Cancellation Of Vestibulo-ocular Reflex Research Articles

Scale for Ocular Motor Disorders in Ataxia (SODA) in Patients with Multiple System Atrophy.

A clinical scale fully dedicated to evaluating ocular motor abnormalities is required for now. We investigated the utility of a recently developed Scale for Ocular motor Disorders in Ataxia (SODA) in patients with multiple system atrophy (MSA). We prospectively assessed SODA in consecutive patients with MSA between August 2021 and August 2023 at the Korea University Medical Center. The results of the clinical exam-based SODA were compared with those measured using video-oculography (VOG-guided SODA). We also compared the findings with other established clinical scales targeting patients with MSA, including the Unified Multiple System Atrophy Rating Scale (UMSARS) I-II, Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor part (UPDRS-III), Scale for Assessment of Rating of Ataxia (SARA), Composite Autonomic Symptom Score-31 (COMPASS-31), and Composite Autonomic Severity Score (CASS). Twenty patients were enrolled in our study (17 with cerebellar-type MSA and three with Parkinson-type MSA). Scores ranged from 1 to 14 (median [interquartile range (IQR)] = 8 [5-10]). Among the subscales, saccades had a median score of 2.5 (IQR = 1-3), followed by ocular pursuit (1 [0-1]), nystagmus (1 [0-2]), saccadic intrusions (1 [0-1]), vestibulo-ocular reflex (VOR) (0.5 [0-1]), ocular alignment (0 [0-1]), and VOR cancellation (1 [0-1]). The clinical-exam-based SODA (p = 0.020) and VOG-guided SODA (p = 0.034) positively correlated with disease duration. No correlation was found between clinical exam-based SODA and other scales. Skew deviation, gaze-evoked nystagmus, VOR cancellation, and smooth pursuit had the highest precision among the items. Ocular misalignment and spontaneous and positional nystagmus were frequently false positive and were poorly detected with clinical exam-based SODA. Six patients with repeated evaluation exhibited higher scores, along with deterioration documented on other clinical scales. The SODA can reliably predict neurodegeneration as an additional clinical surrogate in MSA.

Anti Zic4 Paraneoplastic Neurological Syndrome Presenting as Oscillopsia.

Anti Zic4 Paraneoplastic Neurological Syndrome Presenting as Oscillopsia.

Quantitative oculomotor and nonmotor assessments in late-onset GM2 gangliosidosis.

A cross-sectional study was performed to evaluate whether quantitative oculomotor measures correlate with disease severity in late-onset GM2 gangliosidosis (LOGG) and assess cognition and sleep as potential early nonmotor features. Ten patients with LOGG underwent quantitative oculomotor recordings, including measurements of the angular vestibulo-ocular reflex (VOR), with results compared to age- and sex-matched controls. Disease severity was assessed by ataxia rating scales. Cognitive/neuropsychiatric features were assessed by the cerebellar cognitive affective syndrome (CCAS) scale, Cerebellar Neuropsychiatric Rating Scale, and sleep quality evaluated using subjective sleep scales. Oculomotor abnormalities were found in all participants, including 3/10 with clinically normal eye movements. Abnormalities involved impaired saccadic accuracy (5/10), abnormal vertical (8/10) and horizontal (4/10) pursuit, reduced optokinetic nystagmus (OKN) responses (7/10), low VOR gain (10/10), and impaired VOR cancellation (2/10). Compared to controls, the LOGG group showed significant differences in saccade, VOR, OKN, and visually enhanced VOR gains. Severity of saccadic dysmetria, OKN, and VOR fixation-suppression impairments correlated with ataxia scales (p < 0.05). Nine out of ten patients with LOGG had evidence of the CCAS (5/10 definite, 2/10 probable, 2/10 possible). Excessive daytime sleepiness was present in 4/10 and 8/10 had poor subjective sleep quality. Cerebellar oculomotor abnormalities were present in all patients with LOGG, including those with normal clinical oculomotor examinations. Saccade accuracy (dorsal cerebellar vermis localization), fixation suppression, and OKN gain (cerebellar flocculus/paraflocculus localization) correlated with disease severity, suggesting that quantitative oculomotor measurements could be used to track disease progression. We found evidence of the CCAS, suggesting that cerebellar dysfunction may explain the cognitive disorder in LOGG. Sleep impairments were prevalent and require further study.

