Espace et Action, Institut National de la Santé et de la Recherche Médicale U94, 69500 Bron, France
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ABSTRACT |
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Goffart, Laurent and Denis Pélisson. Orienting gaze shifts during muscimol inactivation of caudal fastigial nucleus in the cat. I. Gaze dysmetria. J. Neurophysiol. 79: 1942-1958, 1998. The cerebellar control of orienting behavior toward visual targets was studied in the head-unrestrained cat by analyzing the deficits of saccadic gaze shifts after unilateral injection of muscimol in the caudal part of the fastigial nucleus (cFN). Gaze shifts are rendered strongly inaccurate by muscimol cFN inactivation. The characteristics of gaze dysmetria are specific to the direction of the movement with respect to the inactivated cFN. Gaze shifts directed toward the injected side are hypermetric. Irrespective of their starting position, all these ipsiversive gaze shifts overshoot the target by a constant horizontal error (or bias) to terminate at a "shifted goal" location. In particular, when gaze is directed initially at the future target's location, a response with an amplitude corresponding to the bias moves gaze away from the actual target. Additionally, when gaze is initially in between the target and this shifted goal location, the response again is directed toward the latter. This deficit of ipsiversive gaze shifts is characterized by a consistent increase in the y intercept of the relationship between horizontal gaze amplitude and horizontal retinal error. Slight increases in the slope sometimes are observed as well. Contraversive gaze shifts are markedly hypometric and, in contrast to ipsiversive responses, they do not converge onto a shifted goal but rather underestimate target eccentricity in a proportional way. This is reflected by a decrease in the slope of the relationship between horizontal gaze amplitude and horizontal retinal error, with, for some experiments, a moderate change in the y-intercept value. The same deficits are observed in a different setup, which permits the control of initial gaze position. Correction saccades rarely are observed when visual feedback is eliminated on initiation of the primary orienting response; instead, they occur frequently when the target remains visible. Like the primary contraversive saccades, they are hypometric and the ever-decreasing series of three to five correction saccades reduces the gaze fixation error but often does not completely eliminate it. We measured the position of gaze after the final correction saccade and found that fixation of a visible target is still shifted toward the inactivated cFN by 4.9 ± 2.4°. This fixation offset is correlated to, but on average 54% smaller than, the hypermetric bias of ipsiversive responses measured in the same experiments. In conclusion, the cFN contributes to the control of saccadic shifts of the visual axis toward a visual target. The hypometria of contraversive gaze shifts suggests a cFN role in adjusting a gain in the translation of retinal signals into gaze motor commands. On the basis of the convergence of ipsiversive gaze shifts onto a shifted goal, the straightness of gaze trajectory during these responses and the production of misdirected or inappropriately initiated responses toward this shifted goal, we propose that the cFN influences the processes that specify the goal of ipsiversive gaze shifts.
Shifting the direction of the eyes in space (= gaze) between relevant objects requires a transformation of sensory signals into appropriate motor commands for eye, head, and eventually body axis. Saccadic eye movements, usually studied in isolation by restraining the head, are by far the best understood component of this gaze-orienting behavior, both at the conceptual and neurophysiological levels. The original notions of a feedback burst generator and a neuronal integrator (Robinson 1975 Subjects
Five adult cats (E-I) were used. The animals were deprived of food overnight before experimental testing, after which they were allowed to eat to satiation. They were cared in accordance with the guidelines from the French Ministry of Agriculture (87/848) and from the European Community (86/609/EEC).
Surgery
Cats were prepared for the chronic recording of orienting movements and pharmacological local injections. A single surgical procedure was performed under general anesthesia [pentobarbital sodium (Nembutal) 30 mg/kg ip] and aseptic conditions. A three-turn coil was sutured on the right eye, another coil was fixed to the skull with acrylic cement, and the leads were soldered to two connectors cemented to the skull. These coils served to record gaze and head position by the search-coil-in-magnetic-field technique (Robinson 1963 Experimental setups and animal training
After recovery, each cat was placed in a hammock that gently restrained the body without constraint on natural movements of the head. The hammock was placed inside a 1-m coil frame (CNC Engineering) with the head situated at the center of the frame. The visual target was a spoon, subtending 3.5° of visual angle, filled with a food puree, fitted with two infrared diodes that permitted continuous recording of its position (Urquizar and Pélisson 1992
Muscimol injections
The injection sites were first determined on a stereotaxical basis (coordinates L = ±1.5, H = 0, P = 10). When a muscimol injection produced a characteristic saccadic dysmetria, subsequent injections were performed either in the same area or 3 mm away on the contralateral side (corresponding to the distance between the 2 cFN). In unsuccessful cases, the injection site for the next experiment was corrected based on the observed behavioral effects: appearance of nystagmus and/or nausea when injection was too deep, ipsilateral hindlimb ataxia when too lateral, no apparent deficit when too high, strong postural deficits when too rostral. In cat H, the electrophysiological identification of the deep cerebellar nucleus was made in the alert, head-fixed, animal to confirm stereotaxical coordinates. Muscimol was injected into, and subsequently around, the region where saccade-related bursts of activity were recorded.
Behavioral tests
After withdrawing the cannula, spontaneous eye movements in light and in darkness were recorded for ~5 min. Then the animal's head was freed and visually triggered gaze shifts were recorded with one of the two setups during a 20- to 120-min period after the onset of the injection. A recording session consisted of a series of 2-s trials, each of which was initiated (data acquisition started) when the animal looked roughly in the direction of the fixation stimulus. The effects on gaze shifts presented in the following text were stable during the entire recording period. Control behavioral responses were measured the day preceding each injection.
