were not evoked from the DMFC while a monkey fixated targets presented in different positions of visual space. Moveover, changing the position of the head with ...
Exp Brain Res (1993) 96:430442
Experimental BrainResearch 9 Springer-Verlag 1993
The dorsomedial frontal cortex of the rhesus monkey: topographic representation of saccades evoked by electrical stimulation Edward J. Tehovnik, Kyoungmin Lee Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, E25-634, Cambridge, MA 02139, USA Received: 15 December 1992 / Accepted: 22 June 1993
Abstract. The dorsomedial frontal cortex (DMFC) of monkeys has been implicated in mediating visually guided saccadic eye movements. The purpose of this study was to determine whether the D M F C has a topographic map coding final eye position, and to ascertain whether this region subserves the maintenance of eye position. The D M F C was stimulated electrically while monkeys fixated a target presented somewhere in visual space. A series of parametric tests was conducted to ascertain the best stimulation parameters to evoke saccades. Electrical stimulation typically produced contraversive saccades that converged onto a region of space, the termination zone. For some stimulation sites, however, stimulation produced ipsiversive saccades. This occurred when the termination zone was located straight ahead of the monkey. Convergence onto an orbital position was never observed during stimulation of the frontal eye fields (FEF), stimulation of which evoked fixed-vector saccades. The latency to evoke a saccade from the D M F C varied with fixation position, such that it increased monotonically the closer the fix spot was to the termination zone. Moreover, the probability of evoking a saccade from the DMFC decreased the closer the fix spot was to the termination zone. The latency for evoking a saccade and the probability of evoking a saccade from the F E F did not vary with fixation position. Horizontal head movements were not evoked from the D M F C while a monkey fixated targets presented in different positions of visual space. Moveover, changing the position of the head with respect to the body did not change the location of a termination zone with respect to the head. The D M F C was found to contain a topographic coding of termination zones, with rostral sites representing zones in extreme contralateral visual space, and caudal sites representing zones straight ahead or ipsilaterally. Furthermore, lateral sites represented zones in upper visual space, whereas medial sites represented zones in lower visual space. Once the eyes were positioned within a termination zone, further stimulation fixed the gaze and inhibited visually evoked sacCorrespondence to: E. J. Tehovnik
cades. Following release from inhibition, which occurred shortly after the end of stimulation, the saccades reached the visual target accurately. This shows that the stimulation delayed the execution of the saccades without actually aborting their execution. We conclude that the DMFC contains a map representing eye position in craniotopic coordinates, and we argue that this map is utilized to maintain eye position.
Key words: Dorsomedial frontal cortex - Saccades - Topography - Electrical stimulation - Rhesus monkey
Introduction The dorsomedial frontal cortex (DMFC) of the macaque occupies a region in the mesial bank of the frontal cortex that is situated rostrocaudally between the upper branch of the arcuate sulcus and the superior precentral dimple, and mediolaterally between the cingulate cortex and prem o t o r cortex (Wiesendanger 1986). Penfield and Welch (1951) found that electrical stimulation of a homologous region in humans evokes contraversive eye, head, and body movements, as well as contraversive limb movements. They also showed that such stimulation arrests ongoing movements of the forelimbs and fingers, and inhibits speech. From these observations, they posited that this part of cortex is not only involved in the execution of movement, but also in its inhibition. Schlag and Schlag-Rey (1987) found that unit activity within a 5 x 5 mm region of the anterior D M F C of monkeys, the supplementary eye field, precedes self-initiated saccades and visually guided saccades. They and others (Bon and Lucchetti 1992; Mann et al. 1988; Mitz and Godschalk 1989; Schall 1991b) observed that electrical stimulation within and about this region elicits convergent saccades that terminate in a common space irrespective of initial eye position [see Russo and Bruce (1993) for a contrary view].
431 Pilot e x p e r i m e n t s c o n d u c t e d in o u r l a b o r a t o r y d e m o n s t r a t e d that s t i m u l a t i o n of a n t e r i o r sites of the D M F C (i.e., a n t e r i o r to the posterior tip of the a r c u a t e sulcus) of the rhesus m o n k e y elicited contraversive saccadic eye m o v e m e n t s w h e n the eyes were centered straight ahead, whereas s t i m u l a t i o n of posterior sites of the D M F C (i.e., posterior to the posterior tip of the arcuate sulcus) did n o t elicit saccadic eye m o v e m e n t s from the s t r a i g h t - a h e a d position, a n d i n s t e a d i n h i b i t e d saccades. We later observed, however, that w h e n the eyes were positioned in the ipsilateral hemifield, saccades could be evoked from posterior regions of the D M F C . This led us to investigate the possibility that the D M F C c o n t a i n s a n a n t e r i o r - p o s t e r i o r t o p o g r a p h y for the g e n e r a t i o n of saccadic eye m o v e m e n t s , a n d that the i n h i b i t o r y effects observed occur only w h e n the eyes are located in a t e r m i n a t i o n z o n e : a region in visual space w i t h i n which saccades t e r m i n a t e following saccadic e v o c a t i o n from different fixa t i o n positions. This study e x a m i n e s w h e t h e r the D M F C is t o p o graphically o r g a n i z e d for the c o d i n g of t e r m i n a t i o n zones, a n d whether once the eyes are p o s i t i o n e d in a t e r m i n a t i o n zone, further electrical s t i m u l a t i o n causes the eyes to r e m a i n fixated, t h e r e b y suppressing all visually evoked saccades. Some d a t a have been reported in a n abstract (Tehovnik a n d Lee 1990).
Materials and methods
Subjects Three adult male rhesus monkeys (MacacamuIatta), AL, Q, and Y, were used. Throughout this study food was freely available. The monkeys were water deprived overnight before each day of experimental testing. After testing, they were allowed to drink to satiation before being returned to the vivarium. The monkeys were provided for in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and the guidelines of the Massachusetts Institute of Technology Committee on Animal Care.
