Suppression of Task-Related Saccades by Electrical Stimulation in the Primate's Frontal Eye Field

Douglas D. Burman and Charles J. Bruce

Section of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8001

    ABSTRACT
Abstract
Introduction
Methods
Results
Discussion
References

Burman, Douglas D. and Charles J. Bruce. Suppression of task-related saccades by electrical stimulation in the primate's frontal eye field. J. Neurophysiol. 77: 2252-2267, 1997. Patients with frontal lobe damage have difficulty suppressing reflexive saccades to salient visual stimuli, indicating that frontal lobe neocortex helps to suppress saccades as well as to produce them. In the present study, a role for the frontal eye field (FEF) in suppressing saccades was demonstrated in macaque monkeys by application of intracortical microstimulation during the performance of a visually guided saccade task, a memory prosaccade task, and a memory antisaccade task. A train of low-intensity (20-50 µA) electrical pulses was applied simultaneously with the disappearance of a central fixation target, which was always the cue to initiate a saccade. Trials with and without stimulation were compared, and significantly longer saccade latencies on stimulation trials were considered evidence of suppression. Low-intensity stimulation suppressed task-related saccades at 30 of 77 sites tested. In many cases saccades were suppressed throughout the microstimulation period (usually 450 ms) and then executed shortly after the train ended. Memory-guided saccades were most dramatically suppressed and were often rendered hypometric, whereas visually guided saccades were less severely suppressed by stimulation. At 18 FEF sites, the suppression of saccades was the only observable effect of electrical stimulation. Contraversive saccades were usually more strongly suppressed than ipsiversive ones, and cells recorded at such purely suppressive sites commonly had either foveal receptive fields or postsaccadic responses. At 12 other FEF sites at which saccadic eye movements were elicited at low thresholds, task-related saccades whose vectors differed from that of the electrically elicited saccade were suppressed by electrical stimulation. Such suppression at saccade sites was observed even with currents below the threshold for eliciting saccades. Pure suppression sites tended to be located near or in the fundus, deeper in the anterior bank of the arcuate than elicited saccade sites. Stimulation in the prefrontal association cortex anterior to FEF did not suppress saccades, nor did stimulation in premotor cortex posterior to FEF. These findings indicate that the primate FEF can help orchestrate saccadic eye movements by suppressing inappropriate saccade vectors as well as by selecting, specifying, and triggering appropriate saccades. We hypothesize that saccades could be suppressed both through local FEF interactions and through FEF projections to subcortical regions involved in maintaining fixation.

    INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References

Although our surroundings include many visual features that we may look at, we tend to move our eyes selectively toward informative features or features of interest (Antes 1974; Buswell 1935; Loftus and Mackworth 1978; Mackworth and Morandi 1967; Yarbus 1967). As we direct our eyes toward one feature, the inclination to initiate a saccade to other potential targets must be suppressed. A saccade to a potential target is also suppressed when we purposely avoid looking at a feature. This occurs frequently in social situations; for example, direct eye contact may be avoided by human or nonhuman rivals, as when monkeys lower their gaze rather than look directly at the face of a more dominant monkey (Mendelson et al. 1982; van Hooff 1972).

A mechanism must exist, then, that suppresses inappropriate or unwanted saccades, or our eyes would be invariably drawn to salient stimuli and we would be unable to direct our eyes at will. Such a disturbance of gaze control has been described in patients with frontal lesions (Guitton et al. 1985; Holmes 1918), suggesting that a mechanism for the suppression of saccades is located somewhere in the frontal lobe, possibly in the frontal eye field (FEF). However, a role of the FEF in suppressing inappropriate saccades has not been directly demonstrated, even though physiological properties consistent with such a role have been described. For example, the properties of FEF cells with foveal receptive fields (Segraves and Goldberg 1987; Suzuki and Azuma 1977) are consistent with an FEF role in suppressing saccades through the process of active fixation, analogous to the role demonstrated for cells with foveal receptive fields in the rostral superior colliculus (Munoz and Wurtz 1992, 1993a). Moreover, stimulation at some FEF sites suppresses the activity of superior colliculus movement cells that encode different saccade vectors (Schlag-Rey et al. 1992). When the target for a saccade is selected, the FEF could use this circuitry to suppress signals for competing saccade vectors.

In the present study, the effects of microstimulation during the performance of oculomotor tasks demonstrate that the FEF is involved in the selective suppression of some saccade vectors. At some sites within the FEF region where no overt behavior was directly elicited, low-intensity stimulation (<= 50 µA) suppressed the execution of task saccades for the entire period of stimulation (typically 450 ms). Typically, memory-guided saccades directed contraversive to the stimulated hemisphere were most effectively suppressed, and cells at these purely suppressive sites most frequently responded to visual stimulation at the fovea (that is, during the fixation part of the tasks). At some of the FEF sites where stimulation did elicit saccades, task-related saccades could also be suppressed, but only when the required saccade's vector differed from that of the electrically elicited saccade. A preliminary report of these experiments has been published in abstract form (Burman and Bruce 1990).

    METHODS
Abstract
Introduction
Methods
Results
Discussion
References

Three female rhesus monkeys were used in this study. Under anesthetic, each monkey was surgically implanted with a stainless steel recording chamber, a head holder for restraining the head during recording, and an eye coil for monitoring eye position with the magnetic search coil technique (Judge et al. 1980; Robinson 1963). Surgical preparation and behavioral techniques were approved by institutional animal care committees and have been described in detail elsewhere (Bruce and Goldberg 1985; Burman and Segraves 1994; Russo and Bruce 1993, 1994).

