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In primates with a small foveal region of densely packed pho-toreceptors in their retinae that provide high acuity vision, eacheye is moved about by six extraocular muscles, innervated byneurons in the brainstem oculomotor centers. Rapid saccadic eyemovements are executed two to four times per second to bringvisual objects into central view, and slower, smooth-pursuit eyemovements are made to keep objects in view when either theobserver or the object is in motion. In the frontal lobe, two areashave been shown to be significant in visually guided eye move-ments: the frontal eye fields (FEF) and the medial eye fields(MEF), both of which make direct projections to brainstem ocu-lomotor centers1–11. The MEF, located in the dorsomedial frontalcortex, are also known as the supplementary eye fields8. Single-cell recording and microstimulation studies have shown that thesetwo areas perform different coding operations for the generationof saccadic eye movements3,7,11. Electrical stimulation of the FEFelicits saccades that have specific directions and amplitudes; pro-longed electrical stimulation yields a staircase of identical sac-cades with intervening fixations. By contrast, electricalstimulation of the MEF produces saccades that take the eyes toa particular orbital position; prolonged stimulation keeps theeyes at that position. These findings indicate that the FEF carry avector code and the MEF a place code10,11. To shed further lighton the functions of these two areas, we examined the effects ofablating them, either singly or in combination, and studied theeffects on visually guided eye movements. Most studies haveshown only mild, temporary deficits after FEF lesions12–16.Deficits in visually guided saccadic eye movements have not pre-viously been demonstrated after MEF lesions in the monkey.

Here we present results obtained on four tasks. The first taskwas saccadic eye movements to single targets. Following fixationof a small central spot, a single target appeared in one of severallocations on the monitor. Execution of an accurate saccadic eye

movement to the target was rewarded with a drop of apple juice.The second task was saccadic eye movements to paired targets.Paired targets were presented with various temporal onset asyn-chronies. Monkeys were rewarded for making a saccadic eyemovement to either target. The onset asynchrony between pairedtargets was varied to determine the temporal delay required toproduce equal probability of eye movements to each target. Thethird task was saccadic eye movements to sequential targets. Oneach trial, two targets were presented in rapid sequence with var-ious temporal durations and with various delays between them.The task was to repeat the order of the target presentations bymaking successive saccadic eye movements to the target loca-tions. The fourth task was saccadic eye movements to targets inarrays. Following fixation, eight stimuli were presented equidis-tant from the fixation spot; one of the stimuli, the target,appeared at various times prior to the other seven stimuli. Themonkey was rewarded only for eye movements directed to thetarget stimulus. In all four tasks tested, we observed prominentdeficits following FEF lesions. Considerably smaller deficits thatrecovered more rapidly were observed after MEF lesions. Theeffects of combined FEF and MEF lesions were no greater thanFEF lesions alone.

ResultsFigure 1 shows the performance of two monkeys on the single-target task. Each panel shows the distribution of rightward andleftward saccadic movement latencies made to individual visualtargets presented randomly in one of four locations. Panels (a)and (b) compare the distributions before and after a left FEFlesion. The insets display eye-movement records that show some-what less accurate saccades to the right after the left FEF lesion; asignificant change in saccadic peak velocities accompanies thisfor right saccades from a preoperative 534 to a postoperative 459

The effects of frontal eye field anddorsomedial frontal cortex lesions on visually guided eye movements

Peter H. Schiller and I-han Chou

Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

Correspondence should be addressed to P.H.S (schiller@wccf.mit.edu)

In the frontal lobe of primates, two areas play a role in visually guided eye movements: the frontaleye fields (FEF) and the medial eye fields (MEF) in dorsomedial frontal cortex. Previously, FEF lesionshave revealed only mild deficits in saccadic eye movements that recovered rapidly. Deficits in eyemovements after MEF ablation have not been shown. We report the effects of ablating these areassingly or in combination, using tests in which animals were trained to make saccadic eye movementsto paired or multiple targets presented at various temporal asynchronies. FEF lesions produced largeand long-lasting deficits on both tasks. Sequences of eye movements made to successively presentedtargets were also impaired. Much smaller deficits were observed after MEF lesions. Our findings indi-cate a major, long-lasting loss in temporal ordering and processing speed for visually guidedsaccadic eye movement generation after FEF lesions and a significant but smaller and shorter-lastingloss after MEF lesions.

