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REPORT
1Institut National de la Santé et de la Recherche Médicale /Université Claude Bernard-Lyon, Institut Fédératif des Neurosciences de Lyon, Bron; and 2Equipe Dynamique de la Vision et de l'Action, Institut de Neurosciences Cognitives de la Méditerranée, Unité Mixte de Recherche 6193 Centre National de la Recherche Scientifique-Université de la Méditerranée, Marseille, France
Submitted 9 July 2004; accepted in final form 21 November 2004
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ABSTRACT |
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INTRODUCTION |
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; Robinson and Fuchs 2001). It consists of the oculomotor vermis (lobules VIc and VII) and the caudal part of the fastigial nuclei ( Noda 1991). Saccade-related neurons have been recorded in both the vermal lobules VI–VII ( Ohtsuka and Noda 1995) and the caudal fastigial nucleus ( Fuchs et al. 1993; Ohtsuka and Noda 1991). Electrical microstimulation of these regions elicits saccadic eye movements in the head-restrained monkey ( Fujikado and Noda 1987; Noda et al. 1988). Unilateral inactivation of the caudal fastigial nucleus (cFN) by local injection of muscimol in the head-restrained monkey impairs the accuracy of saccades aimed at a small visual target: ipsilesional saccades are hypermetric and contralesional saccades are hypometric ( Goffart et al. 2004; Robinson et al. 1993). In the head-unrestrained cat, unilateral inactivation of cFN leads to a dysmetria of gaze (eye in space) that is associated with dysmetric movements of the eyes in the orbit and of the head without any noticeable change in the head contribution to the gaze shifts ( Goffart et al. 1998). The results led the authors to propose that the cFN output influences a neural circuit generating gaze-related motor commands. However, in these cat experiments, the target was a spoon of food and thus triggered a head movement aimed at directing the mouth toward the food target. When orienting toward a food target, both gaze- and head-orienting responses are generated in parallel in the normal animal. It is not known whether they are still independently generated when the medial cerebellar nucleus is lesioned. Part of the change in head amplitude observed in cat's gaze shifts after cFN inactivation could be due to deficits in "orienting movements of the mouth" toward the food target. Consequently, the effects of cFN inactivation on orienting gaze shifts generated in a task that only request to direct the line of sight toward a visual target have not yet been studied in the head-unrestrained animal. The question remains whether the saccade dysmetria after cFN inactivation in the head-restrained monkey corresponds to a central perturbation in issuing a gaze-related command or whether it is a peripheral impairment in generating saccadic oculomotor commands. The goal of this study was to address this question and determine in the head-unrestrained monkey the effects of cFN inactivation on the eye and head components of gaze shifts aimed at a visual target light-emitting diode (LED).
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METHODS |
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Two adult rhesus monkeys (5.7 and 8.8 kg) were used for this experiment. Two surgical procedures under isoflurane anesthesia and aseptic conditions were performed. First, a light titanium head post (7 g) for immobilizing the head was secured by stainless steel screws and bone cement on the top front center of the skull. For the monitoring of eye movements, a three-turn magnetic search coil (Cooner Wire, AS 632) was fixed to the sclera under the conjunctiva of one eye ( Fuchs and Robinson 1966; Judge et al. 1980). Leads were passed under the skin to a connector located on the top of the skull. For the monitoring of head movements, a similar coil was glued to a piece of plastic and fixed to the skull with bone cement. Training was initiated after full recovery. In a second surgical procedure (details in Goffart et al. 2004), a craniotomy was made in the skull, and a recording chamber was stereotaxically implanted for inactivating the caudal part of the fastigial nucleus. All surgical procedures and experiments were in accordance with the guidelines from the French Ministry of Agriculture (87/848) and from the European Community (86/609/EEC).
Behavioral tasks
Animals were seated in a primate chair that prevented movements of the body and permitted unrestrained movements of the head. Gaze and head positions were measured with a phase angle detection system (CNC Engineering, 3-ft-diam coil frame). Two phase detectors were used to independently record gaze and head rotations. Gaze position signals were calibrated by having the animal fixate stationary targets that were placed ±20° horizontally or vertically. The head coil was first calibrated before placement on the top of the animal's head using a gimble and rotating the coil ±30° horizontally and vertically. This calibration was verified after the head coil was embedded in the bone cement by rotating the restrained head with the same angles.
