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Saccades induced by stimulation of the frontal eye fields: Interaction with voluntary and reflexive eye movements
Brain Research, 146 (1978) 23-34 © Elsevier/North-Holland Biomedical Press
23
SACCADES I N D U C E D BY S T I M U L A T I O N OF T H E F R O N T A L EYE F I E L D S : I N T E R A C T I O N W I T H V O L U N T A R Y A N D R E F L E X I V E EYE M O V E M E N T S
RICHARD T. MARROCCO* Department of Physiology-Anatomy, University of California, Berkeley, Calif. 94720 (U.S.A.)
(Accepted August 24th, 1977)
SUMMARY Saccadic eye movements were evoked in alert monkeys by electrical stimulation of the frontal eye fields (FEF). The interaction of F E F movements with voluntary saccades, pursuit, and vestibular nystagmus (VN) was examined. An F E F saccade in one direction could be evoked as little as 10 msec after the onset of a natural rapid movement (saccade, fast phase of VN) in the opposite direction. Thus, refractory periods between similar eye movements are directionally specific. The frequency of evoked FEF saccades following natural slow movements (pursuit, slow phase of VN) in either direction was reduced as though saccade thresholds were elevated. The FEF appears capable of modulating any ongoing eye movement.
INTRODUCTION The role of the frontal eye fields (FEF) in the regulation of eye movements is not well understood. Results from stimulation experiments suggest a motor role. For example, Robinson and Fuchs H showed that stimulation of a small volume of tissue in F E F in the alert monkey with 0.1-l.0 mA current resulted in short-latency, conjugate, contralateral saccades. However, the F E F response was quite stereotyped: once the saccade threshold was reached, saccade amplitude was unaffected by further increases in stimulus strength. This is in strong contrast to all other classic motor regions. For instance, stimulation of area 4 of the baboon cortex produces short-latency movements of the forelimb 10. The amplitude of the movement is monotonically related to the stimulating current. Results from single unit studies are also inconsistent with the idea of a F E F motor center. Two studiesZ, a reported data from a large sample of F E F neurons in
* Present address: Department of Psychology, University of Oregon, Eugene, Oregon 97403, U.S.A.
24 the awake monkey. The activity of approximately 8-10 '~J,~of the cells was clearl3 related either to saccadic or pursuit eye movements. Most importantly, almost all units fired after the initiation of a saccade. In contrast, neurons of the motor area 4 related to a specific muscle fired before the initiation of a muscle movement (e.g. ref. 7). Although the relationship between the stimulation and recording data is as yet unclear, there is little doubt that the frontal eye fields are concerned with some aspects of oculomotor coordination. Unilateral ablation of this region causes conjugate deviation of the eyes away from the lesioned side and disturbances of the fast phase of optokinetic nystagmus in the direction away from the lesion ~, unilateral amblyopia s, and fixational changes 9. Careful measurement of the metrics of induced movements further strengthen the involvement of the F E F in saccade generation. Robinson and Fuchs 1~ have shown that the saccades induced by FEF stimulation are identical in trajectory to those made voluntarily by the monkey. If they are similar, one might expect that they share colnmon neural circuits at some point. If so, interactions, either facilitatory or occlusive, might be expected between F E F and voluntary saccades or brain stern ocular reflexes. The present investigation examines the interactions between F E F saccades and voluntary saccades, pursuit movements, the phases of vestibular nystagmus, and saccades induced by electrical stimulation of brain stem sites. It will be shown that shockand naturally-induced responses from different anatomical locations interact in an occlusive fashion only. The existence of refractory periods is indicated between FEF saccades and like voluntary saccades but not for slow movements in: either direction, nor saccades in the opposite direction. METHODS Three juvenile cynomolgous monkeys (Macaca irus) weighing 1.5-2.5 kg were implanted under sterile conditions with head gear permitting periodic immobilization of their heads. A plastic chamber with a threaded cap was then secured to the skull over the frontal eye fields, similarly to previous techniques 7,a:~ At the time of the experiment, the alert animal was seated in a primate chair and its head immobilized by the head gear. Beckman skin electrodes were firmly attached against the skin bitemporally and vertically. Eye movements were recorded by DC electrooculography and stored on magnetic tape; the system band width was about 200 Hz. E O G records were analyzed by writing the contents of the tapes into a HewlettPackard chart recorder whose frequency response was flat to 90 Hz. The sensitivity of this E O G system was about 2 ° and linear over a :z: 20 ° range. Monkeys were trained to make eye movements of fixed amplitude. An array of pin lights subtending 30' of arc visual angle, arranged to form a cross, was centered directly in front of the animal's head. Bulbs were located at 0 ~, and at 10"~ 20 ~ right. left, up and down. Located immediately below each light was a white button. Animals were first trained to attend to the illuminated 0 ~ light and press its button when its intensity was briefly decreased. When the pressing response latency to dimming reached 0.75 sec, the contingencies were changed. The central light was dimmed as usual and
25 followed by the illumination of a second light at one of the remaining 8 locations. The animals were rewarded only if they made a saccade to the second bulb and pressed its button. The procedure allowed shocks to be delivered during on-going saccades and made frequent calibration of the EOG system possible. Head position was monitored with a linear potentiometer which gave records whose amplitude and polarity specified head position to within 5 ° of arc. Spike-like, downward deflections of the trace indicated head motion toward the right; upward spikes indicated leftward head motion. Glass-coated, platinum-iridium microelectrodes and bipolar concentric macroelectrodes were aseptically introduced into the chamber and hydraulically advanced through the intact dura. Pulses of current were passed through the advancing bipolar electrode; the electrode was assumed to be in the middle cortical layers when lowthreshold contralateral saccades were first evoked. Cathodal pulses were delivered through a constant current network (BME S I04B); unless otherwise noted, a 25 msec train of 0.5 msec square-wave pulses at 200 Hz was used. After each experiment a lesion was placed electrolytically at the point of lowest electrode penetration. After some 15 20 penetrations had been made, the monkey was sacrificed with an overdose of Nembutal, perfused with 0.9'!~i formalin, and decapitated. After one week fixation in formalin the brain was removed, and 50/~m sections cut through the FEF region on a freezing microtome. Sections were stained with cresyl violet. All data reported here were from histologically confirmed locations. RESULTS
(A) Characteristics of FEF saccades Stimulation with short pulse trains yielded single contralateral saccades with an average latency of 20 msec. Amplitudes depended on electrode position and depth within the cortex, and ranged from 5 ° to 30 °. Saccade threshold was defined as that current needed to evoke saccades in 7 out of 10 attempts. Thresholds varied with cortical position and depth, ranging from 50 to 2000/zA. Saccade duration was monotonically related to amplitude. An amplitude-duration plot for 60 F E F saccades was indistinguishable from a similar plot for 100 voluntary saccades. We concluded that similar neural circuits are operative in both types of saccades. The data are in full agreement with those of Robinson and FuchslL
( B) FEF saccades and voluntary eye movements Interaction with spontaneous saccades In order to more fully understand the nature of the mechanisms underlying saccadic movements, pulse trains were delivered to F E F at various intervals before, during and after the onset of saccades in the light. The generation of a FEF saccade depended on the direction of the ongoing movement. If the eyes made a saccade in the ipsilateral (right) direction, a FEF saccade in the opposite direction could be produced as little as 10 msec after the onset of the voluntary movement (see Fig. I A). Within the
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Fig. 1. A: interaction of FEF saccades with voluntary saccades in the opposite direction, A control condition shows the form of a 30° FEF saccade. The lower three traces show the FEF saccade preceded by voluntary saccades at intervals (msec) indicated to the left of the traces. The onset of each voluntary saccade is indicated by a downward arrow. Shock duration is indicated by the black bar below each trace. B: interaction of FEF saccades with voluntary saccades in the s a m e direction. A control saccade (C) is marked by an arrow. Shock duration is indicated below trace. The lower three traces show F E F shocks (hatch mark) delivered at various intervals following voluntary movements. Shock duration indicated by the width of the mark. Distance calibrations for A and B are 20°; time calibrations for A = 50 msec, for B -- 100 msec. C: a plot of FEF saccade amplitude as a function of the intersaccade interval for saccade in the s a m e direction. The amplitude of the FEF shock grows from zero tO within 10% of the control size at 50 msec, and is at maximal amplitude at 100 msec.
