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Subcortical structures mediating the attention response induced by amygdala stimulation
EXPERIMENTAL
2, 109-122
NEUROLOGY
Subcortical Response
(1960)
Structures Mediating Induced by Amygdala HOLGER URSIN
Neuro~hysiological
AND
Laboratory,
the Attention Stimulation
BIRGER R. KAADA~
Anatomical
Institute,
University
of Oslo,
Oslo, Norway Received
January
4, 1960
Electrical stimulation of the amygdaloid nuclear complex in unanesthetized freely moving cats elicits a characteristic searching or attention response. Attempts have been made by combined stimulation-ablation techniques to determine the subcortical structures through which this response is mediated. The only lesion which eliminated the attention response was an almost complete vertical circumcision of the amygdala with interruption of the connections irradiating in the anteromedial, medial, and posteromedial directions. Selective section of any of these connections by lesions placed either anteromedially, medially, or posteromedially to the amygdala, in various combinations, were ineffective. It is concluded that the attention response is mediated through several pathways to widespread subcortical areas. Bilateral lesions of various subcortical nuclei onto which the amygdala is known to project did not abolish the attention response. Such lesions destroyed in various combinations the almost entire thalamus (including all mid-line and intralaminar nuclei), the subthalamus, extensive parts of the hypothalamus (including nucleus ventromedialis), and the preoptic area, the septal nuclei, the reticular formation, and the rostra1 half of the periaquaeductal gray matter of the midbrain, the pretectal area, the superior colliculi, the habenula, the substantia nigra, and the red nuclei. It is suggested that the amygdaloid attention response is mediated through several of these subcortical areas which could not be eliminated in toto in one and the same animal, because such extensive lesions were not compatible with survival. Introduction
Electrical stimulation of the amygdaloid nuclear complex in unanesthetized animals elicits a characteristic pattern of behavior which has variously been termed “the arrest reaction” (16, pp. 106-l 10; 26) and the 1 The research reported the Norwegian Research by the Air Force Office of Command, United States No. AF 61 (514)-1127.
in this communication has been sponsored in part by Council for Science and the Humanities, and in part Scientific Research of the Air Research and Development Air Force, through its European Office, under contract 109
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AND
KAADA
“searching” or “attention” response (3, 10, 18, 27, 29, 30). The same type of behavior response may also be obtained on stimulation of certain areas of the cerebral cortex of the medial, basal, and lateral aspects of the hemisphere.2 Various components of the complex behavior pattern may be distinguished (5, 30). First, there is an immediate arrest of all the animal’s spontaneous occupation such as walking, licking, side-to-side movements of the tail, and shivering. Second, there are outward manifestations of increased alertness or arousal. The animal raises its head, the eyes open and the pupils dilate slowly, the ears erect, and the facial expression and whole attitude of the animal change to one of attention. Even a sleeping animal, within a few seconds of stimulation, may appear awake, alert, and vigilant. The arousal is associated with desynchronization of the electrocortical activity (30). The third component consists of orienting movements. The animal looks around with quick glancing or searching movements in an inquisitive manner, almost invariably towards the contralateral side. Occasionally there are pricking and directional movements of the ears. On stimulation of the amygdala with higher intensities, additional signs may develop, simulating either fear or anger. The behavioral attention response was obtained mainly from the basal and lateral nuclei of the amygdaloid complex, seen in Fig. 1 (30). The responsive zone could be traced medially through the region of the central nucleus of the amygdala and into the ventromedial part of the internal capsule. This medial extension of the positive sites seemed to coincide with the location of fibers, described by Fox (6), coursing through the basal and lateral nuclei and then medially in the region of the central nucleus to the entopeduncular nucleus (Fig. 2, c). In addition to these telencephalic areas, a similar attention or arousal response has been recorded on stimulation of diencephalic and mesencephalic structures. Thus, Akert (2) briefly reported on a similar type of behavioral response, consisting of a slow turning of the head towards the contralateral side, on stimulating the intralaminar nuclei and the adjacent dorsomedial and anterior thalamic nuclei. This has been confirmed by Kaada and Bruland ( 19). Jansen, Andersen, and Kaada ( 13) have shown that the attention response elicited from the medial frontal cortex can be abolished by subcortical electrolytic lesions which include the anterior basal part of the internal capsule on the same side, or by lesions destroying bilaterally part of the intralaminar nuclei of the 2 For
review
and
references,
see Fangel
and
Kaada
(5).
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thalamus, notably nuclei centralis medialis, paracentralis, and centralis lateralis. The method employed was to implant needle electrodes in the responsive cortical field and, on the following days, to make various subcortical lesions followed by repeated cortical stimulation.
p. lot.
p. med.
q
attention
.
no
attention
FIG. 1. Frontal sections through the amygdala in cats indicating points (open squares) from which the behavioral attention response has been produced by electrical stimulation. Dots, no such response. Section C corresponds to the frontal plane shown in E; A, rostral; and D, caudal end of amygdala. From Ursin and Kaada (30).
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From the mesencephalicportion of the reticular substancea behavioral arousal response may be readily elicited on stimulation in the unanesthetized monkey (28) and cat (19, 24). Hassler (12) observed contraversive searching movements in cats on stimulating a fairly narrow zone extending from the entopeduncular nucleus and adjacent portion of the internal capsule rostrally and continuing posteriorly through the zona incerta and the subthalamic nucleus into the region of the tegmenturn and reticular formation of the mesencephalon.As mentioned above, the responsive amygdaloid zone was found to extend medially into the region of the entopeduncular nucleus. Thus, there is a possibility that this zone continues caudally into the field mapped by Hassler. In the present study, using a similar stimulation-ablation technique as described above, attempts have been made to determine those subcortical structures whose integrity is necessary for the elicitation of the amygdaloid attention response. Particular interest was devoted to the thalamic nuclei, the reticular formation and hypothalamus, and other subcortical areas upon which the amygdala is known to project. Further, particular attention was paid to the various known fiber tracts irradiating from the amygdala to the diencephalon and brain stem. Some of the findings have been presented in a preliminary report (20). FIBER PROJECTIONS FROM THE AMYGDALA
The principal projections of the amygdaloid nuclear complex which will have to be taken into account are as follows: (a) The stria terminalis emergesfrom the amygdala in a dorsolateral direction (Fig. 2), and in the cat it appears to contain exclusively efferent fibers with respect to the amygdala (7). The fibers are distributed mainly to the septal, preoptic, and hypothalamic areas. Some fibers possibly also reach the habenula by way of the stria medullaris.3 (b) The longitudinal association bundle (Fig. 2, 1.b.) contains, besidessome intra-amygdaloid association fibers, a larger projection bundle which courses in an anteromedial direction towards the bed nucleus of the stria terminalis in the region of the anterior commissure,the nucleus accumbens, and the medial forebrain bundle (6, 7). Some of its fibers seem to end in the preoptic area (6). (c) A diffuse fiber system radiating from the amygdala in a medial direction towards the entopeduncular nucleus (see above), the hypothala3 For contradictory
results, see Adey and Meyer (1).
