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Retinal image slip during head rotation drives motor learning in the rotational vestibulo-ocular reflex (VOR) and forms the basis of gaze-stability exercises that treat vestibular dysfunction. Clinical exercises, however, are unengaging, cannot easily be titrated to the level of impairment, and provide neither direct feedback nor tracking of the patient's adherence, performance, and progress. To address this, we have developed a custom application for VOR training based on an interactive computer game. In this study, we tested the ability of this game to induce VOR learning in individuals with normal vestibular function, and we compared the efficacy of single-step and incremental learning protocols. Eighteen participants played the game twice on different days. All participants tolerated the game and were able to complete both sessions. The game scenario incorporated a series of brief head rotations, similar to active head impulses, that were paired with a dynamic acuity task and with a visual-vestibular mismatch (VVM) intended to increase VOR gain (single-step: 300 successful trials at x1.5 viewing; incremental: 100 trials each of -x1.13, x1.33, and x1.5 viewing). Overall, VOR gain increased by 15 ± 4.7% (mean ± 95% CI, P < 0.001). Gains increased similarly for active and passive head rotations, and, contrary to our hypothesis, there was little effect of the learning strategy. This study shows that an interactive computer game provides robust VOR training and has the potential to deliver effective, engaging, and trackable gaze-stability exercises to patients with a range of vestibular dysfunctions. [ABSTRACT FROM AUTHOR]

When the demands for visual stabilization during head rotations overwhelm the ability of the vestibuloocular reflex (VOR) to produce compensatory eye movements, the brain produces corrective saccades that bring gaze toward the fixation target, even without visual cues (covert saccades). What triggers covert saccades and what might be the role of prediction in their generation are unknown. We studied 14 subjects with acute vestibular neuritis. To minimize variability of the stimulus, head impulses were imposed with a motorized torque generator with the subject on a bite bar. Predictable and unpredictable (timing, amplitude, direction) stimuli were compared. Distributions of covert corrective saccade latencies were analyzed with a "LATER" (linear approach to threshold with ergodic rate) approach. On the affected side, VOR gain was higher (0.47 ± 0.28 vs. 0.39 ± 0.22, P << 0.001) with predictable than unpredictable head impulses, and gaze error at the end of the head movement was less (5.4 ± 3.3° vs. 6.9 ± 3.3°, P << 0.001). Analyzing trials with covert saccades, gaze error at saccade end was significantly less with predictable than unpredictable head impulses (4.2 ± 2.8° vs. 5.5 ± 3.2°, P << 0.001). Furthermore, covert corrective saccades occurred earlier with predictable than unpredictable head impulses (140 ± 37 vs. 153 ± 37 ms, P << 0.001). Using a LATER analysis with reciprobit plots, we were able to divide covert corrective saccades into two classes, early and late, with a break point in the range of 88-98 ms. We hypothesized two rise-to-threshold decision mechanisms for triggering early and late covert corrective saccades, with the first being most engaged when stimuli are predictable. [ABSTRACT FROM AUTHOR]

Individuals with peripheral or central vestibular dysfunction recruit compensatory saccades (CSs) in response to high acceleration, yaw head impulses. Although CSs have been shown to be an effective strategy for reducing gaze position error (GPE) in individuals with peripheral hypofunction, for individuals with central vestibular dysfunction, the effectiveness of CS is unknown. The purpose of our study was to compare the effectiveness of CS, defined as the ability to compensate for head velocity and eye position errors, between persons with central and peripheral vestibular dysfunction. We compared oculomotor responses during video head impulse testing between individuals with unilateral peripheral vestibular deafferentation, a disorder of the peripheral vestibular afferents, and individuals with multiple sclerosis, a condition affecting the central vestibular pathways. We hypothesized that relative to individuals with peripheral lesions, individuals with central dysfunction would recruit CSs that were delayed and inappropriately scaled to head velocity and GPE. We show that CSs recruited by persons with central vestibular pathology were not uniformly deficient but instead were of a sufficient velocity to compensate for reductions in VOR gain. Compared to those with peripheral vestibular lesions, individuals with central pathology also recruited earlier covert CS with amplitudes that were better corrected for GPE. Conversely, those with central lesions showed greater variability in the amplitude of overt CS relative to GPE. These data point to a unique role for peripheral and central vestibular inputs in the recruitment of CS and suggest that covert CSs are an effective oculomotor strategy for individuals with multiple sclerosis. [ABSTRACT FROM AUTHOR]

Imbalance and dizziness are disabling symptoms for many patients with vestibular schwannomas (VS) but symptom severity typically does not correlate with the vestibulo-ocular reflex (VOR) amplitude-based metrics used to assess peripheral vestibular damage. In this study, we tested the hypothesis that imbalance and dizziness in patients with VS relate to VOR metrics that are not based on response amplitude. Twenty-four patients with unilateral, sporadic VS tumors were studied, and objective (balance) and subjective (dizziness) vestibular dysfunction was quantified. The VOR was tested using two yaw-axis motion stimuli, low-frequency en-bloc sinusoidal, and high-frequency head-on-body impulsive rotations. Imbalance correlated with VOR precision (the inverse of the trial-to-trial variability) and with low-frequency VOR dynamics (quantified with the time constant), and these two metrics were also strongly correlated. Dizziness correlated with the VOR bias caused by an imbalance in static central vestibular tone, but not with dynamic VOR metrics. VOR accuracy (mean response amplitude relative to the ideal response) was not correlated with the severity of imbalance or dizziness or with measures of VOR precision or time constant. Imbalance in patients with VS, therefore, scales with VOR precision and time constant, both of which appear to reflect the central vestibular signal-to-noise ratio, but not with VOR slow-phase accuracy, which is based on the magnitude of the central vestibular signals. Dizziness was related to the presence of a static central tone imbalance but not to any VOR metrics, suggesting that abnormal perception in VS may be affected by factors that are not captured by yaw-axis VOR measurements. NEW & NOTEWORTHY The severity of symptoms associated with unilateral vestibular schwannomas (VS) is poorly correlated with standard yaw-axis vestibulo-ocular reflex (VOR) metrics that are based on response amplitude. In this study, we show that the balance and perceptual dysfunction experienced by patients with VS scales with VOR metrics that capture information about the central signal-to-noise ratio (balance) and central static tone (dizziness), but are not correlated with the VOR gain, which reflects central signal amplitude. [ABSTRACT FROM AUTHOR]

The climbing fiber input to the cerebellum conveys instructive signals that can induce synaptic plasticity and learning by triggering complex spikes accompanied by large calcium transients in Purkinje cells. In the cerebellar flocculus, which supports oculomotor learning, complex spikes are driven by image motion on the retina, which could indicate an oculomotor error. In the same neurons, complex spikes also can be driven by nonvisual signals. It has been shown that the calcium transients accompanying each complex spike can vary in amplitude, even within a given cell, therefore, we compared the calcium responses associated with the visual and nonvisual inputs to floccular Purkinje cells. The calcium indicator GCaMP6f was selectively expressed in Purkinje cells, and fiber photometry was used to record the calcium responses from a population of Purkinje cells in the flocculus of awake behaving mice. During visual (optokinetic) stimuli and pairing of vestibular and visual stimuli, the calcium level increased during contraversive retinal image motion. During performance of the vestibulo-ocular reflex in the dark, calcium increased during contraversive head rotation and the associated ipsiverse eye movements. The amplitude of this nonvisual calcium response was comparable to that during conditions with retinal image motion present that induce oculomotor learning. Thus, population calcium responses of Purkinje cells in the cerebellar flocculus to visual and nonvisual input are similar to what has been reported previously for complex spikes, suggesting that multimodal instructive signals control the synaptic plasticity supporting oculomotor learning. [ABSTRACT FROM AUTHOR]

Feldman AG, Zhang L. Eye and head movements and vestibulo-ocular reflex in the context of indirect, referent control of motor actions. J Neurophysiol 124: 115-133, 2020. First published June 3, 2020; doi:10.1152/jn.00076.2020.--Conventional explanations of the vestibulo-ocular reflex (VOR) and eye and head movements are revisited by considering two alternative frameworks addressing the question of how the brain controls motor actions. Traditionally, biomechanical and/or computational frameworks reflect the views of several prominent scholars of the past, including Helmholtz and von Holst, who assumed that the brain directly specifies the desired motor outcome and uses efference copy to influence perception. However, empirical studies resulting in the theory of referent control of action and perception (an extension of the equilibrium-point hypothesis) revealed that direct specification of motor outcome is inconsistent with nonlinear properties of motoneurons and with the physical principle that the brain can control motor actions only indirectly, by changing or maintaining the values of neurophysiological parameters that influence, but can remain independent of, biomechanical variables. Some parameters are used to shift the origin (referent) points of spatial frames of reference (FRs) or system of coordinates in which motor actions emerge without being predetermined. Parameters are adjusted until the emergent motor actions meet the task demands. Several physiological parameters and spatial FRs have been identified, supporting the notion of indirect, referent control of movements. Instead of integration of velocity-dependent signals, position-dimensional referent signals underlying head motion can likely be transmitted to motoneurons of extraocular muscles. This would produce compensatory eye movement preventing shifts in gaze during head rotation, even after bilateral destruction of the labyrinths. The referent control framework symbolizes a shift in the paradigm for the understanding of VOR and eye and head movement production. [ABSTRACT FROM AUTHOR]

