Downbeat nystagmus is a frequent ocular motor sign in patients with lesions of the vestibulocerebellum. The upward drift in downbeat nystagmus is a combination of a gaze-evoked drift, due to an impaired vertical neural integrator, and a velocity bias. Using a three-dimensional turntable, we analyzed the influence of gravity on these two mechanisms. Patients with cerebellar downbeat nystagmus (n = 6) and healthy subjects (n = 12) were placed in various whole-body positions along the roll, pitch, and oblique vertical planes of the head. Ocular drift was monitored with scleral search coils. Although there was no gravity dependence of the vertical gaze-evoked drift, the vertical velocity bias consisted of two components: a gravity-dependent component that sinusoidally modulated as a function of body position along the pitch plane, and a gravity-independent component that was directed upward. The combination of the two components led to an overall drift that was minimal in supine and maximal in prone position. In healthy subjects, only the gravity-dependent component was present, but in a scaled-down manner. Our results suggest that the intact vestibulocerebellum minimizes an overacting otolith-ocular reflex elicited by pitch tilt and cancels an inherent upward ocular drift that is independent of gravity-modulated otolith signals.

Self-motion perception after a sudden stop from a sustained rotation in darkness lasts approximately as long as reflexive eye movements. We hypothesized that, after an angular velocity step, self-motion perception and reflexive eye movements are driven by the same vestibular pathways. In 16 healthy subjects (25-71 years of age), perceived rotational velocity (PRV) and the vestibulo-ocular reflex (rVOR) after sudden decelerations (90°/s(2)) from constant-velocity (90°/s) earth-vertical axis rotations were simultaneously measured (PRV reported by hand-lever turning; rVOR recorded by search coils). Subjects were upright (yaw) or 90° left-ear-down (pitch). After both yaw and pitch decelerations, PRV rose rapidly and showed a plateau before decaying. In contrast, slow-phase eye velocity (SPV) decayed immediately after the initial increase. SPV and PRV were fitted with the sum of two exponentials: one time constant accounting for the semicircular canal (SCC) dynamics and one time constant accounting for a central process, known as velocity storage mechanism (VSM). Parameters were constrained by requiring equal SCC time constant and VSM time constant for SPV and PRV. The gains weighting the two exponential functions were free to change. SPV were accurately fitted (variance-accounted-for: 0.85 ± 0.10) and PRV (variance-accounted-for: 0.86 ± 0.07), showing that SPV and PRV curve differences can be explained by a greater relative weight of VSM in PRV compared with SPV (twofold for yaw, threefold for pitch). These results support our hypothesis that self-motion perception after angular velocity steps is be driven by the same central vestibular processes as reflexive eye movements and that no additional mechanisms are required to explain the perceptual dynamics.

A model-based theory on the origin of downbeat nystagmus AbstractThe pathomechanism of downbeat nystagmus (DBN), an ocular motor sign typical for vestibulo-cerebellar lesions, remains unclear. Previous hypotheses conjectured various deficits such as an imbalance of central vertical vestibular or smooth pursuit pathways to be causative for the generation of spontaneous upward drift. However, none of the previous theories explains the full range of ocular motor deficits associated with DBN, i.e., impaired vertical smooth pursuit (SP), gaze evoked nystagmus, and gravity dependence of the upward drift. We propose a new hypothesis, which explains the ocular motor signs of DBN by damage of the inhibitory vertical gaze-velocity sensitive Purkinje cells (PCs) in the cerebellar flocculus (FL). These PCs show spontaneous activity and a physiological asymmetry in that most of them exhibit downward on-directions. Accordingly, a loss of vertical floccular PCs will lead to disinhibition of their brainstem target neurons and, consequently, to spontaneous upward drift, i.e., DBN. Since the FL is involved in generation and control of SP and gaze holding, a single lesion, e.g., damage to vertical floccular PCs, may also explain the associated ocular motor deficits. To test our hypothesis, we developed a computational model of vertical eye movements based on known ocular motor anatomy and physiology, which illustrates how cortical, cerebellar, and brainstem regions interact to generate the range of vertical eye movements seen in healthy subjects. Model simulation of the effect of extensive loss of floccular PCs resulted in ocular motor features typically associated with cerebellar DBN: (1) spontaneous upward drift due to decreased spontaneous PC activity, (2) gaze evoked nystagmus corresponding to failure of the cerebellar loop supporting neural integrator function, (3) asymmetric vertical SP deficit due to low gain and asymmetric attenuation of PC firing, and (4) gravity-dependence of DBN caused by an interaction of otolith-ocular pathways with impaired neural integrator function.

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by progressive neurological deficits, including prominent ocular motor dysfunction. Unstable fixation often leads to difficulty reading and blurred vision. Here we characterize the disturbance of visual fixation in A-T. MethodsWe recorded eye movements from 13 A-T patients (with dual search coils in five patients and with video oculography in seven) during attempted fixation. ResultsTwo abnormalities -nystagmus and saccadic intrusions -were common. Horizontal, vertical, and torsional nystagmus was present in straight-ahead (spontaneous nystagmus) and eccentric gaze (gaze-evoked nystagmus). In eight patients the horizontal nystagmus changed directions -periodic alternating nystagmus (PAN). Two types of saccadic intrusions occurred -micro-saccadic oscillations (SO) and squarewave saccadic intrusions (SWSI). SO were small-amplitude (0.1-0.9º) and highfrequency (14-33Hz) back-to-back horizontal saccades. The SWSI ranged between 1-18º (median: 3º) with an intersaccadic interval ranging between 50-800 milliseconds (median: 300 milliseconds). The potential impact of abnormal gaze stabilization on vision was quantified. DiscussionDegeneration of cerebellar Purkinje neurons disinhibit the fastigial (FOR) and vestibular nuclei (VN). Disinhibition of VN can cause nystagmus including PAN, while disinhibition of FOR can affect saccade generating mechanisms leading to SWSI and SO.

Eccentric gaze in darkness evokes minor centripetal eye drifts in healthy subjects, as cerebellar control sufficiently compensates for the inherent deficiencies of the brainstem gaze-holding network. This behavior is commonly described using a leaky integrator model, which assumes that eye velocity grows linearly with gaze eccentricity. Results from previous studies in patients and healthy subjects suggest caution when this assumption is applied to eye eccentricities larger than 20 degrees. To obtain a detailed characterization of the centripetal gaze-evoked drift, we recorded horizontal eye position in 20 healthy subjects. With their head fixed, they were asked to fixate a flashing dot (50 ms every 2 s)that was quasi-stationary displacing(0.5 deg/s) between ±40 deg horizontally in otherwise complete darkness. Drift velocity was weak at all angles tested. Linearity was assessed by dividing the range of gaze eccentricity in four bins of 20 deg each, and comparing the slopes of a linear function fitted to the horizontal velocity in each bin. The slopes of single subjects for gaze eccentricities of ±0−20 deg were, in median,0.41 times the slopes obtained for gaze eccentricities of ±20−40 deg. By smoothing the individual subjects' eye velocity as a function of gaze eccentricity, we derived a population of position-velocity curves. We show that a tangent function provides a better fit to the mean of these curves when large eccentricities are considered. This implies that the quasi-linear behavior within the typical ocular motor range is the result of a tuning procedure, which is optimized in the most commonly used range of gaze. We hypothesize that the observed non-linearity at eccentric gaze results from a saturation of the input that each neuron in the integrating network receives from the others. As a consequence, gaze-holding performance declines more rapidly at large eccentricities.