r e s o l u t i o n o f the r e c o r d i n g system, e v o k e d saccades were seen to override s p o n t a n e o u s saccades at a n y interval. T h e r e a p p e a r e d to be no refractoriness between m o v e m e n t s in the o p p o s i n g directions. Identical results were o b t a i n e d in 12 similar e x p e r i m e n t s at 6 different F E F locations. The m o n k e y was then r e w a r d e d for m a k i n g saccades o f 20 ° a m p l i t u d e in the same direction as those elicited by F E F shock. Pulses were e l e c t r o n i c a l l y triggered by an E O G voltage d i s c r i m i n a t o r at v a r i o u s p o i n t s d u r i n g the c o n t r a l a t e r a l sacCades. In c o n t r a s t to the ipsilateral case, a b o u t 50 msec were n e e d e d before the c o n t r a l a t e r a l F E F saccade c o u l d be induced. N o F E F saccades c o u l d be p r o d u c e d at s h o r t e r d u r a t i o n s , even if the c u r r e n t strength was increased. Fig, I B shows a series o f F E F a n d v o l u n t a r y saccades at different t e m p o r a l intervals, a n d the r e l a t i o n s h i p between F E F saccade a m p l i t u d e a n d intersaccadic i n t e r v a l is shown in Fig. 1CI Intervals shorter t h a n 50 msec p r e c l u d e d F E F saccades a n d only the stimulus artifact ( m a r k s below the E O G records) was seen. A t longer intervals, however, F E F saccades c o u l d be seen rising f r o m the v o l u n t a r y m o v e m e n t . It was often true t h a t the saecade p r o d u c e d after 50-80 msec was slightly smaller in a m p l i t u d e t h a n those i n d u c e d a t later intervals. I n c r e a s e d c u r r e n t d u r i n g the 50-80 msec p e r i o d d i d n o t p r o d u c e larger a m p l i t u d e sac-
27 cades. A f t e r 100 msec, however, saccade a m p l i t u d e h a d r e t u r n e d to c o n t r o l values. This result was replicated at 9 other F E F loci. Thus, the results suggest the existence o f an absolute refractory p e r i o d after v o l u n t a r y saccades during which F E F saccades c a n n o t be elicited a n d a relative refractory p e r i o d d u r i n g which F E F saccades are r e d u c e d in size. Identical results were o b t a i n e d from interactions in a d a r k e n e d r o o m with the saccade targets d i m l y illuminated. Interaction with pursuit movements A t t e m p t s were also m a d e to induce F E F saccades d u r i n g slow, p u r s u i t eye move-
ments m a d e to m o v i n g visual stimuli. Ten F E F cortical sites were e x a m i n e d with similar outcomes. P u r s u i t - s a c c a d e interactions i m m e d i a t e l y following the onset o f pursuit as well as later in the p u r s u i t m o v e m e n t were tested. C o n t r a l a t e r a l l y e v o k e d saccades following the onset o f slow m o v e m e n t s in the o p p o s i t e direction were difficult to obtain. In a p p r o x i m a t e l y 95 ~ o f the cases (80/86 trials in 4 F E F loci) in which saccades were elicited, a second, p r e s u m a b l y voluntary, saccade r e t u r n e d the eyes to their a p p r o x i m a t e prestimulus t r a c k i n g a n d velocity position. In the r e m a i n i n g 5 ~o (6/80 trials in 2 F E F loci) the shape o f the induced m o v e m e n t was such as to d o u b t its classification as a complete saccade. I f the eyes were following a target t o w a r d the contralateral side, the shortest interval following the start o f a pursuit m o v e m e n t at which a F E F saccade could be e v o k e d was 35 msec
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I lOdeg shock SOmsec Fig. 2. Interaction ofFEF saccades with pursuit movements. A: two FEF saccades are shown following pursuit movements in the same direction after 30 msec (top trace) and 50 msec (bottom trace). The dotted lines indicate the paths of the pursuit movements, which follow small voluntary saccades. Stimulating current = 900/zA (top trace), 1.6 mA (bottom trace). Note that the FEF saccade is followed rapidly by a voluntary movement which redirects the eyes to the pursuit path. Time and amplitude calibrations are 50 msec and l0 t'. B: FEF saccades during pursuit movements at different velocities. Stimulating current was 1.3 mA. Numbers on the left show the approximate velocity and the dotted lines show the approximate trajectory of each pursuit movement. The bar beneath the records shows the FEF shock duration, and a spike-shaped shock artifact can be seen preceding each saccade. Failure to evoke saccades occurred at 8 and 20 deg/sec.
28 (Fig. 2A top trace: a F E F saccade after 50 msec is shown in Fig. 2A. lower trace l Thus, ongoing pursuit movements in either direction interferred to some extent with subsequent F E F saccades. Unlike the results for voluntary saccades, the production of a FEF saccade well after the onset of a slow movement in either horizontal direction was not assured. In fact, only 65 ~,, of such attempts (45/70 trials in 3 F E F loci) successfully produced a saccade. Raising the stimulation current to several times threshold or lengthening the pulse train was ineffective m overcoming the apparent threshold elevation caused by the slow movement. Neither the direction of movement, nor the velocity, nor the position of the eyes during the stimulation appeared to have any bearing on the success rate of evoked saccades (see Fig. 2B). Although the reasons for this are unclear at present, the data are thought to be of significant interest to include in this report. Thus. the F E F data contrast with P P R F stimulation results which showed that all ongoing eye movements were overridden ,5.
Interaction with vergence movements With the present recording system it was not possible to simultaneously measure vergence and versional eye movements. Only qualitative observations will be described briefly. The animal was induced to fixate on the mirror reflection of his [~.ce at I m . and a F E F saccade of 20 ° was evoked. The mirror was then moved to a distance of 5 cm and voluntary convergence movements of about 10' were made. A F E F shock was delivered during near point convergence; the eyes again made a contralaterat saccade. One might expect that the contralateral eye, which was adducted by a b o u t 10° would make a larger saccade than the ipsilateral eye. In fact. a comparison of the saccade amplitudes before and during convergence indicated that both eyes made the same size movements (about 20°1 under both conditions. Thus. under the present conditions and limitations of measurement, there appeared to be no interaction between F E F saccades and convergence eye movements. ( C) FEF saccades and ocutomotor reflexes to natural stimulation Eye movements induced by rotation of the animal through a horizontal arc of about 120 ° (60 ° to the right, through the midline, 60 ° to the left, and back) showed the typical 'beating' pattern of slow and fast phases of vestibular nystagmus: There were typically two or three slow-fast pairs (beats) for each 60 ° head displacement. When the direction of the head movement was reversed, the eye movement sequence was repeated with the slow and fast phase directions reversed.
