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JOURNALOF NEUROPHYSIOLOGY Vol. 54, No. 3, September 1985. Printed Primate Frontal Eye Fields. II. Physiological and Anatomical Correlates of Electrically Evoked Eye Movements CHARLES J. BRUCE, MICHAEL M. CATHERINE BUSHNELL, AND E. GOLDBERG, GREGORY B. STANTON Laboratory of SensorimotorResearch,National Eye Institute, National Institutes of Health, Bethesda,MaryZand20205; Sectionof Neuroanatomy, Yale University Schoolof Medicine, New Haven, Connecticut06510; Departmentof Neurology, GeorgetownUniversitySchoolof Medicine, Washington,DC 20007; and Departmentof Anatomy, Howard University, Washington,DC 20059 but corresponds with the union of Walker’s cytoarchitectonic areas 8A and 45. 1. We studied single neurons in the frontal 6. Saccade amplitude was topographically eye fields of awake macaque monkeys and compared their activity with the saccadic eye organized across the frontal eye fields. Ammovements elicited by microstimulation at the plitudes of elicited saccades ranged from < lo to >30”. Smaller saccades were evoked from sites of these neurons. the ventrolateral portion, and larger saccades 2. Saccades could be elicited from electrical stimulation in the cortical gray matter of the were evoked from the dorsomedial portion. frontal eye fields with currents as small as 10 Within the arcuate sulcus, evoked saccades PA. Low thresholds for eliciting saccades were were usually larger near the lip and smaller found at the sites of cells with presaccadic ac- near the fundus. 7. Saccade direction had no global orgativity. Presaccadic neurons classified as visnization across the frontal eye fields; however, uomovement or movement were most assosaccade direction changed in systematic prociated with low (~50 PA) thresholds. gressions with small advances of the micro3. High thresholds (> 100 ,uA) or no elicited saccades were associated with other classes of electrode, and all contralateral saccadic directions were often represented in a single elecfrontal eye field neurons, including neurons trode penetration down the bank of the arcuate responding only after saccades and presaccadic sulcus. Furthermore, the direction of change neurons, classified as purely visual. 4. Throughout the frontal eye fields, the in these progressions periodically reversed, allowing particular saccade directions to be optimal saccade for eliciting presaccadic neural activity at a given recording site pre- multiply represented in nearby regions of dicted both the direction and amplitude of the cortex. 8. These experiments support the hysaccades that were evoked by microstimulapotheses that frontal eye field presaccadic tion at that site. In contrast, the movement neurons have a causal role in the generation fields of postsaccadic cells were usually differof voluntary saccades and that microstimuent from the saccades evoked by stimulation lation in the frontal eye fields elicits eye moveat the sites of such cells. ments by artificially activating these cells, and 5. We defined the low-threshold frontal eye hence their subcortical targets. fields as cortex yielding saccades with stimulation currents 150 PA. It lies along the pos- INTRODUCTION terior portion of the arcuate sulcus and is largely contained in the anterior bank of that It has been known since 1870 (15-17) that sulcus. It is smaller than Brodmann’s area 8 electrical stimulation of the frontal lobes can SUMMARY I14 AND CONCLUSIONS ELECTRICAL STIMULATION elicit contraversive eye movements. Recent studies that have used unanesthetized monkeys (67) and measured eye position accurately (54) have established that these elicited movements are conjugate saccades, indistinguishable from naturally occurring saccades. Deep anesthesia raises the threshold for eliciting saccades, and light anesthesia can give an illusion of elicited nystagmus because the eyes persistently drift back after each saccade. A given electrode site yields saccades with a characteristic direction and amplitude that are largely independent of stimulation parameters. For example, prolonged stimulation repetitively elicits the characteristic saccade for a site (54). Simultaneous stimulation of two frontal eye field loci evokes a saccade that is approximately the mean of the characteristic saccades at the two sites (54). Although the phenomenology of these evoked saccades is well described, it has not been shown how, if at all, they are related to the functional physiology of this cortex. Because there is little presaccadic activity in the frontal eye fields when monkeys make spontaneous eye movements (5, 6, 8), it has been suggested that the frontal eye fields have no role in generation of saccades and that the elicited eye movements reflect the antidromic activation of a corollary discharge pathway (5 1). However, it is now known that substantial frontal eye field activity precedes purposive saccadic eye movements, particularly saccades directed at visual targets (82 1,43,46, 72). In a recent study of the frontal eye fields (8) we identified three distinct types of neural activity preceding visually guided saccades: anticipatory activity, visual activity, and movement activity. Different neurons had different combinations of these activities, and we distinguished three major classes of presaccadic neurons based on them. 1) Visual cells have visual activity only and do not discharge before saccades made without visual guidance. 2) Movement cells have predominantly movement activity; they discharge comparably before purposive saccades made with or without visual guidance but have little response to visual stimuli alone. 3) Visuomovement cells have both visual and movement activity and discharge best before visually guided saccades. Both movement and visuomovement cells often show anticipatory activity in a repetitive saccade task. OF FRONTAL EYE FIELDS 715 In the present study we first analyzed the activity of single neurons, classifying their activity and determining their response fields. We then electrically stimulated through the recording microelectrode to examine whether the properties of neurons were correlated with the eye movements evoked by low-level electrical stimulation at that site. We also used electrical stimulation to map the anatomical location of the low-threshold frontal eye fields. Preliminary reports of these experiments have been published elsewhere (19, 22). METHODS The activity of singleneuronsand the effectsof electricalstimulation through the recordingmicroelectrodewere studied in awake monkeystrained to perform severalvisuomotor tasks for a liquid reward. An on-line digital computer (PDP-1l/34) wasusedto monitor the monkey’sbehavior,control stimulusand rewardpresentation,measureeyepositionand singleneuronactivity, computeperievent rastersand histograms,and storeneuronalandeyeposition information for subsequentanalysisoffline. Most of thesemethods have been fully describedelsewhere(8, 18). Monkeys weretrained on four basicvisuomotor tasks: 1) In the no-saccade(or fixation) task the monkeysgazedat a stationary spotof light and did not make eyemovementswhen a secondspot was flashedon the screen.This task wasusedto study the visual propertiesof neurons.It wasalsousedto test microstimulationduring visual fixation by delivering current in lieu of the secondspot. 2) In the visually guidedsaccadetask the fixation point disappearedwhen the target light went on, and the monkey madea saccadeto fixate the target light. Generally this wasthe initial task usedwhen a cell wasfirst isolated,and it alsowasthe principal task for mappingresponsefields.3) In the stabletarget saccadetaskthe peripheralspotwasalwayspresent, but the monkey madea saccadeto it only whenthe fixation point disappeared.This task was usedto dissociate phasicvisualactivity from activity related to visuallyguidedsaccades. 