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Induction of oculomotor responses by electrical stimulation of the prefrontal cortex in the cat
BRAIN RESEARCH
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Research Reports I N D U C T I O N OF O C U L O M O T O R RESPONSES BY E L E C T R I C A L S T I M U L A T I O N OF T H E P R E F R O N T A L C O R T E X IN T H E CAT
J. SCHLAG AND M. SCHLAG-REY
Departments of Anatomy and Psychology and Brain Research Institute, University of California, Los Angeles, Calif. 90024 (U.S.A.) (Accepted February 16th, 1970)
INTRODUCTION
The cortical frontal eye field (FEF) has been defined as that region of the frontal lobe which gives rise upon stimulation to conjugate ocular movements often accompanied by rotation of the head10,11,14. It has been most extensively studied in the monkey where its location, its correspondence with cytoarchitectural subdivisions, its connections with the thalamus, and the motor effects of its stimulation or destruction have been well explored. Comparatively, much less information is available for the cat and this information is not always consistent. By electrical stimulation, Spiegel and Scala al, Claes 5, Garo112, and Eliasson 9 induced ocular movements from a rather vaguely outlined region of the anterior sigmoid gyrus. Szent/tgothai a3 included the gyrus proteus in the excitable area and Smith z° added the most medial sector of the anterior sigmoid gyrus hidden within the cruciate sulcus. These data imply the existence of a FEF without giving much information on its extent: whether it covers the whole medial region anterior to the cruciate sulcus or a particular portion of it. Some attempts were made to trace the boundaries but the results were not consistent. Whereas Garol lz pointed to a strip of the anterior sigmoid gyrus on the outer surface of the brain, Livingston 20 and Berkowitz and Silvertone 3 located the F E F on a small area of interhemispheric cortex just under the cruciate sulcus (see also refs. 8, 15 and 17). In contrast, Scollo-Lavizzariz8 obtained ocular movements by stimulating laterally within the depth of the presylvian sulcus. Most reports cited were just short abstracts whereas the few full-length articles were only incidentally concerned with the problem of localization. The procedures of stimulation, criteria of responses, and/or anatomical findings were generally insufficiently described to permit an evaluation of the results themselves and of the discrepancies between them. Therefore, it is not surprising that the delineation of a F E F in the cat is still considered as an unresolved question 19. Confronted by the practical necessity to decide where electrodes or lesions should be placed for electrophysiological and behavioral z7 studies on the cat's Brain Research, 22 (1970) 1-13
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FEF, we were forced to admit that the literature did not provide firm indications. Therefore, we undertook to determine the F E F territory as accurately as possible under specified conditions of minimal stimulation. The old-time procedure of cortical stimulation and visual observation of the motor effects seemed to be most appropriate, for it revealed all and any responses, and was relatively free of artifacts. METHODS
These experiments were performed on 14 cats, all surgically prepared under ether anesthesia, and maintained in a stereotaxic apparatus. The spinal cord was completely transected by suction above the C1 level except in one case where the section was made between C4 and Cz (in this case, control of the neck musculature was retained and the body of the animal, lying on a board which could rotate around a vertical axis centered on the neck, could freely turn sideward with respect to the fixed head). The cerebral cortex was widely exposed and immediately covered with mineral oil continuously warmed to about 38°C. The body temperature was maintained by a heating pad. All sites of incision and the pressure points of the stereotaxic headholder were infiltrated with lidocaine. The volume of air supplied for artificial respiration was continuously adjusted to induce either a complete immobility of the eyes with fissurated and oblique pupils, or an active visual exploration with 4-5 mm wide pupils, or else any intermediate state. Shifts from an extreme state to the other could be achieved in less than one min by altering the respiration. But they also occurred spontaneously. The fact that the animals periodically fell in phases of ocular immobility and nonreactivity, indicative of sleep, was taken as clear evidence that they were not suffering. In 2 of the 14 cats, unilateral cortical lesions were performed by suction under sterile conditions one or two weeks prior to the terminal experiment. No infection developed. The rationale of these lesions is presented in the text. The lesions themselves are illustrated in Figs. 3 and 4. Routinely, short trains of 400/sec square pulses of 0.5 msec duration were used to stimulate the cerebral cortex (529 sites). They were applied through concentric electrodes stereotaxically implanted. The 0.15 mm diameter central stainless steel wire, exposed only at the tip and protruding from a 22 gauge needle by 0.4-0.8 mm, was always the cathode. The current of stimulation (50-600 /zA, but usually less than 200 /~A) was continuously monitored on a 502 Tektronix CR oscilloscope. This current and the duration of the trains (25-400 msec) were adjusted at each placement to obtain just suprathreshold immediate effects. Therefore, the ocular responses were practically always small in amplitude. The movements produced were visually observed. Tests were repeated from 10 to about 50 times at each site to evaluate the consistency of the responses and establish their nature. For this purpose, it was found useful to apply the stimulations when the eyes were spontaneously resting at different positions. In addition, the tests were run at different levels of alertness as judged from the diameter of the pupils, the spontaneous fluctuations of the gaze, and, in 4 cats, the E E G recordings. Due to Brain Research, 22 (1970) 1-13
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the length of each test, a maximum of only 6 or 7 tracks could be explored per animal. In a few cases, recordings with silver-silver chloride electrodes were made from the eyeball, mainly to measure the latency and duration of the displacements. But the method proved to be inadequate to detect ocular movements (and much less their direction) because of possible contamination of the records by E M G activity from various parts of the face. The Reinoso-Su~trez atlas of the cat's brain 24 was initially used to guide the placement of the stimulating electrodes. However, considerable variations in stereotaxic coordinates were found between animals in spite of their similarity in size and weight (3-4 kg). For instance, the position of the cruciate sulcus ranged from A23.3 to A29.0 and from H + 11.0 to H + 14.6. Such a wide dispersion apparently is normal 21. To compare the results between animals, it was found most convenient to estimate the coordinate positions with respect to the medial end of the cruciate sulcus. This procedure gave the maximal consistency between coordinate measurements and the general aspect of the histological images. Reference points were marked along each track by electrolytic iron deposits and potassium ferrocyanide reaction. The histological sections were stained with thionine. RESULTS
Type of ocular response All the movements described were saccadic. Slow movements of the pursuit type sometimes followed stimulation. They were not retained for analysis because their inconsistency made it impossible to ascertain that they were not spontaneous. The most common (i.e. 55 ~ of 180 responsive sites) ocular movement elicited by prefrontal stimulation (and also by other cortical stimulation, e.g. of the marginal gyrus) was centering: the gaze returned to center from any off-center position without overshooting, giving the impression of focused visual attention. Such movements could easily pass unnoticed unless the eyeballs were deviated prior to the stimulation. Sometimes they were accompanied by a transient and slight opening of the eyelids. A variant of the eye centering response (20 ~ ) was characterized by the fact that the gaze could come back to center from any off-center position except one. That this may be of functional significance is suggested by the frequent finding that, close to such a site of stimulation, a deviation from midposition could be elicited in that same direction from which return had not been obtained. Practically always, centering was observed in the vicinity of all sites producing ocular deviation. Conjugate ocular deviation in a selective direction was less frequent (25 ~ ) than centering. They lasted for at least the duration of the stimulation after which the eyes most often returned to their original position in the same brisk way and sometimes with a delay. A priori, this type of movement was considered more specific and, therefore, more interesting than centering from which it differed either by its overshooting beyond the central position or by its bypassing it. On 3 occasions (3 sites of stimulation in different animals), the eyes were first centered before deviating,
