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Chapter VII: In Fraslow Processes in the Brain as Part of Its Integrative Activity
141 CHAPTER VII
INFRASLOW PROCESSES IN THE BRAIN AS PART OF ITS INTEGRATIVE ACTIVITY CHANGE IN THE INFRASLOW RHYTHM IN FORMATION O F THE CONDITIONED DEFENSE REFLEX
A major indication of the significance of the infraslow rhythmic processes in the integrative activity of the brain is that they a r e included during certain phases in the formation of temporary connections. The continuous cyclic interaction of the hypothalamus and neocortex through the hippocampus (cf. Chapter V) constitutes one of the substrates of cortical-subcortical integration, This "hippocampal circuit" is found only in mammals and it has evolved as a "mechanism to coordinate the high levels of cortical activity with those integral apparatuses of the emotions which are localized mostly in the subcortical structures" ( h o k h i n , 1958a, p. 309). Since infraslow activity of the brain is associated, in its origin, with the structures involved in the "hippocampal circuit", we thought it would be useful to trace the dynamics of the ISPO in the formation of conditioned reflexes. We (together with Dr. Kol'tsova) recorded ISPO and ECoG in the motor and visual areas of the rabbit cortex and in the deep brain structures, including those forming p a r t of the hippocampal circuit of the same animals. Electrodes were implanted in the hippocampus, thalamus (medial, lateral, and anterior nuclei), and hypothalamus (anterior and posterior) of 7 rabbits. The conditioned defense reflex was formed by combining a light signal with electrical stimulation of a paw. The conditioned reflex (flashes of light at a frequency of 8 c/s) w a s given for 10-15 s e c ; in the last second, reinforcement w a s supplied in the f o r m of an electrical shock applied to a front paw. Some 8-10 combinations at 5 min intervals were presented in each experiment. Paw movement and respiration were recorded on a kymograph. The procedure was carried out every other day on two rabbits. The effect on the ISPO in these cases was weak. W e therefore performed the experiments daily on the other 5 animals; the results were clear-cut. The findings can be most conveniently analyzed by dividing each experiment into four parts: (1) initial period (first 2-3 days) of forming the conditioned reflex; (2) generalization period, from 3 to 7-9 days during which the conditioned reflex could be elicited by several stimuli with occasional closures between signals; (3) fixation period during which there were 5-6 out of 8 possible manifestations of a conditioned reflex; (4) extinction period during which the conditioned stimulus was presented without any reinforcement. During the initial period, infraslow activity became intensified in all a r e a s of the cortex (visual and motor regions of both hemispheres), and the frequency of the rhythm increased from 8 to 11 per min (Fig. 69). At this time the following changes took place in the subcortical structures and hippocampus. A rhythm of about 5 c/s appeared or
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Fig. 69. Change in ISPO in different areas of the rabbit cerebral cortex during formation and extinction of the conditioned defense reflex. (I) left visual cortex; (11) sensorimotor cortex of the left hemisphere; (111) sensorimotor cortex of the right hemisphere. 0 = background before the start of formation of the conditioned reflex; 1 = initial period of formation; 2 = generalization period; 3 = fixation period; 4 = extinction period (the recordings in this and the following figures ,were made before the next presentation of the stimulus).
became intensified in the dorsomedial nucleus of the thalamus (Fig. 70), premammillary area of the hypothalamus (Fig. 71), and hippocampus (Fig. 70). Bursts of more rapid oscillations arose in the supraoptic area. Electrical activity became intensified in the dorsomedial nucleus of the hypothalamus (Fig. 70) and in the anterior thalamus. The activity remained unchanged in the lateral ventral and ventromedial nuclei of the thalamus (Fig. 72). During the generalization period, the amplitude of the ISPO increased markedly in the cortex while the frequency decreased. A rhythm of 3-5 osc/min appeared in some rabbits, "B-waves" (2-3 osc/min) in others. The ISPO's were unstable in thesubcortical structures and indistinct.
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Fig. 70. Changes in the electrical pattern of different subcortical structures of the rabbit brain during formation and extinction of the conditioned defense reflex. 0 = before the start of formation of the conditioned reflex; 1 = initial period of formation; 2 = generalization period; 3 = fixation period; 4 = extinction period. Recording (A) from the supraoptic nucleus of the hypothalamus; (B) from the dorsomedial nucleus of the hypothalamus; (C) from the dorsomedial nucleus of the thalamus; (D) from the hippocampus.
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Fig. 71. Changes in the electrical pattern of different subcortical structures of the rabbit brain during formation and extinction of the conditioned defense reflex. 0 = before the start of formation of the conditioned reflex; 1 = initial period of formation; 2 = generalization period; 3 = fixation period; 4 = extinction period. Recording: (A) from the anteromedial nucleus of the thalamus; (B) from the .anteroventral nucleus of the thalamus; (C) from the premammillary a r e a of the hypothalamus.
The recording of the dorsomedial and ventromedial nuclei of the thalamus and the hippocampus at this time exhibited synchronous oscillations with a frequency of 4-5 c/s (Fig. 70). Activity decreased at the base of the hypothalamus and in the anteroventral nucleus of the
thalamus.
