Vestibulo-ocular Reflex Adaptation Research Articles

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.

The instantaneous training demand drives vestibulo-ocular reflex adaptation.

The vestibulo-ocular reflex (VOR) maintains stable vision during rapid head rotations by rotating the eyes in the opposite direction to the head. The latency between onset of the head rotation and onset of the eye rotation is 5-8ms in healthy humans. However, VOR latency can be 3-4 times larger in patients treated with intra-tympanic gentamicin. A prior study showed that latency can be trained with head rotations at 0.2Hz. We sought to determine how the VOR is affected when a delay between vestibular and visual stimuli is added during adaptation training with high-frequency head rotations (impulses), where the VOR is the main vision-stabilizing system. Using a variant of the incremental VOR adaptation technique, the delay between head rotation onset and movement onset of a visual target was gradually increased. With this training, the instantaneous VOR gain demand (= target/head velocity) varied from less than unity to greater than unity during each head impulse, albeit in a consistent and repeatable way. We measured the active and passive VOR gain and latency before and after VOR adaptation training in healthy normal subjects. There was no significant change in VOR latency across subjects; however, there was a significant decrease in VOR gain of - 6.0 ± 4.5%. These data suggest that during high-frequency head rotations delay/latency is interpreted as a changing instantaneous VOR gain demand. Although the gain demand in this study had a complex trajectory, adaptation was evident with the VOR seeming to use an average of the instantaneous gain demand.

Effects of Vestibular Training on Postural Control of Healthy Adults

Background: Postural stability depends on the integration of multisensory inputs to drive motor outputs. When visual and somatosensory input is available and reliable, this reduces the postural control system’s reliance on the vestibular system. Despite this, vestibular loss can still cause severe postural dysfunction (1,2). Training one or more of the three sensory systems can alter sensory weighting and change postural behavior. Vestibular activation exercises, including horizontal and vertical headshaking, influence vestibular-ocular and -motor responses and have been showed to be effective in vestibular rehabilitation (3–8). 
 Purpose/Hypothesis: To assess sensory reweighting of postural control processing and vestibular-ocular and -motor responses after concurrent vestibular activation with postural training. It was hypothesized that the effect of this training would significantly alter the pattern of sensory weighting by changing the ratio of visual, somatosensory and vestibular dependence needed to maintain postural stability, and significantly decrease vestibular responses.
 Methods: Forty-two young healthy individuals (22 females; 23.0+3.9 years; 1.6+0.1 meters) were randomly assigned into four groups: 1) visual feedback weight shift training (WST) coupled with an active horizontal headshake (HHS), 2) same WST with vertical headshake (VHS), 3) WST with no headshake (NHS) and 4) no training/headshake control (CTL) groups. The headshake groups performed an intensive body WST together with horizontal or vertical rhythmic headshake at 80 to 120 beats/minute. The NHS group performed the WST with no headshake while the controls did not perform any training. Five 15-minute training sessions were performed on consecutive days for one week with the weight shift exercises involving upright limits of stability activities on a flat surface, foam or rocker board (Fig. 1). All groups performed baseline- and post-assessments including sensory organization test (SOT) and force platform ramp perturbations, coupled with electromyographic (EMG) recordings. A video head impulse test was also used to record horizontal vestibulo-ocular reflex (VOR) gain. A between- and within-group repeated measures ANOVA was used to analyze five COP sway variables, the equilibrium and composite scores and sensory ratios of the SOT as well as EMG signals and horizontal VOR gain. Similarly, COP variables, EMG, as well as vestibular reflex data (vertical VOR, vestibulo-collic reflex [VCR] and vestibulo-spinal [VSR] gains) during ramp perturbations were analyzed. Alpha level was set at p<.05.
 Results: The training showed a significant somatosensory downweighting (p=.050) in the headshake groups compared to the other groups. Training also showed significant decreased horizontal VOR gain (p=.040), faster automatic postural response (p=.003) (Figs. 2-4) with improved flexibility (p=.010) in the headshake groups. Muscle activation pattern in medial gastrocnemius (p=.033) was significantly decreased in the headshake.
 Conclusion: The concurrent vestibular activation and weight shift training modifies vestibular-dependent responses after the training intervention as evidenced in somatosensory downweighting, decreased VOR gain, better postural flexibility and faster automatic postural response. Findings suggest this is predominantly due to vestibular adaptation and habituation of VOR, VCR and VSR which induced sensory reweighting.
 Clinical relevance: Findings may be used to guide the development of a vestibular-postural rehabilitation intervention in impaired neurological populations, such as with vestibular disorders or sensory integration problems.