Vestibular and oculomotor function in children with CP: Descriptive study

ObjectiveWe aimed to describe vestibular/oculomotor function of 7–12-year-old children with CP, Gross Motor Function Classification System (GMFCS) levels (I-III), in comparison to an age-matched control group to understand the effect of the vestibular system on activities and participation of children with CP. MethodsVestibular, oculomotor and balance function were tested in children with CP. Central and peripheral vestibular function was examined using an enclosed rotary chair and infrared video goggles (100 Hz) that measured eye movements. Oculomotor tests included smooth pursuit and optokinetic nystagmus (OKN). Vestibulo-Ocular Reflex (VOR) tests, done in complete darkness, included step rotation (STEP), sinusoidal harmonic acceleration (SHA) test, VOR cancellation and enhancement, and subjective visual vertical and horizontal (SVV/SVH). The integrity of the saccule was tested with the Cervical Vestibular Evoked Myogenic Potential. If able, the participants' balance abilities were examined using the Sensory Organization Test (SOT) to determine ability to maintain standing balance during six conditions that challenged the visual, somatosensory and vestibular systems. Independent t-tests and Mann-Whitney U tests were used to compare results between groups. ResultsForty-one children with CP (mean age = 9.44 years, SD = 1.66; 23F/18M; Gross Motor Function Classification System levels: I (n = 19), II (n = 7), III (n = 15) and thirty-three typically developing (TD) children (mean age = 10.16 years, SD = 1.6; 13F/20M) were recruited from the Birmingham, AL community. There was no significant difference between children with CP and TD children in saccular function (i.e. C-VEMP test), and peripheral vestibular end organ (i.e. SHA test and STEP test), VOR enhancement, or OKN gain. Velocity gain for horizontal smooth pursuit was significantly worse in children with CP (p = 0.009), compared to TD children. Poor mediation of central vestibular function were that evident with significantly higher VOR cancellation gain in children with CP (p < 0.0001), compared to TD children and significantly higher SVV variance (p = 0.002), SVH mean (p = 0.001), and SVH variance (p < 0.0001) in children with CP compared to TD children. Compromised balance abilities in children with CP was evident with significantly lower composite scores (p < 0.0001), vestibular ratio (p < 0.0001), and visual ratio (p = 0.021). The somatosensory ratio (p = 0.798) of children with CP was similar to children with TD. ConclusionsAlthough peripheral vestibular function was intact, children with CP had difficulty coupling eye and head movement (VOR cancellation), using the vestibular system for postural control (SOT), demonstrated poor perception of upright (SVV/SVH), and had difficulty following a slow moving target (smooth pursuit eye movement). These results implicate a central vestibular and oculomotor function impairment the severity of which corresponded with severity of the level of CP.

Egocentric vertigo symptoms diminished by multi-modal neurorehabilitation treatment

Egocentric vertigo symptoms diminished by multi-modal neurorehabilitation treatment

Ocular Tilt Reaction in Compensated Vestibular Schwannoma

Ocular Tilt Reaction in Compensated Vestibular Schwannoma

Visual tracking with/without passive whole-body rotation in Parkinson's disease (PD): Dissociation of smooth-pursuit and cancellation of vestibulo-ocular reflex (VOR)