The latency and accuracy of saccades were analyzed during performance of three tasks, each of which was performed with and without electrical stimulation (Fig. 1). For each task, a block of 10-20 stimulation trials was typically preceded by a block of control (no-stimulation) trials. Another block of control trials was often tested after stimulation to ensure that increases in saccade latency during stimulation trials were not due to subject fatigue. In all three tasks, the fixation of a central spot was followed by the appearance of a spot at one of two peripheral positions, with each pair of possible positions separated by an angle of 180° and presented in a quasirandom order. Typically, one position was within the response field of a neuron sampled during the electrode penetration; otherwise, both positions were on the horizontal meridian at eccentricities of 10-15°. In the visually guided saccade task, the peripheral spot was white and appeared as a displacement of the initial fixation spot, which the monkey had to quickly refixate. In both memory tasks, the peripheral spot was presented for 750 ms during central fixation and extinguished, followed by a standard delay period of 1 s before the central fixation spot was extinguished, which was the signal to initiate a saccade. The monkey was rewarded if the eyes moved directly to the remembered stimulus position when the peripheral spot had been green (the memory prosaccade task), or to an equidistant position in the opposite direction when the peripheral spot had been red (the memory antisaccade task). To facilitate the monkey's performance on the memory tasks, the pro- and antisaccade trials were never interspersed, but instead were tested in separate blocks of trials. Furthermore, in both memory tasks a green light appeared at the correct eye position shortly after the completion of a saccade. If the saccade was correct, the green light visually confirmed the behavior, and the monkey was rewarded with two drops of fruit drink. If the saccade was incorrect, the green light was corrective; the monkey was rewarded with a single drop if it made a visually guided saccade to this corrective light, but the trial was counted as incorrect. The monkeys performed at >90% correct on all three tasks before the stimulation experiments were undertaken.


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FIG. 1. Diagrams of the 3 tasks used to test for suppression of saccades by frontal eye field (FEF) stimulation. In all 3, the train of electrical stimulation began concurrently with the central white spot's disappearance, which was always the signal to initiate a saccade. Top: in the visually guided saccade task, a white spot in the periphery appeared simultaneously with the disappearance of the central spot, and the monkey was required to make a saccade to the peripheral spot's location. Middle: in the memory prosaccade task, the peripheral spot was green, appeared for 750 ms, and was extinguished 1 s before the monkey was allowed to move the eyes. On the subsequent disappearance of the fixation light, the monkey was required to make a saccade to the green spot's remembered location. Bottom: in the memory antisaccade task, the peripheral spot was red and the monkey was required to make a saccade in the direction opposite the red spot's remembered location; this task was otherwise identical to the memory prosaccade task. In both memory tasks, the green cue subsequently appeared in the correct location shortly after correct saccades to visually confirm a correct saccade. At each cortical site studied, performance with and without electrical stimulation was compared on each task type tested. Suppression of saccades was indicated by a significant delay in saccade initiation on stimulation trials (- - -) compared with saccade initiation in the absence of stimulation (------).

Electrical stimulation was applied through glass-covered Elgiloy microelectrodes during performance of these oculomotor tasks. Stimulation consisted of 350- to 450-ms trains of biphasic pulses, with each pulse pair 0.4 ms in duration (0.2 ms negative, 0.2 ms positive) and 20-50 µA in intensity (peak negative current). In the suppression testing, stimulation was always applied synchronously with the signal to initiate a saccade (Fig. 1). The latency of saccades was measured relative to this cue, with the beginning of saccades identified as the time when the eye movement velocity exceeded 10°/s. The latency and accuracy on stimulation trials were compared statistically with those from nonstimulation trials with the use of the Mann-Whitney rank-sum test.

All cortical sites were first evaluated for overt electrically elicited saccades with the use of 70-ms trains of stimulation applied during attentive fixation (see Russo and Bruce 1993), thus allowing electrode placement in the FEF to be confirmed by electrophysiological as well as histological criteria (Bruce et al. 1985; Stanton et al. 1989). The electrophysiological criterion identified a site as lying within the FEF if saccades could be elicited by stimulating the site or surrounding sites with low-intensity currents (<= 50 µA), provided that the site could be localized to the gray matter. The depth of a site from the cortical surface was estimated by the distance the electrode traveled after neuronal activity was first recorded, and the position within the FEF was characterized both by the size of elicited saccades and by the electrode's location relative to other FEF penetrations. The nature of neuronal activity at many stimulation sites was identified with the use of the classification of Bruce and Goldberg (1985).

FEF penetrations in one monkey were histologically verified to pass through the anterior bank of the arcuate sulcus; histological verification was not possible with the other two monkeys, which are involved in ongoing investigations. Histological localization of electrode placement was aided by depositing iron at selected sites, accomplished by passing 7- to 15-µA anodal current for 2-3 min. After completion of experiments, the monkey was deeply anesthetized and perfused with saline followed by 10% formaldehyde. The periarcuate region was blocked in situ and sectioned in the coronal plane, and deposit sites were visualized by reacting the iron deposits with ferrocyanide. After counterstaining with neutral red, histological locations of deposit sites were reconstructed with the use of conventional techniques, and the locations of unmarked penetrations both within and outside the boundaries of the FEF were estimated from their microdrive coordinates relative to those of marked sites.

    RESULTS
Abstract
Introduction
Methods
Results
Discussion
References

We tested for suppressive effects of electrical stimulation on task saccades at 77 separate sites in the periarcuate region of the frontal lobes of the three monkeys. These tests were part of a larger set of extracellular recording experiments involving these three monkeys wherein >150 periarcuate electrode penetrations were made and >400 sites were tested for electrically elicited eye movements. This larger data base of elicited eye movements was used to delineate the FEF physiologically in these particular monkeys (see METHODS), but this report principally concerns the testing for suppression of purposive saccades by intracortical microstimulation.

Purely suppressive sites

Most suppression testing was carried out at sites where electrical stimulation did not elicit saccadic eye movements or any other movement. Of 54 such nonmovement sites, 18 yielded significant suppression in at least one of the three saccade tasks. These sites we term "pure suppression" sites. Figure 2 shows a pure suppression site in the left hemisphere of monkey SP tested with the visually guided saccade task. Contraversive visually guided saccades that targeted a spot in the upper right quadrant (Fig. 2, right) were significantly delayed by stimulation [U(20,20) = 368.5, P < 0.001], with a median latency of 388 versus 274 ms for control saccades to the same target location during the nonstimulation trials that immediately followed. The latency of ipsiversive saccades to a spot in the lower left quadrant (Fig. 2, left) was slightly increased in the stimulation condition (median of 370 ms vs. 344 ms for ipsiversive control trials); however, this difference did not achieve statistical significance [U(12,20) = 164, P = 0.088]. The stimulation did not disturb the accuracy of visually guided saccades in either direction, as seen by the plot of saccade endpoints from stimulation and control trials (Fig. 2, bottom).


