Behavior and physiology of the macaque vestibulo-ocular reflex response to sudden off-axis rotation: Computing eye translation

The vestibulo-ocular reflex (VOR) has historically been considered a computationally simple reflex: to stabilize images on the retina against imposed head rotation, the eyes must be counterrotated by an equal amount in the opposite direction. During almost any head rotation, however, the eyes are also translated. We show that the VOR compensates for 90% of this translation, and suggest a computational scheme by which this is done, based on a temporal dissection of the VOR response to sudden head rotation. An initial response that corrects only for imposed rotation is refined by a series of three temporally delayed corrections of increasing complexity. The first correction takes only head rotation and viewing distance into account; the second, head rotation, viewing distance, and otolith translation; and the third, head rotation, viewing distance, otolith translation, and translation of the eyes relative to the otoliths. Responses of type I gaze velocity Purkije (GVP) cells in the cerebellar flocculus and ventral paraflocculus of rhesus monkeys were recorded during sudden head rotation. We show that cell discharge was modulated both by axis location and by viewing distance, suggesting that GVP cells play a role in the VOR response to rotation-induced eye translation.     

Roles of the cerebellum in pursuit-vestibular interactions

This mini-review focuses on cerebellar roles in on-line control of smooth-pursuit eye movements during vestibular stimulation in primates. The smooth-pursuit system is necessary to track smoothly moving targets and must interact with the vestibular system during movement of the head and/or whole body to maintain the precision of eye movements in space (i.e. gaze movements). This interaction requires calculation of gaze velocity commands that match the eye velocity in space to the actual target velocity. Two cerebellar regions, the floccular lobe that consists of the flocculus and ventral paraflocculus, and the dorsal vermis, are known to be involved in smooth-pursuit. However, potential differences in their involvement are incompletely understood. To understand their roles, in particular whether the output of these regions codes gaze velocity or eye velocity, simple-spike activity of Purkinje (P-) cells was examined during smooth-pursuit and pursuit-vestibular interaction tasks in various directions in head-restrained monkeys. The results showed differences in discharge characteristics of vertical and horizontal P-cells within the floccular lobe and between the floccular lobe and dorsal vermis. These differences and other available evidence suggest that the dorsal vermis is involved more in the control of gaze movement whereas the floccular lobe primarily controls eye movement (in the orbit) as a component of the oculomotor neural integrator. Smooth-pursuit without vestibular stimulation cannot dissociate eye movement from gaze movement. To understand the cerebellar role in various aspects of smooth tracking of targets moving in the three dimensional space, more information is needed particularly on how the above mentioned two regions along with the dorsal paraflocclus and underlying deep cerebellar nuclei are involved in vergence tracking, how the cerebellum is involved in prediction and perception of target motion, and whether complex-spike discharge is involved in a fast adaptive process that may be used for prediction in smooth ocular tracking.     

The Floccular Syndrome: Dynamic Changes in Eye Movements and Vestibulo-ocular Reflex in Isolated Infarction of the Cerebellar Flocculus

The cerebellar flocculus is a critical structure involved in the control of eye movements. Both static and dynamic abnormalities of the vestibulo-ocular reflex (VOR) have been described in animals with experimental lesions of the flocculus/paraflocculus complex. In humans, lesions restricted to the flocculus are rare so they can become an exceptional model to contrast with the clinical features in experimental animals or in patients with more generalized cerebellar diseases. Here, we examined a 67-year-old patient with an acute vestibular syndrome due to an isolated infarct of the right flocculus. We evaluated him multiple times over 6 months—to follow the changes in eye movements and vestibular function—with caloric testing, video-oculography and head-impulse testing, and the anatomical changes on imaging. Acutely, he had an ipsilateral-beating spontaneous nystagmus, bilateral gaze-evoked nystagmus, borderline impaired smooth pursuit, and a complete contraversive ocular tilt reaction. The VOR gain was reduced for head impulses directed contralateral to the lesion, and there was also an ipsilesional caloric weakness. All abnormalities progressively improved at follow-up visits but with a considerable reduction in volume of the affected flocculus on imaging. The vestibular and ocular motor findings, qualitatively similar to a previously reported patient, further clarify the “acute floccular syndrome” in humans. We also add new information about the pattern of recovery from such a lesion with corresponding changes in the size of the affected flocculus on imaging.     