4) In the learnedsaccade taskthe monkey madea purposivesaccadewithout visual guidance.The monkey made saccades to a briefly flashedtargetthat appearedwhenthe fixation point went out; however, the flashedtarget was omitted on randomly selectedtrials. The monkey wasrewardedfor makingthe samesaccadeon those trials without a visual target. This taskwasusedto dissociatevisual activity from movement activity. Subjectsfor the single-cellrecordingexperiments werethree adult rhesusmonkeys(Macaca mdatta) and onecynomolgusmonkey(Macaca fascicularis). The rhesusmonkeyswere highly trained and used 716 BRUCE, GOLDBERG, BUSHNELL, AND STANTON each stimulation test. One record contained highfor several months in experiments directed at analyzing both neuronal activity and electrically elicprecision samples of horizontal and vertical eye poited eye movements (8). The cynomolgus monkey sition taken every millisecond for 500 ms following the beginning of the stimulation. The other record was minimally trained and studied for only 1 mo. contained lower-precision samples of the eye poIn three additional untrained cynomolgus monkeys we mapped the frontal eye fields with electrical sition taken every 4 ms over a 2 s epoch surrounding stimulation without studying neuronal activity ex- the stimulation. One bit represented 0.0825” in the high-precision record and 0.33” in the lower-precept to judge if the electrode were in gray or white cision one. When very small eye movements were matter. Conventional techniques for recording extracelstudied, the gain was increased by a factor of two or five. lular neural activity with glass-coated platinum-irWe recorded from each rhesus monkey over a idium microelectrodes were used. The electrode signal went to a BAK DIS-1 window discriminator, period of several months. A few weeks before terand the resultant unit pulses were sampled at a fremination of the experiments we began making small quency of 1 Khz by the computer. Perievent hiselectrolytic marking lesions (20 PA, electrode negative, 30 s) at sites with low thresholds for eliciting tograms were calculated on-line and stored on saccades. The cynomolgus monkeys were studied magnetic media. The data were used to construct plots of neuronal discharge frequency versus saccade for shorter periods of time, and electrolytic lesions amplitude and direction. were made at all low-threshold (~50 PA) sites. Monkeys were anesthetized with a large dose of After analyzing the response properties of a single neuron, we studied the effect of electrical stimulapentobarbital and perfused with 0.85% NaCl foltion at the site of that neuron by microstimulation lowed by 10% formalin in 1% NaCl. Sections, taken to the arcuate sulthrough the recording microelectrode. Trains of either coronally or perpendicular cus at its posterior limit, were stained with cresyl pulse pairs were programmed on a Grass S88 stimviolet, thionine, or Merker’s silver stain (42). Markulator. Each pulse was 0.25 ms in duration, stimulation frequency was 350 Hz, and the standard ing lesions were located on lateral reconstructions of the periarcuate region and transferred to photrain duration was 70 ms. The stimulator outputs tographs of this region. were connected to a pair of constant-current stimulus isolation units (Grass PSIUQ, which were linked together to provide biphasic (negative-posiRESULTS tive) pulses. Current was monitored by the voltage drop across a 1 KQ resistor in series between the Relationship between electrically elicited output of the isolation units and the microelectrode. saccades and cell type Currents were read as half peak-to-peak values, and At 366 frontal eye field sites we studied an the S88 controls were adjusted to equate positive isolated cell and then microstimulated through and negative current. Currents tested ranged from 5 to 150pA. the recording electrode. Using several behavWe electrically stimulated the monkey while it ioral paradigms, we classified these cells into was alert but not performing a task, and took care eight categories as listed in Table 1. These catto stimulate while the monkey was looking roughly egories were put into three more general at the center of the screen. Threshold, defined as groups based on the presence or absence of the lowest current yielding eye movements on half presaccadic movement activity. The 71 cells the applications, was determined, and representative in the first group all had presaccadic moveeye movements were stored. Most records were ment activity. Movement cells (n = 19) distaken using suprathreshold currents sufficient to charged briskly before saccades, even learned evoke saccades on almost every trial. This was ususaccades made without visual guidance, and ally twice the threshold level. The saccade dimenhad little or no response to visual stimuli given sions for each site were taken as the median amplitude and direction of the elicited saccades in these in the no-saccade task. Visuomovement cells stored records. Most sites yielding saccades were (n = 52) also discharged before learned sacfurther tested using a paradigm that applied micades but discharged better before visually crostimulation while the monkey was fixating a guided saccades and also responded to visual small spot of light at the center of the screen. Difstimuli in the no-saccade task. ferential effects of these two stimulation conditions The 2 13 cells in the second group all lacked are reported elsewhere (20). presaccadic movement activity. Visual cells Eye movements were recorded with a search coil (n = 30) discharged in response to visual stim(50) surgically implanted subconjunctivally in one uli, whether or not the stimuli were saccade eye (33). The computer system triggered the stimtargets, and did not discharge before learned ulation train and collected two digital records of ELECTRICAL TABLE Relationship 1. STIMULATION OF FRONTAL EYE 717 FIELDS. of cell type to threshold Current Threshold Cell Type 40 /LA 50- 150 PIA 34 11 45 7 6 13 11 2 13 52 19 71 3 4 3 6 15 9 17 21 20 55 59 30 36 68 79 Total without movement activity 11 47 155 213 Ambiguous cells Uncharacterized presaccadic Pre-post Total ambiguous 32 3 35 20 21 21 5 26 73 9 82 Total all cells 91 81 194 366 Cells with movement activity Visuomovement Movement Total with movement activity Cells without movement activity Visual Postsaccadic Not saccade-related Not driven saccades in the dark. Postsaccadic cells (n = 36) discharged after or during saccades but not before them. Cells not related to saccades (n = 68) responded to fovea1 visual stimuli, auditory stimuli, or in association with smooth pursuit eye movements or particular directions of gaze. Also included in this group were 79 neurons we could not drive. For the third group (n = 82) the presence of movement activity was ambiguous. Uncharacterized presaccadic cells (n = 73) discharged before visually guided saccades but were not further characterized; presumably some but not all of these cells had movement activity. Pre-post cells (n = 9) discharged before visually guided saccades-in one direction but also discharged after saccades in roughly the opposite direction. After studying each neuron we observed eye movements elicited by microstimulation at the recording site. Saccades were elicited by currents as low as 10 PA. To analyze the relationship between cell type and electrically elicited saccades, we classified each stimulation site according to its threshold. Sites with thresholds 150 PA were designated as low threshold, sites with thresholds between 50 and 150 PA, as intermediate threshold, and sites that required currents > 150 PA, or from which saccades could not be elicited, as high threshold. Most high-threshold sites were ones at >150 PA Total which no saccades were evoked because we rarely used currents > 150 PA in order to minimize tissue and electrode damage. Table 1 lists the number of cells of each type recorded at low-, intermediate-, and highthreshold sites. Movement activity was strongly associated with low thresholds; 63% (45/7 1) of visuomovement and movement cells were at low-threshold sites, and only 18% were at high-threshold sites. Conversely, the absence of movement activity was associated with high thresholds; only 5% (1 l/2 13) of the cells lacking movement activity were at lowthreshold sites, whereas 73% ( 155/2 13) were at high-threshold sites. Uncharacterized presaccadic cells were intermediate; 43% (35/82) were at low-threshold sites, and 3 1% (26/82) were at high-threshold sites. This suggests that the uncharacterized presaccadic neurons were a mixture of cells with visual and movement activity. Figure 1 shows an example of eye movements elicited by electrical stimulation at a low-threshold site and the activity of a visuomovement cell recorded at that site during different tasks. The cell discharged briskly on the visually guided saccade task (top) and responded weakly when the same visual stimulus was given in the fixation task (middle-right). These activities are not necessarily indicative of a visuomovement cell as visual cells with 718 BRUCE, GOLDBERG, BUSHNELL, stable trgt . . Sl . AND STANTON fixation ..