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The Journal of Neurophysiology Vol. 80 No. 4 October 1998, pp. 1911-1931
Copyright ©1998 by the American Physiological Society
1 Department of Neurology and 2 Department of Neurosurgery, The Johns Hopkins Hospital, Baltimore, Maryland 21287; and 3 Department of Ophthalmology, Niigata University School of Medicine, Niigata 951, Japan
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ABSTRACT |
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 Abstract
 Introduction
Methods
Results
Discussion
References
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Takagi, Mineo, David S. Zee, and Rafael J. Tamargo. Effects of lesions of the oculomotor vermis on eye movements in primate: saccades. J. Neurophysiol. 80: 1911-1931, 1998. We studied the effects on saccades of ablation of the dorsal cerebellar vermis (lesions centered on lobules VI and VII) in three monkeys in which the deep cerebellar nuclei were spared. One animal, with a symmetrical lesion, showed bilateral hypometric horizontal saccades. Two animals, with asymmetrical lesions, showed hypometric ipsilateral saccades, and saccades to vertically positioned targets were misdirected, usually deviating away from the side to which horizontal saccades were hypometric. Postlesion, all animals showed an increase (2- to 5-fold) in trial-to-trial variability of saccade amplitude. They also showed a change in the ratio of the amplitudes of centripetal to centrifugal saccades (orbital-position effect); usually centrifugal saccades became smaller. In the two animals with asymmetrical lesions, for saccades in the hypometric direction, latencies were markedly increased (up to ~500 ms). There was also an absence of express and anticipatory saccades in the hypometric direction. When overall saccade latency was increased, centrifugal saccades became relatively more delayed than centripetal saccades. The dynamic characteristics of saccades were affected to some extent in all monkeys with changes in peak velocity, eye acceleration, and especially eye deceleration. There was relatively little effect of orbital position on saccade dynamics, however, with the exception of one animal that showed an orbital position effect for eye acceleration. In a double-step adaptation paradigm, animals showed an impaired ability to adaptively adjust saccade amplitude, though increased amplitude variability postlesion may have played a role in this deficit. During a single training session, however, the latency to corrective saccades
which had been increased postlesiongradually decreased and so enabled the animal to reach the final position of the target more quickly. Overall, both in the early postlesion period and during recovery, changes in saccade amplitude and latency tended to vary together but not with changes in saccade dynamics or adaptive capability, both of which behaved relatively independently. These findings suggest that the cerebellum can adjust saccade amplitude and saccade dynamics independently. Our results implicate the cerebellar vermis directly in every aspect of the on-line control of saccades: initiation (latency), accuracy (amplitude and direction), and dynamics (velocity and acceleration) and also in the acquisition of adaptive ocular motor behavior.
The dorsal cerebellar vermis (lobules VI-VII, the "oculomotor vermis") has been long implicated in the control of saccades and pursuit based on single-unit recordings from Purkinje cells and mossy fibers (Baker et al. 1972 General experimental procedures
Experiments were conducted on three male rhesus monkeys weighing from 5 to 6 kg. All surgical and experimental protocols were approved by The Johns Hopkins University committee on animal experimentation, and all aspects of their care complied with the guidelines for veterinary care of The Johns Hopkins University School of Medicine and of the National Institutes of Health Guide for the Care and the Use of Animals including appropriate analgesia after surgical procedures. During the initial period of training, monkeys learned to come out of their cages and to sit quietly in a primate chair for 2-3 h. Then the animals were prepared for chronic experiments. Under pentobarbital anesthesia using aseptic techniques, a head plate was implanted on the skull. Small holes for screws were made with a drill, and the heads of the screws were placed between the inner table of the skull and the dura mater. The head plate was fixed with dental acrylic. The head plate had small holes for pins to hold an opaque lucite patch in front of the eye. In a second operation, a search coil made of three turns of Teflon-coated stainless steel wire was implanted and sutured on the sclera of each eye in front of the insertions of the extraocular muscles. After recovery from the second surgery, the monkey was trained to fix on and follow targets using a water reward. During a recording session, the monkey was seated in a primate chair with its head fixed to the frame of the chair.
Measurement of eye movements
Eye movements were measured by the magnetic field search coil method (Robinson 1963 Stimulus presentation
The target was a red square, 0.3 × 0.3°, presented on the video monitor placed at a distance of 33 cm in front of the animal's eye. Animals viewed with both eyes except during calibration. For saccades, two main paradigms were used. In the first, the target jumped with horizontal or vertical amplitudes of 10, 20, and 30° across the center. The target changed amplitude after every fourth displacement. In the second paradigm, the target jumped with an amplitude of 10°, sequentially, beginning at 20° eccentric on one side and finishing at 20° eccentric on the other, and then going back in the opposite direction. For vertical saccades, the target moved up and down over the same 40° excursion. The target jumped to its new position ~1.9 s after the eye reached the previous target position.