Brain Research, 22 (1970) 1-13
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the two steps occurring in rapid succession (this has also been noticed upon brain stem stimulation2). We recorded as true deviations only those movements which drove the eyes away from the midposition and unequivocably in the same direction. When any doubt remained, the responses were considered as centering, thereby certainly introducing a conservative bias in our evaluation. Hesitation was due mainly to the changes in responsiveness apparently dependent on the level of vigilance. Often an ocular deviation, obvious when the cat was awake, could become a centering response as soon as the pupils contracted and the E E G rhythms slowed down z4. A response could even then fail to appear (Fig. 1). Although this suggests that all observations should be made on fully awake animals, it should be realized that the eyes of such animals wander around, exploring the environment and making the identification of a response difficult. We tried to make our assessments in intermediate states of relative ocular
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Fig. 1. Disappearance of ocular deviation during drowsiness. Stimulus : 400/sec pulses of 0.5 msec duration, 100 pA, for 400 msec, applied close to the medial bank of the presylvian gyrus. Monofocal E E G recordings from contralateral anterior marginal (Ma) and posterior sigmoid (PS) gyri. AC recording of ocular movement monitored through silver ball electrodes applied on both sides of ipsilateral eye (E). Movement was conjugate oblique (ipsiversive and upward) deviation. A and B stimulations separated by 17 sec. Pupils 1 mm wide in A, completely constricted in B; changes were spontaneous. Brain Research, 22 (1970) 1-13
FRONTAL EYE FIELD I N THE CAT
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immobility. Such states could be introduced by fine adjustments of the respiration, but they never lasted very long. Despite these difficulties, there were many unambiguous instances of ocular deviation. Some particular observations deserve mention in this respect: Several times, the eyes could be moved stepwise past the midposition by brief trains applied about every 1/2 sec. In three cats, two electrodes had been implanted simultaneously and alternated displacements in opposite directions were elicited by stimulating the two sites successively. In one cat, contraversive deviation was produced repeatedly with perfect consistency from the same site during a 4 h period. And in the animals with the C3-C4 spinal transection, ocular deviations towards any side were always accompanied by a lateral displacement of the body toward this side (see Methods). The direction of a deviation was specific for a given type of stimulation in a given animal. Displacing the stimulating electrode by 1 mm could sharply alter this direction. Stimulus locations were found for upward, downward, oblique, ipsiversive, and most frequently, contraversive movements (Fig. 2). Movements limited to one eye were rarely seen. They always concerned the contralateral eye and they consisted in either a slight deviation or withdrawal of the eyeball into the orbit. Often they were difficult to ascertain, because of concomitant facial twitches. Convergent movements were suspected more than once, but they were never easily repeatable. Threshold
Clear responses were obtained with as little as 50 #A pulses (in 200 msec trains) or with trains as short as 25 msec (of 200 #A pulses). The threshold was a function of both current magnitude and duration of trains; it increased for frequencies of stimulation under 100/sec. As said above, the type of response elicited depended on the cat's state of wakefulness. This was a matter of degree in responsiveness, for true deviation which gave place to centering when the animal fell asleep could be reestablished by augmenting the current strength. In Fig. 2, such responses have been indicated as deviations (small arrows). The intensity of stimulation could affect the probability of occurrence of a response. Quite generally, 200/zA pulses in 200 msec trains were more than sufficient to elicit eye movements. But, wherever stimulation of that strength yielded no result in an awake cat, increasing the current by as much as 5 times was no more effective. The fact that responses appeared, disappeared, or changed in direction in a span of less than 1 mm should be attributed to the design of the electrodes (particularly to the short interpolar distance). Since variations in the sites of stimulation seemed more determinant than changes in current strength, the experimental conditions were likely suitable for providing valid data on localization. Stimulus location
The maps of Fig. 2 show the distribution of prefrontal points from where ocular responses were elicited. These are raw data, and only those gathered along Brain Research, 22 (1970) 1-13
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tracks histologically identified in their entire length have been plotted. The coronal sections are less than 1 mm from each other; this has to be realized to appreciate the close proximity of the tracks along sagittal planes too. For clarity of presentation, it was necessary to limit the number of symbols used, thereby conveying much less information than actually available. No ocular movements were produced from the posterior sigmoid gyrus, from the buried part of the anterior sigmoid gyrus, from a 2 mm band of the same gyrus just in front of the cruciate sulcus, or from the medial part of the frontal pole under the level of sulcus genualis. At these places, responses were absent even at intensities of stimulation as much as 5 times the threshold values for responses elicited along the same or close tracks. Laterally to the presylvian sulcus, ocular responses were intermingled with - - and progressively gave place to - - facial movements: closing of eyelids, twitching of the nose, opening or closing the jaw, protruding or retracting the tongue, moving the ears (see also Delgado and Livingston8). Most of these facial responses (labeled F or B) were contralateral, but it was incidentally observed that ipsilateral responses (e.g. B : blinking) were obtained from points immediately ventral to those giving contralateral responses. Eye movements were induced from the bottom and the banks (mainly the lateral one, rostrally) of the presylvian sulcus. True deviations were obtained when the electrode reached the gray matter of that folding. The area where stimulation was effective extended medially to the mesial face of the hemisphere above the level of sulcus genualis. The vertical penetration in this region was rather abrupt; it corresponded fairly well to the limit between the cortex of the anterior sigmoid gyrus and the subjacent white matter. In the 1-2 mm wide lamina of the corona radiata at that level run fibers which may connect with various parts of the frontal pole. The fibers responsible for ocular responses could come from the presylvian region, the gyrus proreus, or the rostral mesial wall of the hemisphere. That this mesial cortex itself was involved is suggested by the fact that movements were produced from electrodes running directly through it. The distribution of responses presented in Fig. 2 is not inconsistent with the hypothesis of two fields: one mesial, the other presylvian. On the possibility of establishing distinctions between them, the following observations were made: (1) no single region had a lower threshold within the whole territory; (2) no systematic difference has been detected in terms of direction of induced movements; (3) unilateral movements were elicited only from the lateral bank of the presylvian sulcus; (4) lid opening was frequent with mesial stimulation, whereas lid closure occurred only with presylvian stimulation; (5) eye centering accompanying arousal in animals with fissurated pupils was more often obtained with mesial stimulation; (6) shortest latency movements (evaluated at less than 30 msec by a technique which, admittedly, was not error-proof) were all of presylvian origin whereas 50-150 msec latency movements could be elicited from either regions; and (7) the two regions were united by a bridge of excitable cortex on the upper part of gyrus proreus (the first section in Fig. 2 actually is a cut through that proreal cortex). In one cat, the cortex of the rostral mesial face had been unilaterally removed Brain Research, 22 (1970) 1-13
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b y suction one week before testing (Fig. 3). Eye m o v e m e n t s , including true deviations, were readily elicited f r o m p o i n t s at the lateral b o r d e r o f the lesion. These responses c o u l d n o t be a t t r i b u t e d to the s t i m u l a t i o n o f the mesial wall. In a n o t h e r a n i m a l , the presylvian region was u n i l a t e r a l l y d e s t r o y e d by suction two weeks before testing.
