Downbeat nystagmus becomes attenuated during walking compared to standing.

Downbeat nystagmus (DBN) is a common form of acquired fixation nystagmus related to vestibulo-cerebellar impairments and associated with impaired vision and postural imbalance. DBN intensity becomes modulated by various factors such as gaze direction, head position, daytime, and resting conditions. Further evidence suggests that locomotion attenuates postural symptoms in DBN. Here, we examined whether walking might analogously influence ocular-motor deficits in DBN. Gaze stabilization mechanisms and nystagmus frequency were examined in 10 patients with DBN and 10 age-matched healthy controls with visual fixation during standing vs. walking on a motorized treadmill. Despite their central ocular-motor deficits, linear and angular gaze stabilization in the vertical plane were functional during walking in DBN patients and comparable to controls. Notably, nystagmus frequency in patients was considerably reduced during walking compared to standing (p < 0.001). The frequency of remaining nystagmus during walking was further modulated in a manner that depended on the specific phase of the gait cycle (p = 0.015). These attenuating effects on nystagmus intensity during walking suggest that ocular-motor control disturbances are selectively suppressed during locomotion in DBN. This suppression is potentially mediated by locomotor efference copies that have been shown to selectively govern gaze stabilization during stereotyped locomotion in animal models.

Subliminal Passive Motion Stimulation Improves Vestibular Perception.

Animal studies suggest that the vestibular system autoregulates its sensitivity in response to prolonged low- or high-intensity motion in order to maintain an optimal working range. In humans, corresponding attenuations of vestibular responses after prolonged high-intensity motion exposure have been demonstrated. Here we explored whether a complementary increase in human vestibular sensitivity can be induced by motion conditioning at low-intensity, subliminal amplitudes. In 9 healthy subjects, vestibular perceptual thresholds for translational motion along the inter-aural (IA) axis were determined in a direction-recognition task at baseline as well as immediately and 20-min after subliminal motion stimulation. The subliminal conditioning stimulus consisted of a 20-min 1 Hz sinusoidal IA translation at an amplitude of 70% of each subject's baseline IA threshold (2.09 ±â€¯0.78 cm/s2 peak acceleration). In a second set of experiments, we tested whether IA conditioning also influences perceptual thresholds for yaw rotations. Immediately after conditioning, IA thresholds were effectively lowered (p = 0.002; mean reduction: 28.8 ±â€¯4.5%). These improvements were transient and thresholds had returned to baseline level 20 min after conditioning (p = 0.015). Vestibular sensitivity for yaw rotations remained on average unaltered after IA conditioning indicating that sensitizing effects might be selective for the end-organ-specific vestibular pathways being stimulated during conditioning. These findings demonstrate that human vestibular sensitivity can be enhanced by subliminal sensory conditioning, similar to sensitizing effects observed in other sensory modalities. Conditioning-induced sensitization of vestibular responses may be an effective treatment for decrements in vestibular sensitivity in the elderly and patients with vestibular hypofunction.

Selective suppression of the vestibulo-ocular reflex during human locomotion.

INTRODUCTION: In lower vertebrates, gaze stabilization during locomotion is at least partially driven by a direct coupling of spinal locomotor commands with extraocular motor signals. To what extent locomotor feed-forward mechanisms contribute to gaze stabilization during human locomotion is yet unknown. In principle, the feasibility of a feed-forward regulation of gaze during locomotion should critically depend on the spatiotemporal coupling between body and head kinematics and hence the internal predictability of head movements (HMP). The present study thus investigated whether changes in eye-head coordination during human locomotion can be explained by concurrent changes in HMP. METHODS: Eye and head movements were recorded at different locomotor speeds in light and darkness to obtain the gain and phase of the horizontal and vertical angular VOR (aVOR). Potential correlations between aVOR performance and HMP were analyzed in dependence of locomotor speed and gait cycle phase. RESULTS: Horizontal aVOR responses persisted independent of locomotor speed. In contrast, with increasing locomotor speed vertical eye-head coordination switched from a VOR-driven compensatory mode to a synergistic behavior where head and eyes move in phase. Concurrently, vertical HMP increased with faster locomotion. Furthermore, modulations in vertical aVOR gain across the gait cycle corresponded to simultaneous alterations in vertical HMP. CONCLUSION: The vertical aVOR appears to be suppressed during faster walking and running, whereas at the same time, the predictability of resultant head movements increases. This suggests that during stereotyped human locomotion, internal feed-forward commands supplement or even suppress sensory feedback to mediate gaze stabilization in the vertical plane.

Functional Organization of Vestibulo-Ocular Responses in Abducens Motoneurons.

