Low-intensity ultrasound activates vestibular otolith organs through acoustic radiation force.

The present study examined the efficacy of 5 MHz low-intensity focused ultrasound (LiFU) as a stimulus to remotely activate inner ear vestibular otolith organs. The otolith organs are the primary sensory apparati responsible for detecting orientation of the head relative to gravity and linear acceleration in three-dimensional space. These organs also respond to loud sounds and vibration of the temporal bone. The oyster toadfish, Opsanus tau, was used to facilitate unobstructed acoustic access to the otolith organs in vivo. Single-unit responses to amplitude-modulated LiFU were recorded in afferent neurons identified as innervating the utricle or the saccule. Neural responses were equivalent to direct mechanical stimulation, and arose from the nonlinear acoustic radiation force acting on the otolithic mass. The magnitude of the acoustic radiation force acting on the otolith was measured ex vivo. Results demonstrate that LiFU stimuli can be tuned to mimic directional forces occurring naturally during physiological movements of the head, loud air conducted sound, or bone conducted vibration.

Neuronal thresholds and choice-related activity of otolith afferent fibers during heading perception.

How activity of sensory neurons leads to perceptual decisions remains a challenge to understand. Correlations between choices and single neuron firing rates have been found early in vestibular processing, in the brainstem and cerebellum. To investigate the origins of choice-related activity, we have recorded from otolith afferent fibers while animals performed a fine heading discrimination task. We find that afferent fibers have similar discrimination thresholds as central cells, and the most sensitive fibers have thresholds that are only twofold or threefold greater than perceptual thresholds. Unlike brainstem and cerebellar nuclei neurons, spike counts from afferent fibers do not exhibit trial-by-trial correlations with perceptual decisions. This finding may reflect the fact that otolith afferent responses are poorly suited for driving heading perception because they fail to discriminate self-motion from changes in orientation relative to gravity. Alternatively, if choice probabilities reflect top-down inference signals, they are not relayed to the vestibular periphery.

Neural basis of new clinical vestibular tests: otolithic neural responses to sound and vibration.

Extracellular single neuron recording and labelling studies of primary vestibular afferents in Scarpa's ganglion have shown that guinea-pig otolithic afferents with irregular resting discharge are preferentially activated by 500 Hz bone-conducted vibration (BCV) and many also by 500 Hz air-conducted sound (ACS) at low threshold and high sensitivity. Very few afferent neurons from any semicircular canal are activated by these stimuli and then only at high intensity. Tracing the origin of the activated neurons shows that these sensitive otolithic afferents originate mainly from a specialized region, the striola, of both the utricular and saccular maculae. This same 500 Hz BCV elicits vestibular-dependent eye movements in alert guinea-pigs and in healthy humans. These stimuli evoke myogenic potentials, vestibular-evoked myogenic potentials (VEMPs), which are used to test the function of the utricular and saccular maculae in human patients. Although utricular and saccular afferents can both be activated by BCV and ACS, the differential projection of utricular and saccular afferents to different muscle groups allows for differentiation of the function of these two sensory regions. The basic neural data support the conclusion that in human patients in response to brief 500 Hz BCV delivered to Fz (the midline of the forehead at the hairline), the cervical VEMP indicates predominantly saccular function and the ocular VEMP indicates predominantly utricular function. The neural, anatomical and behavioural evidence underpins clinical tests of otolith function in humans using sound and vibration.

Input-output functions of vestibular afferent responses to air-conducted clicks in rats.

