta-galactosidase reporter cassette. Under the regulatory control of the endogenous Kcna10 promoter and enhancers, beta-galactosidase was expressed in hair cells of the vestibular organs and the organ of Corti. KCNA10 expression develops in opposite tonotopic gradients in the inner and outer hair cells. Kcna10TM45 homozygotes display only a mild elevation in pure tone hearing thresholds as measured by auditory brainstem response (ABR), while heterozygotes are normal. However, Kcna10TM45 homozygotes have absent vestibular evoked potentials (VsEPs) or elevated VsEP thresholds with prolonged peak latencies, indicating significant vestibular dysfunction despite the lack of any overt imbalance behaviors. Our results suggest that Kcna10 is expressed primarily in hair cells of the inner ear, with little evidence of expression in other organs. The Kcna10TM45 targeted allele may be a model of human nonsyndromic vestibulopathy.

The effect of topically applied antimycotic agents on inner ear vestibular and cochlear function

To assess and compare the effect of commonly used topical antimycotic agents and their solvents on the function of the vestibular and cochlear parts of the sand rat's inner ear. Prospective, controlled, animal study. Forty-five fat sand rats were randomly assigned to five major groups, each receiving topical application of a different agent: saline (control), gentamicin (ototoxic control), and three antimycotic agents: nystatin, clotrimazole solution (Agisten), and bifonazole solution (Agispor). All animals underwent a right labyrinthectomy, and a polyethylene tube was inserted into the left middle ear followed by baseline recording of vestibular evoked potentials (VsEPs) and auditory nerve and brainstem responses (ABR). Subsequently, each animal received five consecutive daily applications of the specific agent into the left middle ear. Evoked potential recordings were repeated 3 and 10 days after the last application and compared to baseline. For clotrimazole and bifonazole solutions, the effect of the solvents was assessed by comparing ABR recordings at similar intervals. Administration of saline did not affect VsEPs or ABR. Both could not be recorded following gentamicin application. In all three antimycotic agents, no statistically significant difference was found between VsEPs recordings before and after application. Clotrimazole and bifonazole solutions caused a significant ABR threshold elevation similar to that caused by their solvents. Nystatin caused a less significant ABR threshold elevation. The three commonly used topical antimycotic agents investigated here did not affect vestibular function but had a toxic effect on inner ear cochlear function. It seems the main offenders were the solvents.

HCN Channels Expressed in the Inner Ear Are Necessary for Normal Balance Function

HCN1-4 subunits form Na+/K+-permeable ion channels that are activated by hyperpolarization and carry the current known as I(h). I(h) has been characterized in vestibular hair cells of the inner ear, but its molecular correlates and functional contributions have not been elucidated. We examined Hcn mRNA expression and immunolocalization of HCN protein in the mouse utricle, a mechanosensitive organ that contributes to the sense of balance. We found that HCN1 is the most highly expressed subunit, localized to the basolateral membranes of type I and type II hair cells. We characterized I(h) using the whole-cell, voltage-clamp technique and found the current expressed in 84% of the cells with a mean maximum conductance of 4.4 nS. I(h) was inhibited by ZD7288, cilobradine, and by adenoviral expression of a dominant-negative form of HCN2. To determine which HCN subunits carried I(h), we examined hair cells from mice deficient in Hcn1, 2, or both. I(h) was completely abolished in hair cells of Hcn1⁻/⁻ mice and Hcn1/2⁻/⁻ mice but was similar to wild-type in Hcn2⁻/⁻ mice. To examine the functional contributions of I(h), we recorded hair cell membrane responses to small hyperpolarizing current steps and found that activation of I(h) evoked a 5-10 mV sag depolarization and a subsequent 15-20 mV rebound upon termination. The sag and rebound were nearly abolished in Hcn1-deficient hair cells. We also found that Hcn1-deficient mice had deficits in vestibular-evoked potentials and balance assays. We conclude that HCN1 contributes to vestibular hair cell function and the sense of balance.