Surgery Monkeys were anesthetized with pentobarbital (30 mg/kg). A scleral search coil was implanted subconjunctivally (Judge et al. 1980), and a stainless-steel post to restrain the head was attached to the skull with head bolts and acrylic cement. For monkey AL, a recording chamber was implanted over the left DMFC; for monkeys Q and Y, a chamber was implanted over the midline and centered over the DMFC. For monkey Q, a second chamber was implanted over the left frontal eye field (FEF).
Behavioral tasks Fixation task. A monkey faced a color monitor (Mitsubishi Color Display Monitor) with his head fixed. He had to fixate for 600 ms a square spot of light measuring 0.5 x 0.5 deg of visual angle (Fig. 1A), and that could appear anywhere on the monitor. During fixation, a monkey had to keep his eyes within a I x 1 deg area, otherwise the trial was terminated. Fixation was rewarded with a drop of apple juice. This task allowed us to control the fixation position of a monkey's eyes before electrical stimulation was delivered. Stimulation began 200 ms after fixation began. Typically, a monkey was stimulated on every second trial. All testing was done in darkness. On some stimulation trials, a monkey's head was free to move within 30 deg to the left or right along the horizontal plane during the fixation task. The device used to measure head movements was similar to that used by Stryker and Schiller (1975) i.e. a head holder monitored by a low-torque potentiometer. The head holder could be fastened so that a monkey's head could be fixed at various orientations with respect to the body. Because only horizontal head movements were possible, stimulation was restricted to that part of the DMFC that, when stimulated, evoked eye movements with trajectories falling along the horizontal meridian. Detection task. A monkey fixated a spot for 600 ms after which a punctate target (measuring 0.5 x 0.5 deg of visual angle) appeared 3 deg to the left or right of the fixation spot (Fig. 1B). A correct saccade was recorded when a monkey's eyes entered a 2 x 2 deg area about the target location, and such a saccade was rewarded with a drop of apple juice. The order of presentation of the left and right targets was randomized. Stimulation was delivered to the DMFC on every second trial, 5 ms following the appearance of the target. After stimulation offset, a monkey had 800 ms to saccade to a target: on non-stimulationtrials, a monkey had 800 ms to saccade
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trial. A trial began with the onset of the fixation spot. Electrical stimulation and reward were then delivered in succession. B The detection task for different stages of a trial. A trial began with the onset of the fixation spot. At the offset of the fixation spot, the target and electrical stimulation were presented. A reward was delivered after a saccade was made to the target
432 to a target following target appearance. This paradigm was used to test a monkey on stimulation-evoked saccadic inhibition.
to 1 mm below the first unit encountered on an electrode pass. A total of 270 penetrations were made into the D M F C of the three monkeys. For each penetration, stimulations tests were conducted every 0.5 mm over a depth of 6 mm. For monkey AL, electrodes were introduced through the dura at 25 deg to the vertical and aimed at the medial bank of the DMFC. Additionally, for monkey Q, 20 penetrations were made into the FEF.
Data collection and analysis A PDP 11/73 computer controlled the presentation of visual stimuli, the delivery of electrical stimulation, the display and collection of single units (sampled at 1000 Hz), the assessment of correct saccadic responses using target windows, the storage of task-related events, and the collection of eye movements (sampled at 200 Hz). During off-line analysis, an algorithm was used to sort out saccades from non-saccades. To qualify as a saecade, the eye movement had to achieve a maximal velocity of at least 200 deg/s (Robinson 1970). An eye movement had to occur during the train of stimulation to satisfy as a stimulation-evoked saccade. To qualify as a visually evoked saccade, the eye movement had to occur during the period of target appearance.
Histology Monkey Q was used in the anatomical study of Parthasarathy et al. (1992) in which he was designated M7: they made multiple injections of horseradish peroxidase into the region of the left D M F C from which we evoked saceadic eye movements. Monkey AL has been retained for future study. Monkeys were overdosed with pentobarbital, perfused with 0.9% NaC1, and fixed with 4% para-formaldehyde. Guide pins were inserted into the cortex at specific positions around the recording chamber. The location of the electrode tracts were estimated relative to the pins. Tissue shrinkage, which was about 5%, was accounted for in the anatomical reconstructions. The brains were photographed and sectioned coronally at 40 pm and stained with cresyl violet.
