| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Department of Systems Neurophysiology, Graduate School of Medicine, Tokyo Medical and Dental University, Yushima, Tokyo 113-8519, Japan
Submitted 28 January 2004; accepted in final form 10 May 2004
 |
ABSTRACT |
|---|
|
50 ms after stimulation but did not affect the vector of these saccades. The suppression was stronger for ipsiversive larger saccades and contraversive smaller saccades, and saccades with initial eye positions shifted more in the saccadic direction. The most effective stimulation timing for the suppression of ipsilateral and contralateral Vsacs was 40–50 ms before saccade onset, indicating that the suppression occurred most likely in the superior colliculus and/or the paramedian pontine reticular formation. Suppression sites of bilateral saccades were located in the prearcuate gyrus facing the inferior arcuate sulcus where stimulation induced suppression at 
40 µA but usually did not evoke any saccades at 80 µA and were different from those of ipsilateral saccades where stimulation evoked saccades at 50 µA. The bilateral suppression sites contained fixation neurons. The results suggest that fixation neurons in the bilateral suppression area of the FEF may play roles in maintaining fixation by suppressing saccades in all directions. |
|
INTRODUCTION |
|---|
|
). However, recent findings suggest that a unique mechanism for visual fixation is involved if the object is not moving. Fixation neurons, which show continuous activity during fixation, have been found in the parietal cortex (Mountcastle et al. 1975), frontal eye field (FEF) (Bizzi 1968; Bruce and Goldberg 1985; Suzuki and Azuma 1977), superior colliculus (SC) (Munoz and Guitton 1991; Munoz and Wurtz 1993a), and omnipause neuron (OPN) region in the brain stem (Cohen and Henn 1972; Keller 1974; Luschei and Fuchs 1972). During steady fixation, the threshold for electrical stimulation to elicit saccades in the FEF (Goldberg et al. 1986) or SC (Sparks and Mays 1983) is elevated, suggesting that a visual fixation system may have suppressive effects on the generation of saccades. To investigate the function of these areas containing fixation neurons, microstimulation was performed in the FEF (Azuma et al. 1986; Burman and Bruce 1997), SC (Munoz and Wurtz 1993b; Paré and Guitton 1994) and OPN region (Keller 1977; King and Fuchs 1977). Stimulation of the OPN region interrupted saccades in all directions (Keller et al. 1996) and suppressed both visually guided (Vsacs) (Keller 1977; King and Fuchs 1977) and memory-guided (Msacs) saccades (Gandhi and Keller 1999). Stimulation of the most rostral part of the SC suppressed saccades in bilateral directions, with predominant suppression of ipsilateral saccades (Munoz and Wurtz 1993b; Paré and Guitton 1994), and suppressed both Vsacs and Msacs (Munoz and Wurtz 1993b). Burman and Bruce (1997) reported that stimulation of the FEF mainly suppressed contraversive saccades and effectively suppressed Msacs but not Vsacs, whereas our previous study showed that FEF stimulation suppressed the initiation of ipsiversive saccades of both Vsacs and Msacs at low thresholds (Izawa et al. 2004). Although the preceding discrepancies have not yet been resolved, these suppressive effects of FEF stimulation on the generation of saccades may contribute to maintaining fixation on a target of interest by preventing saccades to other targets in the visual field.
To understand the nature of FEF suppression, we systematically examined the suppressive effects of electrical stimulation of the FEF on saccades in monkeys and reported the unilateral suppression of ipsiversive saccades on FEF stimulation in the previous report (Izawa et al. 2004). Such suppression sites for ipsiversive saccades were distributed widely in the FEF where electrical stimulation could induce saccades at 50 µA. During this mapping of suppression sites, we also found that stimulation of a localized area in the FEF, where electrical stimulation of 80 µA usually could not evoke saccades, suppressed both Vsacs and Msacs in all directions at low intensities. In this report, we describe the characteristic features of this suppression of saccades in all directions, compare the properties of the unilateral and bilateral suppression, and discuss the functional significance of this bilateral FEF suppression area for fixation and saccadic generation.
These results have been briefly reported previously (Izawa et al. 2001).
|
|
METHODS |
|---|
|
We studied sites in the prearcuate gyrus in the classical FEF, where electrical stimulation (50 µA) evoked saccadic eye movements, and its surrounding area, where electrical stimulation of 50 µA did not evoke saccades (see Figs. 1 and 3 for recording area), when monkeys were performing fixation. Constant-current stimulation trains consisted of 40–60 monopolar cathodal pulses of 80 µA, 1-ms duration at 5-ms intervals unless stated otherwise. In this experiment, we examined the suppressive effect of stimulation of the sites in the FEF on saccades at 80 µA even though stimulation of these sites was not effective for eliciting electrically evoked saccades (Esacs).
