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.

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.

A Review of Neural Data and Modelling to Explain How a Semicircular Canal Dehiscence (SCD) Causes Enhanced VEMPs, Skull Vibration Induced Nystagmus (SVIN), and the Tullio Phenomenon.

Angular acceleration stimulation of a semicircular canal causes an increased firing rate in primary canal afferent neurons that result in nystagmus in healthy adult animals. However, increased firing rate in canal afferent neurons can also be caused by sound or vibration in patients after a semicircular canal dehiscence, and so these unusual stimuli will also cause nystagmus. The recent data and model by Iversen and Rabbitt show that sound or vibration may increase firing rate either by neural activation locked to the individual cycles of the stimulus or by slow changes in firing rate due to fluid pumping ("acoustic streaming"), which causes cupula deflection. Both mechanisms will act to increase the primary afferent firing rate and so trigger nystagmus. The primary afferent data in guinea pigs indicate that in some situations, these two mechanisms may oppose each other. This review has shown how these three clinical phenomena-skull vibration-induced nystagmus, enhanced vestibular evoked myogenic potentials, and the Tullio phenomenon-have a common tie: they are caused by the new response of semicircular canal afferent neurons to sound and vibration after a semicircular canal dehiscence.

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 bone-conducted Tullio phenomenon-A bridge to understand skull vibration induced nystagmus in superior canal dehiscence.

Nystagmus produced in response to air-conducted sound (ACS) stimulation-the Tullio phenomenon-is well known in patients with a semicircular canal (SCC) dehiscence (SCD). Here we consider the evidence that bone-conducted vibration (BCV) is also an effective stimulus for generating the Tullio phenomenon. We relate the clinical evidence based on clinical data extracted from literature to the recent evidence about the physical mechanism by which BCV may cause this nystagmus and the neural evidence confirming the likely mechanism. The hypothetical physical mechanism by which BCV activates SCC afferent neurons in SCD patients is that traveling waves are generated in the endolymph, initiated at the site of the dehiscence. We contend that the nystagmus and symptoms observed after cranial BCV in SCD patients is a variant of Skull Vibration Induced Nystagmus (SVIN) used to identify unilateral vestibular loss (uVL) with the major difference being that in uVL the nystagmus beats away from the affected ear whereas in Tullio to BCV the nystagmus beats usually toward the affected ear with the SCD. We suggest that the cause of this difference is a cycle-by-cycle activation of SCC afferents from the remaining ear, which are not canceled centrally by simultaneous afferent input from the opposite ear, because of its reduced or absent function in uVL. In the Tullio phenomenon, this cycle-by-cycle neural activation is complemented by fluid streaming and thus cupula deflection caused by the repeated compression of each cycle of the stimuli. In this way, the Tullio phenomenon to BCV is a version of skull vibration-induced nystagmus.

The Relationship between the Subjective Visual Horizontal and Ocular Vestibular Evoked Myogenic Potentials in Acute Vestibular Neuritis.

OBJECT: Vestibular evoked myogenic potentials (VEMPs) and the subjective visual horizontal (SVH) (or vertical [SVV]) have both been considered tests of otolith function: ocular-VEMPs (oVEMPs) utricular function, cervical VEMPs (cVEMPs) saccular function. Some studies have reported association between decreased oVEMPs and SVH, whereas others have not. DESIGN: A retrospective study of test results. SETTING: A tertiary, neuro-otology clinic, Royal Prince Alfred Hospital, Sydney, Australia. METHOD: We analyzed results in 130 patients with acute vestibular neuritis tested within 5 days of onset. We sought correlations between the SVH, oVEMPs, and cVEMPs to air-conducted (AC) and bone-conducted (BC) stimulation. RESULTS: The SVH deviated to the side of lesion, in 123 of the 130 AVN patients, by 2.5 to 26.7 degrees. Ninety of the AVN patients (70%) had abnormal oVEMPs to AC, BC or both stimuli, on the AVN side (mean asymmetry ratio ± SD [SE]): (64 ± 45.0% [3.9]). Forty-three of the patients (35%) had impaired cVEMPs to AC, BC or both stimuli, on the AVN side, [22 ± 41.6% (4.1)]. The 90 patients with abnormal oVEMP values also had abnormal SVH. Correlations revealed a significant relationship between SVH offset and oVEMP asymmetry (r = 0.80, p < 0.001) and a weaker relationship between SVH offset and cVEMP asymmetry (r = 0.56, p < 0.001). CONCLUSIONS: These results indicate that after an acute unilateral vestibular lesion, before there has been a chance for vestibular compensation to occur, there is a significant correlation between the SVH, and oVEMP results. The relationship between SVH offset and oVEMP amplitude suggests that both tests measure utricular function.

