Assessment of Utricular Nerve, Hair Cell and Mechanical Function, in vivo.

Vestibular research currently relies on single response measures such as ex vivo hair cell and in vivo single unit recordings. Although these methods allow detailed insight into the response properties of individual vestibular hair cells and neurons, they do not provide a holistic understanding of peripheral vestibular functioning and its relationship to vestibular pathology in a living system. For this to take place, in vivo recordings of peripheral vestibular nerve, hair cell and mechanical function are needed. The previous inability to record vestibular hair cell responses stemmed from a difficulty in accessing the vestibular end-organs and stimulating them in isolation of the cochlea. To circumvent this, we developed a ventral surgical approach, removing the cochlea, to provide full access to the basal surface of the utricular macula. This allowed functional and mechanical utricular hair cell recordings, alongside gross utricular nerve responses. Recordings were performed in anaesthetized guinea pigs using Bone Conducted Vibration (BCV) and Air Conducted Sound (ACS) stimuli, providing a clinical link to vestibular reflex testing. We have thus far performed experiments involving: 1) Selective manipulation of vestibular nerve function, using electrical stimulation of the central vestibular system. 2) Glass micropipette recordings from the basal surface of the macular epithelium, which provided a robust and localized measure of extracellular utricular hair cell function. 3) With the macular exposed, we have measured the dynamic motion of the macula using Laser Doppler Vibrometry, which was recorded alongside the hair cell and nerve response recordings. 4) We have used physiological and pharmacological experimental manipulations to selectively modulate utricular nerve, hair cell or mechanical function, demonstrating the ability to differentially diagnose the basis of peripheral vestibular disorders in the mammalian utricle. These tools allow for a more complete understanding of peripheral vestibular function and a first order perspective into clinical disorders effecting the otoliths

A mathematical model for mechanical activation and compound action potential generation by the utricle in response to sound and vibration

IntroductionCalyx bearing vestibular afferent neurons innervating type I hair cells in the striolar region of the utricle are exquisitely sensitive to auditory-frequency air conducted sound (ACS) and bone conducted vibration (BCV). Here, we present experimental data and a mathematical model of utricular mechanics and vestibular compound action potential generation (vCAP) in response to clinically relevant levels of ACS and BCV. Vibration of the otoconial layer relative to the sensory epithelium was simulated using a Newtonian two-degree-of-freedom spring-mass-damper system, action potential timing was simulated using an empirical model, and vCAPs were simulated by convolving responses of the population of sensitive neurons with an empirical extracellular voltage kernel. The model was validated by comparison to macular vibration and vCAPs recorded in the guinea pig, in vivo.ResultsTransient stimuli evoked short-latency vCAPs that scaled in magnitude and timing with hair bundle mechanical shear rate for both ACS and BCV. For pulse BCV stimuli with durations <0.8 ms, the vCAP magnitude increased in proportion to temporal bone acceleration, but for pulse durations >0.9 ms the magnitude increased in proportion to temporal bone jerk. Once validated using ACS and BCV data, the model was applied to predict blast-induced hair bundle shear, with results predicting acute mechanical damage to bundles immediately upon exposure.DiscussionResults demonstrate the switch from linear acceleration to linear jerk as the adequate stimulus arises entirely from mechanical factors controlling the dynamics of sensory hair bundle deflection. The model describes the switch in terms of the mechanical natural frequencies of vibration, which vary between species based on morphology and mechanical factors

Electrophysiological measurements of peripheral vestibular function—A review of electrovestibulography

