Oculomotor Abnormalities and Nystagmus in Brainstem Disease: A Mini Review

1. Eye movements were recorded in four rhesus monkeys, before and after bilateral ablations of the flocculi and portions of the paraflocculi (“flocculectomy”). Animals were trained to fixate and follow targets so that pursuit, saccades, and vestibular and optokinetic nystagmus could be quantitated. 2. The vestibuloocular reflex (VOR) was mildly affected by flocculectomy. In darkness the VOR gain (eye velocity/head velocity) for steps of head velocity (normal range, 0.84-0.96) increased postoperatively in one monkey to 1.17, decreased in another to 0.62, and did not change significantly in the other two (0.96, 0.94). VOR phase lead at 0.05-Hz oscillation in darkness (normal range, O,O--LOO) increased in two monkeys by 12 and 9.5 O but did not change significantly in the others. 3. Visual suppression of inappropriate vestibular nystagmus was impaired. During oscillation at 0.25 Hz with a head-fixed visual scene, the average amount of attenuation of the VOR decreased from 5 1% preoperatively to 20% postoperatively. Visual suppression of caloric nystagmus was comparably affected. 4. Smooth tracking of small targets moving in space was impaired either with the head still (smooth pursuit) or moving (cancellation of the VOR by fixating a target rotating with the head). The average gain (gaze velocity/target velocity) in either case was about 0.65 (normal, 0.95-0.98). The pursuit deficit was less than that reported after total cerebellectomy, suggesting other cerebellar structures also participate in smooth tracking. 5. Optokinetic nystagmus (OKN) was present postoperatively but, in response to a constant-velocity stimulus, the initial slowphase velocity decreased by 50% and the rise time to a steady state nearly doubled. For stimuli belowr 6O”/s the average steady-state gain was only mildly diminished to 0.86 (normal, 0.98) and the time course of optokinetic afternystagmus (OKAN) in darkness was normal. The response to higher velocity optokinetic stimuli was impaired. These abnormalities can largely be attributed to the coexisting pursuit deficit although the protracted rise to a steady state suggests a change in the ability of the brain stem optokinetic system to handle large amounts of retinal slip. 6. Flocculectomized monkeys showed horizontally, gaze-paretic nystagmus with exponentially decaying centripetal drift (time constant, 1.56 s) and vertically, downbeat nystagmus with exponentially decaying (in three monkeys) or exponentially increasing (in one monkey) slow phases. All animals showed rebound nystagmus. These results implicate the flocculus and possibly the paraflocculus in the control of the time constant and stability of the brain stem oculomotor integrators. 7. Saccadic velocities and accuracy were normal but flocculectomized monkeys showed brief (40150 ms duration), approximately exponential, postsaccadic drift with amplitudes up to 15% of the size of the saccade. The eyes usually drifted in the same direction as the saccade but each monkey showed an idiosyncratic pattern depending on saccade direction and eye position. Postsaccadic drift may reflect a mismatch between the phasic (pulse) and tonic (step) innervational changes that create saccades.

Long-term adaptive changes in primate vestibuloocular reflex. III. Electrophysiological observations in flocculus of normal monkeys.

An Elderly Woman With Difficulty Reading and Abnormal Eye Movements

The purpose of this study was to assess the effect of changes in body and head positions on respiratory-related activity of the genioglossus muscle in normal subjects in 8 body and head positions: (1) upright body with head straight, (2) upright body with head rotated to the right, (3) upright body with head rotated to the left, (4) supine body with head straight, (5) supine body with head rotated to the right, (6) supine body with head rotated to the left, (7) lateral recumbent body to the right, and (8) lateral recumbent body to the left. Phasic activity of the genioglossus muscle decreased significantly when subjects rotated their heads and moved from the supine to the lateral recumbent position. It is therefore concluded that genioglossus muscle activity is modulated in response to head rotation and changes in body position.