|
|
|
|
RESULTS |
|---|
|
As reported in the previous article (Izawa et al. 2004), we systematically examined the effects of stimulation of the FEF and its vicinity in the prearcuate gyrus at a track interval of 500 µm and at depth intervals of 200 or 400 µm. At individual stimulation sites, we first determined thresholds for eliciting Esacs by microstimulation and identified a site as being within the classical FEF when stimulation elicited Esacs at 50 µA (Bruce et al. 1985). In this experiment, we examined the effects of stimulation at the same sites on Vsacs and Msacs at 80 µA even though electrical stimulation did not evoke Esacs. We usually found that stimulation of a wide area within the FEF suppressed the initiation of only ipsiversive Vsacs and Msacs as described in the previous article (Izawa et al. 2004). However, during this mapping, we found that stimulation of some sites in the FEF elicited the suppression of not only ipsiversive but also contraversive saccades. A typical example of stimulation at such a site is shown in Fig. 1. In contrast to the typical FEF sites, this stimulation site in the FEF did not evoke any Esacs at 60 µA but evoked small Esacs (2.1°) with long latencies at 70 µA and with slightly shorter latencies at 80 µA in an all-or-none manner (Fig. 1A), indicating that these stimulus intensities were not sufficiently suprathreshold for Esacs. The suppressive effects on Vsacs were examined by stimulating the same site at 80 µA. Stimulation at 15 µA completely suppressed the generation of ipsiversive Vsacs during stimulation and for 50 ms after stimulation offset (Fig. 1B, ipsi). This suppression of ipsiversive Vsacs is very similar to the unilateral suppression of Vsacs reported in the previous paper (Izawa et al. 2004). Stimulation at the same site with the same stimulus parameters also suppressed contraversive Vsacs, and suppression continued for 10–50 ms after stimulation offset (Fig. 1B, contra). Sites at which bilateral Vsacs were suppressed at thresholds of <50 µA were found in 106 of the 279 tracks examined (monkey Sui: 35/136, monkey Bell: 71/143). At such bilateral suppression sites, Esacs were not usually observed at 80 µA, but very small Esacs with the amplitude of <4° were evoked at 
70 µA at 19 stimulation sites.
Stimulus parameters for effective suppression of bilateral Vsacs.
Using a procedure identical to that which we used to examine the effects of suppression on ipsiversive Vsacs (Izawa et al. 2004), we examined the effects of varying the stimulus intensity (Fig. 1C) and the number of stimulus pulses (Fig. 2) on the suppression of bilateral Vsacs. In the example in Fig. 1C, FEF stimulation at 10 µA slightly increased the latency of ipsiversive Vsacs, and stimulation at 15 µA completely suppressed the generation of ipsiversive Vsacs for up to 50 ms after stimulation offset. At the same stimulation site, contraversive Vsacs were also suppressed in some trials at 10 µA. With stimulus intensities of 15 and 20 µA, the suppression of contraversive Vsacs became strong and persisted for 50 ms after the offset of stimulation. However, the latencies of contraversive Vsacs fluctuated slightly even when suppression occurred with stronger stimulus intensities. This phenomenon was not observed for the suppression of ipsiversive Vsacs but was commonly observed for the suppression of contraversive Vsacs. The threshold for suppression was defined as the least current required to produce an increase in the saccade latency that was >2 SDs of the control saccade latency. The mean ± SD of the latency of control Vsacs were 181 ± 24 ms in monkey Sui (n = 261) and 188 ± 19 ms in monkey Bell (n = 245). Based on this criterion, we determined that the threshold for the suppression of both ipsiversive and contraversive Vsacs was 10 µA in the example in Fig. 1C, The thresholds for suppression were compared between ipsi- and contraversive Vsacs at all 106 sites at which the latencies of bilateral Vsacs were significantly increased by stimulation at <50 µA (Fig. 1D). The results showed that there was no significant difference in the suppression threshold between ipsi- and contraversive Vsacs (Wilcoxon signed-ranks test, P = 0.92, n = 106). A comparison of control and stimulation (20 µA) trials showed that the amplitudes of ipsiversive (U test, P = 0.53) and contraversive Vsacs (U test, P = 0.18) and the directions of ipsiversive (U test, P = 0.11) and contraversive Vsacs (U test, P = 0.66) were not significantly different (Fig. 1C). Accordingly, in contrast to the suppressed initiation of Vsacs, neither the amplitudes nor the directions of ipsiversive and contraversive Vsacs were affected by stimulation, indicating that the accuracy of Vsacs was maintained.
|
LOCATION OF BILATERAL SUPPRESSION SITES DEFINED BY DEPTH-THRESHOLD CURVES FOR ELICITING ESACS AND SUPPRESSING VSACS AND NEURONAL ACTIVITY OF FIXATION NEURONS.
To identify the location of bilateral suppression sites in the FEF, we systematically examined depth-thresholds for suppressing bilateral Vsacs in individual tracks. Figure 3C shows a typical example of depth-threshold curves for eliciting Esacs (dotted lines), suppressing ipsiversive Vsacs (thin solid line) and contraversive Vsacs (thick solid line) at a cortical site indicated by an arrow in Fig. 3A. Near the surface of the FEF, Esacs were evoked at 40 µA, and their thresholds decreased to a minimum at depths of 1,200 and 1,600 µm. The thresholds then gradually increased as the electrode was advanced to 2,400 µm deep. Suppression of ipsiversive Vsacs also occurred at the same depths as Esacs, but the thresholds for suppression were lower by 3–17 µA. At 2,800–4,000 µm, Esacs could not be evoked even at 80 µA, but ipsiversive Vsacs were still suppressed at 24 µA. In addition, the suppression of contraversive Vsacs appeared at 36 µA at 2,800 µm, and as the depth increased, the threshold for this contralateral suppression decreased and reached the minimum of 24 µA at 4,000 µm. At 4,400–5,200 µm, Esacs again appeared. As in this example, the bilateral suppression sites were usually found deeper than the unilateral suppression sites at the superficial depths along each track and were adjacent to or sometimes within the marginal area for evoking Esacs at 50 µA. At the depths where the bilateral suppression occurred, background activity was very high in every track (Fig. 3B), indicating that such bilateral suppression sites were located in the cerebral gray matter. In the bilateral suppression sites, we recorded single units and examined their neural activity in relation to visual stimuli, visual fixation, and saccadic eye movements. This study is still going on, but so far we have encountered many fixation neurons. Figure 3D shows a typical example of activity of a neuron observed at such a bilateral suppression site. This neuron discharged during fixation, so that it was classified as a fixation neuron (Suzuki and Azuma 1977). Even when the fixation spot disappeared for 400 ms during steady fixation, this neuron did not decrease its activity, indicating that this activity is not foveal visual-related. The distribution of bilateral suppression sites (double circles) and ipsilateral suppression sites (single circles and double circles) in three planes of the mapping was shown in Fig. 3A. The bilateral suppression sites were distributed at the caudal part of the arcuate gyrus facing the inferior arcuate sulcus and were adjacent to or involved in the classical FEF where Esacs were evoked at low intensities 50 µA.