Data recording and analysis
Search coil signals were linearized and scaled on-line by a computer program, providing four signals proportional to the horizontal and vertical positions of gaze (eye-in-space) and head. The calibration of each coil was performed before implantation by measuring the output voltage while the coil achieved known angular positions. The computed parameters for the linearization algorithm (gain and offset) were checked in vivo and, if necessary, amended by presenting the animal an attractive target at different locations. The overall precision of gaze and head measurement was estimated to be ±0.5°. The same program controlled the infrared emitters fixed on the spoon, processed signals from two remote infrared sensors and delivered on-line signals proportional to horizontal and vertical positions of spoon target relative to the animal's longitudinal body axis (Urquizar and Pélisson 1992 General observations
The data presented in this and the companion paper (Goffart et al. 1998
Ipsilateral deviations of the visual axis
In both the head-restrained and -unrestrained conditions, the direction of the visual axis was deviated toward the inactivated cFN. Figure 3B shows that in the head-restrained animal, the mean orbital eye position was deviated slightly toward the injected side when tested with ambient lights [
Qualitative description of gaze dysmetria
Figure 5 shows the horizontal trajectories of sample gaze shifts elicited in cat I by a target presented straight ahead, i.e., along the body sagittal axis (hemicylindrical setup). For the sake of demonstration, we selected responses starting from different initial positions. During the control session (Fig. 5A), gaze moved accurately toward the target or, when it initially was directed toward the target (initial position = 0°), remained stable. After muscimol injection in the left cFN (Fig. 5B), leftward gaze shifts were hypermetric and overshot the target by ~10°. Remarkably, this error was constant irrespective of initial gaze position. Even when gaze initially was directed at the future target location (0° initial gaze position), the cat moved its gaze away from the target toward the same final position. Furthermore, when gaze initially was aligned with this location where all ipsiversiveresponses ended (shifted goal), the cat did not produce any response at all. Beyond that position, rightward responses were generated that fell short of the target. But contrary to ipsiversive responses, it was clear that these contraversive gaze shifts did not converge onto a common final position. Instead, hypometric gaze error gradually increased as a function of initial target eccentricity relative to gaze.
Gaze displacement amplitude
The pattern of ipsilateral hypermetria/contralateral hypometria induced by muscimol injection was analyzed quantitatively as illustrated in Fig. 8 for two experiments. The horizontal component of each recorded gaze shift was plotted as a function of target eccentricity relative to gaze along the azimuth (horizontal retinal error). Horizontal retinal error is by convention negative, positive or null when the target is presented, in the left hemifield, in the right hemifield, or along the vertical meridian, respectively. Negative and positive horizontal amplitudes correspond to leftward and rightward gaze shifts, respectively. Each data point represents a gaze response recorded either before (
Correction saccades
For all responses presented so far, movement onset triggered the offset of ambient light so that the gaze shifts were performed in complete darkness (see METHODS). In this condition, we observed gaze correction saccades only occasionally. To investigate whether correction saccades compensate for the dysmetria described above, we included some trials where the ambient light remained on. Figure 9 shows two such trials recorded after injection in the left cFN (injection G-L), with the visual target presented at 35° either in the left (Fig. 9A) or in the right (Fig. 9B) visual hemifield. Although visually guided correction saccades were observed in both cases, it appeared that static alignment of gaze with the target was abnormal after correction for the ipsilateral hypermetria: the example in Fig. 9A shows that a single and small correction saccade was made in the contraversive direction and that a large gaze fixation error was left uncorrected for a period of >500 ms. In other cases (not shown), despite the large hypermetria of ipsiversive gaze shifts, no correction saccade was ever produced. For contraversive hypometric movements, staircases saccades were observed most often. In some cases, like the example illustrated in Fig. 9B, these correction saccades eventually brought gaze very close to the target, but in other cases they failed and a significant fixation error remained. Note that the direction of correction saccades is always contraversive.
Fixation offset
As mentioned above, when the cat waited for target presentation, gaze, and head were deviated toward the injected side as compared with the preinjection condition. Because our animals were not specifically reinforced for accurate looking at a fixation point before the visual target is presented (see METHODS) but for orienting toward the target, we investigated this tonic gaze deviation by measuring the position reached after all correction saccades (final gaze position) toward a permanently visible target. This analysis of target fixation by gaze was made for all control and muscimol experiments. The horizontal fixation offset was calculated for each postinactivation trial by the difference between final gaze position and the corresponding mean value obtained in the control condition. This offset always was directed toward the inactivation side (grand mean computed on 13 experiments ± SD: 4.9 ± 2.4°; range: 1.0-9.4°). Then the fixation offset for targets presented in the ipsilesional hemispace was compared with the horizontal constant error of ipsiversive gaze shifts (y intercept of gaze displacement amplitude against retinal error relationship). The absolute value of the fixation offset was correlated with the absolute value of the y intercept (Pearson correlation coefficient r = 0.61, P < 0.001). However, these values did not match as the fixation offset was significantly smaller than the ipsilateral constant error [5.5 ± 2.8° vs. 10.9 ± 4.7°, Student's t(24) = We have shown in this paper that unilateral muscimol injections in the caudal part of the fastigial nucleus lead to marked and consistent impairments in the accuracy of goal-directed saccadic gaze shifts. Like the dysmetria of saccadic eye movements recorded in the head-restrained monkey (Ohtsuka et al. 1994 Ipsiversive movements
After muscimol injection in the cFN, gaze shifts toward the injected side are hypermetric by a constant horizontal error. This striking deficit is illustrated clearly by the convergence of gaze spatial trajectories onto a location that is shifted horizontally from the actual target (shifted goal). The nonzero y intercept in the relationship between horizontal retinal error and horizontal gaze amplitude further indicates that this constant error is present for all gaze shifts, irrespective of target eccentricity. In addition, the horizontal error observed in the gaze shifts having a purely vertical direction and the similarity of this error with that of ipsiversive gaze shifts cannot be accounted for by a deficient braking of the horizontal trajectory of gaze. Moreover, gaze shifts during cFN inactivation all had normally straight trajectories and gaze moved in the direction of the shifted goal from the beginning of the movement. The observation of straight gaze shifts confirms previous reports on saccadic eye movements in fastigial-inactivated monkeys (Ohtsuka et al. 1994 Contraversive movements
The metrics of contraversive gaze shifts reveal two features that distinguish these movements from ipsiversive ones: they undershoot the target and this hypometric error markedly increases as a function of target eccentricity. These characteristics are reflected in the reduced slope of the relationship between horizontal retinal error and horizontal gaze amplitude after cFN inactivation. This type of hypometria is consistent with a reduction of an overall gain in the visuomotor transformation mechanisms, in the line of the proposed cerebellar role in tuning the gain of saccadic system (Dean 1995 Fixation offset
The deficits of gaze shift accuracy during muscimol injection always were associated with a tonic, horizontal deviation of gaze toward the inactivated cFN when the animal attempted to fixate the center of the screen. Note that no spontaneous nystagmus was observed in light or in darkness, in agreement with previous cFN inactivation studies (Kurzan et al. 1993 Possible neurophysiological substrate
Throughout this paper, we have maintained a clear distinction between movements according to their direction because it soon appeared that the corresponding deficits were qualitatively different (Goffart and Pélisson 1994c Conclusions
Saccadic dysmetria after cFN inactivation previously has been interpreted as the result of suppression of the "early" and "late" saccade-related bursts recorded in primate cFN. Our observations about ipsiversive movement hypermetria and fixation offset more directly stress the possible role of cFN tonic discharges. These two hypotheses predict different effects on movement dynamics. Indeed, changes restricted to the control of acceleration or deceleration phases likely would be accompanied by changes in gaze dynamics. In contrast, no modification in movement dynamics is expected if, as suggested here, gaze shift dysmetria results from changes in the desired displacement signal driving eye and head movement generators. Furthermore, analysis of eye/head coordination might indicate whether cFN acts at the level of the eye in the orbit or at the level of both eye and head components. These analyses are presented in the companion paper.