The Craig Hospital Eye Evaluation Rating Scale (CHEERS)

THE ELEMENTARY VESTIBULO-OCULAR REFLEX ARC

Recently we showed that sensitivity for chromatic- and high-spatial frequency luminance stimuli is enhanced during smooth-pursuit eye movements (SPEMs). Here we investigated whether this enhancement is a general property of slow eye movements. Besides SPEM there are two other classes of eye movements that operate in a similar range of eye velocities: the optokinetic nystagmus (OKN) is a reflexive pattern of alternating fast and slow eye movements elicited by wide-field visual motion and the vestibulo-ocular reflex (VOR) stabilizes the gaze during head movements. In a natural environment all three classes of eye movements act synergistically to allow clear central vision during self- and object motion. To test whether the same improvement of chromatic sensitivity occurs during all of these eye movements, we measured human detection performance of chromatic and luminance line stimuli during OKN and contrast sensitivity during VOR and SPEM at comparable velocities. For comparison, performance in the same tasks was tested during fixation. During the slow phase of OKN we found a similar enhancement of chromatic detection rate like that during SPEM, whereas no enhancement was observable during VOR. This result indicates similarities between slow-phase OKN and SPEM, which are distinct from VOR.

The contribution of the flocculus region of the cerebellum to horizontal gaze pursuit was studied in squirrel monkeys. When the head was free to move, the monkeys pursued targets with a combination of smooth eye and head movements; with the majority of the gaze velocity produced by smooth tracking head movements. In the accompanying study we reported that the flocculus region was necessary for cancellation of the vestibuloocular reflex (VOR) evoked by passive whole body rotation. The question addressed in this study was whether the flocculus region of the cerebellum also plays a role in canceling the VOR produced by active head movements during gaze pursuit. The firing behavior of 121 Purkinje (Pk) cells that were sensitive to horizontal smooth pursuit eye movements was studied. The sample included 66 eye velocity Pk cells and 55 gaze velocity Pk cells. All of the cells remained sensitive to smooth pursuit eye movements during combined eye and head tracking. Eye velocity Pk cells were insensitive to smooth pursuit head movements. Gaze velocity Pk cells were nearly as sensitive to active smooth pursuit head movements as they were passive whole body rotation; but they were less than half as sensitive ( approximately 43%) to smooth pursuit head movements as they were to smooth pursuit eye movements. Considered as a whole, the Pk cells in the flocculus region of the cerebellar cortex were <20% as sensitive to smooth pursuit head movements as they were to smooth pursuit eye movements, which suggests that this region does not produce signals sufficient to cancel the VOR during smooth head tracking. The comparative effect of injections of muscimol into the flocculus region on smooth pursuit eye and head movements was studied in two monkeys. Muscimol inactivation of the flocculus region profoundly affected smooth pursuit eye movements but had little effect on smooth pursuit head movements or on smooth tracking of visual targets when the head was free to move. We conclude that the signals produced by flocculus region Pk cells are neither necessary nor sufficient to cancel the VOR during gaze pursuit.