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degrees per second (p < .001, t-test). In (b) an increase of 45 msis evident in the mean latency of saccadic eye movements made tothe right as compared with pre-operative performance (p < .001,t-test); the lesion also produced a broadening in the latency dis-tribution for rightward saccades. Saccadic eye movements madeto the left after the left FEF ablation yielded significantly shorterlatencies than pre-operatively by 13 ms (p < .05). Panels (d), (e),and (f) show pre- and post-operative latency distributions fromanother monkey. The right MEF lesion produced a small, butsignificant increase in latencies for leftward saccadic eye move-ments (11 ms, p < .05, t-test). Saccadic accuracy and velocity wereunaffected by the MEF lesions. The left FEF lesion made in thisanimal subsequent to the bilateral MEF lesion (Fig. 1f) produceddeficits similar to those obtained with a single left FEF lesion,yielding a difference of 54 ms in the mean latencies between leftand right saccades. Four months after the left FEF lesion in mon-key 1, the latency difference between saccades made to the leftand right dropped to 25 ms; four months after the paired FEFand MEF lesions in monkey 2, the difference dropped to 24 ms(both with p < .001, t-test). Saccadic velocity differences for left-ward and rightward saccadic eye movements were also dimin-ished but remained significant.

The paired-target task we devised permitted us to quantify thedegree to which target selection was biased by the cortical lesions.We presented paired targets with different onset asynchronies todetermine the interval required to produce equal probability oftarget selection appearing in the right and left hemifields. Resultsobtained on this task using targets with an angular separation of90 degrees relative to the fixation spot appear in Fig. 2. The pairedtargets appeared either above or below the fixation point, withone stimulus falling in the left and the other in the right visualhemifield. Paired targets were interspersed with single targets thatappeared twice as often; conditions were configured to have the

monkeys execute equal numbers of saccadic eye movements tothe left and to the right during each session, thereby forestallingthe emergence of position biases.

The inset in Fig. 2 shows preoperatively collected eye-move-ment records for paired targets that appeared either simultane-ously or with asynchronies favoring either the left or the rightstimulus in the pair. With simultaneous presentation, the prob-ability of making saccadic eye movements to the left and righttargets was equal, whereas when one target preceded the otherby 33 ms, most saccades were made to the stimulus that hadappeared first. The percent of saccades made to the left target atdifferent asynchronies are plotted in the center of the graphlabeled pre-op. Also plotted is the percent of saccadic eye move-ments made into the left visual field at various times after a leftFEF and a right MEF lesions in two different animals. Two weeksafter the left FEF lesion, the curve shifts to the far left. To achievean equal probability of left and right saccades (50% crossoverpoint), the target in the affected right hemifield had to be pre-sented 116 ms prior to the target in the left hemifield. In theweeks following the lesion, the size of the asynchrony requiredfor equivalent target choice decreased gradually, as shown by thesuccessive curves on the left side of the graph in Fig. 2.

The shift in target choice after a right MEF lesion, as shownby the curves on the right in Fig. 2, was much smaller in magni-tude. Two weeks after the lesion, an asynchrony of 31 ms wasrequired for the monkey to make saccades with equal probabili-ty to either target. Recovery after the MEF lesion was completeby the 16th week. At a comparable time after the left FEF lesion,there was still a strong bias in favor of the ipsilateral target, requir-ing a 54 ms target-onset asynchrony for equal probability per-formance. At comparable post-operative times, the asynchroniesrequired to produce equal probability choice were more thantwice as long as the latency differences between left and right-

Fig. 1. Distribution of sac-cadic latencies to single tar-gets before and after lesions.Data are shown from twomonkeys with (a) and (d) rep-resenting pre-operative data.(b) shows the distribution ofleft and right saccadic eyemovements three weeks afterleft FEF lesion; (e) shows simi-lar data two weeks after aright MEF lesion in the secondanimal. (f) shows data col-lected after a left FEF lesionhad been made in the sameanimal subsequent to bilateralMEF lesions. Eye-movementrecords before and after theleft FEF lesion appear in theinset of (a) and (b). Mean leftand right saccadic latencieswere as follows: (a) L, 125; R,121, (b) L, 112; R, 166, (d) L,130; R, 130, (e) L, 141; R, 130,(f) L, 121; R, 175. The 11-msdifference in mean left and right saccadic latencies two weeks after the right MEF lesion (e) is significant at the .05 level. Differences after FEFlesions (b and f) are significant beyond the .001 level. (c) Reconstruction of an MEF and FEF lesion from a third monkey. The major sulci arelabeled as are the locations of the FEF and MEF. Ant: anterior portion of the brain. Number of trials per histogram: (a) n = 1200, (b) n = 720,(d) n = 1120, (e) n = 2160, (f) n = 1092.

