Electrical Stimulation of the Frontal Eye Field in a Monkey Produces Combined Eye and Head Movements

Tyson A. Tu and E. Gregory Keating

Department of Cell and Developmental Biology and the Program in Neuroscience, SUNY Upstate Medical University, Syracuse, New York 13210


    ABSTRACT
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
REFERENCES

Tu, Tyson A. and E. Gregory Keating. Electrical Stimulation of the Frontal Eye Field in a Monkey Produces Combined Eye and Head Movements. J. Neurophysiol. 84: 1103-1106, 2000. The frontal eye field (FEF), an area in the primate frontal lobe, has long been considered important for the production of eye movements. Past studies have evoked saccade-like movements from the FEF using electrical stimulation in animals that were not allowed to move their heads. Using electrical stimulation in two monkeys that were free to move their heads, we have found that the FEF produces gaze shifts that are composed of both eye and head movements. Repeated stimulation at a site evoked gaze shifts of roughly constant amplitude. However, that gaze shift could be accomplished with varied amounts of head and eye movements, depending on their (head and eye) respective starting positions. This evidence suggests that the FEF controls visually orienting movements using both eye and head rotations rather than just shifting the eyes as previously thought.


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

While the frontal eye field (FEF) has been classically viewed as an eye movement area, recent studies in eye-head coordination of gaze movements have caused a surge of interest in how oculomotor areas (such as the FEF) may control head as well as eye movements. In some early frontal lobe experiments (Ferrier 1874; Rasmussen and Penfield 1947), stimulation of parts of the frontal cortex (including the FEF) was found to produce both contralateral eye and head movements, but these studies lacked well-defined stimulation parameters and provided little data regarding the metrics of these movements. Later stimulation studies were done more systematically, with better description of the eye movements produced by stimulation of the FEF (Bruce et al. 1985; Robinson and Fuchs 1969). However, these experiments were performed on animals that had their heads restrained (head fixed), restricting the ability of the FEF to produce a coordinated eye and head movement.

Recent studies regarding gaze orientation (combined use of eye and head movements) in the superior colliculus and other brain stem areas (Cowie and Robinson 1994; Freedman et al. 1996) have prompted us to look at the possibility that the frontal eye fields are responsible for controlling both eye and head movements when attempting to fixate gaze on a target. Previous work in our lab has shown that ablation of the cortex along both banks of the arcuate sulcus (encompassing both saccadic and smooth eye movement areas of the FEF) produces deficits in both eye and head components of saccades and pursuit movements (Keating et al. 1997). In the present study, we electrically stimulated the FEF using parameters similar to those used to produce fixed-vector eye movements (Bruce et al. 1985; Tehovnik and Sommer 1997) in head-fixed animals, but we allowed the monkeys freedom to rotate their heads ±45° along the horizontal axis (head free). Results showed that evoked movements in these animals were composed of both head and eye components that summed toward the total gaze shift. Some of these data have appeared in abstract form (Tu and Keating 1998).


    METHODS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Two male rhesus monkeys (Macaca mulatta) were each equipped with two search coils during aseptic surgeries using general anesthesia (isoflourane). One coil was implanted in the eye (Judge et al. 1980) to measure gaze position, and one fixed on the head holder (offset from the axis of horizontal rotation by 2 cm) for horizontal head position, with eye position calculated from measured gaze and head positions. Following a period of behavioral training (see following text), recording chambers were implanted first over the left FEF and then the right FEF, and stimulation (biphasic pulses in 50- to 400-ms trains of 25-300 µA, 250 Hz, 0.25-ms pulse duration) was performed using stainless steel or tungsten microelectrodes. Exploration and data collection for stimulation sites in the head-free animal were normally performed with currents of 100-200 µA and train durations of 200 ms (these numbers were arrived at after experimenting with higher and lower currents and durations to establish best range for eliciting reliable head movements). FEF sites were identified by eliciting reliable fixed-vector (similar amplitude and direction regardless of starting position) gaze movements. In many cases, these sites were confirmed to be in the low-threshold FEF (Bruce et al. 1985) by stimulation with 25- to 50-µA pulses. Experimental measurements in the head-free condition were often made using stimulation with higher currents of 200 µA [using the equation i = kr2 and k = 1,292 µA/mm2 (Stoney et al. 1968), current spread at 200 µA can be estimated to be ~0.39 mm].

