Laboratory of Sensorimotor Research, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892-4435
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ABSTRACT |
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Hanes, Doug P. and Robert H. Wurtz. Interaction of the Frontal Eye Field and Superior Colliculus for Saccade Generation. J. Neurophysiol. 85: 804-815, 2001. Both the frontal eye field (FEF) in the prefrontal cortex and the superior colliculus (SC) on the roof of the midbrain participate in the generation of rapid or saccadic eye movements and both have projections to the premotor circuits of the brain stem where saccades are ultimately generated. In the present experiments, we tested the contributions of the pathway from the FEF to the premotor circuitry in the brain stem that bypasses the SC. We assayed the contribution of the FEF to saccade generation by evoking saccades with direct electrical stimulation of the FEF. To test the role of the SC in conveying information to the brain stem, we inactivated the SC, thereby removing the circuit through the SC to the brain stem, and leaving only the direct FEF-brain stem pathway. If the contributions of the direct pathway were substantial, removal of the SC should have minimal effect on the FEF stimulation, whereas if the FEF stimulation were dependent on the SC, removal of the SC should alter the effect of FEF stimulation. By acutely inactivating the SC, instead of ablating it, we were able to test the efficiency of the direct FEF-brain stem pathway before substantial compensatory mechanisms could mask the effect of removing the SC. We found two striking effects of SC inactivation. In the first, we stimulated the FEF at a site that evoked saccades with vectors that were very close to those evoked at the site of the SC inactivation, and with such optimal alignment, we found that SC inactivation eliminated the saccades evoked by FEF stimulation. The second effect was evident when the FEF evoked saccades were disparate from those evoked in the SC, and in this case we observed a shift in the direction of the evoked saccade that was consistent with the SC inactivation removing a component of a vector average. Together these observations lead to the conclusion that in the nonablated monkey the direct FEF-brain stem pathway is not functionally sufficient to generate accurate saccades in the absence of the indirect pathway that courses from the FEF through the SC to the brain stem circuitry. We suggest that the recovery of function following SC ablation that has been seen in previous studies must result not from the use of an already functioning parallel pathway but from neural plasticity within the saccadic system.
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INTRODUCTION |
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A complete understanding of the
systems within the brain that underlie behavior depends on a series of
experimental steps that include the determination of the relation of
neuronal activity to the behavior, the localization of these neurons
within regions of the brain, the verification of the anatomical
connections between the areas, and the determination of the functional
interactions between these areas. One of the systems that is close to
meeting these demanding criteria is that for the visual guidance of
rapid or saccadic eye movements, a system that extends from cerebral cortex through the superior colliculus (SC) to the midbrain and pons
(for reviews see Andersen et al. 1997; Colby and
Goldberg 1999
; Moschovakis and Highstein 1994
;
Schall 1997
; Sparks and Hartwich-Young
1989
). Within the saccadic system, two of the most intensively
studied areas are the frontal eye field (FEF) in prefrontal cortex and
the SC on the roof of the midbrain, and in the present experiments we
have concentrated on the functional interaction between these two areas
in the monkey.
Investigating this interaction is possible because of the substantial
knowledge already available on the FEF and SC. Both structures are well
identified in the monkey, and maps of the visual receptive fields and
movement fields are established for the SC (Ottes et al.
1986; Robinson 1972
) and are known at least in
outline form for the FEF (Bruce and Goldberg 1985
;
Bruce et al. 1985
; Sommer and Wurtz 2000
;
Suzuki and Azuma 1983
). Neurons in both the FEF and SC
respond to visual stimuli, change their discharge in association with
the initiation of saccades, and continue to discharge during the period
in between (for reviews see Schall 1997
; Sparks
and Hartwich-Young 1989
). Electrical microstimulation of either
the FEF or SC elicits saccades whose vectors depend on the site of
stimulation and are consistent with the vectors represented by neurons
in the region stimulated (Bruce et al. 1985
;
Robinson 1972
; Robinson and Fuchs 1969
;
Schiller and Stryker 1972
). Reversible inactivation of
either area results in temporary deficits for saccades made to visual
or remembered targets (Aizawa and Wurtz 1998
;
Dias and Segraves 1999
; Dias et al. 1995
;
Hikosaka and Wurtz 1985
, 1986
; Lee
et al. 1988
; Sommer and Tehovnik 1997
), although
ablations of either area generally lead to only transient deficits
(reviewed by Schiller 1998
). Finally, the close
anatomical connections between the two areas are well established
(Komatsu and Suzuki 1985
; Stanton et al.
1988
), as are the physiological connections (Everling
and Munoz 2000
; Schlag-Rey et al. 1992
; Segraves and Goldberg 1987
; Sommer and Wurtz
2000
).