Data collection and analysis
The amplitude, latency, and dynamic characteristics of saccades always were determined from data sets collected on the same day. Individual trials were displayed on a video monitor. A computer algorithm detected the onset, peak velocity, and end of saccades using velocity criteria after the position data were filtered digitally (3 dB point at 112 Hz). The onset of saccades was chosen when the eye velocity exceeded 40°/s, and the end of the rapid pulse portion of the saccade when saccade velocity dropped to <45°/s. The correctness of these points was verified by the experimenter. Trials were rejected if the saccade was in the wrong direction, if the saccade started before the target jump, or if the record could not be marked because of blinks or other artifacts. To evaluate the dynamic properties of saccades, the position data of individual trials was loaded into Matlab and further processed to produce velocity and acceleration data by differentiating and filtering (3 dB point at 70 Hz). For statistical analysis, the distributions of prelesion and early and late postlesion data were compared using the Kruskal-Wallis one-way analysis of variance on ranks. When there was a significant difference each distribution was compared using Dunn's method.
Cerebellar lesions
The cerebellum was lesioned under pentobarbital anesthesia using aseptic techniques. The midline of the dorsal cerebellum was exposed through a suboccipital approach, and a lesion centering around lobules VI-VII was made by cauterization and aspiration. Corticosteroids and antibiotics were administrated for 1 wk after the surgery. Monkeys showed no defects in their general neurological performance, and recording of eye movements was initiated within the first week after surgery
Histological confirmation
After the experiments were completed, the animals were killed with an overdose of pentobarbital and perfused with 0.1 M phosphate buffered saline containing 1% sodium nitrite as wash, followed by 4% paraformaldehyde. The brains were hardened for 1 wk and then examined grossly to determine the approximate location of the lesions. Subsequently, the tissue was sectioned every 25 µm and every fifth section stained with cresyl violet. The sections were compared with those of a normal brain. We used the atlas of Madigan and Carpenter (1971) Extent of lesion: functional-anatomic correlations
Figure 1 shows the reconstruction of the lesions based on histological examination, with the sagittal extent of the lesions being referenced to Fig. 1, bottom. The black areas reflect either absence of tissue or areas in which neurons appeared destroyed or white matter disrupted. For monkey 1 (M1), the lesion was nearly symmetrical, being deepest in the midline where lobules VII and VIII were lesioned completely. Lobules VI and IX were partially involved. The lesion extended laterally to section 3 on both sides, just encroaching on the simple lobule. The lateral component of the lesion on the left side was slightly more extensive (compare left and right sides in sections L3 and R3). For monkey 2 (M2), near the midline lobules VI-VIII were lesioned on both sides though the lesion was deeper on the right at the R1 level. The lesion, however, extended slightly more laterally on the left side. For monkey 3 (M3), on the midline lobule VII was completely lesioned but there was mild sparing in lobule VI and moderate sparing in lobule VIII. Both near the midline and more laterally, the lesion was more extensive on the right side and reached the paravermis. In all three monkeys, the cerebellar deep nuclei were spared including the posterior portion of the fastigial nucleus. Only in monkey 1 was there some gliosis at the very posterior tip of the fastigial nucleus though the neurons appeared intact.
Fixation
Animals could hold fixation after surgery without spontaneous or gaze-evoked nystagmus. In complete darkness without a fixation target, monkeys 2 and 3 tended to keep the position of their eyes in the upper-left field of gaze, ~20° from straight ahead. With a fixation target straight-ahead, they appeared to be able to hold their eyes on target, though often when a blink occurred, the eyes would deviate slowly a few degrees to the left of the target followed by a corrective saccade back to the target.
Saccade metrics
Saccade metrics will be discussed in terms of accuracy, latency, velocity, and acceleration. These data were obtained from the same set of saccades and hence permit comparison and correlations among various saccade parameters at a given time following the lesion.
SACCADE ACCURACY.
A uniform finding was a change in saccade accuracy. Figure 2 shows 10 consecutive traces of horizontal saccades from monkey 1 before and 14 days after the cerebellar lesion. The target displacement was between right and left 10° on the horizontal meridian. Before the lesion, the gain (amplitude of the initial saccade/target displacement) was 0.97. The variability in amplitude from trial to trial was small (25-75% range for saccade amplitude was 2.5°). After the lesion, the gain was reduced to 0.51. The variability in amplitude was larger (25-75% range, 4.8°).
SACCADE LATENCY.
Data for saccade latencies are shown in Fig. 4. For monkey 1, with bilateral hypometria there was little change in saccade latency. On the other hand, for monkeys 2 and 3 with an asymmetrical hypometria, the latencies of rightward horizontal saccades (the same direction as their hypometria) were considerably prolonged and also more variable. There were no consistent changes in the latency for vertical saccades. Monkey 2 showed some recovery in saccade latency in the late postlesion period, but the values were still much greater than prelesion. For example, performing a linear regression on the data in Fig. 4, the latency for saccades to 30° target displacements was 240 ms before the lesion, 524 ms in the early postlesion period, and 328 ms in the late postlesion period. For monkey 3 there was no recovery in saccade latency. The latency for saccades to 30° target displacements was 237 ms before the lesion, 478 ms in the early postlesion period, and 493 ms in the late postlesion period. In monkey 2, the recovery of saccade latency roughly paralleled the recovery of saccade amplitude. In monkey 3 there was little recovery in either.
SACCADE DYNAMICS.