-- . . m . . . . . . ” . . . I 13-491 Electrical Stimulation 3 10” - I,.,....IIII,,~,,~~~~ I. ..,,,,I,.., ..I..,,.,,, 2oIC;S - I1,,,.a,,.,,,,.,,., ,,,,I 1..,,I,,,,,,,.,,,,b FIG. 1. Activity of a visuomovement neuron during different oculomotor tasks (top two rows) and saccades evoked by low-level microstimulation (50 PA) at the site of this cell (bottom TOW).H labels the horizontal eye position trace, V, the vertical, Sl, the fixation point (up - on; down - off), and S2, the saccade target. Neuron discharges are shown as dots between the eye and stimulus traces. The top two records show the standard saccade task: Sl disappears, and S2 appears simultaneously, and the monkey makes a saccade recognized by the computer as appropriate and marked by ticks on the vertical eye trace. In the top left record, the saccade had a short latency and in the top right, a much longer latency. The stable target saccade task is shown in the left middle record: the target (S2) was continuously present, and the monkey saccaded to it in response to the disappearance of the fixation light (3). The right middle record shows the fixation task: Sl did not disappear, and no saccade was made. The bottom records show the elicited saccade at the site of this neuron. The duration of electrical stimulation is marked by a dark bar beneath the eye traces. enhancement may have similar responses (8, 21, 72). However, the visuomovement cell burst immediately before saccades made to stable targets (middle-left). Movement cells also respond before saccades made in this paradigm, but purely visual cells either do not respond or respond tonically whenever the target lies in their receptive field and do not change their discharge rate before the saccade (8). Therefore, the stable target saccade task distinguishes visuomovement and movement cell types from purely visual ones, and hence is very diagnostic for low-threshold sites. High thresholds were associated with a diverse grouping of cells lacking presaccadic movement activity. Two cell types in this group are of special interest because their responses are nonetheless related to saccades. Visual cells are active before visually guided saccades, yet they lack movement activity as determined by other tasks. Only 10% of visual cells (3/30) were at low-threshold sites, whereas 70% (2 l/30) were at high-threshold sites. Cells with postsaccadic activity are also important as they discharge in conjunction with particular sets of saccades, and it has been hypothesized that electrical stimulation of the frontal eye fields evokes saccades by antidromically activating afferents to such cells (5 1). However, thresholds at postsaccadic sites did not support this hypothesis. Only 3% of 36 sites with purely postsaccadic activity had low thresholds, whereas 56% had high thresholds (Table 2). Relationship between electrically elicited saccades and movement fields of single neurons We studied each cell with presaccadic activity using the visually guided saccade task to determine its visual receptive field or movement field. We varied the target location, thereby eliciting visually guided saccades of ELECTRICAL STIMULATION OF FRONTAL different directions and sizes, and found the “optimal” dimensions associated with the greatest presaccadic discharge. The dimensions we had judged to be optimal usually matched the dimensions of saccades subsequently evoked at that recording site. This relationship is illustrated in Fig. 2. The top row shows saccades elicited by microstimulation, and the middle row shows activity of the cell recorded at that site while the monkey made visually guided saccades using the target location we had judged to be optimal for that cell. Note that the saccades elicited by microstimulation are quite similar, in both size and amplitude, to those elicited in the saccade task by the optimal target placement. The bottom row confirms that the cell was much less responsive when the target location, and hence the saccade direction, differed from the optimal. We quantitatively investigated this relationship by making tuning curves of cell ac- 719 tivity as a function of direction and amplitude. We compiled histogram sets for target locations systematically differing in either direction or eccentricity. Plots of cell discharge as functions of saccade amplitude or direction were later fit with Gaussian curves, and the parameters corresponding to the peaks of the curves were taken as the optimal direction or amplitude for the cell (8). Figure 3 shows four pairs of plots and curves with the median dimensions of electrically elicited saccades indicated for comparison. On the right are representative examples of both the optimal saccades with associated cell discharge and the electrically elicited saccades. As with the sites mapped qualitatively, the elicited saccade dimensions usually matched the optimal saccade as obtained from the tuning curves. Complete direction tuning curves were made for 16 cells at whose sites we subsequently elicited saccades with microstimulation. Figure 4A shows Al A2 A3 Bl 82 83 / Hi VI 4 .- Sl s2 EYE FIELDS , .. I, .-I II -.‘J I I1 . -.- - . . . I ------A I I I I I, I J I I * I I I,, I I I ..w.-I I I * . . .. * T I. x. 12-374 FIG. 2. Relationship of a frontal eye field neuron’s movement field to saccade evoked by electrical stimulation. Al, A2, and A3 show 3 different saccades evoked by electrical stimulation at a single site in the frontal eye fields. H and V denote horizontal and vertical eye position, and the ticks on the vertical eye trace indicate the beginning and end of saccades, as recognized by the computer. The electrical stimulation occurred at the artifact line in the stimulation trace. Note that the eye movement was nearly the same in all 3 records, even though the eye position at the time of stimulation differed considerably. Rows B and C show activity of the neuron studied at this stimulation site. Bl, B2, and B3 show activity during the visually guided saccade judged optimal for the cell. Note that the electrically elicited saccades in A resemble this saccade. Each dot below the eye movement trace represents a neuronal discharge. Sl denotes the fixation point, and S2 denotes the peripheral stimulus to which the monkey made a saccade. When the associated trace is up, the stimulus was on; when it is down, the stimulus was off. Cl shows a much weaker response to the same peripheral stimulus during a fixation task. C2 and C3 show weak (C2) or nonexistent (C3) responses to saccades other than that shown in row B. 720 BRUCE, GOLDBERG, BUSHNELL, AND STANTON 8, 1 8: 13-4e1 ---0 -iL- “+- 8: $ . . ,-no-. . / 52: Ri* . 0, / /6 0 1.. .,...., 0 5 .I.,,... .-,.,....,.... 10 15 20 . . . . 25 30 ,_ 35 40 45 AMPLITUDE 10 15 20 25 30 35 40 is AMPLITUDE --- ,‘...l..“,....,...,,...., 10 15 20 25 30 35 40 45 AMPLITUDE ,....I....,...-,....,.... 0 DIRECTION 5 1Q 15 20 _... .. 