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FIG. 2. Visually guided saccades suppressed by electrical stimulation at a left hemisphere FEF site (SP566) where no eye movement was elicited. Superimposed eye position traces from multiple stimulation trials (top) and multiple control (no stimulation) trials (middle) are illustrated. ver and hor, vertical and horizontal components of eye position, respectively. Solid vertical line: signal to initiate the saccade, which is also the beginning of electrical stimulation in the stimulation trials. Striped horizontal bar: stimulation train (350 ms, 40 µA in this experiment). Dashed vertical line: end of stimulation. Scales at right: relative coordinates of the fixation point and target in each case. Notice that contraversive saccades, directed to a target at the top right, were substantially delayed by the stimulation in comparison with the contralateral control saccades, whereas ipsiversive saccades to the lower left quadrant were not. Bottom: endpoints of saccades in traces above. Note the tight grouping and considerable overlap of the stimulation (bullet ) and control (open circle ) trials in both the ipsiversive and contraversive saccades.

In general, memory-guided saccades were more sensitive to suppressive effects than saccades directed to overt visual targets in the visually guided saccade task. Furthermore, the effects of stimulation on the latency and accuracy of contraversive saccades in both memory tasks were typically more dramatic than the effects of stimulation on ipsiversive saccades. Typical effects on memory saccades are illustrated in Fig. 3. At this site (SP210, left hemisphere), contraversive memory prosaccades were completely suppressed throughout the 450-ms stimulation train, with saccade initiation delayed until 55-110 ms poststimulation (Fig. 3A, top right). The median latency of contraversive saccades on these stimulation trials exceeded that of contraversive saccades on control (no-stimulation) trials to the same cue location by ~250 ms (median latencies of 522 vs. 268 ms, U(12,17) = 204,P < 0.001). Ipsiversive prosaccades were also significantly delayed by stimulation (U(10,13) = 130, P < 0.001). However, ipsiversive saccades were less completely suppressed than contraversive saccades, because ipsiversive saccades were often initiated before the stimulation train ended (Fig. 3A, top left) and had a median latency only 150 ms greater than in the ipsiversive control trials (370 vs. 220 ms).


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FIG. 3. Memory-guided saccades suppressed by stimulation at a left hemisphere FEF site (SP210) at which no overt eye movement was elicited. Effects of stimulation at 25 µA are illustrated for the memory prosaccade task (A) and the memory antisaccade task (B). Peripheral cues were located 13° left or right of fixation in both experiments, as indicated by the scale lines at right of each set of horizontal eye traces; however, in the case of antisaccades the correct eye position is indicated rather than the cue location. A: contraversive prosaccades were all delayed until stimulation ended (top right), beginning 55-110 ms poststimulation except for 1 prosaccade that began ~600 ms poststimulation. Ipsiversive prosaccades were less dramatically delayed and usually began before the end of stimulation (top left). Saccade endpoints are plotted at bottom, excepting the 4 ipsiversive errors on contraversive trials (1 stimulation, 3 control). Contraversive (but not ipsiversive) prosaccades were significantly hypometric on stimulation trials (A, bottom). B: memory antisaccades, both contraversive and ipsiversive, were also significantly delayed by stimulation (top). Contraversive antisaccades were hypometric and elevated on stimulation trials, whereas the accuracy of ipsiversive antisaccades was not significantly affected (B, bottom). Again, endpoints of grossly misdirected saccades are omitted (1 in each ipsiversive condition and 2 in each contraversive condition). Conventions as in Fig. 2.

Stimulation at this and other pure suppression sites had a modest but remarkably consistent effect on the accuracy of memory saccades, without impairing the subject's ability to perform the task. Figure 3A, bottom, shows a two-dimensional plot of the endpoints of all of the correct saccades, i.e., all trials except the four contraversive trials with grossly misdirected saccades. As reported by others (Gnadt et al. 1991; White et al. 1994), the endpoints of memory saccades were considerably more scattered and elevated above the cue location than the endpoints of visually targeted saccades, both for stimulation and control trials. In addition, there was a significant effect of the stimulation on the size of the memory saccades: contraversive memory prosaccades on stimulation trials were ~25% hypometric relative to contralateral saccades on control trials (median size 10.7° vs. 14.1°, U(11,14) = 0.0, P < 0.0001). Ipsiversive prosaccades were rendered hypometric by ~8% (median size of 11.9° on stimulation trials vs. 12.9° on control trials, U(10,13) = 31.5, P < 0.05). Despite these modest changes in accuracy, there were few gross targeting errors during stimulation trials---none for ipsiversive trials and only 1 on the 12 contraversive stimulation trials, compared with 3 gross targeting errors on the 17 contraversive control trials (Fig. 3A, top).

The effects of stimulation at this site on memory antisaccades (Fig. 3B) were similar, increasing latency without disrupting the subject's ability to perform the task. Most contraversive memory antisaccades were not initiated until after the stimulation train ended, with the median latency for contraversive antisaccades increasing from 262 to 492 ms (U(13,14) = 164, P < 0.001). The median latency for ipsiversive antisaccades increased nearly as much, from 242 to 428 ms (U(7,16) = 111, P < 0.001). Few antisaccades were completely misdirected (1 stimulation/1 control trial from the ipsiversive data and 2 stimulation/2 control trials from the contraversive data). In Fig. 3B, bottom, saccade endpoints are plotted, with the grossly misdirected saccades omitted from the plots. Contraversive antisaccades were rendered hypometric by stimulation (U(11,12) = 30, P < 0.05), but the size of ipsiversive antisaccades was not significantly affected. The polar directions of both contraversive and ipsiversive memory antisaccades were significantly rotated upward in the stimulation trials relative to control trials(U(11,12) = 129, P < 0.001 for contraversive saccades;U(6,15) = 11, P < 0.01 for ipsiversive saccades).

Thus stimulation at suppression sites produced changes in both the size and accuracy of memory pro- and antisaccades. These stimulation effects on the size and accuracy of memory saccades were not simply a consequence of the stimulation lengthening the delay time between the presentation of the cue stimulus and saccade initiation. The standard delay during memory task performance was 1 s from disappearance of the peripheral stimulus until the signal to initiate the memory saccade, and the standard duration of stimulation was 0.45 s. If stimulation completely suppressed the ability to initiate a saccade, then the delay from the offset of the peripheral stimulus until the monkey could initiate a saccade would be lengthened to 1.45 s. However, control experiments with different delays (and no stimulation) showed that the accuracy of memory prosaccades following delays of 1.0 and 1.45 s did not significantly differ (Fig. 4A). In fact, the size and elevation of leftward and rightward memory saccades were not significantly changed unless the delay exceeded 2 s (Fig. 4B). Thus changes in the size and direction of saccades did not merely result from stimulation further delaying the saccade, but instead seemed to reflect a more direct influence of FEF stimulation on the specification of saccade metrics.