Figure 6 presents the peak velocity-amplitude relationship (main sequence) (A) and duration-amplitude relationship (B) for horizontal saccades. Using the least-squares method, the data usually could be fit to an exponential using the following formula, Vpk = K[1 + exp(Amp/Lc)] (where Vpk = peak velocity, Amp = saccadic amplitude, Lc = angle constant, K = constant). In monkeys 1 and 2, horizontal saccades became slow bilaterally but the speed of vertical saccades was slightly increased (monkey 1) or not affected (monkey 2). For monkey 3, smaller rightward saccades became slightly slow but there was no change in the peak velocity for leftward or vertical saccades. Note that even postlesion, the data points cluster tightly around the exponential fit, implying no increase in variability of the relationship between the peak velocity and the amplitude of saccades. Changes in the amplitude-duration relationship for horizontal saccades are shown in Fig. 6B; there was an increase in the duration of saccades for monkeys 1 and 2. As for peak velocity, however, there was no increase in the variability of the duration of saccades for a given amplitude. This finding contrasts with the increase in variability of saccade amplitude and latency.
SACCADE TRAJECTORIES.
In addition to changes in saccade dynamics there were also striking changes in saccade trajectories. Before the lesion, saccades made between vertically displaced targets were accurate (Fig. 8, top), though there were high-frequency oscillations in horizontal velocity during purely vertical saccades. Postlesion both monkeys 2 and 3 developed an inappropriate horizontal component to the left (Fig. 8, bottom). A horizontal corrective saccade occurred at a latency of 200-400 ms.
Saccade adaptation
Figure 9 shows the response of monkey 2 in the decreasing saccade adaptation paradigm. The target jumped from right 3.5° to left 6.5° (leftward 10°) and then jumped back by 3° during the initial saccade to the target. In Fig. 9, left, are the early (top) and late (bottom) responses during the training period. Prelesion, after training, the size of the primary saccade had diminished. When adaptation was tested 22 days postlesion, there was an increase in variability of response and an increase in latency to the secondary, corrective saccades. During training there was no decrease in primary saccade amplitude (Fig. 9, right). The relatively increased latency for corrective saccades, however, decreased during training. Figure 10 (monkey 2) shows the progressive change in saccade amplitude during the entire adaptation period for rightward primary saccades (target initially displaced to the right and then jumped back to the left; top) as well as for leftward primary saccades (bottom, same data set as in Fig. 9). The size of the primary saccade at the onset of training was similar in the pre- and postlesion data sets (see initial value at the bottom of each figure). Prelesion there was about a 10% drop in primary saccade amplitude during training. In the early postlesion data (post 1), there was an increased variability of saccade size and a lack of a decrease in the amplitude of the primary saccade with training (percent changes are shown at the bottom of each figure, compare pre- and postlesion). In the late postlesion test (51 days postlesion, post 2), the amplitude of the primary saccade again decreased with training to about the same degree as prelesion (~10%), implying a recovery of adaptive capability. The increased variability in the amplitude of the primary saccade, however, was still present.
The main finding of this study is that lesions restricted to the dorsal vermis of the cerebellum ("the oculomotor vermis"), lead not only to changes in the accuracy of saccades, as has been noted previously, but also to changes in the latency and dynamics of saccades, findings that were relatively unsuspected based on previous work. These effects were independent of any structural damage to the deep cerebellar nuclei, which implicates the cerebellar cortex directly in almost every aspect of the control of saccades. First, we will compare our results to those of previous studies of cerebellar lesions or inactivation. Then we will interpret our findings in light of the current hypotheses about the role of the cerebellum in the control of saccades. Finally, we will discuss issues related to saccade adaptation and the cerebellar vermis.
Comparison of the present findings with those from previous studies of the effects of lesions of the cerebellar vermis and the fastigial nuclei
SACCADE AMPLITUDE.
The effects of our lesions on saccade accuracy are in basic agreement with previous studies (Aschoff and Cohen 1971 SACCADE DYNAMICS AND TRAJECTORIES.
Our animals showed changes in saccade dynamics, which in two animals were striking. Not only were peak velocity-amplitude relationships affected but even more prominent changes were seen in the acceleration of the eyes at the beginning of saccades and, especially, in the deceleration of the eyes at the end of saccades. In the two animals with the more asymmetrical lesions, we also found distorted saccade trajectories with vertical saccades deviating away from the side toward which horizontal saccades had become hypometric. We did not, however, find an orbital-position effect for saccade peak velocity or duration, though there was an orbital-position effect for saccade peak acceleration. The pattern of changes in saccade dynamics and trajectories is similar to that reported for animals with chemical inactivation of the FOR, though, of course, the direction of hypometria and deviation are opposite relative to the side of the lesion (Goffart et al. 1998 SACCADE LATENCY.
Changes in saccade latency were a prominent finding in the two animals (monkeys 2 and 3) that developed asymmetrical dysmetria. There was also a pronounced orbital-position effect for the change in saccade latency: centrifugal saccades became more delayed. The animals also showed defects in generating express and predictive saccades. Until recently (Goffart and Pélisson 1997 How does the cerebellum influence the generation of saccades?
Our results suggest that the oculomotor vermis can influence saccade latency, accuracy, trajectory, and dynamics; in other words, every key aspect of the generation of saccades. It appears to affect these various properties relatively independently; only the changes in saccade initiation and accuracy seemed to vary together, and then only when the hypometria was asymmetrical because there was no change in latency associated with a bilateral lesion that produced bilateral hypometria. Because the influence of the oculomotor vermis on the generation of saccades is almost certainly mediated by its sole projection site and conduit, the FOR, the question becomes how does the FOR influence the mechanisms within the brain stem and superior colliculus that produce the saccadic pulse. These issues have been considered by others (Dean 1995 SACCADE ACCURACY AND THE CEREBELLUM.