Recent evidence has shown that auditory information may be used to improve postural stability, spatial orientation, navigation, and gait, suggesting an auditory component of self-motion perception. To determine how auditory and other sensory cues integrate for selfmotion perception, we measured motion perception during yaw rotations of the body and the auditory environment. Psychophysical thresholds in humans were measured over a range of frequencies (0.1-1.0 Hz) during self-rotation without spatial auditory stimuli, rotation of a sound source around a stationary listener, and selfrotation in the presence of an earth-fixed sound source. Unisensory perceptual thresholds and the combined multisensory thresholds were found to be frequency dependent. Auditory thresholds were better at lower frequencies, and vestibular thresholds were better at higher frequencies. Expressed in terms of peak angular velocity, multisensory vestibular and auditory thresholds ranged from 0.39°/s at 0.1 Hz to 0.95°/s at 1.0 Hz and were significantly better over low frequencies than either the auditory-only (0.54°/s to 2.42°/s at 0.1 and 1.0 Hz, respectively) or vestibular-only (2.00°/s to 0.75°/s at 0.1 and 1.0 Hz, respectively) unisensory conditions. Monaurally presented auditory cues were less effective than binaural cues in lowering multisensory thresholds. Frequency-independent thresholds were derived, assuming that vestibular thresholds depended on a weighted combination of velocity and acceleration cues, whereas auditory thresholds depended on displacement and velocity cues. These results elucidate fundamental mechanisms for the contribution of audition to balance and help explain previous findings, indicating its significance in tasks requiring self-orientation. NEW & NOTEWORTHY Auditory information can be integrated with visual, proprioceptive, and vestibular signals to improve balance, orientation, and gait, but this process is poorly understood. Here, we show that auditory cues significantly improve sensitivity to selfmotion perception below 0.5 Hz, whereas vestibular cues contribute more at higher frequencies. Motion thresholds are determined by a weighted combination of displacement, velocity, and acceleration information. These findings may help understand and treat imbalance, particularly in people with sensory deficits. [ABSTRACT FROM AUTHOR]

From animal experiments by Cohen and Suzuki et al. in the 1960s to the first-in-human clinical trials now in progress, prosthetic electrical stimulation targeting semicircular canal branches of the vestibular nerve has proven effective at driving directionally appropriate vestibulo-ocular reflex eye movements, postural responses, and perception. That work was considerably facilitated by the fact that all hair cells and primary afferent neurons in each canal have the same directional sensitivity to head rotation, the three canals' ampullary nerves are geometrically distinct from one another, and electrically evoked three-dimensional (3D) canal-ocular reflex responses approximate a simple vector sum of linearly independent components representing relative excitation of each of the three canals. In contrast, selective prosthetic stimulation of the utricle and saccule has been difficult to achieve, because hair cells and afferents with many different directional sensitivities are densely packed in those endorgans and the relationship between 3D otolith-ocular reflex responses and the natural and/or prosthetic stimuli that elicit them is more complex. As a result, controversy exists regarding whether selective, controllable stimulation of electrically evoked otolith-ocular reflexes (eeOOR) is possible. Using micromachined, planar arrays of electrodes implanted in the labyrinth, we quantified 3D, binocular eeOOR responses to prosthetic electrical stimulation targeting the utricle, saccule, and semicircular canals of alert chinchillas. Stimuli delivered via near-bipolar electrode pairs near the maculae elicited sustained ocular countertilt responses that grew reliably with pulse rate and pulse amplitude, varied in direction according to which stimulating electrode was employed, and exhibited temporal dynamics consistent with responses expected for isolated macular stimulation. [ABSTRACT FROM AUTHOR]

Head rotation, translation, and tilt with respect to a gravitational field elicit reflexive eye movements that partially stabilize images of Earth-fixed objects on the retinas of humans and other vertebrates. Compared with the angular vestibulo-ocular reflex, responses to translation and tilt, collectively called the otolith-ocular reflex (OOR), are less completely characterized, typically smaller, generally disconjugate (different for the 2 eyes) and more complicated in their relationship to the natural stimuli that elicit them. We measured binocular 3-dimensional OOR responses of 6 alert normal chinchillas in darkness during whole body tilts around 16 Earth-horizontal axes and translations along 21 axes in horizontal, coronal, and sagittal planes. Ocular countertilt responses to 40-s whole body tilts about Earth-horizontal axes grew linearly with head tilt amplitude, but responses were disconjugate, with each eye's response greatest for whole body tilts about axes near the other eye's resting line of sight. OOR response magnitude during 1-Hz sinusoidal whole body translations along Earth-horizontal axes also grew with stimulus amplitude. Translational OOR responses were similarly disconjugate, with each eye's response greatest for whole body translations along its resting line of sight. Responses to Earth-horizontal translation were similar to those that would be expected for tilts that would cause a similar peak deviation of the gravitoinertial acceleration (GIA) vector with respect to the head, consistent with the "perceived tilt" model of the OOR. However, that model poorly fit responses to translations along non-Earth-horizontal axes and was insufficient to explain why responses are larger for the eye toward which the GIA vector deviates. [ABSTRACT FROM AUTHOR]

The vestibulo-ocular reflex (VOR) is the only system that maintains stable vision during rapid head rotations. The VOR gain (eye/head velocity) can be trained to increase using a vestibular-visual mismatch stimulus. We sought to determine whether low-frequency (sinusoidal) head rotation during training leads to changes in the VOR during high-frequency head rotation testing, where the VOR is more physiologically relevant. We tested eight normal subjects over three sessions. For training protocol 1, subjects performed active sinusoidal head rotations at 1.3 Hz while tracking a laser target, whose velocity incrementally increased relative to head velocity so that the VOR gain required to stabilize the target went from 1.1 to 2 over 15 min. Protocol 2 was the same as protocol 1, except that head rotations were at 0.5 Hz. For protocol 3, head rotation frequency incrementally increased from 0.5 to 2 Hz over 15 min, while the VOR gain required to stabilize the target was kept at 2. We measured the active and passive, sinusoidal (1.3Hz) and head impulse VOR gains before and after each protocol. Sinusoidal and head impulse VOR gains increased in protocols 1 and 3; however, although the sinusoidal VOR gain increase was ~20%, the related head impulse gain increase was only ~10%. Protocol 2 resulted in no-gain adaptation. These data show human VOR adaptation is frequency selective, suggesting that if one seeks to increase the higher-frequency VOR response, i.e., where it is physiologically most relevant, then higher-frequency head movements are required during training, e.g., head impulses. NEW & NOTEWORTHY This study shows that human vestibuloocular reflex adaptation is frequency selective at frequencies >0.3 Hz. The VOR in response to mid- (1.3 Hz) and high-frequency (impulse) head rotations were measured before and after mid-frequency sinusoidal VOR adaptation training, revealing that the mid-frequency gain change was higher than high-frequency gain change. Thus, if one seeks to increase the higher-frequency VOR response, where it is physiologically most relevant, then higher-frequency head movements are required during training. [ABSTRACT FROM AUTHOR]

This is a review summarizing the development of vestibulo-ocular reflex (VOR) adaptation behavior with relevance to rehabilitation over the last 10 years and examines VOR adaptation using head-onbody rotations, specifically the influence of training target contrast, position and velocity error signal, active vs. passive head rotations, and sinusoidal vs. head impulse rotations. This review discusses optimization of the single VOR adaptation training session, consolidation between repeated training sessions, and dynamic incremental VOR adaptation. Also considered are the effects of aging and the roles of the efferent vestibular system, cerebellum, and otoliths on angular VOR adaptation. Finally, this review examines VOR adaptation findings in studies using whole body rotations. [ABSTRACT FROM AUTHOR]