Searching for an Internal Representation of Stimulus Kinematics in the Response of Ventral Paraflocculus Purkinje Cells

Motor control theories propose that the central nervous system builds internal representations of the motion of both our body and external objects. These representations, called forward models, are essential for accurate motor control. For instance, to produce a precise reaching movement to catch a flying ball, the central nervous system must build predictions of the current and future states of both the arm and the ball. Accumulating evidence suggests that the cerebellar cortex contains a forward model of an individual’s body movement. However, little evidence is yet available to suggest that it also contains a forward model of the movement of external objects. We investigated whether Purkinje cell simple spike responses in an oculomotor region of the cerebellar cortex called the ventral paraflocculus contained information related to the kinematics of behaviorally relevant visual stimuli. We used a visuomotor task that obliges animals to track moving targets while keeping their eyes fixated on a stationary target to separate signals related to visual tracking from signals related to eye movement. We found that ventral paraflocculus Purkinje cells do not contain information related to the kinematics of behaviorally relevant visual stimuli; they only contain information related to eye movements. Our data stand in contrast with data obtained from cerebellar Crus I, wherein Purkinje cell discharge contains information related to moving visual stimuli. Together, these findings suggest specialization in the cerebellar cortex, with some areas participating in the computation of our movement kinematics and others computing the kinematics of behaviorally relevant stimuli.     

VOR and Fos response during acute vestibular compensation in the Mongolian gerbil in darkness and in light

We measured binocular horizontal eye movements in the gerbil following unilateral labyrinthectomy during the acute phase (1-24 h) of vestibular compensation. Regardless of whether the animals compensated in the light or the dark, VOR gain progressively reduced following the lesion, and normal oculomotor symmetry was disrupted. Initially, the VOR was comparable at 1 h post-lesion for both visual conditions. However, by 3 h post-lesion the VOR response for head turns away from the lesion continued to drop in animals compensating in the dark. By 24 h, both groups displayed reduced VOR gains, but animals compensating in the light had improved frequency response characteristics. Optokinetic responses became unstable but were generally elevated compared to pre-lesion levels. Animals with vision had reduced optokinetic gains by 24 h, while the OKR response for animals in the dark remained elevated. Brainstem Fos labeling generally increased from 1 to 3 h, then decreased by 24 h. However, at 1 h, Fos labeling in the inferior olivary dorsal cap and prepositus contralateral to the lesion was significantly increased in animals compensating in the light. In both visual conditions, flocculus and paraflocculus Purkinje cell labeling was also observed, and some of the Fos-labeled cells in the medial vestibular nucleus were commissural. Fos in the dorsal cap and prepositus could be attributed to the presence of visual input. While the visually related prepositus Fos labeling preceded improved VOR performance, the dorsal cap appeared to be involved in resolving visual and motor deficits from spontaneous nystagmus.     

Voluntary and visual control of the vestibuloocular reflex after cerebral hemidecortication

Horizontal vestibuloocular reflex (VOR) function was studied in five patients after cerebral hemidecortication. In darkness, VOR gain contralateral to the decorticate hemisphere was slightly higher than ipsilateral gain. Voluntary modulation of the reflex by attempted fixation of imaginary targets in darkness increased this VOR asymmetry. Voluntary cancellation of the ipsilateral VOR was better than cancellation of the contralateral VOR. Voluntary enhancement of the contralateral VOR was better than enhancement of the ipsilateral VOR. Visual control of the reflex while viewing foveal targets further increased the VOR asymmetry. Defective visual modulation corresponded to paresis of ipsilateral smooth pursuit. Abnormal voluntary responses in darkness indicate that cerebral control of the reflex can be independent of the pursuit system. The hemispheres may use a corollary discharge of eye position in the orbit and a head velocity signal to direct smooth eye movements toward the perceived location of objects. One hemisphere regulates ipsilateral smooth eye movements that achieve voluntary and visual control of the VOR.     