Electrocochleography (EcochG), incorporating the Cochlear Microphonic (CM), the Summating Potential (SP), and the cochlear Compound Action Potential (CAP), has been used to study cochlear function in humans and experimental animals since the 1930s, providing a simple objective tool to assess both hair cell (HC) and nerve sensitivity. The vestibular equivalent of ECochG, termed here Electrovestibulography (EVestG), incorporates responses of the vestibular HCs and nerve. Few research groups have utilized EVestG to study vestibular function. Arguably, this is because stimulating the cochlea in isolation with sound is a trivial matter, whereas stimulating the vestibular system in isolation requires significantly more technical effort. That is, the vestibular system is sensitive to both high-level sound and bone-conducted vibrations, but so is the cochlea, and gross electrical responses of the inner ear to such stimuli can be difficult to interpret. Fortunately, several simple techniques can be employed to isolate vestibular electrical responses. Here, we review the literature underpinning gross vestibular nerve and HC responses, and we discuss the nomenclature used in this field. We also discuss techniques for recording EVestG in experimental animals and humans and highlight how EVestG is furthering our understanding of the vestibular system

OBJECTIVES AND FUNCTIONS OF THE LATTER-DAY SAINTS INSTITUTES OF RELIGION. - Page 32

[This corrects the article DOI: 10.1371/journal.pone.0225650.]

The Current State of Proteomics and Metabolomics for Inner Ear Health and Disease

Characterising inner ear disorders represents a significant challenge due to a lack of reliable experimental procedures and identified biomarkers. It is also difficult to access the complex microenvironments of the inner ear and investigate specific pathological indicators through conventional techniques. Omics technologies have the potential to play a vital role in revolutionising the diagnosis of ear disorders by providing a comprehensive understanding of biological systems at various molecular levels. These approaches reveal valuable information about biomolecular signatures within the cochlear tissue or fluids such as the perilymphatic and endolymphatic fluid. Proteomics identifies changes in protein abundance, while metabolomics explores metabolic products and pathways, aiding the characterisation and early diagnosis of diseases. Although there are different methods for identifying and quantifying biomolecules, mass spectrometry, as part of proteomics and metabolomics analysis, could be utilised as an effective instrument for understanding different inner ear disorders. This study aims to review the literature on the application of proteomic and metabolomic approaches by specifically focusing on Meniere’s disease, ototoxicity, noise-induced hearing loss, and vestibular schwannoma. Determining potential protein and metabolite biomarkers may be helpful for the diagnosis and treatment of inner ear problems

A Single Fast Test for Semicircular Canal Dehiscence—oVEMP n10 to 4000 Hz—Depends on Stimulus Rise Time

As previously reported, a single test measuring oVEMP n10 to 4000 Hz stimuli (bone-conducted vibration (BCV) or air-conducted sound (ACS)) provides a definitive diagnosis of semicircular canal dehiscence (SCD) in 22 CT-verified patients, with a sensitivity of 1.0 and specificity of 1.0. This single short screening test has great advantages of speed, minimizing testing time, and the exposure of patients to stimulation. However, a few studies of the 4000 Hz test for SCD have reported sensitivity and specificity values which are slightly less than reported previously. We hypothesized that the rise time of the stimulus is important for detecting the oVEMP n10 to 4000 Hz, similarly to what we had shown for 500 and 750 Hz BCV. We measured oVEMP n10 in 15 patients with CT-verified SCD in response to 4000 Hz ACS or BCV stimuli with rise times of 0, 1, and 2 ms. As a result, increasing the rise time of the stimulus reduced the oVEMP n10 amplitude. This outcome is expected from the physiological evidence of guinea pig primary vestibular afferents, which are activated by sound or vibration. Therefore, for clinical VEMP testing, short rise times are optimal (preferably 0 ms)

Using macular velocity measurements to relate parameters of bone conduction to vestibular compound action potential responses

