Sarah Marti

Gravity dependence of ocular drift in patients with cerebellar downbeat nystagmus

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.

Velocity Storage Contribution to Vestibular Self-Motion Perception in Healthy Human Subjects

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

The 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.

Is Vestibular Self-Motion Perception Controlled by the Velocity Storage? Insights from Patients with Chronic Degeneration of the Vestibulo-Cerebellum

Background The rotational vestibulo-ocular reflex (rVOR) generates compensatory eye movements in response to rotational head accelerations. The velocity-storage mechanism (VSM), which is controlled by the vestibulo-cerebellar nodulus and uvula, determines the rVOR time constant. In healthy subjects, it has been suggested that self-motion perception in response to earth-vertical axis rotations depends on the VSM in a similar way as reflexive eye movements. We aimed at further investigating this hypothesis and speculated that if the rVOR and rotational self-motion perception share a common VSM, alteration in the latter, such as those occurring after a loss of the regulatory control by vestibulo-cerebellar structures, would result in similar reflexive and perceptual response changes. We therefore set out to explore both responses in patients with vestibulo-cerebellar degeneration. Methodology/Principal Findings Reflexive eye movements and perceived rotational velocity were simultaneously recorded in 14 patients with chronic vestibulo-cerebellar degeneration (28–81yrs) and 12 age-matched healthy subjects (30–72yrs) after the sudden deceleration (90°/s2) from constant-velocity (90°/s) rotations about the earth-vertical yaw and pitch axes. rVOR and perceived rotational velocity data were analyzed using a two-exponential model with a direct pathway, representing semicircular canal activity, and an indirect pathway, implementing the VSM. We found that VSM time constants of rVOR and perceived rotational velocity co-varied in cerebellar patients and in healthy controls (Pearson correlation coefficient for yaw 0.95; for pitch 0.93, p<0.01). When constraining model parameters to use the same VSM time constant for rVOR and perceived rotational velocity, moreover, no significant deterioration of the quality of fit was found for both populations (variance-accounted-for >0.8). Conclusions/Significance Our results confirm that self-motion perception in response to rotational velocity-steps may be controlled by the same velocity storage network that controls reflexive eye movements and that no additional, e.g. cortical, mechanisms are required to explain perceptual dynamics.

Ataxia telangiectasia: a "disease model" to understand the cerebellar control of vestibular reflexes.

Experimental animal models have suggested that the modulation of the amplitude and direction of vestibular reflexes are important functions of the vestibulocerebellum and contribute to the control of gaze and balance. These critical vestibular functions have been infrequently quantified in human cerebellar disease. In 13 subjects with ataxia telangiectasia (A-T), a disease associated with profound cerebellar cortical degeneration, we found abnormalities of several key vestibular reflexes. The vestibuloocular reflex (VOR) was measured by eye movement responses to changes in head rotation. The vestibulocollic reflex (VCR) was assessed with cervical vestibular-evoked myogenic potentials (cVEMPs), in which auditory clicks led to electromyographic activity of the sternocleidomastoid muscle. The VOR gain (eye velocity/head velocity) was increased in all subjects with A-T. An increase of the VCR, paralleling that of the VOR, was indirectly suggested by an increase in cVEMP amplitude. In A-T subjects, alignment of the axis of eye rotation was not with that of head rotation. Subjects with A-T thus manifested VOR cross-coupling, abnormal eye movements directed along axes orthogonal to that of head rotation. Degeneration of the Purkinje neurons in the vestibulocerebellum probably underlie these deficits. This study offers insights into how the vestibulocerebellum functions in healthy humans. It may also be of value to the design of treatment trials as a surrogate biomarker of cerebellar function that does not require controlling for motivation or occult changes in motor strategy on the part of experimental subjects.

Gaze fixation deficits and their implication in ataxia–telangiectasia

Background and aim: Ataxia–telangiectasia (A-T) is an autosomal recessive disorder characterised by progressive neurological deficits, including prominent ocular motor dysfunction. Unstable fixation often leads to difficulty reading and blurred vision. Here we characterise the disturbance of visual fixation in A-T. Methods: Eye movements were recorded from 13 A-T patients (with dual search coils in five patients and video oculography in seven) during attempted fixation. Results: Two 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 were seen—micro-saccadic oscillations (SO) and square wave saccadic intrusions (SWSI). SO were small amplitude (0.1–0.9°) and high frequency (14–33 Hz) back to back horizontal saccades. SWSI ranged between 1° and 18° (median 3°) with an intersaccadic interval ranging between 50 and 800 ms (median 300 ms). The potential impact of abnormal gaze stabilisation on vision was quantified. Discussion: Degeneration of cerebellar Purkinje neurons disinhibit the caudal fastigial oculomotor region (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.