Although impaired smooth-pursuit in Parkinson's disease (PD) is well known, reports are conflicting on the ability to cancel vestibulo-ocular reflex (VOR) when the target moves with head, requiring gaze-pursuit. To compare visual tracking performance with or without passive whole-body rotation, we examined eye movements of 10 PD patients and 6 age-matched controls during sinusoidal horizontal smooth-pursuit and passive whole-body rotation (0.3 Hz, ± 10°). Three tasks were tested: smooth-pursuit, VOR cancellation, and VORx1 while subjects fixated an earth-stationary spot during whole-body rotation. Mean ± SD eye velocity gains (eye velocities/stimulus velocities) of PD patients during the 3 tasks were 0.32 ± 0.24 0.25 ± 0.22, 0.85 ± 0.20, whereas those of controls were 0.91 ± 0.06, 0.14 ± 0.07, 0.94 ± 0.05, respectively. Difference was significant between the two subject groups only during smooth-pursuit. Plotting eye-velocity gains of individual subjects during VOR cancellation against those during smooth-pursuit revealed significant negative linear correlation between the two parameters in the controls, but no correlation was found in PD patients. Based on the regression equation of the controls, we estimated expected eye velocity gains of individual subjects during VOR cancellation from their smooth-pursuit gains. Estimated gains of PD patients during VOR cancellation were significantly different from their actual gains, suggesting that different neural mechanisms operate during VOR cancellation in the controls and PD.

GABA-A Inhibition Shapes the Spatial and Temporal Response Properties of Purkinje Cells in the Macaque Cerebellum.

Data from in vitro and anesthetized preparations indicate that inhibition plays a major role in cerebellar cortex function. We investigated the role of GABA-A inhibition in the macaque cerebellar ventral-paraflocculus while animals performed oculomotor behaviors that are known to engage the circuit. We recorded Purkinje cell responses to these behaviors with and without application of gabazine, a GABA-A receptor antagonist, near the recorded neuron. Gabazine increased the neuronal responsiveness to saccades in all directions and the neuronal gain to VOR cancellation and pursuit, most significantly the eye and head velocity sensitivity. L-glutamate application indicated that these changes were not the consequence of increases in baseline firing rate. Importantly, gabazine did not affect behavior or efference copy, suggesting that only local computations were disrupted. Our data, collected while the cerebellum performs behaviorally relevant computations, indicate that inhibition is a potent regulatory mechanism for the control of input-output gain and spatial tuning in the cerebellar cortex.

Ophthalmological findings in Joubert syndrome

Joubert syndrome (JS) is an autosomal-recessive inherited complex malformation of the midbrain-hindbrain. It has been associated with ocular and oculomotor abnormalities. The aim of our study was to extend the ophthalmic knowledge in JS and to add new findings. In a retrospective study, 10 consecutive patients, who met the revised diagnostic criteria of JS were included. Mutation analysis was carried out in all the cases. Each patient underwent a comprehensive neuro-ophthalmological examination. Bilateral drusen of the optic disc were found in two patients. Four patients showed bilateral morphological and functional signs of retinal dystrophy (CEP290 mutation in two cases and AHI1 mutation in one case). In nine patients performance during smooth pursuit, saccades, and vestibulo-ocular reflex (VOR) cancellation was poor. To the best of our knowledge, the association of optic disc drusen with JS has not yet been described. In support of the earlier findings, decreased smooth pursuit and VOR cancellation, as well as partial-to-complete oculomotor apraxia seem to be the key oculomotor features of JS. Genotype-phenotype correlations showed the predictive value of CEP290 and AHI1 mutations for retinal involvement.

Directional asymmetry in vertical smooth-pursuit and cancellation of the vertical vestibulo-ocular reflex in juvenile monkeys