SUPPRESSIVE EFFECTS OF FEF STIMULATION ON VSACS WITH DIFFERENT DIRECTIONS. To determine the effective direction of suppression, we examined the suppressive effects of FEF stimulation on Vsacs by changing the direction of Vsacs to one of eight directions with their amplitude (10°) kept constant. The strong suppression of both ipsiversive (Fig. 4A, a–c) and contraversive (Fig. 4A, e–g) Vsacs in any direction was observed in all trials. Purely vertical upward (Fig. 4Ah) and downward Vsacs (Fig. 4Ad) were also sufficiently suppressed by stimulation. Latencies of delayed Vsacs in eight directions indicated that stimulation of this FEF site significantly suppressed Vsacs (Friedman ANOVA, P < 0.0001; Fig. 4B). When the latency difference between Vsacs in control and stimulation trials was used as an index of the strength of the suppression in each direction (dotted line in Fig. 4B), the latency differences were not significantly different in eight directions (Kruskal-Wallis ANOVA, P = 0.43), indicating that this suppression was uniform in all directions. Similar results were obtained at all 20 bilateral suppression sites examined. Stimulation of this bilateral suppression site delayed both the horizontal and vertical components of individual Vsacs in parallel (Fig. 4A), and the correlation between the latencies of horizontal and vertical components of individual oblique Vsacs was significant (y = 1.05x – 17.46, r = 0.97, P < 0.001, n = 24). The slope and intercept of the regression line was not significantly different from 1 and 0 (t-test, P = 0.34 and 0.36, respectively), indicating that both components of Vsacs were synchronously suppressed by stimulation.
|
18 µA). Stimulation at 24 µA suppressed 10–20° Vsacs in some trials for up to 50 ms after stimulation offset, and larger saccadic amplitudes were associated with a greater delay in saccadic onset (Fig. 5B, · · · ). At 30 µA, ipsiversive Vsacs of all amplitudes were completely suppressed for up to 50 ms after stimulation offset. In stimulation trials for contraversive Vsacs, the latencies of Vsacs increased as the stimulus intensities were increased (Friedman ANOVA, P < 0.0001; Steel method, P < 0.05 for 24 µA). Stimulation at 24 µA strongly suppressed 5° Vsacs and weakly 10° and 15° Vsacs, so that smaller saccadic amplitudes were associated with a greater delay in saccadic onset (Fig. 5B, · · · ). Stimulation at 30 µA suppressed contraversive Vsacs of all amplitudes but less constantly those with larger amplitudes (Fig. 5B). Similar results were obtained at the other nine bilateral suppression sites tested: larger ipsiversive and smaller contraversive Vsacs were suppressed at weaker stimulus intensities, although both ipsiversive and contraversive Vsacs were strongly suppressed at sufficiently strong stimulus intensities.
|
15° were significantly longer than those of Vsacs with the central initial eye position (Steel method, P < 0.05). In stimulation trials for ipsiversive Vsacs (Fig. 6, A and C), Vsacs were more delayed with the initial eye position shifted toward the Vsac direction, and an increase of Vsac latencies was saturated as the stimulus intensity was increased (Friedman ANOVA, P < 0.0001; Steel method, P < 0.05 for 35 and 42 µA). For contraversive Vsacs, stimulation of the same site completely suppressed contraversive Vsacs with the initial eye position shifted from the center to the contralateral side (R), but the delay of contraversive Vsacs with the initial eye position shifted to the ipsilateral side (L) tended to decrease (Fig. 6, B and D). Because a similar result was obtained at the other bilateral suppression site examined, it was concluded that the FEF suppression of both ipsiversive and contraversive Vsacs increased as the initial eye position shifted toward the direction of Vsacs.
|
140 ms, the initiation of ipsiversive Vsacs was delayed in almost all trials for up to 50 ms after stimulation offset. This time course of suppression was very similar to that observed for unilateral suppression sites in the FEF (Izawa et al. 2004). The suppression of contraversive Vsacs was induced by stimulation of the same site with the same stimulus parameters (Fig. 7Ba). The median latency of control contraversive Vsacs without stimulation was 171 ms. For contraversive Vsacs, stimulation at 150 ms increased the latencies of some Vsacs relative to those in control trials by 70 ms, and complete suppression, which continued for up to 60 ms after stimulus offset, first appeared at 145 ms (Fig. 7Ba). A further decrease in interval increased the frequency of such trials with complete suppression, and complete suppression was observed in most trials at intervals of 135 ms.
