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The vestibular cerebellum integrates multimodal sensory and motor information with vestibular input to compute internal models of self-motion. Adaptive plasticity in the floccular lobe underlies the vital computation that maintains vestibulo-ocular reflex calibration to ensure gaze stability. The anterior vermis plays a key role in two essential computations: (i) it transforms head-centered vestibular signals into the body-centered reference frame required for postural control, and (ii) it constructs a prediction of the sensory consequences of active self-motion. The nodulus and ventral uvula of the posterior vermis compute an internal representation of our spatial orientation and self-motion relative to gravity. The internal models underlying each of these computations are continually updated to account for constraints imposed by changes in the environment and/or neural mechanical dynamics. The vestibular cerebellum plays an essential role in maintaining our balance and ensuring perceptual stability during activities of daily living. Here I examine three key regions of the vestibular cerebellum: the floccular lobe, anterior vermis (lobules I–V), and nodulus and ventral uvula (lobules X–IX of the posterior vermis). These cerebellar regions encode vestibular information and combine it with extravestibular signals to create internal models of eye, head, and body movements, as well as their spatial orientation with respect to gravity. To account for changes in the external environment and/or biomechanics during self-motion, the neural mechanisms underlying these computations are continually updated to ensure accurate motor behavior. To date, studies on the vestibular cerebellum have predominately focused on passive vestibular stimulation, whereas in actuality most stimulation is the result of voluntary movement. Accordingly, I also consider recent research exploring these computations during active self-motion and emerging evidence establishing the cerebellum's role in building predictive models of self-generated movement. [ABSTRACT FROM AUTHOR]

• Frequency selective VOR motor learning was confirmed in goldfish as in other model species. • Sharper tuning of frequency selectivity was found in VOR gain-up than gain-down. • Frequency competitive VOR motor learning was possible in goldfish as in primates. • The cerebellum was shown to be necessary for frequency competitive VOR motor learning. • Purkinje cell activities changed with gain-down but not with gain-up during frequency competitive VOR motor learning. Biological motions commonly contain multiple frequency components in which each fundamental has to be adjusted by motor learning to acquire a new motor skill or maintain acquired skills. At times during this motor performance one frequency component needs to be enhanced (gain-up) while another is suppressed (gain-down). This pattern of simultaneous gain-up and -down adjustments at different frequencies is called frequency competitive motor learning. Currently we investigated cerebellar roles in this behavior utilizing the goldfish vestibulo-ocular reflex (VOR). Previously, VOR motor learning was shown in primates to be frequency selective and exhibit frequency competitive motor learning. Here we demonstrate that the goldfish VOR performs frequency competitive motor learning when high and low frequency components are trained to gain-up and gain-down, respectively. However, when the two frequency components were trained in the opposite directions only gain-up component was observed. We also found that cerebellectomy precluded any frequency competitive VOR motor learning. Complementary single unit recordings from vestibulo-cerebellar Purkinje cells revealed changes in firing modulation along with gain-down learning, but not with gain-up learning irrespective of frequency. These results demonstrate that the cerebellum is required for all frequency competitive VOR motor learning and Purkinje cell activity therein is well correlated with all gain-down behaviors independent of frequency. However, frequency competitive gain-up learning requires intact, recursive brainstem/cerebellar pathways. Collectively these findings support the idea that VOR gain-up and gain-down learning utilize separate brainstem/cerebellar circuitry that, in turn, clearly underlies the unique ability of the oculomotor system to deal with multiple frequency components. [ABSTRACT FROM AUTHOR]