Interaction of FEF saccades with the fast phase of vestibular nystagmus In this experiment, a pulse train delivered to the F E F while the eyes were at rest produced a contralateral 15° saccade (Fig. 3A). If the eyes made a saccade t o the ipsilaterai (right) side during head movements, a F E F saccade could b e elicited within 20 msec of the onset of the fast phase (Fig, 3B). The direction and amplitude of the
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f Fig. 4. Interaction of FEF saccades with the fast phase of vestibular nystagmus in the x a m e direction. A series of records shows F E F saccades at 15, 30, 40 and 75 msec after the vestibular saceades; a control saccade shows the size of the movement during a vestibular slow phase. Shock duration and location as in Fig. 3. Stimulating current was 200/*A. The FEF movement fails at 15, 30 and 40 msec but can be seen superimposed on the vestibular saccade at 75 msec. Note that the amplitude of the FEF movement in the 75 msec trace is reduced in comparison to the (control) pursuit condition. Movement calibration for 15, 40, 75 and pursuit traces = 10°; for 30 msec record = 5°. Head position is shown in the bottom trace. Vertical calibration mark shows a 1000 head movement to the right.
30 i n d u c e d m o v e m e n t were similar to t h a t of the c o n t r o l saccade. This result was c o n f i r m e d at 6 o t h e r F E F sites. O n the o t h e r hand, a vestibular saccade was r e f r a c t o r y for a F E F saccade in the same direction for a b o u t 50 msec (Fig. 4). The 3 u p p e r traces show that a fast m o v e m e n t occurs to the left as a result o f vestibular stimulation. T h a t no F E F saccade is superi m p o s e d on this m o v e m e n t can be seen in the high gain second trace. The f o u r t h trace shows the F E F saccade 75 msec after the vestibular m o v e m e n t . The 10 ° fast phase m o v e m e n t was followed by a 15 ° F E F saccade a n d the total o c u l a r d e v i a t i o n was a b o u t 25 °. This induced m o v e m e n t , a l t h o u g h o f d e c r e a s e d a m p l i t u d e , closely r e s e m b l e s the c o n t r o l saccade (pursuit) e v o k e d d u r i n g the v e s t i b u l a r slow phase. This f i n d i n g was true o f all 5 F E F sites tested. T h a t the shock has some effect on the o c u l o m o t o r a p p a r a tus is a p p a r e n t f r o m the r a p i d r i g h t w a r d m o v e m e n t s t h a t follow the fast vestibular m o v e m e n t . It w o u l d a p p e a r that t h e v e s t i b u l o - o c u l a r c o m p e n s a t i o n was t e m p o r a r i l y disrupted. Similar m o v e m e n t s following 8th nerve s t i m u l a t i o n have been r e p o r t e d 6.
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of records shows a control FEF movement With the head at rest, Black squares below t r a ~ s denole shock artifact duration and the FEF movement follows, Current was 650 p.A. The lower pair shows an FEF saccade (arrow) evoked 50 msec following a slow vestibular movement in the opposite direction. Three slow phases and two fast phases of the nystagmus are Shown. B: a series ofEOG rec0rdsshowing attempts to elicit FEF saccades during the slow phase of vestibular nystagmus in the same direction: Shock location and duration as in Fig. 3. Current was 1:8 mA. The FEF saccade intrace 1 was successful while that in trace 3 failed. A small compensatory movement follows the hiphasic shock artifact in trace 2. Time and movement calibrations as in A.
31 These results, then, appeared comparable to those found with voluntary saccades. Voluntary saccades and the fast phase of vestibular nystagmus were followed by absolute and relative refractory periods of similar durations for subsequent FEF saccades. Level of illumination had no effect on these results.
Interaction with the slow phase of vestibular nystagmus A F E F saccade reliably elicited during the slow phase of VN in the opposite direction can be seen in Fig. 5A. This occurred at the minimal latencies necessary to identify the initiation of a slow phase (35 msec). The induced saccade was always of maximal amplitude even at the shortest latencies. If there was a period of interference between slow phase of VN and F E F saccades, it was not measurable with the present techniques. Moreover, the occurrence of F E F saccades did not disturb or reset the beating pattern of nystagmus, suggesting that the override was simply superimposed on labyrinthine-induced activity. In general, no refractory periods for subsequent F E F saccades could be demonstrated following slow movements in the same direction. However, the probability of evoking saccades fell to about 5 0 ~ during any part of the slow phase (see Fig. 5B). A full-sized saccade can be seen in trace 1 : trace 2 shows the shock artifact quickly followed by a compensatory movement in the opposite direction; trace 3 shows failure to evoke a saccade (artifact only). Moreover, the amplitude of the shock-induced movement varied from zero to 100 ~ of control values and was independent of the velocity of the slow movement. Once again, the success rate could not be increased by increasing the stimulating current 2-fold. These results are nearly identical to those found with pursuit eye movements. Since the slow phase of VN is visually guided, it was thought that visual input might block saccadic output from the frontal cortex. However, despite a slightly lowered success rate, the same unreliability was evident during vestibular nystagmus in complete darkness. If a refractory period follows voluntary saccades, does one follow FEF saccades as well? Generally, the answer to this question was not as easy to obtain as the reverse situation, for FEF movements were usually followed by a second saccade which returned the eyes to their approximate position prior to the FEF saccade. Occasionally, however, the EOG records showed F E F movement and its stimulus artifact followed by a saccade (voluntary or vestibular) in the same direction. The minimal latency observed was 70-75 msec. More data, however, are required to reach a firm conclusion.
