Michael Fetter

Autosomal dominant cerebellar ataxia type I : oculomotor abnormalities in families with SCA1, SCA2, and SCA3

Abstract Forty-six patients suffering from autosomal dominant cerebellar ataxia type I (ADCA I) underwent to a genotype-phenotype correlation analysis by molecular genetic assignment to the spinocerebellar ataxia type 1, 2, or 3 (SCA1, SCA2, SCA3) genetic locus and electro-oculography. Oculomotor deficits that are attributed to dysfunction of cerebellar structures occurred in all three mutations without major differences between the groups. Gaze-evoked nystagmus, however, was not found to be associated with SCA2. Square wave jerks were exclusively observed in SCA3. The gain in vestibulo-ocular reflex was significantly impaired in SCA3 and SCA1. In SCA3 the severity of vestibular impairment increased with CAG repeat length. Severe saccade slowing was a highly characteristic feature of SCA2. In SCA3 saccade velocity was normal to mildly reduced while SCA1 fell into an intermediate range. The present data show that each mutation is associated with a distinct syndrome of oculomotor deficits. Reduced saccade velocity and the absence of both square-wave jerks and gaze-evoked nystagmus allow one SCA2 to be distinguished from SCA3 patients in almost all cases. The eye movement disorder of SCA1 patients, however, overlaps with both SCA2 and SCA3.

The interactive contribution of neck muscle proprioception and vestibular stimulation to subjective “straight ahead” orientation in man

Seventeen normal subjects were asked to direct a laser point to the position they felt to lie exactly straight ahead of their body. Subjects were seated in complete darkness in an approximately spherical cabin in an upright position with the orientation of the trunk and head aligned. For both the horizontal and vertical plane, “straight ahead” judgements were closely scattered around the objective straight ahead body position. Posterior neck muscle vibration as well as caloric vestibular stimulation with ice water led to (1) an apparent motion and horizontal displacement of a stationary visual target to the side opposite to stimulation and (2) a horizontal deviation of subjective “straight ahead” perception toward the side of stimulation. Only those subjects who experienced an illusion of target motion also showed a deviation of their subjective body orientation. No systematic effect of a displacement of subjective body orientation in the vertical plane was detected. When vestibular stimulation and neck muscle vibration were combined their effects were additive, i.e. the horizontal deviation of subjective body orientation observed when either type of stimulation was applied in isolation, was linearly combined either by summation or by cancellation. The present results clearly support the assumption that afferent visual, vestibular and proprioceptive input converge to the neural generation of an egocentric, body-centred coordinate system that allows us to determine our body position with respect to visual space.

Three-dimensional properties of human pursuit eye movements

For any given location and velocity of a point target, there are infinitely many different eye velocities that the pursuit system could use to track the target perfectly. Three-dimensional recordings of eye position and velocity in 8 normal human subjects showed that the system chooses the unique tracking velocity that keeps eye position vectors (a particular mathematical representation of three-dimensional eye orientation) confined to a single plane, i.e. pursuit obeys Listings law. One advantage of this strategy over other possible ones, such as choosing the smallest eye velocity compatible with perfect tracking, is that it permits continuous pursuit without accumulation of ocular torsion. For nonpoint targets, there is at most one eye velocity compatible with perfect retinal image stabilisation, and the optimal velocity may not fit Listings law; we observed small but consistent deviations from the law during pursuit of rotating line targets.

The motor side of depth vision

To achieve stereoscopic vision, the brain must search for corresponding image features on the two retinas. As long as the eyes stay still, corresponding features are confined to narrow bands called epipolar lines. But when the eyes change position, the epipolar lines migrate on the retinas. To find the matching features, the brain must either search different retinal bands depending on current eye position, or search retina-fixed zones that are large enough to cover all usual locations of the epipolar lines. Here we show, using a new type of stereogram in which the depth image vanishes at certain gaze elevations, that the search zones are retina-fixed. This being the case, motor control acquires a crucial function in depth vision: we show that the eyes twist about their lines of sight in a way that reduces the motion of the epipolar lines, allowing stereopsis to get by with smaller search zones and thereby lightening its computational load.

Ocular exploration of space as a function of neck proprioceptive and vestibular input — observations in normal subjects and patients with spatial neglect after parietal lesions

We recently argued that the specific compensation of spatial neglect by manipulating neck proprioceptive and vestibular input is due to a central “correction” of the disturbed neural transformation process converting the afferent input coordinates from the peripheral sensory organs into a central representation of egocentric space. Both types of stimulation were proposed to induce a reorientation of the deviated or distorted egocentric spatial reference frame. The aim of the present study was to observe this process of reorientation under a condition in which no visual stimulus can attract the subjects attention and thus influence exploration behaviour from outside. We recorded eye movements of normal subjects and of three patients with spatial neglect after right parietal lesions while searching for a non-existent target in complete darkness. It was assumed that the area of the outer space that subjects spontaneously explore under this condition is a direct function of the subjects representation of egocentric space. Ocular space exploration was biased and confined almost entirely to the right side of the midsagittal plane in patients with neglect. This spatial distribution of exploratory eye movements changed remarkably with left-sided neck muscle vibration as well as with left-sided vestibular stimulation using ice water calorics. The spatial area of exploration was significantly enlarged to the contralesional side and the exploration maximum shifted in the same direction. Whereas with both types of stimulation space exploration of patients with neglect was similar to that of normal subjects when not being stimulated, neck proprioceptive and vestibular stimulation in normal subjects induced a quasi neglect-like exploration pattern, i.e. a bias to one side of the objective midsagittal plane. If ocular space exploration was, however, related to the subjectively perceived position of the midsagittal plane in space, eye movements were symmetrically distributed and carried out to both sides of subjective “straight ahead” in all experimental conditions, in normal subjects as well as in patients with neglect. The present results support the above hypothesis and indicate that neck proprioceptive as well as vestibular input directly contribute to the computation of the subjects central representation of egocentric space used for localizing body orientation and for guiding motor behaviour in space.

