Vestibulo-ocular Reflex Adaptation Research Articles

PP2B-Dependent Cerebellar Plasticity Sets the Amplitude of the Vestibulo-ocular Reflex during Juvenile Development.

Throughout life, the cerebellum plays a central role in the coordination and optimization of movements, using cellular plasticity to adapt a range of behaviors. Whether these plasticity processes establish a fixed setpoint during development, or continuously adjust behaviors throughout life, is currently unclear. Here, by spatiotemporally manipulating the activity of protein phosphatase 2B (PP2B), an enzyme critical for cerebellar plasticity in male and female mice, we examined the consequences of disrupted plasticity on the performance and adaptation of the vestibulo-ocular reflex (VOR). We find that, in contrast to Purkinje cell (PC)-specific deletion starting early postnatally, acute pharmacological as well as adult-onset genetic deletion of PP2B affects all forms of VOR adaptation but not the level of VOR itself. Next, we show that PC-specific genetic deletion of PP2B in juvenile mice leads to a progressive loss of the protein PP2B and a concurrent change in the VOR, in addition to the loss of adaptive abilities. Finally, re-expressing PP2B in adult mice that lack PP2B expression from early development rescues VOR adaptation but does not affect the performance of the reflex. Together, our results indicate that chronic or acute, genetic, or pharmacological block of PP2B disrupts the adaptation of the VOR. In contrast, only the absence of plasticity during cerebellar development affects the setpoint of VOR, an effect that cannot be corrected after maturation of the cerebellum. These findings suggest that PP2B-dependent cerebellar plasticity is required during a specific period to achieve the correct setpoint of the VOR.

The vergence-mediated gain increase: Physiology and clinical relevance.

During near-viewing, the vestibulo-ocular reflex (VOR) response/gain increases to compensate for the relatively larger translation of the eyes with respect to the target. To review vergence-mediated gain increase (VMGI) testing methods stimuli and responses (latency and amplitude), peripheral/central pathways and clinical relevance. The authors discuss publications listed in PUBMED since 1980 in the light of their own studies. The VMGI can be measured during rotational, linear and combined head accelerations. It has short-latency, non-compensatory amplitude, and relies on irregularly discharging peripheral afferents and their pathways. It is driven by a combination of perception, visual-context and internal modelling. Currently, there are technical barriers that hinder VMGI measurement in the clinic. However, the VMGI may have diagnostic value, especially with regards to measuring otolith function. The VMGI also may have potential value in rehabilitation by providing insight about a patient's lesion and how to best tailor a rehabilitation program for them, that potentially includes VOR adaptation training during near-viewing.

Assessment of vestibulo-ocular reflex and its adaptation during stop-and-go car rides in motion sickness susceptible passengers

Motion sickness is a physiological condition that negatively impacts a person's comfort and will be an emerging condition in autonomous vehicles without proper countermeasures. The vestibular system plays a key role in the origin of motion sickness. Understanding the susceptibility and (mal) adaptive mechanisms of the highly integrated vestibular system is a prerequisite for the development of countermeasures. We hypothesize a differential association between motion sickness and vestibular function in healthy individuals with and without susceptibility for motion sickness. We quantified vestibular function by measuring the high-frequency vestibulo-ocular reflex (VOR) using video head impulse testing (vHIT) in 17 healthy volunteers before and after a 11 min motion sickness-inducing naturalistic stop-and-go car ride on a test track (Dekra Test Oval, Klettwitz, Germany). The cohort was classified as motion sickness susceptible (n = 11) and non-susceptible (n = 6). Six (out of 11) susceptible participants developed nausea symptoms, while a total of nine participants were free of these symptoms. The VOR gain (1) did not differ significantly between participant groups with (n = 8) and without motion sickness symptoms (n = 9), (2) did not differ significantly in the factor time before and after the car ride, and showed no interaction between symptom groups and time, as indicated by a repeated measures ANOVA (F(1,15) = 2.19, p = 0.16. Bayesian inference confirmed that there was “anecdotal evidence” for equality of gain rather than difference across groups and time (BF10 < 0.77). Our results suggest that individual differences in VOR measures or adaptation to motion sickness provocative stimuli during naturalistic stop-and-go driving cannot predict motion sickness susceptibility or the likelihood of developing motion sickness.