Computational Theory Underlying Acute Vestibulo-ocular Reflex Motor Learning with Cerebellar Long-Term Depression and Long-Term Potentiation

The vestibulo-ocular reflex (VOR) can be viewed as an adaptive control system that maintains compensatory eye movements during head motion. As the cerebellar flocculus is intimately involved in this adaptive motor control of the VOR, the VOR has been a popular model system for investigating cerebellar motor learning. Long-term depression (LTD) and long-term potentiation (LTP) at the parallel fiber–Purkinje cell synapses are considered to play major roles in cerebellar motor learning. A recent study using mutant mice demonstrated cerebellar motor learning with hampered LTD; the study concluded that the parallel fiber–Purkinje cell LTD is not essential. More recently, multiple forms of plasticity have been found in the cerebellum, and they are believed to contribute to cerebellar motor learning. However, it is still unclear how synaptic plasticity modifies the signal processing that underlies motor learning in the flocculus. A computational simulation suggested that the plasticity present in mossy fiber–granule cell synapses improves VOR-related sensory-motor information transferred into granule cells, whereas the plasticity in the molecular layer stores this information as a memory under guidance from climbing fiber teaching signals. Thus, motor learning and memory are thought to be induced mainly by LTD and LTP at parallel fiber–Purkinje cell synapses and by rebound potentiation at molecular interneuron–Purkinje cell synapses among the multiple forms of plasticity in the cerebellum. In this study, we focused on the LTD and LTP at parallel fiber–Purkinje cell synapses. Based on our simulation, we propose that acute VOR motor learning accomplishes by simultaneous enhancement of eye movement signals via LTP and suppression of vestibular signals via LTD to increase VOR gain (gain-up learning). To decrease VOR gain (gain-down learning), these two signals are modified in the opposite directions; namely, LTD suppresses eye movement signals, whereas LTP enhances vestibular signals.     

Neuronal events correlated with long-term adaptation of the horizontal vestibulo-ocular reflex in the primate flocculus

The activity of flocculus Purkinje cells was examined in Japanese monkeys during sustained vestibular-visual stimulation which caused adaptation of the horizontal vestibulo-ocular reflex (H-VOR). In the floccular area related to the H-VOR by microstimulation. Purkinje cells consistently changed their simple spike responsiveness to head rotation in parallel with the adaptive H-VOR gain change. Similar changes occurred even after the H-VOR had been extinguished by lesioning of the vestibular nuclei. The complex spike discharge, on the other hand, modulated during vestibular-visual stimulation with a reciprocal pattern to the adaptive changes in the simple spike discharge. These results support the hypothesis that the flocculus adaptively modifies the H-VOR through their simple spike activity under the influence of visual climbing fiber signals.     

Organization of inferior olivary projections to the flocculus and ventral paraflocculus of the rat cerebellum.

The climbing fiber projection to the rat flocculus and adjacent ventral paraflocculus was investigated by using Phaseolus vulgaris-leucoagglutinin as an anterograde and horseradish peroxidase as a retrograde tracer. Large injections of horseradish peroxidase in the flocculus and ventral paraflocculus indicated that the climbing fibers to this region are derived exclusively from any of the following contralateral olivary regions: the dorsal cap of Kooy, the ventrolateral outgrowth, the caudal half of the ventral leaf of the principal olive near its lateral bend, and the rostral pole of the medial accessory olive. Subsequent anterograde and retrograde studies with small injections demonstrated that the latter area projects to the C2 zone, which runs caudally in the ventral paraflocculus and enters the caudal most aspect of the flocculus. The ventral leaf of the principal olive is connected to a D zone in the cerebellar hemisphere and paraflocculus, which, upon entering the ventral paraflocculus, divides into a caudal and rostral strip, termed FD and FD', respectively. The dorsal cap and the ventrolateral outgrowth each project to two distinct zones in the flocculus and part of the ventral paraflocculus. Two floccular zones, which are continuous with the parafloccular FD and FD' zones, receive their climbing fibers from the ventrolateral outgrowth. Two other zones, (FE and FE') receive their climbing fibers from the dorsal cap. The FE' zone is found at the rostral pole of the flocculus and is followed caudalwards by the FD', FE, FD, and C2 zones, respectively. The rostromedial part of the dorsal cap is connected to the continuation of the FE zone into the ventral paraflocculus. The observation that the dorsal cap and the ventrolateral outgrowth are both connected to a set of two alternating zones of floccular/ventral parafloccular Purkinje cells is in agreement with recent studies in the rabbit, and suggests that these zones reflect functionally distinct and discrete units related to specific aspects of visuomotor control.     

