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Resting discharge pattern and response to stimulation of an irregular and a regular afferent. (A) Time series of an irregular otolith neuron during stimulation by 500 Hz bone-conducted vibration (BCV) and air-conducted sound (ACS). The top trace (a) shows the command voltage, indicating when the stimulus is on. The second trace shows the action potentials by extracellular recording. The three bottom traces (x, y, z) show the triaxial accelerometer recording of the stimulus. The left panel is an example of response to BCV stimulation and the right of the response to ACS stimulation of the same neuron, showing it is clearly activated by both stimulus types. Note the scale of stimulus intensity in g at the left margin between traces x and y. The irregular resting discharge is seen before stimulus onset, followed by a large increase in firing during both BCV and ACS. (B) Time series of a regular semicircular canal neuron during stimulation by BCV and ACS as above. The regular discharge is seen before the stimulus onset. The stimuli are far stronger than in panel (A), but there is no evidence of activation of this regular neuron by these strong stimuli. From Ref. (19), Curthoys and Vulovic, © Springer-Verlag, 2010, reproduced with permission of Springer.
Source publication
Otolithic afferents with regular resting discharge respond to gravity or low-frequency linear accelerations, and we term these the static or sustained otolithic system. However, in the otolithic sense organs, there is anatomical differentiation across the maculae and corresponding physiological differentiation. A specialized band of receptors calle...
Citations
... Multiple lines of evidence indicate that VsEPs are generated by calyx-bearing afferents in the striolar region (Jones et al., 2015;Curthoys et al., 2017;Lee et al., 2017;Ono et al., 2020). ...
The inner ear houses two sensory modalities: the hearing organ, located in the cochlea, and the balance organs, located throughout the vestibular regions of the ear. Both hearing and vestibular sensory regions are composed of similar cell types, including hair cells and associated supporting cells. Recently, we showed that Notch1 is required for maintaining supporting cell survival postnatally during cochlear maturation. However, it is not known whether Notch1 plays a similar role in the balance organs of the inner ear. To characterize the role of Notch during vestibular maturation, we conditionally deleted Notch1 from Sox2 -expressing cells of the vestibular organs in the mouse at P0/P1. Histological analyses showed a dramatic loss of supporting cells accompanied by an increase in type II hair cells without cell death, indicating the supporting cells are converting to hair cells in the maturing vestibular regions. Analysis of 6-week old animals indicate that the converted hair cells survive, despite the reduction of supporting cells. Interestingly, measurements of vestibular sensory evoked potentials (VsEPs), known to be generated in the striolar regions of the vestibular afferents in the maculae, failed to show a response, indicating that NOTCH1 expression is critical for striolar function postnatally. Consistent with this, we find that the specialized type I hair cells in the striola fail to develop the complex calyces typical of these cells. These defects are likely due to the reduction in supporting cells, which have previously been shown to express factors critical for the striolar region. Similar to other mutants that lack proper striolar development, Notch1 mutants do not exhibit typical vestibular behaviors such as circling and head shaking, but do show difficulties in some vestibular tests, including the balance beam and forced swim test. These results indicate that, unlike the hearing organ in which the supporting cells undergo cell death, supporting cells in the balance regions retain the ability to convert to hair cells during maturation, which survive into adulthood despite the reduction in supporting cells.
Significance Statement
Notch signaling regulates the cell fate choices between hair cells and supporting cells during inner ear development. However, little is known about how Notch functions in the mammalian vestibular sensory organs once cell fate has been determined. Here, we examine the role of Notch1 in the maturing balancing organs. We show that deletion of Notch1 results in vestibular physiological and behavioral dysfunction by 3 months of age. Histological analyses reveal supporting cells are converting to type II hair cells in the utricle, and despite a loss of supporting cells, the hair cells survive to adulthood. Additionally, the striolar type I hair cells important for generating a VsEP response are decreased in number and not innervated properly. These results show that Notch continues to function in maintaining supporting cell identity in the vestibular organs postnatally, which may be important in strategies for hair cell regeneration.