|
Suppressive effects of FEF stimulation on bilateral Msacs
We compared the suppressive effects of stimulation of the bilateral suppression area on Vsacs and Msacs because different neural pathways might be responsible for the generation of Vsacs and Msacs. We first identified a bilateral suppression site in the FEF for Vsacs. In the example in Fig. 8A, stimulation at 20 µA delayed the generation of bilateral Vsacs, and stimulation at 40 µA completely suppressed this generation. When the same stimulation was applied at the offset of the central fixation point, which was a cue for the initiation of Msacs, bilateral Msacs were delayed at 20 µA and completely suppressed during stimulation at 40 µA (Fig. 8B). The thresholds for the suppression of bilateral Vsacs and Msacs were 20 µA at this stimulation site. As in this example, the thresholds for the suppression of both ipsi- and contraversive saccades were usually very similar for Msacs (y = 0.87x + 2.27, r = 0.84, P < 0.01, n = 8; Fig. 8D) as well as for Vsacs (y = 0.90x +3.04, r = 0.87, P < 0.01, n = 8; Fig. 8C), and the thresholds for the suppression of both Vsacs and Msacs were also very similar for ipsiversive (y = 0.84x + 4.72, r = 0.83, P < 0.01, n = 8; Fig. 8E) and contraversive saccades (y = 0.88x +1.56, r = 0.85, P < 0.01, n = 8; Fig. 8F) at identical stimulation sites. In addition, the depth-threshold curves for the suppression of Msacs and Vsacs were usually similar along individual penetration tracks (not shown). However, at some stimulation sites, these thresholds were slightly different from each other. Among eight stimulation sites tested, the threshold difference for the suppression of Vsacs and Msacs was 10 µA for ipsiversive saccades (n = 7; identical, 6; lower for Vsacs, 1) and contraversive saccades (n = 7; identical, 5; lower for Vsacs, 1; lower for Msacs, 1). The threshold difference was between 10 and 20 µA for ipsiversive saccades (n = 1) and contraversive saccades (n = 1). In these two cases with a large threshold difference, the thresholds for the suppression of Msacs were much lower than those for the suppression of Vsacs.
|
|
130 ms, and the latencies of Msacs recovered to the level in the control with a time course that depended on the train duration (Fig. 10B). This time course of the suppression of Msacs was very similar to that for the suppression of Vsacs. Because the median latency of ipsiversive Msacs was 170 ms, the latest effective timing corresponds to 40 ms before Msac onset. The period from –200 to –1,000 ms in the Msac task corresponded to the memory period of the target position, during which stimulation applied did not affect the suppression of the generation of Msacs. However, during the period from –150 ms or later, the latencies of Msacs gradually increased significantly (Kruskal-Wallis ANOVA, P < 0.0001; Steel method, P < 0.05), which means that the earliest effective train onset of 295-ms duration should be between –200 and –150 ms. Therefore the earliest effective timing was between 95 (–200 ms) and 145 ms (–150 ms) after the disappearance of the fixation point (see Fig. 7, Ab and Bb).
|
It is known that a saccade is followed by a refractory period for a saccade in the same direction as the preceding saccade (Robinson and Fuchs 1969). Therefore it is possible that stimulation of a bilateral suppression site evokes unnoticeable Esacs whose refractory period might cause the suppression of subsequent contraversive Vsacs. The amplitude of Esacs depends on the initial eye position even when they are evoked by stimulation with identical stimulus parameters. Figure 11A shows an example of the effect of changing the initial eye position on the amplitude of contraversive Esacs. Stimulation of a classical left FEF site produced 19.8° Esacs with only a horizontal component from the center initial eye position. As the initial eye position was shifted toward the direction opposite the Esacs (leftward), the amplitude of Esacs gradually increased and became 30.2° at an initial eye position of left 20°. As the initial eye position was shifted toward the direction of the Esacs (rightward), the amplitude of Esacs gradually decreased and became 6.0° at an initial eye position of right 20° (Fig. 11A). As in this example, the amplitude of Esacs greatly increased as the initial eye position changed toward the direction opposite the Esacs. Taking advantage of this property, we examined the possibility that stimulation of a bilateral suppression site might produce tiny Esacs with an amplitude of <0.3°, which was below the sensitivity of our eye measuring system. Stimulation of a bilateral suppression site suppressed bilateral Vsacs at a threshold of 24 µA but did not evoke any identifiable Esacs at the central fixation position at 42 µA. Even though the initial eye position was shifted to the direction opposite the Esacs, Esacs could not be identified with our recording system (Fig. 11B). This result supports the interpretation that the suppression of contraversive Vsacs and Msacs cannot be attributed to the refractory period of tiny contraversive Esacs.
|
). Accordingly, we examined the effects of preceding Vsacs on Esacs. Changes in the latency and amplitude of Esacs were analyzed by varying the onset of Vsacs relative to the stimulation onset for Esacs (Fig. 12A). The shortest period for evoking Esacs after the onset of Vsacs, namely the refractory period for Vsacs, was 170 ms. The duration of the refractory period of Vsacs depends on the amplitude and direction of the Vsacs. The effects of the amplitude (Fig. 12B) and direction (Fig. 12C) of preceding Vsacs on the latency of Esacs were examined by varying the Vsac amplitude with a fixed direction and the Vsac direction with a fixed amplitude, respectively. Because the latency of Esacs varied depending on the initial eye position, we measured, as a control latency for the different eye positions, the latency of Esacs evoked by stimulation at 600 ms after Vsac onset. We then used the latency difference between Esacs evoked by stimulation at the onset of Vsacs and at 600 ms after Vsacs as a measure of the latency delay caused by the refractoriness of Vsacs with different amplitudes or directions. Generally, Vsacs greater than Esacs (15.7° in this case) had a stronger suppressive effect on the latency of Esacs (Fig. 12B). As to the effect of the Vsac direction on Esac latency, the suppressive effect of preceding Vsacs on the latency of Esacs was strongest when the Vsacs were in the same direction as the Esacs (Fig. 12Ce) and was weaker as the Vsac direction differed from the direction of the Esacs. The influence of preceding Vsacs on the vector of Esacs was different between horizontal and vertical components of saccades. As shown in Fig. 12, B and C, the vector of Esacs turned toward the vicinity of the endpoint of control Esacs with a central initial eye position. This phenomenon was similar to the influence of spontaneous saccades on Esacs reported by Schlag and Schlag-Rey (1987). In addition, the results shown in Fig. 12B, including reversal in direction of the saccades, were similar to the effects of preceding Vsacs on the amplitude of SC-evoked Esacs (Nichols and Sparks 1995). However, the present interaction between Vsacs and Esacs appeared to occur during and after the resettable integrator's discharge period, which was estimated by Nichols and Sparks (1995). These previous studies reported the effects of preceding Vsacs on the amplitude and direction of Esacs but did not systematically analyze the influence of preceding Vsacs on Esac latencies. The present results showed that the effects of refractoriness on saccades were different from those of FEF suppression on Vsacs in several ways. First, refractoriness following Vsacs exerted a stronger suppressive effect on the latency of Esacs that were smaller than the preceding Vsacs. Accordingly, if stimulation of a bilateral suppression site evoked tiny Esacs, the suppression caused by the refractoriness of such tiny Esacs should produce a stronger suppression of smaller Vsacs. However, this is contrary to the present finding that contraversive Vsacs with an amplitude larger than unidentifiable tiny Esacs were strongly suppressed. Second, refractoriness following Vsacs exerted a stronger suppressive effect on the latency of Esacs with a direction similar to that of the preceding Vsacs. In contrast, the suppression of contraversive Vsacs by stimulation of a bilateral suppression site was typically independent of the direction of Vsacs. Third, refractoriness following Vsacs strongly affected the vector of Esacs, whereas the vector of contraversive Vsacs was little influenced by stimulation of a bilateral suppression site. Therefore these findings exclude the possibility that the suppression of contraversive Vsacs might be caused by refractoriness following unidentifiable tiny Esacs.