Fig. 3. Responses evoked 1 week after a unilateral lesion of the mesial interhemispheric wall. Tissue defect indicated by oblique-lined area. Symbols as in Fig. 2.
Fig. 4. Responses evoked 2 weeks after a unilateral destruction of the presylvian region. Tissue defect indicated by oblique-lined area. Symbols as in Fig. 2. Brain Research, 22 (1970) 1-13
FRONTAL EYE FIELD IN THE CAT
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The histological sections showed that the ventroposterior cortex of the presylvian gyrus had been spared (Fig. 4). Rostrally, the medial border of the lesion reached the mesial cortex, certainly interrupting the connections of the remaining bit of gyrus proreus and of the most rostral portion of the mesial wall itself. Nevertheless, ocular responses were produced from more caudal points of the mesial sector, at sites which were separated from the still intact presylvian region by the lesion. For all practical purposes, the mesial oculomotor area can be easily reached by implanting electrodes 0-3 m m behind the cruciate sulcus and 4-7 m m under its horizontal level at 1 or 2 m m from the midline. For the presylvian area, the electrodes should be moved 2 or 3 m m more laterally and 2 or 3 m m deeper; however, some searching may be needed and, unfortunately, testing cannot be done under anesthesia.
Effect of anesthesia Anesthetics were administered at the end of 6 experiments. Small doses of Nembutal (as low as 3 mg/kg i.v.) were found sufficient to suppress all responses of deviation and centering. Chloralose (500-100 mg/kg i.v.) stopped spontaneous movements; deviations were absent although centering could persist. DISCUSSION
The cat's prefrontal region is so small that it is difficult to experiment on any of its parts without involving the other parts. This is probably the reason why previous attempts to locate a F E F have yielded divergent if not conflicting results as shown in the introduction. Effects due to the spread of stimulating current can be expected if intensities as large as 10 m A are used 15. They may occur especially if the electrodes are far apart. In this study, stimulation was minimal and several arguments presented with the results suggested that it remained very localized around the tip of the electrodes. Negative results were useful: they served to delineate rather sharply a zone of low-threshold responsiveness. This is significant in view of the possible claim that, in the cat as in the monkey 3~, eye movements can be induced from almost anywhere on the cortex if sufficient intensities (much higher than those used in this study) are provided. The bottom and the banks of the presylvian sulcus appeared as the most obvious portion of the low-threshold zone determined. Some doubt existed about the interpretation of responses obtained from the white matter situated immediately dorsomedially. But particular features, and mainly the results obtained after surgical elimination of the presylvian region, indicated that the cortex of the rostro-mesial wall is also concerned with ocular motricity. The presylvian and mesial regions are united by a narrow strip of excitable proreal cortex. What could this prefrontal organization correspond to in the monkey's brain? The cat's presylvian area from which eye movements could be induced is very close to the m o t o r representation of the face. In several, though not in all, cases ocular and other facial responses were elicited together. In the monkey, Wagman 34
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stated that the F E F 'blends into the hand-arm-shoulder area' and this blending appears such that Woolsey et al. z7 represented the F E F as a part of the simunculus in their classical figurine of the motor cortex. However, it is generally admitted that no eye representation exists in area 4 itself (with the exception of Beevor and Horsley's study on the orang outangl). The monkey's F E F seems to correspond approximately with area 8 which receives projections from the paralamellar sector of the thalamic mediodorsal nucleus 29. Cytoarchitectural divisions of the cat's prefrontal cortex are not agreed upon : area 8 was located on the rostral orbital gyrus by Winkler and Potter 36, on the proreal gyrus by Reinoso-Su~trez24, and within the presylvian sulcus by Scollo-Lavizzari ~s. If there is any analogy between the primate and carnivore brain, the latter position would seem the most likely: it is just rostral to area 6 (ref. 13) at the height of the motor representation of the face. Anatomical studies of thalamocortical relations are in agreement with this view since the lateral portion of nucleus medialis dorsalis has been claimed to project upon the dorsolateral portion of the orbitofrontal cortex6,23,z6, 3s. Therefore, we submit that the presylvian region outlined in this study corresponds to the cat's FEF, as originally proposed in a short note by ScolloLavizzari zs. The significance of the area of mesial cortex situated between the cruciate and genual sulci is more difficult to assess. For Rose and Woolsey 26 and Warren et al. 35, it does not receive projections from nucleus medialis dorsalis, whereas for Sychowa et al.32, such projections exist and, furthermore, they are coming from the most lateral portion of the nucleus. At the present time, no definite conclusion can be drawn: either this mesial area is an actual part of the F E F (e.g. corresponding to one of the two representations of eye movements in the monkey's prearcuate region according to Crosby et al. 7 and Brucher4), or it is homologous to other simian areas (e.g. laterodorsal prefrontal cortex or interhemispheric cortex~6), or else there is no real equivalence to be traced. Behavioral deficits analogous to some of those provoked by F E F destruction in monkeys have been obtained after frontal lobotomies in dogs 22. In cats Jeannerod et al. 18 found oculomotor dysfunctions and Schlag-Rey and Lindsley 27 observed deficits in visual attending following lesions limited to the prefrontal areas from where eye movements were elicited in the present study. Our results did not reveal any consistent topographic organization in terms of direction of eye movements induced (Fig. 2), despite the fact that direction of an evoked saccade depended strictly on where the cortex was stimulated in any given animal. This may seem to be at variance with results obtained in monkeys. However, the published monkey's F E F maps, each of which has a good deal of internal consistency, show considerable disagreement between each other4,7,25, 34. As far as the cat is concerned, we feel that the F E F is not compartmentalized according to the direction of saccades evoked by short stimulations. But the cat's F E F as a whole appears to be a well delineated territory.