A review of the geometrical basis and the principles underlying the use and interpretation of the video head impulse test (vHIT) in clinical vestibular testing.

This paper is concerned mainly with the assumptions underpinning the actual testing procedure, measurement, and interpretation of the video head impulse test-vHIT. Other papers have reported in detail the artifacts which can interfere with obtaining accurate eye movement results, but here we focus not on artifacts, but on the basic questions about the assumptions and geometrical considerations by which vHIT works. These matters are crucial in understanding and appropriately interpreting the results obtained, especially as vHIT is now being applied to central disorders. The interpretation of the eye velocity responses relies on thorough knowledge of the factors which can affect the response-for example the orientation of the goggles on the head, the head pitch, and the contribution of vertical canals to the horizontal canal response. We highlight some of these issues and point to future developments and improvements. The paper assumes knowledge of how vHIT testing is conducted.

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.

First evidence of the link between internal and external structure of the human inner ear otolith system using 3D morphometric modeling.

Our sense of balance is among the most central of our sensory systems, particularly in the evolution of human positional behavior. The peripheral vestibular system (PVS) comprises the organs responsible for this sense; the semicircular canals (detecting angular acceleration) and otolith organs (utricle and saccule; detecting linear acceleration, vibration, and head tilt). Reconstructing vestibular evolution in the human lineage, however, is problematic. In contrast to considerable study of the canals, relationships between external bone and internal membranous otolith organs (otolith system) remain largely unexplored. This limits our understanding of vestibular functional morphology. This study combines spherical harmonic modeling and landmark-based shape analyses to model the configuration of the human otolith system. Our approach serves two aims: (1) test the hypothesis that bony form covaries with internal membranous anatomy; and (2) create a 3D morphometric model visualizing bony and membranous structure. Results demonstrate significant associations between bony and membranous tissues of the otolith system. These data provide the first evidence that external structure of the human otolith system is directly related to internal anatomy, suggesting a basic biological relationship. Our results visualize this structural relationship, offering new avenues into vestibular biomechanical modeling and assessing the evolution of the human balance system.

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).

Insights into Inner Ear Function and Disease Through Novel Visualization of the Ductus Reuniens, a Seminal Communication Between Hearing and Balance Mechanisms.

The sensory end-organs responsible for hearing and balance in the mammalian inner ear are connected via a small membranous duct known as the ductus reuniens (also known as the reuniting duct (DR)). The DR serves as a vital nexus linking the hearing and balance systems by providing the only endolymphatic connection between the cochlea and vestibular labyrinth. Recent studies have hypothesized new roles of the DR in inner ear function and disease, but a lack of knowledge regarding its 3D morphology and spatial configuration precludes testing of such hypotheses. We reconstructed the 3D morphology of the DR and surrounding anatomy using osmium tetroxide micro-computed tomography and digital visualizations of three human inner ear specimens. This provides a detailed, quantitative description of the DR's morphology, spatial relationships to surrounding structures, and an estimation of its orientation relative to head position. Univariate measurements of the DR, inner ear, and cranial planes were taken using the software packages 3D Slicer and Zbrush. The DR forms a narrow, curved, flattened tube varying in lumen size, shape, and wall thickness, with its middle third being the narrowest. The DR runs in a shallow bony sulcus superior to the osseus spiral lamina and adjacent to a ridge of bone that we term the "crista reuniens" oriented posteromedially within the cranium. The DR's morphology and structural configuration relative to surrounding anatomy has important implications for understanding aspects of inner ear function and disease, particularly after surgical alteration of the labyrinth and potential causative factors for Ménière's disease.