Abstract To examine mechanisms responsible for vestibular afferent sensitivity to transient bone conducted vibration, we performed simultaneous measurements of stimulus-evoked vestibular compound action potentials (vCAPs), utricular macula velocity, and vestibular microphonics (VMs) in anaesthetized guinea pigs. Results provide new insights into the kinematic variables of transient motion responsible for triggering mammalian vCAPs, revealing synchronized vestibular afferent responses are not universally sensitive to linear jerk as previously thought. For short duration stimuli (< 1 ms), the vCAP increases magnitude in close proportion to macular velocity and temporal bone (linear) acceleration, rather than other kinematic elements. For longer duration stimuli, the vCAP magnitude switches from temporal bone acceleration sensitive to linear jerk sensitive while maintaining macular velocity sensitivity. Frequency tuning curves evoked by tone-burst stimuli show vCAPs increase in proportion to onset macular velocity, while VMs increase in proportion to macular displacement across the entire frequency bandwidth tested between 0.1 and 2 kHz. The subset of vestibular afferent neurons responsible for synchronized firing and vCAPs have been shown previously to make calyceal synaptic contacts with type I hair cells in the striolar region of the epithelium and have irregularly spaced inter-spike intervals at rest. Present results provide new insight into mechanical and neural mechanisms underlying synchronized action potentials in these sensitive afferents, with clinical relevance for understanding the activation and tuning of neurons responsible for driving rapid compensatory reflex responses

Development of Ultrasensitive Biomimetic Auditory Hair Cells Based on Piezoresistive Hydrogel Nanocomposites

With an ageing population, hearing disorders are predicted to rise considerably in the following decades. Thus, developing a new class of artificial auditory system has been highlighted as one of the most exciting research topics for biomedical applications. Herein, a design of a biocompatible piezoresistive-based artificial hair cell sensor is presented consisting of a highly flexible and conductive polyvinyl alcohol (PVA) nanocomposite with vertical graphene nanosheets (VGNs). The bilayer hydrogel sensor demonstrates excellent performance to mimic biological hair cells, responding to acoustic stimuli in the audible range between 60 Hz to 20 kHz. The sensor output demonstrates stable mid-frequency regions (∼4–9 kHz), with the greatest sensitivity as high frequencies (∼13–20 kHz). This is somewhat akin to the mammalian auditory system, which has remarkable sensitivity and sharp tuning at high frequencies due to the “active process”. This work validates the PVA/VGN sensor as a potential candidate to play a similar functional role to that of the cochlear hair cells, which also operate over a wide frequency domain in a viscous environment. Further characterizations of the sensor show that increasing the sound amplitude results in higher responses from the sensor while taking it to the depth drops the sensor outputs due to attenuation of sound in water. Meanwhile, the acoustic pressure distribution of sound waves is predicted through finite element analysis, whereby the numerical results are in perfect agreement with experimental data. This proof-of-concept work creates a platform for the future design of susceptible, flexible biomimetic sensors to closely mimic the biological cochlea

Stochastic and sinusoidal electrical stimuli increase the irregularity and gain of Type A and B medial vestibular nucleus neurons, in vitro

Galvanic vestibular stimulation (GVS) has been shown to improve vestibular function potentially via stochastic resonance, however, it remains unknown how central vestibular nuclei process these signals. In vivo work applying electrical stimuli to the vestibular apparatus of animals has shown changes in neuronal discharge at the level of the primary vestibular afferents and hair cells. This study aimed to determine the cellular impacts of stochastic, sinusoidal, and stochastic + sinusoidal stimuli on individual medial vestibular nucleus (MVN) neurons of male and female C57BL/6 mice. All stimuli increased the irregularity of MVN neuronal discharge, while differentially affecting neuronal gain. This suggests that the heterogeneous MVN neuronal population (marked by differential expression of ion channels), may influence the impact of electrical stimuli on neuronal discharge. Neuronal subtypes showed increased variability of neuronal firing, where Type A and B neurons experienced the largest gain changes in response to stochastic and sinusoidal stimuli. Type C neurons were the least affected regarding neuronal firing variability and gain changes. The membrane potential (MP) of neurons was altered by sinusoidal and stochastic + sinusoidal stimuli, with Type B and C neuronal MP significantly affected. These results indicate that GVS-like electrical stimuli impact MVN neuronal discharge differentially, likely as a result of heterogeneous ion channel expression