Young primates exhibit asymmetric eye movements during vertical smooth-pursuit across a textured background such that upward pursuit has low velocity and requires many catch-up saccades. The asymmetric eye movements cannot be explained by the un-suppressed optokinetic reflex resulting from background visual motion across the retina during pursuit, suggesting that the asymmetry reflects most probably, a low gain in upward eye commands (Kasahara et al. in Exp Brain Res 171:306-321, 2006). In this study, we examined (1) whether there are intrinsic differences in the upward and downward pursuit capabilities and (2) how the difficulty in upward pursuit is correlated with the ability of vertical VOR cancellation. Three juvenile macaques that had initially been trained only for horizontal (but not vertical) pursuit were trained for sinusoidal pursuit in the absence of a textured background. In 2 of the 3 macaques, there was a clear asymmetry between upward and downward pursuit gains and in the time course of initial gain increase. In the third macaque, downward pursuit gain was also low. It did not show consistent asymmetry during the initial 2 weeks of training. However, it also exhibited a significant asymmetry after 4 months of training, similar to the other two monkeys. After 6 months of training, these two monkeys (but not the third) still exhibited asymmetry. As target frequency increased in these two monkeys, mean upward eye velocity saturated at approximately 15 degrees /s, whereas horizontal and downward eye velocity increased up to approximately 40 degrees /s. During cancellation of the VOR induced by upward whole body rotation, downward eye velocity of the residual VOR increased as the stimulus frequency increased. Gain of the residual VOR during upward rotation was significantly higher than that during horizontal and downward rotation. The time course of residual VOR induced by vertical whole body step-rotation during VOR cancellation was predicted by addition of eye velocity during pursuit and VOR x1. These results support our view that the directional asymmetry reflects the difference in the organization of the cerebellar floccular region for upward and downward directions and the preeminent role of pursuit in VOR cancellation.

Latency of vestibular responses of pursuit neurons in the caudal frontal eye fields to whole body rotation

The smooth pursuit system and the vestibular system interact to keep the retinal target image on the fovea by matching the eye velocity in space to target velocity during head and/or whole body movement. The caudal part of the frontal eye fields (FEF) in the fundus of the arcuate sulcus contains pursuit-related neurons and the majority of them respond to vestibular stimulation induced by whole body movement. To understand the role of FEF pursuit neurons in the interaction of vestibular and pursuit signals, we examined the latency and time course of discharge modulation to horizontal whole body rotation during different vestibular task conditions in head-stabilized monkeys. Pursuit neurons with horizontal preferred directions were selected, and they were classified either as gaze-velocity neurons or eye/head-velocity neurons based on the previous criteria. Responses of these neurons to whole body step-rotation at 20 degrees/s were examined during cancellation of the vestibulo-ocular reflex (VOR), VOR x1, and during chair steps in complete darkness without a target (VORd). The majority of pursuit neurons tested (approximately 70%) responded during VORd with latencies <80 ms. These initial responses were basically similar in the three vestibular task conditions. The shortest latency was 20 ms and the modal value was 24 ms. These responses were also similar between gaze-velocity neurons and eye/head-velocity neurons, indicating that the initial responses (<80 ms) were vestibular responses induced by semicircular canal inputs. During VOR cancellation and x1, discharge of the two groups of neurons diverged at approximately 90 ms following the onset of chair rotation, consistent with the latencies associated with smooth pursuit. The shortest latency to the onset of target motion during smooth pursuit was 80 ms and the modal value was 95 ms. The time course of discharge rate difference of the two groups of neurons between VOR cancellation and x1 was predicted by the discharge modulation associated with smooth pursuit. These results provide further support for the involvement of the caudal FEF in integration of vestibular inputs and pursuit signals.

Asymmetric short-term adaptation of the vertical vestibulo-ocular reflex in humans