... This different pattern of stimulation is related to the morphology of the hair cell receptors. Type I receptors have short hair bundles that do not reach the gelatinous layer covering the hair cells, but type II receptors have long projections protruding into the gelatinous layer covered by the crystals of dense otoconia [3]. Because of their short projections, type I receptors are sensitive to higher 2 frequency stimulation like sound and vibration while type II receptors are more responsive to low frequency linear acceleration or static tilt against the constant pull of gravity because of the high density of otoconia on the hair cell projections (for review see [2,3]). ...
... Type I receptors have short hair bundles that do not reach the gelatinous layer covering the hair cells, but type II receptors have long projections protruding into the gelatinous layer covered by the crystals of dense otoconia [3]. Because of their short projections, type I receptors are sensitive to higher 2 frequency stimulation like sound and vibration while type II receptors are more responsive to low frequency linear acceleration or static tilt against the constant pull of gravity because of the high density of otoconia on the hair cell projections (for review see [2,3]). ...
... The unique anatomical characteristics of hair cells highlight the significance of otoconia in facilitating the function of type II afferents in particular. These afferents maintain a consistent baseline activity and are sensitive to gravity or low-frequency linear accelerations, forming what is known as the static or sustained otoconial system [3]. A good example of a test using the sustained system is the response to maintained head tilt. ...
The overall contribution of otolith receptors to eye movements, postural control and perceptual functions is the basis for clinical testing of otolith function. With such wide range of contributions, it is important to recognize that the functional outcomes of these tests may vary depending on the specific method employed to stimulate the hair cells. In this article, we review common methods used for clinical evaluation of otolith function and how different aspects of physiology may affect the functional measurements in these tests. We compare the properties and performance of various clinical tests with the emphasis on the newly-developed video ocular counter roll (vOCR), measurement of ocular torsion on fundus photography, and subjective visual vertical or horizontal (SVV/SVH) testing.
... Within the sensory epithelium of each vestibular end-organ is a central region containing type I sensory hair cells. In the otolith organs (the saccule and utricle) this central region, the striola, is innervated by calyx-only ganglion cells (irregular afferent fibers) (Desmadryl and Dechesne, 1992;Eatock et al., 2008;Curthoys et al., 2017;Eatock 2018). These irregular fibers detect rapid linear head motion and therefore are responsive to a jerk stimulus. ...
Reliable methods for repetitive and longitudinal assessment of central vestibular pathway function in vivo are rather limited. Manganese-enhanced magnetic resonance imaging (MEMRI) has been used in various sensory systems to evaluate neuronal activity in central pathways, but MEMRI assessment of central vestibular pathways has been minimal. The present study addressed this gap in knowledge by assessing whether Mn2+ can be taken up in an activity-dependent manner through voltage-gated calcium channels in the vestibular nuclear complex (VNC) and the vestibulocerebellum (VeCb) of rats with and without mild linear acceleration stimulation. R1 maps were collected prior to, one day after, and two weeks after Mn2+ administration in stimulated and non-stimulated rats. Analysis of MRI R1 values showed that one day after Mn2+ administration the VNC and VeCb had significantly greater R1 values that returned to baseline levels after two weeks. Non-stimulated rats had greater R1 values than stimulated rats. Mid rostro-caudal sections of the VNC had greater R1 values than rostral and caudal VNC sections. R1 values also indicated that Mn2+ was differentially taken up across subdivisions of the VNC and VeCb. These results correlate well with expected patterns of neuronal activity after linear acceleration. MEMRI is a sensitive tool that may be used to evaluate activity patterns in central vestibular nuclei, proving useful for studying underlying mechanisms of central vestibular dysfunction.
... Similarly, measurements from toadfish primary afferents show high phaselocking up to 1 kHz (Highstein et al., 1996). Curthoys et al. (2006), Curthoys et al. (2017), and Curthoys et al. (2018) have conducted further investigations into utricle mechanics, fluid dynamics, and the neuroepithelial layer to address the neural basis for phase locking in utricular afferents in response to high-frequency stimuli. Studies by Pastras et al. (2017Pastras et al. ( , 2023 recording utricular vestibular microphonics and on the mathematical model of excitation of the utricular macula, provide additional support to these results, showing that air-conducted stimuli can indeed produce responses in mammalian receptors at such high frequencies. ...