Here we characterize in 80 normal subjects (16-84 yr (means ± SD, 47 ± 19 yr) the vestibulo-ocular reflex (VOR) and saccades in response to three-dimensional head impulses with a monocular video head impulse test (vHIT) of the right eye. Impulses toward the right lateral, right anterior, and left posterior canals (means: 0.98, 0.91, 0.79) had slightly higher mean gains compared with their counterparts (0.95, 0.86, 0.76). In the older age group (>60 yr), gains of the left posterior canal dropped 0.09 and left anterior canals rose 0.09 resulting in symmetry. All canal gains reduced with increasing head velocity (0.02-0.13 per 100°/s). Comparison of lateral canal gains calculated using five published algorithms yielded lower values (~0.80) when a narrow detection window was used. Low-amplitude refixation saccades (amplitude: 1.11 ± 0.98°, peak velocity: 63.9 ± 34.0°/s at 262.0 ± 93.9 ms) were observed among all age groups (frequency: 40.2 ± 23.4%), increasing in amplitude, peak velocity, and frequency in older subjects. Impulses toward anterior canals showed the least frequent saccades and lateral and posterior canals were similar, but lateral canal impulses showed the smallest saccades and the posterior canal showed the largest saccades. Saccade peak-velocity approximate amplitude "main sequence" slope was steeper for the horizontal canals compared with the vertical planes (60 vs. <40°/s per 1°). In summary, we found small but significant asymmetries in monocular vHIT gain that changed with age. Healthy subjects commonly have minuscule refixation saccades that are moderately to strongly correlated with vHIT gain. NEW & NOTEWORTHY Gaze fixation is normally stabilized during rapid "head-impulse" movements by the bisynaptic vestibulo-ocular reflex (VOR), but earlier studies of normal subjects also report small amplitude saccades. We found that with increased age of the subject the vertical VOR became more variable, while in all semicircular canal directions the saccade frequency, amplitude, and peak velocity increased. We also found that the VOR gain algorithm significantly influences values. [ABSTRACT FROM AUTHOR]

Although many studies have reported on tests of the vestibular system a valid and reliable, evidence-based screening battery for easy clinical use remains elusive. Many screening tests attempt to assess the vestibulo-ocular reflex. Therefore, head shaking, the Dix-Hallpike maneuver, the supine roll test, and head impulse tests are discussed. Other tests address the spatial orientation functions of the vestibular system, such as the Bucket Test and the Fukuda Stepping test. Still, other tests are based on the known correlates with balance skills, both static and dynamic, such as tandem walking and the modern variation of the Romberg test, the modified Clinical Test of Sensory Interaction and Balance. This review provides a critical overview of the literature on some of these tests and their value for clinical use and in epidemiological studies. [ABSTRACT FROM AUTHOR]

Although motion of the head and body has been suspected or known as the provocative cause for the production of motion sickness for centuries, it is only within the last 20 yr that the source of the signal generating motion sickness and its neural basis has been firmly established. Here, we briefly review the source of the conflicts that cause the body to generate the autonomic signs and symptoms that constitute motion sickness and provide a summary of the experimental data that have led to an understanding of how motion sickness is generated and can be controlled. Activity and structures that produce motion sickness include vestibular input through the semicircular canals, the otolith organs, and the velocity storage integrator in the vestibular nuclei. Velocity storage is produced through activity of vestibular-only (VO) neurons under control of neural structures in the nodulus of the vestibulo-cerebellum. Separate groups of nodular neurons sense orientation to gravity, roll/tilt, and translation, which provide strong inhibitory control of the VO neurons. Additionally, there are acetylcholinergic projections from the nodulus to the stomach, which along with other serotonergic inputs from the vestibular nuclei, could induce nausea and vomiting. Major inhibition is produced by the GABAB receptors, which modulate and suppress activity in the velocity storage integrator. Ingestion of the GABAB agonist baclofen causes suppression of motion sickness. Hopefully, a better understanding of the source of sensory conflict will lead to better ways to avoid and treat the autonomic signs and symptoms that constitute the syndrome. [ABSTRACT FROM AUTHOR]

The healthy vestibulo-ocular reflex (VOR) ensures that images remain on the fovea of the retina during head rotation to maintain stable vision. VOR behavior can be measured as a summation of linear and nonlinear properties although it is unknown whether asymmetric VOR adaptation can be performed synchronously in humans. The purpose of the present study is twofold. First, examine whether the right and left VOR gains can be synchronously adapted in opposing directions. Second, to investigate whether the adaptation context transfers between both sides. Three separate VOR adaptation sessions were randomized such that the VOR was adapted Up-bilaterally, Down-bilaterally, or Mixed (one side up, opposite side down). Ten healthy subjects completed the study. Subjects were tested while seated upright, 1 meter in front of a wall in complete dark. Each subject made active (self-generated) head impulse rotations for 15 min while viewing a gradually increasing amount of retinal slip. VOR training demand changed by 10% every 90 s. The VOR changed significantly for all training conditions. No significant differences in the magnitude of VOR gain changes between training conditions were found. The human VOR can be simultaneously driven in opposite directions. The similar magnitude of VOR gain changes across training conditions suggests functionally independent VOR circuits for each side of head rotation that mediate simultaneous and opposing VOR adaptations. NEW & NOTEWORTHY Our results indicate that humans have the adaptive capacity for concurrent and opposing directions of vestibuloocular reflex (VOR) motor learning. Context specificity of VOR adaptation is dependent on the error signal being unilateral or bilateral, which we illustrate via a lack of VOR gain transfer using unique adaptive demands. [ABSTRACT FROM AUTHOR]

Our object was to investigate the effect of location and phase on the properties of oVEMPs and cVEMPs evoked by two bone conducted (BC) stimuli, 500 Hz and an impulsive stimulus for midline skull sites from Nz to Iz, in normal volunteers. Compressive and rarefactive onset phases were used and the induced linear and rotational accelerations measured. We confirmed our previous finding of marked changes in the polarity of oVEMPs with location. For cVEMPs using the 500Hz stimulus there were few changes with location or phase, but the impulsive stimulus showed clear phaserelated changes at several locations, with the shortest latencies occurring with compressive stimuli at AFz and Fz and the largest amplitudes at Iz. For oVEMPs, both stimuli showed clear effects of phase, with the shortest latencies with compressive stimuli at AFz and Fz and with the largest negativity at Oz or Iz. Whereas the effectiveness at Iz is consistent with a role in the linear VOR, the inversion of polarity and shorter latency around AFz and Fz is not and could not be explained by changes in acceleration of the head. The latency for BC 500Hz oVEMPs for AFz was the same as that for air-conducted (AC) stimuli. We suggest that whereas BC stimuli at most sites work through displacement of the otolith membrane, BC oVEMPs evoked at AFz and Fz may work through a direct action on utricular hair cells. Our findings have implications for clinical testing of VEMPs using midline BC stimuli. [ABSTRACT FROM AUTHOR]

In response to passive high-acceleration head impulses, patients with low vestibulo-ocular reflex (VOR) gains often produce covert (executed while the head is still moving) corrective saccades in the direction of deficient slow phases. Here we examined 23 patients using passive, and 9 also active, head impulses with acute (< 10 days from onset) unilateral vestibular neuritis and low VOR gains. We found that when corrective saccades are larger than 10℉, the slow-phase component of the VOR is inhibited, even though inhibition increases further the time to reacquire the fixation target. We also found that 1) saccades are faster and more accurate if the residual VOR gain is higher, 2) saccades also compensate for the head displacement that occurs during the saccade, and 3) the amplitude-peak velocity relationship of the larger corrective saccades deviates from that of head-fixed saccades of the same size. We propose a mathematical model to account for these findings hypothesizing that covert saccades are driven by a desired gaze position signal based on a prediction of head displacement using vestibular and extravestibular signals, covert saccades are controlled by a gaze feedback loop, and the VOR command is modulated according to predicted saccade amplitude. A central and novel feature of the model is that the brain develops two separate estimates of head rotation, one for generating saccades while the head is moving and the other for generating slow phases. Furthermore, while the model was developed for gaze-stabilizing behavior during passively induced head impulses, it also simulates both active gaze-stabilizing and active gaze-shifting eye movements. NEW & NOTEWORTHY During active or passive head impulses while fixating stationary targets, low vestibulo-ocular gain subjects produce corrective saccades when the head is still moving. The mechanisms driving these covert saccades are poorly understood. We propose a mathematical model showing that the brain develops two separate estimates of head rotation: a lower level one, presumably in the vestibular nuclei, used to generate the slow-phase component of the response, and a higher level one, within a gaze feedback loop, used to drive corrective saccades. [ABSTRACT FROM AUTHOR]