( D) Interaction of identical FEF saceades evoked by stimu&tion of a single cortical site lntracortical refractory periods it is reasonable to assume that the duration of the refractory period was primarily due to the cycle time of the saccadic pulse generator plus the conduction time of its input and output pathways. There is good evidence to suggest that vestibular and voluntary saccades make use of the same pulse generator 12. Therefore, differences in refractory periods between two voluntary as opposed to two vestibular saccades should
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Fig. 6. Interaction of two FEF saccades elicited from a single intracortical site. A: EOG records showing two nearly identical saccades evoked by double shocks to FEF at different interpulse intervals. Current strength was 1.2 mA. All records have been horizontally aligned on the artifact produced by the shock arbitrarily called pulse one. The time of occurrence of pulse two is shown in msec to the left of the EOG records. B: graphic plot of the amplitude of the saccades (arbitrary units) produced by pulse one (solid lines) as a function of the interval between shocks. The amplitudes of the saccades produced by pulse two are shown by dashed lines. Although there is some variability of amplitude at durations greater than 100 msec. each saccade has returned to its full amplitude between 75 and 125 msec, p r i m a r i l y reflect differences in i n p u t p a t h lengths (assuming similar fiber c o n d u c t i o n velocities). S t i m u l a t i o n o f the l a b y r i n t h induces eye m o v e m e n t s with latencies o f a b o u t 10 msec (ref. 6), less than h a l f t h a t for F E F m o v e m e n t s . T h i s result m i g h t lead us to guess that the r e f r a c t o r y p e r i o d for saccades in a n F E F - v e s t i b u l a r interaction w o u l d be s h o r t e r t h a n the p e r i o d s e p a r a t i n g two F E F saccades. T o further explore these hypotheses, i n t r a c o r t i c a l r e f r a c t o r y p e r i o d s were m e a s u r ed by s t i m u l a t i n g the F E F with d o u b l e pulses s e p a r a t e d by v a r i o u s t e m p o r a l intervals. T h e actual E O G r e c o r d s f r o m one o f 5 cortical sites tested can be seen in Fig. 6A. All traces have been aligned with the a r t i f a c t from one shock (pulse one); the o t h e r artifact (pulse two) can be seen at v a r i o u s intervals before a n d after pulse one. W h e n pulse two p r e c e d e d pulse one by 100 reset, b o t h saccades are elicited with little or n o r e d u c t i o n m a m p l i t u d e . The distinctly different f o r m s o f the stimulus artifacts allowed the origins o f the response to be d e t e r m i n e d with confidence. N o t e that a v o l u n t a r y saccade in the o p p o s i t e direction occurred j u s t p r i o r to that e v o k e d by pulse one in the tO0 c o n d i t i o n A s pulse two t e m p o r a l l y a p p r o a c h e d pulse one, the a m p l i t u d e o f the latter saccade was r e d u c e d (Fig. 6B). A t intervals o f - - 5 0 msec or less. n o saccade c o u l d be elicited with pulse one. I f pulse two followed pulse one by 0 - 5 0 msec, a single saccade was also elicited. ( O c c a s i o n a l l y a short d u r a t i o n , n o n - s a c c a d i c m o v e m e n t occurred which a p p e a r e d to be followed by a c o m p e n s a t o r y m o v e m e n t in the o p p o s i t e direction. Such a m o v e m e n t is shown in the f o u r t h trace, a n d these o c c u r r e d in a p p r o x i m a t e l y 5 °o o f the trials.) A n e x a m i n a t i o n of the stimulus artifacts indicate t h a t the saccade, a t
33 say 50 msec, was now that produced by pulse one. At longer intervals between 50 and 75 msec, a second saccade was evoked, whose amplitude grew with longer intervals. Finally, when at least 100 msec had elapsed between pulses, both saccades of maximal amplitude and duration were elicited. These results indicate an absolute intracortical refractory period of 55 msec ~ 15 msec (mean and S.D. of 5 experiments), and a relative refractory period of 50 ~z 16 msec. The values are in good agreement with those of Robinson and Fuchs 11. Slight differences might be expected from the fact that their electrodes were often positioned as much as 8-10 mm below the cortical surface, thus reducing the conduction time to the oculomotor nuclei. These results were not consistent with the predictions: the addition of the longer F E F path length (involving additional intracortical circuitry as well) did not prolong the saccadic refractory period. As a further test, one electrode was placed in the FEF and a second in the mesencephalic reticular formation (MRF), a region known to produce low-threshold saccadesl, ~ with latencies of 20-25 msec (present results). The interval between shocks to FEF and M R F was varied as before and the size of the resulting saccades measured. Contrary to expectation, the refractory period of these interactions was almost twice (~ = 94.2 ~- 11 msec, 3 experiments) that for intracortical or FEF-vestibular interactions; all interactions were symmetrical. These results show that factors other than the input paths to the pulse generators are involved in the saccadic refractory period. DISCUSSION The principal findings of this study indicate that saccadic eye movements were refractive to subsequent frontal eye field saccades only if both members of the pair were in the same direction. If the first movement was in another direction, there appeared to be no interference with subsequent F E F saccades. F E F saccades were often followed by voluntary saccades of like amplitude but in the opposite direction. From this, one might speculate that an F E F shock was much like an eyeball tap: the visual scene moved abruptly and the monkey compensated by a corrective saccade. The observation that the absolute refractory period was directionally specific suggests that separate pathways were involved in oppositely directed movements. More specifically, there must be at least two saccade generators for horizontal eye movements, one each for ipsilateral and contralateral movements. This suggestion is in addition to the Robinson and Fuchs 11 results, which indicated that there were horizontal and vertical generators on each side of the brain. The present results have extended these observations to include more physiological movements. The comparability of both sets of data is underscored by the absence of refractory periods for bilateral twopoint stimulation (oppositely directed saccades) and for the lack of interaction of F E F saccades with either vestibular or voluntary saccades in opposite directions. An unexpected finding was the decrease in the frequency of FEF saccades following voluntary or reflexive pursuit movements in either direction. The decrease was independent of stimulus parameters and pursuit velocity. This implies that the saccadic and pursuit movement substrates are not as independent as was commonly believed.
34 The same results were obtained for F E F 2nteraction with v o l u n t a r y or vestibular eye movements. This indicates that the pathway for v o l u n t a r y a n d vestibular saccades are the same from the p o i n t of interaction with F E F saccades to the ocular muscles. R o n et al. 1~ have recently reported similar findings in m o n k e y . A similar statement can be made for pursuit m o v e m e n t s a n d the slow phase of vestibular nystagmus. It is concluded that a given site in the frontal eye fields is capable o f m o d u l a t i n g o n g o i n g eye m o v e m e n t to a particular location independently of how the eyes reach their goat. The absolute size o f t h e refractory period deserves some c o m m e n t . If the refractory period reflects the 'cycle time' of the saccade generator, a n d the 'cycle time' or d u r a t i o n of a saccade is roughly p r o p o r t i o n a l to its amplitude, then one w o u l d also expect the refractory period to vary as a f u n c t i o n o f saccadic amplitude, Preliminary results suggest that this hypothesis is approximately true. Thus the average values of r e f r a c t o r y periods should be d e t e r m i n e d only for equal amplitude saccades. ACKNOWLEDGEMENTS Supported by U.S.P.H.S. Postdoctoral Fellowship EY 52866 a n d Research G r a n t EY 00592 to G. Westheimer.
REFERENCES 1 Bender, M. B. and Shanzer, S., Oculomotor pathways defined by electrical stimulation and tes~ons in the brainstem of monkey. In M. B. Bender (Ed.), The Oculomotor System Harper and Row. New York, 1964. 2 Bizzi, E., Discharge of frontal eye field neurons during saccadic and following movements in unanesthetized monkeys, Exp. Brain Res.. 6 (1%8) 69-80. 3 Bizzi, E. and Schiller, P. H., Single unit activity in frontal eye field netu-ons of unanesthetized monkeys during eye and head movements, Exp. Brain Res., 10 (1970) 151-158. 4 Brucher, J. M.. The frontal eye fields in monkey, Int. J. Neurology, 5 (1966) 262--281. 5 Cohen, B. and Komatsuzaki, A., Eye movements induced by stimulation of the pontine reticular formation: evidence for integration in oculomotor pathways, Exp. neurol., 36 ( 1972l 10t - 117. 6 Cohen, B.. Goto, K. and Tokumasu, K., Return eye movements, an ocular compensatory reflex in the alert cat and monkey, Exp. Neurol., 17 (1967) t72-185. 7 Evarts, E. V., Pyramidal tract activity associated with a conditioned hand movement in the monkey, J. NeurophysioL, 29 (1966) 1011-1027. 8 Latto, R. and Cowey, A., Visual field defects after frontal eye field lesions in monkeys, Brain Research., 30 (1971) 1-24. 9 Latto, R. and Cowey, A., Fixation changes after frontal eye field lesions in monkeys, Brain Research, 30 (1971) 25-36. 10 Phillips, C. G,, Motor apparatus of the baboon's hand. The Ferrier Lecture. Proc. roy. Soc. B. 173 (1969) 141-174. 11 Robinson, D. A. and Fuchs, A. F., Eye movements evoked by stimulation of the frontal eyefields, J. Neurophysiol., 32 (1969) 637-648. 12 Ron, S., Robinson. D. A. and Skavenski. A. A., Saccades and the quick phase of nystagmus, Vision Res., 12 (1972) 2015-2022. 13 Westheimer, G. and Blair, S. M., The ocular till reaction - - a brain stem oculomotor routine, Invest. Ophthal., 14 (1974) 833-839.