25 30 35 I‘“., 90 45 AMPLITUDE FIG. 3. Correlation of movement fields of neurons with saccades evoked by electrical stimulation at the site of the neurons. The left sraph in each row shows the relationship between cell discharge and direction of eye movement at the optimum amplitude for each cell. Direction is in degrees of arc, with 0 representing horizontal rightward by convention. The vertical line through the graph shows the median direction of electrically elicited saccades at the site of the cell. The right graph in each row shows the relationship between cell discharge and saccade amplitude at the optimum direction, with the vertical line indicating the median amplitude of electrically elicited saccades. The top, right records show visually guided saccades with horizontal and vertical eye traces and cell discharges (dots below). Saccade recognition ticks are on the vertical eye traces. Saccades evoked by electrical stimulation are shown directly beneath, with the duration of stimulation marked. ELECTRICAL STIMULATION the relationship between the optimum saccade directions determined by tuning curves and the median saccade evoked by suprathreshold electrical stimulation. The correlation between optimal saccade and evoked saccade direction was +0.93. Complete amplitude tuning curves were made for 15 cells at successful stimulation sites. Figure 4B shows the relationship between the optimal saccade amplitude determined by the tuning curves and the median, electrically evoked saccade amplitude. Amplitude was plotted with logarithmic axes because saccade amplitude tuning in the frontal eye fields, like visual eccentricity in visual cortical areas, appears to be logarithmically scaled (59). The correlation between optimal and elicited amplitudes, both logarithmically scaled, was +0.8 1. Although the evoked saccade dimensions and saccade dimensions optimal for presaccadic activity generally were similar, there were exceptions and qualifications to this relationship. First, there was a systematic trend involving cells that preferred fairly vertical saccades, either up or down. Stimulation at the sites of such cells usually evoked saccades somewhat more contralateral (i.e., rotated away from vertical) than the cell’s optimal saccade. In the bottom example of Fig. 3 the cell’s best response preceded vertical (upward) saccades, but elicited saccades from that site were oblique. Second, the saccades evoked by electrical stimulation tended to be shorter than the optimal saccade amplitude for the cells. This was particularly evident at sites with neurons having large, eccentric movement fields (see Fig. 4B). Nevertheless, the saccade evoked by electrical stimulation was one before which the cell at that site had discharged vigorously. Finally, there were some instances of poor correspondence between evoked and optimal saccades besides the two special cases just discussed. Such mismatches were seen, whether the cell’s optimal saccade was judged qualitatively or quantitatively, as evidenced by discrepant points in Fig. 4. Mismatches were more likely at higher-threshold sites and at sites mapped with visual cells. Relationship of elicited saccade dimensions and postsaccadic movement fields We also stimulated at the sites of cells for which we had mapped the movement field for OF FRONTAL EYE FIELDS 721 z2d g P 5 5 E 5QDo _ z 00 $ z 3 6 / n V I Neuron Optimum Direction (Deg) 1 Neuron Optimum Amplitude (Des) FIG. 4. Relationship between amplitude and direction of the saccade associated with the greatest neural activity for quantitatively studied cells and saccades evoked by electrical stimulation at site of those cells. A: the scatter plot of median evoked saccade direction to the neural optimal direction as computed from the amplitude tuning curve for each cell. Dotted line, ideal x = y function; unbr&en line, regression line calculated by the method of least squares. B: the scatter plot of median evoked saccade amplitude versus the optimal saccade amplitude for neuronal activity. Both axes are logarithmic. Both correlation coefficients (r) are significant at P < 0.001. 722 BRUCE, GOLDBERG, BUSHNELL, AND STANTON postsaccadic activity. The results did not sup- ments with both types of saccade-related acport the hypothesis that electrical stimulation tivity. The optimal movements for each of the of the frontal eye fields evokes saccades by an- component activities of these cells are usually tidromically activating the afferents of cells in opposite directions (8). The postsaccadic discharge is obligate, occurring after all sacwith postsaccadic activity. This antidromic hypothesis would predict that the evoked sac- cades of the right dimensions, whereas the cade should match the postsaccadic movepresaccadic component is conditional and is ment field of nearby cells, but this was not the absent or minimal in conjunction with sponcase. When saccades were electrically elicited taneous saccades made in the dark (8). As ilat such sites, their dimensions usually did not lustrated in Fig. 5, the dimensions of elicited agree with the movement field for postsaccadic saccades from the sites of such cells were found activity; in fact, many postsaccadic cells had to be in agreement with the presaccadic field ipsilateral movement fields yet the elicited eye and opposite the postsaccadic movement field. movements were contralateral. Therefore, these combination cells dramatiCells having both pre- and postsaccadic re- tally show that elicited eye movements in the sponses allowed for a direct comparison of the frontal eye fields are related to presaccadic, relationship of electrically elicited eye movebut not postsaccadic, neural activity. PRE-SACCADIC DIRECTION (trigger line = saccade POST-SACCADIC DIRECTION (trigger line = saccade start) end) Visually Guided Saccades Spontaneous Saccades in Dark Electrically Elicited Saccades I ,- --d--- - /’ __1_1_ ] 10” 13-481 FIG. 5. Comparison of neuronal activity and the saccades evoked by electrical stimulation near a cell with pre- and postsaccadic activity. The left column shows activity for saccades in the presaccadic optimum direction, the rig& column for saccades in the optimal postsaccadic direction. Representative eye-position traces are shown above, with the computer saccade recognition ticks on the vertical trace. In the rasters, each dot is a cell discharge, and successive epochs of cell activity are all synchronized on the onset of the saccade. The histograms sum the activity in the rasters and the histogram calibration line signifies a discharge rate of 100 Hz. Eye movements evoked by electrical stimulation at the recording site are shown at the bottom. Note that the electrically evoked saccades are in the presaccadic direction. ELECTRICAL STIMULATION Saccade Iatencies Saccade latencies were measured from the onset of the microstimulation train until the beginning of the evoked saccade. Each site had a consistent, characteristic latency, and site latencies, based on a median of 10 or more successful trials, ranged from 20 to 60 ms, with 30-45 ms being typical. There was no obvious basis for this variation: Short and long latencies were found for sites with large and small saccades, sites with low and high thresholds, sites in different monkeys, and even at different sites within individual electrode penetrations. Likewise, although latencies were somewhat longer and more variable at threshold, further increases in suprathreshold current had little effect. We should emphasize that these observations were made using currents 5 150 PA. Using much higher currents, Robinson and Fuchs (54) found that frontal eye field saccades had uniformly short latencies of 15-25 ms. Relationship of threshold to behavioral state Low saccade thresholds were critically dependent on the state of the monkeys. A lack of alertness raised thresholds for eliciting saccadic eye movements with microstimulation and elicited saccades suffered from the same slowness and postsaccadic drift that characterized spontaneous saccades when the monkeys were not alert. Waking the monkeys with noise or rewards eliminated these effects, at least temporarily. Thresholds also were raised when the animals were tested under fixation, as described elsewhere (20). Anatomical location of the frontal eyeJields We used electrical stimulation to study the extent and topography of the frontal eye fields, both in the untrained monkeys, used solely for such mapping experiments, and in trained monkeys, which were primarily used to study neuronal activity. The emphasis on stimulation in the untrained monkeys enabled us to proceed more rapidly and place more marking lesions than we could in the trained monkeys. We designated cortex where saccades were elicited with currents 5 50 PA as the lowthreshold frontal