The major evidence concerning the possible functional interactions of
the two areas has come from ablation studies. These studies have shown
that while the ability to generate saccades survives the ablation of
either the FEF or SC (Albano et al. 1982; Lynch
1992
; Schiller and Chou 1998
; Schiller et
al. 1980
, 1987
; Wurtz and Goldberg
1972
) when both structures are ablated, saccade generation is
severely impaired (Schiller et al. 1980
). Consistent with this conclusion is the added finding that ablation of the SC has
no effect on saccades generated by stimulating FEF (Schiller 1977
), which was in contrast to the elimination of saccades
evoked by stimulation of occipital cortex following SC ablation
(Keating and Gooley 1988a
; Schiller
1977
). The amalgamation of these studies has led to the
hypothesis that two parallel pathways may control saccades to visual
targets (Keating and Gooley 1988a
,b
; Keating et
al. 1983
; Schiller 1977
; Schiller
and Chou 1998
; Schiller et al. 1980
,
1987
). One pathway goes directly from the FEF to the brain stem premotor circuitry, where saccades are ultimately generated, and the other goes through the SC and then to the brain stem premotor circuitry.
In the course of experiments on the recovery of the ability to make saccades following SC lesions, we made several observations that suggested that this parallel relation between FEF and SC may not be as robust as implied by these previous experiments. In the experiments described here, we tested the contribution of the pathway from the FEF to the brain stem that bypasses the SC. We assayed the contribution of the FEF to saccade generation by evoking saccades with direct electrical stimulation of the FEF. To test the role of the SC in conveying this information to the brain stem saccade generating circuits, we inactivated the SC, thereby removing the circuit through the SC to the brain stem, and leaving only the direct FEF-brain stem pathway. This brief and immediate inactivation of the SC, in contrast to previous ablation experiments, allowed a test of the contribution of the direct FEF-brain stem pathway before any compensatory mechanisms could mask the effect of removing the SC. If the direct FEF to brain stem pathway is sufficient for the generation of saccades, the injection of lidocaine into the SC at a site that represents a saccadic vector similar to the one represented at the FEF stimulation site should not alter the ability to electrically evoke saccades from FEF. The logic of the experiment is illustrated by the schematic drawing of the SC map shown in Fig. 1. The hypothetical extent of SC neurons activated by FEF stimulation (Fig. 1A), which produces a horizontal 10° saccade, is represented by the dark gray circle on the SC movement map. The extent of a hypothetical lidocaine injection made at the same location on the SC map (Fig. 1B) is represented by the light gray circle around the area activated from the FEF. The empirical question is whether saccades of such amplitude and direction can still be evoked from the FEF after that part of the SC has been inactivated.
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We found that SC inactivation substantially altered saccades evoked by FEF stimulation, and we conclude that this alteration is more consistent with the FEF interacting with the SC than being parallel to it. Among the reasons we consider for the difference in the current observations and the conclusions of previous experiments is that our SC inactivations were brief and allowed very little time for recovery, whereas the previous observations probably did allow time for such recovery and reorganization.
A brief report has been published previously (Hanes and Wurtz
1999).
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METHODS |
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In two monkeys, we used standard electrophysiological techniques
to record single cells, electrically stimulate and reversibly inactivate the SC or FEF, and monitor eye movements as described previously (Aizawa and Wurtz 1998; Basso and
Wurtz 1998
). All protocols were approved by the Institute
Animal Care and Use Committee and complied with the Public Health
Service Policy on the humane care and use of laboratory animals.
FEF and SC were first located anatomically with magnetic resonance
imaging (MRI). MRI images of tungsten microelectrodes placed in the
grids (Crist et al. 1988) over FEF or SC guided
exploration of each structure. The two areas were then identified
physiologically by recording from saccade-related neurons and by
evoking saccades at <50 µA threshold. We first mapped the movement
fields of neurons in the FEF and SC by noting where the neural activity
in each area increased before the initiation of saccadic eye movements to visual targets. We then used electrical stimulation through the
microelectrodes in both FEF and SC to estimate the net vector of
saccades represented by the neuronal population near the stimulating microelectrode's tip (biphasic pulses, pulse duration 0.2 ms per phase, and a rate of 350 Hz; ~20 trials). The duration of stimulation was set to be the maximum duration that evoked only one saccade using
suprathreshold stimulation (usually 70-80 ms). The duration was held
constant for the remainder of the experiment.
We injected lidocaine hydrochloride (2%), muscimol (5 µg/µl), or
saline into the SC using a previously described technique (Crist
et al. 1988). For each injection we collected pre- and postinjection files while the monkey performed three interleaved behavioral tasks. In the delayed visually guided saccade task, after
fixation of a central spot (within ±1.5°) for 500-800 ms, the
peripheral visual target appeared and remained present through the end
of the trial. After either a 300- to 500-ms or a 500- to 1,000-ms
delay, the fixation spot disappeared, instructing the monkey to
generate a saccade within 1,000 ms to the target. The target was always
located at approximately the same position as the endpoint of the
evoked saccade from the FEF site being studied. The monkey was given a
liquid reward if the saccade landed within ±8° of the visual target.