Anatomical and electrophysiological studies have demonstrated up-down asymmetries in vertical ocular motor pathways. We investigated whether these asymmetries extend to the capacity for short-term adaptation of the vertical vestibulo-ocular reflex (VVOR) in humans. Specifically, we asked whether smooth pursuit signals are sufficient to asymmetrically adapt the VVOR. Healthy human subjects (N=8), positioned 90 degrees left-ear-down and fixating with their eyes upon a small laser dot (diameter: 0.1 degrees) projected on a sphere (distance: 1.4 m) were trained toward low VVOR gain for 30 min with symmetric and asymmetric visual VVOR cancellation paradigms, while being oscillated (0.2 Hz, +/-20 degrees) on a motorized turntable about the interaural earth-vertical axis. During asymmetric VVOR cancellation, the target was head-fixed in either the pitch-up or pitch-down half-cycles of oscillation (= trained direction) and space-fixed during the other half-cycles (= untrained direction). During symmetric VVOR cancellation, the target was head-fixed throughout the oscillations. Before and after adaptation, the pitch-up and pitch-down VOR gains were assessed during turntable oscillation in complete darkness. Before adaptation, average gains of pitch-up (0.75+/-0.15 SD) and pitch-down (0.79+/-0.19 SD) VOR were not significantly different (paired t test: P>0.05). On an average, relative gain reductions induced by selective pitch-up (pitch-up VOR: 32%; pitch-down VOR: 21%) and pitch-down (pitch-up VOR: 18%; pitch-down VOR: 30%) VOR cancellation were significantly (P<0.05) larger in the trained than in the untrained direction. Symmetric visual VVOR cancellation led to a significantly (P<0.01) larger relative gain reduction of the pitch-down (41%) than the pitch-up (33%) VOR. None of the paradigms led to significant changes of phase or offset. We conclude that, in human subjects, the smooth pursuit system is capable to asymmetrically decrease the gain of the VVOR equally well in both the upward and downward direction. The unexpected asymmetric decrease of the VVOR gain after symmetric visual cancellation may be related to the directional preferences of vertical gaze-velocity sensitive Purkinje cells in the flocculus for the downward direction.

Pursuit—Vestibular Interactions in Brain Stem Neurons During Rotation and Translation

Under natural conditions, the vestibular and pursuit systems work synergistically to stabilize the visual scene during movement. How translational vestibular signals [translational vestibuloocular reflex (TVOR)] are processed in the premotor pathways for slow eye movements continues to remain a challenging question. To further our understanding of how premotor neurons contribute to this processing, we recorded neural activities from the prepositus and rostral medial vestibular nuclei in macaque monkeys. Vestibular neurons were tested during 0.5-Hz rotation and lateral translation (both with gaze stable and during VOR cancellation tasks), as well as during smooth pursuit eye movements. Data were collected at two different viewing distances, 80 and 20 cm. Based on their responses to rotation and pursuit, eye-movement-sensitive neurons were classified into position-vestibular-pause (PVP) neurons, eye-head (EH) neurons, and burst-tonic (BT) cells. We found that approximately half of the type II PVP and EH neurons with ipsilateral eye movement preference were modulated during TVOR cancellation. In contrast, few of the EH and none of the type I PVP cells with contralateral eye movement preference modulated during translation in the absence of eye movements; nor did any of the BT neurons change their firing rates during TVOR cancellation. Of the type II PVP and EH neurons that modulated during TVOR cancellation, cell firing rates increased for either ipsilateral or contralateral displacement, a property that could not be predicted on the basis of their rotational or pursuit responses. In contrast, under stable gaze conditions, all neuron types, including EH cells, were modulated during translation according to their ipsilateral/contralateral preference for pursuit eye movements. Differences in translational response sensitivities for far versus near targets were seen only in type II PVP and EH cells. There was no effect of viewing distance on response phase for any cell type. When expressed relative to motor output, neural sensitivities during translation (although not during rotation) and pursuit were equivalent, particularly for the 20-cm viewing distance. These results suggest that neural activities during the TVOR were more motorlike compared with cell responses during the rotational vestibuloocular reflex (RVOR). We also found that neural responses under stable gaze conditions could not always be predicted by a linear vectorial addition of the cell activities during pursuit and VOR cancellation. The departure from linearity was more pronounced for the TVOR under near-viewing conditions. These results extend previous observations for the neural processing of otolith signals within the premotor circuitry that generates the RVOR and smooth pursuit eye movements.

Purkinje cells of the cerebellar dorsal vermis: simple-spike activity during pursuit and passive whole-body rotation.