Effect of a differential training paradigm with varying frequencies and amplitudes on adaptation of vestibulo-ocular reflex in mice.

The vestibulo-ocular reflex (VOR) functions to maintain eye stability during head movement, and VOR gain can be dynamically increased or decreased by gain-up or gain-down adaptation. In this study, we investigated the impact of a differential training paradigm with varying frequencies and amplitudes on the level of VOR adaptation in mice. Training for gain-up (out of phase) or gain-down (in phase) VOR adaptation was applied for 60min using two protocols: (1) oscillation of a drum and turntable with fixed frequency and differing amplitudes (0.5Hz/2.5°, 0.5Hz/5° and 0.5Hz/10°). (2) Oscillation of a drum and turntable with fixed amplitude and a differing frequency (0.25Hz/5°, 0.5Hz/5° and 1Hz/5°). VOR adaptation occurred distinctively in gain-up and gain-down learning. In gain-up VOR adaptation, the learned increase in VOR gain was greatest when trained with the same frequency and amplitude as the test stimulation, and VOR gain decreased after gain-up training with too high a frequency or amplitude. In gain-down VOR adaptation, the decrease in VOR gain increased as the training frequency or amplitude increased. These results suggest that different mechanisms are, at least in part, involved in gain-up and gain-down VOR adaptation.

Virtual reality set-up for studying vestibular function during head impulse test.

Virtual reality (VR) offers an ecological setting and the possibility of altered visual feedback during head movements useful for vestibular research and treatment of vestibular disorders. There is however no data quantifying vestibulo-ocular reflex (VOR) during head impulse test (HIT) in VR. The main objective of this study is to assess the feasibility and performance of eye and head movement measurements of healthy subjects in a VR environment during high velocity horizontal head rotation (VR-HIT) under a normal visual feedback condition. The secondary objective is to establish the feasibility of VR-HIT recordings in the same group of normal subjects but under altered visual feedback conditions. Twelve healthy subjects underwent video HIT using both a standard setup (vHIT) and VR-HIT. In VR, eye and head positions were recorded by using, respectively, an imbedded eye tracker and an infrared motion tracker. Subjects were tested under four conditions, one reproducing normal visual feedback and three simulating an altered gain or direction of visual feedback. During these three altered conditions the movement of the visual scene relative to the head movement was decreased in amplitude by 50% (half), was nullified (freeze) or was inverted in direction (inverse). Eye and head motion recording during normal visual feedback as well as during all 3 altered conditions was successful. There was no significant difference in VOR gain in VR-HIT between normal, half, freeze and inverse conditions. In the normal condition, VOR gain was significantly but slightly (by 3%) different for VR-HIT and vHIT. Duration and amplitude of head impulses were significantly greater in VR-HIT than in vHIT. In all three altered VR-HIT conditions, covert saccades were present in approximatively one out of four trials. Our VR setup allowed high quality recording of eye and head data during head impulse test under normal and altered visual feedback conditions. This setup could be used to investigate compensation mechanisms in vestibular hypofunction, to elicit adaptation of VOR in ecological settings or to allow objective evaluation of VR-based vestibular rehabilitation.

Molecular and Functional Changes to Postsynaptic Cholinergic Signaling in the Vestibular Sensory Organs of Aging C57BL/6Mice.

Cholinergic circuits in the central nervous system are vulnerable to age-related functional decline, but it is not known if aging impacts cholinergic signaling in the vestibular sensory organs, which are critically important to balance maintenance and visual gaze stability. We have previously shown cholinergic neurotransmission between vestibular efferent terminals and type II mechanosensory hair cells requires the alpha9 (Chrna9) nicotinic receptor subunit. Homozygous knockout of the alpha9 subunit causes vestibulo-ocular reflex adaptation deficits that mirror those observed in aged mice. This prompted examination of cholinergic signaling in the vestibular sensory organs of aged mice. We confirmed older (>24months) mice had impaired performance in a balance beam task compared to young (3-4months) adult mice. While there was no qualitative loss of cholinergic axon varicosities in the crista ampullaris of old mice, qPCR analysis revealed reduced expression of nicotinic receptor subunit genes Chrna1, Chrna9, and Chrna10 in the cristae of old relative to young mice. Functionally, single-cell patch clamp recordings taken from type II vestibular hair cells exposed to acetylcholine show reduced conductance through alpha9/10 subunit-containing nicotinic receptors in older mice, despite preserved passive membrane properties and voltage-activated conductances. These findings suggest that cholinergic signaling in the peripheral vestibular sensory organs is vulnerable to aging processes, manifesting in dynamic molecular and functional age-related changes. Given the importance of these organs to our everyday activities, and the dramatic increase in fall incidence in the older, further investigation into the mechanisms of altered peripheral vestibular function in older humans is warranted.