Brain Research, 22 (1970) 1-13
FRONTAL EYE FIELD IN THE CAT
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SUMMARY The p r e f r o n t a l cortex o f the cat (enc6phale isol6 p r e p a r a t i o n ) was e x p l o r e d using m i n i m a l electrical s t i m u l a t i o n in o r d e r to locate as exactly as possible the critical regions f r o m which r a p i d o c u l a r m o v e m e n t s could be induced. T w o such regions have been f o u n d : one on the mesial face o f the h e m i s p h e r e u n d e r the cruciate sulcus, the o t h e r within the p r e s y l v i a n sulcus. The extent o f these zones a n d their functional characteristics are described. The p r o b l e m o f the o r g a n i z a t i o n o f a f r o n t a l eye field in the cat is discussed with reference to the m o n k e y . ACKNOWLEDGEMENTS W e are very i n d e b t e d to M r . D. K u r o d a for his technical assistance, to Miss C. R u c k e r for the histological p r e p a r a t i o n s , a n d to Miss K. Tani for the drawings. This w o r k was s u p p o r t e d in p a r t b y U.S. Public H e a l t h Service G r a n t s R0104955-06, 2K3-NB21633-06, 5F03-MH37993-02, a n d 1P01-NB08552-01. NOTE ADDED AFTER SUBMISSION A t the time o f this writing, a p a p e r b y R. H a s s l e r : E x t r a p y r a m i d a l m o t o r areas o f cat's f r o n t a l l o b e : their f u n c t i o n a n d architectonic differentiation, bit. J. Neurol., 5 (1966) 301-306, h a d escaped o u r attention. A c t u a l l y , u n d e r this title, H a s s l e r ' s p a p e r essentially concerns cortically i n d u c e d eye m o v e m e n t s . The d a t a on l o c a l i z a t i o n agree r e m a r k a b l y well, except for the a r e a 6 o f the a n t e r i o r s i g m o i d gyrus which we f o u n d c o m p l e t e l y unresponsive in o u r experiments. Hassler f o u n d some system a t i z a t i o n in the cortical r e p r e s e n t a t i o n o f direction o f m o v e m e n t . H o w e v e r , the results c a n n o t be c o m p a r e d directly because o f differences in the size o f electrode tips, in frequency a n d d u r a t i o n o f stimulation.
REFERENCES 1 BEEVOR,C. E., AND HORSLEY, V., A record of the results obtained by electrical excitation of the so-called motor cortex and internal capsule in an orang outang, Phil. Trans. B, 181 (1890) 129-158. 2 BENDER, M. B., AND SHANZER, S., Oculomotor pathways defined by electric stimulation and lesions in the brain stem of monkey. In M. B. BENDER(Ed.), The Oculomotor System, Hoeber, New York, 1964, pp. 81-140. 3 BERKOWITZ, E., AND SILVERTONE,T., Studies of the cortical eye motor fields of the cat, Fed. Proc., 15 (1956) 16. 4 BRUClqER,J. M., L'Aire Oculogyre Frontale du Singe, Arscia, Bruxelles, 1964, 302 pp. 5 CLAES, E., Contribution ~ l'6tude physiologique de la fonction visuelle. II. l~tude des centres oculomoteurs corticaux chez le chat non anesth6si6, Arch. int. PhysioL, 48 (1939) 238-259. 6 CLARK, LEG. W. E., AND BOGGON, R. H., On the connections of the medial cell groups of the thalamus, Brain, 56 (1933) 83-98. 7 CROSBY,E. C., Yoss, R. E., ANDHENDERSON,J. W., The mammalian midbrain and isthmus regions. Part IlI. The fiber connections. D. The pattern for eye movements on the frontal eye field and the discharge of specific portions of this field to and through midbrain levels, J. comp. Neurol., 97 (1952) 357-383. Brain Research, 22 (1970) 1-13
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8 DELGADO, J. M., AND LIVINGSTON, R. B., Motor representation in the frontal sulci of the cat, Yale J. Biol. Med., 28 (1955) 245-252. 9 ELIASSON, S. G., The role of visual impulses in the control of eye muscle activity, Exp. Neurol., 16 (1966) 279-288. 10 FERRIER, D., The localization of function in the brain, Proc. roy. Soc. B, 22 (1874) 229-232. 11 FE~RIER, D., Experiments on the brains of monkeys, Proc. roy. Soc. B, 23 (1875) 409-430. 12 GAROL, H. M., The ~motor cortex' of the cat, J. Neuropath. exp. Neurol., 1 (1942) 139-145. 13 HASSLER, R., UND MUHs-CLEMENT, K., Architektonischer Aufbau des sensomotorischen und parietalen Cortex der Katze, J. Hirnforsch., 6 (1964) 378-420. 14 HITZIG, E., Untersuehungen fiber daM Gehirn, Hirscbwald, Berlin, 1874, 276 pp. 15 HUGHES, J. R., Studies on the supracallosal mesial cortex of unanesthetized, conscious mammals. I. Cat. A. Movements elicited by electrical stimulation, Eleetroenceph. clin. Neurophysiol., 11 (1959) 447-458. 16 HUGHES AND MAZUROWSKI, Studies on the supracallosal mesial cortex of anesthetized, conscious mammals. II. Monkey. Movements elicited by electrical stimulation, Electroenceph. clin. Neurophysiol., 14 (1962) 477-485. 17 JANSEN, J., JR., ANDERSEN. P., AND KAADA, B. R., Subcortical mechanisms in the 'searching' or 'attention' response elicited by prefrontal cortical stimulation in unanesthetized cats, Yale J. Biol. Med., 28 (1955) 331-341. 18 JEANNEROD, M., KIYONO, S., ET MOURET, J., l~ffets des 16sions frontales bilat6rales sur le comportement oculo-moteur chez le chat Vision Res., 8 (1968) 575-583. 19 JUNG, R., Discussion. In M. B. BENDER (Ed.), The Oculonzotor System, Hoeber, New York, 1964, p. 278. 20 LIVINGSTON, R. B., Localization of frontal oculomotor cortex in the cat, Fed. Proc., 9 (1950) 395-396. 21 LOEWENFELD, I. E., AND ALTMAN, R., Variations of Horsley-Clarke coordinates in cat brains, J. Neuropath. exp. Neurol., 15 (1956) 181-189. 22 MORIN, G. DONNET, V. MAFFRE, S., ET NAQUET, R., Sur les troubles de la vision consecutifs aux d6cortications frontales chez le chien, J. Physiol. (Paris), 43 (1951) 825-826. 23 NARKIEWICZ, O., AND BRUTKOWSKI, S., The organization of projections from the thalamic mediodorsal nucleus to the prefrontal cortex of the dog, J. cutup. Neurol., 129 (1967) 361-374. 24 REINOSO-SUAREZ, F., Topographischer Hirnatlas der Katze fiir Experimental-Physiologische Untersuchungen, Merck, Darmstadt, 1961. 25 ROBINSON, D. A., AND FUCHS, A. F., Eye movements evoked by stimulation of frontal eye fields, J. Neurophysiol., 32 (1969) 637-648. 26 RosE, J. E., AND WOOLSEY, C. N., The orbitofrontal cortex and its connections with the mediodorsal nucleus in rabbit, sheep and cat, Res. Publ. Ass. herr. meEt. Dis., 27 (1948) 210-232. 27 SCHLAG-REY, M., AND LINDSLEY, D. B., Effect of prefrontal lesions on trained anticipatory visual attending in cats, Physiol. Behav., in press. 28 SCOLLO-LAvIZZARI, G., Anatomische und physiologische Beobachtungen fiber daM frontale Augenfeld der Katze, Helv. physiol, pharmacol. Acta, 22 (1964) C42-C43. 29 SCOLLO-LAvIZZARI, G., AND AKERT, K., Cortical area 8 and its thalamic projection in Maeaca mulatta, J. comp. Neurol., 121 (1963) 259-270. 30 SMITH, W. K., Electrically responsive cortex within the sulci of the frontal lobe, Anat. Rec., 76, Suppl. (1940) 75-76. 31 SPIEGEL,E. A., AND SCALA, N. P., The cortical innervation of ocular movements, Arch. Ophthal., 16 (1936) 967-981. 32 SYCHOWA,B., STEPIEN, L., AND STEPIEN, I., Degeneration in the thalamus following medial frontal lesions in the dog, Acta Biol. exp. (Warszawa), 28 (1968) 383-399. 33 SZENT.g,GOTHAI, J., Recherches exp6rimentales sur les voies oculogyres, Sere. H6p. Paris, 26 (1950) 2989-2995. 34 WAGMAN,I. H., Eye movements induced by electric stimulation of cerebrum in monkeys and their relationship to bodily movements. In M. B. BENDER (Ed.), The Oculomotor System, Hoeber, New York, 1964, pp. 18-39. 35 WARREN, J. M., WARREN, ]7[., AND AKERT, K., Orbitofrontal cortical lesions and learning in cats, J. cutup. Neurol., 118 (1962) 17-41. 36 WINKLER, C., AND POTTER, A., An Anatomical Guide to Experhnental Researches of the Cat Brain, Versluys, Amsterdam, 1914.