To track a slowly moving object during whole body rotation, smooth-pursuit and vestibularly induced eye movements must interact to maintain the accuracy of eye movements in space (i.e., gaze), and gaze movement signals must eventually be converted into eye movement signals in the orbit. To understand the role played by the cerebellar vermis in pursuit-vestibular interactions, in particular whether the output of the vermis codes gaze-velocity or eye-velocity, we examined simple-spike activity of 58 Purkinje (P-) cells in lobules VI-VII of head-stabilized Japanese monkeys that were trained to elicit smooth-pursuit eye movements and cancel their vestibuloocular reflex (VOR) during passive whole body rotation around horizontal, vertical, or oblique axes. All pursuit-sensitive vermal P-cells also responded during VOR cancellation, and the majority of them had peak modulation near peak stimulus velocity. The directions of maximum modulation during these two tasks were distributed in all directions with a downward preponderance. Using standard criteria, 40% of pursuit-sensitive vermal P-cells were classified as gaze-velocity. Other P-cells were classified either as eye/head-velocity group I (36%) that had similar preferred directions during pursuit and VOR cancellation but that had larger responses during VOR x1 when gaze remained stationary, or as eye/head-velocity group II (24%) that had oppositely directed or orthogonal eye and head movement sensitivity during pursuit and VOR cancellation. Eye/head-velocity group I P-cells contained cells whose activity was correlated with eye velocity. Modulation of many P-cells of the three groups during VOR x1 could be accounted for by the linear addition of their modulations during pursuit and VOR cancellation. When monkeys fixated a stationary target, over half of the P-cells tested, including gaze-velocity P-cells, discharged in proportion to the velocity of retinal motion of a second spot. These observations are in a striking contrast to our previous results for floccular vertical P-cells. Because we used identical tasks, these differences suggest that the two cerebellar regions are involved in very different kinds of processing of pursuit-vestibular interactions.

Computational study on monkey VOR adaptation and smooth pursuit based on the parallel control-pathway theory.

Much controversy remains about the site of learning and memory for vestibuloocular reflex (VOR) adaptation in spite of numerous previous studies. One possible explanation for VOR adaptation is the flocculus hypothesis, which assumes that this adaptation is caused by synaptic plasticity in the cerebellar cortex. Another hypothesis is the model proposed by Lisberger that assumes that the learning that occurs in both the cerebellar cortex and the vestibular nucleus is necessary for VOR adaptation. Lisberger's model is characterized by a strong positive feedback loop carrying eye velocity information from the vestibular nucleus to the cerebellar cortex. This structure contributes to the maintenance of a smooth pursuit driving command with zero retinal slip during the steady-state phase of smooth pursuit with gain 1 or during the target blink condition. Here, we propose an alternative hypothesis that suggests that the pursuit driving command is maintained in the medial superior temporal (MST) area based on MST firing data during target blink and during ocular following blank, and as a consequence, we assume a much smaller gain for the positive feedback from the vestibular nucleus to the cerebellar cortex. This hypothesis is equivalent to assuming that there are two parallel neural pathways for controlling VOR and smooth pursuit: a main pathway of the semicircular canals to the vestibular nucleus for VOR, and a main pathway of the MST-dorsolateral pontine nuclei (DLPN)-flocculus/ventral paraflocculus to the vestibular nucleus for smooth pursuit. First, we theoretically demonstrate that this parallel control-pathway theory can reproduce the various firing patterns of horizontal gaze velocity Purkinje cells in the flocculus/ventral paraflocculus dependent on VOR in the dark, smooth pursuit, and VOR cancellation as reported in Miles et al. at least equally as well as the gaze velocity theory, which is the basic framework of Lisberger's model. Second, computer simulations based on our hypothesis can stably reproduce neural firing data as well as behavioral data obtained in smooth pursuit, VOR cancellation, and VOR adaptation, even if only plasticity in the cerebellar cortex is assumed. Furthermore, our computer simulation model can reproduce VOR adaptation automatically based on a heterosynaptic interaction model between parallel fiber inputs and climbing fiber inputs. Our results indicate that different assumptions about the site of pursuit driving command maintenance computationally lead to different conclusions about where the learning for VOR adaptation occurs. Finally, we propose behavioral and physiological experiments capable of discriminating between these two possibilities for the site of pursuit driving command maintenance and hence for the sites of learning and memory for VOR adaptation.