It is worth remembering that the "default" value of saccade accuracy after total cerebellectomy and bilateral FOR inactivation (Robinson et al. 1993 SACCADE DYNAMICS AND THE CEREBELLUM.
How might the cerebellum influence saccade dynamics. The timing of the discharge of neurons in both the FOR and oculomotor vermis is such that they are poised to influence the acceleration of saccades in one direction and the deceleration of saccades in the other (Fuchs et al. 1994 SACCADE INITIATION AND THE CEREBELLUM.
A striking finding in our study was the increase in latency for saccades in the hypometric direction in the animals that had an asymmetrical dysmetria. Imbalanced tonic FOR inputs to pause cells might sustain pause cell activity inappropriately and so delay saccade initiation. Or when pause cell inhibition is lifted to initiate the saccade, imbalanced FOR outputs would gain access to the brain stem burst neurons and so bias these neurons to facilitate initiation of saccades in one direction and/or retard it in the other. Another possibility would be that changes in saccade latency and defects in production of express saccades might be related to cerebellar projections to the superior colliculus, which has cells that encode activity related to the initiation of saccades including the generation of express saccades (Dorris et al. 1997 Saccade adaptation
For more than 25 years, the cerebellum has been implicated in various types of ocular motor learning including saccadic eye movements (Dean 1995 ADAPTATION OF SACCADE AMPLITUDE.
Goldberg et al. (1993) VARIABILITY OF EFFECTS OF LESIONS AMONG MONKEYS.
The considerable differences in the types of deficits and the patterns of recovery shown by each monkey and the dissociation in the effects of the lesions on the various parameters of saccade generation (only the effects on saccade latency and amplitude were roughly comparable and then only when the lesions were asymmetrical) must reflect, at least in part, differences in the extent and location of lesions. Portions of lobules V and VIII, were inconstantly lesioned, and there is some variability in the location of the oculomotor vermis itself (Noda and Fujikado 1987b ORBITAL POSITION EFFECTS AND CONTEXTUAL LEARNING.
There are other ways in which a learning function of the oculomotor vermis may become apparent. By virtue of its multiplicity of sensory inputs (Yamada and Noda 1987
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
; Helmchen and Büttner 1995; Kase et al. 1980; Llinas and Wolfe 1977; Ohtsuka and Noda 1992b, 1995; Sato and Noda 1992a; Suzuki and Keller 1988a,b), experimental electrical stimulation (Fujikado and Noda 1987; Keller et al. 1983; McElligott and Keller 1984; Noda and Fujikado 1987a,b; Ohtsuka and Noda 1991b; Ron and Robinson 1973), the effects of lesions (Keller 1988; Optican and Robinson 1980; Ritchie 1976; Sato and Noda 1992b; Straube et al. 1997b; Vahedi et al. 1995), and, more recently, in humans with transcranial magnetic stimulation and functional magnetic resonance imaging (Hashimoto and Ohtsuka 1995; Honda et al. 1997; Ohtsuka and Enoki 1998). In addition, axons of Purkinje cells from the oculomotor vermis impinge on cells in the most posterior extension of the fastigial nucleus, called the fastigial oculomotor region (FOR) (Noda and Fujikado 1987b; Noda et al. 1990; Yamada and Noda 1987), which also contains neurons that discharge in relation to saccades and pursuit. Furthermore, focal chemical lesions within the FOR also lead to specific deficits of saccades and pursuit (Goffart and Pélisson 1994, 1997, 1998; Goffart et al. 1998; Ohtsuka et al. 1994; Robinson et al. 1993, 1997).
dysmetric saccades and impaired pursuit during tracking of targets moving in a sinusoidal fashionsuggest a role for the vermis in the on-line control of the accuracy of both pursuit and saccades. But questions remain about the function of the oculomotor vermis. Most prior studies of vermal ablations also have involved the deep nuclei (Optican and Robinson 1980; Ritchie 1976). How do vermal lesions affect eye movements when the underlying FOR remains intact? Because the output of the cerebellar vermis is inhibitory, and solely to the underlying deep nuclei, one might expect vermal lesions to produce reciprocal defects to those after lesions in the FOR. Is this the case? And what might be the role of the cerebellar vermis in saccade initiation and saccade dynamics?
; Dean et al. 1994; Houk et al. 1996; Ito 1993; Keller 1989; Optican and Robinson 1980; Schweighofer et al. 1996a,b). Such a learning capability is critical because during an eye movement, visual feedback about performance is unavoidably slow due to inherent delays in visual processing. So the initiation of smooth tracking (pursuit and vergence) and the generation of movements that are completed before there is time for visual feedback or that have dynamic characteristics that preclude visual feedback during movement (saccades and the vestibuloocular reflex) necessitate adaptive mechanisms for optimizing visuomotor performance. The role of the oculomotor vermis in such ocular motor learning is unknown. Accordingly, a second purpose of the present study was to define the deficits in ocular motor learning that appear after lesions that involve the oculomotor vermis but spare the fastigial nuclei.