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mus, and the preoptic region has been described by various authors (4, 6, 15, 2.5). According to Fox (6) some of these fibers form a more distinct fiber bundle (Fig. 2, c) which appears to correspond to the MV bundle described by Fukuchi (9). (d) Kappers, Huber, and Crosby (2 1) have described an efferent pathway of the amygdala in the diagonal band of Broca distributing fibers to the piriform cortex, the tuberculum olfactorium, and septal areas. nut.
FIG. 2. Frontal section through the middle of the amygdala in the kitten. Note the medially coursing fibers (c) which cut across the commissural component of the stria terminalis. Cajal preparation; after Fox (6; Fig. 25).
(e) An amygdalothalamic path running to the dorsomedial thalamic nucleus, the pulvinar, and the nucleus lateralis posterior of the thalamus has been reported by Fox (8). These findings could not be substantiated in electrophysiological studies ( 11) . On the other hand, responses were recorded from nucleus ventralis medialis and some of the intralaminar nuclei (see below). (f) Amygdalomesencephalic connections have been described in the avian brain and similar projections may exist in the reptilian brain (2 1). Anatomically, such projections have not, to the authors’ knowledge, been demonstrated in the mammalian brain. In electrophysiological studies, Gloor (11) has found evidence of widespread subcortical projections of the basolateral and corticomedial subdivisions of the amygdala. The projection fields of the two subdivisions were found to overlap considerably and extended from the
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septum and the base of the head of the caudate nucleus back to the tegmentum mesencephali. They included the preoptic area, the anterior and posterior hypothalamus, the subthalamus, nucleus ventralis medialis and some of the intralaminar nuclei of the thalamus, the pretectal area, the entopeduncular nucleus, the internal capsule, and the cerebral peduncle. Material
and
Methods
In a series of seventy-five adult cats four bipolar needle electrodes, insulated except for the tips, were implanted into the amygdaloid region of each animal under Nembutal anesthesia. During the following days, in the absence of anesthesia, the freely moving cats were repeatedly stimulated using a square-wave pulse of l- to lo-msec duration and a frequency of 20 to 100 per second. In the animals in which the typical attention response was obtained, various subcortical structures were subsequently destroyed electrolytically, the electrodes being oriented by a stereotaxic instrument. Some lesions were made by means of a blunt instrument. After a complete recovery from the second anesthesia, the amygdaloid stimulation was repeated. In some animals in which the attention response remained unaltered, one or two additional lesions were made with subsequent repeated stimulation. The cats were then sacrificed and the sites of the stimulating electrodes and the extent of the subcortical lesions were identified in thionine-stained serial sections (20 u thick). Altogether such stimulation-ablation experiments were successfully completed in thirty-three animals. The remaining experiments had to be discarded from the present study, partly because no clear-cut attention response was obtained and 1 partly because several animals did not survive the fairly extensive brain-stem lesions. Results
BILATERAL LESIONS OF SUBCORTICAL NUCLEAR MASSES Thalamus. In a first series of experiments electrolytic lesions of thalamic nuclei were made. According to Jansen, Andersen, and Kaada (13), such lesions had to be bilateral in order to abolish the attention response elicited from the medial frontal cortex. Therefore, in this series of the present study the thalamic electrocoagulations were made on both sides and as symmetrical as possible. Figure 3A demonstrates such a lesion, plotted on a series of frontal sections through the brain, which was without influence on the attention response induced from
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points A’ and B’ (in Section IV) of the amygdala. The horizontally hatched areas represent the extent of the lesion on the right and left sides; the smaller horizontally and vertically cross-hatchedfield indicates the area which is common to both sides and therefore destroyed symmetrically. Figure 3B represents a summarizing chart constructed on the basis of the findings in fifteen cats having bilateral and symmetrical lesions which were without effect on the amygdaloid attention response. In each animal the lesion usually included a fairly large portion of the area shown in this figure. From the Sections II to VI in Fig. 3B, it appears that almost complete bilateral removal of all thalamic nuclei did not eliminate the amygdaloid attention response. The only thalamic areas not included in the lesions were a small portion of the most rostrolateral part of the complex (Section III) and a small portion in the region of the pulvinar (Sections V and VI). All mid-line and intralaminar nuclei and the dorsomedial nucleus were, however, destroyed. Reticular Formation and the Hypothalamus. In a second series of experiments attempts were made to eliminate the amygdaloid attention responseby bilateral lesions of the hypothalamus and the mesencephalic portion of the reticular substance (Fig. 3B). Negative results were obtained following an almost complete removal of the reticular substance of the midbrain, the subthalamus, and the dorsal portion of the hypothalamus throughout its entire length, as well as of the rostra1 parts of the ventral hypothalamus, including nucleus ventromedialis. Other Subcortical Structures. In addition to the areas mentioned above, the following structures were similarly destroyed bilaterally without influencing the attention responsefrom the amygdala (Fig. 3B): the septal nuclei posterior to the anterior commissure; a large portion of the preoptic region; the pretectal area; the rostra1 half of the periaquaeductal gray matter; the red nucleus and part of the substantia nigra; the stria medullaris and habenula; and the colliculus superior. UNILATERAL
SECTION OF THE AMYGDALOID PROJECTIONS
In a third series of experiments attempts were made to abolish the amygdaloid attention responseby ipsilateral sectioning of the projections from the amygdala in the anteromedial and posteromedial directions. In only 3 of 33 animals the responsewas obliterated, whereas it persisted unabated in the remaining 30 cats. Figure 3C is a summarizing chart
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>
5
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demonstrating the total extent of the ineffective lesions in these 30 animals. In none of them did the lesion, although usually fairly extensive in each experiment, include the projections in all directions; it was placed either anteromedial, medial, or posteromedial to the amygdala. TABLE ABBREVIATIONS
Ab, n. amygdaloideus basalis Al, n. amygdaloideus lateralis AM, n. anterior medialis AV, n. anterior ventralis CA, commissura anterior CC, corpus callosum Cd, n. caudatus Ch, chiasma opticum CI, capsula interna CL, n. centralis lateralis Cl, claustrum CS, colliculus superior Fx, fcrnix GC, griseum centrale GL, corpus geniculatum laterale GM, corpus geniculatum mediale GP, globus pallidus HL, hypothalamus lateralis Hp, hypothalamus posterior Hvm, hypothalamus ventromedialis