|
|
|
DISCUSSION |
|---|
|
40 µA). The thresholds for suppression were almost the same for both Vsacs and Msacs and also for ipsi- and contraversive saccades. We reported previously the suppression of only ipsiversive Vsacs and Msacs by stimulation of the FEF (Izawa et al. 2004). Electrical stimulation of this unilateral suppression area easily evoked saccades at 50 µA. Therefore the bilateral suppression area was different from this unilateral suppression area in that electrical stimulation did not evoke Esacs at 50 µA. Unilateral suppression sites were distributed widely throughout the classical FEF (Izawa et al. 2004), whereas bilateral suppression sites were localized in the caudal part of the arcuate gyrus facing the inferior arcuate sulcus and deeper than sites for the unilateral suppression. This bilateral suppression area did not correspond to the central area of the classical FEF but may belong to a subregion of the classical FEF where electrical stimulation produces small Esacs and visual neurons there have small receptive fields near the fovea (Azuma et al. 1988) or may be adjacent to it. The exact distribution of bilateral suppression sites in and around the FEF must be determined by the histological reconstruction of stimulation tracks. If this suppression area is related to ocular fixation, this area may be regarded as the subregion of the FEF that should be defined in a broader sense as an area in the arcuate gyrus related to various kinds of eye movements including fixation.
Burman and Bruce (1997) reported that electrical stimulation of the FEF most effectively suppressed Msacs directed contraversive to the stimulated hemisphere. There are several differences between the present suppression and that of Burman and Bruce (1997): the suppression occurred on the initiation of both Vsacs and Msacs and thresholds for suppressing them were almost equal, both ipsi- and contraversive saccades were almost equally suppressed and thresholds for suppression were almost equal for saccades in both directions, and the vectors of Vsacs and Msacs were not usually affected. At some sites in the bilateral suppression area, the suppression thresholds for ipsiversive saccades were higher than those for contraversive saccades. Accordingly, stimulation of such sites appeared to suppress only contraversive saccades at subthreshold for the suppression of ipsiversive saccades. At some of such sites, stimulation evoked ipsiversive slow eye movements, most likely smooth pursuit eye movements (Bruce et al. 1985). If these sites are stimulated, reciprocal inhibition for horizontal smooth pursuits may result in the suppression of contraversive saccades and the facilitation of ipsiversive saccades at the motoneuronal level. Actually, the suppressive effects of FEF stimulation reported by Burman and Bruce (1997) were mainly on contraversive Msacs, and ipsiversive Msacs were facilitated in a reciprocal fashion. Furthermore, the preceding interpretation is consistent with their report that their stimulation sites were mainly located near the spur of the arcuate sulcus (Burman and Bruce 1997) similar to the smooth pursuit subregion of the FEF (MacAvoy et al. 1991). The present bilateral suppression area was located more laterally and was clearly different from their suppression area.
The accuracy of bilateral Vsacs and Msacs was not affected by stimulation of the bilateral suppression sites, although some Msacs tended to be hypometric at some sites. Therefore the results suggest that stimulation of the bilateral suppression sites may suppress the saccadic trigger system for ipsi- and contraversive saccades but does not affect the metric controlling system (Fuchs et al. 1985; Scudder et al. 2002; Sparks et al. 1987). The latest and earliest effective stimulus timings for the suppression were 140 and 135 ms for ipsiversive Vsacs (40 and 45 ms before the saccade onset, respectively), and 135 and 130 ms for contraversive Vsacs (45 and 50 ms before the saccade onset, respectively) from visual target onset, respectively, and the time course of this suppression was similar to the time course after stimulation of the unilateral suppression area. Therefore the neural mechanism responsible for suppression of ipsiversive saccades may be common to both the bi- and unilateral suppression sites in the FEF. Based on the stimulus timings for the bilateral suppression, FEF stimulation are most likely to suppress the SC and/or paramedian pontine reticular formation (PPRF) as discussed for the unilateral suppression in the previous paper (Izawa et al. 2004).