Background and purpose Lateral medullary infarction (LMI) sometimes causes long-lasting dizziness. Although the precise mechanism of chronic post-LMI dizziness is unknown, a cerebellar control disorder of the vestibulo-ocular reflex (VOR) has been reported in such patients. We conducted a proof-of-principle cohort study to assess the potential efficacy of cerebellar repetitive transcranial magnetic stimulation (rTMS) as treatment for chronic post-LMI dizziness. Methods We first applied cerebellar rTMS in healthy volunteers (n = 11) and showed that cerebellar intermittent theta burst stimulation (iTBS) affected vestibulocerebellar neural activity. Then, between September and December 2015, we enrolled six patients (aged≥20 years) with chronic post-LMI dizziness (duration≥6 months), applied cerebellar rTMS (iTBS for 5 days), and followed these patients up for up to 25 months for clinical symptoms (Dizziness Handicap Inventory [DHI]), signs (nystagmus), and VOR gain. Results Four of the six patients completed the study without complications. After rTMS, DHI scores were reduced (mean pre-rTMS DHI score minus post-rTMS DHI score was 13.0 [P = 0.036]) with disappearance of the ipsilesional nystagmus characteristic of the post-LMI dizziness. Reduction in the absolute VOR gain (mean pre- rTMS gain minus post-rTMS gain in the ipsilesional direction was 0.135 [P = 0.036] and that in the contralesional direction was 0.137 [P = 0.031]) were also associated with reduced DHI scores. Relative cerebellar blood flow to the brainstem was increased in four of five patients. The effects of cerebellar rTMS did not always persist, and three of four patients elected to undergo more than one rTMS series. The repeat cerebellar rTMS treatments had same beneficial effects. Conclusion Our study showed, for the first time, the potential efficacy of cerebellar rTMS for treatment of chronic post-LMI dizziness. The short duration of the cerebellar rTMS effects can be compensated for by repeating the rTMS treatment every few months. Further large-scale randomized studies are warranted to confirm our findings. [ABSTRACT FROM AUTHOR]

Some studies have demonstrated that aging is associated with impaired vestibular reflexes, especially otolithic reflexes, resulting in postural instability. However, the neurochemical basis of these age-related changes is still poorly understood. The l -arginine metabolic system has been implicated in changes in the brain associated with aging. In the current study, we examined the levels of l -arginine and its metabolizing enzymes and downstream metabolites in the vestibular nucleus complex (VNC) and cerebellum (CE) of rats with and without behavioral testing which were young (4 months old), middle-aged (12 months old) or aged (24 months old). We found that aging was associated with lower nitric oxide synthase activity in the CE of animals with testing and increased arginase in the VNC and CE of animals with testing. l -citrulline and l -ornithine were lower in the VNC of aged animals irrespective of testing, while l -arginine and l -citrulline were lower in the CE with and without testing, respectively. In the VNC and CE, aging was associated with lower levels of glutamate in the VNC, irrespective of testing. In the VNC it was associated with higher levels of agmatine and putrescine, irrespective of testing. In the CE, aging was associated with higher levels of putrescine in animals without testing and with higher levels of spermine in animals with testing, and spermidine, irrespective of testing. Multivariate analyses indicated significant predictive relationships between the different variables, and there were correlations between some of the neurochemical variables and behavioral measurements. Cluster analyses revealed that aging altered the relationships between l -arginine and its metabolites. The results of this study demonstrate that there are major changes occurring in l -arginine metabolism in the VNC and CE as a result of age, as well as behavioral activity. [ABSTRACT FROM AUTHOR]

[Display omitted] • In utero exposure to VPA results in an increased risk of ASD in humans. • VPA exposure resulted in fewer neurons in vestibular nuclei and fewer CB puncta. • VPA exposure resulted in impaired performance on motor tasks. • VPA exposure resulted in delayed VEMPs and horizontal nystagmus. Autism spectrum disorder (ASD) is a neurodevelopmental disorder that includes several key neuropathological changes and behavioral impairments. In utero exposure to the anti-epileptic valproic acid (VPA) increases risk of an ASD diagnosis in human subjects and timed in utero exposure to VPA is a clinically relevant animal model of ASD. Many human subjects with ASD have cerebellar hypoplasia, fewer Purkinje cells, difficulties with balance, ophthalmic dysfunction and abnormal responses to vestibular stimulation and such vestibular difficulties are likely under reported in ASD. We have recently shown that animals exposed to VPA in utero have fewer neurons in their auditory brainstem, reduced axonal projections to the auditory midbrain and thalamus, reduced expression of the calcium binding protein calbindin (CB) in the brainstem and cerebellum, smaller and occasionally ectopic cerebellar Purkinje cells and ataxia on several motor tasks. Based on these findings, we hypothesized that in utero VPA exposure similarly impacts structure and function of the vestibular brainstem. We investigated this hypothesis using quantitative morphometric analyses, immunohistochemistry for CB, a battery of vestibular challenges, recording of vestibular-evoked myogenic potentials and spontaneous eye movements. Our results indicate that VPA exposure results in fewer neurons in the vestibular nuclei, fewer CB-positive puncta, difficulty on certain motor tasks, longer latency VEMPs and significantly more horizontal eye movements. These findings indicate that the vestibular nuclei are impacted by in utero VPA exposure and provide a basis for further study of vestibular circuits in human cases of ASD. [ABSTRACT FROM AUTHOR]