Vestibulo-ocular reflexes (VORs) are the dominating contributors to gaze stabilization in all vertebrates. During horizontal head movements, abducens motoneurons form the final element of the reflex arc that integrates visuovestibular inputs into temporally precise motor commands for the lateral rectus eye muscle. Here, we studied a possible differentiation of abducens motoneurons into subtypes by evaluating their morphology, discharge properties, and synaptic pharmacology in semi-intact in vitro preparations of larval Xenopus laevis Extracellular nerve recordings during sinusoidal head motion revealed a continuum of resting rates and activation thresholds during vestibular stimulation. Differences in the sensitivity to changing stimulus frequencies and velocities allowed subdividing abducens motoneurons into two subgroups, one encoding the frequency and velocity of head motion (Group I), and the other precisely encoding angular velocity independent of stimulus frequency (Group II). Computational modeling indicated that Group II motoneurons are the major contributor to actual eye movements over the tested stimulus range. The segregation into two functional subgroups coincides with a differential activation of glutamate receptor subtypes. Vestibular excitatory inputs in Group I motoneurons are mediated predominantly by NMDA receptors and to a lesser extent by AMPA receptors, whereas an AMPA receptor-mediated excitation prevails in Group II motoneurons. Furthermore, glycinergic ipsilateral vestibular inhibitory inputs are activated during the horizontal VOR, whereas the tonic GABAergic inhibition is presumably of extravestibular origin. These findings support the presence of physiologically and pharmacologically distinct functional subgroups of extraocular motoneurons that act in concert to mediate the large dynamic range of extraocular motor commands during gaze stabilization.SIGNIFICANCE STATEMENT Outward-directed gaze-stabilizing eye movements are commanded by abducens motoneurons that combine different sensory inputs including signals from the vestibular system about ongoing head movements (vestibulo-ocular reflex). Using an amphibian model, this study investigates whether different types of abducens motoneurons exist that become active during different types of eye movements. The outcome of this study demonstrates the presence of specific motoneuronal populations with pharmacological profiles that match their response dynamics. The evolutionary conservation of the vestibulo-ocular circuitry makes it likely that a similar motoneuronal organization is also implemented in other vertebrates. Accordingly, the physiological and pharmacological understanding of specific motoneuronal contributions to eye movements might help in designing drug therapies for human eye movement dysfunctions such as abducens nerve palsy.

Galvanic Vestibular Stimulation: Cellular Substrates and Response Patterns of Neurons in the Vestibulo-Ocular Network.

UNLABELLED: Galvanic vestibular stimulation (GVS) uses modulated currents to evoke neuronal activity in vestibular endorgans in the absence of head motion. GVS is typically used for a characterization of vestibular pathologies; for studies on the vestibular influence of gaze, posture, and locomotion; and for deciphering the sensory-motor transformation underlying these behaviors. At variance with the widespread use of this method, basic aspects such as the activated cellular substrate at the sensory periphery or the comparability to motion-induced neuronal activity patterns are still disputed. Using semi-intact preparations of Xenopus laevis tadpoles, we determined the cellular substrate and the spatiotemporal specificity of GVS-evoked responses and compared sinusoidal GVS-induced activity patterns with motion-induced responses in all neuronal elements along the vestibulo-ocular pathway. As main result, we found that, despite the pharmacological block of glutamatergic hair cell transmission by combined bath-application of NMDA (7-chloro-kynurenic acid) and AMPA (CNQX) receptor blockers, GVS-induced afferent spike activity persisted. However, the amplitude modulation was reduced by ∼30%, suggesting that both hair cells and vestibular afferent fibers are normally recruited by GVS. Systematic alterations of electrode placement with respect to bilateral semicircular canal pairs or alterations of the bipolar stimulus phase timing yielded unique activity patterns in extraocular motor nerves, compatible with a spatially and temporally specific activation of vestibulo-ocular reflexes in distinct planes. Despite the different GVS electrode placement in semi-intact X. laevis preparations and humans and the more global activation of vestibular endorgans by the latter approach, this method is suitable to imitate head/body motion in both circumstances. SIGNIFICANCE STATEMENT: Galvanic vestibular stimulation is used frequently in clinical practice to test the functionality of the sense of balance. The outcome of the test that relies on the activation of eye movements by electrical stimulation of vestibular organs in the inner ear helps to dissociate vestibular impairments that cause vertigo and imbalance in patients. This study uses an amphibian model to investigate at the cellular level the underlying mechanism on which this method depends. The outcome of this translational research unequivocally revealed the cellular substrate at the vestibular sensory periphery that is activated by electrical currents, as well as the spatiotemporal specificity of the evoked eye movements, thus facilitating the interpretation of clinical test results.

Prolonged vestibular stimulation induces homeostatic plasticity of the vestibulo-ocular reflex in larval Xenopus laevis.

Vestibulo-ocular reflexes (VOR) stabilise retinal images during head/body motion in vertebrates by generating spatio-temporally precise extraocular motor commands for corrective eye movements. While VOR performance is generally robust with a relatively stable gain, cerebellar circuits are capable of adapting the underlying sensory-motor transformation. Here, we studied cerebellum-dependent VOR plasticity by recording head motion-induced lateral rectus and superior oblique extraocular motor discharge in semi-intact preparations of Xenopus laevis tadpoles. In the absence of visual feedback, prolonged sinusoidal rotation caused either an increase or decrease of the VOR gain depending on the motion stimulus amplitude. The observed changes in extraocular motor discharge gradually saturated after 20 min of constant rotation and returned to baseline in the absence of motion stimulation. Furthermore, plastic changes in lateral rectus and superior oblique motor commands were plane-specific for horizontal and vertical rotations, respectively, suggesting that alterations are restricted to principal VOR connections. Comparison of multi- and single-unit activity indicated that plasticity occurs in all recorded units of a given extraocular motor nucleus. Ablation of the cerebellum abolished motoneuronal gain changes and prevented the induction of plasticity, thus demonstrating that both acquisition and retention of this type of plasticity require an intact cerebellar circuitry. In conclusion, the plane-specific and stimulus intensity-dependent modification of the VOR gain through the feed-forward cerebellar circuitry represents a homeostatic plasticity that likely maintains an optimal working range for the underlying sensory-motor transformation.