Retinal Image Slip Must Pass the Threshold for Human Vestibulo-Ocular Reflex Adaptation.

We sought to determine whether repeated vestibulo-ocular reflex (VOR) adaptation training to increase the VOR gain (eye/head velocity) had a lasting effect in normal subjects and whether there was a retinal image slip tolerance threshold for VOR adaptation. We used the unilateral incremental VOR adaptation technique and horizontal active (self-generated, predictable) head impulses as the vestibular stimulus. Both active and passive (imposed, unpredictable) head impulse VOR gains were measured before and after unilateral incremental VOR adaptation training. The adapting side was pseudo-randomized for left or right. We tested ten normal subjects over one block (10 sessions over 12days) of VOR adaptation training and testing, immediately followed by a second block (5 sessions over 19days) of testing only without training. Our findings show robust short-term VOR adaptation of ~ 10% immediately after each 15-min training session, but that the daily pre-adaptation gain was most different on days 1 and 2, and for subsequent training days before saturating to ~ 5% greater than the pre-adaptation gain on day 1. This increase was partially retained for 19days after regular training stopped. The data suggest that stable vision in normal subjects is maintained when there is < 5% deviation in VOR gain from the original baseline, which corresponds to < 9°/s retinal image slip. Below this threshold, there is poor adaptive drive to return the gain to its original baseline value.

Human vestibulo-ocular reflex adaptation is frequency selective

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 vestibulo-ocular 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.

New advances regarding adaptation of the vestibulo-ocular reflex.

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-on-body 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.

Plasticity leading to cerebellum-dependent learning: two different regions, two different types.

In memory research, studying cerebellum-dependent memory is advantageous due to its relatively simple neural architecture compared with that of other memory circuits. To understand how cerebellum-dependent memory develops and is stored in this circuit, numerous hypotheses have been proposed. These hypotheses are generally able to adequately explain most learning and memory processes; however, several reported results are still poorly understood. Recently, the importance of intrinsic plasticity (i.e., plasticity of intrinsic excitability) has been highlighted in several studies. Because the classical view of cerebellum-dependent eye movement learning was focused on synaptic plasticity, it is valuable to consider the intrinsic plasticity for deeper understanding. In the present review, we re-examine the utility and limitations of previous hypotheses, from classic to recent, and propose an updated hypothesis. Integrating intrinsic plasticity into current models of the vestibulo-ocular reflex (VOR) circuit may facilitate deeper understanding of the VOR adaptation process. In particular, during the period of memory transfer, dynamic changes in excitability in both cerebellar Purkinje cells and vestibular nuclear neurons illuminate the role of intrinsic plasticity in the circuit.

Angular vestibuloocular reflex responses in Otop1 mice. I. Otolith sensor input is essential for gravity context-specific adaptation