Sound-evoked vestibular myogenic potentials recorded from the sternocleidomastoid muscles (the cervical vestibular-evoked myogenic potential or cVEMP) and the extraocular muscles (the ocular VEMP or oVEMP) have proven useful in clinical assessment of vestibular function. VEMPs are commonly interpreted as a test of saccular function, based on neurophysiological evidence showing activation of saccular afferents by intense acoustic click stimuli. However, recent neurophysiological studies suggest that the clicks used in clinical VEMP tests activate vestibular end organs other than the saccule. To provide the neural basis for interpreting clinical VEMP testing results, the present study examined the extent to which air-conducted clicks differentially activate the various vestibular end organs at several intensities and durations in Sprague-Dawley rats. Single unit recordings were made from 562 vestibular afferents that innervated the otoliths [inferior branch otolith (IO) and superior branch otolith (SO)], the anterior canal (AC), the horizontal canal (HC), and the posterior canal (PC). Clicks higher than 60 dB SL (re-auditory brainstem response threshold) activated both semicircular canal and otolith organ afferents. Clicks at or below 60 dB SL, however, activated only otolith organ afferents. Longer duration clicks evoked larger responses in AC, HC, and SO afferents, but not in IO afferents. Intra-axonal recording and labeling confirmed that sound sensitive vestibular afferents innervated the horizontal and anterior canal cristae as well as the saccular and utricular maculae. Interestingly, all sound sensitive afferents are calyx-bearing fibers. These results demonstrate stimulus-dependent acoustic activation of both semicircular canals and otolith organs, and suggest that sound activation of vestibular end organs other than the saccule should not be ruled out when designing and interpreting clinical VEMP tests.

Listing's plane and the 3D-VOR in microgravity--the role of the otolith afferences.

The study addresses the question as to what extent the otolith-mediated gravity vector maintains the stability of the coordinate frames of the vestibulo-ocular reflex and the oculomotor system, described by Listing's Plane. Under normal 1 G conditions it has been demonstrated in the monkey that Listing's Plane (LP) and the 3D vestibulo-ocular response (3D-VOR) are close to collinear [10]. In the present study the coordinate frames of the oculomotor system and the three-dimensional vestibulo-ocular reflex (3D-VOR) system were measured under one-g gravity conditions and during a period of prolonged microgravity, on-board the International Space Station (ISS). To this end, the coordinate frame of the oculomotor system is described in Listing's coordinates and that of the 3D-VOR system by the minimal gain vector. The findings demonstrate that under Earthbound, one-g conditions the two coordinate frames diverge by approximately 20° in the human. In the absence of the gravity vector the radical loss in the otolith-mediated contribution to the dynamic VOR leads to a reduction of the torsional VOR component and in turn to a forward tilt of the oculomotor coordinate frame, described by the minimal gain vector. In contrast, the torsional component of LP during horizontal and vertical saccades was found to increase, resulting in a backward tilt of LP. Together with the backward tilt of LP a small but consistent change in LP vergence was observed. The thickness of LP did not appear to change in the absence of gravity. The changes in coordinate frame orientation persisted over the six-month periods spent in zero gravity. The postflight measurements demonstrate that re-adaptation to preflight values proceeds over several days to weeks. The findings demonstrate that the gravity vector represents a common reference for vestibular and oculomotor responses. They also support the idea that the gravity vector provides a central reference for the entire sensorimotor complex.

[The influence of otolithic afferentation on the vestibulo-ocular interaction in the patients presenting with an unilateral lesion in a peripheral vestibular neuron].

The objective of the present work was to study the influence of otolithic afferentation on the vestibulo-ocular interaction in 20 patients with vestibular neuronitis (at the stages of decompensation and subcompensation) and in 30 healthy subjects by the electronystagmographic technique. The sinusoidal (program 1) and eccentric (program 2) rotation was applied with the angular velocity of 10 degrees/s (stimulus 1, rotation rate 0.04 Hz), 30 degrees/s (stimulus II, rotation rate 0.12 Hz), 60 degrees/s (stimulus III) and oscillation periods of 18, 6, and 3 s respectively. No significant changes in the parameters of the vesicular reflex were observed in the patients with vestibular neuronitis and control subjects studied in the phase of decompensation under programs 1 and 2 . The study of the patients presenting with vestibular neuronitis in the subcompensation phase (program 2) revealed a significant increase of nystagmus intensity on the affected side compared with the respective parameters estimated in the framework of program 1 (p<0.001). The enhancement of stimulation did not result in any significant changes in the character of vestibuloocular interactions. The results of the study indicate that otolithic afferentation influences the process of compensation of peripheral vestibular labyrinth dysfunction in the patients presenting with vestibular neuronitis at the stage of decompensation.