In the fixation-stimulation task, the central spot was extinguished
after fixation for 500-800 ms, and electrical stimulation was given
25-125 ms later. Monkeys received a liquid reward 200 ms after
stimulation offset. In the fixation-blink task, after fixation of the
central spot for 500-800 ms, the central spot was turned off for
400-600 ms, and the monkey was required to maintain the same eye
position. After this delay, the fixation spot reappeared, requiring the
monkey to maintain fixation on the central spot for another 500 ms. A
liquid reward was then given. The fixation-blink task served only as a
control to keep the monkey fixating in the absence of a visual
stimulus, and the data from this task will not be discussed further.
Stimulation and injection sites within the FEF and the ipsilateral SC, respectively, were selected so that saccades were evoked by low-threshold stimulation in both areas (~5-10 µA in the SC and ~40-60 µA in the FEF). Once two sites were selected, we determined the current required to evoke saccades from the FEF site during 50% of the fixation-stimulation trials. During data acquisition we stimulated the FEF at currents between 1.3 and 2.3 times this threshold current. Next, we lowered the syringe to approximately 3 mm above the SC and collected the preinjection data. The syringe was then lowered to the SC while stimulating through the internal wire. Once the lowest threshold region of the SC was located, we advanced the syringe 500 µm to compensate for the wire extension beyond the syringe tip and began to pressure inject the liquid into the SC and collect the postinjection data. Volumes ranged from 0.4-4.0 µl for lidocaine and from 0.4-0.8 µl for muscimol. We injected at a rate of 0.3 µl per 30 s. Once the injection was completed and a behavioral effect (e.g., a change in saccade latency or accuracy) on visually guided saccades was evident, the syringe was retracted to ~3 mm above the SC.
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RESULTS |
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Elimination of saccades evoked by FEF stimulation
The first set of experiments tested whether saccades can still be
evoked from the FEF after part of the SC has been inactivated as
outlined in Fig. 1. Figure 2 shows the
results of an experiment (2.4 µl injection) that addressed this
question. We first located regions in the SC and FEF where neurons were
active before saccades to approximately the same part of the visual
field, and determined the amplitude and direction of saccades evoked by
stimulation through the microelectrode. In this experiment stimulation
in the SC evoked saccades to the right with an angle of 30° above the
horizontal and amplitude of 29°. This location on the SC map would
represent the center of the inactivated region following the lidocaine
injection. Stimulation of the FEF evoked saccades to the right that had
an average direction of 2° above horizontal and amplitude of 18°.
Although these vectors appear slightly disparate, they would correspond
to a separation of only ~0.9 mm on the SC motor map (Ottes et
al. 1986) if the projection from FEF to SC is topographically
aligned. This assumption of topography is supported by both anatomical
(Komatsu and Suzuki 1985
; Stanton et al.
1988
) and physiological data (Schlag-Rey et al.
1992
; Segraves and Goldberg 1987
; Sommer
and Wurtz 2000
).
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We next determined that the lidocaine injection had inactivated the SC
by measuring how the saccades generated in a delayed visually guided
saccade task were modified after the injection (Fig. 2A).
This behavioral assay has been shown previously to be a sensitive
indicator of SC inactivation (Aizawa and Wurtz 1998;
Hikosaka and Wurtz 1986
; Lee et al.
1988
). For this experiment we placed the visual target to the
right on the horizontal at an amplitude of 17°, close to the endpoint
of saccades evoked by FEF stimulation, but slightly offset from the
center of the inactivated zone within the SC. As shown in the top
panel of Fig. 2A, prior to the injection the endpoints
of the saccades were within ~0.5° of the 17° visual target.
Within 2-3 min postinjection the error in the saccade endpoints began
to increase, and by about 6 min postinjection the error in the saccade
endpoints peaked at ~3°. The three panels below the graph show the
actual eye movements during the preinjection period, the peak effect
period, and during recovery. During the peak of the effect, the
saccades were consistently short and rotated slightly down; the mean
error was 2.45°, which was significantly different from the 0.48°
error in the preinjection period (t-test, t = 19.9, df = 17, P < 0.01). The observed
hypometria and slight rotation downward would be predicted by the
vector averaging hypothesis of Lee et al. (1988)
since
the inactivated zone on the SC was of slightly larger amplitude and
rotated up compared with the zone activated by the visual target. The
monkey's reaction time to the presentation of the target also
increased significantly (mean preinjection = 184 ms, mean peak
effect = 236 ms, t = 3.5, df = 17, P < 0.01), while the saccadic peak velocity decreased
significantly (mean preinjection = 656°/s, mean peak effect = 584°/s, t = 2.8, df = 17, P < 0.01). These impairments indicate that the lidocaine had inactivated
the region of the SC that includes vectors that are the same as the
vector of saccades evoked by stimulation of the FEF site.