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
), involved in quickly displacing the eyes and holding them in a new position, respectively, are still common to all saccadic control models (see for review van Gisbergen and van Opstal 1989
). Neuronal circuits responsible for the generation of these phasic and tonic motor signals have been identified in the brain stem (Fuchs et al. 1985
; Moschovakis and Highstein 1994
). In addition, the contribution of structures projecting directly and/or indirectly to brain stem premotor neurons, like the superior colliculus (Sparks 1986
), the frontal (Bruce 1990
; Goldberg and Segraves 1989
), and parietal (Andersen and Gnadt 1989
) eye fields of the cerebral cortex, becomes progressively better understood (see also Schall 1991
).
; Stein and Glickstein 1992
; Thach et al. 1992
). There is a large body of clinical and experimental data showing that cerebellar lesions severely interfere with saccade accuracy (reviews in Keller 1989
; Leigh and Zee 1991
; Lewis and Zee 1993
). In conjunction with neurophysiological and anatomic studies, this lesion approach has led to progressively implicate vermal lobules VI-VII and the underlying caudal fastigial nucleus (cFN) as the core of the cerebellar regions involved in the control of saccadic eye movements in the monkey (Noda 1991
). Indeed, any dysfunction of the fastigial nucleus (FN) leads to dysmetric saccades, whether in the case of permanent lesions (Optican and Robinson 1980
; Ritchie 1976
), reversible inactivations induced by cooling or inhibitory pharmacological drugs (Ohtsuka et al. 1994
; Robinson et al. 1993
; Vilis and Hore 1981
), or electrical microstimulation (Ohtsuka and Noda 1991a
). Saccade-related activities have been recorded in both vermal lobules VI-VII and cFN (cat: Gruart and Delgado-Garcia 1994
; Harlay et al. 1974
; Waterhouse and McElligott 1980
; monkey: Fuchs et al. 1993
; Helmchen and Büttner 1995
; Helmchen et al. 1994
; Hepp et al. 1982
; Kase et al. 1990; Llinas and Wolfe 1977
; Ohtsuka and Noda 1991b
, 1995
), and low-intensity electrical microstimulation of either lobules VI-VII or cFN evokes saccadic eye movements (Fujikado and Noda 1987
; Noda and Fujikado 1987a
,b
; Noda et al. 1988
).
; Batini et al. 1978
; Dietrichs and Walberg 1987
; Gerrits and Voogd 1987
; Gould 1980
; Hoddevik et al. 1977
; van Der Want et al. 1987
; monkey: Carpenter and Batton 1982
; Noda et al. 1990
). In turn, Purkinje cells in vermal lobules VI and VII project to and monosynaptically inhibit cFN neurons (Courville and Diakiw 1976
; Dietrichs 1983
; Ito et al. 1970
; Noda et al. 1990
). Finally, cFN was shown to project to many oculomotor-related structures in the brain stem (Blanks 1988
; Carpenter and Batton 1982
; Noda et al. 1990
), many of them projecting back to vermal lobules VI-VII and cFN (Batini et al. 1978
; Gould 1980
). The cFN also issues projections to the perioculomotor area of the mesencephalon (Gruart and Delgado-Garcia 1994
), to the superior colliculus (Hirai et al. 1982
; Kawamura et al. 1982
; May et al. 1990
; Roldan and Reinoso-Suarez 1981
; Sugimoto et al. 1982
), and to the thalamic ventromedian (Jimenez-Castellanos and Reinoso-Suarez 1985
; Kyuhou and Kawaguchi 1987
; Nakano et al. 1980
; Steriade 1995
) and suprageniculate (Katoh and Deura 1993
) nuclei.
; Vilis and Hore 1981
) or from impaired acceleration or deceleration phases (Dean 1995
; Robinson et al. 1993
). Alternatively, the possibility that dysmetria results from a more central deficit, i.e., from a disturbance in the processes that translate retinal signals into commands for the impending movement (Optican 1982
; Pellionisz and Llinas 1982
), is supported by less direct evidence. In this perspective, neuronal activities related to visual and auditory information have been recorded in lobules VI and VII (Buchtel et al. 1972
; Freeman 1970
; Koella 1959
; Snider and Stowell 1944
) and in cFN (Kawamura et al. 1990
), leading some authors to suggest a teleceptive function of these cerebellar areas (Altman et al. 1976
; Donaldson and Hawthorne 1979
; Fadiga and Pupilli 1964
; Wolfe 1972
).
-c
).