Electrical stimulation Glass-coated platinum-iridium electrodes with an impedance of 0.5-1.0 mY2 at 1 KHz were constructed for all experiments. Constant-current biphasic pulses were delivered to the brain tissue using a Grass $88 stimulator attached to a pair of constant-current, stimulus isolation units (Grass PSIU6B): For each biphasic pulse, a cathodal pulse was delivered first followed immediately by an anodal pulse. Both pulses had the same amplitude and duration. Current was monitored by a voltage drop across a 1000 f~ resistor which was in series with the return lead of the stimulator. The current was monitored using a Tektronix Oscilloscope (model 5103N), and read as the amplitude of one pulse (cathode or anode) of a biphasic pair. To study the D M F C as well as the FEF, current, pulse duration, frequency, and train duration were set (unless specified) at 400 gA, 0.1 ms, 150 Hz, and 400 ms, respectively. These values were chosen following parametric tests conducted on the D M F C to optimize the stimulation-evoked responses (see results section for details). Typically, electrodes were introduced perpendicular to the dura surface with a hydraulic microdrive. The action potentials were amplified (Bak A-1B) and filtered (Krohn-Hite 3750). The best stimulation sites were encountered at 2-5 mm lateral to the midline of the DMFC, and from immediately below the first unit encountered
Results
Stimulation sites T h e best s t i m u l a t i o n sites for t h e e v o c a t i o n o f s a c c a d i c eye m o v e m e n t s f r o m a h e m i s p h e r e o f t h e D M F C s p a n n e d r o u g h l y 10 m m r o s t r o c a u d a l l y a n d 5 m m m e d i o l a t e r a l l y (Fig. 2). T y p i c a l l y , t h e eye m o v e m e n t s w e r e c o n t r a v e r s i v e . A l t h o u g h s a c c a d e s c o u l d be e v o k e d c a u d a l to t h e m o s t c a u d a l tip o f t h e a r c u a t e sulcus, it w a s q u i t e c o m m o n to e v o k e b o d y m o v e m e n t s f r o m t h e s e reg i o n s as well. T h e m o v e m e n t s w e r e u s u a l l y c o n t r a v e r s i v e , and stimulation of the most caudal regions evoked lower l i m b m o v e m e n t s t h a t w e r e d e v o i d o f s a c c a d i c eye m o v e ments, whereas stimulation of more anterior regions evoked upper limb and shoulder movement that turned
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Each symbol represents the location of one or more electrode penetrations made into the D M F C of monkeys Q and Y, and into the left F E F of monkey Q. The principal sulcus (Ps), arcuate sulcus (As), and central sulcus (Cs) are indicated. Sites from which saccades (filled circles), upper body movements ( x ), and lower body movements (+) were evoked electrically are illustrated. The movements were evoked while a monkey performed either the fixation task or the detection task. The current, pulse duration, train duration, and frequency of pulses were typically set at 400 gA, 0.1 ms, 400 ms, and 150 Hz, respectively
433 the body. This topographic representation of the body concurs with previous reports (Mitz and Wise 1987; Schlag and Schlag-Rey 1987; Woosley et al. 1952). The evocation of upper limb and shoulder movements was often accompanied by saccadic eye movements. If stimulations were delivered anterior to the most rostral tip of the superior limb of the arcuate sulcus, no saccadic eye movements were evoked. Contraversive saccades were evoked from the FEF. Parametric tests
Since it i s c l a i m e d that stimulation of the D M F C does not evoke behavioral responses reliably (Macpherson et al. 1982; Mitz and Wise 1987), we carried out parametric tests to optimize saccadic responses.
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Pulse Duration (msec) Fig. 3. A Current as a function of pulse duration for a 50% probability of evoking a saccade. For a given pulse duration (i.e., the duration of one pulse of a symmetrical biphasic pair), an ascending and descending series of currents were tested. The current producing five saccades over ten stimulation trials was selected as the datum. This current was calculated by interpolating from the ascending and descending series of currents and by computing a mean of the values obtained from both series. The frequency used was 150 Hz, and the train duration was fixed at 400 ms. Each curve represents data from one stimulation site in the DMFC. Curve a is from monkey Y, and curves b to f are from monkey Q. Using the fixation task, the monkeys were required to fixate a target in the hemifield ipsilateral to the side of stimulation. The same fixation position was tested for each site. B Strength-duration functions from above are normalized and fitted to power functions, which account for more of the variance (indicated by a high r 2 value) than linear, log, or exponential functions. Current (I) is represented as the threshold current over the rheobase current (Io.5) plotted as a function of pulse duration (ms)
Pulse duration. Figure 3A shows strength-duration functions (current traded off against pulse duration) representing a 50% probability of evoking a saccade from six different sites in the D M F C . Each site is represented by a lowercase letter in the figure. The curves decline rapidly between pulse durations of 0.05 and 0.2 ms. Beyond 0.2 ms, the curves level off. Figure 3B illustrates the same strength-duration curves normalized with fitted power functions, in which current is expressed as a threshold value over the rheobase current. Rheobase current was defined as the current necessary to evoke a threshold response at a 0.5 ms pulse duration. The chronaxie was estimated for each curve by determining the pulse duration at twice the rheobase current. For all sites, these values ranged between 0.1 and 0.2 ms with a mean of 0.15 ms and standard deviation of 0.02 ms. The behaviorally determined chronaxies are well within the range of those found for CNS units activated by wire electrodes (Asanuma et al. 1976; Hentall et al. 1984b; Ranck 1975; Shizgal et al. 1991; West and Wolstencroft 1983). For our experiments, we selected a pulse duration (0.1 ms) that equaled the lower limit of the chronaxie range. Stimulating neuronal elements at their chronaxie optimizes the neuronal response (Lapique 1907). We chose a short pulse duration to be used in subsequent experiments for the following reasons: (1) long-duration cathodal pulses can generate multiple action potentials per single cathodal pulse (Matthews 1978), and such pulses are known to increase the refractory period of stimulated axons (Shizgal et al. 1991); (2) cathodal pulse durations must be less than the absolute refractory period of the most excitable axons, which is always greater than 0.3 ms (Hursch 1939; Paintal 1978; Swadlow and W a x m a n 1978), to increase the probability of a one to one ratio between the number of pulses delivered and the number of action potentials evoked (Yeomans 1990); (3) most importantly, shorter pulse durations lower the probability of damaging neuronal tissue (Yeomans 1990). Current. Figure 4 shows the effect of current on saccades evoked from an anterior (a), a middle (b), and a posterior (c) electrode site in the left D M F C of m o n k e y A L from three fixation positions. The pulse duration, frequency, and train duration were set at 0.1 ms, 150 Hz, and 400 ms, respectively. The electrode sites were spaced by 2 mm, and the m o n k e y faced the center fixation position. Figure 4A shows saccades elicited at currents that evoked a saccade on 50% of stimulation trials. The threshold currents tended to be lowest (ranging from 100 to 160/zA) for the left fixation position, and increased as the fixation position was situated rightward in contralateral hemispace. For all three sites, saccades were not evoked from the right fixation position for currents as high as 800 ktA. Figure 4B shows saccades elicited from sites a, b, and c at a fixed current of 400 ~A. C o m p a r e d with the threshold-current condition, these saccades were of larger amplitude, and the ones evoked from the left and center fixation positions for sites a and b terminated in a similar location. Further increases in current up to 800 ~A did not increase the amplitude or change the direc-
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tion of the saccades. Therefore, current was set at 400/~A for our m a p p i n g experiments to maximize the amplitude of saccades, thereby better defining saccadic termination. A fixed current was used to ensure that a similar volume of tissue was being activated for different sites in the D M FC. The latter is based on the assumption that the excitable elements in the D M F C are homogeneously distributed with a similar distribution of current-distance constants (K). K represents the a m o u n t of current at a given pulse duration that is necessary to evoke an action potential from an axon that is 1 m m away from the electrode tip. The passive spread of a 400/~A current was estimated to range from 0.3 to 1.0 m m by using the formula, radius =(current/K)1/2 (Hentall et al. 1984a; Stoney et al. 1968; Yeomans 1990). K values computed by Stoney et al. (1968) for pyramidal tract neurons of cats were used in the estimation of current spread. Since the K values computed by Stoney et al. (1968), which ranged between 250 and 3500 # A / m m 2, were based on a pulse duration of 0.2 ms, a slight modification was necessary, since 0.1 ms pulse durations were used in the present study. The current used to evoke saccades at a 0.1 ms pulse duration was 1.7 times greater (on average) than the current used to evoke a saccade at a pulse duration of 0.2 ms (Fig. 3B). Therefore, the values of Stoney et al. (1968) were adjusted by multiplying each K value by 1.7 to yield a range between 400 and 6000 r 2. The current used in the present study did not damage the brain: First, after repeatedly stimulating the D M F C of m o n k e y Q, the prime subject of this study, Parthasarathy et al. (1992) found that the stimulated areas of m o n k e y Q (illustrated there as m o n k e y M7) transported robust quantities of horseradish peroxidase tracer to terminals within the basal ganglia. Second, for monkeys A L and Y, D M F C units whose activity was correlated with saccadic eye movements and fixation were readily isolated after the D M F C had been stimulated (Lee and Tehovnik 1991). Third, following repeated stimulation of
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the D M F C , the saccadic eye movements evoked did not diminish over time, even after returning to the same stimulation site several times. Hence, the anatomical, physiological, and behavioral integrity of the D M F C was resilient to our methods of electrical stimulation. Train duration. The train duration of stimulation was set at 400 ms for m a p p i n g the D M F C . The reason for selecting this longer than usual train duration was that the latency to evoke saccades from some sites in the D M FC, particularly posterior sites, was over 200 ms. Changes in train duration did not have any noticeable effect on the amplitude and direction of evoked saccades. Pulse frequency. The optimal stimulation frequency was determined by studying the effect of frequency on the probability of evoking a saccade, and on inhibiting a visually evoked saccade. For these experiments, the current, pulse duration, and train duration were set at 400 #A, 0.1 ms, and 400 ms, respectively. Figure 5A shows that the probability of evoking a saccade increased rapidly at 80 Hz and began to drop beyond 200 Hz. Figure 5B shows saccadic latency plotted as a function of stimulation frequency for three sites, when the eyes were positioned in a termination zone, and while a monkey generated visually evoked saccades. The optimal frequency for inhibiting the saccades occurred between 60 and 200 Hz; for these trials, the saccadic latency was greater than the train duration. In summary, for both saccadic excitation and inhibition the optimal stimulation frequency was between 60 and 200 Hz. The stimulation frequency was set at 150 Hz while m a p p i n g the D M F C for saccadic excitation and while testing the D M F C for saccadic inhibition.
Stimulation-evoked saccades compared to visually evoked saccades To ascertain whether saccades evoked electrically from the D M F C were similar to visually evoked saccades, sac-
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Frequency (Hz) Fig. 5. A The probability of evoking a saccade as a function of pulse frequency for three sites in the DMFC. Using the fixation task, monkeys were required to fixate a target in the hemifield ipsilateral to the side of stimulation. The same fixation position was tested for each site. For frequencies ranging from 10 to 800 Hz, the probability was determined by dividing the number of stimulation trials during which a saccade was evoked by the total number of stimulation trials. Each letter in the figure represents a different stimulation site, and cl through to e4 represent four replications for one site. Curves a and b were obtained from monkey Y, and curves el through c4 were obtained from monkey Q. Curves cl and c3 overlap. The pulse duration, train duration, and current were set at 0.1 ms, 400 ms, and 400 gA, respectively, B Saccadic latency as a function of frequency of stimulation for two sites in the DMFC of monkey Q (sites a, b) and one site in the DMFC of monkey Y (site c). Using the detection task, the monkeys were required to fixate a target positioned in a termination zone. For each site, the termination zone was always located in the hemifield contralateral to the side of stimulation. Pulse duration, train duration, and current were fixed at 0.1 ms, 800 ms, and 400 gA, respectively
cadic duration was plotted as a function of saccadic amplitude for each saccade type based on data collected from monkey Q (Fig. 6). The scatter plots of the two saccadic types overlap, suggesting that the average velocity of saccades evoked from the D M F C was similar to that of saccades evoked visually. S t i m u l a t i o n - e v o k e d saccades
Rostrocaudal axis of the D M F C . Vector representation of saccadic eye movements evoked from five sites in the D M F C of monkey Q is illustrated in Fig. 7A. Sites a through to e ran consecutively from anterior to posterior
