Evidence That Ultrafast Nonquantal Transmission Underlies Synchronized Vestibular Action Potential Generation.

Amniotes evolved a unique postsynaptic terminal in the inner ear vestibular organs called the calyx that receives both quantal and nonquantal (NQ) synaptic inputs from Type I sensory hair cells. The nonquantal synaptic current includes an ultrafast component that has been hypothesized to underlie the exceptionally high synchronization index (vector strength) of vestibular afferent neurons in response to sound and vibration. Here, we present three lines of evidence supporting the hypothesis that nonquantal transmission is responsible for synchronized vestibular action potentials of short latency in the guinea pig utricle of either sex. First, synchronized vestibular nerve responses are unchanged after administration of the AMPA receptor antagonist CNQX, while auditory nerve responses are completely abolished. Second, stimulus evoked vestibular nerve compound action potentials (vCAP) are shown to occur without measurable synaptic delay and three times shorter than the latency of auditory nerve compound action potentials (cCAP), relative to the generation of extracellular receptor potentials. Third, paired-pulse stimuli designed to deplete the readily releasable pool (RRP) of synaptic vesicles in hair cells reveal forward masking in guinea pig auditory cCAPs, but a complete lack of forward masking in vestibular vCAPs. Results support the conclusion that the fast component of nonquantal transmission at calyceal synapses is indefatigable and responsible for ultrafast responses of vestibular organs evoked by transient stimuli.SIGNIFICANCE STATEMENT The mammalian vestibular system drives some of the fastest reflex pathways in the nervous system, ensuring stable gaze and postural control for locomotion on land. To achieve this, terrestrial amniotes evolved a large, unique calyx afferent terminal which completely envelopes one or more presynaptic vestibular hair cells, which transmits mechanosensory signals mediated by quantal and nonquantal (NQ) synaptic transmission. We present several lines of evidence in the guinea pig which reveals the most sensitive vestibular afferents are remarkably fast, much faster than their auditory nerve counterparts. Here, we present neurophysiological and pharmacological evidence that demonstrates this vestibular speed advantage arises from ultrafast NQ electrical synaptic transmission from Type I hair cells to their calyx partners.

Meniere's disease: Pathogenesis, treatments, and emerging approaches for an idiopathic bioenvironmental disorder.

Meniere's disease (MD) is a severe inner ear condition known by debilitating symptoms, including spontaneous vertigo, fluctuating and progressive hearing loss, tinnitus, and aural fullness or pressure within the affected ear. Prosper Meniere first described the origins of MD in the 1860s, but its underlying mechanisms remain largely elusive today. Nevertheless, researchers have identified a key histopathological feature called Endolymphatic Hydrops (ELH), which refers to the excessive buildup of endolymph fluid in the membranous labyrinth of the inner ear. The exact root of ELH is not fully understood. Still, it is believed to involve several biological and bioenvironmental etiological factors such as genetics, autoimmunity, infection, trauma, allergy, and new theories, such as saccular otoconia blocking the endolymphatic duct and sac. Regarding treatment, there are no reliable and definitive cures for MD. Most therapies focus on managing symptoms and improving the overall quality of patients' life. To make significant advancements in addressing MD, it is crucial to gain a fundamental understanding of the disease process, laying the groundwork for more effective therapeutic approaches. This paper provides a comprehensive review of the pathophysiology of MD with a focus on old and recent theories. Current treatment strategies and future translational approaches (with low-level evidence but promising results) related to MD are also discussed, including patents, drug delivery, and nanotechnology, that may provide future benefits to patients suffering from MD.

Potential nanotechnology-based diagnostic and therapeutic approaches for Meniere's disease.

