frontal eye field lesions impair predictive and visually-guided pursuit eye movements

Exp Brain Res (1991) 86:311-323

Experimental Brain Research �9 Springer-Verlag 1991

Frontal eye field lesions impair predictive and visually-guided pursuit eye movements

E.G. Keating

Department of Anatomy and Cell Biology, State University of New York, Health Science Center at Syracuse, Syracuse, NY 13210, USA

Received August 14, 1990 / Accepted May 17, 1991

Summary. The study initially explored the frontal eye field's (FEF) control of predictive eye movements, i.e., eye movements driven by previous rather than current sensory signals. Five monkeys were trained to pursue horizontal target motion, including sinusoidal targets and "random-walk" targets which sometimes deviated from a sine motion. Some subjects also tracked other target trajectories and optokinetic motion. FEF ablations or cold lesions impaired predictive pursuit, but also degraded visually guided foveal pursuit of all targets. Unilateral lesions impaired pursuit of targets moving in both horizontal orbital fields and in both directions of movement. Saccadic estimates of target motion were generally accurate. The slow-phase velocity of optokinetic pursuit (collected after 54 s of OKN) also appeared normal. Pursuit recovered over 1-3 weeks after surgery but the deficits were then reinstated by removal of FEF in the other hemisphere. Thereafter, a slight deficit persisted for up to 10 weeks of observation in two subjects. The pattern of symptoms suggests that FEF lies subsequent to parietal area MST and prior to the pontine nuclei in controlling pursuit eye movements.

Key words: Frontal eye field - Eye movements Pursuit - Oculomotor Frontal lobe - Alert monkey

Introduction

Ferrier discovered that electrical stimulation of the arcuate gyrus in the monkey evoked saccadic eye movements (1874). He judged this prefrontal area to be the motor cortex for eye movements, but the "frontal eye field" (FEF) was later demoted to a lesser role by two findings. Lesions of the FEF caused only trivial deficits in saccadic eye movements (Schiller et al. 1980). In early physiological studies the few FEF neurons found to be related to eye movements typically fired after the onset of saccades (Bizzi 1968). These were embarassing attri- butes for an oculomotor command center.

The FEF has recently enjoyed a partial rehabilitation. Only small electrical currents are needed to evoke saccades from stimulation of portions of the frontal eye field. The evoked saccades have a short latency and their dynamics mimic natural saccades (Bruce et al. 1985; Robinson and Fuchs 1969). If monkeys are rewarded for their accurate fixation of visual targets, then neurons in FEF often do fire prior to the onset of the eye movement. Many of the neurons encode the vector of the saccade required to fixate the target (Bruce and Goldberg 1985; Goldberg and Bruce 1990). Prefrontal pathology in patients and monkeys causes deficits which are expressed as abnormal sequences of eye movements, such as neglect, or altered scanning strategies (Deng et al. 1984; Guitton et al. 1985; and Crowne 1983, for review). However, recent studies have confirmed that lesions of FEF have only slight effect on the metrics of individual saccades unless the prefrontal pathology is combined with lesions of the superior colliculus (Schiller et al. 1980; Keating and Gooley 1988).

This study began as a search for a lesion effect that would reveal the unique oculomotor role of the frontal eye fields. The experiment tested the hypothesis that the FEF was especially involved in guiding "internally" generated eye movements, those driven by prior experience rather than by current sensory events (Luria et al. 1966). Predictive pursuit is an example of this kind of movement. Primates will often move their eyes against the actual motion of a visual target, pursuing instead a trajectory expected from prior experience (Eckmiller and Mackeben 1978; Becker and Fuchs 1985; Van den Berg 1989).

The experiment found that FEF lesions did impair predictive pursuit. Such lesions also degraded visually guided pursuit. The latter finding was surprising because there was little prior reason to implicate the FEF in the control of smooth eye movements. At the same time and independently Lynch and Allison reported a similar result (Lynch and Allison 1985). This paper is a fuller description and extension of our original brief report (Keating et al. 1985).

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Methods

Behavioral testing

There were five subjects: 3 adult male cynomolgous monkeys (M. irus; subjects: BIG3, SML, CRY), one male and one female adoles- cent rhesus monkey (M. mulatta; Subjects: BIG1, BIG2).

During daily testing the monkeys sat in a primate restraint chair. Their heads were held stationary. The position of primary gaze was directed toward a red light at the center of a tangent viewing screen. A trial began when the monkey fixated the red light to within 1 deg of accuracy. This extinguished the red light and signalled the monkey to fixate a small white target (20' dia). The monkeys first learned to fixate stationary targets, then to pursue moving targets. Only pursuit of horizontal motion was tested in this experiment.

Before surgery an automated procedure gave a water reward if the monkey matched eye and target position to within a radius of one degree of visual angle for a duration of 0.3-2 s. After surgery, it was necessary to deliver additonal rewards manually to maintain the monkey's motivation.

Sinusoidal targets. Every subject learned to pursue targets that moved with a sinusoidal velocity. The target remained stationary for 300 ms. at an initial position, then oscillated sinusoidally for 6 s with a frequency of 0.4, 0.7, 0.9 or 1.4 Hz. The target's initial position was at the center, or 9 ~ to left or right of the screen's center. It's initial movement was to the left or right. Target amplitude was always 4.5 ~ The target's starting position and initial direction varied unpredictably on each trial. Target frequency remained constant over a block of 4 trials.