The vestibuloocular reflex (VOR) generates compensatory eye movements to stabilize visual images on the retina during head movements. The amplitude of the reflex is calibrated continuously throughout life and undergoes adaptation, also called motor learning, when head movements are persistently associated with image motion. Although the floccular-complex of the cerebellum is necessary for VOR adaptation, it is not known whether this function is localized in its anterior or posterior portions, which comprise the ventral paraflocculus and flocculus, respectively. The present paper reports the effects of partial lesions of the floccular-complex in five macaque monkeys, made either surgically or with stereotaxic injection of 3-nitropropionic acid (3-NP). Before and after the lesions, smooth pursuit eye movements were tested during sinusoidal and step-ramp target motion. Cancellation of the VOR was tested by moving a target exactly with the monkey during sinusoidal head rotation. The control VOR was tested during sinusoidal head rotation in the dark and during 30 degrees/s pulses of head velocity. VOR adaptation was studied by having the monkeys wear x2 or x0.25 optics for 4-7 days. In two monkeys, bilateral lesions removed all of the flocculus except for parts of folia 1 and 2 but did not produce any deficits in smooth pursuit, VOR adaptation, or VOR cancellation. We conclude that the flocculus alone probably is not necessary for either pursuit or VOR learning. In two monkeys, unilateral lesions including a large fraction of the ventral paraflocculus produced small deficits in horizontal and vertical smooth pursuit, and mild impairments of VOR adaptation and VOR cancellation. We conclude that the ventral paraflocculus contributes to both behaviors. In one monkey, a bilateral lesion of the flocculus and ventral paraflocculus produced severe deficits smooth pursuit and VOR cancellation, and a complete loss of VOR adaptation. Considering all five cases together, there was a strong correlation between the size of the deficits in VOR learning and pursuit. We found the strongest correlation between the behavior deficits and the size of the lesion of the ventral paraflocculus, a weaker but significant correlation for the full floccular complex, and no correlation with the size of the lesion of the flocculus. We conclude that 1) lesions of the floccular complex cause linked deficits in smooth pursuit and VOR adaptation, and 2) the relevant portions of the structure are primarily in the ventral paraflocculus, although the flocculus may participate.

Human vestibuloocular reflex and its interactions with vision and fixation distance during linear and angular head movement. J. Neurophysiol. 80: 2391-2404, 1998. The vestibuloocular reflex (VOR) maintains visual image stability by generating eye movements that compensate for both angular (AVOR) and linear (LVOR) head movements, typically in concert with visual following mechanisms. The VORs are generally modulated by the "context" in which head movements are made. Three contextual influences on VOR performance were studied during passive head translations and rotations over a range of frequencies (0.5-4 Hz) that emphasized shifting dynamics in the VORs and visual following, primarily smooth pursuit. First, the dynamic characteristics of head movements themselves ("stimulus context") influence the VORs. Both the AVOR and LVOR operate with high-pass characteristics relative to a head velocity input, although the cutoff frequency of the AVOR (<0.1 Hz) is far below that of the LVOR ( approximately 1 Hz), and both perform well at high frequencies that exceed, but complement, the capabilities of smooth pursuit. Second, the LVOR and AVOR are modulated by fixation distance, implemented with a signal related to binocular vergence angle ("fixation context"). The effect was quantified by analyzing the response during each trial as a linear relationship between LVOR sensitivity (in deg/cm), or AVOR gain, and vergence (in m-1) to yield a slope (vergence influence) and an intercept (response at 0 vergence). Fixation distance (vergence) was modulated by presenting targets at different distances. The response slope rises with increasing frequency, but much more so for the LVOR than the AVOR, and reflects a positive relationship for all but the lowest stimulus frequencies in the AVOR. A third influence is the context of real and imagined targets on the VORs ("visual context"). This was studied in two ways-when targets were either earth-fixed to allow visual enhancement of the VOR or head-fixed to permit visual suppression. The VORs were assessed by extinguishing targets for brief periods while subjects continued to "fixate" them in darkness. The influences of real and imagined targets were most robust at lower frequencies, declining as stimulus frequency increased. The effects were nearly gone at 4 Hz. These properties were equivalent for the LVOR and AVOR and imply that the influences of real and imagined targets on the VORs generally follow low-pass and pursuit-like dynamics. The influence of imagined targets accounts for roughly one-third of the influence of real targets on the VORs at 0.5 Hz.