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37 WOOLSEY, C. N., SETTLAGE, P. H., MEYER, D. R., SENCER, W., PINTO HAMUY, T., AND TRAVIS, A. M., Patterns of localization in precentral and 'supplementary' motor areas and their relation to the concept of a premotor area, Res. PubL Ass. nerv. ment. Dis., 30 (1952) 238-264.
Brain Research, 22 (1970) 1-13
1
Research Reports I N D U C T I O N OF O C U L O M O T O R RESPONSES BY E L E C T R I C A L S T I M U L A T I O N OF T H E P R E F R O N T A L C O R T E X IN T H E CAT
J. SCHLAG AND M. SCHLAG-REY
Departments of Anatomy and Psychology and Brain Research Institute, University of California, Los Angeles, Calif. 90024 (U.S.A.) (Accepted February 16th, 1970)
INTRODUCTION
The cortical frontal eye field (FEF) has been defined as that region of the frontal lobe which gives rise upon stimulation to conjugate ocular movements often accompanied by rotation of the head10,11,14. It has been most extensively studied in the monkey where its location, its correspondence with cytoarchitectural subdivisions, its connections with the thalamus, and the motor effects of its stimulation or destruction have been well explored. Comparatively, much less information is available for the cat and this information is not always consistent. By electrical stimulation, Spiegel and Scala al, Claes 5, Garo112, and Eliasson 9 induced ocular movements from a rather vaguely outlined region of the anterior sigmoid gyrus. Szent/tgothai a3 included the gyrus proteus in the excitable area and Smith z° added the most medial sector of the anterior sigmoid gyrus hidden within the cruciate sulcus. These data imply the existence of a FEF without giving much information on its extent: whether it covers the whole medial region anterior to the cruciate sulcus or a particular portion of it. Some attempts were made to trace the boundaries but the results were not consistent. Whereas Garol lz pointed to a strip of the anterior sigmoid gyrus on the outer surface of the brain, Livingston 20 and Berkowitz and Silvertone 3 located the F E F on a small area of interhemispheric cortex just under the cruciate sulcus (see also refs. 8, 15 and 17). In contrast, Scollo-Lavizzariz8 obtained ocular movements by stimulating laterally within the depth of the presylvian sulcus. Most reports cited were just short abstracts whereas the few full-length articles were only incidentally concerned with the problem of localization. The procedures of stimulation, criteria of responses, and/or anatomical findings were generally insufficiently described to permit an evaluation of the results themselves and of the discrepancies between them. Therefore, it is not surprising that the delineation of a F E F in the cat is still considered as an unresolved question 19. Confronted by the practical necessity to decide where electrodes or lesions should be placed for electrophysiological and behavioral z7 studies on the cat's Brain Research, 22 (1970) 1-13
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J. SCHLAG AND M. SCHLAG-REY
FEF, we were forced to admit that the literature did not provide firm indications. Therefore, we undertook to determine the F E F territory as accurately as possible under specified conditions of minimal stimulation. The old-time procedure of cortical stimulation and visual observation of the motor effects seemed to be most appropriate, for it revealed all and any responses, and was relatively free of artifacts. METHODS
These experiments were performed on 14 cats, all surgically prepared under ether anesthesia, and maintained in a stereotaxic apparatus. The spinal cord was completely transected by suction above the C1 level except in one case where the section was made between C4 and Cz (in this case, control of the neck musculature was retained and the body of the animal, lying on a board which could rotate around a vertical axis centered on the neck, could freely turn sideward with respect to the fixed head). The cerebral cortex was widely exposed and immediately covered with mineral oil continuously warmed to about 38°C. The body temperature was maintained by a heating pad. All sites of incision and the pressure points of the stereotaxic headholder were infiltrated with lidocaine. The volume of air supplied for artificial respiration was continuously adjusted to induce either a complete immobility of the eyes with fissurated and oblique pupils, or an active visual exploration with 4-5 mm wide pupils, or else any intermediate state. Shifts from an extreme state to the other could be achieved in less than one min by altering the respiration. But they also occurred spontaneously. The fact that the animals periodically fell in phases of ocular immobility and nonreactivity, indicative of sleep, was taken as clear evidence that they were not suffering. In 2 of the 14 cats, unilateral cortical lesions were performed by suction under sterile conditions one or two weeks prior to the terminal experiment. No infection developed. The rationale of these lesions is presented in the text. The lesions themselves are illustrated in Figs. 3 and 4. Routinely, short trains of 400/sec square pulses of 0.5 msec duration were used to stimulate the cerebral cortex (529 sites). They were applied through concentric electrodes stereotaxically implanted. The 0.15 mm diameter central stainless steel wire, exposed only at the tip and protruding from a 22 gauge needle by 0.4-0.8 mm, was always the cathode. The current of stimulation (50-600 /zA, but usually less than 200 /~A) was continuously monitored on a 502 Tektronix CR oscilloscope. This current and the duration of the trains (25-400 msec) were adjusted at each placement to obtain just suprathreshold immediate effects. Therefore, the ocular responses were practically always small in amplitude. The movements produced were visually observed. Tests were repeated from 10 to about 50 times at each site to evaluate the consistency of the responses and establish their nature. For this purpose, it was found useful to apply the stimulations when the eyes were spontaneously resting at different positions. In addition, the tests were run at different levels of alertness as judged from the diameter of the pupils, the spontaneous fluctuations of the gaze, and, in 4 cats, the E E G recordings. Due to Brain Research, 22 (1970) 1-13