The role of the otoliths in mammals in the angular vestibuloocular reflex (VOR) has been difficult to determine because there is no surgical technique that can reliably ablate them without damaging the semicircular canals. The Otopetrin1 (Otop1) mouse lacks functioning otoliths because of failure to develop otoconia but seems to have otherwise normal peripheral anatomy and neural circuitry. By using these animals we sought to determine the role of the otoliths in angular VOR baseline function and adaptation. In six Otop1 mice and six control littermates we measured baseline ocular countertilt about the three primary axes in head coordinates; baseline horizontal (rotation about an Earth-vertical axis parallel to the dorsal-ventral axis) and vertical (rotation about an Earth-vertical axis parallel to the interaural axis) sinusoidal (0.2-10 Hz, 20-100°/s) VOR gain (= eye/head velocity); and the horizontal and vertical VOR after gain-increase (1.5×) and gain-decrease (0.5×) adaptation training. Countertilt responses were significantly reduced in Otop1 mice. Baseline horizontal and vertical VOR gains were similar between mouse types, and so was horizontal VOR adaptation. For control mice, vertical VOR adaptation was evident when the testing context, left ear down (LED) or right ear down (RED), was the same as the training context (LED or RED). For Otop1 mice, VOR adaptation was evident regardless of context. Our results suggest that the otolith translational signal does not contribute to the baseline angular VOR, probably because the mouse VOR is highly compensatory, and does not alter the magnitude of adaptation. However, we show that the otoliths are important for gravity context-specific angular VOR adaptation. NEW & NOTEWORTHY This is the first study examining the role of the otoliths (defined here as the utricle and saccule) in adaptation of the angular vestibuloocular reflex (VOR) in an animal model in which the otoliths are reliably inactivated and the semicircular canals preserved. We show that they do not contribute to adaptation of the normal angular VOR. However, the otoliths provide the main cue for gravity context-specific VOR adaptation.

Angular vestibuloocular reflex responses in Otop1 mice. II. Otolith sensor input improves compensation after unilateral labyrinthectomy.

The role of the otoliths in mammals in the normal angular vestibuloocular reflex (VOR) was characterized in an accompanying study based on the Otopetrin1 (Otop1) mouse, which lacks functioning otoliths because of failure to develop otoconia but seems to have otherwise normal peripheral anatomy and neural circuitry. That study showed that otoliths do not contribute to the normal horizontal (rotation about Earth-vertical axis parallel to dorso-ventral axis) and vertical (rotation about Earth-vertical axis parallel to interaural axis) angular VOR but do affect gravity context-specific VOR adaptation. By using these animals, we sought to determine whether the otoliths play a role in the angular VOR after unilateral labyrinthectomy when the total canal signal is reduced. In five Otop1 mice and five control littermates we measured horizontal and vertical left-ear-down and right-ear-down sinusoidal VOR (0.2-10 Hz, 20-100°/s) during the early (3-5 days) and plateau (28-32 days) phases of compensation after unilateral labyrinthectomy and compared these measurements with baseline preoperative responses from the accompanying study. From similar baselines, acute gain loss was ~25% less in control mice, and chronic gain recovery was ~40% more in control mice. The acute data suggest that the otoliths contribute to the angular VOR when there is a loss of canal function. The chronic data suggest that a unilateral otolith signal can significantly improve angular VOR compensation. These data have implications for vestibular rehabilitation of patients with both canal and otolith loss and the development of vestibular implants, which currently only mimic the canals on one side. NEW & NOTEWORTHY This is the first study examining the role of the otoliths (defined here as the utricle and saccule) on the acute and chronic angular vestibuloocular reflex (VOR) after unilateral labyrinthectomy in an animal model in which the otoliths are reliably inactivated and the semicircular canals preserved. This study shows that the otolith signal is used to augment the acute angular VOR and help boost VOR compensation after peripheral injury.

Incremental Vestibulo-ocular Reflex Adaptation Training Dynamically Tailored for Each Individual.