Random-walk sinuoidal targets. Blocks of "random-walk" trials (Lisberger et al. 1981) alternated with blocks of normal sinusoidal targets. Random-walk sinusoids were designed to expose predictive pursuit by presenting unexpected departures from sinusoidal movement. Figure10 shows an example of this type of target. It first moved sinusoidally for one half cycle. Then each time target velocity crossed zero a random number determined the direction of the next half-cycle of movement. At about half of the zero-crossings the target reversed direction like a normal sinusoid; otherwise a "surprise node" occurred. On these occasions the target continued on in the same direction as on the previous half cycle.

Constant velocity targets. Three of the monkeys (BIG2, SML, CRY) learned to pursue constant velocity targets. Periodic targets were created to compare foveal and optokinetic pursuit. On each cycle the target moved with a constant velocity from screen center to a position 20 ~ to the left (or right), remained stationary for 250 ms and returned to the center of the screen. The target oscillated in this way for 6 s. Tested speeds were 5, 10, 20, 30, and 40~ matching those later used with optokinetic stimuli.

Two monkeys pursued step-ramp targets (BIG2, SML). At the start of the trial these targets appeared to one side of the screen's center and immediately moved with a constant velocity for a duration of 700 ms. The target's initial position, its speed, and its direction were chosen randomly on each trial. Tested positions were 5, 10, 15 ~ to either side of screen's center. Target speeds were 15, 30 or 45, or 60~

Optokinetic targets. Optokinetic nystagmus was induced by a texture of small spots that filled the viewing screen (80 ~ x 60 ~ and moved with a constant velocity in an otherwise dark room. The animals were light-adapted prior to each trial. This procedure ren- dered invisible to human observers all other stimuli in the room except an apparent edge induced by the moving texture at the border of the viewing screen.

The moving texture was rear-projected onto the screen from a planetarium rotated by a velocity-servo motor. The trial began when the light inside the rotating planetarium was turned on. Eye position was collected after 54 s of stimulation to allow the op-

tokinetic system's velocity storage mechanism time to saturate (Cohen et al. 1977). Textures moved at 5, 10, 20, 30, and 40~

Stationary targets. The monkeys were also required to fixate stationary targets. At the start of the trial a target appeared to the left or right of the screen's center and remained lit for 2 s. Amplitude of the first saccade to the target was measured for targets positioned at 5 ~ intervals along the horizontal meridian, to an eccentricity of 30 degrees.

Data analysis

Eye position. Eye position was transduced from a scleral coil im- planted in one eye. The eye position signals were led through a low pass filter having a cut-off frequency of 53 Hz for measuring pursuit eye movements or 160 Hz for measuring saccades to stationary targets. The signals were sampled every 3 ms.

Gain and offset of the equipment was calibrated daily by having the monkey fixate a matrix of stationary targets. Prior experience indicated that FEF ablation had no effect on the gain and offset derived by our calibration procedures. After calibration the monkey received 300-500 test trials per day.

Sinusoidal targets. Pursuit was measured in two ways. The crosscorrelation technique of Cassell (1973) provided an index of average tracking performance over the entire 6 second trial. A second analysis measured tracking only during epochs of smooth eye movement.

The cross-correlation technique returned a measure of the gain and phase of pursuit which reflected, respectively, the monkey's average accuracy and lag in replicating the target trajectory over the entire 6 second trial. First, eye and target position traces were differentiated. Saccades in the eye velocity record were then detected by a velocity criterion and removed. A straight line was interpolated between the boundaries of the resulting gap in the record. The target velocity trace was then correlated with itself and the first positive peak of the autocorrelation function was taken as a measure of target velocity (Vt). The autocorrelated target trace was cross- correlated with the monkey's saccade-free eye velocity trace. The first positive peak of the cross-correlation was considered an index of the monkey's best tracking performance (V~) and expressed as a gain:

Gain = Vo/V,

Phase in this analysis was the time of the monkey's best performance (Ve) relative to Vt:

Phase (in ms) = Timeve-Timevt

The monkey's daily performance at each target frequency was the average of 4 trials analyzed in this way.

The second analysis considered only smooth eye movements. The data from a sine target of intermediate frequency (0.9 Hz) was examined for epochs in which eye velocity remained between 2 ~ and 75~ for at least a quarter-cycle of sine tracking. These epochs were sorted according to the orbital field or orbital directon of pursuit. The average of the peak velocity from 20 such epochs was taken as a measure of smooth pursuit in each field and direction of pursuit.

Predictive pursuit. Zero-crossings where the random-walk targets failed to behave sinusoidally (i.e. reverse direction) were called "surprise nodes". The monkey's pursuit often did reverse direction at these nodes as if the monkey were expecting a sinusoidal target motion (e.g. Fig. 10, top). This direction reversal was called an epoch of predictive pursuit if it met certain criteria. The eyes had to reverse their previous direction, and then execute a smooth movement, not a saccade or fixation. The movement had to shift eye position away from the target position. These criteria insured

that prevailing retinal position, retinal velocity, or eye velocity signals were not driving the epoch. These judgments were made by eye inspection of the position records.