Effectiveness and acceptance of Vestibulo-Ocular Reflex adaptation training in children with recurrent vertigo with unilateral vestibular dysfunction and normal balance function.

This was a block randomized controlled study to evaluate the effectiveness and acceptance of Vestibulo-Ocular Reflex (VOR) adaptation training in children with recurrent vertigo with unilateral vestibular dysfunction (UVD) and normal balance function. Thirty children, aged 4-13 years, diagnosed with recurrent vertigo of childhood (RVC) with UVD (according to a caloric test) and normal balance function were analyzed. These 30 children were divided into 10 blocks based on similar age and severity of vertigo. Three children in each block were randomly assigned to one of three groups to receive 1 month of treatment. Group A received vestibular-ocular reflex (VOR) adaptation training, Group B received Cawthorne-Cooksey training, and a control group received no training. All children were administered pharmacotherapy [Ginkgo biloba leaf extract (drops)]. The Dizziness Handicap Inventory (DHI), Visual Analog Scale of Quality of Life with Vertigo (VAS-QLV), and canal paralysis (CP) on the caloric test were recorded before and after treatment, and the effectiveness of treatment was evaluated. The Visual Analog Scale of Acceptance (VAS-A) was used to evaluate the acceptance of the training in the two groups that received training. There were 10 children each in Group A, Group B, and the control group; the male to female ratio was 1, and the average age in each group was 9.0 ± 3.2, 8.4 ± 3.0, and 8.3 ± 2.6 years, respectively. The effective rate was 100% in Group A, 65% in Group B, and 60% in Group C. The recovery rate on caloric testing after treatment was 100, 70, and 50%, respectively. DHI scores before and after training were 56.8 ± 12.4 and 8.8 ± 6.1 in Group A, 57.8 ± 12.6 and 18.8 ± 9.7 in Group B, and 56.8 ± 12.4 and 24.0 ± 15.3 in Group C (all P = 0.000). VAS-QLV scores before and after training were 7.5 ± 1.0 and 0.9 ± 0.9 in Group A, 6.4 ± 2.2 and 2.7 ± 1.1 in Group B, and 6.6 ± 1.6 and 2.6 ± 1.4 in Group C (all P < 0.05). The CP values before and after training were 35.7 ± 15.1 and 12.9 ± 8.7 in Group A, 33.6 ± 20.1 and 23.6 ± 19.3 in Group B, and 38.6 ± 21.1 and 24.8 ± 17.9 in Group C (P = 0.001, P = 0.015, and P = 0.050, respectively). Between-group comparisons showed that the decreases in DHI and VAS-QLV scores after training were significantly different (P = 0.015, P = 0.02), while CP values were not (P = 0.139). After training, the DHI value had decreased significantly more in Group A compared with Group C (P < 0.05), but there were no other differences. After training, VAS-QLV scores in Group A had decreased significantly more compared with Group B and C (P < 0.05). In terms of acceptance, the VAS-A score was 7.6 ± 2.2 in Group A and 3.1 ± 2.8 in Group B (P =0.004), The acceptance rate was 70% in group A and 10% in group B. there was no significant correlation between age and VAS-A in either group A or group B (P > 0.05). This study strongly suggests that vestibular rehabilitation training should be performed in children with vertigo to improve symptoms. For children with RVC with UVD but normal balance function, a single VOR adaptation program can effectively improve vertigo symptoms, and given its simplicity, time-effectiveness, and excellent outcomes, it is associated with better acceptance in children compared to classic Cawthorne-Cooksey training.

Expression of a Form of Cerebellar Motor Memory Requires Learned Alterations to the Activity of Inhibitory Molecular Layer Interneurons.