1 FOR FIG.
3Aa
LD, n. lateralis dorsalis LP, n. lateralis posterior MD, n. medialis dorsalis NCM, n. centralis medialis NR, n. ruber Ped, pedunculus cerebralis Pul, pulvinar PUT, putamen R, n. reticularis Ret Mes, substantia reticularis mesencephalica RPO, regio preoptica SN, substantia nigra St, stria terminalis TO, tractus opticus VA, n. ventralis anterior VL, n. ventralis lateralis VM, n. ventralis medialis VPL, n. ventralis posterolateralis VPM, n. ventralis posteromedialis
e Nomenclature according to Jasper and Ajmone-Marsan
(14)
FIG. 3. A, tracings of frontal sections through the cat’s brain. Electrical stimulation of points A’ and B’ (Section IV) within the amygdaloid nuclear complex elicited the typical attention response. This was unaffected by the bilateral electrolytic lesions indicated by the horizontally shaded areas. The vertically and horizontally cross-hatched zone indicates the regions which were common to both sides and thus destroyed symmetrically. For abbreviations, see Table 1. B, areas which were removed bilaterally without any effect on the behavior attention response induced from the amygdala. The figure represents a summary chart of lesions made in fifteen cats. C, unilateral lesions (indicated by the horizontally shaded area) and cuts which were without influence on the attention response elicited from the ipsilateral amygdala. The figure represents a summary chart of lesions made in thirty animals. D, the lesions shown to the left, drawn from three experiments, abolished the behavioral attention response elicited from the amygdala on the same side. The lesion in each of the three animals distinguished by horizontal, vertical, and diagonal hatching.
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The following fiber tracts were cut: the anterior, posterior, and hippocampal commissures; stria terminalis; stria medullaris; fimbria and fornix, with almost the entire hippocampus; most of the corpus callosum, and the white matter between the amygdala on one side and the diencephalon and brain stem on the other, including the internal capsule and the cerebral peduncle. In addition, these ipsilateral lesions included subcortical nuclear masses, such as a large part of the head of the caudate nucleus, the bed nucleus of the stria terminalis, the preoptic area, all thalamic nuclei, subthalamus, most of the hypothalamus, pulvinar, superior colliculi, mesencephalic reticular substance and periaqueductal gray, habenula, nucleus ruber, and substantia nigra. After extensive lesions of the posterior and medial fibers, the attention response was occasionally somewhat reduced or slightly altered in character. However, the imporant characteristics of the attention response, viz., the awakening effect, the lifting and moving of the head, were never abolished in these cats. In a few animals with posteromedial lesions there was a tendency to ipsilateral head movements on stimulation during the first postoperative days. This was often combined with paresis or reduced control of the musculature on the side contralateral to the lesion. However, this effect usually was a transitory one; in most of these animals the contralateral head movements, elicitable before the operation, reappeared. In order to eliminate the amygdaloid attention response it proved necessary, in one and the same animal, to perform an almost complete vertical circumcision of the amygdala on the ipsilateral side with interruption of the connections in the anteromedial, medial, as well as in the posteromedial directions. The effective lesions in the three cats are shown in Fig. 3D. Persistence of the attention response, induced from the opposite amygdala, proved that the animals were in a good condition and able to respond after the lesion. Compared with the ineffective ipsilateral lesions (Fig. 3C) there is, in the positive experiments, no additional area which is common to the three experiments and which might account for the obliteration of the response. The cuts include all projections severed in the series of ineffective ipsilateral lesions. The only difference is that in the positive experiments of Fig. 3D the lesion involves the anterior, medial, and posterior projections in one and the same animal. The possibility was considered that the elimination of the attention response in these three animals might be due to interference with the
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vascular supply of the amygdala. However, in one of these cats, which survived for 16 days after the lesion and then was killed, the cells of the amygdaloid nucleus showed no signs of anoxic cell changes. The two remaining cats died 36 and 72 hours after the final lesions. In these cats the amygdaloid cells on both sides showed changes which were attributed to postmortal autolysis. Discussion
The abolition of the behavioral attention response elicited from the amygdala by an ipsilateral circumcision anteromedial, medial, and posteromedial to this nuclear complex shows that the response is dependent on some projections coursing through these regions. However, isolated sections of varying sizes confined to either the anteromedial, medial, or posteromedial projections failed to eliminate the amygdaloid attention response. Hence, it is concluded that the response does not depend on one single subcortical projection. Apparently it is mediated through several pathways irradiating from the amygdala in a fanlike manner to various subcortical areas. In order to block the response these projections have to be interrupted in toto. The persistence of the amygdaloid attention response following fairly extensive lesions of subcortical nuclear masses, as shown in Figs. 3B and C, suggests that the response is mediated either through a small crucial area not involved in the lesions in the present experiments, or through several of the destroyed nuclear masses of the diencephalon and brain stem not removed in the one and the same animal. The results of the unilateral sections are in favor of the latter possibility. The crucial experiment would be to remove all of the subcortical tissue destroyed in the experiments of Fig. 3B. These regions include the most likely candidates looked for. Such lesions were made in several animals, but although the electrolysis in most of these experiments were carried out in two or in several stages, none of the cats survived or was left in a sufficiently good condition to allow reliable conclusions. As suggested previously (5, 17)) alertness and directed attention as a result of stimulation are probably related to a great variety of functional activities such. as sensory experience, emotions, and higher mental processes. Hence it is not surprising to find that the same behavioral pattern can be induced from fairly widespread but distinct subcortical and cortical areas. Although these diverse brain areas apparently have some common functions related to alertness and attention, it appears unlikely that these
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are the only functions these areas subserve, or that all effects mediated by them are identical. In view of the great complexity of autonomic, motor, and emotional patterns of behavior that can be induced from the amygdala on the one hand (for review, see reference 30), and the widespread connections of the amygdala with a great variety of subcortical fields on the other hand, the present results are perhaps not surprising. The strongest attention responses induced from the amygdala appear to be associated in particular with emotional reactions. On increasing the stimulus strength the attention response may assume additional features simulating either fear (resulting in flight) or anger (hissing and growling). According to Ursin and Kaada (30)) such emotional behavioral changes occurred in about one-half of the amygdaloid electrode sites yielding the attention response on weaker stimulation. Attentive behavior was occasionally also combined with sniffing, ipsilateral twitching of the face, or with various autonomic effects. Frequently, however, the attention response was the only outward manifestation resulting from stimulation. Very little is known about the subcortical pathways mediating any of these behavioral, autonomic, or motor effects elicited from the amygdala. None of them appears to be mediated via the hippocampus-fornix (30). Some of the autonomic effects, such as the uterine contractions and ovulation (22)) the depression of blood pressure and the strong respiratory inhibition (31), seem to be funneled through the ventromedial hypothalamic area. The areas for fear and anger responses, which were shown to be topographically separated within the amygdala, were both traced medially into the internal capsule (30). This is probably the main pathway for these responses, an assumption which is supported by experiments of Koikegami and Yoshida (23). According to these authors the pupillodilatatory response, which is invariably associated with the induced attention, fear, and anger, and which shows a similar distribution of the effective electrode sites as these behavior changes (30)) is probably mediated through fibers corresponding to the so-called MV and MD bundles described by Fukuchi (9). Of these, the MV bundle is the most important one; this appears to correspond to the c-fibers of Fox (Fig. 2). These observations tend to support the assumption that the behavior responses are mediated through fibers irradiating in a medial direction from the amygdala, the c-bundle being part of these fibers.