Objective: Spatial orientation and navigation depends on information from the vestibular system. Previous work suggested impaired spatial navigation in patients with bilateral vestibular failure (BVF). The aim of this study was to investigate event-related brain activity by functional magnetic resonance imaging (fMRI) during spatial navigation and visual memory tasks in BVF patients. Methods: Twenty-three BVF patients and healthy age- and gender matched control subjects performed learning sessions of spatial navigation by watching short films taking them through various streets from a driver’s perspective along a route to the Cathedral of Cologne using virtual reality videos (adopted and modified from Google Earth®). In the scanner, participants were asked to respond to questions testing for visual memory or spatial navigation while they viewed short video clips. From a similar but not identical perspective depicted video frames of routes were displayed which they had previously seen or which were completely novel to them. Results: Compared with controls, posterior cerebellar activity in BVF patients was higher during spatial navigation than during visual memory tasks, in the absence of performance differences. This cerebellar activity correlated with disease duration. Conclusions: Cerebellar activity during spatial navigation in BVF patients may reflect increased non-vestibular efforts to counteract the development of spatial navigation deficits in BVF. Conceivably, cerebellar activity indicates a change in navigational strategy of BVF patients, i.e. from a more allocentric, landmark or place-based strategy (hippocampus) to a more sequence-based strategy. This interpretation would be in accord with recent evidence for a cerebellar role in sequence-based navigation. [ABSTRACT FROM AUTHOR]

Ocular oscillations often have critical role in diagnostic algorithm of neurodegenerative disorders. Nystagmus, if present in parkinsonian syndrome, suggests cerebellar involvement that is typical of multiple system atrophy. We found vertical jerky oscillations of the eyes during oculographic assessments using head-fixed corneal curvature trackers in six patients with progressive supranuclear palsy. The oscillations were eliminated by adequate head stabilization of the patients. Although this phenomenon gave the initial impression of "downbeat nystagmus", the oscillations were phase locked and frequency matched with subtle jerky head oscillations. We interpreted such jerky eye oscillations as "pseudonystagmus" representing the vestibulo-ocular reflex in response to involuntary subtle jerky head oscillations in our patients. This study further emphasizes the importance of head stabilization during instrumented or clinical assessment of gaze holding. • Ocular oscillations play an important role in diagnosing neurodegenerative disorders. • Oculography showed vertical jerky eye oscillations in progressive supranuclear palsy. • The oscillations were frequency matched with subtle jerky head oscillations. • They were the vestibulo-ocular reflex in response to jerky head oscillations. [ABSTRACT FROM AUTHOR]

Adaptation of the horizontal vestibulo-ocular reflex (HVOR) provides an experimental model for cerebellum-dependent motor learning. We developed an eye movement measuring system and a paradigm for induction of HVOR adaptation for the common marmoset. The HVOR gain in dark measured by 10° (peak-to-peak amplitude) and 0.11–0.5 Hz turntable oscillation was around unity. The gain-up and gain-down HVOR adaptation was induced by 1 h of sustained out-of-phase and in-phase 10°–0.33 Hz combined turntable-screen oscillation in the light, respectively. To examine the role of long-term depression (LTD) of parallel fiber-Purkinje cell synapses, we intraperitonially applied T-588 or nimesulide, which block the induction of LTD in vitro or in vivo preparations, 1 h before the test of HVOR adaptation. T-588 (3 and 5 mg/kg body weight) did not affect nonadapted HVOR gains, and impaired both gain-up and gain-down HVOR adaptation. Nimesulide (3 and 6 mg/kg) did not affect nonadapted HVOR gains, and impaired gain-up HVOR adaptation dose-dependently; however, it very little affected gain-down HVOR adaptation. These findings are consistent with the results of our study of nimesulide on the adaptation of horizontal optokinetic response in mice ( Le et al., 2010 ), and support the view that LTD underlies HVOR adaptation. [ABSTRACT FROM AUTHOR]