Constant velocity and optokinetic targets. The eye and target position traces were digitally filtered (low-pass Butterworth filter with a cutoff frequency of 10 Hz) and differentiated. Performance on the periodic ramp targets and optokinetic motion were analyzed in the same way. First, the eye velocity records were sorted into epochs of pursuit, i.e. intervals in which eye velocity ranged between 2-75~ Then the average velocity of each epoch was calculated. A further averaging of 10 such epochs represented the monkey's performance.

For the step-ramp trials the peak smooth eye velocity following the first 100 ms of eye movement was used as the index of "maintained" pursuit. In a few cases it was also possible to measure "initial" or "open-loop" pursuit. The monkey's first response to target motion was usually a short epoch of smooth pursuit followed by a catch-up saccade to the target. For a few targets the smooth epoch lasted for at least 75 ms without an intervening saccade. If 10 such epochs occurred then the average peak velocity of these epochs served as the measure of "initial" pursuit.

Surgery

Ablation monkeys. The monkeys were trained until the pursuit gain of the fastest sinusoidal target did not improve over 3 days of testing. Four monkeys then received unilateral ablations of the frontal eye field. In three of these (BIG1, BIG2, BIG3) a large ablation encompassed the traditional definition of FEF, i.e. all of area 8a and 45 (Walker 1940).

In the fourth ablation subject (SML) the intent was to remove the portion of FEF from which Bruce et al. evoked saccades with electrical currents of less than 50 microamperes (1985). This region includes only the anterior bank and lip of the arcuate sulcus, termed here "low threshold" FEF. I did not define this area physiologically, but derived a "typical" FEF from the Figures of Bruce et al. (1985).

Surgery was carried out under general anesthesia using aseptic procedures. The cortex was removed by subpial aspiration. The monkeys were tested beginning on the seventh day after surgery.

After the monkeys recovered nearly normal pursuit (about 1 month) the FEF in the other hemisphere was ablated and the animals retested. Recovery was then monitored for 1 3 months. The monkeys were killed under general anesthesia, perfused through the aorta with 10% formalin. Frontal cortex was cut in a horizontal plane at 50 mu and every 10th section stained with cresyl violet. My interpretation of the neuropathology was mapped onto a set of drawings made from normal macaque cortex sectioned along the same plane.

Cold lesion. Subject CRY received temporary cooling lesions combined with an ablation. The procedures for this subject are detailed elsewhere (Keating and Gooley 1988). Briefly, training on pursuit began one month after unilateral ablation of the left FEF in this monkey. After training, a cryode was positioned onto the surface of its right superior colliculus (SC).

The effect of cooling SC was studied for several months. Then another pair of cryodes was placed onto the right FEF. Two probes were required to cool all of the right FEF. One cooled the anterior bank of the arcuate sulcus. It was placed in a trough produced by ablation of the posterior bank of the arcuate sulcus. The second was positioned on the crown of the arcuate gyrus (see Fig. 14).

Each daily session began by measuring eye movements with the cryodes at body temperature (WARM). This procedure controlled for the residual effects of the trauma that attended placement and chronic presence of the cryodes. Eye movements were then measured after the FEF cryodes were cooled to + 5 ~ C. Cooling below this temperature produced a contralateral neglect for visual targets that prevented further measure of guided eye movements. In a few

313

Results

Pursuit of sinusoidal targets

The cross-correlation analysis returned an index of gain and phase that summarized the monkey's tracking performance over the entire 6 s trial of target motion. Con- sidering this analysis first, the 4 normal subjects tracked sine targets quite accurately before surgery. They pursued all but the fastest target with a gain approaching unity (Fig. 1, top). Gains among the four subjects were similar, their range deviating only about 2% from the group average. Variation within a testing session of a single monkey's pursuit gain was also slight, typically ranging about 3% from its daily average (not shown). Before surgery the monkeys lagged these targets by only 7-22 ms. (Fig. 1, bottom). This is much shorter than the 100 ms reaction time attributed to the pursuit system (Lisberger and Westbrook 1985). It suggests that the monkeys were predicting the targets' trajectory.

When measured one week after unilateral FEF ablation, gain was abnormally low in every subject and for every target frequency. The monkeys also lagged further behind most of the targets than normal. However, av-

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Fig. 2. Gain (top) and lag (bottom) of sine pursuit resulting from various lesions shown chronologically in the cryode subject. Two curves depict performance on the slowest and the fastest sine targets. left FEF ablation: best performance achieved during pursuit training which began following left FEF ablation; r. SC cool: pursuit during cooling of right superior colliculus; r. FEF warm: cryodes were in place on right FEF and SC, but remained at body temperature as a control for surgical trauma; r. FEF cool." pursuit during cooling of right FEF. Inset: example of eye position trace (solid line) of CRY in pursuit of a 1.4 hz sine target (dotted line). Traces were collected with FEF cryodes at body temperature (Warm) or cooled to + 5 ~ C. (FEF cold)

erage lag still remained less than the 100 ms reaction time of the pursuit system.

Considerable recovery of sine pursuit occurred over a period of 1-3 weeks after unilateral FEF ablation (described below). One to two months later the FEF of the opposite hemisphere was removed, reinstating the deficits in both gain and lag (Fig. 1).

A regression analysis of the data in figure 1 determined if performance (gain or phase) was a linear function of surgical condition (preoperative, unilateral, or bilateral FEF lesions) or of target frequency, or an in- teraction between these two influences. The results for gain and phase were similar and confirm trends seen in Fig. 1. Performance both before and after surgery de- clined with the faster targets (gain and phase: P<0.0001). FEF ablations degraded tracking (gain: P < 0.0001 ; phase: P < 0.03), and the tracking deficit was worse for the higher target frequencies (gain: P < 0.02; phase: P < 0.0001).

