Microstimulation of the Lateral Wall of the Intraparietal Sulcus Compared With the Frontal Eye Field During Oculomotor Tasks

Hajime Mushiake,1,2 Naotaka Fujii,1 and Jun Tanji1

 1Department of Physiology, Tohoku University School of Medicine, Sendai, 980; and  2Precursory Research for Embryonic Science and Technology, Japan Science and Technology Corporation, Japan


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INTRODUCTION
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Mushiake, Hajime, Naotaka Fujii, and Jun Tanji. Microstimulation of the lateral wall of the intraparietal sulcus compared with the frontal eye field during oculomotor tasks. We compared the effects of intracortical microstimulation (ICMS) of the lateral wall of the intraparietal sulcus (LIP) with those of ICMS of the frontal eye field (FEF) on monkeys performing oculomotor tasks. When ICMS was applied during a task that involved fixation, contraversive saccades evoked in the LIP and FEF appeared similar. When ICMS was applied to the FEF at the onset of voluntary saccades, the evoked saccades collided with the ongoing voluntary saccade so that the trajectory of voluntary saccade was compensated by the stimulus. Thus the resultant saccade was redirected and came close to the endpoint of saccades evoked from the fixation point before the start of voluntary saccade. In contrast, when ICMS was applied to the LIP at the onset of voluntary saccades, the resultant saccade followed a trajectory that was different from that evoked from the FEF. In that case, the colliding saccades were redirected toward an endpoint that was close to the endpoint of saccades evoked when animals were already fixating at the target of the voluntary saccade. This finding suggests that the colliding saccade was directed toward an endpoint calculated with reference to the target of the voluntary saccade. We hypothesize that, shortly before initiation of voluntary saccades, a dynamic process occurs in the LIP so that the reference point for calculating the saccade target shifts from the fixation point to the target of a voluntary saccade. Such predictive updating of reference points seems useful for immediate reprogramming of upcoming saccades that can occur in rapid succession.


    INTRODUCTION
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INTRODUCTION
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As a result of recent studies, the lateral intraparietal area (LIP) of the primate cerebral cortex is now thought to be involved in oculomotor control. Neurons in the LIP are active before saccadic eye movements (Andersen 1995; Snyder et al. 1997), and electrical stimulation of the LIP evokes saccadic eye movements (Thier and Andersen 1996). Anatomically, the LIP is connected with the frontal eye field (FEF) (Stanton and Bruce 1995) and brain stem oculomotor areas. These reports led to the question of how the two cortical oculomotor areas, the LIP and the FEF, differ in their control over saccadic eye movements.

The technique of intracortical microstimulation (ICMS) is useful in revealing the way in which output from the cortical oculomotor areas influences oculomotor behavior, especially if the ICMS is applied during the performance of a variety of oculomotor tasks (Fujii et al. 1995; Schlag and Schlag-Rey 1990). Thus we attempted to compare the properties of saccades evoked by microstimulation of the LIP and FEF under two different conditions. In the first condition, we analyzed saccade vectors evoked by stimulation of the two areas during a task involving eye fixation and compared the effects of eye position on the evoked saccades. In the second, we applied stimulation while monkeys were performing an oculomotor task that produced saccades directed toward memorized targets. By applying stimulation shortly before or at the onset of voluntary saccades, we compared saccade trajectories evoked in the LIP and FEF.


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We studied the effects of ICMS in both hemispheres of two monkeys (Macaca fuscata) during the performance of the trained oculomotor tasks. Eye positions and movements were monitored with an infrared monitor system with a time resolution of 4 ms. The animal sat in a primate chair with its head and arms restrained, facing a panel equipped with five light-emitting diodes (LEDs). The central LED was directly in front of the animal, and the other four LEDs were 9.5 cm (20° of visual angle) above, below, left, and right of the central LED. The animals were trained to perform two tasks: a fixation task and a memory-guided saccade task. In the fixation task, an LED selected randomly from the five LEDs was illuminated as the target of fixation, and the monkey was required to fixate on the target. If fixation was maintained for 1.5-2.0 s within a 2° fixation window, a reward of fruit juice was delivered. In the memory-guided saccade task, the monkeys were first required to maintain fixation on the fixation LED for 1.0-1.5 s. After this, a second LED that served as a cue for a future saccade target was illuminated for 100 ms. If the animals maintained fixation on the original LED for an additional 500-800 ms, the original LED was dimmed. This served as a GO signal. The monkeys were rewarded if the second LED was captured with a saccade within 400 ms of the GO signal.