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FIG. 4. Relationship between saccade accuracy and the duration of delay period in the memory prosaccade task in the absence of stimulation. This experiment tested whether the stimulation-induced changes in the accuracy of memory prosaccades, as illustrated in Fig. 3, were simply due to the stimulation-induced delay in saccade initiation. As in Fig. 3, peripheral stimuli were presented 13° left or right of fixation for 750 ms. A: memory prosaccades following a delay period of 1.45 s (black-diamond ) were no less accurate than those following a delay of 1.0 s (square ). B: size and elevation of leftward (square ) and rightward (black-square) memory prosaccades did not significantly differ for delays <2 s.

Table 1, left, summarizes the laterality of the saccade suppression and the disruption of saccade accuracy for the 18 pure suppression sites we studied. Typically, saccades directed contraversive to the stimulated hemisphere were more strongly suppressed and most likely to be rendered inaccurate. Usually, we tested only one opposing pair of contraversive-ipsiversive directions, but three pairs of directions of memory prosaccades were tested at the pure suppression site illustrated in Fig. 5. In the absence of electrical stimulation, the target direction had little effect on the latency of memory prosaccades (Fig. 5A, open squares); the radius of the large circle indicates the mean latency for all control saccades (275 ms). With stimulation, all three directions of contraversive saccades were suppressed by stimulation, particularly those directed to the right and bottom right (Fig. 5A, filled diamonds). Ipsiversive saccades, however, were not suppressed; in fact, the latency on stimulation trials was slightly shortened for ipsiversive saccades down and to the left (median = 252 vs. 268 ms for control trials, U(10,14) = 87.5, P < 0.05). Whereas the accuracy of ipsiversive memory saccades was unaltered by stimulation, contraversive memory saccades on the stimulation trials were more scattered and often hypometric (Fig. 5B).

 
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TABLE 1. Laterality of suppression effects and incidence of neuronal response properties at suppression sites


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FIG. 5. Directionality of suppression effects for memory prosaccades at an FEF site (SP565) at which no eye movement was elicited. Targets were presented at 13° eccentricity on the horizontal meridian and diagonal axes. A: mean latency for all memory prosaccades in the absence of stimulation is represented by the circle, with the mean latency for each direction plotted with a filled diamond for trials with stimulation (50 µA, 450 ms) and with an open square for trials without stimulation. All contraversive directions were significantly delayed, with the greatest delay observed for prosaccades directed toward the lower right quadrant. Ipsiversive prosaccades were not delayed, and significantly shorter latencies were recorded on stimulation trials for targets down and to the left. B: scatter plot of saccade endpoints. Performance of memory prosaccades was not substantially disturbed by stimulation, although contraversive prosaccades were slightly shortened, scattered, and elevated in comparison with contraversive controls.

At three of the pure suppression sites, stimulation was also applied during spontaneous eye movements in the dark. Under these conditions, saccades in every direction were consistently suppressed for the duration of stimulation, even during loud noises that usually provokedeye movements in the absence of electrical stimulation.

Suppression of purposive saccades at sites with elicited saccadic eye movements

At many sites at which low-threshold saccades could be elicited (12 of 23 sites tested), stimulation produced suppressive effects similar to those described above for pure suppression sites. Figure 6 illustrates this with an example from site SP116, where stimulation consistently elicited small contraversive (rightward) saccades. During trials requiring a contraversive saccade in the memory prosaccade task (Fig. 6A, right), the stimulation train usually elicited a staircase of two small contraversive saccades (open arrows) and suppressed the execution of the voluntary memory prosaccades achieving the cue location (solid arrows) until after the stimulation ended, and thus resulted in a significantly longer latency than on contraversive control trials (U(10,15) = 150, P < 0.001). In contrast, ipsiversive memory prosaccades consistently began well before the stimulation train was over, and with latencies that were not significantly longer than those during ipsilateral control trials (Fig. 6A, left, U(6,15) = 54, P = 0.505). Interestingly, the 450-ms train of electrical stimulation typically elicited only one saccade on the ipsiversive trials.


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FIG. 6. Memory saccades suppressed by FEF stimulation at a left hemisphere site (SP116) at which saccades were elicited (threshold 20 µA). Open arrows beneath eye trace records: electrically elicited saccades, which were small (~5°) and rightward. Solid arrows above horizontal eye trace: task-related saccades. A: prosaccade task. When the task required a contraversive prosaccade (cue at 13° right), a staircase of 2 elicited saccades preceded the memory prosaccade, which was consistently delayed until the stimulation (25 µA) ended (top right). When the task required an ipsiversive prosaccade (cue at 13° left), only 1 saccade was elicited and the prosaccade was not significantly delayed (top left). Compared with control trials, both contraversive and ipsiversive memory prosaccades were slightly hypometric on stimulation trials (bottom). B: antisaccade task. When the task required a contraversive antisaccade, a staircase of 2-3 saccades was usually elicited and the memory antisaccade was suppressed until stimulation ended (top right). Fewer saccades were elicited and the duration of suppression was more variable when ipsiversive antisaccades were required (top left). Neither contraversive nor ipsiversive antisaccades were significantly impaired in accuracy (bottom). Conventions as in Fig. 2.

The endpoints of both ipsi- and contraversive memory prosaccades on stimulation trials were significantly hypometric compared with control trials (Fig. 6A, bottom). The ipsiversive memory prosaccades on stimulation trials were hypometric by ~5° (median = 8.7° on stimulation trials vs. 13.4° on control trials, U(6,15) = 109.5, P < 0.001); these ipsiversive prosaccades apparently failed to compensate for the elicited saccade, which was also ~5° in size. This uncompensated memory prosaccade, however, was subsequently followed by a corrective saccade that reached the correct target position. The endpoints of contraversive memory prosaccades, on the other hand, were hypometric on stimulation trials by ~1° (median = 12.3° on stimulation trials vs. 13.3° on control trials, U(10,15) = 91.0, P < 0.05), and were not followed by a corrective saccade. Thus the contraversive memory prosaccade slightly overcompensated for the preceding two elicited saccades.