The monkeys were trained to orient to visual targets in a darkened room that were back-projected onto a screen with different colored spots of light guiding the head and eyes. Head position was controlled by requiring the monkey to visually guide its head movements to a target (red 0.25° diam spot) using an onscreen cursor (4 white dots in a square 2° to a side) that moved in direct correspondence to its head movements. Eye/gaze fixations were directed to a white target spot that was 0.3° in diameter. Head movements were either completely restricted by the head post (head-fixed condition) or were restricted to ±45° of yaw from center, with limited freedom (<15°) along the pitch or roll axes (head free condition). The torso in one monkey was stabilized by self-fastening plastic straps (Velcro) that held the monkey's arms to the chair, keeping body rotations to a minimum. Torso movements that were observed in the other animal were minimal (this subject usually sat with its torso facing center, with occasional shifts to no more than 15° away from center) even with full 45° head movements.

Given that we wanted the subjects to orient to different head and gaze starting position, trials began with a period during which the animals fixated a head position target using the head tracking cursor (Fig. 1A). Once the head target was fixated, the eye/gaze target was flashed on the screen for one second to constrain initial eye/gaze position (Fig. 1B), after which all visual information (head target, head cursor, and eye target) was extinguished, and stimulation began 70 ms (monkey TM) or 100 ms (monkey PN) later (Fig. 1C; see Fig. 1D for gaze, eye, and head traces). Head and eye targets were separated by either 15° (1 target at center and 1 target at either ±15°) or 20° (both targets at opposite ±10° from center). This behavioral paradigm allowed us to control both head and eye starting positions (monkey PN could maintain at least a 15° head-eye separation at the time of stimulation, although there was a tendency for the head to drift toward the gaze fixation point as can be seen in Fig. 1D). However, it was particularly difficult for monkey TM to maintain divergent eye and head positions, therefore a second paradigm was adopted for this subject in which no eye/gaze targets were used and only initial head position was required (see Fig. 1E). Control trials (50% of trials) for both procedures were run in the same manner but without the application of current, thus allowing the subject to make completely spontaneous movements in the dark. The monkey was rewarded with juice for maintaining initial fixation on either head and eye or head fixation points.



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Fig. 1. Task timing. In each trial, the monkey starts by fixating the head target (top bar; A). In the head/eye position task (D), the gaze target (middle bar) is turned on at trial onset (B), allowing the monkey to fixate its gaze on the target while maintaining head fixation on the head target. After 1 s, both head and gaze targets are turned off (C) and stimulation follows (bottom bar) 100 ms later. In the head position task (E), no gaze fixation is required, so immediately following fixation of the head target, the target is extinguished, and stimulation followed 70 ms later. In A-C, central cross represents the center of the field and is not present on the screen at any time. In D and E, light gray shading shows presentation of screen (A), gray of screen (B), and dark gray of screen (C).

Gaze and head positions were directly monitored via the search coils, and eye position was calculated by subtracting head from gaze position. Saccades from stimulation trials were considered to be evoked by stimulation based on latency (within 100 ms of stimulation) and gaze direction (contralateral to side of stimulation) criteria. For trials containing evoked saccades, gaze and eye amplitude (starting position subtracted from final position) were measured at time of peak displacement, and head amplitude was taken as head position at time of maximum gaze amplitude. Trials with double-stepped or staircase saccades were not used in analysis as there were no discernible breaks in head movement from which to determine the head amplitude from the first saccade. Trials in which saccades occurred immediately preceding (within 100 ms) the start of stimulation were also discarded due to continued movements of the head or eyes during this period. In control trials, the first saccade following the blanking of visual targets was used as an example of a spontaneous saccade for comparison to electrically evoked saccades.