Combined cooling/ablation of the FEF in subject

ablations in the other subjects (Fig. 2). CRY first learned to pursue targets following unilateral FEF ablation. This subject never performed as well as normal monkeys, but it did achieve gains comparable to the other monkeys with unilateral FEF ablations. Subsequent cooling of the right superior colliculus (SC COOL) or the placement of FEF cryodes (FEF WARM) caused little further deficit. This provides some evidence that the pursuit deficits do not result from unspecific neural insult. Finally, cooling the FEF cryode did thoroughly disrupt pursuit of all target frequencies. The inset in Fig. 2 illustrates CRY's poor performance but also its continued attempts to track the target during FEF COOL.

Examples of one ablation subject's eye traces shed further light on the nature of the tracking deficit (Fig. 3). This subject (SML) had the slightest deficit and it had the smallest ablation, a lesion approximately confined to the "low-current" frontal eye field (Bruce et al. 1985). The traces collected after surgery indicate that the lowered tracking gain did not result from some general neglect of the target or disinterest in the task. There was an increase in the number of catch-up saccades and fixations, the latter of which would have influenced the cross-correlation analysis. However, the traces reveal that this could account for but a small portion of the deficit. For most of the trial the monkey attempted to track the target with smooth movements, but did so with slower velocities and greater lag than normal.

The second analysis quantified the portion of the deficit specific to smooth eye movements. It was carried out on the data from a sine target of intermediate frequency (0.9 Hz). The analysis considered only those epochs during a trial in which a complete quarter-cycle of smooth pursuit occurred, uninterrupted by saccades or fixations. The epochs were sorted by the orbital f i e ld or by the orbital direction of pursuit. Figure 4 shows performance after unilateral ablations expressed as a percentage of preoperative peak velocity of these smooth pursuit epochs.

Multiple regression analyses of the smooth epochs found that unilateral surgery significantly degraded the peak velocity of smooth pursuit (P<0.001). Secondly, unilateral ablation had bilateral effects. Statistical tests in individual monkeys found that for every subject pursuit in both fields and in both directions was slower after unilateral FEF ablation (t tests, P< 0.05/k, where k is number of t tests carried out). Thirdly, the group analysis indicated that unilateral lesion affected pursuit symmetrically, i.e. one direction (P<0.52) or one orbital field (P < 0.96) of pursuit was not significantly more slowed by surgery than its opposite. However, on this last point the results were not consistent across individual subjects. Figure 4b suggests a trend for 2 monkeys in which pursuit directed toward the lesioned hemisphere was more slowed than pursuit directed contralaterally.

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FEF lesions also slowed foveal pursuit of constant veloc-

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Sine pursuit epochs, sorted by:

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Fig. 4a, b. Epochs of smooth eye movements during tracking of the 0.9 Hz sine target were sorted by a the horizontal orbital field of gaze during pursuit or, b by the horizontal direction of eye movement, relative to the lesioned hemisphere. The data are plotted as a percentage of preoperative gain achieved by each subject one week after unilateral FEF ablation. Gain is defined as peak eye velocity/ peak target velocity of each epoch, averaged for 20 epochs. In every case smooth pursuit was significantly slower after unilateral FEF ablation (P<0.05). Asterisks mark the two cases where ablation had an asymmetric effect: pursuit ipsilateral to the lesioned hemisphere was statistically worse than contralateral pursuit (P < 0.05). These and subsequently reported levels of significance include the Bonferroni correction for multiple t tests carried out on the same dataset (Ingelfinger et al. 1983)

pursuit for the three subjects trained on step-ramp targets. A regression analysis indicated that unilateral FEF ablation (or FEF cooling in CRY) affected both fields and directions of pursuit symmetrically in each subject. Therefore the data for targets in both horizontal directions have been combined and plotted against target speed in the figure.

The analysis separated initial pursuit, the first 75 ms of eye movement, from maintained pursuit, the peak eye velocity occurring subsequent to the first 100 ms of eye movement. The first 100 ms of pursuit is considered to be the "open-loop" portion of pursuit that is uninflu- enced by later feedback of eye movements. Pursuit during this period is largely driven by retinotopic signals (Lisberger and Westbrook 1985). Analysis of a shorter

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Fig. 5. Average peak smooth eye velocity achieved on 10 trials with step-ramp targets preoperatively (solid symbols) and after unilateral FEF surgery (open symbols). Shapes of symbols distinguish subjects. Data for leftward and rightward target motion were not significantly different and were combined and plotted against target speed. Large symbols depict instances where postoperative pursuit differed significantly (P<0.05) from preoperative pursuit. Top." initial pursuit: peak velocity of the first 75 ms of smooth eye movement during a trial. Bottom: maintained pursuit: peak smooth eye velocity occuring after the first 100 ms of eye movement on a trial

75 ms epoch was forced by the scarcity of longer smooth epochs which were uninterrupted by a saccade. At that, only subject SML and BIG2 provided enough initial smooth epochs for analysis.