Procedural memories formed in the cerebellum in response to motor errors depend on changes to Purkinje cell (PC) spiking patterns that correct movement when the erroneous context is repeated. Because molecular layer interneurons (MLIs) inhibit PCs, learning-induced changes to MLI output may participate in reshaping PC spiking patterns. However, it remains unclear whether error-driven learning alters MLI activity and whether such changes are necessary for the memory engram. We addressed this knowledge gap by measuring and manipulating MLI activity in the flocculus of both sexes of mice before and after vestibulo-ocular reflex (VOR) adaptation. We found that MLIs are activated during vestibular stimuli and that their population response exhibits a phase shift after the instantiation of gain-increase VOR adaptation, a type of error-driven learning thought to require climbing-fiber-mediated instructive signaling. Although acute optogenetic suppression of MLI activity did not affect baseline VOR performance, it negated the expression of gain-increase learning, demonstrating a specific role of MLI activity changes in motor memory expression. This effect was transitory; after a multiday consolidation period, the expression of VOR gain-increase learning was no longer sensitive to MLI activity suppression. Together, our results indicate that error-driven alteration of MLI activity is necessary for labile, climbing-fiber-induced motor memory expression.SIGNIFICANCE STATEMENT In the cerebellum, motor learning induces an associative memory of the sensorimotor context of an erroneous movement that, when recalled, results in a new pattern of output that improves subsequent trials of performance. Our study shows that error-driven motor learning induces changes to the activity pattern of cerebellar molecular layer interneurons (MLIs) and that this new pattern of activity is required to express the corrective motor memory.

Electrical coupling regulated by GABAergic nucleo-olivary afferent fibres facilitates cerebellar sensory–motor adaptation

The inferior olivary (IO) nucleus makes up the signal gateway for several organs to the cerebellar cortex. Located within the sensory–motor-cerebellum pathway, the IO axons, i.e., climbing fibres (CFs), massively synapse onto the cerebellar Purkinje cells (PCs) regulating motor learning whilst the olivary nucleus receives negative feedback through the GABAergic nucleo-olivary​ (NO) pathway. The NO pathway regulates the electrical coupling (EC) amongst the olivary cells thus facilitating synchrony and timing. However, the involvement of this EC regulation on cerebellar adaptive behaviour is still under debate. In our study we have used a spiking cerebellar model to assess the role of the NO pathway in regulating vestibulo-ocular-reflex (VOR) adaptation. The model incorporates spike-based synaptic plasticity at multiple cerebellar sites and an electrically-coupled olivary system. The olivary system plays a central role in regulating the CF spike-firing patterns that drive the PCs, whose axons ultimately shape the cerebellar output. Our results suggest that a systematic GABAergic NO deactivation decreases the spatio-temporal complexity of the IO firing patterns thereby worsening the temporal resolution of the olivary system. Conversely, properly coded IO spatio-temporal firing patterns, thanks to NO modulation, finely shape the balance between long-term depression and potentiation, which optimises VOR adaptation. Significantly, the NO connectivity pattern constrained to the same micro-zone helps maintain the spatio-temporal complexity of the IO firing patterns through time. Moreover, the temporal alignment between the latencies found in the NO fibres and the sensory–motor pathway delay appears to be crucial for facilitating the VOR. When we consider all the above points we believe that these results predict that the NO pathway is instrumental in modulating the olivary coupling and relevant to VOR adaptation.

Vestibulo-Ocular Reflex Short-Term Adaptation Is Halved After Compensation for Unilateral Labyrinthectomy.