While the monkeys performed these tasks, we applied ICMS (330 Hz, 10-50 negative pulses, 0.2-ms duration) under two different conditions. In the first, ICMS was delivered during the fixation task (fixation ICMS), 500 ms after the onset of fixation. In the second, the initiation of ICMS was timed to occur shortly before or to coincide with the onset of the memory-guided saccade (saccade-onset ICMS).

We penetrated the LIP, where ICMS evoked saccades with currents of 30-120 µA. The FEF is located in the anterior wall of the arcuate sulcus, where saccades were elicited by ICMS with low currents (<50 µA). We used two measures for the quantitative analysis of evoked saccades. First, to quantify the effect of eye position on saccade vectors, a regression analysis was performed with the method reported by Russo and Bruce (Fujii et al. 1998; Russo and Bruce 1993). According to a linear regression model, the size of evoked saccades E(P) is expressed as E(P) = EC + (R × P), where EC is constant saccade vector for each stimulation site, P is initial eye position, and R is regression coefficient. If the vector of evoked saccade is not affected by the initial eye position (fixed vector), R is close to 0, and E(P) = EC. On the other hand, if the evoked saccades converge on a point (converging vector), E(P) + P = EC, and R is close to -1. Second, we estimated the point of origin of evoked saccades colliding with voluntary saccades (evoked by saccade-onset ICMS) by using a method devised by Schlag for the analysis of colliding saccades in the FEF (Schlag and Schlag-Rey 1990). This analysis was based on the assumption that the endpoints of the colliding saccades could be determined by the vectorial displacement from reference positions that traversed the trajectory of the voluntary saccades. The reference positions were calculated by subtracting the vectors of saccades evoked during periods of fixation from the endpoints of the colliding saccades. The recording sites were verified by histological analysis (Mushiake 1997).


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We used 96 stimulus sites to localize the FEF to the anterior wall of the arcuate sulcus. There were 58 stimulus sites in the LIP (Fig. 1, A and B), lateral to the transitional border area defined by Thier and Andersen (1996). We first examined the effects of eye positions on evoked saccades from the LIP and the FEF to see whether there was any significant difference in eye position effects in our sampled data from the LIP and FEF. Saccades evoked by fixation ICMS of the LIP were contraversive and appeared similar to saccades evoked form the FEF. To examine the effects of eye position on evoked saccades in the LIP, the horizontal and vertical regression coefficients were plotted in Fig. 1C. The mean (± SD) values were -0.14 ± 0.13 and -0.10 ± 0.11. These values indicated that evoked saccades in our data were only moderately influenced with eye position signals. Statistically, the eye position effects in the FEF and LIP were not significantly different. Although detailed studies of eye position effects on saccades evoked by ICMS of the LIP were not attempted in this study (cf. Kurylo and Skavenski 1991; Shibutani et al. 1984), these data showed that we surveyed the portion of the intraparietal cortex where the position effects were not much different from those observed in the FEF. Thus we did not study the ICMS effects in the intercalated zone (Thier and Andersen 1996) of the intraparietal cortex where the eye position effects are prominent. The latencies of evoked saccades of our samples were also statistically not different in the LIP (55.7 ± 7.7 ms) and FEF (57.3 ± 10.0 ms).



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Fig. 1. A: top view of the cerebral cortex showing the location of the stimulus sites in the frontal eye field (FEF) (left) and lateral wall of the intraparietal sulcus (LIP) (right). B: points of microelectrode entry used for stimulation of the right LIP are shown in an enlarged view. Saccades were elicited from the lateral wall of the intraparietal sulcus (IPS). C: distribution of horizontal and vertical regression coefficients calculated from saccades evoked from the LIP at 19 penetration sites (cf. Russo and Bruce 1993). D, left panels: trajectories of saccades evoked from 3 fixation points (FP0-FP3) by fixation intracortical microstimulation (ICMS) in FEF (top) and LIP (bottom). D, right panels: trajectories of saccades evoked by saccade-onset ICMS in FEF (top) and LIP (bottom). Four examples of saccade trajectories colliding on voluntary saccades directed to 2 targets (T1 and T2) are shown. To the right of each panel, the relationship between the colliding saccades and vectors of saccades evoked by fixation ICMS from the fixation point (FP0) and from two targets of voluntary saccades (T1 and T2) is drawn.