Postnatal expression of TrkB receptor in rat vestibular nuclear neurons responsive to horizontal and vertical linear accelerations.

We examined the maturation expression profile of tyrosine kinase B (TrkB) receptor in rat vestibular nuclear neurons that were activated by sinusoidal linear acceleration along the horizontal or vertical axis. The otolithic origin of Fos expression in these neurons was confirmed with labyrinthectomized controls and normal controls, which showed only sporadically scattered Fos-labeled neurons in the vestibular nucleus. In P4-6 test rats, no Fos-labeled neurons were found in the vestibular nucleus, but the medial and spinal vestibular neurons showed weak immunoreactivity for TrkB. The intensity of TrkB immunoreactivity in vestibular nuclear neurons progressively increased in the second postnatal week but remained low in adults. From P7 onward, TrkB-expressing neurons responded to horizontal or vertical otolithic stimulation with Fos expression. The number of Fos-labeled vestibular nuclear neurons expressing TrkB increased with age, from 13-43% in P7 rats to 85-90% in adult rats. Our results therefore suggest that TrkB/neurotrophin signaling plays a dominant role in modulating vestibular nuclear neurons for the coding of gravity-related horizontal head movements and for the regulation of vestibular-related behavior during postnatal development.

Different effects of head tilt on ocular vestibular-evoked myogenic potentials in response to bone-conducted vibration and air-conducted sound.

The ocular vestibular-evoked myogenic potentials (oVEMPs) in response to air-conducted sound (ACS) and bone-conducted vibration (BCV) have recently been used to assess otolith-ocular pathways in humans. Although the oVEMPs to BCV are considered to reflect the function of the utricle and superior vestibular pathway, the pathway of the oVEMPs to ACS remains controversial. In this study, we compared the effect of different head positions in the roll plane on oVEMPs in response to BCV and ACS in 20 normal subjects. Head tilt in the roll plane significantly increased the asymmetry ratio of oVEMPs to BCV (p < 0.01) but did not affect the asymmetry ratio of oVEMPs to ACS. Head tilt did not affect the latencies of oVEMPs to either BCV or ACS. Rotation of the body in the yaw plane while keeping the head straight ahead did not affect the asymmetry of oVEMPs to BCV (p > 0.6). These results suggest that oVEMPs to BCV reflect the activity of a different population of vestibular afferents to those which are active during oVEMPs to ACS.

Irregular primary otolith afferents from the guinea pig utricular and saccular maculae respond to both bone conducted vibration and to air conducted sound.

This study sought to identify in guinea pig the peripheral sense organ of origin of otolith irregular primary vestibular afferent neurons having a very sensitive response to both air-conducted sound (ACS) and bone-conducted vibration (BCV). Neurons responding to both types of stimuli were labelled by juxtacellular labelling by neurobiotin. Whole mounts of the maculae showed that some vestibular afferents activated by both ACS and BCV originate from the utricular macula and some from the saccular macula - there is no "afferent specificity" by one sense organ for ACS and the other for BCV - instead some afferents from both sense organs have sensitive responses to both stimuli. The clinical implication of this result is that differential evaluation of the functional status of the utricular and saccular maculae cannot rely on stimulus type (ACS vs BCV), however the differential motor projections of the utricular and saccular maculae allow for differential evaluation of each sense organ.

Detection thresholds of macaque otolith afferents.