eye fields and placed most electrolytic marking lesions at low-threshold sites. In all monkeys this low-threshold area lay along the posterior portion of the arcuate sulcus. We saw no difference in frontal eyefield location between Macaca mulatta and Macaca fascicularis, although the exact loca- OF FRONTAL EYE FIELDS 723 tion relative to landmarks such as the principal sulcus varied among monkeys. Figure 6 shows the location of the low-threshold frontal eye fields in five hemispheres. These surface views do not portray the full expanse of the lowthreshold region as it is largely buried in the anterior bank of the arcuate sulcus and extends only a few millimeters onto the surface of the prearcuate gyrus. Based on its approximate extent along the arcuate (10 mm) and extension into this sulcus (8 mm), the low-threshold frontal eye fields encompass -80 mm2 of cerebral cortex in each hemisphere. The frontal eye fields defined by the lowthreshold criterion are considerably smaller than Brodmann’s cytoarchitectonic area 8. Examination of stained sections (cresyl violet, thionin, and Merker’s silver Nissl stain) indicated that the frontal eye fields better correspond to the union of Walker’s area 8A and area 45 (68). Both of these areas are characterized by clusters of very large pyramidal cells in layer V, and area 45 is further distinguished by large pyramids in layer III as well. Both areas have a dysgranular layer IV, which becomes agranular at their posterior border in RIGHT LEFTVIEVERSED) Ml7 1 CM FIG. 6. Location of the frontal eye fields. The lowthreshold frontal eye fields in 5 different hemispheres of 3 cynomolgus monkeys. The surface projection of the arcuate sulcus in which low-threshold saccades were found in the anterior bank is shown as the darkened line between two arrows. Each hemisphere is shown in a view looking directly dotin on the principal sulcus, with the central sulcus shown as the far-left landmark of each drawing, and the front of the brain on the right. 724 BRUCE, GOLDBERG, BUSHNELL, the arcuate fundus and strongly granular at their anterior border on the prearcuate gyrus. Figure 7 shows the cytoarchitecture of areas 8A and 45 in cresyl material using sections with low-threshold marking lesions. In agreement with the overall topography described AND STANTON below, saccades elicited from area 8A were generally large, whereas saccades from area 45 were generally small. The views shown in Figs. 6,7,8, and 9 were taken normal to the surface of the prearcuate gyrus. This view portrays the shape of the ar- Ill IV lmm v FIG. 7. Photomicrographs of the frontal eye fields showing the cytoarchitecture of Walker’s areas 8A and 45. The line drawing insert shows the location, extent, and orientation of the 2 sections. The micrographs, right, are enlargements of the rectangles delineated on the let%micrographs. Micrographs, top, show area 45 in a section near the ventral border of the frontal eye fields. In the low-magnification photograph, notice the strongly granular cortex on the top of the brain, which becomes dysgranular near the sulcal lip. In the high-magnification photograph, notice the clusters of large cells in both layers III and V. Immediately above the region selected for enlargement are part of 2 parallel electrode tracks, each with a pair of microlesions marking low thresholds for elicited saccades, which were small in amplitude. Set of micrographs, bottom, shows area 8A from a section near the dorsal border of the frontal eye fields. In the highmagnification photograph, notice that the clusters of large cells are mostly confined to layer V. Large saccades were elicited along the tracks visible in the low-magnification section. ELECTRICAL STIMULATION OF FRONTAL EYE FIELDS 725 FIG. 8. Eye movements evoked by electrical stimulation at different sites showing the increase in saccade amplitude with dorsal-to-medial movement across the frontal eye fields. Several eye movements evoked while the monkey fixated near the center of the screen are superimposed for each site and are shown in a 2-dimensional coordinate system whose origin is the fixation point. Eye position was sampled at 1 KHz, and the raw sampled values are shown as dots without interpolation. Each set of saccades is connected by a line to the square on the surface of the brain marking the entry point of the penetration in which the saccades were evoked. The median saccade amplitude is written on the line; note that the scales for the different sets of saccades are adjusted from 15O per tick for the largest saccades (upper right) to 3’ per tick for the shortest saccades (lower right). cuate sulcus veridically and emphasizes the broad posterior portion that contains the frontal eye fields. In some monkeys this portion of the arcuate sulcus is gently rounded, as a “(“. In other monkeys it is more squared, as a “[“. In contrast, the commonly used lateral view of the macaque brain offers a sharply angled perspective of the arcuate region, which artificially foreshortens this posterior portion and often causes the arcuate sulcus to appear as a “<” pointing posteriorly. Based on its appearance in the lateral view, the arcuate sulcus has been exhaustively divided into superior and inferior limbs. We think it is misleading to ascribe the frontal eye fields to either of these lrm bs. BRUCE, GOLDBERG, I I I MILLIMETERS I I 1 BUSHNELL, AND STANTON -90” - 1 I I 1 1 MILLIMETERS 15-19 FIG. 9. Systematic changes in the direction of eye movements evoked by electrical stimulation over long electrode penetrations through the frontal eye fields. A and B each show the angle of saccade evoked by electrical stimulation at different sites along a single electrode penetration. In the top graphs, the ordinate is saccade direction, and the abscissa is distance along the electrode track. In the brain section tracings the direction is indicated by the slant of the arrows and marking lesions by dots on the penetration line. Saccades could not be evoked from the 2 sites labeled X in penetration B. The center drawing is a view normal to the cortex in the vicinity of the frontal eye fields with the 2 electrode penetrations marked. CS, central sulcus, PS, principal sulcus. Topography of the frontal eye fields 45. There was also a tendency within individual penetrations that larger saccades were elicNearly any saccade can be elicited by stimulation at some site in the frontal eye fields. ited near the lip of the sulcus and smaller ones near the fundus. Saccade amplitudes ranged from < 1Oto >30”, In contrast to the organization of saccade and all directions of saccades were represented with microstimulation in each frontal eye field amplitude, there was no overall topographic yielding saccades into the contralateral field. mapping of saccade direction. Instead, direcThe typical elicited saccade was oblique and tion was well organized at a local level in that no particular direction, such as along the plane the direction of elicited saccades systematically shifted as the electrode was advanced small of action of the eye muscles, was dominant. Saccade amplitude was topographically or- distances within individual penetrations. This ganized. The largest saccades were elicited shift of saccade direction was most evident in from the most dorsolateral portion of the penetrations that followed the rostra1 bank of frontal eye fields, and the smallest saccades the arcuate, remaining in the low-threshold frontal eye fields for several millimeters. Figure were elicited from its ventrolateral portion. Although this topography was not always ev- 9 shows direction progressions for two penetrations that yielded low-threshold, elicited ident from comparisons of saccades elicited from closely spaced penetrations, it was always saccades for nearly the entire depth of the arobserved in an extended series of penetrations cuate sulcus. Although the direction of the first along the rostra1 lip of the arcuate, such as saccade elicited in a penetration seemed unthose shown in Fig. 8. This topographical or- predictable (see Fig. 8), thereafter saccade direction varied continuously with small shifts ganization dictates that saccades elicited