All experimental and surgical procedures were approved by the Committee for Humane Use of Animals in our institution and followed the National Institutes of Health guidelines regarding the care and use of laboratory animals.


    RESULTS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Active stimulation sites were found in both frontal eye fields (Fig. 2A) of monkey TM and the left FEF of the monkey PN. The sites from monkey TM were identified as lying largely within the upper limb of the arcuate sulcus. Explorations in more ventral areas of the prearcuate gyrus did not elicit any saccadic responses or had current thresholds too high to consider as valid sites. Sites that evoked largely vertical gaze responses were also not considered in this study as the monkeys had limited freedom of head movement along the vertical axes. Stimulation sites were found between 1.0 and 7.0 mm below the surface of the dura, and many penetration tracks yielded multiple stimulation locations along their depths.



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Fig. 2. A: penetration sites from monkey TM showing the 25 sites (of a total of 94 penetrations) from which eye movements were elicited. As, arcuate sulcus; Ps, principal sulcus. Sites from monkey PN have not yet been recovered. Gaze (B) and head (C) position plots from a trial run from monkey PN [stimulation start and end are shown (down-arrow ), time axis starts at point when all targets are extinguished].

Of 124 electrode penetrations explored (in both monkeys), 45 penetrations yielded a total of 98 sites from which we could elicit eye or gaze movements. Of these, 51 sites produced large horizontal gaze movements that included a head component (see Fig. 2, B and C, for example of 1 such site). In monkey PN, 14 other sites were found that either produced head movements in the absence of any gaze movements [i.e., fully compensated by the vestibuloocular reflex (VOR)] or had gaze movements that were initiated by head movements (with initial VOR) that were then followed (within 60 ms) by eye movements (both conditions could be observed during stimulation of a single site). Stimulation of these sites during a head-fixed condition was able to produce eye movements that resembled the fixed vector movements normally elicited by stimulation of the FEF. Additionally, in monkey PN we found four sites from which we were able to elicit smooth eye movements (SEM) similar to those found by others (Gottlieb et al. 1993). These sites were located more ventral and deeper in cortex than the saccade related sites. The remaining 29 sites produced gaze movements that were too small or were oriented more vertically and so did not contain a head component.

All evoked eye and head movements (i.e., components of gaze shift) were toward the side contralateral to stimulation with large variations in gaze direction and amplitude between sites. Most saccades were directed toward the upper two quadrants (there were very few downward directed saccades in the sites we stimulated), with more vertical saccades producing little or no horizontal head movement. Saccades that exhibited larger horizontal gaze shifts were more likely to produce consistent and larger head movements. Using currents of 200 µA and train durations of 200 ms, we found sites with gaze amplitudes of <= 70° (from a contralateral gaze starting position) with head contributions approaching 25°. At lower currents or train durations, head contributions decreased in size, while total gaze amplitudes stayed relatively constant (data to be presented in a later report). Head contributions at a single site decreased toward zero when horizontal gaze amplitudes approached 15-20° (Fig. 3A).



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Fig. 3. A: effect of evoked gaze amplitude on amplitude of head component for a set of trials in monkey TM. Gaze, head, and eye (B-D) initial position versus movement amplitude, showing a larger effect of starting position on head and eye with gaze showing a much smaller effect.

Initial positions of eye, head, and gaze had an influence on their respective evoked movement amplitudes (Fig. 3, B-D). In general, for gaze and its separate eye and head components, an initial position in the hemifield opposite to the direction of movement caused a larger evoked movement than a starting position toward the side of movement. This relationship was observed for all movements, though the eye and head components exhibited a stronger position effect than the overall gaze movements (with data from 20 sites, average slope ± SE of initial position vs. movement amplitude was found to be -0.457 ± 0.069 for eye, -0.165 ± 0.024 for head, and -0.080 ± 0.020 for gaze).