The effects of stimulating the bilateral suppression sites were usually similar for both Vsacs and Msacs in terms of thresholds and directionality of suppression. These findings suggest that the neural mechanism for the present bilateral suppression is different from that for the previously reported unilateral suppression (Izawa et al. 2004), and a single neural mechanism may be responsible for the suppression of ipsi- and contraversive saccades. Stimulation of the OPN area interrupts saccades in any direction (Keller 1977; Keller et al. 1996; King and Fuchs 1977). Therefore the present omnidirectional suppression of Vsacs and Msacs may be conveyed via OPNs if neurons in the FEF project to OPNs directly (Stanton et al. 1988) or indirectly via the SC (Gandhi and Keller 1997; Langer and Kaneko 1990; Paré and Guitton 1994; Raybourn and Keller 1977). The preceding finding of the omnidirectional interruption of saccades by stimulation of the OPN area (Keller et al. 1996) does not necessarily mean that single OPNs project bilaterally. OPNs projecting ipsi- or contralaterally might be intermingled on one side. If OPNs project to contralateral excitatory burst neurons (EBNs), stimulation of the midline area will activate bilateral OPNs and result in either the equal or asymmetric suppression of bilateral saccades. In fact, the present suppressive effect was different in some respects for contra- and ipsiversive Vsacs. First, ipsiversive Vsacs were almost totally suppressed during FEF stimulation, whereas contraversive Vsacs were not suppressed in all trials with the same stimulation. Second, the suppression threshold was lower for ipsiversive Vsacs with larger amplitudes and contraversive Vsacs with smaller amplitudes. These findings suggest that the neural mechanism for the suppression of contraversive Vsacs at least partly differs from that for the suppression of ipsiversive Vsacs. In this regard, the bilateral suppression area might be a part of the unilateral suppression area and contain an additional neural mechanism for the suppression of contraversive saccades. The ipsilateral suppression of the bilateral suppression area should not be ascribed to reciprocal inhibition of Esacs because stimulation did not evoke Esacs at 80 µA but induced suppression at 40 µA. Regarding the suppression of contraversive saccades, we were able to exclude the possibility of interaction between Vsacs and refractoriness of tiny Esacs (Fig. 11). Using an optical imaging method, Seidemann et al. (2002) reported that electrical stimulation of the FEF evoked hyperpolarization after depolarization in the stimulated FEF. Therefore this inhibition in the stimulated FEF might be partially responsible for the suppression of contraversive saccades. The rostral SC receives input from the FEF (Segraves and Goldberg 1987), and the SC has intracollicular inhibitory connections (Munoz and Istvan 1998). FEF stimulation inhibits saccade-related neurons in the ipsilateral SC (Schlag-Rey et al. 1992) or may activate neurons in the substantia nigra reticulata via the subthalamus (Carpenter et al. 1968; Kitano et al. 1998; Künzle and Akert 1977) and thereby inhibit SC output neurons. Stimulation of the rostral pole of the SC suppresses bilateral saccades (Gandhi and Keller 1999; Munoz and Wurtz 1993b; Paré and Guitton 1994), although the functional contribution of collicular projection to OPNs for fixation is controversial (Gandhi and Keller 1999; Kaneko 1996). If the rostral SC receives input from the present bilateral suppression area, this pathway will produce suppression of bilateral saccades.
Recently the FEF has been shown to contain neurons that are related to smooth pursuit eye movement (Bruce et al. 1985; Tanaka and Fukushima 1998; Tanaka and Lisberger 2002) and convergence (Fukushima et al. 2002; Gamlin and Yoon 2000). In addition, the FEF also contains neurons that are related to fixation (Bizzi 1968; Bruce and Goldberg 1985; Suzuki and Azuma 1977). The act of fixation makes the brain stem saccadic system less susceptible to the effects of extraneous commands to make a saccade (Goldberg et al. 1986). Actually, the present bilateral suppression area of the FEF contained fixation neurons and therefore may be responsible for controlling fixation and modulating other eye-movement systems. In humans, it has been reported that patients with a unilateral frontal lobe lesion have difficulty in suppressing reflexive saccades to both sides in an anti-saccade task (Guitton et al. 1985). This finding may be related to dysfunction of the present bilateral suppression area. Conversely, abnormal function of the bilateral suppression area might explain the clinical disorder known as spasm of fixation, which causes an impaired initiation of saccades in the presence of a fixation target (Johnston et al. 1992).
Suppression of bilateral Vsacs increased when the initial eye position was shifted toward the direction of Vsacs. Because the initial position of the eyes in the orbits affects the ratio of the eye and head contribution to the large gaze shift (Freedman and Sparks 1997), this mechanism may also be involved in the present initial eye position effects that may contribute to eye and head coordination. Shifting the initial eye position toward the direction of Vsac induces motoneuronal depolarization, which might inactivate sodium currents and low-threshold calcium currents (Gueritaud 1994; Russier et al. 2003) and delay spike initiation. In addition, a certain class of pause neurons whose activity is correlated with eye position has higher discharge rates with a more ipsilateral eye position (Keller 1974). Therefore these pause neurons may cause the stronger suppression of centrifugal Vsacs if they project to ipsilateral EBNs. During fixation, this mechanism may contribute to eye centering (Bender 1955).
Larger ipsiversive Vsacs were suppressed at lower thresholds by FEF stimulation. This finding suggests that fixation neurons at the bilateral suppression sites may decrease their activity during smooth pursuits so that only small catch-up saccades are allowed to occur during ipsiversive smooth pursuits to follow a target accurately. This decrease in activity of the fixation neurons may account for decrease in the activity of OPNs during smooth pursuit (Missal and Keller 2002). On the other hand, smaller contraversive Vsacs were suppressed at lower thresholds by FEF stimulation. This property may assure the maintenance of fixation by suppressing the generation of small saccades to distracting objects near the fixation point, although it may help generate saccades to change a line of sight to targets that appear in the periphery of a contralateral visual field. To further understand the functional role of the bilateral suppression area in the FEF, further studies are required to analyze activity of neurons in the FEF and the SC in relation to fixation and various kinds of eye movements.
|
|
GRANTS |
|---|
|
|
|
ACKNOWLEDGMENTS |
|---|
|
|
|
FOOTNOTES |
|---|
Address for reprint requests and other correspondence: Y. Shinoda, Dept. of Systems Neurophysiology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan (E-mail: yshinoda.phy1{at}med.tmd.ac.jp).
|
|
REFERENCES |
|---|
|
Azuma M, Nakayama H, and Suzuki H. Suppression of visually triggered saccades by electrical stimulation of the monkey frontal eye field (Abstract). J Physiol Soc Jpn 48: 266, 1986.