Figure 2B shows the effect of this SC lidocaine injection on the ability to evoke saccades by FEF stimulation. As shown in the top panel, suprathreshold (1.7 times threshold) stimulation at this FEF site prior to the injection elicited saccades during 100% of the fixation-stimulation trials. Within 1-2 min postinjection the percent of saccades evoked began to decline, and by about 5 min postinjection, saccades were rarely made. The three panels below the graph show the actual evoked eye movements; during the peak effect no saccades were elicited.
To determine whether the absence of evoked saccades was simply due to a threshold shift, we increased the current level to 4.3 times threshold (150 µA) for a few trials during the peak lidocaine effect. We did not evoke saccades even at these high current levels. We did not test currents higher than this level for fear of causing tissue damage. Thus this inactivation/stimulation result suggests that the direct FEF-brain stem pathway is not sufficient to generate stimulation-induced saccades in the absence of the pathway that projects through the SC to the brain stem.
One question that inevitably arises when looking at the results shown
in Fig. 2 is why the monkey was able to make visually guided saccades
after inactivation of the SC at the same time that FEF stimulation
failed to evoke them. If the FEF output for generating saccades passes
through the SC, how can this be? The first point to emphasize is that
the monkey did not make normal visually guided saccades:
they were hypometric, had lower velocity, and had longer latency. The
second point is that, unlike the classic ablation experiments, we are
not removing all of the SC, just the region centered on the saccadic
vector that is close to that of the saccade resulting from FEF
stimulation. The rest of the SC remains intact and since the area
active before each saccade may be as large as a quarter of the SC
(Munoz and Wurtz 1995), there should be unaltered SC
available to make a visually guided saccade. The saccades should not be
accurate, however, and they are not. The third point is that with FEF
stimulation only the contribution of this area to saccade generation is
invoked, whereas for the visually guided saccades the presentation of
the visual target is activating the entire oculomotor system. One might
hypothesize that the amount of SC recruited by the entire oculomotor
system for a visually guided saccade may be greater than during a FEF stimulation-evoked saccade. This could easily result in the monkey continuing to produce visually guided saccades, although quite inaccurate, at the same time that FEF stimulation fails to evoke saccades.
Two factors that should influence the ability of FEF stimulation to
evoke a saccade after a SC lidocaine injection are the proximity of the
FEF and SC sites and the size of the injection. The probability of FEF
stimulation failing to evoke a saccade should increase with closer
proximity of FEF and SC sites and with larger SC injections. This is
what we found (Table 1). For ease of
presentation, we divided the 14 lidocaine injections into three
groups based on the volume: large (>2 µl), medium (2 µl, but >1
µl), small (
1 µl). During all five large volume injections, FEF
suprathreshold stimulation failed to evoke saccades postinjection. The
average distance between the FEF and SC sites for these five injections
was 1.1 mm. During two of seven medium volume injections, FEF
suprathreshold stimulation failed to evoke saccades postinjection. The average distance between the FEF and SC sites for these two medium
volume injections was 0.1 mm, while the average distance was 1.4 mm for
the other five injections during which saccades were always evoked.
Thus for medium volume injections, when the distance between the FEF
and SC sites was shorter, the likelihood of failing to evoke saccades
from FEF postinjection was greater. Finally, we always evoked saccades
from the FEF for the two smallest injections (average FEF-SC distance
was 0.4 mm). Figure 3 shows these same
relationships on a graph that relates distance between injections sites
(as indicated by the difference in the vectors) and injection volumes
with a boundary line drawn between those injections that did and did
not lead to the failure of FEF stimulation to evoke saccades.
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One alternative interpretation of these results is that the SC
injections result in the inability to evoke saccades from the FEF
because the lidocaine is deactivating fibers that pass from the FEF
deeper into the brain stem premotor circuitry just rostral to the SC
(Leichnetz 1981). To control for this, we made four injections of the GABA agonist muscimol, which acts on the GABA receptors found on the cell body but not the axon. The muscimol injections also resulted in the inability to evoke saccades from the
FEF (although the effect of muscimol generally lasted around 6 h;
Table 1), which is consistent with lidocaine acting on cell bodies
within the SC rather than axons of passage. Three saline injections had
negligible effects (Table 1), indicating that pressure injection alone
did not produce the deficit.