Partial ablations of the flocculus and ventral paraflocculus in monkeys cause linked deficits in smooth pursuit eye movements and adaptive modification of the VOR.

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.

Role of the cerebellar flocculus region in cancellation of the VOR during passive whole body rotation.

A series of studies were carried out to investigate the role of the cerebellar flocculus and ventral paraflocculus in the ability to voluntarily cancel the vestibuloocular reflex (VOR). Squirrel monkeys were trained to pursue moving visual targets and to fixate a head stationary or earth stationary target during passive whole body rotation (WBR). The firing behavior of 187 horizontal eye movement-related Purkinje (Pk) cells in the flocculus region was recorded during smooth pursuit eye movements and during WBR. Half of the Pk cells encountered were eye velocity Pk cells whose firing rates were related to eye movements during smooth pursuit and WBR. Their sensitivity to eye velocity during WBR was reduced when a visual target was not present, and their response to unpredictable steps in WBR was delayed by 80-100 ms, which suggests that eye movement sensitivity depended on visual feedback. They were insensitive to WBR when the VOR was canceled. The other half of the Purkinje cells encountered were sensitive to eye velocity during pursuit and to head velocity during VOR cancellation. They resembled the gaze velocity Pk cells previously described in rhesus monkeys. The head velocity signal tended to be less than half as large as the eye velocity-related signal and was observable at a short ( approximately 40 ms) latency when the head was unpredictably accelerated during ongoing VOR cancellation. Gaze and eye velocity type Pk cells were found to be intermixed throughout the ventral paraflocculus and flocculus. Most gaze velocity Pk cells (76%) were sensitive to ipsilateral eye and head velocity, but nearly half (48%) of the eye velocity Pk cells were sensitive to contralateral eye velocity. Thus the output of flocculus region is modified in two ways during cancellation of the VOR. Signals related to both ipsilateral and contralateral eye velocity are removed, and in approximately half of the cells a relatively weak head velocity signal is added. Unilateral injections of muscimol into the flocculus region had little effect on the gain of the VOR evoked either in the presence or absence of visual targets. However, ocular pursuit velocity and the ability to suppress the VOR by fixating a head stationary target were reduced by approximately 50%. These observations suggest that the flocculus region is an essential part of the neural substrate for both visual feedback-dependent and nonvisual mechanisms for canceling the VOR during passive head movements.

Dissociation of smooth pursuit and vestibulo-ocular reflex cancellation in SCA-6

To study gaze in SCA-6 patients during pursuit and passive whole-body rotation. Smooth pursuit and vestibularly induced eye movements interact to maintain the accuracy of eye movements in space (i.e., gaze). Previous studies have implicated the cerebellum, particularly the floccular lobe and dorsal vermis, in the control of gaze velocity during pursuit and vestibulo-ocular reflex (VOR) cancellation. SCA-6 has recently been identified genetically and characterized as pure cerebellar ataxia that affects the cerebellar cortex selectively. Using infrared oculography, eye movements of five SCA-6 patients and five age-matched normal control subjects were recorded during sinusoidal pursuit and passive whole-body rotation in the horizontal plane (amplitude, +/- 10 deg; frequency, 0.2 Hz). Eye and gaze gain (eye and gaze velocity/stimulus velocity) were calculated after deleting saccades. Eye gain of all SCA-6 patients during pursuit was significantly lower than those of the control subjects (mean +/- SD, 0.26+/-0.06 versus 0.91+/-0.07). In contrast, eye gain of the patients was not significantly different from that of the control subjects either during VOR cancellation, when the subjects tracked a target that moved with the same amplitude and phase, like a chair (0.21+/-0.05 versus 0.12+/-0.07), or during visually enhanced VOR (x1), when the target remained stationary in space (0.85+/-0.06 versus 0.95+/-0.05). Moreover, there was no significant difference in mean VOR gain in total darkness between the two groups. Gaze gain of patients (0.26+/-0.06 versus 0.81+/-0.06) but not control subjects (0.91+/-0.07 versus 0.88+/-0.08), was significantly different during pursuit and VOR cancellation. SCA-6 patients show dissociation in the control of gaze tracking during smooth pursuit and VOR cancellation.