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aspects of the right D M F C (Fig. 2). For all sites shown, the saccades were contraversive with respect to the side of stimulation. The size of a saccade varied with fixation position; namely, as the fixation position changed from the ipsilateral to the contralateral hemifield, the size of a saccade decreased with the eyes converging onto a termination zone. Systematic exploration of the D M F C revealed that different portions of the D M F C coded different termination zones: as the electrode was moved from anterior to posterior sites in the D M F C (i.e., from site a to site e), the termination zone moved systematically from the extreme contralateral hemifield to the straight-ahead position. Similar observations were made for both hemispheres of monkeys Q and Y, and for the left hemisphere of monkey AL. It is noteworthy that in some cases (not shown here), stimulations of the caudal D M F C also represented termination zones in the ipsilateral hemifield. Unlike the saccades evoked from the D M F C , those evoked from the F E F had an amplitude and direction that did not vary systematically with fixation position (Fig. 7A, J). Saccades elicited from the F E F exhibited staircase properties. If stimulation was continued for long periods (e.g., 1600 ms), staircase saccades were generated until the eyes reached the oculomotor limit. These observations have been documented by others (Bruce et al. 1985; Marrocco 1978; Robinson and Fuchs 1969; Schall 1991b). Not only did the amplitude of the saecadic eye movements evoked from the D M F C vary with fixation position, but the probability of evoking a saccade and saccadic latency also varied. When the fixation position approached the termination zone (moving from fixation position 24 to - 2 4 deg), the probability of evoking a saccade decreased once the eyes were within the termination zone of each site of the D M F C (Fig. 7B, a-c). Yet for the FEF, the probability of evoking saccades did not vary with fixation position, and always remained at 100%
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Fig. 7. A Vector representations of saccadic eye movements evoked from sites a through to e of the right D M F C of monkey Q. Each site was separated from an adjacent site by 2 mm and each site was about 4 mm off the midline. Three sites (a, b, and c) were situated anterior to the posterior tip of the arcuate, and two sites (d and e) were situated at or posterior to the tip. For comparison, saccadic eye movements evoked from one site in the F E F of monkey Q are illustrated in f. For each panel, an upright rectangle depicts a fixation position. Each line, starting at a rectangle, represents the entire excursion of the eyes during the 400-ms train of stimulation. For the D M F C , each line represents one saccade only, whereas for the FEF, each line represents numerous saccades, since staircase saccades were evoked. The dots confined to a rectangle indicate that eye movements were not evoked from those positions. The monkey always faced the region between the four central fixation positions, such that four fixation positions were located to the right of the monkey and four were located to the left. B The probability of evoking a saccade as a function of fixation position. The probability was determined by dividing the number of trials during which a saccade was evoked by the total number of stimulation trials, which was 20. The fixation positions that occurred in the ipsilateral hemifield are indicated by 24 and 8 deg, and those that occurred in the contralateral hemifield are indicated by - 2 4 and - 8 deg. The plots are based on the saccades depicted in A for the F E F (d) and for sites a, c, and e for the D M F C (a through c) of monkey Q. Since the saccades evoked from the top and bottom fixation positions were similar, the probability values from each were combined
-24-8 8 24 -24-8 8 24 Fixation Position (degrees)
(Fig. 7B, d). As the electrode was moved from anterior to posterior D M F C sites (a-c), the overall probability of evoking saccades decreased as the termination zone shifted toward the midline. This decrease was most noticeable for contralateral fixation positions (i.e., - 2 4 and - 8 deg). These observation were also made of monkeys A L and Y. Figure 8A shows the latency between stimulation onset and saccade onset, the saccadic latency, plotted as a function of fixation position for the F E F (curve d) and the D M F C (curves a-c). The latency to evoke saccades from the F E F did not vary with fixation position. The observed latencies are consistent with those reported by other investigators (Bruce et al. 1985; Marrocco 1978; Robinson and Fuchs 1969). For the D M F C , however, the latency to evoke a saccade increased as the fixation position neared the termination zone. Furthermore, as the electrode was moved from anterior to posterior sites in the D M F C , the overall latency increased. These observation were also made of monkeys A L and Y. Saccadic latency was found to decrease monotonically with saccadic amplitude for monkey Q (Fig. 8B). Saccadic amplitude is the distance between the fixation position and saccade endpoint which is within the termination zone. As already noted in Fig. 8A, the closer the eyes
were to the termination zone, the higher the latency. Once the eyes were within 10 deg of the termination zone, the number of saccades evoked decreased dramatically: in this case, they decreased to zero. This dramatic decrease was also observed in monkeys AL and Y. Lateromedial axis of the D M F C . In monkey AL, the bank of the left D M F C was stimulated to determine whether termination zones along vertical space are represented along the lateral-medial axis of the D M F C (Fig. 9). Saccades evoked from lateral to medial and deep sites in the D M F C are shown for anterior (I), middle (II), and posterior (III) regions of the D M F C . The anterior region and middle region were 5 and 3 mm anterior to the posterior region, respectively. The left of the figure shows coronal sections of the D M F C each with four stimulation sites, a through to d. Panels a through d show saccades evoked from the corresponding site, while the monkey fixated different positions. As the electrode was positioned more medially and deeply in the D M F C , the direction of saccades changed from an upward trajectory to a downward trajectory. This was most apparent for anterior (I) and middle (II) regions, and less so for posterior regions (III). A similar medial to lateral topography representing saccadic direction was observed in monkey Y.
437
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The foregoing shows that the D M F C is topographically organized for the coding of termination zones (Fig. 10). The anterior D M F C codes for termination zones in the contralateral hemifield, the posterior D M F C codes for termination zones straight a h e a d or ipsilaterally, the lateral D M F C codes for termination zones in the upper field, and the medial D M F C codes for termination zones in the lower field.