Change of saccadic vector evoked by FEF stimulation
The results so far are consistent with the SC lying in the
functional pathway between the FEF and the brain stem premotor circuits
because inactivation of the SC with well-positioned large injections of
lidocaine blocked the effect of FEF stimulation. In the other
experiments where the SC lidocaine injections did not block the evoked
saccades (7 of the 14 lidocaine injections; see Table 1 and Fig. 3), we
would still expect to see a change in the saccades evoked from the FEF
after the SC inactivation. There should be a predictable rotation
caused by inactivation of part of the SC map that is
normally activated by FEF stimulation. We can predict what the nature
of the rotation should be by returning to the example used previously
that considered the hypothetical extent of SC neurons activated by
stimulation of an FEF site that represents 10° horizontal saccades
(Fig. 4A). Now, however, we consider SC injection sites that represent vectors below (Fig. 4B) and above (Fig. 4C) the FEF stimulation site,
and assume that the interaction of the FEF and SC follow the vector
averaging hypothesis of Lee et al. (1988). This
hypothesis, which has been supported empirically by experiments on SC
(Lee et al. 1988
), holds that the computation of the
metrics of the saccade is based on a weighted average of the
saccade-related discharges of the entire active population. If this
hypothesis is correct, the consequence of the inactivation of the SC
site representing saccadic vectors below and longer than those produced
by FEF stimulation (Fig. 4B) should be a rotation of the net
vector upward because the component vectors pointing to the lower part
of the field had been blocked. Additionally, one would expect a
decrease in the amplitude of the FEF-evoked vector because the site
representing longer saccades had been inactivated by the injection. In
contrast, Fig. 4C shows a hypothetical injection that was
made at a SC site that represents vectors above and of shorter
amplitude than the FEF site. In this case, FEF-evoked saccades after
the injection should be rotated down and be of longer amplitude than
the FEF preinjection saccades.
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Figure 5 shows the results of an
experiment in which such a rotation was observed following a small
lidocaine injection (0.4 µl) in which saccades were always evoked by
FEF stimulation. Preinjection saccades evoked from the FEF site had an
average direction of 40° (down-right) and amplitude of 15° (Fig.
5A, Fpre), while saccades evoked from the SC site had an
average direction and amplitude of
51 and 22°, respectively (Fig.
5A, S). This corresponds to a separation of 0.6 mm on the SC
map. The mean direction and amplitude during the visually guided
saccade trials (not shown) were not altered noticeably after the
injection, although reaction time became more variable and the peak
saccadic velocity was decreased. Figure 5B shows examples of
saccades evoked by FEF stimulation preinjection and during the peak
injection effect. Immediately after the injection, the vector of the
FEF-evoked saccade rotated upward toward the horizontal meridian and
the amplitude decreased (Fig. 5, C and D). At the
time of the peak effect, saccades evoked by FEF stimulation had an
average direction and amplitude of
16 and 11°, respectively. Thus
the evoked vector rotated upward 24° and the amplitude decreased by
4°.
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Figure 6 shows the results of another experiment in which the FEF-evoked vector rotated following a lidocaine injection (1.6 µl). Preinjection saccades evoked from the FEF site had an average direction of 27° (up-right) and an amplitude of 9° (Fig. 6A, Fpre), while saccades evoked from the SC site had an average direction and amplitude of 52 and 3° (Fig. 6A, S), corresponding to a separation of 1.1 mm on the SC map. Immediately after the injection, the vector of the FEF-evoked saccade rotated downward toward the horizontal meridian (Fig. 6, B and C), and the amplitude increased (Fig. 6, B and D). At the time of the peak effect, the evoked vector had rotated downward 26°, and the amplitude increased by 2°.
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A change in the direction and amplitude of the FEF-evoked vector following a lidocaine injection was observed in all seven injections during which saccades continued to be evoked from the FEF after an SC injection (Fig. 7). Figure 7A plots the size and direction of the rotation on the ordinate so that upward rotation is indicated by positive values, downward by negative values. The abscissa shows the relative direction of the FEF and SC vectors. Cases where the FEF vector was below that of the SC are given minus values in the left half of the graph, and those in which the FEF vector was above the SC vector are positive and on the right. From the logical consideration of the direction of rotation that should result from vector averaging, we would expect the points to fall into only two quadrants of the graph. The bottom left quadrant should contain data points where the FEF preinjection vectors were below the SC vector, and the rotation following the injection was down. The top right quadrant should contain data points where the FEF preinjection vector was above the SC vector, and the rotation following the injection was up. This is what we found: all of the points in Fig. 7A fell into these two quadrants. The FEF vector never rotated down when the FEF preinjection vector was above the vector evoked at the SC site (bottom right quadrant) and never rotated up when the FEF preinjection vector was below the vector evoked at the SC site (top left quadrant). A similar effect occurred with the amplitude of the FEF evoked vector (Fig. 7B). The amplitude of the FEF vector decreased during the three injections in which the amplitude of the FEF preinjection vector was less than the vector evoked at the SC site (bottom left quadrant). Additionally, the amplitude of the FEF vector increased during three of four injections in which the amplitude of the FEF preinjection vector was greater than the vector evoked at the SC site (top right quadrant). These results show that the vector of the evoked saccade is modified in the way that would be predicted by the vector-averaging hypothesis.