23
SACCADES I N D U C E D BY S T I M U L A T I O N OF T H E F R O N T A L EYE F I E L D S : I N T E R A C T I O N W I T H V O L U N T A R Y A N D R E F L E X I V E EYE M O V E M E N T S
RICHARD T. MARROCCO* Department of Physiology-Anatomy, University of California, Berkeley, Calif. 94720 (U.S.A.)
(Accepted August 24th, 1977)
SUMMARY Saccadic eye movements were evoked in alert monkeys by electrical stimulation of the frontal eye fields (FEF). The interaction of F E F movements with voluntary saccades, pursuit, and vestibular nystagmus (VN) was examined. An F E F saccade in one direction could be evoked as little as 10 msec after the onset of a natural rapid movement (saccade, fast phase of VN) in the opposite direction. Thus, refractory periods between similar eye movements are directionally specific. The frequency of evoked FEF saccades following natural slow movements (pursuit, slow phase of VN) in either direction was reduced as though saccade thresholds were elevated. The FEF appears capable of modulating any ongoing eye movement.
INTRODUCTION The role of the frontal eye fields (FEF) in the regulation of eye movements is not well understood. Results from stimulation experiments suggest a motor role. For example, Robinson and Fuchs H showed that stimulation of a small volume of tissue in F E F in the alert monkey with 0.1-l.0 mA current resulted in short-latency, conjugate, contralateral saccades. However, the F E F response was quite stereotyped: once the saccade threshold was reached, saccade amplitude was unaffected by further increases in stimulus strength. This is in strong contrast to all other classic motor regions. For instance, stimulation of area 4 of the baboon cortex produces short-latency movements of the forelimb 10. The amplitude of the movement is monotonically related to the stimulating current. Results from single unit studies are also inconsistent with the idea of a F E F motor center. Two studiesZ, a reported data from a large sample of F E F neurons in
* Present address: Department of Psychology, University of Oregon, Eugene, Oregon 97403, U.S.A.
24 the awake monkey. The activity of approximately 8-10 '~J,~of the cells was clearl3 related either to saccadic or pursuit eye movements. Most importantly, almost all units fired after the initiation of a saccade. In contrast, neurons of the motor area 4 related to a specific muscle fired before the initiation of a muscle movement (e.g. ref. 7). Although the relationship between the stimulation and recording data is as yet unclear, there is little doubt that the frontal eye fields are concerned with some aspects of oculomotor coordination. Unilateral ablation of this region causes conjugate deviation of the eyes away from the lesioned side and disturbances of the fast phase of optokinetic nystagmus in the direction away from the lesion ~, unilateral amblyopia s, and fixational changes 9. Careful measurement of the metrics of induced movements further strengthen the involvement of the F E F in saccade generation. Robinson and Fuchs 1~ have shown that the saccades induced by FEF stimulation are identical in trajectory to those made voluntarily by the monkey. If they are similar, one might expect that they share colnmon neural circuits at some point. If so, interactions, either facilitatory or occlusive, might be expected between F E F and voluntary saccades or brain stern ocular reflexes. The present investigation examines the interactions between F E F saccades and voluntary saccades, pursuit movements, the phases of vestibular nystagmus, and saccades induced by electrical stimulation of brain stem sites. It will be shown that shockand naturally-induced responses from different anatomical locations interact in an occlusive fashion only. The existence of refractory periods is indicated between FEF saccades and like voluntary saccades but not for slow movements in: either direction, nor saccades in the opposite direction. METHODS Three juvenile cynomolgous monkeys (Macaca irus) weighing 1.5-2.5 kg were implanted under sterile conditions with head gear permitting periodic immobilization of their heads. A plastic chamber with a threaded cap was then secured to the skull over the frontal eye fields, similarly to previous techniques 7,a:~ At the time of the experiment, the alert animal was seated in a primate chair and its head immobilized by the head gear. Beckman skin electrodes were firmly attached against the skin bitemporally and vertically. Eye movements were recorded by DC electrooculography and stored on magnetic tape; the system band width was about 200 Hz. E O G records were analyzed by writing the contents of the tapes into a HewlettPackard chart recorder whose frequency response was flat to 90 Hz. The sensitivity of this E O G system was about 2 ° and linear over a :z: 20 ° range. Monkeys were trained to make eye movements of fixed amplitude. An array of pin lights subtending 30' of arc visual angle, arranged to form a cross, was centered directly in front of the animal's head. Bulbs were located at 0 ~, and at 10"~ 20 ~ right. left, up and down. Located immediately below each light was a white button. Animals were first trained to attend to the illuminated 0 ~ light and press its button when its intensity was briefly decreased. When the pressing response latency to dimming reached 0.75 sec, the contingencies were changed. The central light was dimmed as usual and
25 followed by the illumination of a second light at one of the remaining 8 locations. The animals were rewarded only if they made a saccade to the second bulb and pressed its button. The procedure allowed shocks to be delivered during on-going saccades and made frequent calibration of the EOG system possible. Head position was monitored with a linear potentiometer which gave records whose amplitude and polarity specified head position to within 5 ° of arc. Spike-like, downward deflections of the trace indicated head motion toward the right; upward spikes indicated leftward head motion. Glass-coated, platinum-iridium microelectrodes and bipolar concentric macroelectrodes were aseptically introduced into the chamber and hydraulically advanced through the intact dura. Pulses of current were passed through the advancing bipolar electrode; the electrode was assumed to be in the middle cortical layers when lowthreshold contralateral saccades were first evoked. Cathodal pulses were delivered through a constant current network (BME S I04B); unless otherwise noted, a 25 msec train of 0.5 msec square-wave pulses at 200 Hz was used. After each experiment a lesion was placed electrolytically at the point of lowest electrode penetration. After some 15 20 penetrations had been made, the monkey was sacrificed with an overdose of Nembutal, perfused with 0.9'!~i formalin, and decapitated. After one week fixation in formalin the brain was removed, and 50/~m sections cut through the FEF region on a freezing microtome. Sections were stained with cresyl violet. All data reported here were from histologically confirmed locations. RESULTS
(A) Characteristics of FEF saccades Stimulation with short pulse trains yielded single contralateral saccades with an average latency of 20 msec. Amplitudes depended on electrode position and depth within the cortex, and ranged from 5 ° to 30 °. Saccade threshold was defined as that current needed to evoke saccades in 7 out of 10 attempts. Thresholds varied with cortical position and depth, ranging from 50 to 2000/zA. Saccade duration was monotonically related to amplitude. An amplitude-duration plot for 60 F E F saccades was indistinguishable from a similar plot for 100 voluntary saccades. We concluded that similar neural circuits are operative in both types of saccades. The data are in full agreement with those of Robinson and FuchslL
( B) FEF saccades and voluntary eye movements Interaction with spontaneous saccades In order to more fully understand the nature of the mechanisms underlying saccadic movements, pulse trains were delivered to F E F at various intervals before, during and after the onset of saccades in the light. The generation of a FEF saccade depended on the direction of the ongoing movement. If the eyes made a saccade in the ipsilateral (right) direction, a FEF saccade in the opposite direction could be produced as little as 10 msec after the onset of the voluntary movement (see Fig. I A). Within the
26 A
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Fig. 1. A: interaction of FEF saccades with voluntary saccades in the opposite direction, A control condition shows the form of a 30° FEF saccade. The lower three traces show the FEF saccade preceded by voluntary saccades at intervals (msec) indicated to the left of the traces. The onset of each voluntary saccade is indicated by a downward arrow. Shock duration is indicated by the black bar below each trace. B: interaction of FEF saccades with voluntary saccades in the s a m e direction. A control saccade (C) is marked by an arrow. Shock duration is indicated below trace. The lower three traces show F E F shocks (hatch mark) delivered at various intervals following voluntary movements. Shock duration indicated by the width of the mark. Distance calibrations for A and B are 20°; time calibrations for A = 50 msec, for B -- 100 msec. C: a plot of FEF saccade amplitude as a function of the intersaccade interval for saccade in the s a m e direction. The amplitude of the FEF shock grows from zero tO within 10% of the control size at 50 msec, and is at maximal amplitude at 100 msec.