Several prior studies, including those from this laboratory, have suggested that vestibulo-ocular reflex (VOR) adaptation and compensation are two neurologically related mechanisms. We therefore hypothesised that adaptation would be affected by compensation, depending on the amount of overlap between these two mechanisms. To better understand this overlap, we examined the effect of gain-increase (gain = eye velocity/head velocity) adaptation training on the VOR in compensated mice since both adaptation and compensation mechanisms are presumably driving the gain to increase. We tested 11 cba129 controls and 6 α9-knockout mice, which have a compromised efferent vestibular system (EVS) known to affect both adaptation and compensation mechanisms. Baseline VOR gains across frequencies (0.2 to 10Hz) and velocities (20 to 100°/s) were measured on day 28 after unilateral labyrinthectomy (UL) and post-adaptation gains were measured after gain-increase training on day 31 post-UL. Our findings showed that after chronic compensation gain-increase adaptation, as a percentage of baseline, in both strains of mice (~14%), was about half compared to their previously reported healthy, non-operated counterparts (~32%). Surprisingly, there was no difference in gain-increase adaptation between control and α9-knockout mice. These data support the notion that adaptation and compensation are separate but overlapping processes. They also suggest that half of the original adaptation capacity remained in chronically compensated mice, regardless of EVS compromise associated with α9-knockout mice, and strongly suggest VOR adaptation training is a viable treatment strategy for vestibular rehabilitation therapy and, importantly, augments the compensatory process.

Adaptation of vestibulo-ocular and optokinetic reflexes after massed and spaced vestibulo-ocular motor learning

Although the superiority of spaced training over massed training has been established in many forms of learning, the learning efficacy between the two with respect to time efficiency may not be simply compared because a longer total duration of learning is required in spaced training than massed training due to spacing intervals intervening between training sessions in the former. The purpose of the present study was to evaluate the differences in the adaptation of the vestibulo-ocular reflex (VOR) and optokinetic reflex (OKR) after visuo-vestibular training, and to investigate the efficacy of spaced and massed training in mice. Associative visuo-vestibular stimulation was applied to induce VOR and OKR motor learning. Training paradigms were categorized into five groups according to the duration of the spacing interval, keeping the total training time including spacing equal in all training paradigms. Both gain-up VOR training, which increased VOR gain and gain-down VOR training, which decreased VOR gain, increased OKR gain in the massed and spaced learning paradigms. While the increment in OKR gain after gain-up and gain-down training was maintained at 48 h after the end of the last training session, the change in VOR gain by gain-up or gain-down training recovered gradually after training. The OKR adaptation was still in progress during the spacing interval, and the amount of gain increase was greater with longer spacing interval. On the other hand, the VOR gain change after gain-up and gain-down training substantially recovered during the spacing interval. In conclusion, the present study, using learning paradigms with same total duration of training, demonstrated that the spacing effect was more robust in the adaptation of OKR than that of VOR, and the learning effect was maintained longer in OKR than in VOR. These differences in the adaptation of VOR and OKR following identical training conditions suggest that multiple plasticity mechanisms may be differentially involved in the gaze stabilization circuitry.

The Clinical Concept of LTDpathy: Is Dysregulated LTD Responsible for Prodromal Cerebellar Symptoms?

Long-term depression at parallel fibers-Purkinje cells (PF-PC LTD) is essential for cerebellar motor learning and motor control. Recent progress in ataxiology has identified dysregulation of PF-PC LTD in the pathophysiology of certain types of immune-mediated cerebellar ataxias (IMCAs). Auto-antibodies towards voltage-gated Ca channel (VGCC), metabotropic glutamate receptor type 1 (mGluR1), and glutamate receptor delta (GluR delta) induce dysfunction of PF-PC LTD, resulting in the development of cerebellar ataxias (CAs). These disorders show a good response to immunotherapies in non-paraneoplastic conditions but are sometimes followed by cell death in paraneoplastic conditions. On the other hand, in some types of spinocerebellar ataxia (SCA), dysfunction in PF-PC LTD, and impairments of PF-PC LTD-related adaptive behaviors (including vestibulo-ocular reflex (VOR) and prism adaptation) appear during the prodromal stage, well before the manifestations of obvious CAs and cerebellar atrophy. Based on these findings and taking into account the findings of animal studies, we re-assessed the clinical concept of LTDpathy. LTDpathy can be defined as a clinical spectrum comprising etiologies associated with a functional disturbance of PF-PC LTD with concomitant impairment of related adaptative behaviors, including VOR, blink reflex, and prism adaptation. In IMCAs or degenerative CAs characterized by persistent impairment of a wide range of molecular mechanisms, these disorders are initially functional and are followed subsequently by degenerative cell processes. In such cases, adaptive disorders associated with PF-PC LTD manifest clinically with subtle symptoms and can be prodromal. Our hypothesis underlines for the first time a potential role of LTD dysfunction in the pathogenesis of the prodromal symptoms of CAs. This hypothesis opens perspectives to block the course of CAs at a very early stage.