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FEF and three sites in the DMFC. Fixation positions in the ipsilateral hemifield are represented by the 8 and 24 deg positions, and those in the contralateral hemifield are represented by the - 8 and - 2 4 deg positions. These data are based on saccades illustrated in Fig. 7A, i.e., those of the FEF (d) and those of sites a, c, and e of the DMFC (a, b, and c, respectively). Since the latencies for the top and bottom fixation position were similar, they were combined. The latencies are based on 20 trials. Standard error bars are shown where the errors are larger than the symbols. If fewer than three saccades were evoked from a fixation position, as was the case for fixation positions occurring in the contralateral hemifield for sites c and e of the DMFC (b, c), then a latency value was not computed. B Saccadic latency as a function of saccadic amplitude for the DMFC of monkey Q. These data are based on saccades illustrated in Fig. 7A, namely, those evoked from sites a, b, c, d, and e of the DMFC. The data (n =230) are fitted to a power function (y =x ~ 1.55) * 20,570, n =230) that accounts for 67% of the variance (r2= 0.67). The r value, 0.82, is significantly different from zero (P < 0.01). Other functions tested (i.e., linear, log, and exponential) accounted for less variance The saccades evoked from the D M F C did n o t always terminate at a c o m m o n location in space. For instance, saccades evoked from the anterior region (I) of the D M F C at site b failed to terminate o n t o a c o m m o n location, a l t h o u g h the size of the saccades decreased and the latency to evoke saccades increased as the fixation position was m o v e d into the contralateral hemifield. Furthermore, even for sites where there was a clearly defined termination zone (e.g., region II, site d), the zone occupied a substantial part of visual space and was far from punctate. Finally, stimulation of posterior sites in the D M F C of m o n k e y A L evoked convergent saccades (i.e., region III, sites a, b, c). The contraversive saccades always occurred at a shorter latency and h a d a higher probability of occurrence than did the ipsiversive saccades.
Anterior and posterior sites, separated by 5 m m along the r o s t r o c a u d a l axis, were stimulated in the left D M F C of m o n k e y A L while he fixated targets presented along the horizontal meridian. Current, pulse duration, train duration, and frequency were set at 400 #A, 0.1 ms, 400 ms, and 150 Hz, respectively. The head was free to m o v e left and right within 30 deg of the midline. H e a d movements were not evoked from any of the sites stimulated in the D M F C , while the m o n k e y fixated targets located at 30 and 15 deg to the left and right of center of gaze. Saccadic eye movements, however, were evoked from all sites tested. Finally, changing the position of the head with respect to the b o d y did not change the position of a termination zone with respect to the head.
Saccadic inhibition Once the stimulation-evoked saccades reached their term i n a t i o n zone, further stimulation fixed the eyes to the termination zone, and inhibited all visually evoked saccades. After the termination zone was found (Fig. l l A ) , m o n k e y Y was required to do the detection task with the fixation spot positioned within the termination zone. The eyes remained on the fixation spot for the d u r a t i o n of stimulation, and only after conclusion of stimulation did the m o n k e y m a k e a saccade to the target. Moreover, saccadic latency was f o u n d to increase linearly with train d u r a t i o n (Fig. l l B , curve Y). O n trials without stimulation, m o n k e y Y m a d e brisk visually evoked saccades that exhibited latencies well below 300 ms. After stimulation, the m o n k e y was still able to perform the detection task at an accuracy rate of 100%. The same experiment was c o n d u c t e d on m o n k e y Q at three different sites in the D M F C . As with m o n k e y Y, when the f x a t i o n spot was positioned in a termination zone, eye position was maintained for the d u r a t i o n of stimulation up to 1.2 s (Fig. 11B). Also the performance level remained high at above 90%. B e y o n d a train duration of 1.2 s, m o n k e y Q tended to break fixation: the saccadic latency was less t h a n the train d u r a t i o n and the performance level d r o p p e d below 80%. To test h o w saccadic inhibition varies as a function of fixation position, an 800 ms train of stimulation was delivered to the right D M F C of m o n k e y Y as he performed the detection task from six different fixation positions,
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Fig. 9. Saccades evoked from anterior (I), middle (H), and posterior (III) regions of the left D M F C of monkey AL. The left panel represents coronal sections through the D M F C . Since monkey A L is being used for further study, the locations of sites a through to d are estimated here. Rows a through to d show vector representations of saccades evoked from corresponding sites in the D M F C . Each of the 12 boxes illustrated in a plate represents a fixation position. The monkey was facing a position between the central two boxes. The array of fixation positions measured 46 deg along horizontal space and 32 deg along vertical space
midline
Fig. 10. Simplified view of the topographic arrangement of termination zones within the D M F C . Each dotted circle, situated over a stimulation site, represents the spatial field of a monkey. Each black circle represents the location of the termination zone for that site. For medial sites the termination zones are in the lower field, for lateral sites the termination zones are in the upper field, for anterior sites the termination zones are in the extreme contralateral field, and for posterior sites the termination zones are in the central field. The principal sulcus (Ps) and arcuate sulcus (As) are indicated
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Fig. 11. A Saccadie eye movements evoked from different fixation positions following stimulation of the left D M F C of monkey Y. Each rectangle represents a fixation position. The saccades, represented here by the vectors, converge onto a region in space, the termination zone. The top portion of the figure shows a magnified version of the detection task. The fixation spot (F) was centered within the termination zone, as shown by the arrow. The monkey was required to make a saccade to either the left or fight target
0
0
0.5 1.0 1.5 Train Duration (sec)
(depicted by a circle) which was 3 deg from the fixation spot. Five milliseconds after the target was presented, electrical stimulation was delivered to the D M F C to test for saccadic inhibition. B Saccadic latency is plotted as a function of train duration. The results from one D M F C site in monkey Y (Y) and three D M F C sites in monkey Q (Q1, Q2, and Q3) are shown. Each point represents 20 trials. Standard errors are shown when they are greater than a data point
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Fig. 12. A The whole array of tested fixation and target positions for the detection task. The target (large square) occurred 3 deg to the left or right of the fixation spot (small square). The circle indicates the termination zone. B Saccadic latency is plotted as a function of fixation position. Each bar is based on ten trials, and standard error bars are shown. Each panel represents data obtained at a given current: 0, 100, or 400 gA
three located in the upper field and three located in the lower field (Fig. 12A). When no current was applied, the latency of saccades made to the targets was between 200 and 250 ms for all fixation positions tested (Fig. 12B, 0 /tA). When a 100-/~A current was applied, the latency of saccades made to the targets was increased for all positions (Fig. 12B, 100/~A). When the current was increased to 400/~A, an entirely different pattern emerged. Contraversive, leftward saccades were now evoked electrically from all fixation positions, except from the position that fell within the termination zone (Fig. 12B, 400/~A: - 2 4 deg, lower field). The saccadic latencies increased as the fixation position neared the termination zone, which is similar to that illustrated for monkey Q in Fig. 8A. For the fixation position within the termination zone, the saccadic latency just surpassed 800 ms, the duration of stimulation, and only after the stimulation were saccades generated to the targets. Saccadic inhibition was not dependent on the position of a target with respect to the fixation spot. Even when targets were located 20 30 deg outside of the termination zone, visually evoked saccades were inhibited. Discussion
Termination zones One of the distinguishing characteristics of the DMFC is that electrical stimulation of this region evoked saccades that converged onto a termination zone that is usually
well within the oculomotor range (Bon and Lucchetti 1992; Mann et al. 1988; Mitz and Godschalk 1989; Schall 1991b; Schlag and Schlag-Rey 1987). Its size, however, is variable and usually very large. A termination zone overlaps with the area in visual space where the probability of evoking a saccade with stimulation drops to zero and where the latency to evoke a saccade with stimulation increases dramatically. Moreover, this is the region from where the execution of visually evoked saccades is inhibited by stimulation. In contrast to the DMFC, stimulation of the FEF does not evoke saccades that reach a termination zone (Bruce et al. 1985; Marrocco 1978; Robinson and Fuchs 1969; Russo and Bruce 1993; Schall 1991b). Irrespective of the initial eye position, the probability of evoking a saccade and the latency to evoke a saccade with stimulation does not vary. Furthermore, delivering long trains of stimulation to the FEF produced a staircase of saccades, and these saccades continued until the eyes reached the oculomotor limit. Hence, the concept of termination zone is not at all applicable to the FEF.