Why Should Constant Stimulation of Saccular Afferents Modify the Posture and Gait of Patients with Bilateral Vestibular Dysfunction? The Saccular Substitution Hypothesis.

An ongoing EU Horizon 2020 Project called BionicVEST is investigating the effect of constant electrical stimulation (ES) of the inferior vestibular nerve in patients with bilateral vestibular dysfunction (BVD). The evidence is that constant ES results in improved postural stability and gait performance, and so the question of central importance concerns how constant ES of mainly saccular afferents in these BVD patients could cause this improved performance. We suggest that the constant ES substitutes for the absent saccular neural input to the vestibular nuclei and the cerebellum in these BVD patients and indirectly via these structures to other structures, which have been of great recent interest in motor control. One target area, the anterior midline cerebellum (the uvula), has recently been targeted as a location for deep-brain stimulation in human patients to improve postural stability and gait. There are projections from midline cerebellum to basal ganglia, including the striatum, which are structures involved in the initiation of gait. It may be that the effect of this activation of peripheral saccular afferent neurons is analogous to the effect of deep-brain stimulation (DBS) by electrodes in basal ganglia acting to help alleviate the symptoms of patients with Parkinson's disease.

Three-dimensional visualization of the human membranous labyrinth: The membrana limitans and its role in vestibular form.

The inner ear contains the end organs for balance (vestibular labyrinth) and hearing (cochlea). The vestibular labyrinth is comprised of the semicircular canals (detecting angular acceleration) and otolith organs (utricle and saccule, which detect linear acceleration and head tilt relative to gravity). Lying just inferior to the utricle is the membranous membrana limitans (ML). Acting as a keystone to vestibular geometry, the ML provides support for the utricular macula and acts as a structural boundary between the superior (pars superior) and inferior (pars inferior) portions of the vestibular labyrinth. Given its importance in vestibular form, understanding ML morphology is valuable in establishing the spatial organization of other vestibular structures, particularly the utricular macula. Knowledge of the 3D structure and variation of the ML, however, remain elusive. Our study addresses this knowledge gap by visualizing, in 3D, the ML and surrounding structures using micro-CT data. By doing so, we attempt to clarify: (a) the variation of ML shape; (b) the reliability of ML attachment sites; and (c) the spatial relationship of the ML to the stapes footplate using landmark-based Generalized Procrustes, Principal Component and covariance analyses. Results indicate a consistent configuration of three distinct bony ML attachments including an anterolateral, medial, and posterior attachment which all covary with bony structure. Our results set the stage for further understanding into vestibular and more specifically, utricular macula spatial configuration within the human head, offering the potential to aid in clinical and evolutionary studies which rely on a 3D understanding of vestibular spatial configuration.

Vestibular semicircular canal function as detected by video Head Impulse Test (vHIT) is essentially unchanged in people with Parkinson's disease compared to healthy controls.

BACKGROUND: Parkinson's disease (PD) is a common multi-system neurodegenerative disorder with possible vestibular system dysfunction, but prior vestibular function test findings are equivocal. OBJECTIVE: To report and compare vestibulo-ocular reflex (VOR) gain as measured by the video head impulse test (vHIT) in participants with PD, including tremor dominant and postural instability/gait dysfunction phenotypes, with healthy controls (HC). METHODS: Forty participants with PD and 40 age- and gender-matched HC had their vestibular function assessed. Lateral and vertical semicircular canal VOR gains were measured with vHIT. VOR canal gains between PD participants and HC were compared with independent samples t-tests. Two distinct PD phenotypes were compared to HC using Tukey's ANOVA. The relationship of VOR gain with PD duration, phenotype, severity and age were investigated using logistic regression. RESULTS: There were no significant differences between groups in vHIT VOR gain for lateral or vertical canals. There was no evidence of an effect of PD severity, phenotype or age on VOR gains in the PD group. CONCLUSION: The impulsive angular VOR pathways are not significantly affected by the pathophysiological changes associated with mild to moderate PD.