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DISCUSSION |
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We stimulated the FEF before and after reversibly inactivating the SC to investigate the relative contributions of the direct pathway from FEF to the brain stem premotor circuitry and the indirect pathway through the SC. Our logic was that by inactivating the SC we temporarily removed the indirect pathway and thereby revealed the contribution of the direct pathway. We found that inactivation of the SC alters the effect of FEF stimulation, and we made two principle observations. First, the FEF-evoked saccades were eliminated when the FEF and SC vectors were similar or when the volume injected into the SC was large. Second, SC inactivation did not eliminate saccades evoked by FEF stimulation when the FEF and SC vectors were more widely separated, or the injection was small. Instead, the inactivation led to a rotation of the vectors of the FEF-evoked saccades away from the vector represented at the SC injection site. We think that these observations provide insight into the relative contributions of the direct and indirect FEF pathways to the brain stem premotor circuits, the interaction between the signals conveyed by the FEF and SC, and the nature of the recovery process following lesions, and we will discuss each in turn.
Do the FEF and SC represent parallel pathways?
When the SC region that we inactivated represented nearly the same saccadic vector as the saccade evoked from the FEF, we were able to block the saccades normally elicited by FEF stimulation. Whatever remaining pathways outside of this inactivated region of the SC that pass from the FEF to the brain stem premotor circuits were not sufficient to generate saccades. We conclude that this does not support the idea of the direct and indirect pathways functioning in parallel but rather is more consistent with the output of the FEF being dependent on the pathway through the SC.
There are, however, several assumptions in our experiments that have to
be made before such a conclusion can be accepted. With respect to the
FEF, we assume that evoking saccades by electrical stimulation, rather
than relying on those naturally occurring, does not in some substantial
fashion alter the way in which the FEF communicates with the brain
stem. We did such stimulation to specifically involve one brain region,
as has been done in many previous FEF experiments (e.g.,
Robinson and Fuchs 1969; Schiller 1977
;
Schlag and Schlag-Rey 1990
). We cannot, however, reject
the notion that this produces abnormal output from the area. For the SC
inactivation that eliminated the effect of FEF stimulation, we assume
that the lidocaine injection functionally removes neurons with the same
set of saccade vectors as the area stimulated in the FEF, but since we
do not know the exact size of each injection, we can only infer that
this was the case. In fact the necessity of indicating not only the
alignment of the FEF and SC vectors but the size of the injection as
well serves to emphasize this uncertainty. We tested the efficacy of
the injection by the effect on visually guided saccades to targets in
the region of the visual field that should have been affected by the
injection, but the limited points tested due to the brevity of the
lidocaine effect limited our assessment of the size of the inactivated
area. The finding that larger lesions were required to eliminate the effect of the FEF stimulation makes sense in that a larger lesion should remove a larger fraction of neurons that share vectors with the
site of FEF stimulation. Finally, with the SC lidocaine injections, we
also assume that we are inactivating the pathway through the SC and not
inadvertently the direct pathway. The opportunity for this to occur
would lie primarily in the spread of the lidocaine into fibers passing
below the SC. While the brevity of the lidocaine effect makes
substantial spread unlikely, we also did several experiments using
muscimol, a GABA agonist that would act on synapses not on fibers of
passage, and we obtained essentially the same results as with
lidocaine. The possibility also exists that the lidocaine could spread
to the burst neurons in the brain stem; however, given the brevity of
the injection and the distance that the lidocaine would need to spread
to influence the burst neurons, this possibility seems implausible.
Thus while our experiments require specific assumptions for their
interpretation, we regard the assumptions as both reasonable and
frequently made.
Our conclusion that the failure to elicit saccades from the FEF
following inactivation of the SC indicates that the direct FEF to brain
stem pathway is not sufficient to generate saccades is clearly in
conflict with the previous conclusions based on joint FEF and SC
lesions and the effect of FEF stimulation following SC ablation (see
review by Schiller 1998). We believe that this apparent
conflict can be explained by differences in the experiments, particularly in the time at which the FEF function was tested after
removal of the SC.
The previous stimulation/lesion results (Keating and Gooley
1988a; Schiller 1977
) or the paired lesion
results of Schiller et al. (1980
; see review by
Schiller 1998
) are well established and based on not one
but a series of related experiments. Several permanent lesion
experiments have shown that ablation of the SC or FEF alone largely
spared the monkey's ability to make saccades to simple visual targets
(Albano et al. 1982
; Lynch 1992
;
Schiller and Chou 1998
; Schiller et al.
1980
, 1987
; Wurtz and Goldberg 1972
). Several other combinations of lesion and stimulation
experiments have also lent support to the concept of parallel pathways.
In a series of experiments that tested the ability of occipital and parietal cortex stimulation to evoke saccades following combinations of
posterior parietal, FEF, and SC lesions, Keating and Gooley (1988a)
concluded that visual cortex appears to guide saccades through either of two routes, one through the tectum and the other through the frontal lobe (see Keating et al. 1983
;
Schiller 1977
). Similarly, Lynch (1992)
showed that ablation of FEF and posterior parietal cortex also
precludes initiation of visually guided saccades that could be
interpreted as eliminating both the parietal pathway through the SC and
the pathway from FEF that does not require the SC. Thus the picture
that emerges from this series of ablation experiments is that there is
one pathway from occipital and parietal cortex that is dependent on the
SC and another pathway that emanates from the frontal cortex that
is not.