Introduction
Cervical vestibular evoked myogenic potentials (cVEMPs) provide an objective measure of the integrity of the sacculo-collic pathway leading to their widespread use as a clinical tool in the diagnostic vestibular test battery. Though the application of cVEMPs in preclinical models to assess vestibular function, as performed in relevant clinical populations, remains limited. The present study aimed to establish a rodent model of cVEMP with standardized methods and protocols, examine the neural basis of the responses, and characterize and validate important features for interpretation and assessment of vestibular function.
Methods
We compared air-conducted sound (ACS)-evoked VEMPs from the sternocleidomastoid muscles in naïve Brown Norway rats. A custom setup facilitated repeatable and reliable measurements which were carried out at multiple intensities with ACS between 1 and 16 kHz and over 7 days. The myogenic potentials were identified by the presence of a positive (P1)-negative (N1) waveform at 3–5 ms from the stimulus onset. Threshold, amplitude, and latency were compared with intensity- and frequency-matched responses within and between animals.
Results
cVEMP responses were repeatedly evoked with stimulus intensities between 50–100 dB SPL with excellent test-retest reliability and across multiple measurements over 7 days for all frequencies tested. Suprathreshold, cVEMP responses at 90 dB SPL for 6–10 kHz stimuli demonstrated significantly larger amplitudes ( p < 0.01) and shorter latencies ( p < 0.001) compared to cVEMP responses for 1–4 kHz stimuli. Latency of cVEMP showed sex-dependent variability, but no significant differences in threshold or amplitude between males and females was observed.
Discussion
The results provide a replicable and reliable setup, test protocol, and comprehensive characterization of cVEMP responses in a preclinical model which can be used in future studies to elucidate pathophysiological characteristics of vestibular dysfunctions or test efficacy of therapeutics.
... We asked whether other funcLonal response metrics might be altered by the loss of M3mAChRs. VesLbular sensory-evoked potenLals (VsEPs) are compound acLon potenLal in response to linear acceleraLon of the head and they are thought to originate in irregularly-discharging calyx-bearing afferents (Curthoys et al., 2019;Curthoys et al., 2017;Jones et al., 2011;Jones et al., 2015;Lee et al., 2017;Ono et al., 2020). So, we recorded VsEPs in our control, M3Het, and M3KO animals to evaluate the funcLonal impact of a blunted EVS-mediated slow excitaLon in irregular afferents. ...
The peripheral vestibular system detects head position and movement through activation of vestibular hair cells (HCs) in vestibular end organs. HCs transmit this information to the CNS by way of primary vestibular afferent neurons. The CNS, in turn, modulates HCs and afferents via the efferent vestibular system (EVS) through activation of cholinergic signaling mechanisms. In mice, we previously demonstrated that activation of muscarinic acetylcholine receptors (mAChRs), during EVS stimulation, gives rise to a slow excitation that takes seconds to peak and tens of seconds to decay back to baseline. This slow excitation is mimicked by muscarine and ablated by the non-selective mAChR blockers scopolamine, atropine, and glycopyrrolate. While five distinct mAChRs (M1-M5) exist, the subtype(s) driving EVS-mediated slow excitation remain unidentified and details on how these mAChRs alter vestibular function is not well understood. The objective of this study is to characterize which mAChR subtypes drive the EVS-mediated slow excitation, and how their activation impacts vestibular physiology and behavior. In C57Bl/6J mice, M3mAChR antagonists were more potent at blocking slow excitation than M1mAChR antagonists, while M2/M4 blockers were ineffective. While unchanged in M2/M4mAChR double KO mice, EVS-mediated slow excitation in M3 mAChR-KO animals were reduced or absent in irregular afferents but appearing unchanged in regular afferents. In agreement, vestibular sensory-evoked potentials, known to originate from irregular afferents, were much less enhanced by mAChR activation in M3mAChR-KO mice compared to controls. Finally, M3mAChR-KO mice display distinct behavioral phenotypes in open field activity, and thermal profiles, and balance beam and forced swim test. M3mAChRs mediate efferent-mediated slow excitation in irregular afferents, while M1mAChRs may drive the same process in regular afferents.