r e s o l u t i o n o f the r e c o r d i n g system, e v o k e d saccades were seen to override s p o n t a n e o u s saccades at a n y interval. T h e r e a p p e a r e d to be no refractoriness between m o v e m e n t s in the o p p o s i n g directions. Identical results were o b t a i n e d in 12 similar e x p e r i m e n t s at 6 different F E F locations. The m o n k e y was then r e w a r d e d for m a k i n g saccades o f 20 ° a m p l i t u d e in the same direction as those elicited by F E F shock. Pulses were e l e c t r o n i c a l l y triggered by an E O G voltage d i s c r i m i n a t o r at v a r i o u s p o i n t s d u r i n g the c o n t r a l a t e r a l sacCades. In c o n t r a s t to the ipsilateral case, a b o u t 50 msec were n e e d e d before the c o n t r a l a t e r a l F E F saccade c o u l d be induced. N o F E F saccades c o u l d be p r o d u c e d at s h o r t e r d u r a t i o n s , even if the c u r r e n t strength was increased. Fig, I B shows a series o f F E F a n d v o l u n t a r y saccades at different t e m p o r a l intervals, a n d the r e l a t i o n s h i p between F E F saccade a m p l i t u d e a n d intersaccadic i n t e r v a l is shown in Fig. 1CI Intervals shorter t h a n 50 msec p r e c l u d e d F E F saccades a n d only the stimulus artifact ( m a r k s below the E O G records) was seen. A t longer intervals, however, F E F saccades c o u l d be seen rising f r o m the v o l u n t a r y m o v e m e n t . It was often true t h a t the saecade p r o d u c e d after 50-80 msec was slightly smaller in a m p l i t u d e t h a n those i n d u c e d a t later intervals. I n c r e a s e d c u r r e n t d u r i n g the 50-80 msec p e r i o d d i d n o t p r o d u c e larger a m p l i t u d e sac-
27 cades. A f t e r 100 msec, however, saccade a m p l i t u d e h a d r e t u r n e d to c o n t r o l values. This result was replicated at 9 other F E F loci. Thus, the results suggest the existence o f an absolute refractory p e r i o d after v o l u n t a r y saccades during which F E F saccades c a n n o t be elicited a n d a relative refractory p e r i o d d u r i n g which F E F saccades are r e d u c e d in size. Identical results were o b t a i n e d from interactions in a d a r k e n e d r o o m with the saccade targets d i m l y illuminated. Interaction with pursuit movements A t t e m p t s were also m a d e to induce F E F saccades d u r i n g slow, p u r s u i t eye move-
ments m a d e to m o v i n g visual stimuli. Ten F E F cortical sites were e x a m i n e d with similar outcomes. P u r s u i t - s a c c a d e interactions i m m e d i a t e l y following the onset o f pursuit as well as later in the p u r s u i t m o v e m e n t were tested. C o n t r a l a t e r a l l y e v o k e d saccades following the onset o f slow m o v e m e n t s in the o p p o s i t e direction were difficult to obtain. In a p p r o x i m a t e l y 95 ~ o f the cases (80/86 trials in 4 F E F loci) in which saccades were elicited, a second, p r e s u m a b l y voluntary, saccade r e t u r n e d the eyes to their a p p r o x i m a t e prestimulus t r a c k i n g a n d velocity position. In the r e m a i n i n g 5 ~o (6/80 trials in 2 F E F loci) the shape o f the induced m o v e m e n t was such as to d o u b t its classification as a complete saccade. I f the eyes were following a target t o w a r d the contralateral side, the shortest interval following the start o f a pursuit m o v e m e n t at which a F E F saccade could be e v o k e d was 35 msec
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I lOdeg shock SOmsec Fig. 2. Interaction ofFEF saccades with pursuit movements. A: two FEF saccades are shown following pursuit movements in the same direction after 30 msec (top trace) and 50 msec (bottom trace). The dotted lines indicate the paths of the pursuit movements, which follow small voluntary saccades. Stimulating current = 900/zA (top trace), 1.6 mA (bottom trace). Note that the FEF saccade is followed rapidly by a voluntary movement which redirects the eyes to the pursuit path. Time and amplitude calibrations are 50 msec and l0 t'. B: FEF saccades during pursuit movements at different velocities. Stimulating current was 1.3 mA. Numbers on the left show the approximate velocity and the dotted lines show the approximate trajectory of each pursuit movement. The bar beneath the records shows the FEF shock duration, and a spike-shaped shock artifact can be seen preceding each saccade. Failure to evoke saccades occurred at 8 and 20 deg/sec.
28 (Fig. 2A top trace: a F E F saccade after 50 msec is shown in Fig. 2A. lower trace l Thus, ongoing pursuit movements in either direction interferred to some extent with subsequent F E F saccades. Unlike the results for voluntary saccades, the production of a FEF saccade well after the onset of a slow movement in either horizontal direction was not assured. In fact, only 65 ~,, of such attempts (45/70 trials in 3 F E F loci) successfully produced a saccade. Raising the stimulation current to several times threshold or lengthening the pulse train was ineffective m overcoming the apparent threshold elevation caused by the slow movement. Neither the direction of movement, nor the velocity, nor the position of the eyes during the stimulation appeared to have any bearing on the success rate of evoked saccades (see Fig. 2B). Although the reasons for this are unclear at present, the data are thought to be of significant interest to include in this report. Thus. the F E F data contrast with P P R F stimulation results which showed that all ongoing eye movements were overridden ,5.
Interaction with vergence movements With the present recording system it was not possible to simultaneously measure vergence and versional eye movements. Only qualitative observations will be described briefly. The animal was induced to fixate on the mirror reflection of his [~.ce at I m . and a F E F saccade of 20 ° was evoked. The mirror was then moved to a distance of 5 cm and voluntary convergence movements of about 10' were made. A F E F shock was delivered during near point convergence; the eyes again made a contralaterat saccade. One might expect that the contralateral eye, which was adducted by a b o u t 10° would make a larger saccade than the ipsilateral eye. In fact. a comparison of the saccade amplitudes before and during convergence indicated that both eyes made the same size movements (about 20°1 under both conditions. Thus. under the present conditions and limitations of measurement, there appeared to be no interaction between F E F saccades and convergence eye movements. ( C) FEF saccades and ocutomotor reflexes to natural stimulation Eye movements induced by rotation of the animal through a horizontal arc of about 120 ° (60 ° to the right, through the midline, 60 ° to the left, and back) showed the typical 'beating' pattern of slow and fast phases of vestibular nystagmus: There were typically two or three slow-fast pairs (beats) for each 60 ° head displacement. When the direction of the head movement was reversed, the eye movement sequence was repeated with the slow and fast phase directions reversed.