The Neural Basis of Skull Vibration Induced Nystagmus (SVIN).

I list a summary of the major clinical observations of SVIN in patients with total unilateral vestibular loss (TUVL) and show how basic results from neurophysiology can explain these clinical observations. The account integrates results from single neuron recordings of identified semicircular canal and otolith afferent neurons in guinea pigs in response to low frequency skull vibration with evidence of the eye movement response in cats to selective semicircular canal stimulation (both individual and combined) and a simple model of nystagmus generation to show how these results explain most of the major characteristics of SVIN.

Using virtual reality to assess vestibulo-visual interaction in people with Parkinson's disease compared to healthy controls.

People with Parkinson's disease (PD) have increased visual dependency for balance and suspected vestibular dysfunction. Immersive virtual reality (VR) allows graded manipulation of visual sensory inputs during balance tasks, and hence VR coupled with portable force platforms have emerged as feasible, affordable, and validated tools for assessing sensory-motor integration of balance. This study aims to determine (i) how people with PD perform on a VR-based visual perturbation standing balance task compared to healthy controls (HC), and (ii) whether balance performance is influenced by vestibular function, when other known factors are controlled for. This prospective observational study compared the balance performance under varying sensory conditions in 40 people with mild to moderate PD with 40 age-matched HC. Vestibular function was assessed via Head Impulse Test (HIMP), cervical and ocular vestibular evoked myogenic potentials (cVEMPs and oVEMPs) and subjective visual vertical (SVV). Regression analyses were used to determine associations between VR balance performance on firm and foam surfaces with age, group, vestibular function, and lower limb proprioception. PD failed at significantly lower levels of visual perturbation than HC on both surfaces. In PD, greater disease severity was significantly associated with lower fall thresholds on both surfaces. Multiple PD participants failed prior to visual perturbation on foam. On firm, PD had a greater visual dependency. Increasing age, impaired proprioception, impaired SVV, abnormal HIMP and cVEMP scores were associated with worse balance performance. The multivariate model containing these factors explained 29% of the variability in balance performance on both surfaces. Quantitative VR-based balance assessment is safe and feasible in PD. Balance performance on both surfaces was associated with age, HIMP abnormality and proprioception.

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.

Vestibular contributions to the Romberg test: Testing semicircular canal and otolith function.

Normal stance relies on three sensory inputs: vision, proprioception and vestibular function. The Romberg test, trying to stand with feet together and eyes closed, is familiar to every medical student as a test of distal proprioceptive impairment. It remains the best known of Romberg's many remarkable contributions to clinical neurology. In Romberg's time almost nothing was known about the function of the vestibular system. We now know that standing with the eyes closed on a compliant rather than a firm surface is more a test of vestibular than proprioceptive function. Peripheral vestibular function tests in clinical use today all rely on measurements of oligosynaptic brainstem reflexes. Short-latency eye rotations in response to rapid, brief head rotations (head impulses) give an accurate, robust and reproducible measure of the function of any and each of the six semicircular canals. Short-latency evoked potentials from sternomastoid and inferior oblique muscles in response to loud clicks or skull taps (vestibular evoked myogenic potentials) give an accurate and reproducible measure of the function of each and any of the four otolith organs. In the present paper, we briefly review what is now known about the anatomy and physiology of the peripheral receptors and brainstem pathways mediating these reflexes and examine how this knowledge can help interpret the Romberg test.