Unilateral incremental vestibulo-ocular reflex (VOR) adaptation (IVA) increases the VOR gain (= eye/head velocity) for head rotations to one side by ∼10%. Prior IVA studies involved setting the initial VOR training gain demand at the subject's starting value (= 1 in a healthy subject), with the gain preset to increment by 0.1 every 90 seconds over 15 minutes, defined as Static IVA. We determined whether a dynamically calculated gain demand (= "actual gain" + 0.1) would result in greater adaptation, defined as Dynamic IVA. Using a hybrid video-oculography and StableEyes training system, we measured the active (self-generated head impulse) and passive (imposed, unpredictable head impulse) VOR gain in 8 healthy subjects before and after 15 minutes of Static (ie, preset) and Dynamic IVA training consisting of active, leftward and rightward, horizontal head impulses (peak amplitude 15°, peak velocity 150°/s, and peak acceleration 3000°/s). We also measured the active VOR gain during training. The VOR gain increase toward the adapting side was ∼5% larger after Dynamic compared with Static IVA training (Dynamic: 13.9% ± 5.2%, Static: 9.4% ± 7.3%; P < 0.05). Our data suggest that 17°/s retinal image slip (due to the 0.1 gain difference between demand and actual gain) is sufficient to drive robust VOR adaptation. The implications for vestibular rehabilitation are that Dynamic IVA training not only produces better VOR adaptation but also allows more flexible training, for example, training can be spread over several smaller time blocks, without undoing prior adaptation.

Human Vestibulo-Ocular Reflex Adaptation Training: Time Beats Quantity.

The vestibulo-ocular reflex (VOR) is the main gaze stabilising system during rapid head movements. The VOR is highly plastic and its gain (eye/head velocity) can be increased via training that induces an incrementally increasing retinal image slip error signal to drive VOR adaptation. Using the unilateral incremental VOR adaptation technique and horizontal active head impulses as the vestibular stimulus, we sought to determine the factors important for VOR adaptation including: the total training time, ratio and number of head impulses to each side (adapting and non-adapting sides; the adapting side was pseudo-randomised left or right) and exposure time to the visual target during each head impulse. We tested 11 normal subjects, each over 5 separate sessions and training protocols. The basic training protocol (protocol one) consisted of unilateral incremental VOR adaptation training lasting 15min with the ratio of head impulses to each side 1:1. Each protocol varied from the basic. For protocol two, the ratio of impulses were in favour of the adapting side by 2:1. For protocol three, all head impulses were towards the adapting side and the training only lasted 7.5min. For protocol four, all impulses were towards the adapting side and lasted 15min. For protocol five, all head impulses were to the adapting side and the exposure time to the visual target during each impulse was doubled. We measured the active and passive VOR gains before and after the training. Albeit with small sample size, our data suggest that the total training time and the visual target exposure time for each head impulse affected adaptation, whereas the total number and repetition rate of head impulses did not. These data have implications for vestibular rehabilitation, suggesting that quality and duration of VOR adaptation exercises are more important than rapid repetition of exercises.

17 beta-estradiol synthesis modulates cerebellar dependent motor memory formation in adult male rats.

Neurosteroid 17 beta-estradiol (E2) is a steroid synthesized de novo in the nervous system that might influence neuronal activity and behavior. Nevertheless, the impact of E2 on the functioning of those neural systems in which it is slightly synthesized is less questioned. The vestibulo-ocular reflex (VOR) adaptation, may provide an ideal arena for investigating this issue. Indeed, E2 modulates cerebellar parallel fiber-Purkinje cell synaptic plasticity that underlies encoding of VOR adaptation. Moreover, aromatase expression in the cerebellum of adult rodents is maintained at very low levels and localized to Purkinje cells. The significance of age-related maintenance of low levels of aromatase expression in the cerebellum on behavior, however, has yet to be explored. Our aim in this study was to determine whether E2 synthesis exerts an effective and persistent modulation of VOR adaptation in adult male rats. To answer this question, we investigated the acute effect of blocking E2 synthesis on gain increases and decreases in VOR adaptation using an oral dose (2.5 mg/kg) of the aromatase inhibitor Letrozole in peri-pubertal and post-pubertal male rats. We found that Letrozole acutely impaired gain increases and decreases in VOR adaptation without altering basal ocular-motor performance and that these effects were similar in peri-pubertal and post-pubertal rats. Thus, in adult male rats neurosteroid E2 effectively modulates VOR adaptation in both of the periods studied. These findings imply that the adult cerebellum uses E2 synthesis for modulating motor memory formation and suggest that low and extremely localized E2 production may play a role in adaptive phenomena.

Human Vestibulo-Ocular Reflex Adaptation: Consolidation Time Between Repeated Training Blocks Improves Retention.