Bender MB. The eye-centering system. AMA Arch Neurol Psychiatry 73: 685–699, 1955.[Medline]
Bizzi E. Discharge of frontal eye field neurons during saccadic and following eye movements in unanesthetized monkeys. Exp Brain Res 6: 69–80, 1968.[Web of Science][Medline]
Bruce CJ and Goldberg ME. Primate frontal eye fields. I. Single neurons discharging before saccades. J Neurophysiol 53: 603–635, 1985.
Bruce CJ, Goldberg ME, Bushnell MC, and Stanton GB. Primate frontal eye fields. II. Physiological and anatomical correlates of electrically evoked eye movements. J Neurophysiol 54: 714–734, 1985.
Burman DD and Bruce CJ. Suppression of task-related saccades by electrical stimulation in the primate's frontal eye field. J Neurophysiol 77: 2252–2267, 1997.
Carpenter MB, Fraser RAR, and Shriver JE. The organization of the pallidosubthalamic fibers in the monkey. Brain Res 11: 522–559, 1968.[CrossRef][Medline]
Cohen B and Henn V. Unit activity in the pontine reticular formation associated with eye movements. Brain Res 46: 403–410, 1972.[CrossRef][Web of Science][Medline]
Freedman EG and Sparks DL. Eye-head coordination during head-unrestrained gaze shifts in rhesus monkeys. J Neurophysiol 77: 2328–2348, 1997.
Fuchs AF, Kaneko CRS, and Scudder CA. Brain stem control of saccadic eye movements. Annu Rev Neurosci 8: 307–337, 1985.[CrossRef][Web of Science][Medline]
Fukushima K, Yamanobe T, Shinmei Y, Fukushima J, Kurkin S, and Peterson BW. Coding of smooth eye movements in three-dimensional space by frontal cortex. Nature 419: 157–162, 2002.[CrossRef][Medline]
Gamlin PD and Yoon K. An area for vergence eye movement in primate frontal cortex. Nature 407: 1003–1007, 2000.[CrossRef][Medline]
Gandhi NJ and Keller EL. Spatial distribution and discharge characteristics of superior colliculus neurons antidromically activated from the omnipause region in monkey. J Neurophysiol 78: 2221–2225, 1997.
Gandhi NJ and Keller EL. Comparison of saccades perturbed by stimulation of the rostral superior colliculus, the caudal superior colliculus, and the omnipause neuron region. J Neurophysiol 82: 3236–3253, 1999.
Goldberg ME, Bushnell MC, and Bruce CJ. The effect of attentive fixation on eye movements evoked by electrical stimulation of the frontal eye fields. Exp Brain Res 61: 579–584, 1986.[CrossRef][Web of Science][Medline]
Gueritaud JP. Barium-induced bistability in rat ocular motoneurones in vitro. Neurosci Lett 170: 158–162, 1994.[CrossRef][Web of Science][Medline]
Guitton D, Buchtel HA, and Douglas RM. Frontal lobe lesions in man cause difficulties in suppressing reflexive glances and in generating goal-directed saccades. Exp Brain Res 58: 455–472, 1985.[Web of Science][Medline]
Izawa Y, Suzuki H, and Shinoda Y. Suppression of saccades by stimulation of the frontal eye field (Abstract). Jpn J Physiol 51, Suppl: S19, 2001.
Izawa Y, Suzuki H, and Shinoda Y. Suppression of visually and memory-guided saccades induced by electrical stimulation of the monkey frontal eye field. I. Suppression of ispilateral saccades. J Neurophysiol 92: 2248–2260, 2004.
Johnston JL, Sharpe JA, and Morrow MJ. Spasm of fixation: a quantitative study. J Neurol Sci 107: 166–171, 1992.[CrossRef][Web of Science][Medline]
Kaneko CRS. Effect of ibotenic acid lesions of the omnipause neurons on saccadic eye movements in rhesus macaques. J Neurophysiol 75: 2229–2242, 1996.
Keller EL. Participation of medial pontine reticular formation in eye movement generation in monkey. J Neurophysiol 37: 316–332, 1974.
Keller EL. Control of saccadic eye movements by midline brain stem neurons. In: Control of Gaze by Brain Stem Neurons, edited by Baker R and Berthoz A. Amsterdam: Elsevier, 1977, p. 327–336.
Keller EL, Gandhi NJ, and Shieh JM. Endpoint accuracy in saccades interrupted by stimulation in the omnipause region in monkey. Vis Neurosci 13: 1059–1067, 1996.[Web of Science][Medline]
King WM and Fuchs AF. Neuronal activity in the mesencephalon related to vertical eye movements. In: Control of Gaze by Brain Stem Neurons, edited by Baker R and Berthoz A. Amsterdam: Elsevier, 1977, p. 319–326.
Kitano H, Tanibuchi I, and Jinnai K. The distribution of neurons in the substantia nigra pars reticulata with input from the motor, premotor and prefrontal areas of the cerebral cortex in monkeys. Brain Res 784: 228–238, 1998.[CrossRef][Web of Science][Medline]
Künzle H and Akert K. Efferent connections of cortical area 8 (frontal eye field) in Macaca fascicularis. A reinvestigation using the autoradiographic technique. J Comp Neurol 173: 147–164, 1977.[CrossRef][Web of Science][Medline]
Langer TP and Kaneko CRS. Brain stem afferents to the oculomotor omnipause neurons in monkey. J Comp Neurol 295: 413–427, 1990.[CrossRef][Web of Science][Medline]
Luschei ES and Fuchs AF. Activity of brain stem neurons during eye movements of alert monkeys. J Neurophysiol 35: 445–461, 1972.