If horizontal saccades or smooth-pursuit eye movements are made with the line-of-sight at different elevations, the three-dimensional (3D) angular rotation axis of the globe tilts by half the vertical eye eccentricity. This phenomenon is named "half-angle rule" and is a consequence of Listing's law. It was recently found that the ocular rotation axis during the horizontal vestibulo-ocular reflex (VOR) on a turntable also tilts in the direction of the line-of-sight by about a quarter of the eye's vertical eccentricity. This is surprising, since, in a "perfect" VOR, the angular rotation axis of the eye should be independent from the position of the eye to fully compensate for the 3D angular head rotation. We asked whether this quarter-angle strategy is a general property of the VOR or whether the 3D kinematics of ocular movements evoked by vestibular stimulation would be less eye-position dependent at higher stimulus frequencies. Nine healthy subjects were exposed to horizontal head impulses (peak velocity approximately 250 degrees /s). The line-of-sight was systematically changed along the vertical meridian of a tangent screen. Three-dimensional eye and head movements were monitored with dual search coils. The 3D orientation of the angular eye-in-head rotation axis was determined by calculating the average angular velocity vectors of the initial 10 degrees displacements. Then, the difference between the tilt angles of the ocular rotation axis during upward and downward viewing was determined and divided by the difference of vertical eccentricity ("tilt angle coefficient"). Control experiments included horizontal saccades, smooth-pursuit eye movements, and eye movements evoked by slow, passive head rotations at the same vertical eye eccentricities. On average, the ocular rotation axis during horizontal head-impulse testing at different elevations of the line-of-sight was closely aligned with the rotation axis of the head (tilt angle coefficient of pooled abducting and adducting eye movements: 0.11+/-0.17 SD). Values for slow head impulses, however, exceeded somewhat the quarter angle (0.33+/-0.12), while smooth-pursuit movements (0. 50+/-0.09) and saccades (0.44+/-0.11) were closest to the half angle. These results demonstrate that the 3D orientation of the ocular rotation axis during rapid head thrusts is relatively independent of the direction of the line-of-sight and that ocular rotations elicited by head impulses are kinematically different from saccades, despite similar movement dynamics.

1. The single-unit activity of neurons in the vestibular nucleus, the prepositus nucleus, and the abducens nucleus, whose activity was primarily related to horizontal eye movements, was recorded in alert squirrel monkeys that were trained to track a small visual target by generating smooth pursuit eye movements and to cancel their horizontal vestibuloocular reflex (VOR) by fixating a head stationary target. 2. The spiking behavior of each cell was recorded during 1) spontaneous eye movements, 2) horizontal smooth pursuit of a target that was moved sinusoidally +/- 20 degrees/s at 0.5 Hz, 3) horizontal VOR evoked by 0.5-Hz sinusoidal turntable rotations +/- 40 degrees/s (VORs), and 4) voluntary cancellation of the VOR by fixation of a head-stationary target during 0.5-Hz sinusoidal turntable rotation at +/- 40 degrees/s (VORCs). The responses of most (28/42) of the units were recorded during unpredictable 100-ms steps in head acceleration (400 degrees/s2) that were generated while the monkey was fixating a target light. The acceleration steps were generated either when the monkey was stationary or when the turntable was already rotating (VORt trials), and the monkey was canceling its VOR (VORCt trials). 3. The firing behavior of all 12 of the abducens neurons recorded was closely related to horizontal eye position and eye velocity during all of the behavioral paradigms used, although there was a small but significant increase in the eye position sensitivity of many of these units when the eye was moving (smooth pursuit) versus when the eye was stationary (fixation). 4. Many neurons in the prepositus nucleus and the medial vestibular nucleus (n = 15) were similar to abducens neurons, in that their firing rate was related primarily to horizontal eye position and eye velocity, regardless of the behavioral paradigm used. These cells were, on average, more sensitive to eye position and smooth pursuit eye velocity than were abducens neurons. 5. The firing rate of 15 other neurons in the prepositus and medial vestibular nucleus was related primarily to horizontal smooth pursuit eye movements. The tonic firing rate of all of these smooth pursuit (SP) cells was related to horizontal eye position, and the majority generated bursts of spikes during saccades in all directions but their off direction. Six of the SP neurons fired in phase with ipsilateral eye movements, whereas the remaining nine were sensitive to eye movements in the opposite direction.(ABSTRACT TRUNCATED AT 400 WORDS)