Discharges of Purkinje cells in monkey's flocculus during smooth-pursuit eye movements and visual stimulus movements

Modulations in discharges of Purkinje cells (P cells) associated with movements of visual patterns were studied in the flocculus of monkeys trained to execute smooth-pursuit eye movements and to suppress optokinetic nystagmus. One class of P cells responded to the movements of visual stimulus regardless of whether the eyes remained stationary (produced retinal-slip velocity) or moved with the stimulus produced eye velocity). These P cells processed high-order information concerning the absolute velocity of stimulus movements and thereby the eye velocity had already been incorporated in the visual responses (visuomotor P cells). The other class of P cells responded to visual inputs resulting from the retinal slip (visual P cells). The majority of visual P cells (82%) also modulated their activities during smooth pursuit. When sinusoidal trackings were executed against a stationary visual background, various types of interactions occurred in the P-cell responses between the converging visual and oculomotor inputs. The type of interaction was related to the preferred direction for the P cell during eye movements and the side of the peripheral receptive field.     

Simple spike and complex spike activity of floccular Purkinje cells during the optokinetic reflex in mice lacking cerebellar long-term depression

Cerebellar long-term depression (LTD) at parallel fibre-Purkinje cell (P-cell) synapses is thought to embody neuronal information storage for motor learning. Transgenic L7-protein kinase C inhibitor (PKCI) mice in which cerebellar LTD is selectively blocked do indeed exhibit impaired adaptation in the vestibulo-ocular reflex (VOR) while their default oculomotor performance is unaffected. Although supportive, these data do not definitively establish a causal link between memory storage required for motor learning and cerebellar LTD. As the L7-PKCI transgene is probably activated from the early stages of P-cell development, an alternative could be that P-cells develop abnormal signals in L7-PKCI mutants, disturbing mechanisms of motor learning that rely on proper P-cell outputs. To test this alternative hypothesis, we studied simple spike (SS) and complex spike (CS) activity of vertical axis P-cells in the flocculus of L7-PKCI mice and their wild-type littermates during sinusoidal optokinetic stimulation. Both SS and CS discharge dynamics appeared to be very similar in wild-type and transgenic P-cells at all stimulus frequencies (0.05-0.8 Hz). The CS activity of all vertical axis cells increased with contralateral stimulus rotation and lagged ipsiversive eye velocity by 165-180 degrees. The SS modulation was roughly reciprocal to the CS modulation and lagged ipsiversive eye velocity by approximately 15 degrees. The baseline SS and CS discharge characteristics were indistinguishable between the two genotypes. We conclude that the impaired VOR learning in L7-PKCI mutants does not reflect fundamental aberrations of the cerebellar circuitry. The data thus strengthen the evidence that cerebellar LTD is implicated in rapid VOR learning but not in the development of normal default response patterns.     