... Table 1 is a summary of the major clinical observations after SCD and their probable neural bases. Enhanced oVEMP to 500 Hz or clicks (ACS or BCV) [30] Cycle-by-cycle phase-locked activation of irregular canal afferent neurons to ACS and BCV after SCD to 500 Hz [2,3,8,15,[23][24][25]33,[45][46][47][48][49] Enhanced oVEMP to very high-frequency ACS or BCV (4000 Hz) [48,50] Cycle-by-cycle phase-locked activation of irregular canal afferent neurons to ACS and BCV to very high frequencies after SCD [21,25,45] Nystagmus and vertigo in response to maintained ACS or BCV (Tullio phenomenon). The direction of quick phases usually towards the ear with the SCD but may be opposite (determined by many factors, such as skull location of BCV stimulation (see text)) [9,[51][52][53][54] Acoustic streaming of endolymph generated by repeated compression of the semicircular duct. ...
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.
... Primary otolithic afferent neurons can be categorized into two main systems, transient vs sustained, according to the regularity of their resting discharge. Afferents with irregular resting discharge constitute the transientsystem and afferents with regular resting discharge constitute the sustained-system (35). These two parallel systems signal different characteristics of the stimulus and originate from different regions of each otolithic macula (35). ...
... Afferents with irregular resting discharge constitute the transientsystem and afferents with regular resting discharge constitute the sustained-system (35). These two parallel systems signal different characteristics of the stimulus and originate from different regions of each otolithic macula (35). For both utricular and saccular maculae, irregular afferents of the transient system synapse on type-I receptors at the striola (13,36,37) and regular afferents of the sustained system synapse on extrastriolar type-II receptors (37). ...
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.
... Extrinsic noise can also be applied during experimental or clinical manipulations to stimulate the vestibular system. This is the case of the random mechanical vibrations of the head and body (15,16), air-conducted sound associated with loud clicks or tone bursts (17,18), boneconducted vibrational waves (17,19,20), percutaneous application of galvanic currents at the mastoids (21,22), irrigation of cold or warm water or gas injection into the external auditory canal (23). ...
... Extrinsic noise can also be applied during experimental or clinical manipulations to stimulate the vestibular system. This is the case of the random mechanical vibrations of the head and body (15,16), air-conducted sound associated with loud clicks or tone bursts (17,18), boneconducted vibrational waves (17,19,20), percutaneous application of galvanic currents at the mastoids (21,22), irrigation of cold or warm water or gas injection into the external auditory canal (23). ...
... This is because humans are extremely sensitive to minute vibrations (102). Hair cells and vestibular afferents respond not only to fluid-conducted stimuli, but also to bone-conducted vibrational waves (especially irregular afferents) (17,19,20). However, mechanical vibrations can engage multiple receptors (auditory, cutaneous, muscular, visceral) in addition to the vestibular ones. ...
Noise defined as random disturbances is ubiquitous in both the external environment and the nervous system. Depending on the context, noise can degrade or improve information processing and performance. In all cases, it contributes to neural systems dynamics. We review some effects of various sources of noise on the neural processing of self-motion signals at different stages of the vestibular pathways and the resulting perceptual responses. Hair cells in the inner ear reduce the impact of noise by means of mechanical and neural filtering. Hair cells synapse on regular and irregular afferents. Variability of discharge (noise) is low in regular afferents and high in irregular units. The high variability of irregular units provides information about the envelope of naturalistic head motion stimuli. A subset of neurons in the vestibular nuclei and thalamus are optimally tuned to noisy motion stimuli that reproduce the statistics of naturalistic head movements. In the thalamus, variability of neural discharge increases with increasing motion amplitude but saturates at high amplitudes, accounting for behavioral violation of Weber’s law. In general, the precision of individual vestibular neurons in encoding head motion is worse than the perceptual precision measured behaviorally. However, the global precision predicted by neural population codes matches the high behavioral precision. The latter is estimated by means of psychometric functions for detection or discrimination of whole-body displacements. Vestibular motion thresholds (inverse of precision) reflect the contribution of intrinsic and extrinsic noise to perception. Vestibular motion thresholds tend to deteriorate progressively after the age of 40 years, possibly due to oxidative stress resulting from high discharge rates and metabolic loads of vestibular afferents. In the elderly, vestibular thresholds correlate with postural stability: the higher the threshold, the greater is the postural imbalance and risk of falling. Experimental application of optimal levels of either galvanic noise or whole-body oscillations can ameliorate vestibular function with a mechanism reminiscent of stochastic resonance. Assessment of vestibular thresholds is diagnostic in several types of vestibulopathies, and vestibular stimulation might be useful in vestibular rehabilitation.