,b) at the Association for Research in Vision and Ophthalmology and the Society for Neuroscience.
METHODS
Abstract
Introduction
Methods
Results
Discussion
References
). The output signal from the phase detectors was filtered with a bandwidth of 0-90 Hz, sampled by a digital computer at 500 Hz with 12-bit resolution, and then stored to disk for later off-line analysis. System noise limited resolution to ~0.05°. The coil signal was calibrated by requiring the animal to fix successively on targets at 2.5° intervals over a range of ±25° horizontal and ±22.5° vertical. Calibration data were obtained with one eye viewing and the other occluded. In the later off-line analysis, a calibration index was obtained using a third-order polynomial curve fit.
).
; Straube et al. 1997a). Other variations of the target stimuli are detailed in RESULTS.
). Because the form of the adaptation curve is not known (although often assumed to be a decaying exponential), we wished to make the assumption only that it is monotonic (i.e., the saccade gain increased or decreased steadily with each trial). Under this assumption, a regression was performed on the ranks of the data. A t-test then was performed to test for differences between slopes of the regression lines before and after adaptation (Glantz 1992).
as a guide for the interpretation of the extent of lesions.
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
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FIG. 1.
Extent of lesion in monkey 1 (M1), monkey 2 (M2), and monkey 3 (M3). Sagittal sections of vermis and paravermis (Nissl stain). Extent of the lesion is indicated by the black area on the template of normal anatomy. Lateral extent of the sections is depicted on the dorsal view (Fig. 1, bottom). Middle far left section: on the midline; top sections: on the left side; bottom sections: on the right side. VI, VII, VIII are vermis lobules. FN, fastigial nucleus; AIN, anterior interposed nucleus; PIN, posterior interposed nucleus; SL, simple lobule; PML, paramedian lobule. Distribution of the lesions is discussed in the text.
)], it is difficult, without recording from or stimulating neurons in the vermis, to know exactly where the oculomotor vermis was in each of our animals. Furthermore, portions of the paravermis were variably lesioned in our animals, and part of lobule VIII was lesioned in every animal. Lobule VIII is not usually considered to be part of the oculomotor vermis, but it may be that some of our findings might be attributed to involvement of this structure. At any rate, for the purposes of placing the somewhat variable results among animals into context, we propose the following scheme. Based on the pattern of asymmetry of saccadic dysmetria and the trajectories of attempted vertical saccades, monkey 1 behaved as if it had a bilateral lesion and monkeys 2 and 3 behaved as if each had a predominantly right-sided lesion.
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FIG. 2.
Representative traces of horizontal saccades in response to leftward 20° target jump (monkey 1). Ten consecutive trials were plotted. Left: prelesion data. Right: early postlesion data. Saccades were realigned to the same starting position. Note the hypometria and larger variability postlesion.
), and the results from each were similar. Early postlesion data 
were obtained at 14, 12, and 3 days after surgery for horizontal saccades and 9, 13, and 12 days after surgery for vertical saccades for monkeys 1-3, respectively.
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FIG. 3.
Amplitude of horizontal saccades for monkey 1 (M1), monkey 2 (M2), and monkey 3 (M3). Bar graphs show median values and 25-75% range of values (error bars). Target displacements (direction and amplitude are shown on the abscissa) were all centered about 0 (across midline). Two sets of prelesion data (pre1, pre2) are shown. Approximate times of collection of the postlesion data are early, in the 1st few weeks (post1), or late, in the 3rd month (post2), after surgery. *Statistically significant difference between pre- and postlesion values (P < 0.05). For each bar, the number of values averaged ~35. Note the various patterns of dysmetria that developed after the lesion. See text.
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FIG. 4.
Horizontal saccade latency (ordinate) as a function of saccade amplitude (abscissa). Positive amplitudes are for rightward and negative for leftward saccades. Prelesion and early postlesion results are shown. Data also are sorted by the size of the target displacement as shown in the legend on the figure. Regression lines are drawn through the pre- and postlesion data. Panels are for monkeys 1-3 (M1-M3). See text.
0.44, P < 0.05). Finally, there was an orbital-position effect for saccade latency. For both monkeys 2 and 3, for rightward saccades, centrifugal saccades were more delayed than centripetal saccades. The difference in median latency between 10
20° centrifugal saccades and 2010° centripetal saccades increased from 31 ms prelesion to 85 ms postlesion for monkey 2 and from 16 ms prelesion to 144 ms postlesion for monkey 3. The change was due to an increase in latency for centrifugally directed saccades.
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FIG. 5.
Latency for horizontal saccades from monkey 3 (M3), postlesion, in response to random 20° target jumps, random 20° target jumps with a gap (200 ms), and predictive 20° target jumps with a gap (200 ms). Abscissa, saccade latency; left ordinate, saccadic amplitude corresponding to the data points; right ordinate, frequency corresponding to the histogram. Note the difference between right and left saccades with express saccades and anticipatory saccades only occurring for leftward target displacements.
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FIG. 6.
Relationship between saccade amplitude and peak velocity (A) and duration (B) for horizontal saccades, prelesion and early postlesion. Panels are for monkeys 1-3 (M1-M3). Data also are sorted by target displacement (see legend on the figure). In A, exponential curves could be fit to each scatter plot, except for monkey 1 postlesion, rightward saccades. In B, data are fit by a linear regression.