Development of vertical vestibulo-ocular reflex characteristics in intact and flocculectomized rabbits visually deprived from birth

The vertical vestibulo-ocular reflex (VOR) was recorded in dark-reared rabbits 3 months of age submitted in the dark to lateral sinusoidal oscillations of different frequencies and fixed amplitude. While the phase of the response was perfectly adequate to ensure head movements compensation, the gain values recorded showed a clear reduction with respect to the values obtained in a normally raised control group of the same age. After exposure to light, the visually deprived animals showed a complete and rapid recovery of normal VOR gain values. Another group of animals was flocculectomized prior to light exposure. The bilateral ablation of flocculus and paraflocculus did not affect the VOR characteristics of the deprived animals. After exposure to light, in the flocculectomized animals, no recovery of the VOR gain values was observed. The present results confirm that visual experience in early life is necessary for a correct development of the VOR. If visual deprivation is limited to the first few months of life, the impairment of the reflex characteristics is completely reversible. Finally our data suggest that in the rabbit, the flocculus controls the early life development of the VOR.     

Electrophysiologic identification of projections from the midbrain to the paraflocculus and midvermis in the rat

Regions of the midbrain in the rat were stimulated electrically with bipolar electrodes to identify responsive, single neurons in the parafloccular lobule of the cerebellum. Eighty four percent ( ) of the cells recorded in the paraflocculus showed evidence of a modulation in simple spike discharge activity (mossy fiber activations) following stimulation with a bipolar electrode whose tip was placed in the ventral layers of the contralateral superior colliculus. Mossy fiber (MF) evoked responses were indicated by the presence of an excitation followed by an inhibition of simple spike frequency at latencies of 5–16 msec and by the demonstration of responsiveness to stimulus frequencies up to 50 Hz. Ten percent ( ) of identified Purkinje cells in the paraflocculus demonstrated activation of complex spike potentials following stimulation of regions in the ventral superior colliculus. Experiments involving stimulation of the midbrain and visual cortices indicated that 70% of the parafloccular neurons are responsive to inputs from both the cortex and deep regions of the colliculus. Electrophysiologic evidence also is presented that demonstrates the existence of a midbrain projection to midvermal lobules VI and VII of the cerebellum.     

Abnormalities of smooth eye and head movement control in parhson's disease

The control of horizontal head and eye movements was examined in 13 nondemented patients with Parkinson's disease (PD) of mild to moderate severity. During pursuit of single-frequency sine waves, smooth component eye velocity was lower in the PD group at frequencies of 1.2 Hz and above; but the differences in overall eye displacement were even greater, indicating an impaired ability to generate catch-up saccades at high frequencies. A corresponding deficit in saccadic performance was observed during a high-frequency saccadic tracking task where predictive saccades of reduced gain and variable timing were generated. During pursuit of pseudo-random target motion with varying degrees of predictability, small differences in smooth component eye velocity were observed, but prediction was otherwise well preserved in the patient group. Vestibulo-ocular reflex (VOR) suppression was also normal during head-free pursuit. No major improvement in smooth pursuit gain could be attributed to drug treatment, based on a comparison of patient results before and after administration of levodopa.     

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.     

Spontaneous Gaze Shifts in Intact Head-free Rats and Following Inferior Olive and Cerebellar Lesions

Recent experiments have shown that after lesions of the inferior olive or of the flocculus and paraflocculus of the cerebellum, in the pigmented rat, spontaneous saccades made when the head is completely restrained are followed by a large postsaccadic drift. The aims of the present paper were to study (i) the strategies and the characteristics of spontaneous eye – head coordinated gaze shifts in intact pigmented rats and to compare them with those described in other mammals, (ii) how they are affected by inferior olive and flocculus – paraflocculus lesions, and (iii) whether in these groups of animals the stability of the gaze is more deficient when the head is free to rotate in the horizontal plane (head-free condition) relative to the head-fixed condition. Three types of gaze shift strategy of intact rats are described and characterized. Following inferior olive or flocculus – paraflocculus lesion the dynamic parameters of such gaze shifts (the main sequences of head, gaze and eye and the timing of eye and head movement onset) are not significantly affected. The main deficits of lesioned animals affect the stability of gaze at the end of gaze shifts. After inferior olive lesion the amplitude of the postsaccadic drift of the gaze is 43.2% of the gaze saccade in the head-fixed condition, which is reduced to 22.9% in the head-free condition. Following flocculus – paraflocculus lesion the postsaccadic drift of gaze is even more reduced than after inferior olive lesion, changing from 39.2% in the head-fixed condition to only 9.7% in the head-free condition.     