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ward saccades made to single targets (see Fig. 1). There was nofurther improvement on the paired target task when the mon-key was tested five months after FEF lesions.

When two targets have an angular separation of 90 degrees,most of the time monkeys generate accurate saccadic eye move-ments to one target or the other, as shown in the inset in Fig. 2.However, when the target separation is decreased, animalsbegin to make averaging saccades that land the center of gaze atintermediate positions between the two targets17. Such vector-averaged saccades are presumably the product of simultane-ously arriving commands from the cortex to the superiorcolliculus or the brainstem to move the eyes to each target.Studies have shown that concurrent electrical stimulation oftwo sites in the superior colliculus of the FEF produces sac-cadic eye movements that are a vector average of saccades elicit-ed by stimulating each site alone18,19. Figure 3 shows datacollected with targets that had an angular separation of 40degrees; under such conditions vector- averaged saccadesbecome common. In the unlesioned monkey, vector-averagedsaccades occur most frequently when the targets appear simul-taneously; the frequency of such saccades falls off rapidly astarget-onset asynchrony is increased. The consequence of anFEF lesion is a dramatic shift in the asynchrony between the

targets at which vector-averaged saccades occur most com-monly; as a result of the lesion there are now no vector-aver-aged saccades when the targets are simultaneous; instead, theybecome most frequent when the target in the hemisphere con-tralateral to the lesion is presented 67–100 ms prior to the tar-get in the left hemisphere. These findings suggest that FEFlesions retard the rate at which information can be processedfor the generation of visually guided eye movements.

The dorsomedial frontal area within which the MEF resideshas been implicated in the temporal processing of events, par-ticularly in the execution of sequential motor acts20–22. We there-fore wanted to determine how MEF and FEF lesions alter theproduction of a sequence of eye movements to successively pre-sented targets. In Fig. 4, data from the sequential task are pre-sented. Four different sequences with several different durationswere presented in randomized order. Pre-operative and post-operative data collected at various times after the lesions areshown. The results demonstrate a significant but mild deficitafter MEF lesions, which is consistent with findings in humans20.However, a much larger deficit was evident after the FEF lesion.The inset shows eye-movement records collected two monthsafter a left FEF lesion using four sets of sequentially presentedtargets with a sequence duration of 117 ms. Performance on

Fig. 3. Data collected with paired targets having a 40% angular separation. (a) Eye-movement records obtained at various target asyn-chronies; text shows which target appeared first (L, left; R, right) and by how many milliseconds (ms). (b) Plot of the frequency of vector-averaged saccades as a function of target asynchrony. The data were obtained from an intact animal and from an animal with a left FEF lesion.We counted as vector averaged those saccades that fell within plus or minus nine angular degrees of the midpoint between the two targets.

Fig. 2. Pairedtargets pre-sented with var-ied asynchronies.The percent ofsaccades madeto the left targetas a function oftemporal offsetbetween thepaired targets isplotted. Data areshown at varioustimes afterrecovery from FEF and MEF lesions as well as pre-operatively (pre-op). Squares and solid lines depict data from the animal with the FEFlesion; circles and dotted lines depict data from the animal with the MEF lesion. Records of saccadic eye movements made to paired targetswith various temporal offsets in the intact animal appear as an inset. For each of the post-operative weeks plotted (wk 2–wk 16), data werecollected for 5 or 6 successive days.

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sequences presented to the right was severely impaired. The mostcommon error was the execution of a single saccade, instead ofa sequence of saccades, that landed the center of gaze near eitherof the target locations or between them.

Examination of saccadic latencies made to the first target inthe sequence suggests that target reaction times make only a smallcontribution to the deficit. For example, three weeks after the leftFEF lesion, the mean latencies to the first target in the sequenceswe used were 130 ms to the left and 198 ms to the right (a laten-cy difference of 68 ms). Yet the comparable performance to theleft and right occurs with a sequence duration difference of morethan 200 ms (Fig. 4).