Colliding saccades were analyzed in the FEF and LIP in the two monkeys. As reported previously, when ICMS was delivered in the FEF at the onset of a voluntary saccade (saccade-onset ICMS), the evoked saccade collided with the ongoing voluntary saccade. The colliding saccades were directed toward the endpoints (E0) of saccades evoked by fixation ICMS for each fixation point (Fig. 1D, top right). In other words, the initial part of an ongoing voluntary saccade was compensated by the saccade-onset ICMS. The properties of these compensatory saccades observed in the FEF were consistent with previous reports (Dassonville et al. 1992; Schlag and Schlag-Rey 1990). In contrast, when saccade-onset ICMS was delivered in the LIP, the evoked colliding saccade behaved differently, as shown in Fig. 1D (bottom right). Compensation for the initial part of the voluntary saccade was not observed in the LIP. Instead the colliding saccades were first directed toward the target of voluntary saccades (T1 or T2), and the evoked saccade was subsequently directed toward an endpoint (E1 or E2). The endpoint of colliding saccade corresponded to the endpoint (E1 or E2) of saccades evoked from the target of voluntary saccades by fixation ICMS (see Fig. 1D, left). Thus the colliding saccades evoked in the FEF and LIP terminated at entirely different endpoints.

We further examined saccade trajectories evoked in the FEF and LIP by changing initial eye positions and direction of voluntary saccades. As shown in the Fig. 2A, left panel, saccade-onset ICMS was delivered to the left FEF when voluntary saccades were directed from the central fixation point (F0) to four peripheral targets (T1-T4). The resultant saccades were redirected and came close to the endpoint (E0) of saccades evoked by fixation ICMS from the central fixation point (F0), regardless of where the targets of voluntary saccades were located, and similarly in Fig. 2A, right panel. Four evoked saccades collided with voluntary saccades from the peripheral fixation points (F1-F4) toward the central target (T0). Colliding saccades were redirected toward the endpoints (E1-E4) of saccades evoked from the peripheral fixation points by fixation ICMS. These results indicated that the endpoint of evoked saccades in the FEF was determined with reference to fixation points. On the other hand, saccade-onset ICMS was delivered to the LIP, when voluntary saccades were directed from the central fixation point (F0) to peripheral targets. As shown in Fig. 2B (left), trajectories of colliding saccades were redirected toward endpoints (E1-E4) of saccades evoked from the targets (T1-T4) of voluntary saccades by fixation ICMS. When voluntary saccades started from four peripheral fixation points to an central target (Fig. 2B, right), the colliding saccades evoked by saccade-onset ICMS were redirected to the endpoint (E0) of saccades evoked from the central target point (F0) by fixation ICMS. These results indicated that endpoints of evoked saccades in the LIP were determined with reference to the target of voluntary saccades.



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Fig. 2. A: trajectories of saccades evoked by saccade-onset ICMS of the left FEF. Left: evoked saccades colliding on voluntary saccades starting from the central fixation point (F0) to 4 peripheral targets (T1-T4). Dashed arrow represents saccades evoked from the central fixation point (F0) by fixation ICMS. Right: evoked saccades colliding on voluntary saccades starting from 4 peripheral fixation points (F1-F4) to the central target. Dashed arrows are the vectors of saccades evoked from the peripheral fixation points by fixation ICMS. B: trajectories of saccades evoked by saccade-onset ICMS of the right LIP. Left: evoked saccades colliding on voluntary saccades starting from the central fixation points (F0) to 4 peripheral targets (T1-T4). Dashed arrows represent saccades evoked from the peripheral target points (T1- T4) by fixation ICMS. Right: evoked saccades colliding on with voluntary saccades starting from the peripheral fixation points (F1-F4) to the central target. Dashed arrow indicates the vector of saccades evoked from the central target by fixation ICMS. C, left panel: trajectories of saccades evoked by stimulation of the LIP shortly before the onset of voluntary saccades (presaccade ICMS). On the right, reference points (Rn) were estimated from the endpoints of evoked saccades (En). The reference points are represented by small dots along the trajectory of the voluntary saccade. The timing of the presaccade ICMS relative to the onset of the voluntary saccade is indicated to the right of each reference point.