Neuronal pathway from floccular caudal zone contributing to vertical eye movements in cats—role of group y nucleus of vestibular nuclei

In ketamine-anesthetized cats, electric microstimulation of the group y nucleus of the vestibular nuclei evoked a slow and smooth upward eye movement. Destruction of the group y nucleus eliminated a slow and smooth downward eye movement evoked by stimulation of the caudal zone of the flocculus. These data support the interpretation that Purkinje cell activity in the caudal zone of the flocculus can evoke vertical eye movements by inhibiting the activity of neurons of the group y nucleus.     

The effect of lesions of the dorsal cap of the inferior olive on the vestibulo-ocular and optikinetic systems of the cat

The gain (eye velocity/head velocity) of the vestibulo-ocular reflex (VOR) of cats was measured in the dark and light for sinusoidal head oscillations at 0.05 and 1.2 Hz with peak velocity of about 30 deg/sec. Animals wore visual reversing prisms chronically and were also subjected to forced oscillation in the light at 0.05 Hz for 2 h per day. Such experience produced adaptive reduction in VOR gain in the dark from 0.85 to 0.10 within about 4 days; qualitatively similar effects were observed at 1.2 Hz. In 4 cats, the dorsal cap of the inferior olive was located electrophysiologically by its responses to visual motion, and bilateral electrolytic lesions were made in or near this structure. The location of lesions was subsequently identified by histology. After lesions, 3 cats were unable to make adaptive changes in VOR gain when confronted with the same reversing prism paradigm; the fourth exhibited appreciable retardation of adaptation. These results imply that the dorsal cap is essential for plastic adaptation of the VOR. However, all cats retained the ability to use reversed vision to reduce VOR gain in the light after lesions.Optokinetic nystagmus (OKN) and optokinetic after nystagmus (OKAN) were measured in a striped optokinetic drum, before and after dorsal cap lesions, at drum velocities of 20 and 40 deg/sec. Lesions of the dorsal cap in 4 cats did not impair either OKN or OKAN. This result indicates that the climbing fiber system reaching the flocculus from the inferior olive is not essential for such optokinetic movements.     

Visual facial grasp

Some patients with degenerative neurological diseases have a release of the vestibular-ocular reflex (VOR), as detected by passive head movement during visual fixation on a moving target ("doll's eyes"maneuver). However, a positive doll's eyes sign might be induced by other defects and the purpose of this article is to describe a new ocular sign of cortical dysfunction, the visual facial grasp. We observed three patients, one with progressive supranuclear palsy (PSP), another with probable Alzheimer's disease (AD) and a third with cortico-basal degeneration (CBD) all of whom appeared to demonstrate a release of the vestibulo-ocular reflex (VOR) with passive head movements. Whereas the patient with PSP, who was unable to inhibit the VOR regardless of the visual target used probably had a true release of the VOR, the patients with AD and CBD were able to inhibit this reflex when the visual target was the examiner's moving face. These two patients also exhibited spontaneous preference for visual fixation on the examiner's face and improvement in smooth pursuit when the examiner's face was the visual target. This clinical observation suggests that the deficits in these two patients with AD and CBD were related to the emergence of a primitive stimulus-bound behavior, the visual facial grasp.     

Vestibulo-ocular reflex (VOR) induced by passive head rotation and goal-directed saccadic eye movements do not simply add in man

Additivity between vestibulo-ocular reflex (VOR) and saccadic eye movements was quantified in man by passively rotating the subject's head as he tracked a stepping target. A systematically increased gaze (i.e. eye + head) saccadic velocity was observed when the head was rotated toward the target, as compared to a head-fixed condition, indicating that VOR and saccades do not fully add. Moreover, although VOR was assumed to be inhibited during ocular saccades, mean gaze saccadic amplitude remained unchanged. This would suggest an on-line computation of gaze position to be fed back to the saccadic system in order to stop the saccade once gaze reaches its goal.