Full recovery on the sequential task is evident five weeksafter MEF lesions. Following FEF lesions, considerable recov-ery occurs by week 11. Combined MEF and FEF lesions pro-duced deficits and recovery times similar to those obtainedfrom the FEF lesion alone. The results from the sequential task

Fig. 4. Pre and post-operative datafor percent correct performance areshown for left and right saccadic eyemovements made to sequential tar-gets before and after a right MEFlesion (a, b) and before and after aleft FEF lesion (c, d). Two stimuliappeared in succession using four dif-ferent sets of locations and severaldifferent overall durations. The insetshows eye movements made to oneset of target sequences after a left FEFlesion, when presented for asequence duration of 117 ms, whichis completed well before the initiationof the first eye movements. The foursets of sequential targets, as indicatedin the inset, appeared at positionsA2–B1, E2–D1, A4–B5 and E4–D5.Each trial began with a central fixationspot followed by the appearance ofone sequence. The eye movementsshown in the inset demonstrate cor-rect sequences made to the intact leftside and mostly incorrect eye move-ments made for sequences presentedto the right.

suggest that for the generation of sequences of eye movements,the FEF are more important than the MEF.

The paired-target and sequential tasks do not directly test theability of animals to make a temporal discrimination. To assessdeficits in ascribing temporal order to successively appearingevents, we devised a task that required the animals to discrimi-nate stimuli on the basis of the order in which they appeared.Eight identical stimuli were presented equidistant from fixation,one of which preceded the others by various times. Only a directsaccadic eye movement made to the stimulus that appeared firstwas rewarded. This task explicitly requires that the animal dis-criminate the relative onset of the stimuli. Data collected fourmonths after a left FEF and paired MEF and left FEF lesionsappear in Fig. 5a and b. A major impairment is evident for eyemovements made into the contralateral visual field. This deficit isnot due to loss of perception of high-frequency temporal infor-mation per se, as the monkeys were unimpaired on flicker sen-

sitivity. This suggests that thedeficit lies not in perceiving tem-poral discontinuity but in a dis-ability to assess the temporal orderof presentations for the generationof saccadic eye movements.

In addition to the four testsdescribed here, the performance ofmonkeys was also assessed for eyemovements made to targets thatmoved at various velocities, onsensitivity to stimuli of varied con-trasts, on their ability to discrimi-nate targets that were of a differentsize, shape or color from other,simultaneously appearing stimuli,and their ability to discriminateflickering stimuli from steadily illu-

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minated ones. Except for an increase in saccadic latencies, per-formance on these tasks was largely unaffected by the lesions.

DiscussionIn foveate animals, with each shift in gaze not only are stimuli incentral vision analyzed but a decision has to be made as to whereto look next. The findings we report here suggest that the FEFare central to this process of target selection. Particularly, the FEFare involved in the timing of saccadic eye-movement generationand in optimizing the speed with which eye movements can beinitiated to objects in the visual scene. In intact animals, there iscooperative interaction between the two FEF23. Following a uni-lateral FEF lesion, target selection and processing speed are biasedin favor of the intact hemisphere. Even five months after thelesion, sizeable deficits remained on our tasks that tapped thiscompetition. In contrast, the MEF lesions yielded much smallerdeficits suggesting that this area is not as centrally involved intarget selection and in the execution of sequences of eye move-ments. This is consistent with single-cell recording studies show-ing that neuronal activity in the FEF is more predictive of saccadegeneration and timing than is the MEF (ref. 24, 25, Patterson,W.F. II & Schall, J.D. Soc. Neurosci. Abstr., 185.8, 1997).

Our paired-stimulus task is similar to a task used to studypatients with brain lesions in which paired visual or tactile stimuliare presented in the right and left hemifields or parts of the body.The tendency to ignore the stimulus that appears in space con-tralateral to the lesion has been termed the ‘extinction phenome-non.’26 Adding precisely defined temporal asynchronies to thepresentation of paired targets, as we did in this study, makes it pos-sible to obtain exact measurements of the temporal factors involved.As a result, it is possible to ascribe an exact value in time for themagnitude of the deficit incurred and its recovery. Our results raisethe possibility that the extinction phenomenon seen after frontaland parietal lesions is due not to a loss of attention per se, but to aloss in the speed of processing in the impaired hemisphere.

What brain structures might be responsible for bringing aboutthe gradual improvement in performance found on the tasks wehad used? It has been proposed that two major cortical streamscontribute to the control of visually guided saccadic eye move-ments, the anterior and the posterior27. Because even afterremoval of both major areas of the anterior stream, the FEF andthe MEF, there is notable improvement in performance over time,it is probable that the posterior stream is involved in the recovery.This stream originates in the occipital and parietal lobes andreaches the brainstem oculomotor areas predominantly throughthe superior colliculus28–30.