FRONTAL EYE FIELD IN THE CAT
3
the length of each test, a maximum of only 6 or 7 tracks could be explored per animal. In a few cases, recordings with silver-silver chloride electrodes were made from the eyeball, mainly to measure the latency and duration of the displacements. But the method proved to be inadequate to detect ocular movements (and much less their direction) because of possible contamination of the records by E M G activity from various parts of the face. The Reinoso-Su~trez atlas of the cat's brain 24 was initially used to guide the placement of the stimulating electrodes. However, considerable variations in stereotaxic coordinates were found between animals in spite of their similarity in size and weight (3-4 kg). For instance, the position of the cruciate sulcus ranged from A23.3 to A29.0 and from H + 11.0 to H + 14.6. Such a wide dispersion apparently is normal 21. To compare the results between animals, it was found most convenient to estimate the coordinate positions with respect to the medial end of the cruciate sulcus. This procedure gave the maximal consistency between coordinate measurements and the general aspect of the histological images. Reference points were marked along each track by electrolytic iron deposits and potassium ferrocyanide reaction. The histological sections were stained with thionine. RESULTS
Type of ocular response All the movements described were saccadic. Slow movements of the pursuit type sometimes followed stimulation. They were not retained for analysis because their inconsistency made it impossible to ascertain that they were not spontaneous. The most common (i.e. 55 ~ of 180 responsive sites) ocular movement elicited by prefrontal stimulation (and also by other cortical stimulation, e.g. of the marginal gyrus) was centering: the gaze returned to center from any off-center position without overshooting, giving the impression of focused visual attention. Such movements could easily pass unnoticed unless the eyeballs were deviated prior to the stimulation. Sometimes they were accompanied by a transient and slight opening of the eyelids. A variant of the eye centering response (20 ~ ) was characterized by the fact that the gaze could come back to center from any off-center position except one. That this may be of functional significance is suggested by the frequent finding that, close to such a site of stimulation, a deviation from midposition could be elicited in that same direction from which return had not been obtained. Practically always, centering was observed in the vicinity of all sites producing ocular deviation. Conjugate ocular deviation in a selective direction was less frequent (25 ~ ) than centering. They lasted for at least the duration of the stimulation after which the eyes most often returned to their original position in the same brisk way and sometimes with a delay. A priori, this type of movement was considered more specific and, therefore, more interesting than centering from which it differed either by its overshooting beyond the central position or by its bypassing it. On 3 occasions (3 sites of stimulation in different animals), the eyes were first centered before deviating,
Brain Research, 22 (1970) 1-13
4
J. SCI-ILAG AND M. SCI-ILAG-REY
the two steps occurring in rapid succession (this has also been noticed upon brain stem stimulation2). We recorded as true deviations only those movements which drove the eyes away from the midposition and unequivocably in the same direction. When any doubt remained, the responses were considered as centering, thereby certainly introducing a conservative bias in our evaluation. Hesitation was due mainly to the changes in responsiveness apparently dependent on the level of vigilance. Often an ocular deviation, obvious when the cat was awake, could become a centering response as soon as the pupils contracted and the E E G rhythms slowed down z4. A response could even then fail to appear (Fig. 1). Although this suggests that all observations should be made on fully awake animals, it should be realized that the eyes of such animals wander around, exploring the environment and making the identification of a response difficult. We tried to make our assessments in intermediate states of relative ocular
A
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Fig. 1. Disappearance of ocular deviation during drowsiness. Stimulus : 400/sec pulses of 0.5 msec duration, 100 pA, for 400 msec, applied close to the medial bank of the presylvian gyrus. Monofocal E E G recordings from contralateral anterior marginal (Ma) and posterior sigmoid (PS) gyri. AC recording of ocular movement monitored through silver ball electrodes applied on both sides of ipsilateral eye (E). Movement was conjugate oblique (ipsiversive and upward) deviation. A and B stimulations separated by 17 sec. Pupils 1 mm wide in A, completely constricted in B; changes were spontaneous. Brain Research, 22 (1970) 1-13
FRONTAL EYE FIELD I N THE CAT
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6
J. SGHLAG AND M. SCI-ILA.G-REY
immobility. Such states could be introduced by fine adjustments of the respiration, but they never lasted very long. Despite these difficulties, there were many unambiguous instances of ocular deviation. Some particular observations deserve mention in this respect: Several times, the eyes could be moved stepwise past the midposition by brief trains applied about every 1/2 sec. In three cats, two electrodes had been implanted simultaneously and alternated displacements in opposite directions were elicited by stimulating the two sites successively. In one cat, contraversive deviation was produced repeatedly with perfect consistency from the same site during a 4 h period. And in the animals with the C3-C4 spinal transection, ocular deviations towards any side were always accompanied by a lateral displacement of the body toward this side (see Methods). The direction of a deviation was specific for a given type of stimulation in a given animal. Displacing the stimulating electrode by 1 mm could sharply alter this direction. Stimulus locations were found for upward, downward, oblique, ipsiversive, and most frequently, contraversive movements (Fig. 2). Movements limited to one eye were rarely seen. They always concerned the contralateral eye and they consisted in either a slight deviation or withdrawal of the eyeball into the orbit. Often they were difficult to ascertain, because of concomitant facial twitches. Convergent movements were suspected more than once, but they were never easily repeatable. Threshold