In testing memory antisaccades at this site (Fig. 6B), both ipsiversive and contraversive saccades were significantly delayed by the stimulation train. The contraversive memory antisaccades, however, were suppressed much more, with a median latency of 516 ms for contraversive versus 328 ms for ipsiversive antisaccades. The volitional saccades on the stimulation trials were seldom grossly misdirected, and were fairly comparable in accuracy with the corresponding control trials (Fig. 6B, bottom).

There was no suppressive effect at 11 of the 23 elicited saccade sites tested. Thus, when stimulation of a saccade site did delay memory saccades, the delay was not simply the result the oculomotor system being incapable of generating a saccade for some refractory period following the elicited saccade. During stimulation trials at site SP097 (Fig. 7), for example, memory saccades were initiated with normal latencies and accuracy in both directions, despite the intervening elicited saccade. Furthermore, suppressive effects from stimulation were not limited to saccade sites with small elicited saccades (as in Fig. 6); four of eight test sites with elicited saccades >6° showed suppressive effects, including one of two sites with elicited saccades >20°.


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FIG. 7. Memory prosaccades not delayed by FEF stimulation at a left hemisphere site (SP097) where saccades were elicited (threshold 20 µA). Despite the intervening saccade elicited by stimulation, neither contraversive nor ipsiversive memory prosaccades were delayed by 20-µA stimulation at this site. Thus the delay in the task-related saccade at other saccade sites (e.g., Fig. 6) was not due to a generalized refractory period of the oculomotor system following an elicited saccade. Conventions as in Fig. 2. Notice that only 1 saccade was elicited on each trial (even though the stimulation lasted 450 ms) and that the monkey usually made a reflexive saccade back to the original fixation location (even though the fixation light was still extinguished) shortly after the elicited saccade and before executing the memory saccade appropriate for that trial.

At four of five saccade sites tested with subthreshold currents, stimulating with a current subthreshold for eliciting saccades nonetheless produced suppressive effects. Figure 8 shows an example in which the visually guided saccade task was used to test many different saccade vectors. At this site (02148) suprathreshold stimulation elicited a saccade of 15° amplitude directed down and to the right (latency 20-40 ms). With subthreshold currents, about a third of the task-related saccades directed to targets 15° down and to the right were facilitated (i.e., initiated with latencies shorter than any recorded during nonstimulation trials), whereas saccades directed to targets 15° eccentric in every other direction were significantly suppressed (Fig. 8A). The effect of the subthreshold stimulation on latency also depended on the task-related saccade's amplitude relative to that of saccades elicited by suprathreshold stimulation. Even for targets in the site's characteristic direction, saccades of 5° amplitude (thus smaller than those elicited by suprathreshold stimulation) were similarly suppressed by subthreshold stimulation (Fig. 8B, left, U(10,19) = 34, P < 0.01). By contrast, saccades of 15-25° amplitude were within the range of saccades elicited by suprathreshold stimulation, and 25° saccades were significantly facilitated by subthreshold stimulation (Fig. 8B, right, U(14,16) = 172.5, P < 0.01). As summarized in Fig. 8, C and D, saccades directed 15-25° down and to the right into the site's characteristic direction were facilitated by subthreshold stimulation, whereas all other saccade directions were suppressed.


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FIG. 8. Effects of subthreshold stimulation on the latency and accuracy of visually guided saccades. Suprathreshold stimulation at this left hemis p h e r e   s i t e   ( 0 2 1 4 8 )   e l i c i t e d   c o n t r a v e r s i v e ,rightward saccades directed at an angle of ~35° below the horizontal meridian and with a median size of 15°. The effect of subthreshold stimulation on saccades directed to targets 15° eccentric depended on the target direction (A). Ipsiversive saccades directed either up-left or down-left were delayed by stimulation. Often contraversive saccades directed up to the right were also delayed, whereas contraversive saccades directed to targets 15° down-right were never delayed and often facilitated. The vectors of these latter saccades were nearly identical to the vector of a typical saccade elicited by suprathreshold stimulation. The effect of subthreshold stimulation on saccades directed down to the right depended on the size of the saccade (B). If a task-related saccade was smaller than the smallest elicited saccade, then its latency was sometimes unaltered and sometimes delayed slightly by stimulation. In contrast, the latency of larger task-related saccades was usually shortened by stimulation; the size of these larger saccades was between that of the smallest and largest elicited saccades. In general, the effect of subthreshold stimulation on the latency was to facilitate down-right saccades to targets within the site's movement field and to suppress saccades directed outside the movement field (C, D). The effect of subthreshold stimulation on saccade metrics also depended on the direction of the saccade (E). Ipsiversive saccades during stimulation trials were in the correct direction but hypometric, whereas contraversive saccades had the correct size but an altered direction. During stimulation trials, contraversive saccades were directed between the target spot and the site's movement field. This site's threshold for eliciting saccades was 50 µA when gaze was unrestricted, but higher when performing a task; current applied during stimulation trials was 50 µA. Conventions as in Figs. 2 and 5.

Subthreshold stimulation also altered the accuracy of these task-related saccades (Fig. 8E). The direction of contraversive saccades was significantly altered by subthreshold stimulation; by contrast, ipsiversive saccades became significantly hypometric but did not change direction. The direction of contraversive saccades during stimulation trials was intermediate between the direction of the target and that of saccades elicited by suprathreshold stimulation. Specifically, saccades targeting a stimulus at an angle of 45° below the horizontal meridian were deflected 3-5° upward by subthreshold stimulation, compared with control trials, whereas saccades targeting a stimulus at an angle of 45° above the horizontal meridian were deflected 16° downward (P < 0.01 for each target location). Latency and accuracy were not significantly correlated across individual trials.