Meniere's disease (MD) is a progressive inner ear disorder involving recurrent and prolonged episodes or attacks of vertigo with associated symptoms, resulting in a significantly reduced quality of life for sufferers. In most cases, MD starts in one ear; however, in one-third of patients, the disorder progresses to the other ear. Unfortunately, the etiology of the disease is unknown, making the development of effective treatments difficult. Nanomaterials, including nanoparticles (NPs) and nanocarriers, offer an array of novel diagnostic and therapeutic applications related to MD. NPs have specific features such as biocompatibility, biochemical stability, targetability, and enhanced visualization using imaging tools. This paper provides a comprehensive and critical review of recent advancements in nanotechnology-based diagnostic and therapeutic approaches for MD. Furthermore, the crucial challenges adversely affecting the use of nanoparticles to treat middle ear disorders are investigated. Finally, this paper provides recommendations and future directions for improving the performances of nanomaterials on theragnostic applications of MD.

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.

A review of mechanical and synaptic processes in otolith transduction of sound and vibration for clinical VEMP testing.

Older studies of mammalian otolith physiology have focused mainly on sustained responses to low-frequency (<50 Hz) or maintained linear acceleration. So the otoliths have been regarded as accelerometers. Thus evidence of otolithic activation and high-precision phase locking to high-frequency sound and vibration appears to be very unusual. However, those results are exactly in accord with a substantial body of knowledge of otolith function in fish and frogs. It is likely that phase locking of otolith afferents to vibration is a general property of all vertebrates. This review examines the literature about the activation and phase locking of single otolithic neurons to air-conducted sound and bone-conducted vibration, in particular the high precision of phase locking shown by mammalian irregular afferents that synapse on striolar type I hair cells by calyx endings. Potassium in the synaptic cleft between the type I hair cell receptor and the calyx afferent ending may be responsible for the tight phase locking of these afferents even at very high discharge rates. Since frogs and fish do not possess full calyx endings, it is unlikely that they show phase locking with such high precision and to such high frequencies as has been found in mammals. The high-frequency responses have been modeled as the otoliths operating in a seismometer mode rather than an accelerometer mode. These high-frequency otolithic responses constitute the neural basis for clinical vestibular-evoked myogenic potential tests of otolith function.

Artificial Hair Cell Sensor Based on Nanofiber-Reinforced Thin Metal Films.

Engineering artificial mechanosensory hair cells offers a promising avenue for developing diverse biosensors spanning applications from biomedicine to underwater sensing. Unfortunately, current artificial sensory hair cells do not have the ability to simultaneously achieve ultrahigh sensitivity with low-frequency threshold detection (e.g., 0.1 Hz). This work aimed to solve this gap by developing an artificial sensory hair cell inspired by the vestibular sensory apparatus, which has such functional capabilities. For device characterization and response testing, the sensory unit was inserted in a 3D printed lateral semicircular canal (LSCC) mimicking the environment of the labyrinth. The sensor was fabricated based on platinum (Pt) thin film which was reinforced by carbon nanofibers (CNFs). A Pi-shaped hair cell sensor was created as the sensing element which was tested under various conditions of simulated head motion. Results reveal the hair cell sensor displayed markedly higher sensitivity compared to other reported artificial hair cell sensors (e.g., 21.47 mV Hz-1 at 60°) and low frequency detection capability, 0.1 Hz < f < 1.5 Hz. Moreover, like the LSCC hair cells in biology, the fabricated sensor was most sensitive in a given plane of rotational motion, demonstrating features of directional sensitivity.

Wicking pumps for microfluidics.

This review describes mechanisms for pulling fluids through microfluidic devices using hydrophilic structures at the downstream end of the device. These pumps enable microfluidic devices to get out of the lab and become point-of-care devices that can be used without external pumps. We briefly summarize prior related reviews on capillary, pumpless, and passively driven microfluidics then provide insights into the fundamental physics of wicking pumps. No prior reviews have focused on wicking pumps for microfluidics. Recent progress is divided into four categories: porous material pumps, hydrogel pumps, and 2.5D- and 3D-microfabricated pumps. We conclude with a discussion of challenges and opportunities in the field, which include achieving constant flow rate, priming issues, and integration of pumps with devices.

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.

Performance of personalised prosthesis under static pressure: Numerical analysis and experimental validation.