In the LIP, when ICMS was delivered at the same time as the GO-signal appeared (~250 ms before the onset of a voluntary saccade), the evoked saccades appeared to be fixed vector and were identical to the saccades evoked by fixation ICMS. These saccades differ from saccades evoked by saccade-onset ICMS. This difference suggests that dynamic alterations occurred in the LIP and/or its output structures during the reaction interval between the appearance of the GO-signal and the onset of a saccade, altering the effect of ICMS. To determine exactly how and when the fixed vector saccades are transformed to colliding saccades during the reaction interval, we systematically applied ICMS at various times between the appearance of the GO-signal and the onset of a voluntary saccade (presaccade ICMS). We found that the evoked saccades and the intended saccades interacted, giving rise to the interactive saccades shown in Fig. 2C. The endpoint of the evoked saccades shifted gradually, depending on the length of time that the ICMS preceded the onset of the saccade. At greater intervals (-30 ms to -74 ms), the evoked saccade was directed toward an endpoint (E1-E4) that was closer to the endpoint of the saccade elicited at the fixation point. Next we determined the reference points (R1-R4) for interactive saccades evoked in the LIP. As shown in Fig. 2C, we did this by drawing a line from the endpoint of the interactive saccade (Ei) parallel to the saccade vector evoked by the saccade-onset ICMS. The reference point (Ri) was where this line intersected the trajectory of the voluntary saccade. Subsequently, we obtained data on 40 reference points calculated from saccades that were evoked shortly before and after the onset of voluntary saccades. In Fig. 3, we plotted the distance between the reference point and the FP (expressed as a relative value by dividing by the distance from the fixation point to the saccade target) against the time relative to the saccade onset. We used an exponential curve fitting method that was previously used to evaluate the time course of changes in the reference point in the FEF (Schlag and Schlag-Rey 1990). The reference points obtained by LIP stimulation (y) were fitted (goodness of fit >90%) by the curve y = 0.992-0.051exp(-x/28.8), where x is the time in milliseconds relative to the saccade onset. Shifts in the reference points were initiated ~85 ms before the onset of a saccade and completed just around its offset. In Fig. 3, we include the function y = 0.963-0.753exp(-x/76.9), reported by Schlag for FEF stimulation data, with our LIP data. The onset of a reference shift in the FEF is estimated to start 18 ms before the saccade. Thus the reference shift in the LIP started 67 ms sooner than in the FEF.



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Fig. 3. Reference points for saccades that were evoked simultaneously with or close to the onset of voluntary saccades are plotted against time, relative to the onset of the voluntary saccade. The ordinate shows the normalized distance between the reference points (Rn) and the fixation point (FP) relative to the distance between the fixation point and the target of each voluntary saccade (Tg). The 40 reference points represent the data obtained from 14 stimulus sites.


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The main discovery of our study is that colliding saccades evoked at the onset of voluntary saccades in the LIP terminated at positions that were determined by the target of an intended saccade. This is different from the colliding saccades evoked in the FEF, where the endpoint is determined by the point of fixation. As Schlag demonstrated in the FEF (1990), the compensation occurs in the initial part of the saccade. This difference is not due to the latency of the evoked saccades nor due to the eye position effect because the latencies and eye position effects of saccades evoked in the LIP were not significantly different from those of saccades evoked in the FEF. During fixation, the reference point for saccade generation was the fixation point. However, shortly before the initiation of a voluntary saccade, the reference point shifted to the saccade target. Further analysis suggested that the shift in the reference point from the fixation point to the target of a voluntary saccade started 85 ms before the onset of the voluntary saccade, and 67 ms ahead of the shift in the FEF (Schlag and Schlag-Ray 1990). We propose that the LIP is involved in dynamic functional alterations that update the reference point before the initiation of a voluntary saccade. Updating reference points in the LIP seems to be consistent with the idea of predictive remapping in the LIP proposed by Duhamel et al. (Colby et al. 1995; Duhamel et al. 1992a). The predictive remapping of visual responses was also reported in the FEF by Umeno and Goldberg (1997). However, in their studies, it was not clear whether there were any differences in predictive visual responses of the LIP and FEF neurons. Quantitative studies on the timing of anticipatory responses are necessary to establish whether the process in the LIP may lead that of the FEF.

What is the implication of these findings for the role of the LIP in controlling voluntary saccades? Our data suggest that the LIP is useful in programming the second saccade in double-step saccades by an anticipatory shift of the reference point. This view is consistent with reports on parietal lesions (Colby et al. 1995; Duhamel et al. 1992b) in which patients had difficulty in generating the second saccade during double-step saccades. Neurons in the LIP were selectively activated before the second saccade of double-step saccades (Gnat and Andersen 1988; Mazzoni et al. 1996). Reference points are important for the vector calculation involved in the generation of multiple saccades. As reviewed by Schlag and Schlag-Rey in 1990, different effects of colliding saccades suggest that evoked saccades are directed to virtual targets from different internal reference points. If the reference point in the LIP is updated before the reference point in the FEF, the LIP would use this advantage to reprogram the second saccade in a double-step saccade before reprogramming occurred in the FEF.

Combining our results with those of previous studies, one aspect of LIP function seems to reside in anticipatory remapping of reference points for impending saccades. Further experiments are necessary to understand how the LIP is involved in the actual performance of oculomotor tasks.


    ACKNOWLEDGMENTS

We thank M. Kurama and Y. Takahashi for technical assistance.

This work was supported by PRESTO, JST, and the Ministry of Education, Science and Culture of Japan (09680809, 08279101, 09308032, and 08044236).


    FOOTNOTES

Address reprint requests to J. Tanji.

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 24 August 1998; accepted in final form October 1998.


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