METHODS
Abstract
Introduction
Methods
Results
Discussion
References
). A craniotomy was made just over the cerebellum and a recording chamber (10 mm ID) was centered on the midline and aimed at the cFN with a 20° backward angle. The intact dura was cleaned and a drop of framycetin sulfate (Soframycin) local antibiotic was administrated before sealing the chamber. Finally, a U-shaped piece of plastic was fixed to the head with cement and screws. This head holder, which had transverse holes drilled into it, permitted painless restraint of the animal's head during some experimental phases (see further). Some animals also were implanted, either during the same or in a subsequent surgical procedure, with stimulation electrodes in the superior colliculus for experiments to be reported in the future.
1·24 h
1 im), and the right eye was cleaned twice daily with an eyewash. Thereafter, both the chamber and the skin regularly were inspected and cleaned.
). The cat's task was to orient its gaze toward the target on its sudden presentation. Two experimental setups were used for target presentation. In the first one (Fig. 1A, screen setup), the animal had to orient its gaze toward a target presented to either side of an opaque screen situated in a fronto-parallel plane at a distance of 41 cm. Different screen sizes were used to elicit gaze shifts toward targets located at 7, 15, 19, 27, and 35° from the animal's body sagittal plane. During conditioning, cats were trained to first look at a small white plastic bolt (~3° of visual angle) located at the center of the screen before the target is presented to one side. In the second setup (Fig. 1B, hemicylindrical setup), an opaque hemicylindrical panel (radius = 41 cm) was placed in front of the animal with the head placed at its center. The food target could appear in one of nine holes made in the panel, located at the cat's eye level and at eccentricities of 0, ±12, ±24, ±36, or ± 48° with respect to the animal's sagittal plane. In practice, three target positions were regularly used (0 and ±24°). Sometimes, another object or an experimenter's finger was presented before the food target to ensure that the animal initially looked at the desired location. In such trials, initial fixation was varied among the nine positions. In both setups, the ambient room light illuminating the setup was provided through optical fibers. In ~90% of the trials, this light beam was interrupted by an electronic shutter (response time = 5 ms) at the beginning of the gaze shift, so that the orienting response was completed in darkness. The lights were turned on again 2 s after target presentation, and the animal was rewarded directly from the food target. No strict temporal or spatial windows were used to assess fixation and orientation performances: a trial was considered as correct when the animal oriented in the direction of the target (up, down, right, or left in the first setup; right or left in the second setup) between 0.1 to 1.5 s after target presentation. Anticipatory responses (latency <80 ms) were discarded from the analysis (Goffart and Pélisson 1997
). On average, 2-3 wk of training were necessary before the actual recording could begin, which included the habituation period to the experimental apparatus and to the containment hammock. Depending on the animal, 150-400 correct trials were performed during each experimental session.
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FIG. 1.
Experimental setups used for target presentation. This view from above represents the planar (A, screen setup) or hemicylindrical (B, hemicylindrical setup) opaque screen placed in front of the animal and the visual target (spoon filled with cat food) hidden behind. The experimenter moved the visual target to 1 edge of the planar screen or placed the target inside 1 of 9 holes made in the hemicylindrical panel (*). In the 1st setup, different screen sizes are used to explore different target eccentricities.
).
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
) result from the analysis of 13 experiments. For practical purposes each experiment was labeled according to cat (E to I) and cFN (e.g., E-L stands for left cFN inactivation in cat E). Postmortem histological reconstruction confirmed that the sites of muscimol injection were located inside the caudal part of the fastigial nucleus. Examples of electrolytic lesions and reconstructed injection sites are indicated on parasagittal sections of the cerebellum in cats G and H (Fig. 2).
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FIG. 2.
Histological reconstruction of injection sites in caudal part of the fastigial nucleus (cFN) of cat G (A) and cat H (B). Parasagittal section through the cerebellum showing a marking lesion ( ) and the estimated site of muscimol injection (*) reconstructed from the electrolytical lesion. Caudal border is to the right. Scale bar = 1 mm.
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FIG. 3.
Characteristics of spontaneous eye movements recorded in the head-restrained cat (left cFN inactivation, experiment I-L2). A: polar plots of the direction of spontaneous saccades recorded in the light (left) or in darkness (right). Proportion of saccades (scale bar = 10%) is plotted along the direction (30° bins). Control data shown by open area delimited by heavy line, pharmacological data shown by shaded area. B: orbital eye position at the beginning of each spontaneous saccade recorded during periods of ~5 min in the light (left) or in complete darkness (right). Data recorded before (control) and just after (muscimol) cFN inactivation are superimposed. During the control session, average horizontal and vertical eye positions are 2.3 ± 6.7 (mean ± SD) and
10.6 ± 9.5°, respectively (light condition, n = 128); and0.5 ± 8.1° and
2.9 ± 9.4°, respectively (dark condition, n = 109). After muscimol injection, there is a horizontal deviation of the eye toward the injected side both in light (
5.9 ± 7.4°, n = 58) and in darkness (
7.5 ± 8.7°, n = 76). Average vertical eye positions are
10.1 ± 10.4° (light) and
9.0 ± 8.7° (darkness).
5.9 ± 7.4 (mean ± SD) vs.
2.3 ± 6.7 for muscimol and control data respectively, Student's t (184) = 3.16,P < 0.01; Fig. 3B]. The magnitude of this deviation increased in darkness [
7.5 ± 8.7 vs. 0.5 ± 8.1, Student's t(183) = 6.33, P < 0.001]. When the head was unrestrained and the animal waited for target presentation, both gaze and head positions were deviated toward the injected side. Although systematically observed, these deviations could not be quantified as the animals had not been trained through reinforcement to align gaze or head with the fixation point. The issue of target fixation by gaze will be further documented later in the fixation offset section. Nevertheless, the deviation of the eye in the orbit observed in the head-restrained condition disappeared in the head-unrestrained condition as illustrated by the relationship between eye position in the orbit (Eh) and head position (Hh; Fig. 4). The data reported in Fig. 4 were collected with the hemicylindrical setup in a left cFN experiment (injection I-L2 in cat I), by attracting gaze to different initial positions before target presentation (see METHODS). Eye deviation in the orbit increased with head deviation according to a similar linear relationship in the control condition (Eh = 0.20·Hh
1.24; r2 = 0.85; P < 0.001) and in the muscimol condition(Eh = 0.21·Hh
1,26; r2 = 0.79; P < 0.001).