Clear responses were obtained with as little as 50 #A pulses (in 200 msec trains) or with trains as short as 25 msec (of 200 #A pulses). The threshold was a function of both current magnitude and duration of trains; it increased for frequencies of stimulation under 100/sec. As said above, the type of response elicited depended on the cat's state of wakefulness. This was a matter of degree in responsiveness, for true deviation which gave place to centering when the animal fell asleep could be reestablished by augmenting the current strength. In Fig. 2, such responses have been indicated as deviations (small arrows). The intensity of stimulation could affect the probability of occurrence of a response. Quite generally, 200/zA pulses in 200 msec trains were more than sufficient to elicit eye movements. But, wherever stimulation of that strength yielded no result in an awake cat, increasing the current by as much as 5 times was no more effective. The fact that responses appeared, disappeared, or changed in direction in a span of less than 1 mm should be attributed to the design of the electrodes (particularly to the short interpolar distance). Since variations in the sites of stimulation seemed more determinant than changes in current strength, the experimental conditions were likely suitable for providing valid data on localization. Stimulus location
The maps of Fig. 2 show the distribution of prefrontal points from where ocular responses were elicited. These are raw data, and only those gathered along Brain Research, 22 (1970) 1-13
FRONTAL EYE FIELD IN THE CAT
7
tracks histologically identified in their entire length have been plotted. The coronal sections are less than 1 mm from each other; this has to be realized to appreciate the close proximity of the tracks along sagittal planes too. For clarity of presentation, it was necessary to limit the number of symbols used, thereby conveying much less information than actually available. No ocular movements were produced from the posterior sigmoid gyrus, from the buried part of the anterior sigmoid gyrus, from a 2 mm band of the same gyrus just in front of the cruciate sulcus, or from the medial part of the frontal pole under the level of sulcus genualis. At these places, responses were absent even at intensities of stimulation as much as 5 times the threshold values for responses elicited along the same or close tracks. Laterally to the presylvian sulcus, ocular responses were intermingled with - - and progressively gave place to - - facial movements: closing of eyelids, twitching of the nose, opening or closing the jaw, protruding or retracting the tongue, moving the ears (see also Delgado and Livingston8). Most of these facial responses (labeled F or B) were contralateral, but it was incidentally observed that ipsilateral responses (e.g. B : blinking) were obtained from points immediately ventral to those giving contralateral responses. Eye movements were induced from the bottom and the banks (mainly the lateral one, rostrally) of the presylvian sulcus. True deviations were obtained when the electrode reached the gray matter of that folding. The area where stimulation was effective extended medially to the mesial face of the hemisphere above the level of sulcus genualis. The vertical penetration in this region was rather abrupt; it corresponded fairly well to the limit between the cortex of the anterior sigmoid gyrus and the subjacent white matter. In the 1-2 mm wide lamina of the corona radiata at that level run fibers which may connect with various parts of the frontal pole. The fibers responsible for ocular responses could come from the presylvian region, the gyrus proreus, or the rostral mesial wall of the hemisphere. That this mesial cortex itself was involved is suggested by the fact that movements were produced from electrodes running directly through it. The distribution of responses presented in Fig. 2 is not inconsistent with the hypothesis of two fields: one mesial, the other presylvian. On the possibility of establishing distinctions between them, the following observations were made: (1) no single region had a lower threshold within the whole territory; (2) no systematic difference has been detected in terms of direction of induced movements; (3) unilateral movements were elicited only from the lateral bank of the presylvian sulcus; (4) lid opening was frequent with mesial stimulation, whereas lid closure occurred only with presylvian stimulation; (5) eye centering accompanying arousal in animals with fissurated pupils was more often obtained with mesial stimulation; (6) shortest latency movements (evaluated at less than 30 msec by a technique which, admittedly, was not error-proof) were all of presylvian origin whereas 50-150 msec latency movements could be elicited from either regions; and (7) the two regions were united by a bridge of excitable cortex on the upper part of gyrus proreus (the first section in Fig. 2 actually is a cut through that proreal cortex). In one cat, the cortex of the rostral mesial face had been unilaterally removed Brain Research, 22 (1970) 1-13
8
J. SCHLAG AND M. SCHLAG-REY
b y suction one week before testing (Fig. 3). Eye m o v e m e n t s , including true deviations, were readily elicited f r o m p o i n t s at the lateral b o r d e r o f the lesion. These responses c o u l d n o t be a t t r i b u t e d to the s t i m u l a t i o n o f the mesial wall. In a n o t h e r a n i m a l , the presylvian region was u n i l a t e r a l l y d e s t r o y e d by suction two weeks before testing.
Fig. 3. Responses evoked 1 week after a unilateral lesion of the mesial interhemispheric wall. Tissue defect indicated by oblique-lined area. Symbols as in Fig. 2.
Fig. 4. Responses evoked 2 weeks after a unilateral destruction of the presylvian region. Tissue defect indicated by oblique-lined area. Symbols as in Fig. 2. Brain Research, 22 (1970) 1-13
FRONTAL EYE FIELD IN THE CAT
9
The histological sections showed that the ventroposterior cortex of the presylvian gyrus had been spared (Fig. 4). Rostrally, the medial border of the lesion reached the mesial cortex, certainly interrupting the connections of the remaining bit of gyrus proreus and of the most rostral portion of the mesial wall itself. Nevertheless, ocular responses were produced from more caudal points of the mesial sector, at sites which were separated from the still intact presylvian region by the lesion. For all practical purposes, the mesial oculomotor area can be easily reached by implanting electrodes 0-3 m m behind the cruciate sulcus and 4-7 m m under its horizontal level at 1 or 2 m m from the midline. For the presylvian area, the electrodes should be moved 2 or 3 m m more laterally and 2 or 3 m m deeper; however, some searching may be needed and, unfortunately, testing cannot be done under anesthesia.