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References
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11.
ADEY, W. R., and M. MEYER, Hippocampal and hypothalamic connexions of the temporal lobe in the monkey. Brain 75: 358-384, 1952. AKERT, IL, Experimentelles zum Thema Epilepsie. Sclazeeiz. Arch. New. Psych&. 69: 365-367, 1952. ANDERSEN, P., J. JANSEN, JR., and B. R. KAADA, Electrical stimulation of the amygdaloid nuclear complex in unanesthetized cats. Acta psychiut. new. stand. 29: 55, 1952. CROSBY, E. C., and R. T. WOODBTJRNE, The comparative anatomy of the preoptic area and the hypothalamus. Res. Pub. Ass. New. Ment. Dis. 20: 52-169, 1940. FANGEL, C., and B. R. KAADA, Behavior “attention” and fear induced by cortical stimulation in the cat. Electroencephalography, Montreal, 1960 (in press), Fox, C. A., Certain basal telencephalic centres in the cat. J. Camp. Neur. 72: l-62, 1940. FOX, C. A., The stria terminalis, longitudinal association bundle and precommissural fornix fibers in the cat. J. Camp. Neur. 79: 277-295, 1943. Fox, C. A., Amygdalo-thalamic connections in Macaca wtulatta. Anat. Rec. 103: 537538, 1949. FUKUCHI, S., Comparative-anatomical studies on the amygdaloid complex in mammals, especially in ungulata. Fol. psych&. new. jap. 6: 241-262, 1952. GASTAUT, H., R. NAQUET, R. VIGOUROUX, and J. CORRIOL, Provocation de comportements Cmotionnels divers par stimulation rbinendphalique chez le chat avec electrodes a demeure. Rev. new. 86: 319-327, 1952. GLOOR, P., Electrophysiological studies on the connections of the amygdaloid nucleus in the cat. Electroencephalography, Montreal 7: 223-242; 243-264. 1955.
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HASSLER, R., Die zentralen Berl. 194: 481-516, 1956.
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JANSEN, J., JR., P. ANDERSEN, and B. R. KAADA, Subcortical mechanisms involved in the “searching” or “attention” response elicited by prefrontal cortical Yale J. Biol. 26: 331-341, 1955/56. stimulation in unanesthetized cats. JASPER, H. H., and C. AJMONE-MARSAN, “4 Stereotaxic Atlas of the Diencephalon of the Cat.” Ottawa, The National Research Council of Canada, 1954. JOHNSTON, J. B., Further contributions to the study of the evolution of the forebrain. J. Comp. New. 96: 337-481, 1923. KAADA, B. R., Somato-motor, autonomic and electrocorticographic responses to electrical stimulation of ‘rhinencephalic’ and other structures in primates, cat and dog. Acta physiol. stand. 24 (Suppl. 83): 1-285, 1951. KAADA, B. R., Cingulate, posterior orbital, anterior insular and temporal polar cortex. In “Handbook of Physiology,” J. Field, H. W. Magoun, and V. E. Hall (eds.), Vol. II, Baltimore, Williams and Wilkins Co., 1960 (ref. pp. 1345-1372). KAADA, B. R., P. ANDERSEN, and J. JANSEN, JR., Stimulation of the amygdaloid nuclear complex in unanesthetized cats. Neurology 4: 48-64, 1954.
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19. KAADA, B. R., and H. BRULAND. Blocking of the cortically induced behavioral attention (orienting) response by chlorpromazine. (In preparation), 1960. 20. KAADA, B. R., and H. URSIN, Subcortical mechanisms in the “attention” response induced from the amygdala in cats. Acta physiol. stand. 42: 79-80, 1957. 21. KAPPERS, C. U. A., G. C. HUBER, and E. C. CROSBY, “The Comparative Anatomy of the Nervous System of Vertebrates, Including Man.” New York, The MacMillan Co., 1936. 22. KOIKEGAMI, H., T. YAMADA, and K. USUI, Stimulation of amygdaloid nuclei and periamygdaloid cortex with special reference to its effects on uterine movements and ovulation. Fol. psych&. new. japon. 8: 7-31, 1954. H., and K. YOSHIDA, Pupillary dilatation induced by stimulation 23. KOIKECA~, of the amygdaloid nuclei. Fol. psych&. new. jap. 7: 109-126, 1953. 24. KUROKI, T., Arrest reaction elicited from the brain stem. Fol. psych&. new. jap. 12: 317-340, 1958. 25. LAUER, E. W., Nuclear pattern and fiber connections of certain basal telencephalic centers in the macaque. J. Comp. New. 82: 215-254, 1945. 26. MACLEAN, P. D., and J. M. R. DELGADO, Electrical and chemical stimulation of frontotemporal portion of limbic system in the waking animal. Electroencephalogruphy, Montreal 6: 91-100, 1953. 27. MAGNUS, O., and H. J. LAMMERS, The amygdaloid-nuclear complex. FoZ. psychiat. neerl. 69: 555-582, 1956. 28. SEGUNDO, J. P., R. ARANA, and J. D. FRENCH, Behavioral arousal by stimulation of the brain in the monkey. J. Neurosurg. 12: 601-613, 1955. 29. SHEALY, C. N., and T. L. PEELE, Studies on amygdaloid nucleus of cat. J. Neurophysiob 20: 125-139, 1957. 30. URSIN, H., and B. R. &4DA, Functional localization within the amygdaloid complex in the cat. Electroencephalography, Montreal (In press), 1960. 31. WOOD, C. D., B. SCHOTTELIUS, L. L., FROST, and M. BALDWIN, Localization within the amygdaloid complex of anesthetized animals. Neurology 8: 477-480, 1958.