The vestibular system is our sixth sense and is important for spatial perception functions, yet the sensory detection and discrimination properties of vestibular neurons remain relatively unexplored. Here we have used signal detection theory to measure detection thresholds of otolith afferents using 1 Hz linear accelerations delivered along three cardinal axes. Direction detection thresholds were measured by comparing mean firing rates centered on response peak and trough (full-cycle thresholds) or by comparing peak/trough firing rates with spontaneous activity (half-cycle thresholds). Thresholds were similar for utricular and saccular afferents, as well as for lateral, fore/aft, and vertical motion directions. When computed along the preferred direction, full-cycle direction detection thresholds were 7.54 and 3.01 cm/s(2) for regular and irregular firing otolith afferents, respectively. Half-cycle thresholds were approximately double, with excitatory thresholds being half as large as inhibitory thresholds. The variability in threshold among afferents was directly related to neuronal gain and did not depend on spike count variance. The exact threshold values depended on both the time window used for spike count analysis and the filtering method used to calculate mean firing rate, although differences between regular and irregular afferent thresholds were independent of analysis parameters. The fact that minimum thresholds measured in macaque otolith afferents are of the same order of magnitude as human behavioral thresholds suggests that the vestibular periphery might determine the limit on our ability to detect or discriminate small differences in head movement, with little noise added during downstream processing.

When up is down in 0g: how gravity sensing affects the timing of interceptive actions.

Humans are known to regulate the timing of interceptive actions by modeling, in a simplified way, Newtonian mechanics. Specifically, when intercepting an approaching ball, humans trigger their movements a bit earlier when the target arrives from above than from below. This bias occurs regardless of the ball's true kinetics, and thus appears to reflect an a priori expectation that a downward moving object will accelerate. We postulate that gravito-inertial information is used to tune visuomotor responses to match the target's most likely acceleration. Here we used the peculiar conditions of parabolic flight--where gravity's effects change every 20 s--to test this hypothesis. We found a striking reversal in the timing of interceptive responses performed in weightlessness compared with trials performed on ground, indicating a role of gravity sensing in the tuning of this response. Parallels between these observations and the properties of otolith receptors suggest that vestibular signals themselves might plausibly provide the critical input. Thus, in addition to its acknowledged importance for postural control, gaze stabilization, and spatial navigation, we propose that detecting the direction of gravity's pull plays a role in coordinating quick reactions intended to intercept a fast-moving visual target.

Acoustically induced streaming flows near a model cod otolith and their potential implications for fish hearing.

The ears of fishes are remarkable sensors for the small acoustic disturbances associated with underwater sound. For example, each ear of the Atlantic cod (Gadus morhua) has three dense bony bodies (otoliths) surrounded by fluid and tissue, and detects sounds at frequencies from 30 to 500 Hz. Atlantic cod have also been shown to localize sounds. However, how their ears perform these functions is not fully understood. Steady streaming, or time-independent, flows near a 350% scale model Atlantic cod otolith immersed in a viscous fluid were studied to determine if these fluid flows contain acoustically relevant information that could be detected by the ear's sensory hair cells. The otolith was oscillated sinusoidally at various orientations at frequencies of 8-24 Hz, corresponding to an actual frequency range of 280-830 Hz. Phase-locked particle pathline visualizations of the resulting flows give velocity, vorticity, and rate of strain fields over a single plane of this mainly two-dimensional flow. Although the streaming flows contain acoustically relevant information, the displacements due to these flows are likely too small to explain Atlantic cod hearing abilities near threshold. The results, however, may suggest a possible mechanism for detection of ultrasound in some fish species.

The basis for using bone-conducted vibration or air-conducted sound to test otolithic function.

Extracellular single neuron recordings of primary vestibular neurons in Scarpa's ganglion in guinea pigs show that low-intensity 500 Hz bone-conducted vibration (BCV) or 500 Hz air-conducted sound (ACS) activate a high proportion of otolith irregular neurons from the utricular and saccular maculae but few semicircular canal neurons. In alert guinea pigs, and humans, 500 Hz BCV elicits otolith-evoked eye movements. In humans, it also elicits a myogenic potential on tensed sternocleidomastoid muscles. Although BCV and ACS activate both utricular and saccular maculae, it is possible to probe the functional status of these two sense organs separately because of their differential neural projections. Saccular neurons have a strong projection to neck muscles and a weak projection to the oculomotor system. Utricular afferents have a strong projection to eye muscles. So measuring oculomotor responses to ACS and BCV predominantly probes utricular function, while measuring neck muscle responses to these stimuli predominantly probes saccular function.