Effect of anesthesia Anesthetics were administered at the end of 6 experiments. Small doses of Nembutal (as low as 3 mg/kg i.v.) were found sufficient to suppress all responses of deviation and centering. Chloralose (500-100 mg/kg i.v.) stopped spontaneous movements; deviations were absent although centering could persist. DISCUSSION
The cat's prefrontal region is so small that it is difficult to experiment on any of its parts without involving the other parts. This is probably the reason why previous attempts to locate a F E F have yielded divergent if not conflicting results as shown in the introduction. Effects due to the spread of stimulating current can be expected if intensities as large as 10 m A are used 15. They may occur especially if the electrodes are far apart. In this study, stimulation was minimal and several arguments presented with the results suggested that it remained very localized around the tip of the electrodes. Negative results were useful: they served to delineate rather sharply a zone of low-threshold responsiveness. This is significant in view of the possible claim that, in the cat as in the monkey 3~, eye movements can be induced from almost anywhere on the cortex if sufficient intensities (much higher than those used in this study) are provided. The bottom and the banks of the presylvian sulcus appeared as the most obvious portion of the low-threshold zone determined. Some doubt existed about the interpretation of responses obtained from the white matter situated immediately dorsomedially. But particular features, and mainly the results obtained after surgical elimination of the presylvian region, indicated that the cortex of the rostro-mesial wall is also concerned with ocular motricity. The presylvian and mesial regions are united by a narrow strip of excitable proreal cortex. What could this prefrontal organization correspond to in the monkey's brain? The cat's presylvian area from which eye movements could be induced is very close to the m o t o r representation of the face. In several, though not in all, cases ocular and other facial responses were elicited together. In the monkey, Wagman 34
Brain Research, 22 (1970) 1-13
10
J. SCHLAG AND M. SCttLAG-REY
stated that the F E F 'blends into the hand-arm-shoulder area' and this blending appears such that Woolsey et al. z7 represented the F E F as a part of the simunculus in their classical figurine of the motor cortex. However, it is generally admitted that no eye representation exists in area 4 itself (with the exception of Beevor and Horsley's study on the orang outangl). The monkey's F E F seems to correspond approximately with area 8 which receives projections from the paralamellar sector of the thalamic mediodorsal nucleus 29. Cytoarchitectural divisions of the cat's prefrontal cortex are not agreed upon : area 8 was located on the rostral orbital gyrus by Winkler and Potter 36, on the proreal gyrus by Reinoso-Su~trez24, and within the presylvian sulcus by Scollo-Lavizzari ~s. If there is any analogy between the primate and carnivore brain, the latter position would seem the most likely: it is just rostral to area 6 (ref. 13) at the height of the motor representation of the face. Anatomical studies of thalamocortical relations are in agreement with this view since the lateral portion of nucleus medialis dorsalis has been claimed to project upon the dorsolateral portion of the orbitofrontal cortex6,23,z6, 3s. Therefore, we submit that the presylvian region outlined in this study corresponds to the cat's FEF, as originally proposed in a short note by ScolloLavizzari zs. The significance of the area of mesial cortex situated between the cruciate and genual sulci is more difficult to assess. For Rose and Woolsey 26 and Warren et al. 35, it does not receive projections from nucleus medialis dorsalis, whereas for Sychowa et al.32, such projections exist and, furthermore, they are coming from the most lateral portion of the nucleus. At the present time, no definite conclusion can be drawn: either this mesial area is an actual part of the F E F (e.g. corresponding to one of the two representations of eye movements in the monkey's prearcuate region according to Crosby et al. 7 and Brucher4), or it is homologous to other simian areas (e.g. laterodorsal prefrontal cortex or interhemispheric cortex~6), or else there is no real equivalence to be traced. Behavioral deficits analogous to some of those provoked by F E F destruction in monkeys have been obtained after frontal lobotomies in dogs 22. In cats Jeannerod et al. 18 found oculomotor dysfunctions and Schlag-Rey and Lindsley 27 observed deficits in visual attending following lesions limited to the prefrontal areas from where eye movements were elicited in the present study. Our results did not reveal any consistent topographic organization in terms of direction of eye movements induced (Fig. 2), despite the fact that direction of an evoked saccade depended strictly on where the cortex was stimulated in any given animal. This may seem to be at variance with results obtained in monkeys. However, the published monkey's F E F maps, each of which has a good deal of internal consistency, show considerable disagreement between each other4,7,25, 34. As far as the cat is concerned, we feel that the F E F is not compartmentalized according to the direction of saccades evoked by short stimulations. But the cat's F E F as a whole appears to be a well delineated territory.
Brain Research, 22 (1970) 1-13
FRONTAL EYE FIELD IN THE CAT
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SUMMARY The p r e f r o n t a l cortex o f the cat (enc6phale isol6 p r e p a r a t i o n ) was e x p l o r e d using m i n i m a l electrical s t i m u l a t i o n in o r d e r to locate as exactly as possible the critical regions f r o m which r a p i d o c u l a r m o v e m e n t s could be induced. T w o such regions have been f o u n d : one on the mesial face o f the h e m i s p h e r e u n d e r the cruciate sulcus, the o t h e r within the p r e s y l v i a n sulcus. The extent o f these zones a n d their functional characteristics are described. The p r o b l e m o f the o r g a n i z a t i o n o f a f r o n t a l eye field in the cat is discussed with reference to the m o n k e y . ACKNOWLEDGEMENTS W e are very i n d e b t e d to M r . D. K u r o d a for his technical assistance, to Miss C. R u c k e r for the histological p r e p a r a t i o n s , a n d to Miss K. Tani for the drawings. This w o r k was s u p p o r t e d in p a r t b y U.S. Public H e a l t h Service G r a n t s R0104955-06, 2K3-NB21633-06, 5F03-MH37993-02, a n d 1P01-NB08552-01. NOTE ADDED AFTER SUBMISSION A t the time o f this writing, a p a p e r b y R. H a s s l e r : E x t r a p y r a m i d a l m o t o r areas o f cat's f r o n t a l l o b e : their f u n c t i o n a n d architectonic differentiation, bit. J. Neurol., 5 (1966) 301-306, h a d escaped o u r attention. A c t u a l l y , u n d e r this title, H a s s l e r ' s p a p e r essentially concerns cortically i n d u c e d eye m o v e m e n t s . The d a t a on l o c a l i z a t i o n agree r e m a r k a b l y well, except for the a r e a 6 o f the a n t e r i o r s i g m o i d gyrus which we f o u n d c o m p l e t e l y unresponsive in o u r experiments. Hassler f o u n d some system a t i z a t i o n in the cortical r e p r e s e n t a t i o n o f direction o f m o v e m e n t . H o w e v e r , the results c a n n o t be c o m p a r e d directly because o f differences in the size o f electrode tips, in frequency a n d d u r a t i o n o f stimulation.
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