A Once-Daily High Dose of Intraperitoneal Ascorbate Improves Vestibulo-ocular Reflex Compensation After Unilateral Labyrinthectomy in the Mouse.

Ascorbate potentiates the response of nicotinic-acetylcholine-receptors containing α9 and α10 subunits found predominantly in the efferent systems of the inner ear, such as the efferent vestibular system (EVS). Prior mouse studies have shown that an attenuated EVS results in reduced vestibulo-ocular reflex (VOR) gain (=eye_velocity/head_velocity) plasticity in intact (VOR adaptation) and surgically-lesioned (VOR compensation) mice. We sought to determine whether ascorbate-treatment could improve VOR recovery after vestibular organ injury, possibly through potentiation of the EVS pathway. We tested 10 cba129 mice, 5 received ascorbate-treatment and 5 did not, but otherwise experienced the same conditions. Ascorbate-treatment comprised a once-daily intraperitoneal injection of L-form reduced ascorbate (4 g/kg) in 0.2 ml saline starting 1 week before, and ending 4 weeks after, unilateral labyrinthectomy surgery. These were deliberately high doses to determine the ascorbate effects on recovery. Baseline, acute, and chronic sinusoidal VOR gains (frequency and velocity ranges: 0.2-10 Hz, 20-100 deg/s) were measured 3-5 days before, 3-5 days after, and 28-31 days after labyrinthectomy. Mice treated with ascorbate had acute ipsilesional VOR gains 12 % higher compared to control mice (+45.2 ± 14.9 % from baseline versus +33.7 ± 15.4 %, P < 0.001). Similarly, chronic ipsilesional and contralesional VOR gains were respectively 16 % (+74.3 ± 16.3 % from baseline versus +58.1 ± 15.8 %, P < 0.001) and 13 % (+78.6 ± 16.0 % versus +65.6 ± 10.9 %, P < 0.001) higher compared to control mice. These data suggest ascorbate-treatment had a prophylactic effect reducing acute loss, and helped recovery during acute to chronic stages of compensation. One possible mechanism is that an ascorbate-enhanced EVS drives an increase in the number and sensitivity of irregular-discharging primary vestibular afferents, important for VOR plasticity.

Computational epidemiology study of homeostatic compensation during sensorimotor aging

The vestibulo-ocular reflex (VOR) stabilizes vision during head motion. Age-related changes of vestibular neuroanatomical properties predict a linear decay of VOR function. Nonetheless, human epidemiological data show a stable VOR function across the life span. In this study, we model cerebellum-dependent VOR adaptation to relate structural and functional changes throughout aging. We consider three neurosynaptic factors that may codetermine VOR adaptation during aging: the electrical coupling of inferior olive neurons, the long-term spike timing-dependent plasticity at parallel fiber – Purkinje cell synapses and mossy fiber – medial vestibular nuclei synapses, and the intrinsic plasticity of Purkinje cell synapses Our cross-sectional aging analyses suggest that long-term plasticity acts as a global homeostatic mechanism that underpins the stable temporal profile of VOR function. The results also suggest that the intrinsic plasticity of Purkinje cell synapses operates as a local homeostatic mechanism that further sustains the VOR at older ages. Importantly, the computational epidemiology approach presented in this study allows discrepancies among human cross-sectional studies to be understood in terms of interindividual variability in older individuals. Finally, our longitudinal aging simulations show that the amount of residual fibers coding for the peak and trough of the VOR cycle constitutes a predictive hallmark of VOR trajectories over a lifetime.

Anti Zic4 Paraneoplastic Neurological Syndrome Presenting as Oscillopsia.

Anti Zic4 Paraneoplastic Neurological Syndrome Presenting as Oscillopsia.

Comparison of Incremental Vestibulo-ocular Reflex Adaptation Training Versus x1 Training in Patients With Chronic Peripheral Vestibular Hypofunction: A Two-Year Randomized Controlled Trial.