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FIG. 4.
Relationship between orbital eye position and head position at the onset of orienting gaze responses (left cFN inactivation, experiment I-L2). These data have been collected when the head-unrestrained animal, in the hemicylindrical setup, was fixating various locations along the azimuth both before ( , - - -) and after cFN inactivation (
,
). Overlap of data points and the similarity of the regression lines (equations in text), suggest similar eye to head position relationships in both conditions.
).
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FIG. 5.
Temporal trajectories of horizontal component of gaze shifts (left cFN inactivation, experiment I-L2). These responses were elicited by presenting the visual target at the central location (along the animal's sagittal plane) in the hemicylindrical setup while the animal was fixating at various locations along the horizontal meridian. In the control condition (A), gaze responses converge onto the target. However, after left cFN inactivation (B), leftward responses are hypermetric and converge onto a position that is shifted ~10° to the left of target location (- - -). Note that gaze reaches a similar location even when its initial position corresponds to that of the target. Rightward gaze shifts are hypometric with an error that increases with initial gaze location.
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FIG. 6.
Spatial trajectories of gaze shifts directed toward the inactivated cFN (right cFN inactivation, experiment F-R). Visual target (*) was presented at the right edge of the opaque panel in the screen setup (horizontal position of 19°) while the animal was fixating at various locations ( ). These 5 ipsiversive gaze trajectories all terminate (
) at a location that is shifted horizontally from the target location. Average final position of control gaze shifts (ellipse indicates mean ± SD) is shown for comparison.
), by a target located 27° up (*). These upward gaze shifts were directed toward a final position that was shifted by ~10° leftward (
9.95 ± 2.42, n = 20) with respect to the target and to the final position of control responses as well (dashed ellipse). The time course of horizontal and vertical components, shown in Fig. 7B for four selected responses, indicates that initial movement direction already was aligned with this shifted position. For example, although starting from the same azimuth as the visual target, response labeled c had a large leftward component synchronized with the vertical one; and conversely, responses a and d that started from the same azimuth as the shifted goal showed almost no horizontal deviation. A significant shift can be noted on the vertical component as well, but it is smaller than the horizontal one.
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FIG. 7.
Trajectories of gaze shifts directed toward a target (*) at an elevation of 27° along the vertical meridian (left cFN inactivation, cat H). A: spatial plot showing average end points (ellipses indicate mean ± SD) of gaze shifts recorded before (control) or after (muscimol) pharmacological injection. Initial location of gaze responses in the pharmacological session is shown ( ), some of these responses are labeled and replotted in B. B: temporal plot of 4 gaze responses recorded during the postinactivation session. Horizontal and vertical components are plotted in top and bottom, respectively. Onset of these 4 movements, estimated when resultant velocity exceeds a 30°/s threshold, is aligned on time 0. - - -, target location.
) or after (
) muscimol injection (Fig. 8, A and B, injection G-L in the left cFN; Fig. 8, C and D, injection F-R in the right cFN). Linear regression analyses of the relationship between horizontal retinal error (x) and horizontal gaze amplitude (y) were performed separately for leftward (Fig. 8, A and C) and rightward gaze shifts (Fig. 8, B and D). After muscimol injection in the left cFN of cat G, leftward gaze shifts (Fig. 8A) were hypermetric by a constant error. As reported qualitatively above, this bias is illustrated clearly by the presence of inappropriate movements (0° abscissa), misdirected gaze shifts elicited by a visual target presented to the right (abscissa in the 0-15° range) and by the absence of an horizontal component for responses toward a target presented at the shifted-goal location (abscissa in the 15-20° range). This leftward bias of gaze final position relative to the control condition was confirmed by a 19° downward shift of the regression line (y intercept negative) (see regression equations in Table 1). A similar, although smaller (10°), change in the regression line y intercept was observed for rightward gaze responses recorded in cat F after muscimol injection in the right cFN (Fig. 8D). The slopes of the regression lines for ipsiversive responses were, as compared with the y intercept, much less (cat G) or not at all (cat F) affected. Note also an increase in the scatter of the data points around the regression lines in the muscimol condition. For contraversive gaze shifts, the deficit was clearly different and an opposite pattern was found. As previously shown qualitatively in Fig. 5, error increased with larger target eccentricities. This is demonstrated here by a change in the slope of the relationship between horizontal retinal error and horizontal gaze amplitude: the slope decreased by 37% for cat G (Fig. 8B) and by 53% for cat F (Fig. 8C). The hypometria of contraversive gaze shifts also can be related to a change in the regression line y intercept (
4.24 vs.
0.40° for cat G), but this effect accounts for a small part of gaze inaccuracy. Finally, the scatter of the data points around the regression lines was much larger in the muscimol condition than in the control one; and this increase of variability seems larger than for ipsiversive movements.
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FIG. 8.
Relationships between horizontal retinal error and horizontal gaze amplitude illustrated for 2 experiments: left cFN inactivation, experiment G-L (A and B) and right cFN inactivation, experiment F-R (C and D). In each panel, the amplitude of horizontal gaze displacement is plotted vs. horizontal retinal error (i.e., actual vs. desired amplitude of horizontal gaze shift component); pre- and postinactivation data are shown by and
, respectively. Leftward (negative values) and rightward (positive values) movement directions are shown in separate panels (A and C and B and D, respectively). Equations of regression lines drawn on the plots are indicated in Table 1. Note that cFN inactivation resulted in changes in the intercept for ipsiversive movements (A and D) and in the slope for contraversive movements (B and C).
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TABLE 1.
Relationships between horizontal retinal error and horizontal gaze amplitude
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FIG. 9.
Temporal trajectories of orienting movements recorded in "permanent target" trials after left cFN inactivation (experiment G-L). A: horizontal trajectories of eye, head, and gaze movements (top) and corresponding gaze and head velocity profiles (bottom), generated after the presentation of the target at 35° to the left(- - -). Note that the large overshoot of the primary ipsiversive saccade is left essentially uncorrected after the contraversive correction saccade. B: responses toward a target located at 35° to the right are shown with the same conventions as in A. In this trial, the large hypometria, typical of contraversive primary gaze shifts, is suppressed almost completely after termination of a series of 3 hypometric correction saccades.