Table 1, right, summarizes the incidence and laterality of the suppression effects and effects on saccade accuracy for the 23 saccade sites we tested. Overall, suppression effects were observed at about half the saccade sites. At saccade sites, the presence and properties of suppression from stimulation were mixed and variable, depending on the site, the saccade vectors tested, and the current intensity used. At saccade sites with suppression effects, stimulation suppressed saccades directed outside the site's movement field, and the accuracy of suppressed saccades was often (but not always) altered. Inaccuracies induced by stimulation at saccade sites could be unilateral or bilateral. Bilateral effects either rendered all saccades hypometric (3 sites), rendered all task-related saccades inaccurate by the vector of the elicited saccade (2 sites), or affected the saccade vector differentially depending on target location (1 site).

Suppression of purposive saccades at sites with elicited smooth eye movements

Task-related saccades were suppressed by stimulation at all four FEF sites with elicited smooth eye movements that were tested. However, because so few such smooth movement sites were tested, we did not include these sites in our data summaries, including Table 1.

Neuronal properties at pure suppression and elicited saccade sites

The incidence of the various neuronal properties at both the pure suppression sites and the saccade sites are summarized in Table 1, bottom. At pure suppression sites, cells with foveal or postsaccadic responses were most prevalent. By contrast, all cell types except such foveal cells were observed at saccade sites with suppression effects. No neuron was isolated and/or studied at about half the sites of both groups.

Anatomic location of pure suppression and elicited saccade sites

Both the suppression and the conventional elicited saccade sites were limited to the lip, anterior bank, and fundus of the arcuate sulcus, whereas stimulation of nearby regions of premotor cortex in the posterior bank of the arcuate and of prefrontal cortex anterior to the arcuate had no effect on the initiation of saccades. Pure suppression sites were more restricted in their distribution than elicited saccade sites. All but three pure suppression sites were located in the ventrolateral FEF near the arcuate spur; the remaining three were located dorsally along the superior limb of the arcuate sulcus. Furthermore, pure suppression sites often appeared to be the endpoint in a continuum. Often, as the electrode descended down the bank of the arcuate sulcus, elicited saccades decreased progressively in size, and on several penetrations the smallest elicited saccades (0.5-3°) were followed within 1 mm by a pure suppression site. When verified histologically in such cases, pure suppression sites were located deep in the anterior bank of the arcuate, in or near the fundus. Sites eliciting smooth eye movement (see Gottlieb et al. 1993; MacAvoy et al. 1991) were also found deep in the arcuate sulcus of these monkeys on some penetrations, with one such site verified to lie within 0.5 mm of a pure suppression site. The data, however, were not sufficiently extensive to make inferences about the anatomic relationship between the smooth eye movement region and the location of pure suppression sites.

    DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References

These results provide a physiological mechanism for an FEF role in suppressing voluntary saccades, as previously postulated from clinical studies in humans (e.g., Guitton et al. 1985) and from the delay of saccades caused by transcranial magnetic stimulation (TCMS) over the human FEF (e.g., Priori et al. 1993). In our experiments, suppression was characterized by a stimulation-induced delay in the initiation of task-related saccades and was sometimes accompanied by changes in saccade accuracy. The suppression of task-related saccades was the primary effect of stimulation at pure suppression sites, with contraversive saccades typically suppressed more than ipsiversive saccades. Stimulation at other sites ("saccade sites") elicited saccades with a characteristic vector; at half the saccade sites, stimulation additionally suppressed some task-related saccades.

Are pure suppression sites in the FEF proper?

The FEF in the macaque monkey has been defined as the arcuate region at which saccades can be elicited with fairly low currents (<= 50 µA) (Bruce et al. 1985; Huerta et al. 1986, 1987; Stanton et al. 1989). Strictly speaking, many pure suppression sites would be excluded by this definition because they lie deeper within the arcuate's anterior bank than the low-threshold area. However, suppression of saccades was limited to the general region of the FEF, consistent with prior reports of suppression in abstract form (Azuma et al. 1986; Burman and Bruce 1990). Moreover, characteristics of suppression at pure suppression sites and at elicited saccade sites were similar (namely, the preferential suppression of some saccade vectors and their altered accuracy). We would therefore expand the definition of the FEF to include sites where saccades are robustly suppressed by low-threshold stimulation. Most of these deep, purely suppressive sites were located near the spur of the arcuate sulcus, suggesting that there may be a distinct FEF subregion for the suppression of saccades, similar (and perhaps adjacent) to the smooth pursuit subregion of FEF (Gottlieb et al. 1993, 1994; MacAvoy et al. 1991).

Anatomic basis for the suppression effect

Known subcortical projections of FEF could provide the anatomic basis for the delay and inhibition of saccades caused by stimulation at pure suppression sites. Most pure suppression sites were located deep within the anterior bank of the arcuate near the representation of small saccades, a region of FEF that projects to the rostral part of the superior colliculus (Komatsu and Suzuki 1985; Stanton et al. 1988b) and to the pontine omnipause region (Stanton et al. 1988b). Furthermore, cells with foveal receptive fields were recorded at some pure suppression sites, and this type of FEF cell projects to both the pontine omnipause region and the superior colliculus (Segraves 1993; Segraves and Goldberg 1987). The suppression of saccades caused by stimulation at FEF suppression sites could be mediated through either of these subcortical projections: activation of the pontine omnipause region suppresses saccades in all directions (Keller 1974), whereas activation of the rostral superior colliculus by bicuculline preferentially delays contraversive saccades, which are also rendered hypometric (Munoz and Wurtz 1993b). FEF projections to the neostriatum (Huerta et al. 1986; Stanton et al. 1988a) provide an indirect subcortical pathway that could suppress contraversive saccades, because the neostriatum projects to the substantia nigra pars reticulata which in turn inhibits collicular movement cells (Hikosaka and Wurtz 1985). Thus FEF suppression sites could act through multiple subcortical pathways, but the preferential suppression of contraversive saccades and hypometria characteristic of FEF stimulation at pure suppression sites is most consistent with the routes through the rostral superior colliculus.

Conflicting oculomotor signals might also be suppressed locally within the FEF, similar to the local network for suppressing competing signals within the superior colliculus (Mascetti and Arriagada 1981; Munoz and Wurtz 1993a). In such a local network, saccade sites and pure suppression sites mutually inhibit each other's activity. Because a foveal stimulus increases neuronal activity at pure suppression sites, activity at saccade sites would be inhibited from network interactions whenever a spot is foveated. These interactions would raise the electrical threshold for eliciting saccades from saccade sites during active fixation, as observed by Goldberg et al. (1986). Disinhibition through this local network could also explain the elevated activity of presaccadic movement cells at saccade sites following removal of the foveal target in the gap paradigm (Dias and Bruce 1993, 1994), which in turn may account for the diminished reaction time in this paradigm (e.g., Saslow 1967). Finally, FEF projections to the nearby supplementary eye field (e.g., Stanton et al. 1993) and to the parietal eye field area (e.g., Stanton et al. 1995) could help effect saccade suppression throughout the cerebral cortex's distributed oculomotor network.