Treatment of the gravity dependence of downbeat nystagmus with 3,4-diaminopyridine

The authors examined the effect of 3,4-diaminopyridine (DAP) on the gravity-dependent (GD) vertical ocular drift component of downbeat nystagmus in 11 patients with idiopathic cerebellar ataxia. With the head tilted downward (45°), DAP reduced slow phase velocity (SPV) in 7 of 11 patients by 36%. Its efficacy correlated with the GD modulation. DAP minimizes the gravity-independent velocity bias and may improve deficient inhibitory cerebellar control on overacting otolith–ocular reflexes.

Rotational vertebral artery syndrome: 3D kinematics of nystagmus suggest bilateral labyrinthine dysfunction.

Whether the rotational vertebral artery syndrome (RVAS), consisting of attacks of vertigo, nystagmus and tinnitus elicited by head-rotation induced compression of the dominant vertebral artery (VA), reflects ischemic dysfunction of uni- or bilateral peripheral or central vestibular structures, is still debated. We report on a patient with bilateral high-grade carotid stenoses, in whom rightward headrotation led to RVAS symptoms including a prominent nystagmus. Three-dimensional kinematic analysis of the nystagmus pattern, recorded with search coils, revealed major downbeat nystagmus with minor horizontal and torsional components. Magnetic resonance angiography demonstrated a hypoplastic right VA terminating in the posterior inferior cerebellar artery, a dominant left VA, and a hypoplastic P1-segment of the left posterior cerebral artery (PCA) that was supplied by the left posterior communicating artery (PCoA). The right PCA and both anterior inferior cerebellar arteries were supplied by the basilar artery. The right PCoA originated from the right internal carotid artery. Color duplex sonography showed severe reduction of diastolic blood flow velocities in the left VA during RVAS attacks. The nystagmus pattern can be best explained by vectorial addition of 3D sensitivity vectors of stimulated right and left anterior and horizontal semicircular canals with slightly stronger stimulation on the left side. We hypothesize that in RVAS, compression of dominant VA leads to acute vertebrobasilar insufficiency with bilateral, but asymmetric ischemia of the superior labyrinth. With regard to RVAS etiology, our case illustrates a type of pure vascular RVAS. Severity of attacks markedly decreased after successful bilateral carotid endarterectomy.

Up–Down Asymmetry of Cerebellar Activation During Vertical Pursuit Eye Movements

Animal experiments have demonstrated that the vast majority of vertical gaze-velocity Purkinje cells in the cerebellar floccular lobe, whose firing rate is modulated during vertical smooth pursuit eye movements, show a preference for downward pursuit. Here we validate the functional vertical asymmetry of the cerebellar flocculus in humans using functional magnetic resonance imaging by demonstrating a significantly higher activation of the floccular lobe for downward than for upward pursuit. The findings corroborate our recent hypothesis on the pathogenesis of cerebellar downbeat nystagmus.

Modulation of internal estimates of gravity during and after prolonged roll-tilts.

Perceived direction of gravity, as assessed by the subjective visual vertical (SVV), shows roll-angle dependent errors that drift over time and a bias upon return to upright. According to Bayesian observer theory, the estimated direction of gravity is derived from the posterior probability distribution by combining sensory input and prior knowledge about earth-vertical in a statistically optimal fashion. Here we aimed to further characterize the stability of SVV during and after prolonged roll-tilts. Specifically we asked whether the post-tilt bias is related to the drift pattern while roll-tilted. Twenty-nine healthy human subjects (23-56yo) repetitively adjusted a luminous arrow to the SVV over periods of 5min while upright, roll-tilted (±45°, ±90°), and immediately after returning to upright. Significant (p<0.05) drifts (median absolute drift-amplitude: 10°/5min) were found in 71% (±45°) and 78% (±90°) of runs. At ±90° roll-tilt significant increases in absolute adjustment errors were more likely (76%), whereas significant increases (56%) and decreases (44%) were about equally frequent at ±45°. When returning to upright, an initial bias towards the previous roll-position followed by significant exponential decay (median time-constant: 71sec) was noted in 47% of all runs (all subjects pooled). No significant correlations were found between the drift pattern during and immediately after prolonged roll-tilt. We conclude that the SVV is not stable during and after prolonged roll-tilt and that the direction and magnitude of drift are individually distinct and roll-angle-dependent. Likely sensory and central adaptation and random-walk processes contribute to drift while roll-tilted. Lack of correlation between the drift and the post-tilt bias suggests that it is not the inaccuracy of the SVV estimate while tilted that determines post-tilt bias, but rather the previous head-roll orientation relative to gravity. We therefore favor central adaptation, most likely a shift in prior knowledge towards the previous roll orientation, to explain the post-tilt bias.