A crossover, double-blinded randomized controlled trial to investigate once-daily incremental vestibulo-ocular reflex (VOR) adaptation (IVA) training over 2 years in people with stable and chronic peripheral vestibular hypofunction. Twenty-one patients with peripheral vestibular hypofunction were randomly assigned to intervention-then-control (n = 12) or control-then-intervention (n = 9) groups. The task consisted of either x1 (control) or IVA training, once daily every day for 15 minutes over 6-months, followed by a 6-month washout, then repeated for arm 2 of the crossover. Primary outcome: vestibulo-ocular reflex gain. Secondary outcomes: compensatory saccades, dynamic visual acuity, static balance, gait, and subjective symptoms. Multiple imputation was used for missing data. Between-group differences were analyzed using a linear mixed model with repeated measures. On average patients trained once daily 4 days per week. IVA training resulted in significantly larger VOR gain increase (active: 20.6% ± 12.08%, P = 0.006; passive: 30.6% ± 25.45%, P = 0.016) compared with x1 training (active: -2.4% ± 12.88%, P = 0.99; passive: -0.6% ± 15.31%, P = 0.68) (P < 0.001). The increased IVA gain did not significantly reduce with approximately 27% persisting over the washout period. x1 training resulted in greater reduction of compensatory saccade latency (P = 0.04) and increase in amplitude (P = 0.02) compared with IVA training. There was no difference between groups in gait and balance measures; however, only the IVA group had improved total Dizziness Handicap Inventory (P = 0.006). Our results suggest IVA improves VOR gain and reduces perception of disability more than conventional x1 training. We suggest at least 4 weeks of once-daily 4 days-per-week IVA training should be part of a comprehensive vestibular rehabilitation program.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A356).

Clinical dynamic visual acuity in patients with cerebellar ataxia and vestibulopathy.

Deterioration of dynamic visual acuity (DVA) as a result of impaired vestibulo-ocular reflex (VOR) has been well described in peripheral vestibulopathies, however, changes in DVA in patients with degenerative cerebellar ataxias (CA) and its relation to VOR impairment in these patients has not yet been evaluated. Our aim was to assess the alterations of DVA in CA and to evaluate its relation to vestibular function. 32 patients with CA and 3 control groups: 13 patients with unilateral and 13 with bilateral vestibulopathy and 21 age matched healthy volunteers were examined by clinical DVA test, VOR was assessed by video Head Impulse Test and caloric irrigation. The severity of ataxia in CA was assessed by Scale for the assessment and rating of ataxia (SARA). Relationship between DVA and vestibular function in CA patients was examined by linear regressions. DVA impairment was highly prevalent in CA patients (84%) and its severity did not differ between CA and bilateral vestibulopathy patients. The severity of DVA impairment in CA was linked mainly to VOR impairment and only marginally to the degree of ataxia. However, DVA impairment was present also in CA patients without significant vestibular lesion showing that central mechanisms such as impairment of central adaptation of VOR are involved. We suggest that the evaluation of DVA should be a standard part of clinical evaluation in patients with progressive CA, as this information can help to target vestibular and oculomotor rehabilitation.

Once-Daily Incremental Vestibular-Ocular Reflex Adaptation Training in Patients With Chronic Peripheral Vestibular Hypofunction: A 1-Week Randomized Controlled Study

This was a double-blinded randomized controlled study to investigate the effects of once-daily incremental vestibulo-ocular reflex (VOR) training over 1 week in people with chronic peripheral vestibular hypofunction. A total of 24 patients with peripheral vestibular hypofunction were randomly assigned to intervention (n = 13) or control (n = 11) groups. Training consisted of either x1 (control) or incremental VOR adaptation exercises, delivered once daily for 15 minutes over 4 days in 1 week. Primary outcome: VOR gain with video-oculography. Secondary outcomes: Compensatory saccades measured using scleral search coils, dynamic visual acuity, static balance, gait, and subjective symptoms. Between-group differences were analyzed with a linear mixed-model with repeated measures. There was a difference in the VOR gain increase between groups (P < 0.05). The incremental training group gain increased during active (13.4% ± 16.3%) and passive (12.1% ± 19.9%) head impulse testing (P < 0.02), whereas it did not for the control group (P = 0.59). The control group had reduced compensatory saccade latency (P < 0.02). Both groups had similarly improved dynamic visual acuity scores (P < 0.05). Both groups had improved dynamic gait index scores (P < 0.002); however, only the incremental group had improved scores for the 2 walks involving head oscillations at approximately 2 Hz (horizontal: P < 0.05; vertical: P < 0.02), increased gait speed (P < 0.02), and step length (P < 0.01) during normal gait, and improved total Dizziness Handicap Inventory (P < 0.05). Our results suggest incremental VOR adaptation significantly improves gain, gait with head rotation, balance during gait, and symptoms in patients with chronic peripheral vestibular hypofunction more so than conventional x1 gaze-stabilizing exercises.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A336).