The α9-nicotinic acetylcholine receptor (α9-nAChR) subunit is expressed in the vestibular and auditory periphery, and its loss of function could compromise peripheral input from the predominantly cholinergic efferent vestibular system (EVS). A recent study has shown that α9-nAChRs play an important role in short-term vestibulo-ocular reflex (VOR) adaptation. We hypothesize that α9-nAChRs could also be important for other forms of vestibular plasticity, such as that needed for VOR recovery after vestibular organ injury. We measured the efficacy of VOR compensation in α9 knockout mice. These mice have deletion of most of the gene (chrna9) encoding the nAChR and thereby lack α9-nAChRs. We measured the VOR gain (eye velocity/head velocity) in 20 α9 knockout mice and 16 cba129 controls. We measured the sinusoidal (0.2–10 Hz, 20–100°/s) and transient (1,500–6,000°/s2) VOR in complete darkness before (baseline) unilateral labyrinthectomy (UL) and then 1, 5, and 28 days after UL. On day 1 after UL, cba129 mice retained ~50% of their initial function for contralesional rotations, whereas α9 knockout mice only retained ~20%. After 28 days, α9 knockout mice had ~50% lower gain for both ipsilesional and contralesional rotations compared with cba129 mice. Cba129 mice regained ~75% of their baseline function for ipsilesional and ~90% for contralesional rotations. In contrast, α9 knockout mice only regained ~30% and ~50% function, respectively, leaving the VOR severely impaired for rotations in both directions. Our results show that loss of α9-nAChRs severely affects VOR compensation, suggesting that complimentary central and peripheral EVS-mediated adaptive mechanisms might be affected by this loss. [ABSTRACT FROM AUTHOR]

During gaze shifts, the eyes and head collaborate to rapidly capture a target (saccade) and fixate it. Accordingly, models of gaze shift control should embed both saccadic and fixation modes and a mechanism for switching between them. We demonstrate a model in which the eye and head platforms are driven by a shared gaze error signal. To limit the number of free parameters, we implement a model reduction approach in which steady-state cerebellar effects at each of their projection sites are lumped with the parameter of that site. The model topology is consistent with anatomy and neurophysiology, and can replicate eye-head responses observed in multiple experimental contexts: 1) observed gaze characteristics across species and subjects can emerge from this structure with minor parametric changes; 2) gaze can move to a goal while in the fixation mode; 3) ocular compensation for head perturbations during saccades could rely on vestibular-only cells in the vestibular nuclei with postulated projections to burst neurons; 4) two nonlinearities suffice, i.e., the experimentally-determined mapping of tectoreticular cells onto brain stem targets and the increased recruitment of the head for larger target eccentricities; 5) the effects of initial conditions on eye/head trajectories are due to neural circuit dynamics, not planning; and 6) "compensatory" ocular slow phases exist even after semicircular canal plugging, because of interconnections linking eye-head circuits. Our model structure also simulates classical vestibulo-ocular reflex and pursuit nystagmus, and provides novel neural circuit and behavioral predictions, notably that both eye-head coordination and segmental limb coordination are possible without trajectory planning. [ABSTRACT FROM AUTHOR]

We investigated how vestibulospinal reflexes (VSRs) and vestibulo-ocular reflexes (VORs) measured through vestibular evoked myogenic potentials (VEMPs) and video head impulse test (vHIT) outcomes, respectively, are modulated during standing under conditions of increased postural threat. Twentyfive healthy young adults stood quietly at low (0.8 m from the ground) and high (3.2 m) surface height conditions in two experiments. For the first experiment (n = 25) VEMPs were recorded with surface EMG from inferior oblique (IO), sternocleidomastoid (SCM), trapezius (TRP), and soleus (SOL) muscles in response to 256 air-conducted short tone bursts (125 dB SPL, 500 Hz, 4 ms) delivered via headphones. A subset of subjects (n = 19) also received horizontal and vertical head thrusts (~150°/s) at each height in a separate session, comparing eye and head velocities by using a vHIT system for calculating the functional VOR gains. VEMP amplitudes (IO, TRP, SOL) and horizontal and vertical vHIT gains all increased with high surface height conditions (P < 0.05). Changes in IO and SCM VEMP amplitudes as well as horizontal vHIT gains were correlated with changes in electrodermal activity (ρ = 0.44-0.59, P < 0.05). VEMP amplitude for the IO also positively correlated with fear (ρ = 0.43, P = 0.03). Threat-induced anxiety, fear, and arousal have significant effects on VSR and VOR gains that can be observed in both physiological and functional outcome measures. These findings provide support for a potential central modulation of the vestibular nucleus complex through excitatory inputs from neural centers involved in processing fear, anxiety, arousal, and vigilance. [ABSTRACT FROM AUTHOR]

Although anatomically well described, the functional role of the mammalian efferent vestibular system (EVS) remains unclear. Unlike in fish and reptiles, the mammalian EVS does not seem to play a role in modulation of primary afferent activity in anticipation of active head movements. However, it could play a role in modulating long-term mechanisms requiring plasticity such as vestibular adaptation. We measured the efficacy of vestibuloocular reflex (VOR) adaptation in α9-knockout mice. These mice carry a missense mutation of the gene encoding the 9 nicotinic acetylcholine receptor (nAChR) subunit. The α9 nAChR subunit is expressed in the vestibular and auditory periphery, and its loss of function could compromise peripheral input from the predominantly cholinergic EVS. We measured the VOR gain (eye velocity/head velocity) in 26 α9-knockout mice and 27 cba129 control mice. Mice were randomly assigned to one of three groups: gain-increase adaptation (1.5x), gain-decrease adaptation (0.5x), or no adaptation (baseline, 1x). After adaptation training (horizontal rotations at 0.5 Hz with peak velocity 20°/s), we measured the sinusoidal (0.2-10 Hz, 20-100°/s) and transient (1,500-6,000°/s²) VOR in complete darkness. 9- Knockout mice had significantly lower baseline gains compared with control mice. This difference increased with stimulus frequency (~5% <1 Hz to ~25% >1 Hz). Moreover, vestibular adaptation (difference in VOR gain of gain-increase and gain-decrease adaptation groups as % of gain increase) was significantly reduced in α9-knockout mice (17%) compared with control mice (53%), a reduction of ~70%. Our results show that the loss of α9 nAChRs moderately affects the VOR but severely affects VOR adaptation, suggesting that the EVS plays a crucial role in vestibular plasticity. [ABSTRACT FROM AUTHOR]

Goal-directed movements, such as pointing and saccades, have been shown to share similar neural architectures, in spite of the different neuromuscular systems producing them. Such structure involve an inverse model of the actuator being controlled, which produces the commands innervating the muscles, and a forward model of the actuator, which predicts the sensory consequences of such commands and allows online movement corrections. Recent studies have shown that goal-directed movements also share similar motor-learning and motor-memory mechanisms, which are based on multiple timescales. The hypothesis that also the rotational vestibulo-ocular reflex (rVOR) may be based on a similar architecture has been presented recently. We hypothesize that multiple timescales are the brain's solution to the plasticity-stability dilemma, allowing adaptation to temporary and sudden changes while keeping stable motor-control abilities. If that were the case, then we would also expect the adaptation of reflex movements to follow the same principles. Thus we studied rVOR gain adaptation in eight healthy human subjects using a custom paradigm aimed at investigating the existence of spontaneous recovery, which we considered as the hallmark of multiple timescales in motor learning. Our experimental results show that spontaneous recovery occurred in six of eight subjects. Thus we developed a mathematical model of rVOR adaptation based on two hidden-states processes, which adapts the cerebellar-forward model of the ocular motor plant, and show that it accurately simulates our experimental data on rVOR gain adaptation, whereas a single timescale learning process fails to do so. [ABSTRACT FROM AUTHOR]

Mutation of the Cacna1a gene for the P/Q (CaV2.1) calcium channel invariably leads to cerebellar dysfunction. The dysfunction has been attributed to disrupted rhythmicity of cerebellar Purkinje cells, but the hypothesis remains unproven. If irregular firing rates cause cerebellar dysfunction, then the irregularity and behavioral deficits should covary in a series of mutant strains of escalating severity. We compared firing irregularity in floccular and anterior vermis Purkinje cells in the mildly affected rocker and moderately affected tottering Cacna1a mutants and normal C57BL/6 mice. We also measured the amplitude and timing of modulations of floccular Purkinje cell firing rate during the horizontal vestibuloocular reflex (VOR, 0.25-1 Hz) and the horizontal and vertical optokinetic reflex (OKR, 0.125-1 Hz). We recorded Purkinje cells selective for rotational stimulation about the vertical axis (VAPCs) and a horizontal axis (HAPCs). Irregularity scaled with behavioral deficit severity in the flocculus but failed to do so in the vermis, challenging the irregularity hypothesis. Mutant VAPCs exhibited unusually strong modulation during VOR and OKR, the response augmentation scaling with phenotypic severity. HAPCs exhibited increased OKR modulation but in tottering only. The data contradict prior claims that modulation amplitude is unaffected in tottering but support the idea that attenuated compensatory eye movements in Cacna1a mutants arise from defective transfer of Purkinje cell signals to downstream circuitry, rather than attenuated synaptic transmission within the cerebellar cortex. Shifts in the relative sizes of the VAPC and HAPC populations raise the possibility that Cacna1a mutations influence the development of floccular zone architecture. [ABSTRACT FROM AUTHOR]