Abstract: Compensatory eye movements (CEMs) stabilize the field of view enabling visual sharpness despite self-induced motion or environmental perturbations. The vestibulocerebellum makes it possible to adapt these reflex behaviors to perform optimally under novel circumstances that are sustained over time. Because of this and the fact that the eye is relatively insensitive to fatigue and musculoskeletal aging effects, CEMs form an ideal motor system to assess aging effects on cerebellar motor learning. In the present study, we performed an extensive behavioral examination of the impact of aging on both basic CEMs and oculomotor-based learning paradigms spanning multiple days. Our data show that healthy aging has little to no effect on basic CEM performance despite sensory deterioration, suggesting a central compensatory mechanism. Young mice are capable of adapting their oculomotor output to novel conditions rapidly and accurately, even to the point of reversing the direction of the reflex entirely. However, oculomotor learning and consolidation capabilities show a progressive decay as age increases. [Copyright &y& Elsevier]

Abstract: Compensatory counter-rotations of the eyes provoked by head turns are commonly attributed to the vestibulo-ocular reflex (VOR). A recent study in guinea pigs demonstrates, however, that this assumption is not always valid. During voluntary head turns, guinea pigs make highly accurate compensatory eye movements that occur with zero or even negative latencies with respect to the onset of the provoking head movements. Furthermore, the anticipatory eye movements occur in animals with bilateral peripheral vestibular lesions, thus confirming that they have an extra vestibular origin. This discovery suggests the possibility that anticipatory responses might also occur in other species including humans and non-human primates, but have been overlooked and mistakenly identified as being produced by the VOR. This review will compare primate and guinea pig vestibular physiology in light of these new findings. A unified model of vestibular and cerebellar pathways will be presented that is consistent with current data in primates and guinea pigs. The model is capable of accurately simulating compensatory eye movements to active head turns (anticipatory responses) and to passive head perturbations (VOR induced eye movements) in guinea pigs and in human subjects who use coordinated eye and head movements to shift gaze direction in space. Anticipatory responses provide new evidence and opportunities to study the role of extra vestibular signals in motor control and sensory–motor transformations. Exercises that employ voluntary head turns are frequently used to improve visual stability in patients with vestibular hypofunction. Thus, a deeper understanding of the origin and physiology of anticipatory responses could suggest new translational approaches to rehabilitative training of patients with bilateral vestibular loss. [Copyright &y& Elsevier]

Abstract: Objective: We examined the emerging vertical component after cross-axis vestibulo-ocular reflex (VOR) adaptation. Methods: For the adaptive conditioning, the whole body of a subject was rotated horizontally while a visual pattern was rotated vertically for 1h. Results: During the conditioning period, the vertical component in response to the vertical visual stimulation was an up-down asymmetric, and its amplitude gradually increased as the stimulus progressed. After conditioning, the direction of VOR was changed via an emerging vertical component during horizontal head rotation in total darkness. Even though the retinal slip-velocity was greater for downward than for upward during the conditioning period, the emerging upward component was significantly larger than the emerging downward component. Conclusion: These results may be helpful for developing an optimal vestibular-compensation system by visual–vestibular mismatch/optokinetic training. [Copyright &y& Elsevier]