We sought to determine if separating vestibulo-ocular reflex (VOR) adaptation training into training blocks with a consolidation (rest) period in between repetitions would result in improved VOR adaptation and retention. Consolidation of motor learning refers to the brain benefitting from a rest period after prior exposure to motor training. The role of consolidation on VOR adaptation is unknown, though clinicians often recommend rest periods as a part of vestibular rehabilitation. The VOR is the main gaze stabilising system during rapid head movements. The VOR is highly plastic and its gain (eye/head velocity) can be increased via training that induces an incrementally increasing retinal image slip error signal to drive VOR adaptation. The unilateral incremental adaptation technique typically consists of one 15-min training block leading to an increase in VOR gain of ~ 10% towards the training side. We tested nine normal subjects, each over six separate sessions/days. Three training protocols/sessions were 5min each (1 × 5-min training) and three training protocols/sessions were 55min each. Each 55-min protocol comprised 5-min training, 20-min rest, 5-min training, 20-min rest, 5-min training (3 × 5-min training). Active and passive VOR gains were measured before and after training. For training with consolidation breaks, VOR gain retention was measured over 1h. The VOR gain increase after 1 × 5-min training was 3.1 ± 2.1% (P < 0.01). One might expect that repeating this training three times would result in × 3 total increase of 9.3%; however, the gain increase after 3 × 5-min training was only 7.1 ± 2.8% (P < 0.001), suggesting that consolidation did not improve VOR adaptation for our protocols. However, retention was improved by the addition of consolidation breaks, i.e. gains did not decrease over 1h (P = 0.43). These data suggest that for optimal retention VOR adaptation exercises should be performed over shorter repeated blocks.

A Cerebellar Spiking Neural Model for Phase Reversal of Vestibulo-ocular Reflex.

Cerebellum possesses very rich motor control and learning capability which is critical for animals. In this study, we proposed a spiking neural network model of cerebellum for gain and phase adaptation in vestibulo-ocular reflex (VOR). VOR is a critical adaptive reflexive eye movement for maintaining a stable visual field. In this model (with neuron number at the order of 104), synaptic plasticity at parallel fiber-Purkinje cell synapses was considered. In particular, we have shown that the inhibitory inputs from molecular layer interneurons on Purkinje cells play a critical role in phase adaptation of VOR. The inhibitory input from interneurons indirectly affects the strength of long-term potentiation (LTP) and long-term depression (LTD), resulting in more drastic phase shift upon learning and hence allowing phase reversal of VOR. The strength of inhibitory input also affects the maximum phase shift that can be achieved. Our result is consistent with experiments in mutant mice with blocked inhibitory inputs.

Simultaneous and opposing horizontal VOR adaptation in humans suggests functionally independent neural circuits.

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 vestibulo-ocular 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.

Cerebellar transcranial direct current stimulation interacts with BDNF Val66Met in motor learning