A common characteristic of these experiments, which might be critical
in comparing those results to the present results, is that the
ablations were followed by a period of days to weeks before the
behavioral effects of the lesions on the saccadic system were tested.
This time interval may have been sufficient to allow recovery that
involves more efficient use of existing pathways or a reorganization of
those pathways. These pathways would then be sufficient for the
generation of saccades after this recovery even though they are
not sufficient in the intact animal. In contrast in our
experiments, the lidocaine injection removed the SC functionally within
minutes, allowing very little time for recovery, and may have thus
revealed the nature of the interactions in the normal monkey more
accurately. We cannot rule out the possibility that short-term plastic
changes, such as second-messenger systems up- or down-regulating
various receptor mechanisms, may occur during the lidocaine injections.
The fact that SC inactivation precluded FEF stimulation, however,
suggests that these short-term changes did not significantly influence
the neural system. Only one previous experiment has looked at the
interaction of the FEF and SC without such time for recovery. In an
elegant dual cooling probe experiment, Keating and Gooley
(1988b) explored the effects of separate and combined
inactivation of both structures. As in the previous ablation experiments, inactivation of either structure produced mild saccadic deficits, and the deficits were greater when the FEF and SC were cooled
simultaneously. While inactivation of both FEF and SC did not eliminate
visually guided saccades as might be expected if the two areas act in
parallel, on this point the experiment is inconclusive because the
inactivated regions only partly overlapped. As shown in Fig. 3 of
Keating and Gooley (1988b)
, the FEF probe affected
mainly saccades to the upper left hemifield while the SC probe affected
the lower left hemifield. The additive effect of cooling both the FEF
and SC does not preclude the FEF and SC being entirely serial. From the
visual field deficit map it is apparent that part of the SC remains
intact, and since the area active before each saccade may be as large
as a quarter of the SC (Munoz and Wurtz 1995
), there
should be unaltered SC available to make a visually guided saccade. If
the input to the remaining active SC comes from the FEF and those
inputs are cooled, one would expect to see an increase in the saccadic
deficit as they found. If this interpretation of their results is
correct, we would also expect the affected zone of the visual field to
increase in size following the combined FEF and SC inactivation, and
this is in fact what they observed. While these experiments do not unequivocally support a serial organization of the FEF and SC, they
also do not lend support to a parallel organization either, nor were
they designed to do so.
It is important to point out that we are not suggesting that the FEF
has no influence on saccade generation in the nonablated monkey. Brief
inactivations of the FEF (Dias and Segraves 1999; Dias et al. 1995
; Sommer and Tehovnik
1997
) or the SC (Aizawa and Wurtz 1998
;
Hikosaka and Wurtz 1985
, 1986
; Lee
et al. 1988
) have shown substantial changes in the monkey's
ability to generate saccades, which in itself suggests that the direct
and indirect pathways from FEF to the brain stem are not strictly
parallel. Our results simply imply that in the nonablated monkey the
direct FEF to brain stem pathway is not sufficient to generate a
saccade. Thus we conclude that the predominate functional output from
the FEF to the brain stem is funneled through the SC. This conclusion is consistent with both of the two principle findings of the present experiments and with a number of previous observations. First, the
anatomical connections to the SC from the FEF are clear and prominent
and repeatedly demonstrated (Huerta et al. 1986
;
Komatsu and Suzuki 1985
; Leichnetz 1981
;
Stanton et al. 1988
). Second, the physiological
connections between FEF and SC have been demonstrated by antidromic
stimulation (Segraves and Goldberg 1987
), and these are
topographically organized (Schlag-Rey et al. 1992
;
Sommer and Wurtz 2000
).
The implication is that over time after SC ablation the connections
other than those through the SC would become more efficient, and the
metrics of saccades would return to almost normal values. The exact
nature of the pathways participating in such a recovery following SC
lesions has not been determined. Anatomical studies (Büttner-Ennever and Horn 1997; Moschovakis
and Highstein 1994
) have shown that the FEF projects directly
to the omnipause neurons in the brain stem, and this has been confirmed
physiologically (Segraves 1992
). Neither anatomy nor
physiology has revealed any direct projection from FEF to
the brain stem burst neurons that ultimately generate saccades in a
given direction. The direct projection to the omnipause neurons could
not convey the directional information necessary for saccade
generation since, by definition, they discharge for saccades of all
directions. Other multi-step pathways are available, however, and might
be strengthened over time. One such multi-step pathway would pass
through the nucleus reticularis tegmenti pontis (Huerta et al.
1986
; Stanton et al. 1988
), and a lesion along
this pathway in conjunction with one in the SC would be expected to
eliminate saccade generation, as does the joint FEF and SC lesion. On
the other hand, if the SC were only partially instead of completely
removed, as is the case in many of the lesion experiments (for example,
Wurtz and Goldberg 1972
), then the reorganization may
occur within the SC itself. Neither of these mechanisms of recovery has
yet been investigated.