2, 109-122
NEUROLOGY
Subcortical Response
(1960)
Structures Mediating Induced by Amygdala HOLGER URSIN
Neuro~hysiological
AND
Laboratory,
the Attention Stimulation
BIRGER R. KAADA~
Anatomical
Institute,
University
of Oslo,
Oslo, Norway Received
January
4, 1960
Electrical stimulation of the amygdaloid nuclear complex in unanesthetized freely moving cats elicits a characteristic searching or attention response. Attempts have been made by combined stimulation-ablation techniques to determine the subcortical structures through which this response is mediated. The only lesion which eliminated the attention response was an almost complete vertical circumcision of the amygdala with interruption of the connections irradiating in the anteromedial, medial, and posteromedial directions. Selective section of any of these connections by lesions placed either anteromedially, medially, or posteromedially to the amygdala, in various combinations, were ineffective. It is concluded that the attention response is mediated through several pathways to widespread subcortical areas. Bilateral lesions of various subcortical nuclei onto which the amygdala is known to project did not abolish the attention response. Such lesions destroyed in various combinations the almost entire thalamus (including all mid-line and intralaminar nuclei), the subthalamus, extensive parts of the hypothalamus (including nucleus ventromedialis), and the preoptic area, the septal nuclei, the reticular formation, and the rostra1 half of the periaquaeductal gray matter of the midbrain, the pretectal area, the superior colliculi, the habenula, the substantia nigra, and the red nuclei. It is suggested that the amygdaloid attention response is mediated through several of these subcortical areas which could not be eliminated in toto in one and the same animal, because such extensive lesions were not compatible with survival. Introduction
Electrical stimulation of the amygdaloid nuclear complex in unanesthetized animals elicits a characteristic pattern of behavior which has variously been termed “the arrest reaction” (16, pp. 106-l 10; 26) and the 1 The research reported the Norwegian Research by the Air Force Office of Command, United States No. AF 61 (514)-1127.
in this communication has been sponsored in part by Council for Science and the Humanities, and in part Scientific Research of the Air Research and Development Air Force, through its European Office, under contract 109
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“searching” or “attention” response (3, 10, 18, 27, 29, 30). The same type of behavior response may also be obtained on stimulation of certain areas of the cerebral cortex of the medial, basal, and lateral aspects of the hemisphere.2 Various components of the complex behavior pattern may be distinguished (5, 30). First, there is an immediate arrest of all the animal’s spontaneous occupation such as walking, licking, side-to-side movements of the tail, and shivering. Second, there are outward manifestations of increased alertness or arousal. The animal raises its head, the eyes open and the pupils dilate slowly, the ears erect, and the facial expression and whole attitude of the animal change to one of attention. Even a sleeping animal, within a few seconds of stimulation, may appear awake, alert, and vigilant. The arousal is associated with desynchronization of the electrocortical activity (30). The third component consists of orienting movements. The animal looks around with quick glancing or searching movements in an inquisitive manner, almost invariably towards the contralateral side. Occasionally there are pricking and directional movements of the ears. On stimulation of the amygdala with higher intensities, additional signs may develop, simulating either fear or anger. The behavioral attention response was obtained mainly from the basal and lateral nuclei of the amygdaloid complex, seen in Fig. 1 (30). The responsive zone could be traced medially through the region of the central nucleus of the amygdala and into the ventromedial part of the internal capsule. This medial extension of the positive sites seemed to coincide with the location of fibers, described by Fox (6), coursing through the basal and lateral nuclei and then medially in the region of the central nucleus to the entopeduncular nucleus (Fig. 2, c). In addition to these telencephalic areas, a similar attention or arousal response has been recorded on stimulation of diencephalic and mesencephalic structures. Thus, Akert (2) briefly reported on a similar type of behavioral response, consisting of a slow turning of the head towards the contralateral side, on stimulating the intralaminar nuclei and the adjacent dorsomedial and anterior thalamic nuclei. This has been confirmed by Kaada and Bruland ( 19). Jansen, Andersen, and Kaada ( 13) have shown that the attention response elicited from the medial frontal cortex can be abolished by subcortical electrolytic lesions which include the anterior basal part of the internal capsule on the same side, or by lesions destroying bilaterally part of the intralaminar nuclei of the 2 For
review
and
references,
see Fangel
and
Kaada
(5).
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thalamus, notably nuclei centralis medialis, paracentralis, and centralis lateralis. The method employed was to implant needle electrodes in the responsive cortical field and, on the following days, to make various subcortical lesions followed by repeated cortical stimulation.
p. lot.
p. med.
q
attention
.
no
attention
FIG. 1. Frontal sections through the amygdala in cats indicating points (open squares) from which the behavioral attention response has been produced by electrical stimulation. Dots, no such response. Section C corresponds to the frontal plane shown in E; A, rostral; and D, caudal end of amygdala. From Ursin and Kaada (30).
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From the mesencephalicportion of the reticular substancea behavioral arousal response may be readily elicited on stimulation in the unanesthetized monkey (28) and cat (19, 24). Hassler (12) observed contraversive searching movements in cats on stimulating a fairly narrow zone extending from the entopeduncular nucleus and adjacent portion of the internal capsule rostrally and continuing posteriorly through the zona incerta and the subthalamic nucleus into the region of the tegmenturn and reticular formation of the mesencephalon.As mentioned above, the responsive amygdaloid zone was found to extend medially into the region of the entopeduncular nucleus. Thus, there is a possibility that this zone continues caudally into the field mapped by Hassler. In the present study, using a similar stimulation-ablation technique as described above, attempts have been made to determine those subcortical structures whose integrity is necessary for the elicitation of the amygdaloid attention response. Particular interest was devoted to the thalamic nuclei, the reticular formation and hypothalamus, and other subcortical areas upon which the amygdala is known to project. Further, particular attention was paid to the various known fiber tracts irradiating from the amygdala to the diencephalon and brain stem. Some of the findings have been presented in a preliminary report (20). FIBER PROJECTIONS FROM THE AMYGDALA
The principal projections of the amygdaloid nuclear complex which will have to be taken into account are as follows: (a) The stria terminalis emergesfrom the amygdala in a dorsolateral direction (Fig. 2), and in the cat it appears to contain exclusively efferent fibers with respect to the amygdala (7). The fibers are distributed mainly to the septal, preoptic, and hypothalamic areas. Some fibers possibly also reach the habenula by way of the stria medullaris.3 (b) The longitudinal association bundle (Fig. 2, 1.b.) contains, besidessome intra-amygdaloid association fibers, a larger projection bundle which courses in an anteromedial direction towards the bed nucleus of the stria terminalis in the region of the anterior commissure,the nucleus accumbens, and the medial forebrain bundle (6, 7). Some of its fibers seem to end in the preoptic area (6). (c) A diffuse fiber system radiating from the amygdala in a medial direction towards the entopeduncular nucleus (see above), the hypothala3 For contradictory
results, see Adey and Meyer (1).