Eye and head movements during DMFC stimulation Even though early stimulation experiments have implicated the DMFC in head-movement control (Brown 1922; Levinsohn 1909; Penfield and Welch 1951), we were unable to evoke head movements from the DMFC while a monkey fixated different positions in visual space. These results are similar to those reported by Schlag and Schlag-Rey (1987). This led them to the conclusion that the DMFC is primarily an eye field. Our results support their interpretation.
Topographic organization Since Penfield and Welch (1951), it has been known that eye movements can be evoked from the DMFC. Recent studies have confirmed this finding in the rhesus monkey using scleral search coil techniques (Bon and Lucchetti 1992; Mann et al. 1988; Schall 1991b; Schlag and SchlagRey 1987). The general finding is that convergent saccades are elicited electrically from this region. Hitherto it remained unclear whether the DMFC has a topographic order for the evocation of saccades, something that is true for both the FEF and superior colliculus. The current study shows that the DMFC is topographically organized for the execution of saccadic eye movements, with the anterior DMFC coding for termination zones in the extreme contralateral hemifield, and with the posterior DMFC coding for termination zones straight ahead or ipsilaterally. Furthermore, the lateral DMFC codes for termination zones in the upper field, whereas the medial DMFC codes for termination zones in the lower field. This topography bolsters our findings (Lee and Tehovnik 1991) that units in the anterior DMFC are best modulated when the eyes fixate targets in the extreme contralateral hemifield, that units in the posterior DMFC are best modulated when the eyes fixate targets straight-ahead or
440
in the ipsilateral hemifield, that units in the lateral DMFC are best modulated when the eyes fixate targets in upper space, and that units in the medial DMFC are best modulated when they eyes fixate targets in lower space.
Comparisons with previous studies Schlag and Schlag-Rey (1987) were the first to investigate systematically the role of the DMFC in the execution of saccadic eye movements. They found that units responsive to saccadic eye movements were situated within an anterior 5 x 5ram area of the DMFC (Schlag and Schlag-Rey 1985); they were able to evoke eye movements electrically from a somewhat larger area that spanned 7 mm rostrocaudally and 5 mm mediolaterally (Schlag and Schlag-Rey 1987). The area investigated by the present study spanned 10 mm rostrocaudally and 5 mm mediolaterally; this overlapped with the region studied by Schlag and Schlag-Rey but also included more caudal sites in the DMFC. There are two differences between our results and those of Schlag and Schlag-Rey. First, we did not evoke fixed-vector saccades from our DMFC sites, whereas Schlag and Schlag-Rey reported that such saccades were evoked from over 40% of their sites (also see Russo and Bruce 1993, whose stimulation was confined to a 3 x 3 mm region of the anterior DMFC). Second, they did not find a topographic order for the evocation of saccadic eye movements. There are numerous methodological differences between the present study and that of Schlag and SchlagRey (1987). First, the train duration used in the current study (400 ms), was greater than the longest durations used by Schlag and Schlag-Rey (120 ms). They reported no correlation between the latency to evoke a saccade and the amplitude of an evoked saccade (r = 0.29, n = 61, P > 0.01). The present study, on the other hand, found a robust negative correlation (Fig. 8B, r = -0.82, n = 230, P < 0.001). In our experiment, train durations of 120 ms or less were too short to capture the long-latency saccades which resulted when the eyes fixated a spot near a termination zone. Second, Schlag and Schlag-Rey used a pulse frequency of 250 Hz which is greater than the frequency of 150 Hz that was used here. We have found that frequencies greater than 200 Hz tend to decrease the probability of evoking saccades (Fig. 5A). As shown by Schlag and Schlag-Rey (as well as: Bon and Lucchetti 1992; Lee and Tehovnik 1991; Schall 1991a; Schlag et al. 1992) DMFC units that discharged before saccadic eye movements and during fixation did not exhibit average spike frequencies that are higher than 200 spikes/s. Third, the current used in the present study, i.e., 400 pA, was higher than the currents used by Schlag and Schlag-Rey. The highest current they used, after standardizing to 0.1-ms pulse duration (Fig. 3B), was 170 pA (1.7 x 100 gA current with 0.2-ms pulse duration). We found that at currents below 200 gA, the evoked saccades were shorter (compare Fig. 4A with 4B). These saccades terminated short of the termination zone and they could easily have been interpreted as fixed-vector saccades (see Fig. 4A, site b).