Interaction of FEF and SC
Our second principle finding is that when the vector of the
saccade resulting from FEF stimulation was not well aligned with the
net vector of the area removed by the SC inactivation, a saccade was
always evoked from the FEF stimulation, but its vector was rotated. The
rotation was consistent with the removal of a fraction of the SC
movement map that is normally activated by FEF stimulation (Figs.
5-7). The nature of this rotation is what would be expected if the
region activated by the FEF stimulation had its effect on saccade
generation by acting directly on the SC movement map. In fact, these
interactions between the FEF and SC vectors in our experiments are
remarkably similar to the interactions within the SC shown by
Lee et al. (1988) following SC inactivation, and lend
indirect support to their interpretation of vector averaging within the
SC. This vector average effect is also consistent with the vector
averaging effects seen between two stimulation sites in the SC
(Robinson 1972
) and, more importantly, the vector
average seen with combined stimulation of FEF and SC (Schiller
et al. 1979
).
A series of stimulation and recording experiments by Schlag,
Schlag-Rey, and their collaborators (summarized in Dominey et al. 1997) revealed several features of the interaction of FEF and SC, some of which are directly relevant to the present
observations. First, they found that stimulation of FEF produced
excitation in SC neurons that had the same vector as the site
stimulated in the FEF (Schlag-Rey et al. 1992
), and this
observation was one of the key facts in designing our experiments.
Second, evidence obtained with the use of the colliding saccade
paradigm (see review by Schlag and Schlag-Rey 1990
)
provides evidence for an interaction between FEF and SC that occurs
below the level of the SC, and would appear to be evidence for a direct
pathway from FEF to the brain stem premotor circuits. In this paradigm,
FEF stimulation given while another saccade is in flight can generate a
saccade that has a different vector than the one that would be elicited from the FEF when the eye is stationary. When neurons were recorded in
the SC during such colliding saccades (Schlag-Rey et al.
1992
), their activity followed that expected for the site of
FEF stimulation and not the actual saccade made. Thus since there is an
apparent conflict between the signals generated by the FEF and SC, the authors conclude that the FEF overrides the signal generated by the SC
(Dominey et al. 1997
). If this were the case, in our
experiment FEF stimulation should continue to evoke saccades following
SC inactivation. Additionally, in the seven cases in which saccades continued to be evoked following SC inactivation, the vector should not
rotate as we observed because the FEF should override the SC
(Dominey et al. 1997
). Further experiments will be
required to resolve this issue.
Our experiments, however, do not preclude the possibility that the interaction of the FEF and SC occurs at a point other than within the SC. For example, one possibility is that the interaction of FEF and SC occurs at a brain stem site where the SC and the FEF pathways come together. If this were the case, this target site would require that the projections from FEF and SC be in register (but not necessarily on a SC-like map) to obtain the vector rotations we found following SC inactivation. Another possible interaction between the FEF and SC is that the brain stem premotor circuit must receive input from both the FEF and SC to initiate a visually guided saccade. In one variant of this interaction, SC inactivation would result in a localized suppression within the brain stem so that a saccade could not be generated from FEF activation. Note that such a hypothesized suppression would have to be localized because it is only saccades to one part of the visual field that are modified. Note also that, while both of these interpretations (i.e., that the FEF and SC interact within the SC or outside of the SC) are viable given our results and current knowledge of the saccadic system, in both interpretations the normal functioning of the FEF is still dependent on the integrity of the SC.
Recovery of function
Our inference is that over time reorganization within the saccadic system can compensate for the loss of the SC and produce the apparent parallel pathways that have been clear when the behavioral effects of permanent lesions have been tested weeks to months after the lesions. If this inference is correct, then the recovery of function is due to neural plasticity within the saccadic system, and this reorganization opens the possibility of using this system as a model to study recovery of function following brain damage. The precision in measuring the output of the saccadic system, the outline of a circuit in the brain that underlies it, and the identity of a number of areas that interact provides a system that can be evaluated for changes following brain damage. Such issues as where the plasticity occurs (e.g., within the SC) and what factors control recovery (e.g., behavioral practice) can be directly investigated.
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ACKNOWLEDGMENTS |
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We thank our colleagues at the Laboratory of Sensorimotor Research and J. Schall for discussions of previous versions of the manuscript and the staff of the Laboratory of Sensorimotor Research for facilitating this work. We thank the Laboratory of Diagnostic Radiology for providing the MRIs.
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FOOTNOTES |
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Address for reprint requests: D. P. Hanes, National Eye Institute, National Institutes of Health, Bldg. 49, Rm. 2A50, Bethesda, MD 20892 (E-mail: dph{at}lsr.nei.nih.gov).
Received 8 August 2000; accepted in final form 18 October 2000.
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REFERENCES |
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