Interaction of FEF saccades with the fast phase of vestibular nystagmus In this experiment, a pulse train delivered to the F E F while the eyes were at rest produced a contralateral 15° saccade (Fig. 3A). If the eyes made a saccade t o the ipsilaterai (right) side during head movements, a F E F saccade could b e elicited within 20 msec of the onset of the fast phase (Fig, 3B). The direction and amplitude of the
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f Fig. 4. Interaction of FEF saccades with the fast phase of vestibular nystagmus in the x a m e direction. A series of records shows F E F saccades at 15, 30, 40 and 75 msec after the vestibular saceades; a control saccade shows the size of the movement during a vestibular slow phase. Shock duration and location as in Fig. 3. Stimulating current was 200/*A. The FEF movement fails at 15, 30 and 40 msec but can be seen superimposed on the vestibular saccade at 75 msec. Note that the amplitude of the FEF movement in the 75 msec trace is reduced in comparison to the (control) pursuit condition. Movement calibration for 15, 40, 75 and pursuit traces = 10°; for 30 msec record = 5°. Head position is shown in the bottom trace. Vertical calibration mark shows a 1000 head movement to the right.
30 i n d u c e d m o v e m e n t were similar to t h a t of the c o n t r o l saccade. This result was c o n f i r m e d at 6 o t h e r F E F sites. O n the o t h e r hand, a vestibular saccade was r e f r a c t o r y for a F E F saccade in the same direction for a b o u t 50 msec (Fig. 4). The 3 u p p e r traces show that a fast m o v e m e n t occurs to the left as a result o f vestibular stimulation. T h a t no F E F saccade is superi m p o s e d on this m o v e m e n t can be seen in the high gain second trace. The f o u r t h trace shows the F E F saccade 75 msec after the vestibular m o v e m e n t . The 10 ° fast phase m o v e m e n t was followed by a 15 ° F E F saccade a n d the total o c u l a r d e v i a t i o n was a b o u t 25 °. This induced m o v e m e n t , a l t h o u g h o f d e c r e a s e d a m p l i t u d e , closely r e s e m b l e s the c o n t r o l saccade (pursuit) e v o k e d d u r i n g the v e s t i b u l a r slow phase. This f i n d i n g was true o f all 5 F E F sites tested. T h a t the shock has some effect on the o c u l o m o t o r a p p a r a tus is a p p a r e n t f r o m the r a p i d r i g h t w a r d m o v e m e n t s t h a t follow the fast vestibular m o v e m e n t . It w o u l d a p p e a r that t h e v e s t i b u l o - o c u l a r c o m p e n s a t i o n was t e m p o r a r i l y disrupted. Similar m o v e m e n t s following 8th nerve s t i m u l a t i o n have been r e p o r t e d 6.
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of records shows a control FEF movement With the head at rest, Black squares below t r a ~ s denole shock artifact duration and the FEF movement follows, Current was 650 p.A. The lower pair shows an FEF saccade (arrow) evoked 50 msec following a slow vestibular movement in the opposite direction. Three slow phases and two fast phases of the nystagmus are Shown. B: a series ofEOG rec0rdsshowing attempts to elicit FEF saccades during the slow phase of vestibular nystagmus in the same direction: Shock location and duration as in Fig. 3. Current was 1:8 mA. The FEF saccade intrace 1 was successful while that in trace 3 failed. A small compensatory movement follows the hiphasic shock artifact in trace 2. Time and movement calibrations as in A.
31 These results, then, appeared comparable to those found with voluntary saccades. Voluntary saccades and the fast phase of vestibular nystagmus were followed by absolute and relative refractory periods of similar durations for subsequent FEF saccades. Level of illumination had no effect on these results.
Interaction with the slow phase of vestibular nystagmus A F E F saccade reliably elicited during the slow phase of VN in the opposite direction can be seen in Fig. 5A. This occurred at the minimal latencies necessary to identify the initiation of a slow phase (35 msec). The induced saccade was always of maximal amplitude even at the shortest latencies. If there was a period of interference between slow phase of VN and F E F saccades, it was not measurable with the present techniques. Moreover, the occurrence of F E F saccades did not disturb or reset the beating pattern of nystagmus, suggesting that the override was simply superimposed on labyrinthine-induced activity. In general, no refractory periods for subsequent F E F saccades could be demonstrated following slow movements in the same direction. However, the probability of evoking saccades fell to about 5 0 ~ during any part of the slow phase (see Fig. 5B). A full-sized saccade can be seen in trace 1 : trace 2 shows the shock artifact quickly followed by a compensatory movement in the opposite direction; trace 3 shows failure to evoke a saccade (artifact only). Moreover, the amplitude of the shock-induced movement varied from zero to 100 ~ of control values and was independent of the velocity of the slow movement. Once again, the success rate could not be increased by increasing the stimulating current 2-fold. These results are nearly identical to those found with pursuit eye movements. Since the slow phase of VN is visually guided, it was thought that visual input might block saccadic output from the frontal cortex. However, despite a slightly lowered success rate, the same unreliability was evident during vestibular nystagmus in complete darkness. If a refractory period follows voluntary saccades, does one follow FEF saccades as well? Generally, the answer to this question was not as easy to obtain as the reverse situation, for FEF movements were usually followed by a second saccade which returned the eyes to their approximate position prior to the FEF saccade. Occasionally, however, the EOG records showed F E F movement and its stimulus artifact followed by a saccade (voluntary or vestibular) in the same direction. The minimal latency observed was 70-75 msec. More data, however, are required to reach a firm conclusion.