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FIG. 7.
Prelesion and early postlesion, average traces of rightward (A) and leftward (B) horizontal saccades with position, velocity, and acceleration. Ten saccades were chosen of roughly corresponding amplitudes (10°, thin lines and 20°, thick lines, except monkey3, left saccades, 29°) and then averaged to produce the traces shown above. Left: monkey 1. Middle: monkey 2. Right: monkey 3. Solid line indicates prelesion and dashed line indicates postlesion. Traces are aligned at saccade onset and x axis shows time after saccade onset. See text.
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FIG. 8.
Saccades to vertically displaced targets are shown for up and downward movements, prelesion and early postlesion for monkey 3. Ten to 20 saccades are shown. Horizontal and vertical eye positions are plotted against each other. Velocity trace also is shown and aligned with saccade onset. Vertical arrow, correct direction of the saccade. Note that prelesion there are some horizontal oscillations at a high frequency during the pure vertical saccades (best seen on the horizontal velocity traces). Postlesion, saccades are biased to the left for upward saccades (bottom left) especially toward the end of the saccade. Downward saccades show a deviation to the left with the initial part of the saccade. Any corrective saccades needed to bring the eye to the target are reflected in the velocity traces late in the trial. H and V capped with filled dots indicate horizontal and vertical velocity.
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FIG. 9.
Saccade adaptation to a gain-reduction, double-step (10° forward, 3° backward) paradigm (monkey 2). Prelesion and early postlesion performance is shown, both early (initial 12 saccades) and late (final 12 saccades) during the training period (200 trials total). Prelesion the animal shows a decrease in saccade amplitude during training. Postlesion there is an increase in variability of saccade amplitude and an increase in latency to corrective saccades. During training there is little change in saccade amplitude but the latency to corrective saccades gradually decreased during the training period. Saccade traces were aligned at saccade onset.
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FIG. 10.
Time course of adaptation for monkey 2 in gain-reduction double-step paradigm for rightward initial target jumps with a backward target jump (top) and for leftward initial target jumps (bottom, same data as Fig. 9). Note that the increased variability of response, as reflected in the scatter of amplitude values, in the early postlesion period (post 1), persists even in the late postlesion period (post 2). On the other hand, the deficit in adaptation of saccade amplitude in the early postlesion period recovered in the late postlesion testing period. Initial value and percentage change in saccade amplitude after training are based on an exponential fit and are shown at the bottom of each figure. See text.
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FIG. 11.
Percentage change in saccade amplitude after training in gain-reduction double-step paradigm for all 3 monkeys (M1-M3) in the early and late postlesion period. The initial and final values (at the end of training) were based on exponential fits to the data as shown in Fig. 10. For horizontal saccades, note the bilateral changes in monkeys 1 and 2 and the change for rightward saccades in monkey 3. Vertical adaptation also was studied in monkey 3 (M3) and was found to be impaired in the downward direction. *Statistically significant difference (P < 0.05) in the slopes of the regression lines fit to the pre2 and post1 data. Data for early postlesion adaptation were taken within the 1st month after surgery (except monkey 3, vertical at 41 days) and for late postlesion adaptation, in the late 2nd to 3rd month after surgery.
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FIG. 12.
Change in latency of corrective saccades during training in the double-step amplitude-decrease paradigm. Top: rightward saccades (corrective saccades are leftward). Bottom: leftward saccades (corrective saccades are rightward). On the abscissa is the trial number during training and on the ordinate is the latency of the corrective saccade from the primary saccade (ms). 
and 
, prelesion and early postlesion data, respectively. Note the striking relative decrease in latency for monkey 2 (M2) and a lesser change for monkeys 1 and 3 (M1, M3) during the training period.
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
; Sato and Noda 1992b; Vahedi et al. 1995; Waespe and Müller-Meisser 1996), if one assumes that the lesion in monkey 1 was relatively symmetrical and in monkeys 2 and 3 asymmetrical and larger on the right side. Based on histological examination, this appeared to be the case. Hypometria is the main finding with vermal lesions, usually most prominent for centrifugal saccades. This pattern contradicts the report of Ritchie (1976), who found various patterns of saccadic hypermetria and hypometria in monkeys with dorsal vermis lesions. Most of the data shown in his paper, however, are from a monkey in which there was also extensive involvement of both fastigial nuclei. Hence, attributing functions to the oculomotor vermis using the results of Ritchie may be incorrect.
; Goffart and Pélisson 1994; Goldberg et al. 1993; Ohtsuka et al. 1994; Optican and Robinson 1980; Robinson et al. 1993; Vilis and Hore 1981). This is not surprising because the saccade-related activity of vermal Purkinje cells (which is inhibitory) and the results of experimental stimulation are the reciprocal to those of the neurons in the underlying FOR (Fuchs et al. 1993; Fujikado and Noda 1987; Hashimoto and Ohtsuka 1995; Helmchen and Büttner 1995; Helmchen et al. 1994; Keller et al. 1983; McElligott and Keller 1984; Noda et al. 1988; Ohtsuka and Noda 1991a,b, 1992a, 1995; Ohtsuka et al. 1994).