from area 8A are larger than those elicited from area generally being evident after electrode move- ELECTRICAL STIMULATION ments of 0.25 or 0.5 mm. The direction of change usually held for several millimeters but often reversed on reaching a vertical direction (up or down). Most long penetrations showed at least one reversal in direction of change; consequently, many penetrations encountered large sets of directions more than once. Most lesions marking low-threshold sites were found to lie in infragranular laminae, and electrode penetrations with low thresholds for an extended distance usually were found to have traversed the infragranular cortical laminae (see Fig. 9). At many sites we retested microstimulation after making the electrolytic lesion. Threshold was invariably raised, and often no eye movement could be elicited by 150-PA currents at what had been a lowthreshold site (40 PA). Subsequent electrode movements of 0.25-0.5 mm usually restored low-threshold, elicited saccades, as well as bringing back a normal level of background neuronal activity. Slow eye movements and other evoked behaviors Microstimulation elicited slow, smooth eye movements at 21 sites. These movements lacked the all-or-none property of elicited saccades; they continued for the duration of stimulation (up to 2 s) without evidence of a staircase. Furthermore, eye velocity increased Visually Guided’ Smooth Pursuit OF FRONTAL EYE FIELDS 727 with increases in current (up to 150 PA). These movements cannot be characterized as either slow saccades or nystagmus produced by a lack of alertness because they were elicited both during alert spontaneous behavior and even during visual-fixation paradigms. Nor were they vergence movements; although a search coil was present in only one eye, it was clear from direct observation that these movements were conjugate. Finally, differentiation of the eye-position trace showed that the eye velocity was continuously low, and hence the movement was not a stream of minute saccades undetectable in the position domain. We think these slow movements are artificial elicitations of smooth pursuit eye movements that enable monkeys to track moving visual targets. Neuronal activity supported this hypothesis; at 12 of these sites, cells discharged preferentially during smooth pursuit of a small target moving in particular directions. Figure 10 shows the activity of a cell during visually guided pursuit eye movements and the slow eye movements subsequently elicited by electrical stimulation at that site. Smooth movement sites were very deep within the arcuate sulcus; however, small saccadic eye movements were also elicited at, or near most of, these sites. Therefore, it is not clear whether slow movements are interspersed within the saccadic frontal eye fields or if they comprise V- . . . . .. ..... . .. .. ........ . .. .... .. Stimulation H (50 pa) v . . . . . . . 0. Stimulation (100 pa) 17-025 loo1 lOi& FIG. 10. Smooth pursuit eye movements evoked by electrical stimulation in the frontal eye fields. The top pair of records show horizontal (H) and vertical (V) eye-position traces and the neuron discharges for that movement (dots below). The cell discharged more during upward-to-left pursuit than during pursuit in other directions. The left record shows activity in this direction, and the right diagram shows activity associated with pursuit down and to the right. The middle trace shows the smooth eye movements elicited by stimulation (50 PA current, 500 ms duration) through the recording microelectrode at the site of this cell. Stimulation is i ndicated by the dark line beneath the eye-position traces. The bottom traces show higher velocity movements evoked by increasing the current to 100 /LA. 728 BRUCE, GOLDBERG, BUSHNELL, a contiguous, but separate, area adjacent to the small saccade region. Stimulation in the posterior bank of the arcuate sulcus did not evoke eye movements. Instead, arm and hand movements, mouth movements, or blinks were often evoked from this cortex. Stimulation anterior to the frontal eye fields usually evoked saccades at high thresholds or failed to elicit any overt behavior. AND STANTON ison with thresholds near neurons with presaccadic activity. Furthermore, postsaccadic movement fields did not match the elicited eye movements. For example, many postsaccadic neurons were selective for ipsilaterally directed eye movements, whereas the direction of both presaccadic response fields and elicited saccades were nearly always contralateral. For cells with both pre- and postsaccadic activity, the elicited saccade went into the presaccadic movement field. We therefore suggest that the DISCUSSION antidromic hypothesis is untenable. Because of the close relationship between presaccadic Relationship between elicited saccades and activity and elicited eye movements, it is also neuronal activity unnecessary. Our data indicate that electrically These results indicate that saccades elicited evoked saccades reflect the activation of preby electrical stimulation of the frontal eye saccadic cells in the frontal eye fields and orfields reflect a functional role of this cortex in thodromic conduction to their targets in the triggering saccadic eye movements, as origisuperior colliculus and brain stem preocunally postulated by Ferrier, Holmes, and oth- lomotor centers. ers (12, 15, 16,26,27,62). The lowest threshLike cells with postsaccadic activity, cells olds for eliciting saccades were found near with visual activity alone were rarely found at neurons that discharged before saccades, in low-threshold sites. This implies that frontal particular, visuomovement and movement eye-field visual activity is not directly relayed cells. Moreover, the dimensions of saccades to the subcortical oculomotor targets of the evoked by electrical stimulation matched the frontal eye fields. Instead, we think that this movement fields of the cells at the site stimvisual activity is processed within the frontal ulated. We postulate that activity of visuo- eye fields and has the potential to be transmovement and movement cells constitutes the formed into movement activity destined for frontal eye-field signal that triggers particular subcortical oculomotor centers. Recent work saccades and that electrical stimulation of the from this laboratory directly supports this hyfrontal eye fields elicits saccades of the same pothesis. Visuomovement and movement direction and amplitude by exciting these cells, but not visual cells, can be activated anneurons and their efferent processes. tidromically by electrical stimulation of the Contrasted with thresholds near visuo- intermediate layers of the superior collicumovement and movement cells, thresholds lus (60). near visual cells, postsaccadic cells, and other Lesions marking low thresholds for micell types lacking presaccadic movement ac- crostimulation saccades were usually located tivity were much higher. It is significant that in infragranular laminae. Cortical projections low thresholds for electrically eliciting eye to the colliculus, thalamus, and brain stem movements were not found at sites having originate in the pyramidal cells of laminae V postsaccadic neuronal activity. This was the and VI; therefore the low thresholds probably first functional activity reported in the frontal reflect the proximity of the electrode to these eye fields (5,6) and has been postulated to be output cells. Because low thresholds were asa corollary discharge signal originating in sub- sociated with visuomovement and movement cortical eye movement structures (5, 6, 66). cells, we infer that these cell types are preferBecause activity preceding saccades was not entially located in infragranular cortical layers yet reported, it was hypothesized that the eye and that visual and postsaccadic cells are more movements evoked by frontal eye-field stimconcentrated in supragranular laminae. More ulation were caused by antidromic conduction definitive experiments are needed to determine over fibers carrying this corollary discharge to exactly how cell types are distributed across the frontal eye fields (5 1). Our study argues laminae and which types project to