Dissociation between the perception of body verticality and the visual vertical in acute peripheral vestibular disorder in humans

Estimates of the subjective visual and postural vertical were obtained from five patients with acute peripheral vestibular lesions and 20 normal subjects. The visual vertical was assessed by asking the subjects to align a target line to earth vertical by means of remote control. Postural vertical judgments were obtained by exposing them to rotational displacements in the roll plane while sitting on a motor-driven chair and requiring them to align their body to vertical using a joystick control. While the patients showed strong deviations of the visual vertical towards the lesion side, their postural vertical judgments remained veridical. We conclude that the above perceptions are not processed identically and that the participating sensory systems are differently weighted during these tasks.

Saccade velocity is controlled by polyglutamine size in spinocerebellar ataxia 2.

We assessed maximal saccade velocity (MSV) in 82 spinocerebellar ataxia type 2 (SCA2) patients and 80 controls, correlating it to disease duration, polyglutamine expansion size, age at onset, ataxia score, age, and sex. Little overlap with normal values was found even at earliest stages. Stepwise linear regression analysis showed that 60‐degree MSV was strongly influenced by polyglutamine size and less by disease duration, whereas the reverse was found for ataxia score. Saccade velocity thus is a sensitive, quite specific, and objective endophenotype, useful to search polyglutamine modifier genes. Ann Neurol 2004;56:444–447

Vestibular perception of passive whole-body rotation about horizontal and vertical axes in humans: goal-directed vestibulo-ocular reflex and vestibular memory-contingent saccades.

This study was aimed at complementing the existing knowledge about vestibular perception of self-motion in humans. Both goal-directed vestibulo-ocular reflex and vestibular memory-contingent saccade (VM-CS) tasks were used, respectively as concurrent and retrospective magnitude estimators for passive whole-body rotation. Rotations were applied about the earth-vertical and earth-horizontal axes to study the effect of the otolith signal in self-rotation evaluation, and both in yaw and pitch to examine the horizontal and vertical semi-circular canals. Two different magnitudes of constant angular acceleration (50°/s2 and 100°/s2) were used. The main findings were (1) strong correlation between both oculomotor responses of both tasks, (2) greater accuracy with rotations about the earth-vertical than the earth: -horizontal axis, (3) greater accuracy for yaw than for pitch rotations, (4) greater accuracy for high acceleration than for low, and (5) no effect of the delay (2s or 12s) in the VMCS task. Adequacy of both tasks as subjective magnitude estimators of vestibular perception of self-motion is discussed.

The clinical significance of head-shaking nystagmus in the dizzy patient.

The clinical significance of horizontal head-shaking nystagmus (HSN) was evaluated in 85 patients who complained of dizziness and vertigo. This was done by comparison of the horizontal head-shaking test with routine rotatory and caloric vestibular testing. We found that HSN evoked by horizontal head-shaking is a highly sensitive way to detect unilateral vestibular hypofunction. Except in patients with additional central vestibular imbalance or in patients with Menieres disease, the direction of horizontal HSN is highly significant in indicating the side of the lesion, with the fast phase beating toward the intact side. However, horizontal HSN is not specific in distinguishing peripheral hypofunction from more central vestibular imbalances. Peripheral vestibular hypofunction as well as a central asymmetry of the vestibular velocity storage mechanism can each separately or in combination produce horizontal HSN. Thus, while the head-shaking manoeuvre is an excellent bedside-test to detect unilateral vestibular hypofunction, further rotatory and caloric testing is still necessary to clarify the patients condition.

Non-commutativity in the brain

In non-commutative algebra, order makes a difference to multiplication, so that a × b ≠ b × a (refs 1, 2). This feature is necessary for computing rotary motion, because order makes a difference to the combined effect of two rotations. It has therefore been proposed that there are non-commutative operators in the brain circuits that deal with rotations, including motor circuits that steer the eyes, head and limbs,,, and sensory circuits that handle spatial information,. This idea is controversial,,: studies of eye and head control have revealed behaviours that are consistent with non-commutativity in the brain,, but none that clearly rules out all commutative models. Here we demonstrate non-commutative computation in the vestibulo-ocular reflex. We show that subjects rotated in darkness can hold their gaze points stable in space, correctly computing different final eye-position commands when put through the same two rotations in different orders, in a way that is unattainable by any commutative system.