Abstract: Following unilateral vestibular damage (UVD), vestibular compensation restores both static and dynamic vestibular reflexes. The cerebellar cortex provides powerful GABAergic inhibitory input to the vestibular nuclei which is necessary for compensation. Metabotropic GABA type B (GABAB) receptors in the vestibular nuclei are thought to be involved. However, the contribution of GABAB receptors may differ between static and dynamic compensation. We tested static and dynamic postural reflexes and gait in young mice, while they compensated for UVD caused by injection of air into the vestibular labyrinth. The effects of an agonist (baclofen), an antagonist (CGP56433A) and a positive allosteric modulator (CGP7930) of the GABAB receptor were evaluated during compensation. Static postural reflexes recovered very rapidly in our model, and baclofen slightly accelerated recovery. However, CGP56433A significantly impaired static compensation. Dynamic reflexes were evaluated by balance-beam performance and by gait; both showed significant decrements following UVD and performance improved over the next 2 days. Both CGP56433A and baclofen temporarily impaired the ability to walk on a balance beam after UVD. Two days later, there were no longer any significant effects of drug treatments on balance-beam performance. Baclofen slightly accelerated the recovery of stride length on a flat surface, but CGP7930 worsened the gait impairment following UVD. Using immunohistochemistry, we confirmed that GABAB receptors are abundantly expressed on the vestibulospinal neurons of Deiters in mice. Our results suggest that GABAB receptors contribute to the compensation of static vestibular reflexes following unilateral peripheral damage. We also conclude that impairment of the first stage of compensation, static recovery, does not necessarily result in an impairment of dynamic recovery in the long term. [Copyright &y& Elsevier]

Abstract: Internal models are a key feature of most modern theories of motor control. Yet, it has been challenging to localize internal models in the brain, or to demonstrate that they are more than a metaphor. In the present review, I consider a large body of data on the cerebellar floccular complex, asking whether floccular output has features that would be expected of the output from internal models. I argue that the simple spike firing rates of a single group of floccular Purkinje cells could reflect the output of three different internal models. (1) An eye velocity positive feedback pathway through the floccular complex provides neural inertia for smooth pursuit eye movements, and appears to operate as a model of the inertia of real-world objects. (2) The floccular complex processes and combines input signals so that the dynamics of its average simple spike output are appropriate for the dynamics of the downstream brainstem circuits and eyeball. If we consider the brainstem circuits and eyeball as a more broadly conceived “oculomotor plant,” then the output from the floccular complex could be the manifestation of an inverse model of “plant” dynamics. (3) Floccular output reflects an internal model of the physics of the orbit where head and eye motion sum to produce gaze motion. The effects of learning on floccular output suggest that it is modeling the interaction of the visually-guided and vestibular-driven components of eye and gaze motion. Perhaps the insights from studying oculomotor control provide groundwork to guide the analysis of internal models for a wide variety of cerebellar behaviors. [Copyright &y& Elsevier]

Abstract: The vestibulo-ocular reflex (VOR) exhibits motor learning that initially depends on synaptic plasticity in the cerebellar cortex. Learned decreases in VOR gain can be disrupted by rotation in darkness immediately following learning, but consolidate rapidly if the disruption stimulus is delayed. Disruption may simply reverse the synaptic changes that have recently occurred, or it may reflect new learning at other sites. The alternative to disruption, rapid consolidation, also may take place by altering the existing memory trace or may require changes at other locations. To test these possibilities, we induced decreases in the gain of the VOR in cats that wore miniaturizing goggles. Using a range of frequencies of rotation, we investigated the patterns of generalization for disruption and for rapid consolidation of the learned changes in gain. Learning was most effective at the particular frequencies that were used during training. However, disruption and rapid consolidation were not more effective at the rotation frequencies that were used during training. Instead, after consolidation, the memory retained the frequency tuning that had been established during the learning process. We conclude that disruption and rapid consolidation may not require new learning. [Copyright &y& Elsevier]