Unilateral F EF ablation had a variable effect on initial pursuit (Fig. 5, top). A regression analysis consider- ing all of SML's data indicated no significant decrease in peak velocity of this monkey's initial pursuit (P < 0.36). However, t tests at individual target speeds in SML revealed significant slowing of pursuit of the fastest target. For subject BIG2, initial pursuit was slowed at the single target speed available for analysis (P < 0.0001).

Maintained pursuit (subsequent to 100 ms of eye movement) was more consistently slowed following unilateral F EF ablation (Fig. 5, bottom). A regression analysis revealed a significant decrement in each of the 3 subjects (P<0.0001), and individual t tests showed significant slowing at nearly every target speed. The deficit was proportional to the speed of the target in SML

(P<0.0001) but was not selective for target speed in CRY (P < 0.17).

Optokinetic pursuit

In contrast to the foveal pursuit deficits, the "late" phase of optokinetic pursuit (i.e. collected after 54 s of OKN) was quite competent and in one case improved after FEF lesions. Figure 6 compares postoperative foveal pursuit of a periodic ramp target with optokinetic pursuit of a moving texture. Average smooth eye velocity of "late" OKN (i.e., collected after 54 s of OKN) was notably faster than was foveal pursuit of the point target. Preop- erative data from each subject would be needed to con- clude with certainty that postoperative "late" OKN was normal. However, the Figure shows that smooth eye

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Fig. 7. Curves contrast SML's foveal (filled symbols) and late optokinetic (open symbols) pursuit of a constant-velocity target during the course of the experiment. OKN improved following ablations which degraded foveal pursuit. Average eye velocity of each epoch of saccade-free pursuit was divided by the average target velocity. Plotted gain is the average of 10 such epochs. Error bars are standard deviations

317

velocity during "late" OKN nearly matched the stimulus velocity up to 30~ suggesting that it could not have been much impaired by surgery.

Preoperative OKN data were available for subject SML. In this monkey "late" optokinetic pursuit seemed improved by the same FEF lesions that degraded foveal pursuit (Fig. 7). SML demonstrated variable and mediocre optokinetic pursuit before surgery. Smooth eye velocity during "late" OKN increased after unilateral FEF ablation, and increased again after a second ablation. Thereafter, OKN pursuit slowed as foveal pursuit recovered.

Saccades to stationary and moving targets

Unilateral FEF lesions shortened the amplitude of the first saccade toward stationary targets located in the field contralateral to the lesion (Fig. 8), as reported previously (Schiller et al. 1980; Keating and Gooley 1988). Targets were eventually fixated, usually with the next saccade. Initial saccades made to ipsilateral targets were normal.

The initial saccade to moving targets was measured in two subjects. In subject BIG2 saccadic estimates of step- ramp target motion remained accurate after surgery (not shown). Saccadic gain after unilateral FEF ablation (i.e. eye position/target position, at the end of the saccade) was never less than 0.95 and was statistically no different from preoperative values for this subject.

The other subject's (SML) saccades to moving targets were less consistently accurate after surgery (Fig. 9). Saccades made to targets moving in the visual field ipsilateral to the lesion were accurate, regardless of the target's direction (Fig. 9, left panels). Thus, slowed pursuit could sometimes occur together with accurate saccades, the saccades serving to correct errors caused by the pursuit system. In contrast, saccades made to all targets appearing in the contralateral field were consistently shorter than required (Fig. 9, right). For the present, the

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Fig. 10. Example of predictive pursuit. Top: arrows point to "surprise nodes", i.e. zero-crossings where random-walk targets failed to reverse direction. At these points the normal monkey (top panel) often tracked away from the actual target and pursued in the direction expected of a sine target. Bottom." such "predictive pursuit" largely disappeared after bilateral FEF ablation in this subject (BIG1). In its place the eyes slowed, fixated for a long reaction time and then typically made a saccade in the direction of the actual target (broken arrows)

deficit seems best summarized as a comprehensive truncation of all saccades made into the contralateral field, rather than a specific motion deficit. This charac- terization is based first on the observation that inaccurate saccades occurred for stationary as well as moving targets. Secondly, saccades into the contralateral field un~ dershot targets moving in both directions (Fig. 9, right). Target undershoot represents an underestimate of target speed for targets moving away from the fovea but an overestimate of target motion toward the fovea. Therefore, the saccadic error had no simple relationship to target dynamics. In summary, the smooth pursuit deficits do not appear to reflect a comprehensive error in computing visual motion, since saccadic estimates of target motion were consistently accurate in BIG2, and frequently accurate in subject SML.

Predictive pursuit

As reported above, normal monkeys pursued sine targets with an average lag of only a few milliseconds. The arrows in Fig. 10 (top panel) point to another example of eye movements driven by previous experience with the target. At "surprise nodes" the random-walk targets failed to reverse direction in a sinusoidal fashion. The monkey often tracked away from the actual target at

these nodes, and toward the trajectory expected of a sine target. The formal definition of a predictive epoch required that gaze move against the target's direction, but also that it widen the positional gap between eye and target. Finally, the eyes had to reverse direction from their prior movement. Thus predictive epochs could not have been driven by prevailing visual or oculomotor signals.

The lower panel of Fig. 10 illustrates the disappearance of predictive epochs from the eye position record of BIG1 when tested one week after bilateral F E F ablation. After surgery pursuit slowed to a halt at the target's surprise nodes, and was usually followed by a saccade in the direction of the actual target. The monkey neither pursued nor made a saccade in the direction expected of a sine target. Fig. 11 summarizes this result for the four tested subjects. Before surgery predictive epochs occurred at 25-65% of the surprise nodes. Their frequency was reduced by unilateral F EF ablation. Bilat- eral ablations nearly eliminated predictive epochs from the records of BIG1 and BIG2, but they survived in some number in subject SML.