The interaction between the magnetic field of a magnetic resonance imaging (MRI) machine and ion currents within the inner-ear endolymph results in a Lorentz force. This force produces a pressure that pushes on the cupula within the semicircular canals causing nystagmus and vertigo. Here I discuss several implications of this unique and noninvasive way to stimulate the vestibular system in experimental neurophysiology and clinical neurology. [ABSTRACT FROM AUTHOR]

The gain of the vertical angular vestibulo-ocular reflex (aVOR) was adaptively increased and decreased in a side-down head orientation for 4 h in two cynomolgus monkeys. Adaptation was performed at 0.25, 1, 2, or 4 Hz. The gravity-dependent and -independent gain changes were determined over a range of head orientations from left-side-down to right-sidedown at frequencies from 0.25 to 10 Hz, before and after adaptation. Gain changes vs. frequency data were fit with a Gaussian to determine the frequency at which the peak gain change occurred, as well as the tuning width. The frequency at which the peak gravity-dependent gain change occurred was approximately equal to the frequency of adaptation, and the width increased monotonically with increases in the frequency of adaptation. The gravity-independent component was tuned to the adaptive frequency of 0.25 Hz but was uniformly distributed over all frequencies when the adaptation frequency was 1-4 Hz. The amplitude of the gravity-independent gain changes was larger after the aVOR gain decrease than after the gain increase across all tested frequencies. For the aVOR gain decrease, the phase lagged about 4° for frequencies below the adaptation frequency and led for frequencies above the adaptation frequency. For gain increases, the phase relationship as a function of frequency was inverted. This study demonstrates that the previously described dependence of aVOR gain adaptation on frequency is a property of the gravity-dependent component of the aVOR only. The gravity-independent component of the aVOR had a substantial tuning curve only at an adaptation frequency of 0.25 Hz. [ABSTRACT FROM AUTHOR]

How the brain processes signals in the presence of noise impacts much of behavioral neuroscience. Thresholds provide one way to assay noise. While perceptual thresholds have been widely investigated, vestibuloocular reflex (VOR) thresholds have seldom been studied and VOR threshold dynamics have never, to our knowledge, been reported. Therefore, we assessed VOR thresholds as a function of frequency. Specifically, we measured horizontal VOR thresholds evoked by yaw rotation in rhesus monkeys, using standard signal detection approaches like those used in earlier human vestibular perceptual threshold studies. We measured VOR thresholds ranging between 0.21 and 0.76°/s; the VOR thresholds increased slightly with frequency across the measured frequency range (0.2–3 Hz). These results do not mimic the frequency response of human perceptual thresholds that have been shown to increase substantially as frequency decreases below 0.5 Hz. These reported VOR threshold findings could indicate a qualitative difference between vestibular responses of humans and nonhuman primates, but a more likely explanation is an additional dynamic neural mechanism that does not influence the VOR but, rather, influences perceptual thresholds via a decision-making process included in direction recognition tasks. [ABSTRACT FROM AUTHOR]

A proprioceptive representation of eye position exists in area 3a of primate somatosensory cortex (Wang X, Zhang M, Cohen IS, Goldberg ME. Nat Neurosci 10: 640-646, 2007). This eye position signal is consistent with a fusimotor response (Taylor A, Durbaba R, Ellaway PH, Rawlinson S. J Physiol 571: 711-723, 2006) and has two components during a visually guided saccade task: a short-latency phasic response followed by a tonic response. While the early phasic response can be excitatory or inhibitory, it does not accurately reflect the eye's orbital position. The late tonic response appears to carry the proprioceptive eye position signal, but it is not clear when this component emerges and whether the onset of this signal is reliable. To test the temporal dynamics of the tonic proprioceptive signal, we used an oculomotor smooth pursuit task in which saccadic eye movements and phasic proprioceptive responses are suppressed. Our results show that the tonic proprioceptive eye position signal consistently lags the actual eye position in the orbit by 60 ms under a variety of eye movement conditions. To confirm the proprioceptive nature of this signal, we also studied the responses of neurons in a vestibuloocular reflex (VOR) task in which the direction of gaze was held constant; response profiles and delay times were similar in this task, suggesting that this signal does not represent angle of gaze and does not receive visual or vestibular inputs. The length of the delay suggests that the proprioceptive eye position signal is unlikely to be used for online visual processing for action, although it could be used to calibrate an efference copy signal. [ABSTRACT FROM AUTHOR]

Experimental animal models have suggested that the modulation of the amplitude and direction of vestibular reflexes are important functions of the vestibulocerebellum and contribute to the control of gaze and balance. These critical vestibular functions have been infrequently quantified in human cerebellar disease. In 13 subjects with ataxia telangiectasia (A-T), a disease associated with profound cerebellar cortical degeneration, we found abnormalities of several key vestibular reflexes. The vestibuloocular reflex (VOR) was measured by eye movement responses to changes in head rotation. The vestibulocollic reflex (VCR) was assessed with cervical vestibular-evoked myogenic potentials (cVEMPs), in which auditory clicks led to electromyographic activity of the sternocleidomastoid muscle. The VOR gain (eye velocity/head velocity) was increased in all subjects with A-T. An increase of the VCR, paralleling that of the VOR, was indirectly suggested by an increase in cVEMP amplitude. In A-T subjects, alignment of the axis of eye rotation was not with that of head rotation. Subjects with A-T thus manifested VOR cross-coupling, abnormal eye movements directed along axes orthogonal to that of head rotation. Degeneration of the Purkinje neurons in the vestibulocerebellum probably underlie these deficits. This study offers insights into how the vestibulocerebellum functions in healthy humans. It may also be of value to the design of treatment trials as a surrogate biomarker of cerebellar function that does not require controlling for motivation or occult changes in motor strategy on the part of experimental subjects. [ABSTRACT FROM AUTHOR]

Large conductance K+(BK) channels are a key determinant of neuronal excitability. Medial vestibular nucleus (MVN) neurons regulate eye movements to ensure image stabilization during head movement, and changes in their intrinsic excitability may play a critical role in plasticity of the vestibulo-ocular reflex. Plasticity of intrinsic excitability in MVN neurons is mediated by kinases, and BK channels influence excitability, but whether endogenous BK channels are directly modulated by kinases is unknown. Double somatic patch-clamp recordings from MVN neurons revealed large conductance potassium channel openings during spontaneous action potential firing. These channels displayed Ca2+and voltage dependence in excised patches, identifying them as BK channels. Recording isolated single channel currents at physiological temperature revealed a novel kinase-mediated bidirectional control in the range of voltages over which BK channels are activated. Application of activated Ca2+/calmodulin-dependent kinase II (CAMKII) increased BK channel open probability by shifting the voltage activation range towards more hyperpolarized potentials. An opposite shift in BK channel open probability was revealed by inhibition of phosphatases and was occluded by blockade of protein kinase C (PKC), suggesting that active PKC associated with BK channel complexes in patches was responsible for this effect. Accordingly, direct activation of endogenous PKC by PMA induced a decrease in BK open probability. BK channel activity affects excitability in MVN neurons and bidirectional control of BK channels by CAMKII, and PKC suggests that cellular signaling cascades engaged during plasticity may dynamically control excitability by regulating BK channel open probability. [ABSTRACT FROM AUTHOR]