Experiments were conducted in a dimly illuminated room (illuminance = 0.05cd/m2) where the monkey was facing a spherical array of LEDs (0.16° visual angle, luminance = 10.7cd/m2) that were all located at a distance of 110 cm from the glabella. The animal was trained to perform a saccade task that shifted gaze from a central fixation LED (located straight ahead) toward a peripheral target LED. The straight ahead direction is defined as the intersection between the midsagittal plane of the subject (vertical meridian) and the orthogonal plane passing through both eyes (horizontal meridian). For each trial, a warning tone preceded the onset of the fixation LED. The monkey's task was to maintain gaze within a spatial window around the fixation LED (3° radius) for a variable fixation interval (1,000–2,000 ms varied in increments of 500 ms). After this interval, the fixation LED was extinguished, and after a gap interval (200 ms), the target LED was turned on. In 80% of the trials, the target LED was flashed for 100 ms. In the remaining trials, the target LED stayed on for the duration of the trial (permanent target LED). Reward was delivered after a fixation interval (300 ms) within a spatial window around the target LED (4–8° radius). The location of target LEDs was pseudorandomly selected among several predefined positions along the horizontal meridian (8, 16, 24, 32, and 40° to the left or to the right of the central fixation LED) or along the vertical meridian (8, 16, 24, and 32° above or below the fixation LED). In the head-unrestrained condition, reward was delivered with a very light system (weight: 50 g) that was attached to the head post. This system smoothly delivered water into the mouth with minimal visual obstruction and allowed the animal to freely move the head.
Because of the muscimol-induced dysmetria, several saccades were required to acquire the fixation LED and saccades toward the target LED frequently terminated outside the acceptance window around it. Therefore the radius of the windows was increased after the injection (10–20 and 12–30° around the fixation and target LEDs, respectively). Moreover, to increase the number of gaze movements aimed at flashed target LEDs, the percentage of trials with a permanent target LED was reduced to <10% after muscimol injection. These trials were useful for the experimenters because the correction saccades that followed the primary saccades provided a visual feedback of the amount of dysmetria during the running of the experiments.
Muscimol injections
Before the injection of muscimol, the location of the saccade-related region of FN was identified after several experimental sessions involving electrophysiological recording and electrical microstimulation. The caudal fastigial nucleus was located using the following criteria: the presence of saccade-related neurons that discharged burst activity for omnidirectional saccades ( Fuchs et al. 1993; Ohtsuka and Noda 1991) and low current thresholds for electrically evoking saccades ( Goffart et al. 2003; Noda et al. 1988). The identification was confirmed by the effects of local injection of muscimol in the head-restrained condition: hypermetric ipsilesional saccades and hypometric contralesional saccades ( Goffart et al. 2004; Robinson et al. 1993). During pharmacological injections, the head of the monkey was restrained. A thin cannula (230 µm OD, bevelled tip) and polyethylene tubing were filled with a solution of muscimol (2 µg/µl) and connected to a Hamilton syringe. A small bubble of air in the tubing permitted verification of the injection of muscimol. The cannula was lowered through the recording chamber and aimed at the saccade related region. Small volumes (0.5–1.1 µl, details in Table 1) of muscimol were injected by small pulses (during 4–16 min). The volume of the injection was checked by the displacement of the meniscus in the tubing (1 mm/0.1 µl). After withdrawing of the cannula (2–5 min after the last pulse), visually guided saccades were first recorded in the head-restrained condition for a companion study. Then, gaze shifts in the head-unrestrained condition were tested 29–88 min after the testing in the head-restrained condition. Before each injection, control responses were recorded daily during three to four sessions (
30 trials per target location). No fewer than 6 days separated two consecutive muscimol injections.
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The results presented in this paper are based on the data obtained before and after eight unilateral muscimol injections performed in the cFN of two monkeys. The data were first measured and collated using a software program that detected the onset and offset of saccades and head movements on the basis of a velocity threshold (15°/s). The results of the automatic detection were checked by inspecting each trial individually and corrected when required. Several parameters such as the amplitude, the duration, and the peak velocity of each displacement (horizontal, vertical, and tangential) of the gaze, the head, and the eye were extracted automatically from detected movements. Eye position relative to the head was computed as the difference between the gaze- and head-position signals. The present report is focused on gaze shifts aimed at the most eccentric target LEDs (40°) recorded in trials where the target was flashed. Indeed, these movements were associated with the largest head movement. Gaze shifts made toward the other targets showed similar changes except in experiments B4 and E2 (details in RESULTS).
For each experiment, the behavioral performance during the control session was compared with the performance after the injection of muscimol. The nonparametric Mann-Whitney U test was used because in a few cases the number of measured movements after muscimol injection was <10 (details in Table 1). To take into account differences in the behavioral effects of injections on different days, a paired comparison (nonparametric Wilcoxon test) was performed between the mean values of the pre- and postinjection data (Statistica, Statsoft). Statistical significance threshold was set to P < 0.05 (P values are provided when the comparison failed to reveal any change that reached level of statistical significance).