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mus, and the preoptic region has been described by various authors (4, 6, 15, 2.5). According to Fox (6) some of these fibers form a more distinct fiber bundle (Fig. 2, c) which appears to correspond to the MV bundle described by Fukuchi (9). (d) Kappers, Huber, and Crosby (2 1) have described an efferent pathway of the amygdala in the diagonal band of Broca distributing fibers to the piriform cortex, the tuberculum olfactorium, and septal areas. nut.
FIG. 2. Frontal section through the middle of the amygdala in the kitten. Note the medially coursing fibers (c) which cut across the commissural component of the stria terminalis. Cajal preparation; after Fox (6; Fig. 25).
(e) An amygdalothalamic path running to the dorsomedial thalamic nucleus, the pulvinar, and the nucleus lateralis posterior of the thalamus has been reported by Fox (8). These findings could not be substantiated in electrophysiological studies ( 11) . On the other hand, responses were recorded from nucleus ventralis medialis and some of the intralaminar nuclei (see below). (f) Amygdalomesencephalic connections have been described in the avian brain and similar projections may exist in the reptilian brain (2 1). Anatomically, such projections have not, to the authors’ knowledge, been demonstrated in the mammalian brain. In electrophysiological studies, Gloor (11) has found evidence of widespread subcortical projections of the basolateral and corticomedial subdivisions of the amygdala. The projection fields of the two subdivisions were found to overlap considerably and extended from the
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septum and the base of the head of the caudate nucleus back to the tegmentum mesencephali. They included the preoptic area, the anterior and posterior hypothalamus, the subthalamus, nucleus ventralis medialis and some of the intralaminar nuclei of the thalamus, the pretectal area, the entopeduncular nucleus, the internal capsule, and the cerebral peduncle. Material
and
Methods
In a series of seventy-five adult cats four bipolar needle electrodes, insulated except for the tips, were implanted into the amygdaloid region of each animal under Nembutal anesthesia. During the following days, in the absence of anesthesia, the freely moving cats were repeatedly stimulated using a square-wave pulse of l- to lo-msec duration and a frequency of 20 to 100 per second. In the animals in which the typical attention response was obtained, various subcortical structures were subsequently destroyed electrolytically, the electrodes being oriented by a stereotaxic instrument. Some lesions were made by means of a blunt instrument. After a complete recovery from the second anesthesia, the amygdaloid stimulation was repeated. In some animals in which the attention response remained unaltered, one or two additional lesions were made with subsequent repeated stimulation. The cats were then sacrificed and the sites of the stimulating electrodes and the extent of the subcortical lesions were identified in thionine-stained serial sections (20 u thick). Altogether such stimulation-ablation experiments were successfully completed in thirty-three animals. The remaining experiments had to be discarded from the present study, partly because no clear-cut attention response was obtained and 1 partly because several animals did not survive the fairly extensive brain-stem lesions. Results
BILATERAL LESIONS OF SUBCORTICAL NUCLEAR MASSES Thalamus. In a first series of experiments electrolytic lesions of thalamic nuclei were made. According to Jansen, Andersen, and Kaada (13), such lesions had to be bilateral in order to abolish the attention response elicited from the medial frontal cortex. Therefore, in this series of the present study the thalamic electrocoagulations were made on both sides and as symmetrical as possible. Figure 3A demonstrates such a lesion, plotted on a series of frontal sections through the brain, which was without influence on the attention response induced from
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points A’ and B’ (in Section IV) of the amygdala. The horizontally hatched areas represent the extent of the lesion on the right and left sides; the smaller horizontally and vertically cross-hatchedfield indicates the area which is common to both sides and therefore destroyed symmetrically. Figure 3B represents a summarizing chart constructed on the basis of the findings in fifteen cats having bilateral and symmetrical lesions which were without effect on the amygdaloid attention response. In each animal the lesion usually included a fairly large portion of the area shown in this figure. From the Sections II to VI in Fig. 3B, it appears that almost complete bilateral removal of all thalamic nuclei did not eliminate the amygdaloid attention response. The only thalamic areas not included in the lesions were a small portion of the most rostrolateral part of the complex (Section III) and a small portion in the region of the pulvinar (Sections V and VI). All mid-line and intralaminar nuclei and the dorsomedial nucleus were, however, destroyed. Reticular Formation and the Hypothalamus. In a second series of experiments attempts were made to eliminate the amygdaloid attention responseby bilateral lesions of the hypothalamus and the mesencephalic portion of the reticular substance (Fig. 3B). Negative results were obtained following an almost complete removal of the reticular substance of the midbrain, the subthalamus, and the dorsal portion of the hypothalamus throughout its entire length, as well as of the rostra1 parts of the ventral hypothalamus, including nucleus ventromedialis. Other Subcortical Structures. In addition to the areas mentioned above, the following structures were similarly destroyed bilaterally without influencing the attention responsefrom the amygdala (Fig. 3B): the septal nuclei posterior to the anterior commissure; a large portion of the preoptic region; the pretectal area; the rostra1 half of the periaquaeductal gray matter; the red nucleus and part of the substantia nigra; the stria medullaris and habenula; and the colliculus superior. UNILATERAL
SECTION OF THE AMYGDALOID PROJECTIONS
In a third series of experiments attempts were made to abolish the amygdaloid attention responseby ipsilateral sectioning of the projections from the amygdala in the anteromedial and posteromedial directions. In only 3 of 33 animals the responsewas obliterated, whereas it persisted unabated in the remaining 30 cats. Figure 3C is a summarizing chart
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>
5
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demonstrating the total extent of the ineffective lesions in these 30 animals. In none of them did the lesion, although usually fairly extensive in each experiment, include the projections in all directions; it was placed either anteromedial, medial, or posteromedial to the amygdala. TABLE ABBREVIATIONS
Ab, n. amygdaloideus basalis Al, n. amygdaloideus lateralis AM, n. anterior medialis AV, n. anterior ventralis CA, commissura anterior CC, corpus callosum Cd, n. caudatus Ch, chiasma opticum CI, capsula interna CL, n. centralis lateralis Cl, claustrum CS, colliculus superior Fx, fcrnix GC, griseum centrale GL, corpus geniculatum laterale GM, corpus geniculatum mediale GP, globus pallidus HL, hypothalamus lateralis Hp, hypothalamus posterior Hvm, hypothalamus ventromedialis