Plasticity in neuronal responses is necessary for compensation following brain lesions and adaptation to new conditions and motor learning. In a previous study, we showed that compensatory changes in the vestibuloocular reflex (VOR) following unilateral vestibular loss were characterized by dynamic reweighting of inputs from vestibular and extravestibular modalities at the level of single neurons that constitute the first central stage of VOR signal processing. Here, we studied another class of neurons, i.e., the vestibular-only neurons, in the vestibular nuclei that mediate vestibulospinal reflexes and provide information for higher brain areas. We investigated changes in the relative contribution of vestibular, neck proprioceptive, and efference copy signals in the response of these neurons during compensation after contralateral vestibular loss in Macaca mulata monkeys. We show that the time course of recovery of vestibular sensitivity of neurons corresponds with that of lower extremity muscle and tendon reflexes reported in previous studies. More important, we found that information from neck proprioceptors, which did not influence neuronal responses before the lesion, were unmasked after lesion. Such inputs influenced the early stages of the compensation process evidenced by faster and more substantial recovery of the resting discharge in proprioceptive-sensitive neurons. Interestingly, unlike our previous study of VOR interneurons, the improvement in the sensitivity of the two groups of neurons did not show any difference in the early or late stages after lesion. Finally, neuronal responses during active head movements were not different before and after lesion and were attenuated relative to passive movements over the course of recovery, similar to that observed in control conditions. Comparison of compensatory changes observed in the vestibuloocular and vestibulospinal pathways provides evidence for similarities and differences between the two classes of neurons that mediate these pathways at the functional and cellular levels. [ABSTRACT FROM AUTHOR]

Self-motion perception after a sudden stop from a sustained rotation in darkness lasts approximately as long as reflexive eye movements. We hypothesized that, after an angular velocity step, self-motion perception and reflexive eye movements are driven by the same vestibular pathways. In 16 healthy subjects (25–71 years of age), perceived rotational velocity (PRV) and the vestibulo-ocular reflex (rVOR) after sudden decelerations (90°/s2) from constant-velocity (90°/s) earth-vertical axis rotations were simultaneously measured (PRV reported by hand-lever turning; rVOR recorded by search coils). Subjects were upright (yaw) or 90° left-ear-down (pitch). After both yaw and pitch decelerations, PRV rose rapidly and showed a plateau before decaying. In contrast, slow-phase eye velocity (SPV) decayed immediately after the initial increase. SPV and PRV were fitted with the sum of two exponentials: one time constant accounting for the semicircular canal (SCC) dynamics and one time constant accounting for a central process, known as velocity storage mechanism (VSM). Parameters were constrained by requiring equal SCC time constant and VSM time constant for SPV and PRV. The gains weighting the two exponential functions were free to change. SPV were accurately fitted (variance-accounted-for: 0.85 ± 0.10) and PRV (variance-accounted-for: 0.86 ± 0.07), showing that SPV and PRV curve differences can be explained by a greater relative weight of VSM in PRV compared with SPV (twofold for yaw, threefold for pitch). These results support our hypothesis that self-motion perception after angular velocity steps is be driven by the same central vestibular processes as reflexive eye movements and that no additional mechanisms are required to explain the perceptual dynamics. [ABSTRACT FROM AUTHOR]

Bidirectional changes in synaptic transmission have the potential to optimize the control of movement. However, it can be difficult to establish a causal relationship between the bidirectionality of synaptic plasticity and bidirectional changes in the speed of actual movements. We asked whether metabotropic glutamate receptor 1 (mGluR1) receptors, which participate in cerebellar long-term depression (LTD), are necessary for bidirectional motor learning in the vestibulo-ocular reflex (VOR). Cerebellar LTD and long-term potentiation (LTP) are thought to cause increases and decreases, respectively, in the gain of the VOR; the direction of learning depends on the behavioral protocol. We injected either the mGluR1 agonist (S)-DHPG or the antagonist YM 298198 bilaterally into the flocculus of alert cats, and then induced motor learning. In the presence of YM 298198, the VOR gain decreased in gain-up, as well as in gain-down protocols. (S)-DHPG augmented gain-up learning. Gain-down learning was not significantly affected by either drug. These results supported the hypothesis that gain-up learning relies on cerebellar LTD, but gain-down learning relies on a different mechanism. In the absence of mGluR1 activity, cerebellar LTD may be replaced with LTP, permitting learning in only one direction. [ABSTRACT FROM AUTHOR]

Mechanical occlusion (plugging) of the slender ducts of semicircular canals has been used in the clinic as well as in basic vestibular research. Here, we investigated the effect of canal plugging in two macaque monkeys on the horizontal vestibuloocular reflex (VOR) and the responses of vestibular-nerve afferents during passive head rotations. Afferent responses to active head movements were also studied. The horizontal VOR gain decreased after plugging to <0.1 for frequencies <2 Hz but rose to about 0.6 as frequency was increased to 15 Hz. Afferents innervating plugged horizontal canals had response sensitivities that increased with the frequency of passive rotations from <0.01 (spikes/s)/(°/s) at 0.5 Hz to values of about 0.2 and 0.5 (spikes/s)/(°/s) at 8 Hz for regular and irregular afferents, respectively (<50% of responses in controls). An increase in phase lead was also noted following plugging in afferent discharge, but not in the VOR. Because the phase discrepancy between the VOR and afferent discharge is much larger than that seen in control animals, this suggests that central adaptation shapes VOR dynamics following plugging. The effect of canal plugging on afferent responses can be modeled as an increase in stiffness and a reduction in the dominant time constant and gain in the transfer function describing canal dynamics. Responses were also evident during active head rotations, consistent with the frequency content of these movements. We conclude that canal plugging in macaques is effective only at frequencies <2 Hz. At higher frequencies, afferents show significant responses, with a nearly 90° phase lead, such that they encode near-rotational acceleration. Our results demonstrate that afferents innervating plugged canals respond robustly during voluntary movements, a finding that has implications for understanding the effects of canal plugging in clinical practice. [ABSTRACT FROM AUTHOR]

Little is known about the dependence of the roll angular vestibuloocular reflex (aVOR) on gravity or its gravity-dependent adaptive properties. To study gravity-dependent characteristics of the roll aVOR, monkeys were oscillated about a naso-occipital axis in darkness while upright or tilted. Roll aVOR gains were largest in the upright position and decreased by 7–15% as animals were tilted from the upright. Thus the unadapted roll aVOR gain has substantial gravitational dependence. Roll gains were also decreased or increased by 0.25 Hz, in- or out-of-phase rotation of the head and the visual surround while animals were prone, supine, upright, or in side-down positions. Gain changes, determined as a function of head tilt, were fit with a sinusoid; the amplitudes represented the amount of the gravity-dependent gain change, and the bias, the gravity-independent gain change. Gravity-dependent gain changes were absent or substantially smaller in roll (5%) than in yaw (25%) or pitch (17%), whereas gravity-independent gain changes were similar for roll, pitch, and yaw (20%). Thus the high-frequency roll aVOR gain has an inherent dependence on head orientation re gravity in the unadapted state, which is different from the yaw/pitch aVORs. This inherent gravitational dependence may explain why the adaptive circuits are not active when the head is tilted re gravity during roll aVOR adaptation. These behavioral differences support the idea that there is a fundamental difference in the central organization of canal-otolith convergence of the roll and yaw/pitch aVORs. [ABSTRACT FROM AUTHOR]

Recently we showed that sensitivity for chromatic- and high-spatial frequency luminance stimuli is enhanced during smooth-pursuit eye movements (SPEMs). Here we investigated whether this enhancement is a general property of slow eye movements. Besides SPEM there are two other classes of eye movements that operate in a similar range of eye velocities: the optokinetic nystagmus (OKN) is a reflexive pattern of alternating fast and slow eye movements elicited by wide-field visual motion and the vestibulo-ocular reflex (VOR) stabilizes the gaze during head movements. In a natural environment all three classes of eye movements act synergistically to allow clear central vision during self- and object motion. To test whether the same improvement of chromatic sensitivity occurs during all of these eye movements, we measured human detection performance of chromatic and luminance line stimuli during OKN and contrast sensitivity during VOR and SPEM at comparable velocities. For comparison, performance in the same tasks was tested during fixation. During the slow phase of OKN we found a similar enhancement of chromatic detection rate like that during SPEM, whereas no enhancement was observable during VOR. This result indicates similarities between slow-phase OKN and SPEM, which are distinct from VOR. [ABSTRACT FROM AUTHOR]

The mammalian orienting response to sounds consists of a gaze shift that can be a combination of head and eye movements. In animals with mobile pinnae, the ears also move. During head movements, vision is stabilized by compensatory rotations of the eyeball within the head because of the vestibulo-ocular reflex (VOR). While studying the gaze shifts made by cats to sounds, a previously uncharacterized compensatory movement was discovered. The pinnae exhibited short-latency, goal-directed movements that reached their target while the head was still moving. The pinnae maintained a fixed position in space by counter-rotating on the head with an equal but opposite velocity to the head movement. We call these compensatory ear movements the vestibulo-auricular reflex (VAR) because they shared many kinematic characteristics with the VOR. Control experiments ruled out efference copy of head position signals and acoustic tracking (audiokinetic) of the source as the cause of the response. The VAR may serve to stabilize the auditory world during head movements. [ABSTRACT FROM AUTHOR]