This study investigates the performance of personalised middle ear prostheses under static pressure through a combined approach of numerical analysis and experimental validation. The sound transmission performances of both normal and reconstructed middle ears undergo changes under high positive or negative pressure within the middle ear cavity. This pressure fluctuation has the potential to result in prosthesis displacement/extrusion in patients. To optimise the design of middle ear prostheses, it is crucial to consider various factors, including the condition of the middle ear cavity in which the prosthesis is placed. The integration of computational modelling techniques with non-invasive imaging modalities has demonstrated significant promise and distinct prospects in middle ear surgery. In this study, we assessed the efficacy of Finite Element (FE) analysis in modelling the responses of both normal and reconstructed middle ears to elevated static pressure within the ear canal. The FE model underwent validation using experimental data derived from human cadaveric temporal bones before progressing to subsequent investigations. Afterwards, we assessed stapes and umbo displacements in the reconstructed middle ear under static pressure, with either a columella-type prosthesis or a prosthetic incus, closely resembling a healthy incus. Results indicated the superior performance of the prosthetic incus in terms of both sound transmission to the inner ear and stress distribution patterns on the TM, potentially lowering the risk of prosthesis displacement/extrusion. This study underscores the potential of computational analysis in middle ear surgery, encompassing aspects such as prosthesis design, predicting outcomes in ossicular chain reconstruction (OCR), and mitigating experimental costs.

Vestibular Testing-New Physiological Results for the Optimization of Clinical VEMP Stimuli.

Both auditory and vestibular primary afferent neurons can be activated by sound and vibration. This review relates the differences between them to the different receptor/synaptic mechanisms of the two systems, as shown by indicators of peripheral function-cochlear and vestibular compound action potentials (cCAPs and vCAPs)-to click stimulation as recorded in animal studies. Sound- and vibration-sensitive type 1 receptors at the striola of the utricular macula are enveloped by the unique calyx afferent ending, which has three modes of synaptic transmission. Glutamate is the transmitter for both cochlear and vestibular primary afferents; however, blocking glutamate transmission has very little effect on vCAPs but greatly reduces cCAPs. We suggest that the ultrafast non-quantal synaptic mechanism called resistive coupling is the cause of the short latency vestibular afferent responses and related results-failure of transmitter blockade, masking, and temporal precision. This "ultrafast" non-quantal transmission is effectively electrical coupling that is dependent on the membrane potentials of the calyx and the type 1 receptor. The major clinical implication is that decreasing stimulus rise time increases vCAP response, corresponding to the increased VEMP response in human subjects. Short rise times are optimal in human clinical VEMP testing, whereas long rise times are mandatory for audiometric threshold testing.

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

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.

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

Introduction: Calyx 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. Results: Transient 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. Discussion: Results 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.

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).

Recent advancements in bioelectronic devices to interface with the peripheral vestibular system.

Balance disorders affect approximately 30% of the population throughout their lives and result in debilitating symptoms, such as spontaneous vertigo, nystagmus, and oscillopsia. The main cause of balance disorders is peripheral vestibular dysfunction, which may occur as a result of hair cell loss, neural dysfunction, or mechanical (and morphological) abnormality. The most common cause of vestibular dysfunction is arguably vestibular hair cell damage, which can result from an array of factors, such as ototoxicity, trauma, genetics, and ageing. One promising therapy is the vestibular prosthesis, which leverages the success of the cochlear implant, and endeavours to electrically integrate the primary vestibular afferents with the vestibular scene. Other translational approaches of interest include stem cell regeneration and gene therapies, which aim to restore or modify inner ear receptor function. However, both of these techniques are in their infancy and are currently undergoing further characterization and development in the laboratory, using animal models. Another promising translational avenue to treating vestibular hair cell dysfunction is the potential development of artificial biocompatible hair cell sensors, aiming to replicate functional hair cells and generate synthetic 'receptor potentials' for sensory coding of vestibular stimuli to the brain. Recently, artificial hair cell sensors have demonstrated significant promise, with improvements in their output, such as sensitivity and frequency selectivity. This article reviews the history and current state of bioelectronic devices to interface with the labyrinth, spanning the vestibular implant and artificial hair cell sensors.

Summating potentials from the utricular macula of anaesthetized guinea pigs.