Ocular and oculomotor signs in Joubert syndrome.

A number of oculomotor defects have been described in Joubert syndrome. This study systematically examined the oculomotor systems of 13 individuals previously diagnosed with Joubert syndrome. Twelve had the characteristic "molar tooth sign" seen on magnetic resonance imaging scan. In all individuals, smooth pursuit gain and vestibulo-ocular reflex cancellation were decreased in the horizontal and vertical directions and volitional saccades, when generated, were hypometric. We believe that these defects arise from a disorder in the posterior cerebellar vermis. All individuals also had partial to complete oculomotor apraxia in which initiation of saccades was prolonged or impaired. The oculomotor apraxia in Joubert syndrome differs from congenital idiopathic oculomotor apraxia in that both volitional saccades and quick phases of nystagmus were impaired both in the horizontal and vertical directions, and the defects did not resolve with time. We believe that the oculomotor apraxia arises from a disorder involving the projections from the superior colliculus to the parapontine reticular formation and rostral interstitial nucleus of the medial longitudinal fasciculus. A subset of individuals also had severe visual loss, pendular nystagmus, pigmentary changes in the fundus, and decreased vestibulo-ocular reflexes. We believe that this is a form of Leber's amaurosis occasionally associated with Joubert syndrome. In summary, key oculomotor features of Joubert syndrome are decreased smooth pursuit and vestibulo-ocular reflex cancellation, partial to complete oculomotor apraxia both in the horizontal and vertical directions, and hypometric saccades if oculomotor apraxia is not complete.

Influence of gaze rotation on the visual response of primate MSTd neurons.

When we move forward, the visual image on our retina expands. Humans rely on the focus, or center, of this expansion to estimate their direction of heading and, as long as the eyes are still, the retinal focus corresponds to the heading. However, smooth rotation of the eyes adds nearly uniform visual motion to the expanding retinal image and causes a displacement of the retinal focus. In spite of this, humans accurately judge their heading during pursuit eye movements and during active, smooth head rotations even though the retinal focus no longer corresponds to the heading. Recent studies in macaque suggest that correction for pursuit may occur in the dorsal aspect of the medial superior temporal area (MSTd) because these neurons are tuned to the retinal position of the focus and they modify their tuning during pursuit to compensate partially for the focus shift. However, the question remains whether these neurons also shift focus tuning to compensate for smooth head rotations that commonly occur during gaze tracking. To investigate this question, we recorded from 80 MSTd neurons while monkeys tracked a visual target either by pursuing with their eyes or by vestibulo-ocular reflex cancellation (VORC; whole-body rotation with eyes fixed in head and head fixed on body). VORC is a passive, smooth head rotation condition that selectively activates the vestibular canals. We found that neurons shift their focus tuning in a similar way whether focus displacement is caused by pursuit or by VORC. Across the population, compensation averaged 88 and 77% during pursuit and VORC, respectively (tuning shift divided by the retinal focus to true heading difference). Moreover the degree of compensation during pursuit and VORC was correlated in individual cells (P < 0.001). Finally neurons that did not compensate appreciably tended to be gain-modulated during pursuit and VORC and may constitute an intermediate stage in the compensation process. These results indicate that many MSTd cells compensate for general gaze rotation, whether produced by eye-in-head or head-in-world rotation, and further implicate MSTd as a critical stage in the computation of heading. Interestingly vestibular cues present during VORC allow many cells to compensate even though humans do not accurately judge their heading in this condition. This suggests that MSTd may use vestibular information to create a compensated heading representation within at least a subpopulation of cells, which is accessed perceptually only when additional cues related to active head rotations are also present.