BackgroundVestibular reflexes coordinate movements or sensory input with changes in body or head position. Vestibular-evoked responses that involve the extraocular muscles include the vestibulo-ocular reflex (VOR), a compensatory eye movement to stabilize retinal images. Although an angular VOR attributable to semicircular canal stimulation was reported to be absent in free-swimming zebrafish larvae, recent studies reveal that vestibular-induced eye movements can be evoked in zebrafish larvae by both static tilts and dynamic rotations that tilt the head with respect to gravity.ResultsWe have determined herein the basis of sensitivity of the larval eye movements with respect to vestibular stimulus, developmental stage, and sensory receptors of the inner ear. For our experiments, video recordings of larvae rotated sinusoidally at 0.25 Hz were analyzed to quantitate eye movements under infrared illumination. We observed a robust response that appeared as early as 72 hours post fertilization (hpf), which increased in amplitude over time. Unlike rotation about an earth horizontal axis, rotation about an earth vertical axis at 0.25 Hz did not evoke eye movements. Moreover, vestibular-induced responses were absent in mutant cdh23 larvae and larvae lacking anterior otoliths.ConclusionsOur results provide evidence for a functional vestibulo-oculomotor circuit in 72 hpf zebrafish larvae that relies upon sensory input from anterior/utricular otolith organs.

The smooth pursuit system interacts with the vestibular system to maintain the accuracy of eye movements in space. To understand neural mechanisms of short-term modifications of the vestibulo-ocular reflex (VOR) induced by pursuit-vestibular interactions, we used a cross-axis procedure in trained monkeys. We showed earlier that pursuit training in the plane orthogonal to the rotation plane induces adaptive cross-axis VOR in complete darkness. To further study the properties of adaptive responses, we examined here the initial eye movements during tracking of a target while being rotated with a trapezoidal waveform (peak velocity 30 or 40 degrees/s). Subjects were head-stabilized Japanese monkeys that were rewarded for accurate pursuit. Whole body rotation was applied either in the yaw or pitch plane while presenting a target moving in-phase with the chair with the same trajectory but in the orthogonal plane. Eye movements induced by equivalent chair rotation with or without the target were examined before and after training. Before training, chair rotation alone resulted only in the collinear VOR, and smooth eye movement-tracking of orthogonal target motion during rotation had a normal smooth pursuit latency (ca 100 ms). With training, the latency of orthogonal smooth tracking eye movements shortened, and the mean latency after 1 h of training was 42 ms with a mean gain, at 100 ms after stimulus onset, of 0.4. The cross-axis VOR induced by chair rotation in complete darkness had identical latencies with the orthogonal smooth tracking eye movements, but its gains were <0.2. After cross-axis pursuit training, target movement alone without chair rotation induced smooth pursuit eye movements with latencies ca 100 ms. Pursuit training alone for 1 h using the same trajectory but without chair rotation did not result in any clear change in pursuit latency (ca 100 ms) or initial eye velocity. When a new target velocity was presented during identical chair rotation after training, eye velocity was correspondingly modulated by just 80 ms after rotation onset, which was shorter than the expected latency of pursuit (ca 100 ms). These results indicate that adaptive changes were induced in the smooth pursuit system by pursuit-vestibular interaction training. We suggest that this training facilitates the response of pursuit-related neurons in the cortical smooth pursuit pathways to vestibular inputs in the orthogonal plane, thus enabling smooth eye movements to be executed with shorter latencies and larger eye velocities than in normal smooth pursuit driven only by visual feedback.

Chapter 6.5 - Mechanisms of vestibulo-ocular reflex (VOR) cancellation in spinocerebellar ataxia type 3 (SCA-3) and episodic ataxia type 2 (EA-2)