MethodsFour monkeys were trained on a variety of visually guided eye-movementtasks that allowed us to assess the relative effects of frontal eye field, dor-somedial frontal cortex and combined lesions on the execution of sac-cadic eye movements to single and paired target stimuli. Followingtraining, in the first animal, a unilateral lesion was made of the left FEF. Inthe second animal, successive lesions of the left dorsomedial frontal cor-tex and of the right FEF were made several months apart. In the third ani-mal, three lesions were made, also several months apart; initially the leftdorsomedial frontal cortical area containing the left MEF was ablated,then the right MEF area, and finally the left FEF. The monkeys were test-ed extensively after each lesion for several months before the second andthird lesions were made. The fourth monkey served as a control animal.

All but one of the lesions were made by aspiration under aseptic con-ditions in anesthetized animals with the aid of a surgical microscope.The FEF was removed by aspirating the anterior bank of the arcuate sul-

cus 6 mm medial and 6 mm lateral from the posterior tip of the princi-pal sulcus as well as the gray matter between the arcuate and the posteriortip of the principalis. The fundus and the posterior bank of the arcuateinvolved in smooth pursuit eye movements were spared31–33. Anteriorlythese lesions encroached upon area 46. In the second animal, the leftdorsomedial cortex area was destroyed after we recorded and stimulatedthe area extensively to establish the exact location of the MEF; this par-ticular lesion was produced by repeated, closely spaced lidocaine injec-tions until neural activity was permanently shut down, resulting in alesion verified histologically and shown in Fig.1c. Subsequently in thisanimal, the right FEF was removed by aspiration and was also verifiedhistologically. In the third animal, the same region of dorsomedial frontalcortex was removed as in the second animal. The lesions extended 8 mmlaterally from the midline and 6 mm anterior and posterior from a pointthat was in the same coronal plane as the posterior tip of the principalsulcus. Detailed photographs were taken during surgery before and aftereach aspiration. Electrophysiological mapping was carried out only inthe second animal. All protocols were approved by the MIT Animal CareCommittee and followed NIH guidelines.

The animals were tested using a color monitor placed at a distance of57 cm. The head was restrained during testing, and eye movements weremeasured using the scleral search coil method. Monkeys readily per-formed 800–3000 trials per day. Background luminance for the single,paired and multiple target tasks was 2.26 cd per m2. The targets weresmall, 0.34 degree of visual angle squares with a luminance of 90.27 cd perm2. Saccadic latencies were computed from the time of target onset tothe time of departure of the eye-movement trace from an electronic win-dow set around the fixation spot. The targets most commonly appearedat an eccentricity of 12 degrees from fixation.

The sequential task was made distinct from the other tasks in fourways. First, twenty-five equally spaced small outline squares of low con-trast were present on the screen throughout. Second, the targets appearedinside the selected squares and were bright red in color. Third, the tar-gets flashed on briefly in rapid succession, with a gap between them.Fourth, the animal was rewarded only when two correct successive sac-cadic eye movements were made to the successively appearing targetpositions. The target durations and the delays introduced between thefirst and second target were arrived at experimentally and were chosento optimize the ability of monkeys to perform the sequential task suc-cessfully. Several different sets or paired target locations were studied,which were run in blocks always using four pairs arranged in a mirror-image fashion to allow us to compare performance in the left and righthemispheres. The first target duration ranged between 33 and 300 ms,the interval between 50 and 117 ms and the second target between 33and 83 ms using 16.7 ms steps (the frame rate for the monitor). Withineach block the sequence durations as well as the mirror-imaged pair loca-tions appeared in randomized order. (See inset in Fig. 4 showing eyemovements made to one set of four pairs used in a block.)

For the temporal-discrimination task, eight stimuli appeared, one ofwhich preceded the others by various times ranging from 16 ms to 300ms. The eight stimuli were identical and the same size and luminance asthe targets presented in the single- and paired-target case. All the stimuliwere equally spaced around a circle with a radius of 12 degrees centeredon the fixation spot.

AcknowledgementsWe thank J. Colby and W. Slocum for their technical assistance.

RECEIVED 3 MARCH: ACCEPTED 18 MAY 1998

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