To distinguish evoked from spontaneous movements, half of all trials were run without electrical stimulation, and these data were compared with the stimulation data. Eye and head movements were each found to have very different latency and amplitude distributions during the stimulation and the control trials, with control trials showing a much wider distribution of movements and latencies. Mean stimulated eye/gaze latency was 47.0 ± 2.4 ms (n = 72) versus 152.2 ± 21.1 ms (n = 83) for controls; mean stimulated head latency was 58.3 ± 5.3 (n = 59) ms versus 171.6 ± 21.1 ms (n = 83) for controls. Mean stimulated gaze amplitude was 21.82 ± 0.39° (n = 77) versus 8.36 ± 1.59° (n = 83) for controls; mean stimulated head amplitude was 4.28 ± 0.39° (n = 77) versus 0.80 ± 0.55° (n = 83) for controls (P < 0.001 for all comparisons).


    DISCUSSION
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

There have been earlier hints from stimulation experiments that the FEF is involved with both head and eye movement control in both primates/humans (Ferrier 1874; Rasmussen and Penfield 1947) and cats (Guitton and Mandl 1978). Lesion data from head-free monkeys has also shown that the FEF is part of the system for coordination of head and eye movements (Van der Steen et al. 1986). Recent work from our lab found that FEF lesioned animals (the lesion included the posterior bank of arcuate sulcus) had significant deficits in movement amplitude toward the side contralateral to the most recent surgery. Even though the monkeys displayed different strategies for compensating for these deficits, they all exhibited a prolonged deficit for either head or eye movements (Keating et al. 1997).

In this study, we have shown that stimulation of the low threshold and other areas of FEF studied in earlier experiments (Bruce et al. 1985; Robinson and Fuchs 1969) produce not only eye movements but a gaze movement composed of both eye and head components. The head and eye movements we observed were all directed contralateral to the side of stimulation but were seen to be affected by starting position. Given that the gaze shifts we evoked were still approximately `fixed vector` (i.e., were not as affected by starting position), this suggests that the FEF is producing a gaze vector signal rather than two separate eye and head signals. More work is needed to clarify this point, however, and further work is also being done to clarify the effects of stimulation intensity, duration, and location on the relative contributions of eye and head to evoked gaze movements.

Thus far, our head-movement results bear a strong resemblance to those found in the superior colliculus (SC) (Freedman et al. 1996). This should not be surprising considering the seemingly parallel functioning of the two areas and the discovery of increasingly complex interactions (via reciprocal connections) between them (Lynch et al. 1994; Segraves and Goldberg 1987; Sommer and Wurtz 1998). The latencies we have recorded for both gaze and head shifts put the FEF firmly upstream from the SC, but it would be interesting to measure the gaze responses to FEF stimulation in the absence of the SC, given the direct connections of the FEF to oculomotor centers in the brain stem.

To conclude, these results show that the FEF can control at least one other component of the gaze movement system (in this case the head, although body/torso movements may also play a role), rather than solely controlling the eyes, as previously thought. It remains to establish whether the FEF controls the eyes and head separately or if its output is in the form of a gaze signal as our results suggest. For the time being, however, the idea of a purely eye-movement-oriented FEF can no longer be supported.


    ACKNOWLEDGMENTS

We are grateful for the technical support of G. Rygiel.

This research was supported by National Science Foundation Grant IBN9807787 and the SUNY Research Fund.


    FOOTNOTES

Address for reprint requests: T. A. Tu, Dept. of Cell and Developmental Biology, SUNY Upstate Medical University, Syracuse, NY 13210 (E-mail: tut{at}mail.upstate.edu).

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 18 January 2000; accepted in final form 2 May 2000.


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0022-3077/00 $5.00 Copyright © 2000 The American Physiological Society