The Summating Potential (SP) was first recorded in the cochlea in the 1950s and represents an objective measure of cochlear hair cell function, in vivo. Despite being a regular tool in hearing research, a similar response has not yet been recorded from the vestibular system. This is mainly due to the lack of experimental techniques available to record electrical vestibular hair cell responses in isolation from the much larger cochlear potentials. Here we demonstrate the first recordings of the vestibular SP, evoked by Bone-Conducted Vibration (BCV) and Air-Conducted Sound (ACS) stimuli, in anaesthetized guinea pigs. Field potential measurements were taken from the basal surface of the utricular macula, and from the facial nerve canal following surgical or chemical ablation of the cochlea. SPs were evoked by stimuli with frequencies above ~200 Hz, and only with moderate to high intensity (~0.005-0.05 g) BCV and ACS (~120-140 dB SPL). Neural blockade abolished the Vestibular short-latency Evoked Potential (VsEP) and Vestibular Nerve Neurophonic (VNN) from the facial nerve canal recordings but did not abolish the vestibular SP nor the vestibular microphonic. Importantly, the vestibular SP was irreversibly abolished from the utricle and facial nerve canal recordings following local gentamicin application, highlighting its hair cell origin. This is the first study to record the Summating Potential from the mammalian vestibular system, in vivo, providing a novel research tool to assess vestibular hair cell function during experimental manipulations and animal models of disease.

Similarities and Differences Between Vestibular and Cochlear Systems - A Review of Clinical and Physiological Evidence.

The evoked response to repeated brief stimuli, such as clicks or short tone bursts, is used for clinical evaluation of the function of both the auditory and vestibular systems. One auditory response is a neural potential - the Auditory Brainstem Response (ABR) - recorded by surface electrodes on the head. The clinical analogue for testing the otolithic response to abrupt sounds and vibration is the myogenic potential recorded from tensed muscles - the vestibular evoked myogenic potential (VEMP). VEMPs have provided clinicians with a long sought-after tool - a simple, clinically realistic indicator of the function of each of the 4 otolithic sensory regions. We review the basic neural evidence for VEMPs and discuss the similarities and differences between otolithic and cochlear receptors and afferents. VEMPs are probably initiated by sound or vibration selectively activating afferent neurons with irregular resting discharge originating from the unique type I receptors at a specialized region of the otolithic maculae (the striola). We review how changes in VEMP responses indicate the functional state of peripheral vestibular function and the likely transduction mechanisms allowing otolithic receptors and afferents to trigger such very short latency responses. In section "ELECTROPHYSIOLOGY" we show how cochlear and vestibular receptors and afferents have many similar electrophysiological characteristics [e.g., both generate microphonics, summating potentials, and compound action potentials (the vestibular evoked potential, VsEP)]. Recent electrophysiological evidence shows that the hydrodynamic changes in the labyrinth caused by increased fluid volume (endolymphatic hydrops), change the responses of utricular receptors and afferents in a way which mimics the changes in vestibular function attributed to endolymphatic hydrops in human patients. In section "MECHANICS OF OTOLITHS IN VEMPS TESTING" we show how the major VEMP results (latency and frequency response) follow from modeling the physical characteristics of the macula (dimensions, stiffness etc.). In particular, the structure and mechanical operation of the utricular macula explains the very fast response of the type I receptors and irregular afferents which is the very basis of VEMPs and these structural changes of the macula in Menière's Disease (MD) predict the upward shift of VEMP tuning in these patients.

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.

Polymeric piezoresistive airflow sensor to monitor respiratory patterns.