... These firing properties arise from a multitude of factors, including number of synaptic contacts (few vs. many, respectively), shape of synaptic endings (calyx vs. bouton), size of dendritic arbors (condensed vs. extensive), and complement of ion channels present in cell membranes. The differences in spike timing regularity are known to represent different sensory encoding strategies best suited for distinct ranges of sensory information (i.e., high vs. low frequencies) (Jamali et al., 2016;Curthoys et al., 2017). ...
... Results from Tanimoto et al., 2022 indicate that striolar hair cells and interiorly located neurons in the SAG (which, according to Tanimoto et al., 2022;Liu et al., 2022, synapse on striolar hair cells) have a strong response preference to high frequency, dynamic stimulation. This functional data in zebrafish aligns with responses seen in striolar Type I hair cells and calyx-ending irregular-spiking afferents in mammals, in which this channel is specialized for encoding and transmitting high frequency sensory information (Songer and Eatock, 2013;Jamali et al., 2016;Curthoys et al., 2017). There are several key differences in the afferents in this channel: in zebrafish, there are no calyx endings and no known differences in number synaptic endings when compared to the extrastriola (Liu et al., 2022), although this has not been investigated in adult fish. ...
The vestibular system of the inner ear provides information about head motion and spatial orientation relative to gravity to ensure gaze stability, balance, and postural control. Zebrafish, like humans, have five sensory patches per ear that serve as peripheral vestibular organs, with the addition of the lagena and macula neglecta. The zebrafish inner ear can be easily studied due to its accessible location, the transparent tissue of larval fish, and the early development of vestibular behaviors. Thus, zebrafish are an excellent model for studying the development, physiology, and function of the vestibular system. Recent work has made great strides to elucidate vestibular neural circuitry in fish, tracing sensory transmission from receptors in the periphery to central computational circuits driving vestibular reflexes. Here we highlight recent work that illuminates the functional organization of vestibular sensory epithelia, innervating first-order afferent neurons, and second-order neuronal targets in the hindbrain. Using a combination of genetic, anatomical, electrophysiological, and optical techniques, these studies have probed the roles of vestibular sensory signals in fish gaze, postural, and swimming behaviors. We discuss remaining questions in vestibular development and organization that are tractable in the zebrafish model.
... 6,9 Exactly the stereocilia of a certain SH can bend the most to the kinocilium due to its unique polarity and position, which causes an increase in the impulse release of some specific afferent nerve fibers. 4,12 Based on this mechanism, the human brain can judge the position change of the head with reference to the action of head gravity. Most of the swing frequencies of the head are in the range of 0.05-1 Hz, 13 therefore, these SH cells are particularly sensitive to the swing with a frequency in this range. ...
A human vestibular system is a group of devices in the inner ear that govern the balancing movement of the head, in which the saccule is responsible for sensing gravity accelerations. Imitating the sensing principle and structure of the Sensory Hair (SH) cell in the saccule, a Bionic Sensory Hair (BSH) was developed, and 9 BSH arrays were arranged in the bionic macular at the bottom of the spherical shell to prepare a Bionic Saccule (BS). Based on the piezoelectric equation, the electromechanical theoretical models of the BSH cantilever and BS were deduced. They were subjected to impact oscillations using an exciter, and their output charges were analyzed to check their sensing ability. The results showed that BSH could sense its bending deflection, and the BS could sense its position change in the sagittal plane and in space. They exhibited a sensitivity of 1.6104 Pc s ² /m and a fast response and similar sensing principles and low resonance frequency to those of the human saccule. The BS is expected to be used in the field of robotics and clinical disease diagnosis as a part of the artificial vestibular system in the future.