To understand how the brain learns, we need to identify the full neural circuit for a behavior; characterize how neural responses in the circuit change during behavioral learning; and understand the nature, location, and control of the cellular changes that are responsible for learning. This goal seems attainable for the vestibuloocular reflex (VOR), where the neural circuit basis for learning is already partially understood. The current hypothesis for VOR learning postulates cellular changes in the cerebellar cortex and the vestibular nucleus. It suggests that the brain stem contains two parallel pathways that have been modeled on the basis of extensive biological data as unmodified and modified VOR pathways with frequency-dependent internal gains and different time delays. We now show a correspondence between the responses of different groups of neurons in the vestibular nucleus and the signals emanating from the two pathways in the model. Floccular target neurons (FTNs) and position-vestibular-pause neurons (PVPs) were identified by their discharge during eye movements and by the presence or absence of inhibition by floccular stimulation. FTNs had response gains and phases that coincided with predictions for pathways that are modified in association with learning, whereas PVPs had responses in agreement with predictions for the unmodified pathways. The quantitative agreement of prior model predictions and new data supports the identity of FTNs and PVPs as brain stem interneurons in the modified and unmodified VOR pathways. Other aspects of the data make predictions about how vestibular inputs are transformed as they pass through the two pathways. [ABSTRACT FROM AUTHOR]

The term "vestibular compensation" refers to the resolution of motor deficits resulting from a peripheral vestibular lesion. We investigated the role of the cerebellum in the compensation process by characterizing the vestibuloocular reflex (VOR) evoked by head rotations at frequencies and velocities similar to those in natural behaviors in wild-type (WT) versus cerebellar-deficient Lurcher (Lc/+) mice. We found that during exploratory activity, normal mice produce head rotations largely consisting of frequencies ≤4 Hz and velocities and accelerations as large as 400°/s and 5,000°/s2, respectively. Accordingly, the VOR was characterized using sinusoidal rotations (0.2–4 Hz) as well as transient impulses (∼400°/s; ∼2,000°/s2). Before lesions, WT and Lc/+ mice produced similar VOR responses to sinusoidal rotation. Lc/+ mice, however, had significantly reduced gains for transient stimuli. After unilateral labyrinthectomy, VOR recovery followed a similar course for WT and Lc/+ groups during the first week: gain was reduced by 80% for ipsilesionally directed head rotations on day 1 and improved for both strains to values of ∼0.4 by day 5. Moreover, responses evoked by contralesionally directed rotations returned to prelesion in both strains within this period. However, unlike WT, which showed improving responses to ipsilesionally directed rotations, recovery plateaued after first week for Lc/+ mice. Our results show that despite nearly normal recovery in the acute phase, long-term compensation is compromised in Lc/+. We conclude that cerebellar pathways are critical for long-term restoration of VOR during head rotation toward the lesioned side, while noncerebellar pathways are sufficient to restore proper gaze stabilization during contralesionally directed movements. [ABSTRACT FROM AUTHOR]

Little is known about the three-dimensional characteristics of vestibulocollic reflexes during natural locomotion. Here we determined how well head stability is maintained by the angular and linear vestibulocollic reflexes (aVCR, lVCR) during quadrupedal locomotion in rhesus and cynomolgus monkeys. Animals walked on a treadmill at velocities of 0.4–1.25 m/s. Head rotations were represented by Euler angles (Fick convention). The head oscillated in yaw and roll at stride frequencies (1–2 Hz) and pitched at step frequencies (2–4 Hz). Head angular accelerations (100–2,500°/s2) were sufficient to have excited the aVOR to stabilize gaze. Pitch and roll head movements were <7°, peak to peak, and the amplitude was unrelated to stride frequency. Yaw movements were larger due to spontaneous voluntary head shifts and were smaller at higher walking velocities. Head translations were small (≤4 cm). Cynomolgus monkeys positioned their heads more forward in pitch than the rhesus monkeys. None of the animals maintained a forward head fixation point, indicating that the lVCR contributed little to compensatory head movements in these experiments. Significantly, aVCR gains in roll and pitch were close to unity and phases were 180° over the full frequency range of natural walking, which is in contrast to previous findings using anesthesia or passive trunk rotation with body restraint. We conclude that the behavioral state associated with active body motion is necessary to maintain head stability in pitch and roll over the full range of stride/step frequencies encountered during walking. [ABSTRACT FROM AUTHOR]

Alexander's Law states that the slow-phase velocity of the nystagmus caused by unilateral vestibular lesion increases with gaze in the beat direction. Two studies have shown that this gaze effect is generalized to the nystagmus caused by unilateral cold water irrigation. This indicates that the gaze effect is not the result of central changes associated with a peripheral lesion but rather because of unilateral vestibular peripheral inhibition. In this study, we show that there is a similar gaze effect on the nystagmus produced by unilateral warm water ear irrigation. Furthermore, we examined the two hypotheses of Alexander's Law proposed in the two studies. One hypothesis is based on the gaze-dependent modulation of the vestibulo-ocular reflex (VOR) response to unbalanced canal input. The other hypothesis, however, is based on the leaky neural integrator caused by unilateral vestibular peripheral inhibition. These two hypotheses predict the same gaze effect on the nystagmus produced by cold water irrigation, but opposite gaze effects on the nystagmus produced by warm water irrigation. Our results support the first hypothesis and suggest that the second hypothesis needs to be modified. [ABSTRACT FROM AUTHOR]

Many motion related behaviors, such as gaze stabilization, balance, orientation, and navigation largely depend on a properly functioning vestibular system. After vestibular insult, many of these responses are compromised but can return during the regeneration of vestibular receptors and afferents as is known to occur in birds, reptiles, and amphibians. Here we characterize gaze stability in pigeons to rotational motion during regeneration after complete bilateral vestibular loss via an ototoxic antibiotic. Immediate postlesion effects included severe head oscillations, postural ataxia, and total lack of gaze control. We found that these abnormal behaviors gradually subsided, and gaze stability slowly returned to normal function according to a temporal sequence that lasted several months. We also found that the dynamic recovery of gaze function during regeneration was not homogeneous for all types of motion. Instead high-frequency motion stability was first achieved, followed much later by slow movement stability. In addition, we found that initial gaze stability was established using almost exclusive head-response components with little eye-movement contribution. However, that trend reversed as recovery progressed so that when gaze stability was complete, the eye component had increased and the head response had decreased to levels significantly different from that observed in normal birds. This was true even though the head-fixed VOR response recovered normally. Recovery of gaze stability coincided well with the three stage temporal sequence of morphologic regeneration previously described by our laboratory. [ABSTRACT FROM AUTHOR]

To investigate the role of noncommutative computations in the oculomotor system, three-dimensional (3D) eye movements were measured in seven healthy subjects using a memory-contingent vestibulooculomotor paradigm. Subjects had to fixate a luminous point target that appeared briefly at an eccentricity of 20° in one of four diagonal directions in otherwise complete darkness. After a fixation period of ∼1 s, the subject was moved through a sequence of two rotations about mutually orthogonal axes in one of two orders (30° yaw followed by 30° pitch and vice versa in upright and 30° yaw followed by 20° roll and vice versa in both upright and supine orientations). We found that the change in ocular torsion induced by consecutive rotations about the yaw and the pitch axis depended on the order of rotations as predicted by 3D rotation kinematics. Similarly, after rotations about the yaw and roll axis, torsion depended on the order of rotations but now due to the change in final head orientation relative to gravity. Quantitative analyses of these ocular responses revealed that the rotational vestibuloocular reflexes (VORs) in far vision closely matched the predictions of 3D rotation kinematics. We conclude that the brain uses an optimal VOR strategy with the restriction of a reduced torsional position gain. This restriction implies a limited oculomotor range in torsion and systematic tilts of the angular eye velocity as a function of gaze direction. [ABSTRACT FROM AUTHOR]

Motor memory is relatively labile immediately after learning but can become more stable through consolidation. We investigated consolidation of motor memory in the vestibuloocular reflex (VOR). Cats viewed the world through telescopic lenses during 60 min of passive rotation. Learned decreases (gain-down learning) and increases in the VOR gain (gain-up learning) were measured during sinusoidal rotation at 2 Hz. We found that if rotation in darkness immediately followed learning, the gain of the VOR reverted toward its prelearning value, indicating that expression of the memory was disrupted. If after gain-down learning the cat spent another 60 min stationary without form vision, subsequent disruption did not occur, suggesting that memory had consolidated. Consolidation was less robust for gain-up learning. We conclude that memory in the VOR is initially labile but consolidates rapidly and consistently after gain-down learning. [ABSTRACT FROM AUTHOR]