Monitoring human respiratory patterns is of great importance as it gives essential information for various medical conditions, e.g. sleep apnoea syndrome and chronic obstructive pulmonary disease and asthma, etc. Herein, we have developed a polymeric airflow sensor based on nanocomposites of vertically grown graphene nanosheets (VGNs) with polydimethylsiloxane (PDMS) and explored their applications in monitoring human respiration. The sensing performance of the VGNs/PDMS nanocomposite was characterized by exposing to a range of airflow rates (20-130 l min-1), and a linear performance with high sensitivity and low response time (mostly below 1 s) was observed. To evaluate the experimental results, finite-element simulation models were developed in the COMSOL Multiphysics package. The piezoresistive properties of VGNs/PDMS thin film and fluid-solid interaction were thoroughly studied. Laser Doppler vibrometry measures of sensor tip displacement closely approximated simulated deflection results and validated the dynamic response of the sensor. By comparing the proposed sensor and some other airflow sensors in the literature, it is concluded that the VGNs/PDMS airflow sensor has excellent features in terms of sensor height, detection range and sensitivity. The potential application of the VGNs/PDMS airflow sensor in detecting the respiration pattern of human exercises like walking, jogging and running has been demonstrated.

Utricular Sensitivity during Hydrodynamic Displacements of the Macula.

To explore the effects of cochlear hair cell displacement, researchers have previously monitored functional and mechanical responses during low-frequency (LF) acoustic stimulation of the cochlea. The induced changes are believed to result from modulation of the conductance of mechano-electrical transduction (MET) channels on cochlear hair cells, along with receptor potential modulation. It is less clear how, or if, vestibular hair cell displacement affects vestibular function. Here, we have used LF (<20 Hz) hydrodynamic modulation of the utricular macula position, whilst recording functional and mechanical responses, to investigate the effects of utricular macula displacement. Measured responses included the Utricular Microphonic (UM), the vestibular short-latency evoked potential (VsEP), and laser Doppler vibrometry recordings of macular position. Over 1 cycle of the LF bias, the UM amplitude and waveform were cyclically modulated, with Boltzmann analysis suggesting a cyclic modulation of the vestibular MET gating. The VsEP amplitude was cyclically modulated throughout the LF bias, demonstrating a relative increase (~20-50 %; re baseline) and decrease (~10-20 %; re baseline), which is believed to be related to the MET conductance and vestibular hair cell sensitivity. The relationship between macular displacement and changes in UM and VsEP responses was consistent within and across animals. These results suggest that the sensory structures underlying the VsEP, often thought to be a cranial jerk-sensitive response, are at least partially sensitive to LF (and possibly static) pressures or motion. Furthermore, these results highlight the possibility that some of the vestibular dysfunction related to endolymphatic hydrops may be due to altered vestibular transduction following mechanical (or morphological) changes in the labyrinth.

Are viral-infections associated with Ménière's Disease? A systematic review and meta-analysis of molecular-markers of viral-infection in case-controlled observational studies of MD.

Despite considerable research, it remains controversial as to whether viral-infections are associated with Meniere's Disease (MD), a clinically heterogeneous set of chronic inner-ear disorders strongly associated with endolymphatic hydrops. Here, we investigated whether viral-infections are associated with MD through a systematic review and meta-analysis of observational clinical studies using molecular-diagnostics. Eligible for inclusion were case-controlled studies which ascertained molecular-determinants of past or present viral-infection through either viral nucleic acids or host serological marker in MD cases and non-MD controls. Across online databases and grey literature, we identified 210 potentially relevant articles in the English language, from which a total of 14 articles fully satisfied our eligibility criteria such that meta-groups of 611 MD-cases and 373 controls resulted. The aggregate quality of the modest-sized (14 studies) body of evidence was limited and varied considerably with regards to participant selection, matching, and ascertainment(s) and determinant(s) of viral-infection. Most data identified concerned the human cytomegalovirus (CMV), and meta-analysis of eligible studies revealed that evidence of CMV-infection was associated approximately three-fold with MD compared to controls, however the timing of the infections was indeterminate as the pooled analyses combined antiviral serological markers with viral nucleic acid markers. No association was found for any of HSV-1, -2, VZV, or EBV. Associative analyses of any viral species not aforementioned were precluded by limited data, and thus potential associations between other viral species and MD, especially other than Herpesviridae, are yet to be characterised. Overall, we have found a small association between CMV-infection and MD, however it is to be determined for what sub-groups of MD this finding may be relevant, and ideally the reported association remains would be reproduced by a greater volume of higher quality evidence.