Velocity traces available for subject SML indicated that F EF ablation could degrade predictive epochs without eliminating them. Left F EF ablation in SML reduced the peak velocity of the remaining leftvard directed ep-

Proportion of surprise nodes 0.8 evoking predictive pursuit

0 . 4

0.0

Normal

UniL FEF

Biiat. FEF

BIG1 BIG2 BIG3 SML Subjects

Fig. 11. Proportion of surprise nodes which evoked predictive pursuit before and after FEF ablations. Asterisks mark data that differ from normal (P < 0.05, corrected for multiple t tests)

ochs from 9.8-5.5~ (P<0.001), but did not slow rightward predictive epochs (from 8.6-8.5~ Subsequent right FEF ablation slowed the peak velocity of remaining predictive epochs to both the left and the right (4.5 and 2.3~ respectively).

Recovery and neuropathology

Figure 12 plots tracking performance over time in those subjects that were tested at several intervals after surgery. Performance is expressed as a percentage of the preoperative gain achieved while tracking the fastest sine target (as defined by the crosscorrelation technique). The measure is used to describe the recovery and to relate performance to the varying neuropathology in the ablation subjects. The brain of subject BIG3 was lost in a labora- tory fire. Comparisions between the other three ablation subjects is best made for performance after their first FEF lesion. In all three subjects the first ablation was the more successful in achieving the intended pathology.

In SML the ablation attempted to remove "low- threshold" FEF. In BIG1 and BIG2 the ablations were intended to include this same area but also to extend more widely to include an older definition of FEF (areas 8a and 45 of Walker 1940).

1 0 0

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Recovery of Sine Pursuit

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B I G 2

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Fig. 12. Recovery in tracking the fastest sine target (1.4 Hz). The percentage of its preoperative gain recovered by each subject at various times after surgery. Index of gain was that returned by the cross-correlation analysis (see Methods)

A

1

319

BIG1

9 BIG2

SML

2

c Fig. 13. Neuropathology. Three panels depict the neuropathology in three of the four ablation subjects. The brain of BIG3 was lost in a lab fire before analysis. Pathology was read from horizontal cortical sections and mapped onto drawings of a normal macaque brain. The extent of the ablation is mapped in black onto the drawing of the hemisphere. Horizontal lines indicate the level of the surrounding cross-sections, with the most superior section shown uppermost in the drawing. Stippling on the cross-sections depicts tissue that was either removed or damaged (i.e., gliosis, cell loss exceeding 50 %, or loss of laminar structure). Numbers give the chronological sequence of the ablations

320

Judging from the drawings of Bruce et al. (1985), the left hemisphere lesion in SML did succeed in removing all of the "low-threshold" frontal eye field. The lesion was also largely confined within this area with the excep- tion that tissue removal extended about 1 mm more anteriorly onto the convexity of the arcuate gyrus than does the "low- threshold" field. There was also a slight invasion of premotor area 6 and the underlying white matter in the fundus of the arcuate sulcus (Fig. 13).

The first ablations in BIG1 and BIG2 (left side in BIG1, right side in BIG2) succeeded in removing areas 8a and 45, the older definition of FEF (Crowne 1983). These lesions also extended into the principal sulcus (area 46) and invaded premotor area 6 and the white matter underlying the arcuate gyrus. Areas 8b dorsal to FEF and area 12 ventral to it were not damaged.

Unilateral ablations reduced sine pursuit gain to 50-60% of normal (Fig. 12). There was no statistical difference in the three subjects' gain for the fastest sine target (Fig. 12) or for any of the other three sine frequencies tested (not shown). This suggests that the smaller ablation of "low-threshold" FEF represents the critical tissue for producing the pursuit deficits.

Following their second ablation performance and recovery rate did differ among the three subjects. The bigger lesions degraded sine pursuit more than did the second "low-threshold" FEF lesion in SML. Perfor- mance also recovered more quickly in SML (Fig. 12). However, it is difficult to interpret the results of the bilateral ablations. In SML the second (right) lesion spared much of "low-threshold" FEF by failing to reach deeply into the fundus of the arcuate sulcus. In BIG1 and BIG2 the second lesion (right and left sides, respectively) did not completely remove all of areas 8a and 45 as intended, but did remove virtually all of "low-threshold" FEF. Therefore, the better performance and shorter recovery in SML could be related either to its smaller ablation overall or to the incomplete removal of "low- threshold" portion of FEF.

In summary, the sine pursuit data offer the most comparable index of performance across subjects. Per- formance on this measure does not offer evidence that larger ablations cause more severe pursuit deficits than does removal of just the "low-threshold" FEF.