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RESULTS |
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Figure 1 illustrates the time course of representative gaze shifts recorded before (control session, - - -) and after muscimol injection (—) in the left cFN of monkey B (experiment B3) and in the right cFN of monkey E (experiment E1). A–C show the horizontal position of gaze, of the eye in the orbit and of the head, respectively. After muscimol injection, ipsilesional gaze shifts were hypermetric. They overshot the final gaze position that was reached during the control session ( · · · ). Contralesional gaze shifts were hypometric and undershot the control final gaze position. Similarly, ipsilesional saccadic movements of the eye in the orbit were hypermetric and contralesional ocular saccades were hypometric. Finally, ipsilesional head movements were hypometric after inactivation of the left or right cFN, whereas contralesional head movements were not changed in a consistent way: they were hypometric in experiment B3 and hypermetric in experiment E1. In the following text, the consistency of the deficits induced by cFN inactivation is quantitatively examined for all experiments.
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) and after (
) each muscimol injection. The head contribution is defined as the amplitude of the head movement from gaze shift onset time until gaze shift end (head contribution differs from the amplitude of the complete head movement because head movements and gaze shifts do not start and end at the same times). Concerning ipsilesional gaze shifts (left), the horizontal gaze amplitude was significantly increased in six of the eight experiments, decreased in one experiment (E2) and was not significantly altered in one experiment (B4). It is noteworthy that the ipsilesional hypometria observed in experiment E2 only concerned gaze shifts aimed at the 40° eccentric target and not those directed toward the less eccentric targets (8, 16, 24, and 32° eccentric targets). For these other targets and for both experiments B4 and E2, the amplitude of gaze shifts was significantly increased (data not shown). This lack of consistency was associated with a failure of the Wilcoxon test to show any significant effect of muscimol injection on the horizontal amplitude of gaze shifts (average difference = 3.8 ± 5.0° corresponding to a 10% increase, P = 0.06). The horizontal amplitude of the eye saccade was increased after all injections, and the paired comparison between control and postinjection average amplitudes confirmed a significant increase in the amplitude of eye saccades (average difference = 7.2 ± 4.1°, 24% increase). This consistent increase in the horizontal amplitude of eye saccades contrasts with the consistent reduction in the amplitude of head movements (head contribution and complete head movement, C and D). Significant reductions in the horizontal amplitude of head contribution (average difference = –3.8 ± 1.5°, 58% decrease) and of the complete head movement (average difference = –6.4 ± 2.9°, 57% decrease) were indeed observed after all injections of muscimol. There was no significant relationship between the changes in head-movement amplitude and the changes in starting head position: the correlations between the average changes in initial horizontal head position and 1) the average changes in the horizontal amplitude of complete head movements or 2) the average changes in horizontal amplitude of head contributions were both not statistically significant [Pearson correlation coefficients R(X,Y) = 0.40, P = 0.31 and R(X,Y) = 0.52, P = 0.17, respectively].
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After muscimol injection, there was no significant change in the vertical component of horizontal gaze shifts aimed at these 40° eccentric targets. The average postinjection changes in vertical gaze amplitude were negligible for both ipsilesional and contralesional gaze shifts (0.7 ± 1.6 and 0.4 ± 4.0°, respectively).
Figure 3 compares the change in horizontal eye amplitude with the change in horizontal gaze amplitude induced by the muscimol injections in the cFN for ipsilesional (A) and contralesional (B) gaze shifts. The difference in gaze amplitude varied from –3.0 to 11.9° for ipsilesional movements and from –8.0 to –19.5° for contralesional ones. The difference in eye saccade amplitude varied from 1.6 to 14.3° for ipsilesional gaze shifts and from –6.6 to –18.2° for contralesional ones. The difference in eye amplitude was strongly correlated with the difference in gaze amplitude for both ipsilesional and contralesional movements [Pearson correlation coefficient R(X,Y) = 0.97; R(X,Y) = 0.96, respectively]. For ipsilesional gaze shifts, the change in gaze amplitude was 47% smaller than the change in eye saccade amplitude (average difference = –3.4 ± 1.5°, P < 0.05), corroborating the reduction in the contribution of the head to gaze-shift amplitude. There was no statistically significant correlation between the average changes in eye amplitude and the average changes in head contribution [R(X,Y) = 0.51, P = 0.19]. For contralesional gaze shifts, the reduction in gaze amplitude was 12% larger than the decrease in eye amplitude (average difference = 1.8 ± 1.3°, P < 0.05). This difference is also compatible with the reduction in the head contribution to the amplitude of gaze shifts. There was no statistically significant correlation between the average changes in eye amplitude and the average changes in head contribution [R(X,Y) = –0.27, P = 0.51].