Development of otolith receptors in Japanese quail.

This study examined the morphological development of the otolith vestibular receptors in quail. Here, we describe epithelial growth, hair cell density, stereocilia polarization, and afferent nerve innervation during development. The otolith maculae epithelial areas increased exponentially throughout embryonic development reaching asymptotic values near posthatch day P7. Increases in hair cell density were dependent upon macular location; striolar hair cells developed first followed by hair cells in extrastriola regions. Stereocilia polarization was initiated early, with defining reversal zones forming at E8. Less than half of all immature hair cells observed had nonpolarized internal kinocilia with the remaining exhibiting planar polarity. Immunohistochemistry and neural tracing techniques were employed to examine the shape and location of the striolar regions. Initial innervation of the maculae was by small fibers with terminal growth cones at E6, followed by collateral branches with apparent bouton terminals at E8. Calyceal terminal formation began at E10; however, no mature calyces were observed until E12, when all fibers appeared to be dimorphs. Calyx afferents innervating only Type I hair cells did not develop until E14. Finally, the topographic organization of afferent macular innervation in the adult quail utricle was quantified. Calyx and dimorph afferents were primarily confined to the striolar regions, while bouton fibers were located in the extrastriola and Type II band. Calyx fibers were the least complex, followed by dimorph units. Bouton fibers had large innervation fields, with arborous branches and many terminal boutons.

Responses of rostral fastigial nucleus neurons of conscious cats to rotations in vertical planes.

The rostral fastigial nucleus (RFN) of the cerebellum is thought to play an important role in postural control, and recent studies in conscious nonhuman primates suggest that this region also participates in the sensory processing required to compute body motion in space. The goal of the present study was to examine the dynamic and spatial responses to sinusoidal rotations in vertical planes of RFN neurons in conscious cats, and determine if they are similar to responses reported for monkeys. Approximately half of the RFN neurons examined were classified as graviceptive, since their firing was synchronized with stimulus position and the gain of their responses was relatively unaffected by the frequency of the tilts. The large majority (80%) of graviceptive RFN neurons were activated by pitch rotations. Most of the remaining RFN units exhibited responses to vertical oscillations that encoded stimulus velocity, and approximately 50% of these velocity units had a response vector orientation aligned near the plane of a single vertical semicircular canal. Unlike in primates, few feline RFN neurons had responses to vertical rotations that suggested integration of graviceptive (otolith) and velocity (vertical semicircular canal) signals. These data indicate that the physiological role of the RFN may differ between primates and lower mammals. The RFN in rats and cats in known to be involved in adjusting blood pressure and breathing during postural alterations in the transverse (pitch) plane. The relatively simple responses of many RFN neurons in cats are appropriate for triggering such compensatory autonomic responses.

Sympathetic responses to vestibular activation in humans.

Activation of sympathetic neural traffic via the vestibular system is referred to as the vestibulosympathetic reflex. Investigations of the vestibulosympathetic reflex in humans have been limited to the past decade, and the importance of this reflex in arterial blood pressure regulation is still being determined. This review provides a summary of sympathetic neural responses to various techniques used to engage the vestibulosympathetic reflex. Studies suggest that activation of the semicircular canals using caloric stimulation and yaw rotation do not modulate muscle sympathetic nerve activity (MSNA) or skin sympathetic nerve activity (SSNA). In contrast, activation of the otolith organs appear to alter MSNA, but not SSNA. Specifically, head-down rotation and off-vertical axis rotation increase MSNA, while sinusoidal linear accelerations decrease MSNA. Galvanic stimulation, which results in a nonspecific activation of the vestibule, appears to increase MSNA if the mode of delivery is pulse trained. In conclusion, evidence strongly supports the existence of a vestibulosympathetic reflex in humans. Furthermore, attenuation of the vestibulosympathetic reflex is coupled with a drop in arterial blood pressure in the elderly, suggesting this reflex may be important in human blood pressure regulation.