We studied the effect of cerebellar lesions on the 3-D control of the rotational vestibuloocular reflex (RVOR) to abrupt yaw-axis head rotation. Using search coils, three-dimensional (3-D) eye movements were recorded from nine patients with cerebellar disease and seven normal subjects during brief chair rotations (200°/s2to 40°/s) and manual head impulses. We determined the amount of eye-position dependent torsion during yaw-axis rotation by calculating the torsional-horizontal eye-velocity axis for each of three vertical eye positions (0°, ±15°) and performing a linear regression to determine the relationship of the 3-D velocity axis to vertical eye position. The slope of this regression is the tilt angle slope. Overall, cerebellar patients showed a clear increase in the tilt angle slope for both chair rotations and head impulses. For chair rotations, the effect was not seen at the onset of head rotation when both patients and normal subjects had nearly head-fixed responses (no eye-position-dependent torsion). Over time, however, both groups showed an increasing tilt-angle slope but to a much greater degree in cerebellar patients. Two important conclusions emerge from these findings: the axis of eye rotation at the onset of head rotation is set to a value close to head-fixed (i.e., optimal for gaze stabilization during head rotation), independent of the cerebellum and once the head rotation is in progress, the cerebellum plays a crucial role in keeping the axis of eye rotation about halfway between head-fixed and that required for Listing's Law to be obeyed. [ABSTRACT FROM AUTHOR]

Multiplicative computation is a basic operation that is crucial for neural information processing, but examples of multiplication by neural pathways that perform well-defined sensorimotor transformations are scarce. Here in behaving monkeys, we identified a multiplication of vestibular and eye position signals in the vestibulo-ocular reflex (VOR). Monkeys were trained to maintain fixation on visual targets at different horizontal locations and received brief unilateral acoustic clicks (1 ms, rarefaction, 85∼110 db NHL) that were delivered into one of their external ear canals. We found that both the click-evoked horizontal eye movement responses and the click-evoked neuronal responses of the abducens neurons exhibited linear dependencies on horizontal conjugate eye position, indicating that the interaction of vestibular and horizontal conjugate eye position was multiplicative. Latency analysis further indicated that the site of the multiplication was within the direct VOR pathways. Based on these results, we propose a novel neural mechanism that implements the VOR gain modulation by fixation distance and gaze eccentricity. In this mechanism, the vestibular signal from a single labyrinth interacts multiplicatively with the position signals of each eye (Principle of Multiplication). These effects, however, interact additively with the other labyrinth (Principle of Addition). Our analysis suggests that the new mechanism can implement the VOR gain modulation by fixation distance and gaze eccentricity within the direct VOR pathways. [ABSTRACT FROM AUTHOR]

Brief smooth eye-velocity responses to target position steps have been reported during smooth pursuit. We investigated position-error responses in eight healthy human subjects, comparing the effects of a step–ramp change in target position when imposed on steady-state smooth pursuit, vestibuloocular reflex (VOR) slow phases, or fixation. During steady-state pursuit or VOR, the target performed a step–ramp movement in the same or in the opposite direction relative to ongoing eye movements. When the step was directed backward relative to steady-state smooth pursuit, eye velocity transiently decreased (1.3 ± 0.4°/s; average peak change in amplitude ± SD), beginning about 100 ms after the step. The amplitude of position-error responses varied inversely with the step size. In contrast, there was little or no response in trials with forward steps during steady-state smooth pursuit, when step–ramps were imposed on VOR or when smooth pursuit began from fixation. We hypothesize that during ongoing smooth tracking when a sudden shift in target position is detected the pursuit system compares the direction of ongoing eye velocity with the relative positional error on the retina. In the case of different relative directions between ongoing tracking and a new target eccentricity, a position-error response toward the new target is initiated. Such a mechanism might help the smooth pursuit system to respond better to changes in target direction. These experimental findings were simulated by a mathematical model of smooth pursuit by implementing direction-dependent behavior with a position-error gating mechanism. [ABSTRACT FROM AUTHOR]

The translational linear vestibuloocular reflex compensates most accurately for high frequencies of head translation, with response magnitude decreasing with declining stimulus frequency. However, studies of the perception of translation typically report robust responses even at low frequencies or during prolonged motion. This inconsistency may reflect the incorporation of nondirectional sensory information associated with the vibration and noise that typically accompany translation, into motion perception. We investigated the perception of passive translation in humans while dissociating nondirectional cues from actual head motion. In a cue-dissociation experiment, interaural (IA) motion was generated using either a linear sled, the mechanics of which generated noise and vibration cues that were correlated with the motion profile, or a multiaxis technique that dissociated these cues from actual motion. In a trajectory-shift experiment, IA motion was interrupted by a sudden change in direction (±30° diagonal) that produced a change in linear acceleration while maintaining sled speed and therefore mechanical (nondirectional) cues. During multi-axis cue-dissociation trials, subjects reported erroneous translation perceptions that strongly reflected the pattern of nondirectional cues, as opposed to nearly veridical percepts when motion and nondirectional cues coincided. During trajectory-shift trials, subjects' percepts were initially accurate, but erroneous following the direction change. Results suggest that nondirectional cues strongly influence the perception of linear motion, while the utility of cues directly related to translational acceleration is limited. One key implication is that "path integration" likely involves complex mechanisms that depend on nondirectional and contextual self-motion cues in support of limited and transient otolith-dependent acceleration input. [ABSTRACT FROM AUTHOR]

Chronic motor learning in the vestibuloocular reflex (VOR) results in changes in the gain of this reflex and in other eye movements intimately associated with VOR behavior, e.g., the velocity storage generated by optokinetic stimulation (OKN velocity storage). The aim of the present study was to identify the plastic sites responsible for the change in OKN velocity storage after chronic VOR motor learning. We studied the neuronal responses of vertical eye movement flocculus target neurons (FTNs) during the optokinetic afternystagmus (OKAN) phase of the optokinetic response (OKR) before and after VOR motor learning. Our findings can be summarized as follows. 1) Chronic VOR motor learning changes the horizontal OKN velocity storage in parallel with changes in VOR gain, whereas the vertical OKN velocity storage is more complex, increasing with VOR gain increases, but not changing following VOR gain decreases. 2) FTNs contain an OKAN signal having opposite directional preferences after chronic high versus low gain learning, suggesting a change in the OKN velocity storage representation of FTNs. 3) Changes in the eye-velocity sensitivity of FTNs during OKAN are correlated with changes in the brain stem head-velocity sensitivity of the same neurons. And 4) these changes in eye-velocity sensitivity of FTNs during OKAN support the new behavior after high gain but not low gain learning. Thus we hypothesize that the changes observed in the OKN velocity storage behavior after chronic learning result from changes in brain stem pathways carrying head velocity and OKN velocity storage information, and that a parallel pathway to vertical FTNs changes its OKN velocity storage representation following low, but not high, gain VOR motor learning. [ABSTRACT FROM AUTHOR]

To investigate the neural mechanisms that humans use to process the ambiguous force measured by the otolith organs, we measured vestibuloocular reflexes (VORs) and perceptions of tilt and translation. One primary goal was to determine if the same, or different, mechanisms contribute to vestibular perception and action. We used motion paradigms that provided identical sinusoidal inter-aural otolith cues across a broad frequency range. We accomplished this by sinusoidally tilting (20°, 0.005– 0.7 Hz) subjects in roll about an earth-horizontal, head-centered, rotation axis (“Tilt") or sinusoidally accelerating (3.3 m/s2, 0.005– 0.7 Hz) subjects along their inter-aural axis (“Translation"). While identical inter-aural otolith cues were provided by these motion paradigms, the canal cues were substantially different because roll rotations were present during Tilt but not during Translation. We found that perception was dependent on canal cues because the reported perceptions of both roll tilt and inter-aural translation were substantially different during Translation and Tilt. These findings match internal model predictions that rotational cues from the canals influence the neural processing of otolith cues. We also found horizontal translational VORs at frequencies >0.2 Hz during both Translation and Tilt. These responses were dependent on otolith cues and match simple filtering predictions that translational VORs include contributions via simple high-pass filtering of otolith cues. More generally, these findings demonstrate that internal models govern human vestibular “perception" across a broad range of frequencies and that simple high-pass filters contribute to human horizontal translational VORs (“action") at frequencies above ~0.2 Hz. [ABSTRACT FROM AUTHOR]