, 1998) studied the effect of unilateral muscimol inactivation of the caudal fastigial nucleus on relatively large gaze (eye plus head) shifts in the head-unrestrained cat. As is the case for saccades in the monkey with the head fixed, they found that contralateral gaze shifts became hypometric and ipsilateral gaze shifts became hypermetric. The pattern of dysmetria, however, was different for the two directions. The change in gain for contralateral, hypometric shifts in gaze was independent of the positions of the gaze in space and the target relative to the head, suggesting that the shifts in gaze were encoded in a retinal or motor-error frame of reference. On the other hand, the change in amplitude for ipsilateral, hypermetric gaze shifts depended on the positions of the gaze in space and the target relative to the head and could be attributed to a bias in the amplitude of the gaze shift. This finding suggested that the ipsilateral shifts in gaze were goal directed, albeit to an erroneous one. Whether or not a similar process occurs in the monkey with FOR inactivation is not yet settled. Nevertheless experimental stimulation studies have suggested such a goal-directed function for the cerebellum (McElligott and Keller 1984; Ron and Robinson 1973).
) and in many of the experimental studies described in the preceding text, our lesioned monkeys showed a change in the effect of the position of the eye in the orbit on saccade amplitude. The usual postlesion pattern for a target displacement of a given amplitude was for centrifugally directed saccades to become relatively (compared with prelesion performance) smaller than centripetally directed saccades, but in monkey 2 the opposite occurred. With respect to the findings of Goffart and Pélisson (1994, 1998a), it is difficult to use our results either to support or refute the hypothesis that the cerebellum is involved with programming goal-directed saccades. The lesions in our monkeys usually led to hypometric saccades, whereas Goffart and Pélisson found that only hypermetric saccades appeared goal directed. The fact that the lesions in our animals were chronic, bilateral (albeit asymmetrical) and involved vermal and possibly some paravermal cortex precludes using our data to draw definitive conclusions about a role for the oculomotor vermis in producing goal-directed saccades.
; Robinson et al. 1993).
; Waespe and Müller-Meisser 1996), defects in the initiation of saccades were not considered part of the ocular motor syndrome of the cerebellum. In the work of Robinson et al. (1993), no consistent changes in saccade latency were found. There are hints, however, of disturbances in saccade latencies in the work of Sato and Noda (1992b) in which they described animals having difficulty initiating saccades in the hypometric direction after functional ablation of the oculomotor vermis. Goffart and Pélisson (1997) reported that after unilateral inactivation of the FOR, contralateral, hypometric gaze shifts were delayed with the increase in latency proportional to the decrease in gain. Ipsilateral gaze shifts were initiated earlier than normal, but the decrease in latency was independent of the increase in gain. Why similar changes in saccade latency have not been reported with FOR inactivation in monkeys is unexplained. Perhaps, the degree of stimulus predictability may play a role. Our results, however, clearly indicate that a lesion in the oculomotor vermis of the monkey can influence the time to initiate saccades, if the saccade is hypometric and if the dysmetria is asymmetrical. It is worth noting again that although the changes in saccade latency in our monkeys roughly paralleled those in saccade amplitude, there was no relationship between changes in saccade latency (or amplitude) and saccade dynamics.
; Fuchs et al. 1993; Goffart and Pélisson 1998; Goffart et al. 1998; Keller 1989; Ohtsuka and Noda 1995; Quaia et al. 1996; Robinson et al. 1993); here we will only review features relevant to the findings in the present study.
) is extreme hypermetria (Büttner and Straube 1995; Optican and Robinson 1980). Hence, a clear function of the FOR must be to overcome the inherent hypermetria of the brain stem saccadic pulse generator. Presumably the FOR acts to stop the saccade when it reaches its desired position and thus prevents hypermetria. It has been suggested that the FOR computes the instantaneous position of the eye during the saccade by a mathematical integration of a velocity command, presumably coming from pons. Using this estimate of where the eye is and also a knowledge of the desired eye position derived from the superior colliculus via the nucleus reticularis tegmenti pontis, the FOR can apply a "brake" or a "choke" to stop the eye when it reaches the desired position. This inhibition could be mediated by virtue of a projection of FOR to inhibitory burst neurons within the brain stem saccadic pulse generator (Quaia et al. 1996; Van Gisbergen et al. 1981) or by projections to omnidirectional pause neurons within the pons. In either case, bilateral removal of the oculomotor vermis, with the loss of its inhibitory effect on the FOR, would lead to hypometria as is suggested by our results.
). One might then expectand this is what we foundthat the animals with more marked hypometria would show larger effects of the loss of the influence of Purkinje cells on activity in the FOR and hence more trial-to-trial variability in saccade amplitude.