The cryode placements in CRY appear in Fig. 14. No direct measurement was made of the spatial extent of the cooling. In other regions of the cortex a cryode temperature of 0 ~ C. produces a tissue temperature between 8 ~ and 19 ~ C. for a radius of 1.5 mm surrounding the cryode (Horel 1984). Synaptic transmission stops at these tissue temperatures, but axonal signals are not disrupted (Benita and Conde 1972). In the present study cooling the cryode to 0 ~ C. produced a visual neglect that prevented further experiment. Thereafter, and for the results reported here the cryode was cooled instead to + 5 ~ C. The effective radius of this type of cryode cooled to 5 ~ C. is unknown, but it would be no greater than 1.5 mm (Horel 1984). Using this value, the FEF cooling effects would have been centered on "low-threshold" FEF and would have cooled all but the most ventral portion of it. The cooling effects would also would have also extended more anteriorly onto areas 8a and 45, and perhaps the

CRY

A C

. . . . , , , , ~

B D

i Fig. 14A-D. Surgical protocol for CRY, the subject with cooling lesions. A the portion of the cryode designed to cool the crown of the arcuate gyrus. The blackened area depicts the trench lesion along the posterior bank of the arcuate sulcus made to provide room for the sulcul cryode shown in B. B The sulcul portion of the FEF cryode as it appears on a dissected specimen. C Left FEF ablation placed at the outset of the experiment. D Cryode placed onto the crown of the right superior colliculus. White portion of the probe was in contact with neural tissue (from Keating and Gooley 1988, with permission by Elsevier Science Publishers)

posterior portion of area 46. Portions of area 6 were ablated in order to seat the cooling probe in the arcuate sulcus, and the cryode also cooled a more ventral portion of premotor cortex on the posterior lip of the arcuate sulcus (Fig. 14).

Discussion

For a century the frontal eye field has been studied for its role in guiding saccadic eye movements. The original report of these findings, together with those of Lynch and Allison (1985) and Lynch (1987), provided the first sus- picion that the FEF might also control smooth eye movements. Should the FEF be considered important for the control of pursuit eye movements on the strength of these tracking deficits? How do the results constrain further study into the nature of the deficit?

It does seem from these observations that the FEF should be added to the list of cortical areas controlling visually guided pursuit eye movements. The tracking errors reported here are not easily laid to some other kind of problem such as an attentional or motivational deficit. The monkeys showed a preserved interest in tracking

321

moving targets after surgery. Saccades to the moving target were often accurate during the same trial that smooth pursuit of it was slowed (Fig. 9, and Lynch 1987). Visual neglect, although sometimes a symptom of prefrontal lesions (Crowne 1983, for review), did not cause the present pursuit deficits. The monkeys oriented to stationary targets with enough accuracy to indicate there was no scotoma of visual neglect (Fig. 8).

Secondly, part of the tracking deficits were directly attributable to degraded smooth pursuit movements. Thirdly, the deficits were robust. Unilateral FEF ablation reduced sine tracking gain to approximately 70% of normal (on the middle range of tested frequencies). Peak velocity during maintained pursuit of step-ramp targets decreased to about 50 % of normal (Fig. 5). Deficits after unilateral ablation persisted for 1-2 weeks of daily testing. Decrements of similar proportions and longevity occur from focal chemical lesions of MT and MST, two other cortical areas thought important for controlling pursuit eye movements (Newsome et al. 1985a; Dursteler and Wurtz 1988). Bilateral ablation in the present study reduced tracking gain to 50 % of normal and in two cases some deficit persisted for up to 10 weeks.

Some indirect evidence links FEF to the control of pursuit. The FEF has reciprocal anatomical connections with parietal MT and MST, areas where lesions also cause pursuit deficits (Newsome et al. 1985a; Dursteler and Wurtz 1988). FEF connects reciprocally with parietal area LIP whose function has been related to the detection of motion (Andersen et al. 1985; Andersen 1989). Efferents from FEF descend to the pretectal nucleus of the optic tract, and to the dorsal lateral pontine nuclei (Huerta et al. 1986; Stanton et al. 1988; Leichnetz 1989), two brainstem regions implicated in the control of smooth eye movements (Kato et al. 1986; May et al. 1988).

However, as presently understood, the unit physiol- ogy of FEF does not make a strong case for its involve- ment in pursuit eye movements. It should be noted that few studies have searched for such a role, instead relating unit responses to saccadic eye movements. Most of the cells recorded in these studies fire in relation to some parameter of saccadic eye movements. Many are visually triggered and encode motor error, i.e. the saccadic vector needed to foveate a target. However, a small population of cells encodes current eye position, from which eye velocity might plausibly be derived (Bruce and Goldberg 1985; Goldberg and Bruce, 1990). Also, an ensemble of cells in the fundus of the arcuate sulcus is reported to fire during smooth eye movements (Gottlieb et al. 1989). While stimulation of FEF typically evokes saccades, stimulation of this ensemble evoked smooth pursuit movements (MacAvoy and Bruce 1989).

Overall, there is sufficient evidence to warrant further study of the FEF's control of pursuit. However, it should be emphasized that considerable recovery of pursuit occurred after FEF lesions. This argues that FEF is not critically necessary for the kind of pursuit measured here. This is a common finding in cortical lesion studies (New- some et al. 1985a, 1985b; Dursteler and Wurtz 1988). Considerable recovery even follows complete bilateral ablation of striate cortex (Zee et al. 1987). These data

suggest that we have not yet captured the critical function served by the cerebral cortex in the control of visually guided pursuit eye movements.