: centripetal saccades) or generated after a contraversive primary saccade and directed away from the body sagittal plane (Fig. 9B; Fig. 10,
: centrifugal saccades). This is reflected by a statistically significant lower saccadic gain (amplitude of correction saccade to residual retinal error ratio) for centripetal correction saccades than for centrifugal ones: 0.13 ± 0.06 versus 0.64 ± 0.06 [Student's t(41) = 10.6, P < 0.001]for cat G and 0.30 ± 0.17 versus 0.54 ± 0.15 [Student'st(28) = 3.4, P < 0.001] for cat F. It is noteworthy that the same analysis applied to primary contraversive saccades of cat G revealed a similar difference between centrifugal and centripetal saccades. These two types of primary contraversive gaze shifts were obtained, respectively, by having the animal initially gazing close to the center of the screen or gazing more eccentrically than the target toward the ipsilesional side. The gain of centripetal primary saccades (Fig. 10,
) was statistically significantly lower than the gain of centrifugal primary saccades (
): 0.13 ± 0.06 versus0.50 ± 0.09 [Student's t(148) = 12.6, P < 0.001]. Third, centrifugal correction saccades show a similar degree of hypometria as centrifugal primary saccades (cat G: 0.64 ± 0.17 vs. 0.50 ± 0.09; cat F: 0.54 ± 0.15 vs. 0.54 ± 0.10).
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FIG. 10.
Relationships between horizontal retinal error and horizontal gaze amplitude for primary and correction gaze shifts in the contraversive direction. A: left cFN inactivation, experiment G-L, B: right cFN inactivation, injection F-R. Primary and correction gaze shifts are represented by and
and
and
, respectively. Both primary and correction gaze shifts are distinguished according to whether they are directed away from (centrifugal responses) or toward (centripetal responses) the body sagittal axis.
3.49, P < 0.01]. On average, the constant error of the primary ipsiversive saccades was corrected by a factor of 45 ± 29% (range:
5-81%). The correction exceeded 50% in 9 of 13 cases (range: 50-81%). Altogether, these results suggest that the visual feedback provides information that help to compensate for the hypermetria of the primary ipsiversive gaze shifts.
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
; Robinson et al. 1993
), this gaze dysmetria depends on the direction of the movement with respect to the injected side: ipsiversive gaze shifts are hypermetric, whereas contraversive ones are hypometric. Our observations therefore illustrate the key role of this cerebellar area in the control of feline saccadic gaze shifts and extend the dysmetria observed in the head-restrained monkey (Ohtsuka et al. 1994
; Robinson et al. 1993
; Vilis and Hore 1981
) to the head-unrestrained condition.
), three times larger than the volume used in the present experiments. In addition, different deficits were observed when injections were made 2 mm apart: for example, in an investigation of the rostral part of FN (which will be reported in a subsequent paper), we showed that injecting muscimol 2 mm more rostral than in the present study did not induce any bias in ipsiversive gaze shifts (Goffart 1996
).
; Vilis and Hore 1981
; but see Robinson et al. 1993
) and in cerebellar patients (Ranalli and Sharpe 1986
). Altogether, these observations suggest that muscimol injection in cFN interferes with the elaboration and/or the maintenance of control signals generated upstream from or at the level(s) where the motor commands, leading to horizontal and vertical motions, interact.
). Finally, the fact that, for a given target, these inappropriately triggered and misdirected gaze shifts end at the same final position as the final location of hypermetric ipsiversive gaze shifts leads us to propose that a common target specification process was affected in all these ipsiversive gaze shifts.
or final position
of gaze) during movement preparation.
; Robinson et al. 1993
; Vilis and Hore 1981
). Indeed, it was proposed that the FN controls the trajectory of the on-going saccade: hypermetria would result either from an impaired feedback control of the saccade (Vilis and Hore 1981
; see also Keller 1989
for a similar interpretation of cerebellar role in the control of contraversive saccades) or from a flawed control of its deceleration phase (Ohtsuka et al. 1994
; Robinson et al. 1993
). In the first case, hypermetria would be the consequence of the internal feedback signal of current eye position underestimating actual eye position, leading to an incorrect updating of dynamic motor error. In the second case, saccadic hypermetria would result from the absence of the "late" neuronal burst of fastigial activity that normally is produced during ipsiversive saccades (Fuchs et al. 1993
; Helmchen et al. 1994
; Ohtsuka and Noda 1991b
) and that is supposed to help decelerate the eyes.
observed that cooling the fastigial nucleus essentially results in a hypermetria of saccadic eye movements in all directions. This deficit, which resembles the generalized hypermetria described after bilateral inactivation of cFN by muscimol (Robinson et al. 1993
), can be explained by simultaneous inactivation of neuronal bodies in the ipsilateral FN and of fibers originating from the contralateral FN (Sugita and Noda 1991
). In addition, because the cooling probe was located between the fastigial and interposed nuclei, the inactivation area was larger than in pharmacological experiments and most likely not confined to the cFN. Robinson et al. (1993)
used the same method as ours to specifically inactivate cFN and found a similar ipsiversive hypermetria/contraversive hypometria pattern. However, they described the hypermetria of ipsiversive saccades as an increase in gain (ratio of actual to desired eye displacement). We wonder whether this analysis captured the essential features of their results because computation of a gain value could not test the existence of a constant error in saccadic hypermetria. It is remarkable that in their two animals (see their Fig. 3), the computed value of saccadic gain after cFN inactivation was larger for responses to a 10° than for those to a 20° target displacement (1.31 vs. 1.15 in monkey M1 and 1.58 vs. 1.19 in monkey M2), just as can be expected if the hypermetria of ipsiversive responses comprised a constant term. Such a constant error in monkey ipsiversive saccades can be found in a brief report on saccadic dysmetria induced by muscimol inactivation of the cFN (Ohtsuka et al. 1994
). It was shown clearly that the tested monkey made saccades toward a terminal location that was shifted horizontally by ~7° from the location of the flashed target (see their Fig. 2H). Altogether, these observations in the monkey do not rule out the existence of a saccadic ipsiversive constant error and suggest that the deficits described in the present paper are not specific to the cat behaving in a head-unrestrained condition. Conversely, our proposal that cFN inactivation impairs the specification of the metrics of the impending gaze shift does not exclude the possibility of additional deficits affecting gaze shift dynamics. Indeed, in some experiments, the slope of the relationship between horizontal retinal error and horizontal gaze amplitude increased for ipsiversive responses. This gain increase tendency could, as previously suggested (Robinson et al. 1993
), result from a flawed control of the movement deceleration phase (see companion paper).