( D) Interaction of identical FEF saceades evoked by stimu&tion of a single cortical site lntracortical refractory periods it is reasonable to assume that the duration of the refractory period was primarily due to the cycle time of the saccadic pulse generator plus the conduction time of its input and output pathways. There is good evidence to suggest that vestibular and voluntary saccades make use of the same pulse generator 12. Therefore, differences in refractory periods between two voluntary as opposed to two vestibular saccades should
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Fig. 6. Interaction of two FEF saccades elicited from a single intracortical site. A: EOG records showing two nearly identical saccades evoked by double shocks to FEF at different interpulse intervals. Current strength was 1.2 mA. All records have been horizontally aligned on the artifact produced by the shock arbitrarily called pulse one. The time of occurrence of pulse two is shown in msec to the left of the EOG records. B: graphic plot of the amplitude of the saccades (arbitrary units) produced by pulse one (solid lines) as a function of the interval between shocks. The amplitudes of the saccades produced by pulse two are shown by dashed lines. Although there is some variability of amplitude at durations greater than 100 msec. each saccade has returned to its full amplitude between 75 and 125 msec, p r i m a r i l y reflect differences in i n p u t p a t h lengths (assuming similar fiber c o n d u c t i o n velocities). S t i m u l a t i o n o f the l a b y r i n t h induces eye m o v e m e n t s with latencies o f a b o u t 10 msec (ref. 6), less than h a l f t h a t for F E F m o v e m e n t s . T h i s result m i g h t lead us to guess that the r e f r a c t o r y p e r i o d for saccades in a n F E F - v e s t i b u l a r interaction w o u l d be s h o r t e r t h a n the p e r i o d s e p a r a t i n g two F E F saccades. T o further explore these hypotheses, i n t r a c o r t i c a l r e f r a c t o r y p e r i o d s were m e a s u r ed by s t i m u l a t i n g the F E F with d o u b l e pulses s e p a r a t e d by v a r i o u s t e m p o r a l intervals. T h e actual E O G r e c o r d s f r o m one o f 5 cortical sites tested can be seen in Fig. 6A. All traces have been aligned with the a r t i f a c t from one shock (pulse one); the o t h e r artifact (pulse two) can be seen at v a r i o u s intervals before a n d after pulse one. W h e n pulse two p r e c e d e d pulse one by 100 reset, b o t h saccades are elicited with little or n o r e d u c t i o n m a m p l i t u d e . The distinctly different f o r m s o f the stimulus artifacts allowed the origins o f the response to be d e t e r m i n e d with confidence. N o t e that a v o l u n t a r y saccade in the o p p o s i t e direction occurred j u s t p r i o r to that e v o k e d by pulse one in the tO0 c o n d i t i o n A s pulse two t e m p o r a l l y a p p r o a c h e d pulse one, the a m p l i t u d e o f the latter saccade was r e d u c e d (Fig. 6B). A t intervals o f - - 5 0 msec or less. n o saccade c o u l d be elicited with pulse one. I f pulse two followed pulse one by 0 - 5 0 msec, a single saccade was also elicited. ( O c c a s i o n a l l y a short d u r a t i o n , n o n - s a c c a d i c m o v e m e n t occurred which a p p e a r e d to be followed by a c o m p e n s a t o r y m o v e m e n t in the o p p o s i t e direction. Such a m o v e m e n t is shown in the f o u r t h trace, a n d these o c c u r r e d in a p p r o x i m a t e l y 5 °o o f the trials.) A n e x a m i n a t i o n of the stimulus artifacts indicate t h a t the saccade, a t
33 say 50 msec, was now that produced by pulse one. At longer intervals between 50 and 75 msec, a second saccade was evoked, whose amplitude grew with longer intervals. Finally, when at least 100 msec had elapsed between pulses, both saccades of maximal amplitude and duration were elicited. These results indicate an absolute intracortical refractory period of 55 msec ~ 15 msec (mean and S.D. of 5 experiments), and a relative refractory period of 50 ~z 16 msec. The values are in good agreement with those of Robinson and Fuchs 11. Slight differences might be expected from the fact that their electrodes were often positioned as much as 8-10 mm below the cortical surface, thus reducing the conduction time to the oculomotor nuclei. These results were not consistent with the predictions: the addition of the longer F E F path length (involving additional intracortical circuitry as well) did not prolong the saccadic refractory period. As a further test, one electrode was placed in the FEF and a second in the mesencephalic reticular formation (MRF), a region known to produce low-threshold saccadesl, ~ with latencies of 20-25 msec (present results). The interval between shocks to FEF and M R F was varied as before and the size of the resulting saccades measured. Contrary to expectation, the refractory period of these interactions was almost twice (~ = 94.2 ~- 11 msec, 3 experiments) that for intracortical or FEF-vestibular interactions; all interactions were symmetrical. These results show that factors other than the input paths to the pulse generators are involved in the saccadic refractory period. DISCUSSION The principal findings of this study indicate that saccadic eye movements were refractive to subsequent frontal eye field saccades only if both members of the pair were in the same direction. If the first movement was in another direction, there appeared to be no interference with subsequent F E F saccades. F E F saccades were often followed by voluntary saccades of like amplitude but in the opposite direction. From this, one might speculate that an F E F shock was much like an eyeball tap: the visual scene moved abruptly and the monkey compensated by a corrective saccade. The observation that the absolute refractory period was directionally specific suggests that separate pathways were involved in oppositely directed movements. More specifically, there must be at least two saccade generators for horizontal eye movements, one each for ipsilateral and contralateral movements. This suggestion is in addition to the Robinson and Fuchs 11 results, which indicated that there were horizontal and vertical generators on each side of the brain. The present results have extended these observations to include more physiological movements. The comparability of both sets of data is underscored by the absence of refractory periods for bilateral twopoint stimulation (oppositely directed saccades) and for the lack of interaction of F E F saccades with either vestibular or voluntary saccades in opposite directions. An unexpected finding was the decrease in the frequency of FEF saccades following voluntary or reflexive pursuit movements in either direction. The decrease was independent of stimulus parameters and pursuit velocity. This implies that the saccadic and pursuit movement substrates are not as independent as was commonly believed.
34 The same results were obtained for F E F 2nteraction with v o l u n t a r y or vestibular eye movements. This indicates that the pathway for v o l u n t a r y a n d vestibular saccades are the same from the p o i n t of interaction with F E F saccades to the ocular muscles. R o n et al. 1~ have recently reported similar findings in m o n k e y . A similar statement can be made for pursuit m o v e m e n t s a n d the slow phase of vestibular nystagmus. It is concluded that a given site in the frontal eye fields is capable o f m o d u l a t i n g o n g o i n g eye m o v e m e n t to a particular location independently of how the eyes reach their goat. The absolute size o f t h e refractory period deserves some c o m m e n t . If the refractory period reflects the 'cycle time' of the saccade generator, a n d the 'cycle time' or d u r a t i o n of a saccade is roughly p r o p o r t i o n a l to its amplitude, then one w o u l d also expect the refractory period to vary as a f u n c t i o n o f saccadic amplitude, Preliminary results suggest that this hypothesis is approximately true. Thus the average values of r e f r a c t o r y periods should be d e t e r m i n e d only for equal amplitude saccades. ACKNOWLEDGEMENTS Supported by U.S.P.H.S. Postdoctoral Fellowship EY 52866 a n d Research G r a n t EY 00592 to G. Westheimer.
REFERENCES 1 Bender, M. B. and Shanzer, S., Oculomotor pathways defined by electrical stimulation and tes~ons in the brainstem of monkey. In M. B. Bender (Ed.), The Oculomotor System Harper and Row. New York, 1964. 2 Bizzi, E., Discharge of frontal eye field neurons during saccadic and following movements in unanesthetized monkeys, Exp. Brain Res.. 6 (1%8) 69-80. 3 Bizzi, E. and Schiller, P. H., Single unit activity in frontal eye field netu-ons of unanesthetized monkeys during eye and head movements, Exp. Brain Res., 10 (1970) 151-158. 4 Brucher, J. M.. The frontal eye fields in monkey, Int. J. Neurology, 5 (1966) 262--281. 5 Cohen, B. and Komatsuzaki, A., Eye movements induced by stimulation of the pontine reticular formation: evidence for integration in oculomotor pathways, Exp. neurol., 36 ( 1972l 10t - 117. 6 Cohen, B.. Goto, K. and Tokumasu, K., Return eye movements, an ocular compensatory reflex in the alert cat and monkey, Exp. Neurol., 17 (1967) t72-185. 7 Evarts, E. V., Pyramidal tract activity associated with a conditioned hand movement in the monkey, J. NeurophysioL, 29 (1966) 1011-1027. 8 Latto, R. and Cowey, A., Visual field defects after frontal eye field lesions in monkeys, Brain Research., 30 (1971) 1-24. 9 Latto, R. and Cowey, A., Fixation changes after frontal eye field lesions in monkeys, Brain Research, 30 (1971) 25-36. 10 Phillips, C. G,, Motor apparatus of the baboon's hand. The Ferrier Lecture. Proc. roy. Soc. B. 173 (1969) 141-174. 11 Robinson, D. A. and Fuchs, A. F., Eye movements evoked by stimulation of the frontal eyefields, J. Neurophysiol., 32 (1969) 637-648. 12 Ron, S., Robinson. D. A. and Skavenski. A. A., Saccades and the quick phase of nystagmus, Vision Res., 12 (1972) 2015-2022. 13 Westheimer, G. and Blair, S. M., The ocular till reaction - - a brain stem oculomotor routine, Invest. Ophthal., 14 (1974) 833-839.