1 FOR FIG.
3Aa
LD, n. lateralis dorsalis LP, n. lateralis posterior MD, n. medialis dorsalis NCM, n. centralis medialis NR, n. ruber Ped, pedunculus cerebralis Pul, pulvinar PUT, putamen R, n. reticularis Ret Mes, substantia reticularis mesencephalica RPO, regio preoptica SN, substantia nigra St, stria terminalis TO, tractus opticus VA, n. ventralis anterior VL, n. ventralis lateralis VM, n. ventralis medialis VPL, n. ventralis posterolateralis VPM, n. ventralis posteromedialis
e Nomenclature according to Jasper and Ajmone-Marsan
(14)
FIG. 3. A, tracings of frontal sections through the cat’s brain. Electrical stimulation of points A’ and B’ (Section IV) within the amygdaloid nuclear complex elicited the typical attention response. This was unaffected by the bilateral electrolytic lesions indicated by the horizontally shaded areas. The vertically and horizontally cross-hatched zone indicates the regions which were common to both sides and thus destroyed symmetrically. For abbreviations, see Table 1. B, areas which were removed bilaterally without any effect on the behavior attention response induced from the amygdala. The figure represents a summary chart of lesions made in fifteen cats. C, unilateral lesions (indicated by the horizontally shaded area) and cuts which were without influence on the attention response elicited from the ipsilateral amygdala. The figure represents a summary chart of lesions made in thirty animals. D, the lesions shown to the left, drawn from three experiments, abolished the behavioral attention response elicited from the amygdala on the same side. The lesion in each of the three animals distinguished by horizontal, vertical, and diagonal hatching.
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The following fiber tracts were cut: the anterior, posterior, and hippocampal commissures; stria terminalis; stria medullaris; fimbria and fornix, with almost the entire hippocampus; most of the corpus callosum, and the white matter between the amygdala on one side and the diencephalon and brain stem on the other, including the internal capsule and the cerebral peduncle. In addition, these ipsilateral lesions included subcortical nuclear masses, such as a large part of the head of the caudate nucleus, the bed nucleus of the stria terminalis, the preoptic area, all thalamic nuclei, subthalamus, most of the hypothalamus, pulvinar, superior colliculi, mesencephalic reticular substance and periaqueductal gray, habenula, nucleus ruber, and substantia nigra. After extensive lesions of the posterior and medial fibers, the attention response was occasionally somewhat reduced or slightly altered in character. However, the imporant characteristics of the attention response, viz., the awakening effect, the lifting and moving of the head, were never abolished in these cats. In a few animals with posteromedial lesions there was a tendency to ipsilateral head movements on stimulation during the first postoperative days. This was often combined with paresis or reduced control of the musculature on the side contralateral to the lesion. However, this effect usually was a transitory one; in most of these animals the contralateral head movements, elicitable before the operation, reappeared. In order to eliminate the amygdaloid attention response it proved necessary, in one and the same animal, to perform an almost complete vertical circumcision of the amygdala on the ipsilateral side with interruption of the connections in the anteromedial, medial, as well as in the posteromedial directions. The effective lesions in the three cats are shown in Fig. 3D. Persistence of the attention response, induced from the opposite amygdala, proved that the animals were in a good condition and able to respond after the lesion. Compared with the ineffective ipsilateral lesions (Fig. 3C) there is, in the positive experiments, no additional area which is common to the three experiments and which might account for the obliteration of the response. The cuts include all projections severed in the series of ineffective ipsilateral lesions. The only difference is that in the positive experiments of Fig. 3D the lesion involves the anterior, medial, and posterior projections in one and the same animal. The possibility was considered that the elimination of the attention response in these three animals might be due to interference with the
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vascular supply of the amygdala. However, in one of these cats, which survived for 16 days after the lesion and then was killed, the cells of the amygdaloid nucleus showed no signs of anoxic cell changes. The two remaining cats died 36 and 72 hours after the final lesions. In these cats the amygdaloid cells on both sides showed changes which were attributed to postmortal autolysis. Discussion
The abolition of the behavioral attention response elicited from the amygdala by an ipsilateral circumcision anteromedial, medial, and posteromedial to this nuclear complex shows that the response is dependent on some projections coursing through these regions. However, isolated sections of varying sizes confined to either the anteromedial, medial, or posteromedial projections failed to eliminate the amygdaloid attention response. Hence, it is concluded that the response does not depend on one single subcortical projection. Apparently it is mediated through several pathways irradiating from the amygdala in a fanlike manner to various subcortical areas. In order to block the response these projections have to be interrupted in toto. The persistence of the amygdaloid attention response following fairly extensive lesions of subcortical nuclear masses, as shown in Figs. 3B and C, suggests that the response is mediated either through a small crucial area not involved in the lesions in the present experiments, or through several of the destroyed nuclear masses of the diencephalon and brain stem not removed in the one and the same animal. The results of the unilateral sections are in favor of the latter possibility. The crucial experiment would be to remove all of the subcortical tissue destroyed in the experiments of Fig. 3B. These regions include the most likely candidates looked for. Such lesions were made in several animals, but although the electrolysis in most of these experiments were carried out in two or in several stages, none of the cats survived or was left in a sufficiently good condition to allow reliable conclusions. As suggested previously (5, 17)) alertness and directed attention as a result of stimulation are probably related to a great variety of functional activities such. as sensory experience, emotions, and higher mental processes. Hence it is not surprising to find that the same behavioral pattern can be induced from fairly widespread but distinct subcortical and cortical areas. Although these diverse brain areas apparently have some common functions related to alertness and attention, it appears unlikely that these
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are the only functions these areas subserve, or that all effects mediated by them are identical. In view of the great complexity of autonomic, motor, and emotional patterns of behavior that can be induced from the amygdala on the one hand (for review, see reference 30), and the widespread connections of the amygdala with a great variety of subcortical fields on the other hand, the present results are perhaps not surprising. The strongest attention responses induced from the amygdala appear to be associated in particular with emotional reactions. On increasing the stimulus strength the attention response may assume additional features simulating either fear (resulting in flight) or anger (hissing and growling). According to Ursin and Kaada (30)) such emotional behavioral changes occurred in about one-half of the amygdaloid electrode sites yielding the attention response on weaker stimulation. Attentive behavior was occasionally also combined with sniffing, ipsilateral twitching of the face, or with various autonomic effects. Frequently, however, the attention response was the only outward manifestation resulting from stimulation. Very little is known about the subcortical pathways mediating any of these behavioral, autonomic, or motor effects elicited from the amygdala. None of them appears to be mediated via the hippocampus-fornix (30). Some of the autonomic effects, such as the uterine contractions and ovulation (22)) the depression of blood pressure and the strong respiratory inhibition (31), seem to be funneled through the ventromedial hypothalamic area. The areas for fear and anger responses, which were shown to be topographically separated within the amygdala, were both traced medially into the internal capsule (30). This is probably the main pathway for these responses, an assumption which is supported by experiments of Koikegami and Yoshida (23). According to these authors the pupillodilatatory response, which is invariably associated with the induced attention, fear, and anger, and which shows a similar distribution of the effective electrode sites as these behavior changes (30)) is probably mediated through fibers corresponding to the so-called MV and MD bundles described by Fukuchi (9). Of these, the MV bundle is the most important one; this appears to correspond to the c-fibers of Fox (Fig. 2). These observations tend to support the assumption that the behavior responses are mediated through fibers irradiating in a medial direction from the amygdala, the c-bundle being part of these fibers.