Fourth, it is noteworthy that Schlag and Schlag-Rey (1987) found that doubling the current intensity doubles the size of saccades evoked from the DMFC (see their Fig. 9). In the present study, current was always held constant. Fifth, in the experiments of Schlag and Schlag-Rey, no standard method of fixation was employed during stimulation: on some trials no fixation spot was used, and on others a fixation spot was used. The current threshold to evoke a saccade while stimulating the DMFC is higher when a monkey fixates a target than when a monkey does not fixate a target (Bon and Lucchetti 1992; Schlag and Schlag-Rey 1987; also observed in the current study). Furthermore, an evoked saccade is shorter when a monkey fixates a target than when it does not fixate a target (Bon and Lucchetti 1992). In the present study, we always stimulated the DMFC after a monkey acquired a fixation spot. Sixth, Schlag and Schlag-Rey illustrated that saccades evoked well within the oculomotor range seemed to be of the fixed-vector type, and those evoked from extreme aspects of the oculomotor range tended to be of the convergent type (see their Fig. 5). Large-amplitude saccades are generated best from the anterior DMFC when the eyes are fixated in extreme aspects of the oculomotor range, and large-amplitude saccades exhibit a higher degree of convergence than small-amplitude saccades (Russo and Bruce 1993). Since the location of the fixation positions varied for each stimulation site in their study, it is possible that more convergent saccades would have been observed if a standard array of fixation positions that tested extreme aspects of the oculomotor range had been used. Finally, Schlag and Schlag-Rey did not evoke saccades from a region in the DMFC caudal to the posterior tip of the arcuate sulcus. To evoke saccades from this region, two conditions are necessary: the train duration must be much greater than 120 ms, and, the fixation positions must fall in the extreme part of visual space. These conditions are vital to evoke saccades from the caudal DMFC and to observe a topographic arrangement.
Neural coding and function The neural code exhibited by the DMFC is distinctly different from that of the FEF and superior colliculus, both of which represent saccadic size and direction retinocentrically (Bruce and Goldberg 1984; Schiller 1984; Sparks 1986). In the DMFC, there is an orderly representation of eye position that is in craniotopic coordinates, since the orientation of the head with respect to the body did not change the location of a termination zone with respect to the head. The temporal properties of saccades evoked from the DMFC differ radically from those of the FEF and superior colliculus. Whereas saccades evoked from the FEF and superior colliculus have latencies that range between 15 and 60 ms and are invariant to fixation position (Bruce et al. 1985; Marrocco 1978; Robinson 1972; Robinson and Fuchs 1969; Schiller and Stryker 1972), those evoked from the DMFC vary uniformly with fixa-
441 tion position such that the closer the eyes are to a termination zone the longer the latency to saccade. Latencies between 15 and 400 ms were observed for the D M F C . Clearly, such long latencies are inadequate for the brisk evocation of saccades to visual targets. Perhaps one function of the D M F C is to maintain fixation. Some evidence supports this notion. First, visually evoked saccades are inhibited by electrical stimulation, if the eyes are fixated in a termination zone. This stimulation does not abort the visual responsivity of the monkey, however, since once the monkey is released from inhibition, it produces saccades to targets accurately. Second, the D M F C contains an abundance of neurons whose activity is modulated during attentive fixation (Bon and Lucchetti 1992; Lee and Tehovnik 1991 ; Schlag et al. 1992). Third, the intralaminar nuclei of the thalamus, in which neurons respond during attentive fixation and changes in eye position (Schlag and Schlag-Rey 1984; Schlag-Rey and Schlag 1984), send extensive projections to the D M F C (Huerta and Kaas 1990; Wiesendanger and Wiesendanger 1985). Fourth, the D M FC projects to the raphe interpositus of the brainstem (Huerta and Kaas 1990; Shook et al. 1988), which harbors the omnipause neurons (Buttner-Ennever et al. 1988). These neurons remain tonically active during periods of fixation, but are silent during the execution of saccades (Fuchs et al. 1985). Finally, the D M F C innervates, albeit sparsely, the nucleus prepositus hypoglossi (Shook et al. 1990), which has been implicated in providing an eye position signal to the motoneurons (Cannon and Robinson 1987; Lopez-Barneo et al. 1982). It remains to be seen whether a lesion confined to the D M F C disrupts the maintenance of fixation. Nonetheless, studies have been conducted that address this issue indirectly. Humans with lesioned frontal lobes have been tested on the antisaccade task, a task that requires a subject to make a saccade away from a visual target. To perform such a task expediently, it is first necessary to suppress a saccade to the visual target; namely, fixation has to be maintained before the antisaccade can be generated. Results from such studies with respect to the D M FC have proved equivocal, however. Whereas G a y m a r d et al. (1990) reported that lesions confined to the D M F C of two h u m a n subjects did not disrupt performance on the antisaccade task, Guitton et al. (1985) showed that such lesions gravely impaired the performance in one human subject such that the patient had difficulty suppressing reflexive saccades to the visual target. It should be noted, however, that in most of Guitton's patients who showed deficits in the antisaccade task, cortical damage included the D M F C as well as the FEF. In summary, electrical stimulation of the D M F C revealed that this region is topographically organized for coding termination zones, and that continued stimulation maintains fixation within a termination zone and inhibits all visually evoked saccades.
Acknowledgements. We thank P. H. Schiller for support. R. Dolan, A. M. Graybiel, O. Kofman, P. H. Schiller, W. M. Slocum, M. A. Sommer, J. S. Yeomans, and K. Zipser reviewed the manuscript. We thank H. B. Parthasarathy and A. M. Graybiel for the histological
examination of monkey Q. Funded by a Fairchild fellowship and a McDonnell-Pew fellowship to E.J.T.
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