BackgroundCerebellar transcranial direct current stimulation has been reported to enhance motor associative learning and motor adaptation, holding promise for clinical application in patients with movement disorders. However, behavioral benefits from cerebellar tDCS have been inconsistent. ObjectiveIdentifying determinants of treatment success is necessary. BDNF Val66Met is a candidate determinant, because the polymorphism is associated with motor skill learning and BDNF is thought to mediate tDCS effects. MethodsWe undertook two cerebellar tDCS studies in subjects genotyped for BDNF Val66Met. Subjects performed an eyeblink conditioning task and received sham, anodal or cathodal tDCS (N = 117, between-subjects design) or a vestibulo-ocular reflex adaptation task and received sham and anodal tDCS (N = 51 subjects, within-subjects design). Performance was quantified as a learning parameter from 0 to 100%. We investigated (1) the distribution of the learning parameter with mixture modeling presented as the mean (M), standard deviation (S) and proportion (P) of the groups, and (2) the role of BDNF Val66Met and cerebellar tDCS using linear regression presented as the regression coefficients (B) and odds ratios (OR) with equally-tailed intervals (ETIs). ResultsFor the eyeblink conditioning task, we found distinct groups of learners (MLearner = 67.2%; SLearner = 14.7%; PLearner = 61.6%) and non-learners (MNon-learner = 14.2%; SNon-learner = 8.0%; PNon-learner = 38.4%). Carriers of the BDNF Val66Met polymorphism were more likely to be learners (OR = 2.7 [1.2 6.2]). Within the group of learners, anodal tDCS supported eyeblink conditioning in BDNF Val66Met non-carriers (B = 11.9% 95%ETI = [0.8 23.0]%), but not in carriers (B = 1.0% 95%ETI = [-10.2 12.1]%). For the vestibulo-ocular reflex adaptation task, we found no effect of BDNF Val66Met (B = −2.0% 95%ETI = [-8.7 4.7]%) or anodal tDCS in either carriers (B = 3.4% 95%ETI = [-3.2 9.5]%) or non-carriers (B = 0.6% 95%ETI = [-3.4 4.8]%). Finally, we performed additional saccade and visuomotor adaptation experiments (N = 72) to investigate the general role of BDNF Val66Met in cerebellum-dependent learning and found no difference between carriers and non-carriers for both saccade (B = 1.0% 95%ETI = [-8.6 10.6]%) and visuomotor adaptation (B = 2.7% 95%ETI = [-2.5 7.9]%). ConclusionsThe specific role for BDNF Val66Met in eyeblink conditioning, but not vestibulo-ocular reflex adaptation, saccade adaptation or visuomotor adaptation could be related to dominance of the role of simple spike suppression of cerebellar Purkinje cells with a high baseline firing frequency in eyeblink conditioning. Susceptibility of non-carriers to anodal tDCS in eyeblink conditioning might be explained by a relatively larger effect of tDCS-induced subthreshold depolarization in this group, which might increase the spontaneous firing frequency up to the level of that of the carriers.

The Effect of Visual Contrast on Human Vestibulo-Ocular Reflex Adaptation.

The vestibulo-ocular reflex (VOR) is the main retinal image stabilising mechanism during rapid head movement. When the VOR does not stabilise the world or target image on the retina, retinal image slip occurs generating an error signal that drives the VOR response to increase or decrease until image slip is minimised, i.e. VOR adaptation occurs. Visual target contrast affects the human smooth pursuit and optokinetic reflex responses. We sought to determine if contrast also affected VOR adaptation. We tested 12 normal subjects, each over 16 separate sessions. For sessions 1-14, the ambient light level (lx) during adaptation training was as follows: dark, 0.1, 0.2, 0.3, 0.5, 0.7, 1, 2, 8, 16, 32, 64, 128 and 255lx (light level for a typical room). For sessions 15-16, the laser target power (related to brightness) was halved with ambient light at 0 and 0.1lx. The adaptation training lasted 15min and consisted of left/right active head impulses. The VOR gain was challenged to increment, starting at unity, by 0.1 every 90s for rotations to the designated adapting side and fixed at unity towards the non-adapting side. We measured active and passive VOR gains before and after adaptation training. We found that for both the active and passive VOR, there was a significant increase in gain only towards the adapting side due to training at contrast level 1.5k and above (2lx and below). At contrast level 261 and below (16lx and above), adaptation training resulted in no difference between adapting and non-adapting side gains. Our modelling suggests that a contrast threshold of ~1000, which is 60 times higher than that provided by typical room lighting, must be surpassed for robust active and passive VOR adaptation. Our findings suggest contrast is an important factor for adaptation, which has implication for rehabilitation programs.