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References
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ADEY, W. R., and M. MEYER, Hippocampal and hypothalamic connexions of the temporal lobe in the monkey. Brain 75: 358-384, 1952. AKERT, IL, Experimentelles zum Thema Epilepsie. Sclazeeiz. Arch. New. Psych&. 69: 365-367, 1952. ANDERSEN, P., J. JANSEN, JR., and B. R. KAADA, Electrical stimulation of the amygdaloid nuclear complex in unanesthetized cats. Acta psychiut. new. stand. 29: 55, 1952. CROSBY, E. C., and R. T. WOODBTJRNE, The comparative anatomy of the preoptic area and the hypothalamus. Res. Pub. Ass. New. Ment. Dis. 20: 52-169, 1940. FANGEL, C., and B. R. KAADA, Behavior “attention” and fear induced by cortical stimulation in the cat. Electroencephalography, Montreal, 1960 (in press), Fox, C. A., Certain basal telencephalic centres in the cat. J. Camp. Neur. 72: l-62, 1940. FOX, C. A., The stria terminalis, longitudinal association bundle and precommissural fornix fibers in the cat. J. Camp. Neur. 79: 277-295, 1943. Fox, C. A., Amygdalo-thalamic connections in Macaca wtulatta. Anat. Rec. 103: 537538, 1949. FUKUCHI, S., Comparative-anatomical studies on the amygdaloid complex in mammals, especially in ungulata. Fol. psych&. new. jap. 6: 241-262, 1952. GASTAUT, H., R. NAQUET, R. VIGOUROUX, and J. CORRIOL, Provocation de comportements Cmotionnels divers par stimulation rbinendphalique chez le chat avec electrodes a demeure. Rev. new. 86: 319-327, 1952. GLOOR, P., Electrophysiological studies on the connections of the amygdaloid nucleus in the cat. Electroencephalography, Montreal 7: 223-242; 243-264. 1955.
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JANSEN, J., JR., P. ANDERSEN, and B. R. KAADA, Subcortical mechanisms involved in the “searching” or “attention” response elicited by prefrontal cortical Yale J. Biol. 26: 331-341, 1955/56. stimulation in unanesthetized cats. JASPER, H. H., and C. AJMONE-MARSAN, “4 Stereotaxic Atlas of the Diencephalon of the Cat.” Ottawa, The National Research Council of Canada, 1954. JOHNSTON, J. B., Further contributions to the study of the evolution of the forebrain. J. Comp. New. 96: 337-481, 1923. KAADA, B. R., Somato-motor, autonomic and electrocorticographic responses to electrical stimulation of ‘rhinencephalic’ and other structures in primates, cat and dog. Acta physiol. stand. 24 (Suppl. 83): 1-285, 1951. KAADA, B. R., Cingulate, posterior orbital, anterior insular and temporal polar cortex. In “Handbook of Physiology,” J. Field, H. W. Magoun, and V. E. Hall (eds.), Vol. II, Baltimore, Williams and Wilkins Co., 1960 (ref. pp. 1345-1372). KAADA, B. R., P. ANDERSEN, and J. JANSEN, JR., Stimulation of the amygdaloid nuclear complex in unanesthetized cats. Neurology 4: 48-64, 1954.
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19. KAADA, B. R., and H. BRULAND. Blocking of the cortically induced behavioral attention (orienting) response by chlorpromazine. (In preparation), 1960. 20. KAADA, B. R., and H. URSIN, Subcortical mechanisms in the “attention” response induced from the amygdala in cats. Acta physiol. stand. 42: 79-80, 1957. 21. KAPPERS, C. U. A., G. C. HUBER, and E. C. CROSBY, “The Comparative Anatomy of the Nervous System of Vertebrates, Including Man.” New York, The MacMillan Co., 1936. 22. KOIKEGAMI, H., T. YAMADA, and K. USUI, Stimulation of amygdaloid nuclei and periamygdaloid cortex with special reference to its effects on uterine movements and ovulation. Fol. psych&. new. japon. 8: 7-31, 1954. H., and K. YOSHIDA, Pupillary dilatation induced by stimulation 23. KOIKECA~, of the amygdaloid nuclei. Fol. psych&. new. jap. 7: 109-126, 1953. 24. KUROKI, T., Arrest reaction elicited from the brain stem. Fol. psych&. new. jap. 12: 317-340, 1958. 25. LAUER, E. W., Nuclear pattern and fiber connections of certain basal telencephalic centers in the macaque. J. Comp. New. 82: 215-254, 1945. 26. MACLEAN, P. D., and J. M. R. DELGADO, Electrical and chemical stimulation of frontotemporal portion of limbic system in the waking animal. Electroencephalogruphy, Montreal 6: 91-100, 1953. 27. MAGNUS, O., and H. J. LAMMERS, The amygdaloid-nuclear complex. FoZ. psychiat. neerl. 69: 555-582, 1956. 28. SEGUNDO, J. P., R. ARANA, and J. D. FRENCH, Behavioral arousal by stimulation of the brain in the monkey. J. Neurosurg. 12: 601-613, 1955. 29. SHEALY, C. N., and T. L. PEELE, Studies on amygdaloid nucleus of cat. J. Neurophysiob 20: 125-139, 1957. 30. URSIN, H., and B. R. &4DA, Functional localization within the amygdaloid complex in the cat. Electroencephalography, Montreal (In press), 1960. 31. WOOD, C. D., B. SCHOTTELIUS, L. L., FROST, and M. BALDWIN, Localization within the amygdaloid complex of anesthetized animals. Neurology 8: 477-480, 1958.