MacAvoy MG, Gottlieb JP, and Bruce CJ. Smooth-pursuit eye movement representation in the primate frontal eye field. Cereb Cortex 1: 95–102, 1991.
Missal M and Keller EL. Common inhibitory mechanism for saccades and smooth-pursuit eye movements. J Neurophysiol 88: 1880–1892, 2002.
Mountcastle VB, Lynch JC, Georgopoulos A, Sakata H, and Acuna C. Posterior parietal association cortex of the monkey: command functions for operations within extrapersonal space. J Neurophysiol 38: 871–908, 1975.
Munoz DP and Guitton D. Control of orienting gaze shifts by the tectoreticulospinal system in the head-free cat. II. Sustained discharges during motor preparation and fixation. J Neurophysiol 66: 1624–1641, 1991.
Munoz DP and Istvan PJ. Lateral inhibitory interactions in the intermediate layers of the monkey superior colliculus. J Neurophysiol 79: 1193–1209, 1998.
Munoz DP and Wurtz RH. Fixation cells in monkey superior colliculus. I. Characteristics of cell discharge. J Neurophysiol 70: 559–575, 1993a.
Munoz DP and Wurtz RH. Fixation cells in monkey superior colliculus. II. Reversible activation and deactivation. J Neurophysiol 70: 576–589, 1993b.
Nichols MJ and Sparks DL. Nonstationary properties of the saccadic system: new constraints on models of saccadic control. J Neurophysiol 73: 431–435, 1995.
Paré M and Guitton D. The fixation area of the cat superior colliculus: effects of electrical stimulation and direct connection with brain stem omnipause neurons. Exp Brain Res 101: 109–122, 1994.[Web of Science][Medline]
Raybourn MS and Keller EL. Colliculoreticular organization in primate oculomotor system. J Neurophysiol 40: 861–878, 1977.
Robinson DA and Fuchs AF. Eye movements evoked by stimulation of frontal eye fields. J Neurophysiol 32: 637–648, 1969.
Russier M, Carlier E, Ankri N, Fronzaroli L, and Debanne D. A-, T-, and H-type currents shape intrinsic firing of developing rat abducens motoneurons. J Physiol 549: 21–36, 2003.
Schlag J and Schlag-Rey M. Does microstimulation evoke fixed-vector saccades by generating their vector or by specifying their goal? Exp Brain Res 68: 442–444, 1987.[Web of Science][Medline]
Schlag-Rey M, Schlag J, and Dassonville P. How the frontal eye field can impose a saccade goal on superior colliculus neurons. J Neurophysiol 67: 1003–1005, 1992.
Scudder CA, Kaneko CRS, and Fuchs AF. The brain stem burst generator for saccadic eye movements. Exp Brain Res 142: 439–462, 2002.[CrossRef][Web of Science][Medline]
Segraves MA and Goldberg ME. Functional properties of corticotectal neurons in the monkey's frontal eye field. J Neurophysiol 58: 1387–1419, 1987.
Seidemann E, Arieli A, Grinvald A, and Slovin H. Dynamics of depolarization and hyperpolarization in the frontal cortex and saccade goal. Science 295: 862–865, 2002.
Sparks DL and Mays LE. Spatial localization of saccade targets. I. Compensation for stimulation-induced perturbations in eye position. J Neurophysiol 49: 45–63, 1983.
Sparks DL, Mays LE, and Porter JD. Eye movements induced by pontine stimulation: interaction with visually triggered saccades. J Neurophysiol 58: 300–318, 1987.
Stanton GB, Goldberg ME, and Bruce CJ. Frontal eye field efferents in the macaque monkey. II. Topography of terminal fields in midbrain and pons. J Comp Neurol 271: 493–506, 1988.[CrossRef][Web of Science][Medline]
Suzuki H and Azuma M. Prefrontal neuronal activity during gazing at a light spot in the monkey. Brain Res 126: 497–508, 1977.[CrossRef][Web of Science][Medline]
Tanaka M and Fukushima K. Neuronal responses related to smooth pursuit eye movements in the periarcuate cortical area of monkeys. J Neurophysiol 80: 28–47, 1998.
Tanaka M and Lisberger SG. Role of arcuate frontal cortex of monkeys in smooth pursuit eye movements. I. Basic response properties to retinal image motion and position. J Neurophysiol 87: 2684–2699, 2002.
Yabus AL. Eye Movements and Vision. New York: Plenum, 1967.
This article has been cited by other articles:
|
|
 |
|
  Y. Izawa, H. Suzuki, and Y. Shinoda Response Properties of Fixation Neurons and Their Location in the Frontal Eye Field in the Monkey J Neurophysiol, October 1, 2009; 102(4): 2410 - 2422. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. McPeek Incomplete Suppression of Distractor-Related Activity in the Frontal Eye Field Results in Curved Saccades J Neurophysiol, November 1, 2006; 96(5): 2699 - 2711. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Isoda Context-Dependent Stimulation Effects on Saccade Initiation in the Presupplementary Motor Area of the Monkey J Neurophysiol, May 1, 2005; 93(5): 3016 - 3022. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Sugiuchi, Y. Izawa, M. Takahashi, J. Na, and Y. Shinoda Physiological Characterization of Synaptic Inputs to Inhibitory Burst Neurons From the Rostral and Caudal Superior Colliculus J Neurophysiol, February 1, 2005; 93(2): 697 - 712. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
TOP
ABSTRACT
INTRODUCTION