Unusual Vestibulo-Ocular Reflex Responses in Patients With Peripheral Vestibular Disorders Detected by the Caloric Step Stimulus Test.

The caloric step stimulus test consists of the changes in head position from the sitting to supine positions and continuous caloric irrigation. This test can provide a single labyrinth with a stimulus similar to constant head acceleration in rotational testing and, therefore, can evaluate vestibulo-ocular reflex (VOR) dynamics more precisely than can conventional methods. To assess the clinical utility of the test in the assessment of the VOR dynamics of diseases, we performed the test in patients with peripheral vestibular disorders, including sudden idiopathic hearing loss, vestibular neuritis, Meniere disease, vestibular Meniere disease, or chronic unilateral idiopathic vestibulopathy and normal controls. Slow-phase eye velocity (SPV) was measured with videonystagmography. We fitted the time course of SPV across 2 min to a mathematical model containing two exponential components and time constants: the caloric step VOR time constant (T1) and caloric step VOR adaptation time constant (T2). All responses of normal controls (n = 15 ears) were fit to the model. Several responses of the 101 ears of the patients differed from the time courses predicted by the model. We divided the data of 116 ears into four patterns based on SPV, T1, and T2. The thresholds for the classification were determined according to the lower limits of the capability of curve fitting for SPV and the upper limits of normal controls for T1 and T2. Seventy-eight ears followed pattern A (normal T1 and T2): the SPV trajectory formed a rapid rise with subsequent decay. Nineteen followed pattern B (normal T1 and prolonged T2): the SPV trajectory formed a rapid rise without decay. Six followed pattern C (prolonged T1 and T2): the SPV trajectory formed a slow rise. Thirteen ears followed pattern D: a low VOR response. There were no significant differences in time constants between the affected and healthy ears in patients with each disease. However, prolonged T1 and T2 were significantly more frequent in the affected ears than the healthy ears. In conclusion, the caloric step stimulus test can be potentially useful in detecting unusual VOR responses and thus reflect some pathological changes in the vestibular system.

Human Vestibulo-Ocular Reflex Adaptation Reduces when Training Demand Variability Increases.

One component of vestibular rehabilitation in patients with vestibulo-ocular reflex (VOR) hypofunction is gaze-stabilizing exercises that seek to increase (adapt) the VOR response. These prescribed home-based exercises are performed by the patient and thus their use/training is inherently variable. We sought to determine whether this variability affected VOR adaptation in ten healthy controls (× 2 training only) and ten patients with unilateral vestibular hypofunction (× 1 and × 2 training). During × 1 training, patients actively (self-generated, predictable) move their head sinusoidally while viewing a stationary fixation target; for × 2 training, they moved their outstretched hand anti-phase with their head rotation while attempting to view a handheld target. We defined the latter as manual × 2 training because the subject manually controls the target. In this study, head rotation frequency during training incrementally increased 0.5-2Hz over 20min. Active and passive (imposed, unpredictable) sinusoidal (1.3-Hz rotations) and head impulse VOR gains were measured before and after training. We show that for controls, manual × 2 training resulted in significant sinusoidal and impulse VOR adaptation of ~ 6% and ~ 3%, respectively, though this was ~two-thirds lower than increases after computer-controlled × 2 training (non-variable) reported in a prior study. In contrast, for patients, there was an increase in impulse but not sinusoidal VOR response after a single session of manual × 2 training. Patients had more than double the variability in VOR demand during manual × 2 training compared to controls, which could explain why adaptation was not significant in patients. Our data suggest that the clinical × 1 gaze-stabilizing exercise is a weak stimulus for VOR adaptation.