What is the nature of the deficit? These results are insufficient to define the pursuit deficit in terms of the individual control signals thought to drive pursuit. How- ever, they do somewhat constrain the alternatives. They confirm that FEF does not lie at the sensory extreme of the circuit where retinotopic motion is first computed nor at the motor extreme where smooth eye velocities are finally assembled. The deficit reported here did not repre- sent a global loss in the detection of visual motion, as occurs, for example, with lesions of parietal MT and striate cortex (Newsome et al. 1985a, 1985b; Zee et al. 1987). Saccades to moving targets were frequently accurate indicating that visual motion could be correctly calculated. When the saccades were not accurate the pattern of error was not a function of target dynamics.

Steady-state optokinetic pursuit was also normal in our subjects. This finding does not conclusively argue against a deficit in detecting visual motion since only late OKN was measured, a time when "velocity storage" rather than retinal signals could be the primary driver of eye velocity. However, the normal OKN does argue against a global motor deficit. It is clear that in some circumstances fast smooth eye velocities could be achieved after FEF surgery, ones that matched target velocities.

The results only hint about the position of FEF between the sensory and motor extremes of a visual pursuit circuit. The FEF deficit differed in some aspects from the effects of lesions in the parietal and occipital lobes. In contrast to the present results, lesions in the visual cortex and in parietal areas MT and MST impair both foveal pursuit and steady-state optokinetic pursuit (Dursteler and Wurtz 1988). In further contrast, lesions of visual cortex and area MT impair both smooth pursuit and saccadic estimates of target motion (Newsome et al. 1985a; Zee et al. 1987). A final distinction is that unilateral FEF lesions had bilateral effects, slowing pursuit in both orbital fields and directions. Lesions in the pontine nuclei also degrade pursuit bilaterally, whereas unilateral lesions in the posterior hemisphere affect only a single field or direction of pursuit (Newsome et al. 1985a, 1985b; Dursteler and Wurtz 1988).

It seems that after parietal MT the visual pursuit circuit divides permitting subsequent lesions to spare saccadic responses to target motion but to degrade smooth movements. The circuit divides again after parietal MST in such a way that faults in it can impair foveal pursuit but spare steadystate optokinetic pursuit. The FEF is hypothesized, tentatively, to lie subsequent to this latter division in the parietal lobe and prior to the pontine nuclei in the visual control of pursuit.

Predictive eye movements

This study began as a test of the hypothesis that the FEF controls eye movements guided by prior experience rather than current sensory signals. Humans with prefrontal pathology which includes FEF can foveate lights accurately. However, they have difficulty fixating remem-

322

bered target positions (Guit ton et al. 1985), sometimes can not shift their gaze on verbal command (Holmes 1938), or draw on previous experience to scan a scene appropriately (Luria et al. 1966).

The predictive pursuit epochs revealed by the random-walk targets are similarly not driven by current retinotopic or eye velocity signals. Their loss after F E F surgery can be characterized as a loss of remembered eye velocities. In these terms it is analogous to the saccadic deficits in fixating remembered target positions suffered by prefrontal patients and monkeys with FEF ablations (Guit ton et al. 1985; Deng et al. 1984). However, in this study visually guided pursuit was also impaired. Thus, it is not yet proven that F E F has a selective role in guiding remembered pursuit movements.

However, even when tracking a visible target smooth pursuit is driven by a mix of current mot ion signals and experience whose influence is not easily separated. The reaction time of the pursuit system is about 100 ms (Lisberger and Westbrook 1985) yet normal subjects pursue sine targets with little or no lag (Lisberger et al. 1981 ; Van den Berg 1989). Accuracy too is influenced by predictions, accounting for as much as 70% of the gain with which subjects can pursue sine targets (Van den Berg 1989; Morris and Lisberger 1989).

Visual pursuit of the regular targets in this study would have received a large contribution f rom such predictive influences. The loss in visually-guided pursuit after surgery could still be largely attributable to the loss of this benefit. Two future strategies would help to separate the effect of F E F lesions on predictive and sensory signals. Future confirmation of a deficit in the first 100 ms of pursuit of ramp targets would indicate a loss unrelated to prediction. Prediction would not on average benefit initial pursuit as long as target velocity was kept unpredictable at the start of the trial. Converse- ly, a deficit in predictive saccades could be laid to the selective loss of predictive signals, since visually guided saccades into the ipsilateral field are normal after FEF surgery. Such a deficit could not be measured here since the tested targets did not evoke predictive saccades even in normal monkeys.

What is the nature of the predictive deficit? Velocity traces available for subject SML revealed that predictive epochs could be at tenuated as well as eliminated by F E F surgery. The finding that prediction could be vulnerable to graded insult supports theoretical models which characterize it as a scaled signal, a gain injected into the visual pursuit circuit (Bahill and McDonald 1983; Van den Berg 1989).

Models which simulate predictive pursuit also characterize the predictive element as a remembered eye trajectory rather than as a remembered sequence of retinal mot ion (Bahill and McDonald 1983; Van den Berg 1989). A consequence of storing the prediction as an eye trajectory is that the fidelity of the predictive trace de- pends on the accurate monitoring of eye position or velocity. This allows for the possibility that the predictive deficit (and its consequences for visual pursuit) can be laid to corruption of some extra-retinal signal, e.g., an internal encoding of eye velocity.

Acknowledgements. The research was supported by USPHS grant EY-02941 and NSF BNS-8603915. I would like to thank Stephen Gooley, Douglas Kenney, Jennifer Ryan, and Jeannie Chorsky who did most of the real work.

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frontal eye field lesions impair predictive and visually-guided pursuit eye movements

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