Selective facilitation of saccades

Stimulation at FEF saccade sites often facilitated contraversive saccades directed into the site's movement field while suppressing ipsiversive saccades (see Fig. 8). Thus ipsiversive and contraversive saccades were both regulated by the FEF, but in a reciprocal fashion. Reciprocal regulation of ipsiversive and contraversive saccades sometimes occurred at pure suppression sites as well; for example, stimulation at suppression site SP565 (Fig. 5) facilitated ipsiversive saccades down to the left while suppressing contraversive saccades.

Unlike the facilitation resulting from stimulation of some subcortical structures, facilitation of task-related saccades from stimulation of the FEF was directionally selective. Stimulation of the paramedian pontine reticular formation or the abducens nucleus facilitates initiation of a visually guided saccade, even when the target direction differs from the direction of electrically elicited movements (Sparks et al. 1987). These facilitated ("premature") saccades are directed toward a location intermediate between the visual target's location and the vector of the elicited saccade, with the amplitude of the visually guided component inversely proportional to the delay between target appearance and the onset of stimulation. Stimulating these pontine sites, then, produces a trigger signal for initiating a visually guided saccade before its vector has been fully specified (Sparks et al. 1987). By contrast, stimulating FEF saccade sites in our study facilitated only those saccades whose vector was consistent with the target location; stimulation otherwise delayed the saccade while contributing to the specification of an intermediate saccade vector. Thus FEF activation reduces competition from signals for alternative saccades, suggesting that the selection of the appropriate saccade vector occurs either within the FEF or before the vectorial signal reaches the FEF.

Effects of stimulation on saccade accuracy

Memory saccades delayed by FEF stimulation were frequently less accurate than saccades in the same task without stimulation. At pure suppression sites, the accuracy of contraversive saccades was altered by stimulation, with contraversive memory saccades rendered hypometric by as much as 25% of the target distance by stimulation. The memory of the target location and the saccade program were not indiscriminately disrupted by stimulation at suppression sites, however, because changes in saccade metrics were generally not accompanied by large increases in the scatter of saccade endpoints or the incidence of error trials (e.g., see Figs. 3, 6, and 8). Instead, stimulation at these sites consistently and reproducibly altered the specification of saccade metrics as well as delaying their execution.

Changes in the accuracy of task-related saccades from stimulating suppression sites were not the result of the same mechanism that delayed the saccades. Three observations verify this hypothesis. First, adding a task delay that was equal to the duration of stimulation did not result in inaccurate saccades, confirming that changes in the saccade's accuracy were not merely a consequence of delaying the saccade (see Fig. 4). Second, stimulation at some sites delayed saccades without significantly altering their accuracy (see Fig. 2). Third, the metrics of saccades were not significantly correlated with latency during stimulation at any FEF site. In Fig. 8, for example, the amplitude of ipsiversive saccades and the direction of contraversive saccades were both altered by stimulation, but neither the amplitude nor direction of these saccades were correlated with latency across individual trials. Consistent with previous suggestions that the signals specifying the metrics and timing of a saccade are generated independently (Glimcher and Sparks 1992, 1993a; Sparks et al. 1987), these findings indicate that FEF stimulation altered the signal specifying saccade metrics independently of the way it affected the saccade's trigger signal.

Interactions between saccade signals

Within the saccadic system, interaction between two signals often produces a saccade whose vector represents a weighted average of the component signals. Such interactions occur, for example, with simultaneous stimulation of two FEF sites (Dias et al. 1992; Robinson and Fuchs 1969), an FEF and a superior colliculus site (Schiller et al. 1979), or two superior colliculus sites (Robinson 1972). Saccade signals generated in conjunction with visually guided saccades can also be averaged with a signal from stimulation of a site in the superior colliculus (Glimcher and Sparks 1993b; Schlag-Rey et al. 1989; Sparks and Mays 1983), the FEF (Marrocco 1978), or the paramedian pontine reticular formation (Sparks et al. 1987). Finally, averaging can be obtained by presenting two visual targets close together in rapid succession (Becker and Jürgens 1979; Ottes et al. 1984). An averaging effect was also evident in the present study, where subthreshold stimulation at elicited saccade sites biased the direction of contraversive task-related saccades toward that of the vector specified at the stimulation site.

An averaging interaction between vectorial signals could also explain why task saccades were sometimes hypometric when pure suppression sites were stimulated. FEF visual activity functions to specify the location of a target for an impending saccade (Burman and Segraves 1994; Dassonville et al. 1992; Goldberg and Bruce 1990), and because neurons at pure suppression sites often had a foveal receptive field, their activity might correspond to a saccade of 0° amplitude. Hypometric saccades would then result from averaging the task-related signal specifying the correct saccade with the stimulation-produced signal for a 0° saccade. Averaging the vectorial signal from suppression sites could similarly explain why hypometric saccades are elicited by FEF stimulation during attentive fixation of a visual stimulus (Goldberg et al. 1986), because the FEF signal for a 0° saccade resulting from attentive fixation would be averaged with the FEF stimulation-produced signal for a saccade.

The directional properties observed at suppression sites may result from the brain's method of specifying saccade metrics. Just as FEF saccade sites nearly always specify a contraversive saccade (Bruce et al. 1985; Schall 1991), suppression sites may specify a "contraversive saccade of 0° amplitude." This possibility is supported by the progression of smaller and smaller contraversive saccade vectors elicited as the electrode approached these sites. When a contraversive saccade of 0° amplitude was specified, the activity of suppression sites would interact preferentially with other signals specifying contraversive saccades, because saccade metrics are specified only after the left-right direction of the target is known (Becker and Jürgens 1979).