A place principle for vertigo.

OBJECTIVE: To provide a road map of the vestibular labyrinth and its innervation leading to a place principle for different forms of vertigo. METHOD: The literature describing the anatomy and physiology of the vestibular system was reviewed. RESULTS: Different forms of vertigo may be determined by the type of sense organ, type of ganglion cell and location in the vestibular nerve. CONCLUSION: Partial lesions (viral) of the vestibular ganglion are manifested as various forms of vertigo.

The recordability of two sonomotor responses in young normal subjects.

BACKGROUND: It has been reported that up to 40% of patients over age 60 fail to generate a vestibular evoked myogenic potential (VEMP; Su et al, 2004). When this occurs it is difficult to determine whether the absent VEMP represents evidence of bilateral impairment of the vestibulocollic reflex pathway or a normal age-related variant (i.e., idiopathic absence). PURPOSE: The purpose of the present investigation was to determine whether both VEMPs and PAMs could be recorded reliably in a sample of neurologically and otologically intact young adults. If both could be obtained with high reliability in normal subjects, then the bilateral presence of PAM in the bilateral absence of VEMP, at least in younger patients, could be used to support the contention that the absent VEMP represented evidence of bilateral impairment. RESEARCH DESIGN: A descriptive study. STUDY SAMPLE: Attempts were made to record both the VEMP and a second sonomotor response, the postauricular muscle potential (PAM) from 20 young adults. RESULTS: Results showed both the VEMP and the PAM were present in 90% of the ears. Both the VEMP and PAM responses were bilaterally absent for one subject. Also, the VEMP and PAM were unilaterally absent for two subjects. Subjects who generated VEMPs also generated a PAM in at least one ear. CONCLUSIONS: The present investigation represents an initial step in the determination of whether the presence of PAMs in the absence of VEMPs can be used as a method of validating the presence of an impairment affecting the vestibulocollic reflex pathway.

[Neuronal plasticity of otolith-related vestibular system].

This review focuses on our effort in addressing the development and lesion-induced plasticity of the gravity sensing system. After severance of sensory input from one inner ear, there is a bilateral imbalance in response dynamics and spatial coding behavior between neuronal subpopulations on the two sides. These data provide the basis for deranged spatial coding and motor deficits accompanying unilateral labyrinthectomy. Recent studies have also confirmed that both glutamate receptors and neurotrophin receptors within the bilateral vestibular nuclei are implicated in the plasticity during vestibular compensation and development. Changes in plasticity not only provide insight into the formation of a spatial map and recovery of vestibular function but also on the design of drugs for therapeutic strategies applicable to infants or vestibular disorders such as vertigo and dizziness.

Head-tilting stabilometry in patients with benign paroxysmal positional vertigo.

OBJECTIVE: One of the pathologic conditions underlying benign paroxysmal positional vertigo (BPPV) is degeneration of the otolith organs. In this study, we examined changes in the parameters of stabilometry under an upright condition and head-tilt conditions in patients with BPPV. METHODS: We performed stabilometry on 21 patients with right BPPV, on 21 patients with left BPPV and on 21 controls. First, the subject stood barefoot in an upright position with both feet together on the platform with eyes closed. Next, tilting of the head about 30 degrees to the left was added. Then, tilting about 30 degrees to the right was performed. RESULTS: In right BPPV patients, the total length of velocity vectors in the right or left direction on right or left head-tilt were significantly smaller than those in an upright position. The enveloped area and total length of velocity vectors in the right or left direction were significantly larger than those in controls. In left BPPV patients, there were no parameters that showed any significant difference. CONCLUSIONS: In this study, lesions of right BPPV patients were coincidentally more severe than those in left BPPV patients, and velocity vectors with head-tilts were significantly smaller than in an upright position. Using the total length of the velocity vectors, head-tilting stabilometry has the potential to become a reliable otolith function examination method.