the differagainst this antidromic hypothesis. Thresholds ent subcorticai and cortical targets of the fronnear postsaccadic cells were high in compartal eye fields. ELECTRICAL STIMULATION Although we have correlated the effects of electrical stimulation with the properties of the cell nearest the recording microelectrode, our levels of microstimulation obviously excited more than this one cell. There are two ways that the effects of electrical stimulation can spread: I) By passive current spread or 2) by active spread over neural processes. Workers in this field (47) begin by analyzing passive current spread. One model holds that the threshold current needed to excite a cell body or axon with monopolar stimulation obeys a distance square law i= a + kr2 where i is the threshold current needed to excite a neuron that is r microns away from the electrode, and a and k are constants. Stony, Thompson, and Asanuma (64) investigated the parameters of this equation for the motor cortex of the cat using glass-coated electrodes similar to those used in this study. They calculated that single pulses of 10 PA excite cells up to 110 pm distant, 50 PA excites cells up to 300 pm away, and 100 PA, to 450 pm. We accept these distances as estimates of our sphere of effective passive current spread. Because electrolytic lesions, which were roughly 250 p in extent, raised thresholds for eliciting saccades considerably, these estimates may be large. Active spread over neural axes, for example, via cortical interneurons, is more difficult to estimate; however, for the current levels used here, passive current spread may predominate. Cortical organization is predominantly radial (1 l), and except for layer I, the horizontal spread of neural processes is usually ~300 p (40). Therefore the horizontal spread of activation from currents 250 PA should largely reflect passive current spread. Because lowthreshold sites were predominantly confined to infragranular laminae, it appears that active spread is limited radially as well. Therefore we estimate that microstimulation at 50 JLA, our criterion for the low-threshold frontal eye fields, excites a cortical neighborhood on the order of 300 pm in radius. The close relationship we found between neuronal activity and elicited saccades indicates that the one cell we happened to study was usually representative of cells in the stimulated ensemble. Use of larger stimulating currents mav Preclude or weaken such a relationshin. OF FRONTAL EYE FIELDS 729 For example, much higher currents are required to elicit saccades in posterior parietal cortex, and the correlation between elicited saccade dimensions and receptive fields there (6 1) appears to be much lower than it is in the frontal eye fields. Extent and topography of the frontal eye fields The frontal eye fields have been mapped many times since their discovery over a century ago (9, 12, 15-17,54,62,67,72). In some reports, elicited eye movements were obtained over large expanses of the frontal lobe; however, it is difficult to compare our results with these previous studies because radically different techniques were used: for example, surface stimulation, macroelectrodes, high currents, anesthetized subjects, and informal observations of eye movements. The lowthreshold frontal eye fields, which we define as that region from which intracortical microstimulation at (50 PA evokes saccades, is a more discrete region nestled in the posterior aspect of the arcuate sulcus. It largely agrees with Robinson and Fuchs’s map (54), which also was based on intracortical stimulation in awake subjects, except that the low-threshold frontal eye fields are less extensive anteriorly and are largely confined to the anterior bank of the arcuate sulcus. These differences probably reflect the criteria employed. Robinson and Fuchs (54) used currents up to 3 mA, whereas our map is based on 50 PA thresholds. Furthermore, we ignored sites subsequently found to be in white matter, as the deep sulci in this region make it uncertain where such fibers originate. These low-threshold frontal eye fields do not extend into the strongly granular cortex of primate prefrontal cortex and hence do not encompass all of Brodmann’s area 8, which historically has been equated with the frontal eye fields. They better correspond to the union of Walker’s areas 8A and 45 (68), both of which are characterized by large pyramidal cells in layer V and a dysgranular layer IV. Thus the rostra1 border of the low-threshold frontal eye fields is at the transition to the granular cortex of Walker’s area 46, where more intense stimulation is required to elicit saccades, It is unclear whether these higher-threshold saccades are mediated by the subcortical projections of area 46 (24. 38). short association moiections 730 BRUCE, GOLDBERG, BUSHNELL, back to the frontal eye fields, by current spread to frontal eye field efferents in the white matter below area 46, or even by spread to the frontal eye fields themselves or to the supplementary oculomotor area recently described by Schlag and Schlag-Rey (5 7). The posterior boundary within the fundus of the arcuate approximately coincides with the transition to the agranular cortex of Brodmann’s area 6. Electrical stimulation in the posterior bank of the arcuate produced hand, face, or mouth movements. Cells in area 6 often respond to somesthetic stimuli, visual stimuli near the monkey’s body (48, 49), or visual stimuli that cue limb movements (69, 70). The frontal eye fields could be considered the eye-movement specialization of this premotor region. The pattern of larger saccades being elicited from the most dorsomedial portion of the frontal eye fields and the smaller ones from the ventrolateral portion is consistent with the mapping of Robinson and Fuchs (54) and also parallels the topography of visual receptive fields in granular cortex immediately anterior to the frontal eye fields (65). Furthermore, this amplitude topography accords with the afferent and efferent connections of the frontal eye fields and adjacent prefrontal cortex. Several anatomical studies (4,3 1,32) indicate that the ventrolateral frontal eye fields receive cortical afferents preferentially from visual areas with central receptive fields (e.g., TE, TEO), whereas visual areas with peripheral receptive fields project preferentially to dorsomedial frontal eye fields and neighboring prefrontal cortex. We have recently found that tectal projections of the frontal eye fields (63) further reflect this frontal eye-field topography. The dorsomedial frontal eye fields project preferentially to the caudomedial superior colliculus, where large saccades are represented, whereas the ventrolateral frontal eye fields project more to the rostrolateral colliculus, where small saccades are represented (13, 23, 52, 7 1). Saccade direction did not have an overall topographic organization. In this respect the frontal eye fields differ from the superior colliculi, where upwardly and downwardly oblique saccades are segregated, with the representation of purely horizontal (contralateral) saccades dividing the colliculus in half. In contrast, upwardly oblique and downwardly oblique saccades were interspersed throughout AND STANTON the frontal eye fields. Suzuki and Azuma (65) reported a similar indeterminancy for the direction of visual receptive fields in the prearcuate cortex, anterior to the frontal eye fields. The point-to-line topography of visual fields in the lateral suprasylvian gyrus of the cat (45) is another example of such directional indeterminancy. Saccade direction was well organized at a more local level of observation. Small advances of the microelectrode produced small shifts in the direction of elicited saccades, and these small shifts added up to systematic progressions through a large range of directions, with periodic reversals in the direction of change. This organization of saccade direction resembles the organization of orientation specificity in primary visual cortex, where all orientations are systematically represented over a set of columns, termed a hypercolumn, and orientation hypercolumns are repeated throughout the area (28-30). Specificity for the direction of stimulus movement in prestriate area MT is organized in a similar fashion (1). However, the complete concept of a cortical column also reflects the observation that cells along a radial penetration are similar with respect to a physiological feature, e.g., orientation or ocular dominance in visual cortex. Because few of our penetrations traversed the frontal eye-field cortex radially, we can only infer that the frontal eye fields may have a columnar organization analogous to those found in visual (28, 29, 30), somatosensory (44), and motor (2) cortices. That direction is organized locally, but lacks an overall topographic organization, may explain why some previous reports (9,54) found a preponderance of horizontal (contralateral) saccades and also why Robinson and Fuchs (54) observed that saccades became more horizontal as stimulation current was increased. If the saccade elicited from the frontal eye fields reflects an average of all sites stimulated, then large currents would stimulate over all contralateral directions, and the average would tend to be a horizontal saccade, with the upward and downward components canceling each other. In contrast, a global topography, such as in the superior colliculus, should have larger neighborhoods of similar cells and therefore allow elicitation of oblique saccades even with high currents. A similar argument may explain why mi- ELECTRICAL STIMULATION crostimulation near cells responsive before vertical saccades elicited movements slightly more oblique than the optimal saccade for the cell. Movement fields in the frontal eye fields are quite broad, as indicated by tuning curves for amplitude and direction both here and in our previous report (8). Therefore, natural saccades will be preceded by activity in a large ensemble of frontal eye-field cells and for saccades having a significant vertical component, this ensemble will include many cells in both hemispheres. If unilateral microstimulation does not effectively stimulate cells in the contralateral hemisphere, then it will not mimic the bilateral activity that precedes natural vertical saccades, and the elicited saccades will be oblique because the horizontal components fail to cancel. Others have found that bilateral stimulation of the frontal eye fields readily elicits vertical eye movements (9). Finally, we were surprised that stimulation of some sites elicited slow eye movements that were clearly distinct from the rapid saccades typically obtained and resembled the smooth pursuit eye movements that are used to track moving visual targets. A small population of neurons also discharged in association with pursuit at these sites. The frontal eye fields have not generally been thought to participate in smooth pursuit, although there is a report of patients having smooth pursuit disorders following damage to the frontal lobes (41). Bizzi (5) described neurons that discharged during smooth pursuit, but these neurons (type II) also discharge in association with tonic eye position (6) and are therefore distinct from the smooth pursuit neurons described here. Nonsaccadic eye movements and other behaviors (vergence, centering, pupil dilation, blinking, and nystagmus), previously described as elicited by frontal eye-field stimulation, appear to reflect the use of extremely high currents and anesthetized subjects (7, 9, 12, 62). However, slow movements in this study were elicited with currents as low as 25 PA in fully awake subjects and were even obtained while the monkeys fixated a stationary light and therefore were quite alert. Moreover, neuronal activity at slow-movement sites suggested a relationship between cell function and elicited eye movements analogous to that we showed for rapid, saccadic eye movements. Too few of these cells were studied to answer several basic questions about them, such as if they OF FRONTAL EYE FIELDS 731 discharge in response to the visual surround motion created by eye movements ( 10, 55), and if they respond during smooth eye movements elicited by optokinetic or vestibular stimuli (34). Saccade latencies and frontal eye-jield eflerents The wide range of evoked saccade latencies found here could reflect the different pathways whereby the frontal eye fields can effect saccadic eye movements. Three principal sets of frontal eye-field efferents project to subcortical oculomotor structures, and all originate in the infragranular layers where low thresholds for evoked saccades were found. First, there is a massive projection to the intermediate layers of the superior colliculus (3, 35, 36, 38). This collicular zone is strongly related to saccadic eye movements (7 1). The frontal eye-field projection to the caudate also can influence the colliculus via the substantia nigra. Second, the frontal eye fields project to the extreme lateral zone of the mediodorsal nucleus of the thalamus (35). Neural activity in this thalamic region is also related to eye movements (56, 58). Third, there are direct projections to several premotor nuclei in the brain stem (37,39, 63), including the paramedian pontine reticular formation, which contains the saccade generator of the brain stem (25, 53). The longer-latency saccades are consistent with a midbrain or thalamic route; however, the shorter-latency saccades are not consistent with such an indirect route because eye movements elicited by collicular stimulation are at least as long (52). Therefore, we hypothesize that short latencies were obtained when the electrode was near neurons projecting to the brain stem and, conversely, that longer latenties were obtained when the electrode was near cells projecting to the colliculus or thalamus. The frontal eye-field saccade latencies found by Robinson and Fuchs (54) complement ours regarding this hypothesis. With the use of much higher stimulation currents they report uniformly short latencies of 15-25 ms. High currents may always recruit frontal eye-field cells with direct projections to the brain stem, whereas low currents may activate these quicker pathways only if the electrode is in the immediate vicinity of cells projecting to the brain stem. The scattered clusters of large pyramidal cells in layer V of the frontal eye fields 732 BRUCE, GOLDBERG, BUSHNELL, AND STANTON suggest a patchy organization of frontal eye field efferents, which might underlie the different saccade latencies. In conclusion, this study strongly supports the hypothesis that the frontal eye fields have a causal role in initiating saccades. The classic phenomenon of eye movements elicited by frontal eye-field stimulation is most directly explained as electrical activation of presaccadic neurons in this cortex. All possible saccades are represented within the frontal eye fields; but this representation is not a simple topographic map like the representation of the visual field in structures where visual stimuli are analyzed. Because the organization of saccades in the brain stem is also complex (25, 53), we are still far from understanding how particular patterns of frontal eye-field activity translate into particular eye movements. ACKNOWLEDGMENTS We are grateful to Jean Steinberg and Pam Brown for manuscript preparation, Allison Abood, Geary Fitzpatrick, and Rashid Mahdi for assistance with the monkeys, Laura Cooper, Alvin Ziminsky, and George Creswell for technical assistance, and to Joshua Goldberg for flicking the switch between stimulate and record countless times. This paper was supported in part by the National Eye Institute EY-04740 to Charles J. Bruce, and EY-03763 to Gregory B. Stanton. Dr. Bushnell’s current address is: Faculte de Medecine Dentaire, Universite de Montreal, C.P. 6209, Succ. A, Montreal, Quebec H3C 3T9, Canada. Address reprint requests to Michael E. Goldberg, M.D., Laboratory of Sensorimotor Research, National Eye Institute, Building 10, Room 1OB-09, Bethesda, MD 20205. Received 3 1 December 1984; accepted in final form 12 April 1985. REFERENCES 1. ALBRIGHT, T.D., DESIMONE, R., ANDGROSS,C.G. Columnar organization of directionally selective cells in visual area MT of the macaque. 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