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DISCUSSION |
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). The horizontal error that systematically affected all saccades likely contributed to the ipsilesional deviation of starting gaze position (see DISCUSSION in Goffart et al. 2004). For both ipsilesional and contralesional gaze shifts, the dysmetria of monkey gaze shifts was mostly due to dysmetric saccades of the eye. During ipsilesional gaze shifts, the amplitude of saccadic eye movements was always hypermetric and the amplitude of the head contribution always reduced. The saccadic movement of the eyes is thus the sole parameter responsible for the hypermetria of ipsilesional gaze shifts. In experiment E2, gaze shifts aimed at the 40° eccentric target were hypometric, but those directed toward the less eccentric targets were hypermetric (data not shown). This observation suggests that the postlesional change in eye saccade amplitude in experiment E2 could not be further increased beyond the 32° eccentric target. For contralesional movements, the reduction in gaze amplitude was associated with a reduction in the amplitude of saccadic eye movements for all experiments and a reduction in head contribution for five of eight experiments. We could not find any satisfactory explanation why a significant change in the head contribution was not observed in three experiments. The observation that the change in saccade amplitude accounted for 88% of the gaze hypometria indicates that the change in saccade amplitude was the major parameter responsible for the hypometria of contralesional gaze shifts.
A significant decrease in the amplitude of the head contribution was observed in ipsilesional gaze shifts. Our data did not provide any evidence supporting the possibility that this reduction resulted from the ipsilesional deviation of the starting head position. Indeed, there was no correlation between the changes in starting head position and the changes in head amplitude. Neither did our data support the possibility that the reduction in the amplitude of head contribution reflected a compensation for the large changes in eye amplitude. The gaze hypometria observed in experiment E2 and the lack of (negative) correlation between the changes in eye amplitude and the changes in head contribution are not compatible with this possibility. The decrease in head amplitude concerned the contribution of the head to the gaze shifts and the complete head movement. These observations, the change in starting head position and the anatomical projections of fastigial neurons to the neck motoneuron pools at spinal level C2 ( Robinson et al. 1994) suggest an involvement of cFN in head motor control. However, further studies are required to conclude whether cFN inactivation really depressed the generation of ipsilesional head movements or whether the reduction in head amplitude was simply due to the facts that ipsilesional gaze shifts were mostly accomplished by eye movements and that our monkeys were not specifically trained to move their head.
The lack of correlation between the changes in eye amplitude and the changes in head contribution is a negative result on which it is hazardous to raise conclusions. This result does not support the hypothesis that cFN inactivation impaired a gaze-related command feeding premotor neurons innervating the eye and neck motoneurons ( Goffart et al. 1998). Instead, it would be compatible with an impairment of neural stages after gaze commands have been decomposed into commands for moving the eye and the head. However, because cFN inactivation changed the starting position of the head, it was difficult to test whether the pattern of eye-head coordination was also altered. Further studies controlling the starting position of the head and showing a difference in eye-head coordination would be required to support this alternative hypothesis. Moreover, it would be very informative to extend the present study to very large gaze shifts requiring larger head movements and determine to which extent the ipsilesional and contralesional dysmetria remain restricted to the sole saccadic eye movements.
Finally, the effects of unilateral cFN inactivation in the head-unrestrained monkey differ from those observed in the head-unrestrained cat in several ways ( Goffart and Pélisson 1994, 1998; Goffart et al. 1998). First, the amplitude of ipsilesional gaze shifts aimed at a 40° eccentric target was not consistently increased (see experiments B4 and E2). Second, instead of being increased like in cat gaze shifts, the amplitude of ipsilesional head movements was decreased after each injection of muscimol in the monkey cFN. Third, the hypometria of contralesional gaze shifts was not associated with a significant change in the amplitude of head movements. Presumably, the dysmetria that affected head movements in the cat experiments corresponded to an additional deficit in orienting the mouth toward the food target. This deficit in orienting head movements had the same pattern as the deficit in orienting gaze shifts (ipsilesional hypermetria/contralesional hypometria).
In conclusion, after muscimol inactivation of cFN and within the range of target eccentricities that was tested in the present study, the dysmetria of gaze shifts aimed at a visual target LED was mostly due to dysmetric amplitude of saccadic eye movements.
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GRANTS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: L. Goffart, Equipe DyVA, C.N.R.S. I.N.C.M., 31 chemin Joseph Aiguier, 13402 Marseille Cédex 20, France (E-mail: Laurent.Goffart{at}incm.cnrs-mrs.fr)
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REFERENCES |
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ABSTRACT
INTRODUCTION