Much literature has studied the relationship between the organization of neurons in the flocculus/ventral paraflocculus and vestibulo-ocular reflex pathways. Although activation of a flocculus central zone produces ipsilateral horizontal eye movement, anatomical tracing evidence in rats suggests that there may not be a simple one-to-one correspondence between flocculus/ventral paraflocculus zones and control of single extraocular muscles or coplanar pairs of antagonistic extraocular muscles. This study used the retrograde transynaptic transport of pseudorabies virus to identify the topographical organization of Purkinje cells in the flocculus/ventral paraflocculus that control the lateral rectus (LR) and medial rectus (MR) muscles in rats. A survival time of 80 h and 84 h was necessary to observe consistent transynaptically labeled cells in the flocculus/ventral paraflocculus following injections of pseudorabies virus into the MR and LR, respectively. The organization of Purkinje cells in the dorsal flocculus and ventral paraflocculus abided by the traditional boundaries, whereas the labeling pattern in the ventral flocculus showed a more complex, interdigitated arrangement. In agreement with prior studies, transynaptically labeled neurons were also observed in specific vestibular nuclear regions within the medial and superior vestibular nuclei and dorsal Y group. The distribution of labeled neurons in ipsilateral and contralateral vestibular nuclei was associated with features of ipsilateral and contralateral retrograde labeling of Purkinje cells in flocculus/ventral paraflocculus. Importantly, this study provides the first evidence of vestibulo-cerebellar zones controlling individual extraocular muscles and also overlapping distribution of neurons in flocculo-vestibular zones that influence the LR and MR motoneuron pools. This suggests that some of these neurons may be responsible for controlling both muscles. [Copyright &y& Elsevier]

Metabotropic glutamate receptor subtype 1 (mGluR1) plays an essential role in the cerebellar long-term depression (LTD). We examined the dynamic characteristics and adaptability of horizontal vestibulo-ocular reflex (HVOR) and optokinetic response (HOKR) eye movements in mGluR1 knockout mice. A mild difference was seen in the HOKR/HVOR dynamics between the wild-type and mGluR1(−/−) mice. Exposure to 1 h of sustained screen oscillation, which induced HOKR adaptation in wild-type mice, induced no change in mutant mice. These results suggest that the mGluR1 plays an essential role in the adaptation of HOKR, and LTD underlies the adaptation of ocular reflexes. [Copyright &y& Elsevier]

Introduction Downbeat nystagmus (DBN) is the most common form of acquired fixation nystagmus. Patients typically suffer from oscillopsia and postural instability. Postural symptoms are known to improve during walking, in particular at fast speeds ( Schniepp et al., 2014 ); however, it is unknown whether locomotion also influences ocular motor symptoms in these patients. We thus investigated the frequency and timing of DBN occurrence during standing and walking at different speeds in patients with DBN. Methods Eye movements of DBN patients with clear central-gaze nystagmus were recorded using video-oculography during standing as well as treadmill walking at individual slow, preferred and fast speeds. Subjects were instructed to fixate on a target straight in front of them at 2 m distance. We analyzed the frequency and timing of occurrence of compensatory quick-phases (downbeats) throughout the gait cycle as well as the angular and linear components of the vestibulo-ocular-reflex (VOR) to assess general gaze stabilization performance during walking in these patients. Results were compared to healthy controls. Results Compared to rest, slow walking significantly lowered the frequency of DBN occurrence in all patients. With increasing walking speed, DBN frequency was further reduced and in some subjects even fully suppressed during fast walking. In addition, DBN events predominantly occurred at the start of the swing phase, indicating that DBN occurrence is phase-coupled to distinct periods of the gait cycle. Whereas angular VOR gains of patients during walking were comparable to those of healthy subjects, linear VOR components were found to be significantly decreased. Conclusion DBN ocular-motor symptoms improve during walking, in particular at fast speeds, indicating a speed-dependent re-weighting of the involved vestibulo-cerebellar pathways during locomotion. In addition, compensatory quick-phase eye movements (downbeats) most frequently occur during distinct phases of the gait cycle, suggesting that a phase-coupled locomotor feedback such as spinal motor efference copies influences the brain networks associated with downbeat nystagmus. Notable deficits in compensating linear head motion during walking indicate impairments in pathways processing otolithic inputs, despite an intact integration of vestibular cues from the semicircular canals ( Glasauer et al., 2004 ). [ABSTRACT FROM AUTHOR]