Acute inhibition of estradiol synthesis impacts vestibulo-ocular reflex adaptation and cerebellar long-term potentiation in male rats

The vestibulo-ocular reflex (VOR) adaptation is an ideal model for investigating how the neurosteroid 17 beta-estradiol (E2) contributes to the modification of behavior by regulating synaptic activities. We hypothesized that E2 impacts VOR adaptation by affecting cerebellar synaptic plasticity at the parallel fiber–Purkinje cell (PF) synapse. To verify this hypothesis, we investigated the acute effect of blocking E2 synthesis on gain increases and decreases in adaptation of the VOR in male rats using an oral dose (2.5 mg/kg) of the aromatase inhibitor letrozole. We also assessed the effect of letrozole on synaptic plasticity at the PF synapse in vitro, using cerebellar slices from male rats. We found that letrozole acutely impaired both gain increases and decreases adaptation of the VOR without altering basal ocular-motor performance. Moreover, letrozole prevented long-term potentiation at the PF synapse (PF-LTP) without affecting long-term depression (PF-LTD). Thus, in male rats neurosteroid E2 has a relevant impact on VOR adaptation and affects exclusively PF-LTP. These findings suggest that E2 might regulate changes in VOR adaptation by acting locally on cerebellar and extra-cerebellar synaptic plasticity sites.

Impairment of Long-Term Plasticity of Cerebellar Purkinje Cells Eliminates the Effect of Anodal Direct Current Stimulation on Vestibulo-Ocular Reflex Habituation.

Anodal direct current stimulation (DCS) of the cerebellum facilitates adaptation tasks, but the mechanism underlying this effect is poorly understood. We have evaluated whether the effects of DCS effects depend on plasticity of cerebellar Purkinje cells (PCs). Here, we have successfully developed a mouse model of cerebellar DCS, allowing us to present the first demonstration of cerebellar DCS driven behavioral changes in rodents. We have utilized a simple gain down vestibulo-ocular reflex (VOR) adaptation paradigm, that stabilizes a visual image on the retina during brief head movements, as behavioral tool. Our results provide evidence that anodal stimulation has an acute post-stimulation effect on baseline gain reduction of VOR (VOR gain in sham, anodal and cathodal groups are 0.75 ± 0.12, 0.68 ± 0.1, and 0.78 ± 0.05, respectively). Moreover, this anodal induced decrease in VOR gain is directly dependent on the PP2B medicated synaptic long-term potentiation (LTP) and intrinsic plasticity pathways of PCs.

Pseudo-spontaneous nystagmus in horizontal semicircular canal canalolithiasis.

Benign paroxysmal positional vertigo (BPPV) involving horizontal semicircular canal (HSCC) is characterized by direction-changing positional nystagmus (DCPN) in a supine roll test, and the occurrence of spontaneous nystagmus in HSCC BPPV has been reported recently. The aim of this study is to investigate the characteristics of pseudo-spontaneous nystagmus (PSN) in patients with HSCC canalolithiasis, and evaluate the effect of the presence of PSN on treatment outcome.Between April 2014 and January 2016, 75 and 59 patients with HSCC canalolithiasis and cupulolithiasis, respectively, were enrolled. Spontaneous and positional nystagmus were examined.PSN was observed in 31 of 75 patients (41%) with HSCC canalolithiasis, and 55 of 59 patients (93%) with HSCC cupulolithiasis. PSN persisted during the period of observation, which was at least 1 minute in all patients with PSN. In HSCC canalolithiasis, direction-reversing nystagmus was observed in 58 patients (25 bilateral and 33 unilateral). Nine of 25 patients with bilateral direction-reversing nystagmus, and 22 of 33 patients with unilateral direction-reversing nystagmus showed PSN. None of 17 patients without direction-reversing nystagmus showed PSN. The direction of PSN corresponded to that of direction-reversing nystagmus in all 22 patients with unilateral direction-reversing nystagmus. The proportion of patients who recovered after 1 session of repositioning maneuver was not significantly different between patients with and without PSN (P = .867).PSN was observed more commonly in HSCC cupulolithiasis than canalolithiasis. The pathophysiologic mechanism underlying PSN can be explained by natural inclination of HSCC and medial to lateral orientation of the HSCC cupular axis in cupulolithiasis, and by spontaneous reversal of initial positional nystagmus (direction-reversing nystagmus) generated by short-term adaptation of vestibulo-ocular reflex in canalolithiasis. The presence of PSN in HSCC canalolithiasis may not affect the treatment outcome.