Functional considerations of the suppression effects

Possible functional roles for FEF suppression sites include 1) maintaining fixation on a foveated stimulus, 2) actively avoiding a saccade to a salient stimulus, 3) canceling and resetting the signal specifying a saccade vector once the saccade is completed, and 4) ensuring that the duration of fixation following a saccade is sufficient to allow visual information to be extracted.

Stimulating FEF suppression sites resulted in the eyes remaining fixated at the current locus. Fixation was maintained throughout stimulation in the dark---even during loud noises that would otherwise provoke eye movements---as well as during saccade tasks. As described earlier, these effects may be mediated through projections to subcortical areas that are involved in actively maintaining fixation, areas such as the pontine omnipause region, the rostral superior colliculus, and the substantia nigra pars reticulata. Together with cortical areas that have suppressive sites, these areas may comprise nodes of a distributed network for active fixation (Munoz and Wurtz 1992, 1993a). Cortical areas with such sites include parts of the superior temporal sulcus (Komatsu and Wurtz 1989) and the parietal cortex (Kurylo 1991). Unlike fixation cells at the other nodes, however, activation of fixation cells in the FEF requires the presence of a foveal stimulus (Segraves and Goldberg 1987; Suzuki and Azuma 1977). As such, a role for FEF suppression sites in active fixation must be limited to conditions where a stimulus is foveated. The properties of FEF suppression sites suggest a role in feature avoidance. In feature avoidance, a subject maintains its current fixation even though attention has been drawn to a salient peripheral feature. A saccade to the salient stimulus is actively avoided, and when an eye movement is eventually made, it is typically directed away from the attended feature. FEF suppression sites could be involved in feature avoidance by competing with and suppressing signals that might otherwise direct the eyes toward a salient feature. The directional preference of the suppression effect observed at most suppression sites is consistent with such a role.

In addition to these two roles, FEF suppression sites could also have a postsaccadic role in canceling and resetting signals that specify a saccade vector. If the specification signal is not canceled once the saccade is completed, another saccade with the same vector could erroneously occur, or the residual signal could be erroneously averaged into the signal for the next saccade. The signal at suppression sites could effectively cancel the specification signal from the previous saccade, resetting the specification to 0° and preventing further saccades until a new saccade vector is specified. The postsaccadic activity sometimes observed at suppression sites would be appropriate for such a function, because postsaccadic activity signals the completion of a saccade with a particular vector (Bruce 1988, 1990; Goldberg and Bruce 1990). The vectorial specificity of postsaccadic activity could also explain why the oculomotor refractory period following a saccade is longer if the subsequent saccade has the same vector (Becker and Jürgens 1979; Dorris et al. 1996; Marrocco 1978): the specification for a saccade with a different vector could begin immediately after the completion of a saccade, whereas another saccade with the same vector could not be specified until the previous signal had been canceled by a suppression site's postsaccadic activity.

Finally, activation of suppression sites could ensure that the duration of fixation following a saccade is sufficient to allow visual information to be extracted before another saccade is initiated. A fixation duration of >= 150 ms is required for perceptual processes to occur (Salthouse and Ellis 1980; Salthouse et al. 1981; Shioiri 1993; White 1967). By preventing successive saccades from occurring too quickly, suppression sites could ensure that visual information from a fixation can be perceived, and will not be masked by visual stimuli appearing at the same retinal location during the subsequent fixation (Irwin et al. 1988).

Clinical relevance

This study demonstrates that stimulating some FEF sites can selectively suppress task-related saccades by delaying their occurrence and altering their accuracy. By suppressing as well as generating saccades, the FEF provides high-level control over volitional saccades similar to that observed for Broca's area in controlling speech, or for premotor areas in controlling skeletal movements; stimulation in any of these regions can either elicit or suppress motor activity, depending on the site of stimulation (Penfield and Rasmussen 1950). Also, our results help to relate primate neurophysiology to the modern neurological technique of TCMS. Although it is difficult to elicit saccades with TCMS over the FEF region of humans (e.g., Wessel and Kömph 1991), TCMS over the FEF region does delay visually guided saccades (Priori et al. 1993) and interferes with the production of both antisaccades (Müri et al. 1991) and memory saccades (Pascual-Leone and Hallett 1994).

As discussed above, cell properties and the effects of stimulation at suppression sites are consistent with several possible functions. The functional importance of these sites may be best evaluated from the clinical symptomology arising from their loss, or from the loss of their regulation. The loss of FEF suppression sites may underlie the inability of patients with frontal lobe damage to suppress reflexive saccades to salient targets (Guitton et al. 1985). Conversely, damage to a region of the frontal lobe that limits the activation of suppression sites may underlie the rare clinical syndrome known as "spasm of fixation," characterized by the involuntary delay of saccades in the presence of a fixation target. Consistent with this explanation, a small lesion in the right frontal lobe of a recent patient resulted in leftward saccades that were preferentially delayed and hypometric when a fixation target was present (Johnston et al. 1992). In both syndromes there is a deficit in the patient's ability to voluntarily redirect the gaze to a target or target location of the patient's own choosing.

Because eye movements are normally directed toward informative features and our pattern of fixations changes when we seek new information (Antes 1974; Buswell 1935; Loftus and Mackworth 1978; Mackworth and Morandi 1967; Yarbus 1967), a loss in our ability to direct our eyes toward objects of our choosing limits our ability to interact with and learn from our environment. Thus the inability to systematically scan a picture results in difficulty in analyzing its content, as demonstrated in a patient with a frontal lobe lesion (Luria et al. 1966). In the context of these clinical findings, the present results suggest that suppressive mechanisms within FEF have an important role in regulating the volitional eye movements that facilitate visual perception.

    ACKNOWLEDGEMENTS

  We thank H. R. Friedman for valuable criticisms of the manuscript.

  This work was supported in part by National Eye Institute Grant EY-04740.

    FOOTNOTES

   Present address of D. D. Burman: Institute for Scientific Research and Education, 801 South Lyman Ave., Oak Park, IL 60304-1615.

  Address for reprint requests: C. J. Bruce, Section of Neurobiology, Yale University School of Medicine, 333 Cedar St., Room C303 SHM, PO Box 208001, New Haven, CT 06520-8001.

  Received 9 May 1996; accepted in final form 9 January 1997.

    REFERENCES
Abstract
Introduction
Methods
Results
Discussion
References

0022-3077/97 $5.00 Copyright ©1997 The American Physiological Society