; Keller 1989
; Keller et al. 1983
; Optican and Robinson 1980
; Robinson et al. 1993
; Schweighofer et al. 1996
; Selhorst et al. 1976
; Vilis and Hore 1981
).
; Ohtsuka and Noda 1991a
). In the first study (Keller et al. 1983
), a subthreshold stimulation (i.e., with an intensity insufficient to evoke any saccade) was applied to lobules V and VI during on-going visually triggered saccades. Stimulations delivered during contraversive saccades resulted in a shortening of eye displacement that was proportional to the intended saccade size. Ohtsuka and Noda (1991a)
have extended these stimulation tests of visually directed saccades to stimulations of the oculomotor vermis (lobules VIc-VII) during the latency period of contraversive saccades. They showed a saccade shortening associated with a truncation of the presaccadic burst of cFN neurons. Noteworthy, a similar, although more subtle, saccadic amplitude modification recently was reported in man by applying transcranial magnetic stimulation over the cerebellar vermis (Hashimoto and Ohtsuka 1995
). It has been proposed that the "early burst" of cFN neurons help the initiation of simian contraversive saccades by excitation of burst neurons and inhibition of omnipause neurons of the reticular formation (Fuchs et al. 1993
; Ohtsuka and Noda 1995
). This hypothesis is compatible with the increased latency of contraversive movements during cFN inactivation in the cat (Goffart and Pélisson 1997
). However, although suprathreshold stimulation of these vermal lobules also evokes ipsiversive saccades in the cat (Cohen et al. 1965
; Gauthier and Stark 1979
), no data are available about the effect of transient vermal stimulation on visually triggered saccades, and the presence of an early burst associated with contraversive saccades is not well established. Indeed, in a systematic study of oculomotor properties of deep cerebellar nuclei neurons in the cat, Gruart and Delgado-Garcia (1994)
show that, among antidromically identified output neurons located in the caudal part of FN, the majority burst only after the initiation of contraversive saccades (type I eye position velocity neurons). Comparatively, they found only a few saccadic neurons that started their phasic discharge before contraversive saccade onset. Based on the similarity of gain reduction for both monkey saccades and cat gaze shifts after cFN inactivation, it can be hypothesized that future unit recording and stimulation studies in the cat will provide more compelling evidence for an early neuronal burst contributing to the acceleration of contraversive saccades.
; Ohtsuka et al. 1994
; Robinson et al. 1993
). A fixation offset of gaze also was observed after completion of the total orienting response. A similar, although smaller, ipsilesional offset in target fixation was reported after unilateral cFN inactivation in the head-fixed monkey (Ohtsuka et al. 1994
; Robinson et al. 1993
) and a contralesional fixation offset was described after permanent (Aschoff and Cohen 1971
) or reversible decortication of lobules VI-VII in monkey (Sato and Noda 1992
). This deficit seemingly results from the suppression (during cFN inactivation) or the disinhibition (during decortication) of fastigial tonic discharges that have been recorded in both cat (Gruart and Delgado-Garcia 1994
) and monkey (Noda et al. 1988
; Ohtsuka and Noda 1991b
). Finally, we systematically observed an ipsilesional shift in head positioning when the animal approached its mouth toward the spoon to get its reward; and for several experiments, the path followed by the animal when walking toward a goal was curved in the ipsilesional direction (Goffart and Pélisson 1994a
).
, 1997
). This dichotomy must be related somehow to the pattern of efferent projections from cFN. On the one hand, the cFN issues efferent projections toward oculomotor areas of the contralateral pontine and mesencephalic reticular formations (Carpenter and Batton 1982
; Gruart and Delgado-Garcia 1994
; Homma et al. 1995
; Noda et al. 1990
) and to the contralateral nucleus prepositus hypoglossi (McCrea and Baker 1985
). These crossed projections could mediate cFN inactivation-related deficits of contraversive gaze shifts. On the other hand, the cFN also sends bilateral projections toward both superior colliculi (Hirai et al. 1982
; Kawamura et al. 1982
; May et al. 1990
; Roldan and Reinoso-Suarez 1981
; Sugimoto et al. 1982
; but see Noda et al. 1990
) and thalamic nuclei (Jimenez-Castellanos and Reinoso-Suarez 1985
; Kyuhou and Kawaguchi 1987
; Katoh and Deura 1993
; Nakano et al. 1980
; Steriade 1995
), providing a possible substrate both for the ipsiversive gaze shift deficits and for a component of the contraversive gaze shift deficits as well.1 We discuss in the following text the possibilities of the cFN acting at the collicular level or downstream of the superior colliculus (SC).