; Helmchen and Büttner 1995; Helmchen et al. 1994; Ohtsuka and Noda 1991a, 1995; Ohtsuka et al. 1994). In both cases, however, the effect would likely be on the same set of burst neurons. Defects in this cerebellar input to brain stem burst neurons could lead to a decreased acceleration, decreased deceleration, and increased duration of saccades, which is what we found. Based on the dissociation of the findings in our animalsthat changes in saccade dynamics and saccade accuracy can be independentthe dorsal vermis may be able to influence the output of the FOR so that the calculation of when (during the saccade) the FOR should act to stop the movement, which would determine saccade accuracy, could be separate from the effect on the total amount of FOR activity being projected to the brain stem, which would determine saccade dynamics. Critical to confirming such a scheme will be the anatomic localization of the "resettable" mathematical integrator, which provides the signal needed for determining when the eye has reached its desired position. The cerebellum, brain stem, and superior colliculus have all been suggested as possible loci (Handel and Glimcher 1997; Kaneko 1996, 1997; Kokkoroyannis et al. 1996; Kustov and Robinson 1995; Nichols and Sparks 1995; Quaia et al. 1996; Waitzman et al. 1996).
both in the acceleration and deceleration phases of the saccadeon the brain stem burst neurons during vertical saccades. This pattern of oblique saccade dysmetria also reflects a disturbance in the directional accuracy of saccades, which could be dissociated from the effects of the cerebellar lesion on saccade dynamics.
). The change in the orbital-position effect for latency also might be related to imbalanced cerebellar outputs, perhaps to the superior colliculus, which also has position-related activity though primarily in its most rostral portion (Van Opstal et al. 1995).
; Dean et al. 1994; Goldberg et al. 1993; Houk et al. 1996; Optican and Robinson 1980; Optican et al. 1986; Raymond et al. 1996; Schweighofer et al. 1996a,b; Straube et al. 1995; Waespe 1995; Waespe and Müller-Meisser 1996). One contentious issue has been the relative roles of the cerebellar cortex and the underlying deep nuclei in ocular motor learning. One part of the cerebellar cortex, the flocculus/paraflocculus, has been shown to have a role in the adaptive control of the amplitude of the vestibuloocular reflex (Lisberger et al. 1984) and of the pulse-step match of innervation that prevents postsaccadic drift (Optican et al. 1986). This adaptation is probably mediated via projections from the flocculus to the brain stem. Our study addresses the issue of differential function in saccade adaptation of the oculomotor vermis and the underlying fastigial nucleus.
reported in a single monkey with a large bilateral lesion of the deep nuclei that adaptation of saccade amplitude in a double-step paradigm was impaired. Waespe (1995) studied saccade adaptation with a similar paradigm in patients with Wallenberg's syndrome who had lesions in the lateral medulla. He found a loss of the capability for saccade adaptation. In these patients, the climbing fiber input to the cerebellum is interrupted. This is thought to result in an increase in the simple-spike activity of Purkinje cells, resulting in a functional ablation of the ipsilateral fastigial nucleus. Waespe attributed the defect in adaptation to a decrease in the activity in the fastigial nucleus and to the loss of the climbing fiber input from the inferior olive, which presumably provides an error signal necessary for adaptation (Raymond et al. 1996). With respect to the cerebellar cortex, Waespe and Müller-Meisser (1996) reported a decreased adaptive capability in a patient with a lesion that presumably involved the dorsal cerebellar vermis. The defect in adaptation of saccade amplitude in our lesioned monkeys also indicates that the cerebellar vermis plays a role in ocular motor learning.
).
). In monkeys 1 and 3, the vermal lesions extended far enough laterally to involve paravermal cortex, which overlies and probably projects to the posterior interpositus nucleus. Lesions in this nucleus also lead to disturbance of saccade accuracy, although vertical saccades seem to be more affected (Robinson et al. 1996). There also may be a compartmentalization within the oculomotor vermis of the various types of influences that the cerebellum can have on saccades.
be they neurons in the brain stem, in the fastigial nucleus, or in the Purkinje cells themselveson which learned behaviors are stored. It may well be that there are multiple locations for saccade learning, as has been suggested for the vestibuloocular reflex (Lisberger et a. 1994; Partsalis and Highstein 1996; Raymond et al. 1996).
) and its access to efferent copies of motor commands (Ohtsuka and Noda 1992b), the dorsal vermis is poised optimally to learn to recognize contexts in which a movement is to occur and then to provide any immediate adjustment in innervation needed for that particular context (Houk et al. 1996). The position of the eye in the orbit would be one such context for which the vermis could provide the correction. The discharge of some Purkinje cells in the oculomotor vermis does vary with orbital position during saccades (McElligott and Keller 1982); and the vermis also has access to proprioceptive signals that could be used in the long term for adjusting orbital-position-dependent innervation and so help assure saccade conjugacy and prevent ocular misalignment (Baker et al. 1972; Lewis et al. 1994). Other "higher-level" contexts, e.g., saccades generated to the appearance of a visual target versus saccades generated volitionally without a novel target, also may depend on the cerebellum for their proper elaboration (Houk et al. 1996; Melis and Van Gisbergen 1996; Straube et al. 1995).
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ACKNOWLEDGEMENTS |
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C. Bridges, D. Roberts, R. Lewis, and A. Lasker provided invaluable assistance. M. Shelhamer helped with statistical analyses. D. Ryugo and K. Ohtsuka helped with the preparation and interpretation of the histology. Professor H. Abe provided continuous support.
D. S. Zee was supported by National Eye Institute Grant EY-01849. M. Takagi was supported by the Uehara Memorial Foundation.
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FOOTNOTES |
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Address for reprint requests: D. S. Zee, Path 2-210, The Johns Hopkins Hospital, Baltimore, MD 21287.
Received 29 December 1997; accepted in final form 24 June 1998.
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REFERENCES |
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Abstract
Introduction
Methods
Results
Discussion
References
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