; Freedman et al. 1996
; Munoz and Guitton 1991
; Sparks and Mays 1990
). Second, these collicular layers also are involved strongly in the control of head and body movements that contribute to shifting gaze in space (Guitton 1991
; Sparks 1986
; Stein and Meredith 1993
). Third, the deep SC has been involved in the target selection process and in keeping in memory information about the selected goal until initiation of the saccadic response (Glimcher and Sparks 1992
, 1993
; van Opstal and van Gisbergen 1990
). Through the direct or indirect tectal projections, discussed in the following text, the cFN is in a position to modify the activity of SC neurons during the "preparation phase" of the orienting saccade. Indeed, although previous unit recording studies have emphasized the late burst of cFN neurons occurring just before the end of ipsiversive saccades, a strong tonic activity also is observed in the cFN in both cat (Gruart and Delgado-Garcia 1994
; unpublished observations) and monkey (Fuchs et al. 1993
; Ohtsuka and Noda 1991b
). Suppression of this tonic activity by muscimol could alter the collicular mechanisms that keep accurate information about the saccade goal in memory, resulting in the bias of ipsiversive gaze shifts and in the fixation offset. Besides the direct fastigio-collicular projections, other indirect pathways can be involved. One such possible pathway involving the thalamic ventromedian nucleus and the frontal eye field (FEF) has been demonstrated in the cat (Kyuhou and Kawaguchi 1987
). Another indirect pathway involves a crossed cFN projection to the contralateral nucleus prepositus hypoglossi that, in turn, bilaterally projects to the SC (Hardy and Corvisier 1996
; Stechison et al. 1985
). Also, there are some indications in the literature that fixation offset could result from alteration of the SC and/or thalamus. Indeed, a tonic ipsilateral head deviation and severe head-orienting deficit have been reported in the cat after a SC lesion (Isa et al. 1992
). In the monkey, a moderate fixation offset was observed after lesions of the SC (Keating and Gooley 1988
) and of FEF (Dias et al. 1995
; Latto and Cowey 1971
). A much larger fixation error appeared when the SC lesion was combined with a lesion of either the dorsomedial thalamus area (Albano and Wurtz 1982
) or the FEF (Keating and Gooley 1988
). In these cases, however, the fixation error depended on target position relative to the head (Albano and Wurtz 1982
; Keating and Gooley 1988
; Optican 1982
). In any case, irrespective of the routes that functionally connect the cFN to the SC, this collicular hypothesis of cerebellar dysmetria leads to specific predictions regarding the pattern of collicular activity in cFN-inactivated animals. For a given target eccentricity, the population of active presaccadic neurons should not be located on the same site of the collicular map as the one encoding accurate gaze shifts during the control behavior.
; Ohtsuka and Noda 1995
), the activity of cFN neurons could normally help the initiation of contraversive saccades by excitation of burst neurons and inhibition of omnipause neurons. This hypothesis, which implicitly requires some perturbation in the dynamic feedback control (Jürgens et al. 1981
; Zee et al. 1976
), has some predictions on saccade dynamics that will be tested in the companion paper. Note that the straightness of dysmetric gaze shifts already suggests that cFN inactivation does not basically affect neurons that exclusively drive the horizontal motoneurons pool. Regarding fixation offset, the fastigio-ponto-medullary projections that terminate in the contralateral medial vestibular nuclei or prepositus hypoglossi nuclei (cat: Carleton and Carpenter 1983
; McCrea and Baker 1985
; squirrel monkey: Belknap and McCrea 1988
; see, however, Noda et al. 1990
for macaque monkey) also could be involved, as suggested by Ohtsuka and Noda (1995)
. This offset indeed was attributed to an unbalanced tonic bilateral activation of abducens neurons by prepositus hypoglossi neurons. Note further that a cFN projection toward vestibulospinal neurons in the contralateral median vestibular nucleus might account for the deviation of the head we observed in the cat. However, beside the arguments mentioned above in favor of an alternative, collicular hypothesis, this "medullar" hypothesis of fixation offset requires some adjustments. First, the absence of a postsaccadic glissade suggests that the cFN does not influence only the output of the neural integrator but also contributes to the pulse of activity that drives the eyes during the saccade. In other words, the unchanged pulse-step matching suggests a cFN influence upstream from the neural integrator, at a level where pulse and step commands have not been dissociated yet. In any case, if the dysmetria observed after muscimol cFN inactivation is the consequence of changes (through various pathways) downstream of the SC, a pronounced modification of the movement fields of tectospinal and tecto-reticulospinal neurons should be observed. Moreover, saccades evoked by electrical microstimulation of the SC should have different amplitude and direction properties after cFN inactivation.
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ACKNOWLEDGEMENTS |
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We thank Dr. Rimas Kalesnykas for improving the quality of this paper. We also gratefully acknowledge N. Boyer-Zeller for providing essential support for histology and M. L. Loyalle for animal care.
This research was supported by Institut National de la Santé et de la Recherche Médicale U94 and by Human Frontier Science Program Grant RG 58/92B. L. Goffart was supported by a fellowship from the French Ministry of Research and Technology.
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FOOTNOTES |
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Present address of L. Goffart: Division of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77025.
1
The observation made by Noda et al. (1990) in the monkey, that neurons in the fastigial oculomotor region (FOR) project only to the contralateral SC, contrasts with the other anatomic studies quoted in the preceding sections. One way to reconcile these findings would be to assume that in the monkey, fastigial neurons sending a projection to the contralateral SC are confined within a circumscribed zone of the cFN corresponding to the FOR and that some of the neurons lying ouside this zone would project to the ipsilateral SC. However, this hypothesis is not supported by the following experimental data: first, Noda et al. (1990)
reported that a large wheat germ agglutinin-horseradish peroxidase (WGA-HRP) injection involving the caudal two-thirds of the fastigial nucleus (FN) led to an anterograde labeling restricted to the contralateral SC similar to that resulting from smaller injections confined to the FOR; second, the data by May et al. (1990)
strongly suggest that retrogradely labeled fastigial neurons after HRP injections in the SC are located symetrically on both sides, in a cFN zone very similar to the FOR. Regarding the cat, there is a good agreement between studies using anterograde and/or retrograde labeling techniques in showing a bilateral projection of the cFN to the SC (Hirai et al. 1982
; Kawamura et al. 1982
; Roldan and Reinoso-Suarez 1981
; Sugimoto et al. 1982
). In summary, all studies agree on the fact that cFN neurons project to the contralateral SC and thus provide a neuroanatomic basis for a collicular involvement in the dysmetria of gaze saccades directed toward an inactivated cFN. A projection from the cFN to the ipsilateral SC also can be taken as a neuroanatomic substrate for a collicular involvement in the gaze contraversive dysmetria in the cat, but the extention of this hypothesis to the monkey is uncertain and requires further anatomic studies.
Address for reprint requests: D. Pélisson, Espace et Action, INSERM U94, 16 Ave. Doyen Lépine, 69500 Bron, France.
Received 18 February 1997; accepted in final form 8 December 1997.
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REFERENCES |
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