During the period when the conditioned reflex was being fixed, the ISPO disappeared. Electrical activity decreased in the subcortical
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Fig. 72. Changes in the electrical pattern of different subcortical structures of the rabbit brain during formation and extinction of the conditioned defense reflex. 0 = before the start of formation of the conditioned reflex; 1 = initial period of formation; 2 = generalization period; 3 = fixation period; 4 = extinction period. Recording (A) from the dorsomedial nucleus of the thalamus; (B) from the ventromedial nucleus of the thalamus; (C) from the lateral ventral nucleus of the thalamus.
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structures and hippocampus. An increased level of activity w a s noted in the anterior nuclei of the thalamus and in the premammillary a r e a of the hypothalamus. The ISPO reintensified in the cortex of both hemispheres the second day after the start of extinction. During the extinction period a distinct rhythm of 4-5 c/s again appeared in the pattern of the medial thalamus and in the posterior hypothalamus. There were no appreciable changes in the other nuclei of these structures during the extinction period. On the fifth day after the s t a r t of extinction, infraslow oscillations in the cortex were like those in an intact animal prior to the formation of conditioned reflexes. There is a period of ISPO intensification in the cerebral cortex during the formation of conditioned reflexes in rabbits. Electrical activity intensifies in the thalamic and hypothalamic areas, as confirmed by the findings of Trofimov et a l . (1958). Our facts show very clearly that the greatest changes in frequency of the ISPO occur during the f i r s t 2 or 3 days after the stimuli are presented. During this time the ISPO's in the cortex increase (from 8 to 12 per min); they a r e paralleled by higher amplitude activity in the electrical pattern of certain nuclei of the hypothalamus and thalamus. After 3-4 days (generalization period) the frequency of the ISPO decreases markedly (to 2 per min), but their amplitude increases. Characteristic synchronous slow oscillations with a frequency of 4-5 c/s continue to be recorded in the record of the medial nuclei of the thalamus, posterior hypothalamus, and hippocampus. The activity is considerably reduced in the lateral and ventral nuclei of the thalamus and in certain hypothalamic structures. Changes in frequency of the ISPO in different phases of the formation of temporary connections apparently signify a different degree of involvement of the slow control system of the brain in these processes. The initial phases in the formation of the conditioned defense reflex a r e presumably accompanied by high activity of the brain structures concerned with control over the hormonal level and making considerable use of the neurosecretory mechanisms of the brain. As the conditioned reflex becomes fixed, the activity of these structures diminishes and the processes in the high-speed systems of the brain gain in importance. Analysis in the light of comparative physiology reveals that at all stages of evolution the metabolic elements involved in the formation of conditioned reflexes are realized by the slow processes (Koshtoyants, 1957). As soon as the organism experiences the need to adapt to environmental conditions, these "lower self -regulatory devices, which functioned well in maintaining certain functions at a constant level, must immediately adapt to the requirements of the particular behavioral act" (Anokhin, 1958a, p. 186). An organized behavioral act undoubtedly involved the neurohormonal complex (whisksupplies the energy needed for this act) in the reaction through the connections of the cerebral cortex with the subcortical structures. Our findings illustrate this view. The intensification of electrical activity in the supraoptic area, paraventricular hypothalamus, and dorsomedial thalamic nucleus during the generalization stages indicates that these structures may be the neural mechanism of generalized hormonal reactions,
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Intensification of the ISPO in the formation of conditioned connections and in "stress" reactions (cf. Chapter 111) suggests that the ISPO's r e flect the effect of the higher functions of the cerebral cortex being combined with the autonomic influences through the region of hypothalamic integration; they may well be connected with the emotional sphere. Thus, infraslow activity reflects the processes that play a major role in the integrative activity of the brain. SLOW CONTROL SYSTEM O F THE BRAIN
In studying the control mechanisms of the brain, it is convenient to distinguish the main types of systems, the components and interrelations. Warm-blooded animals have a rapid system and a slow system. The former controls the quick reactions to stimulation, many of which have been studied in detail, e . g . , the orienting reflex. The second evaluates more or less systematically active environmental factors and r e o r ganizes the level of activity s o as to regulate resistance and homeostasis. The slow control system influences the parameters of the rapid system, changing the latter's level of activity. If the brain were to be regarded solely as the organ of adaptation, its task would be to organize the conditions required to keep the variables of the organism within normal limits. In other words, the brain in this case would function as a homeostatic regulator. In this monograph we shall not discuss the properties of the brain and mechanisms as a whole that enable it to function as a regulator. We shall focus only on a few manifestations of such activity, specifically on what we have called the "C-fluctuations" of electrical activity in brain structures. We pointed out in earlier chapters that infraslow brain activity is intensified by certain actions after a long latency period, 30-100 and 120-200 min later. We conjectured that this phenomenon reflects the activity of the slow control system of the brain, one of the functions s e e m s to be not only to automatically adjust themsystemto keeping the internal environment constant but actively to establish a new level of activity. To characterize this system, it was necessary to analyze the electrical activity of certain brain structures whose involvement in the phenomenon of intensification of infraslow activity takes place, we assume, under the conditions of directed functioning of the system. The dynamic properties of this system were investigated by introducing artificial disturbances which disrupted its equilibrium. The subsequent behavior of the system was observed for a considerable period of time. Such a disturbance, which took place in the form of a pulse function and lasted for several seconds, was electrical stimulation of one of the brain structures by pulses of current with a duration of 10 p e c , frequency of 30 and 100 c/s, and amplitude of 4 V. Experiments were performed on 15 nonanesthetized rabbits. Bipolar electrodes were implanted in the sensorimotor cortex of both hemispheres and some parts of the thalamus and hypothalamus. Additionally, a pair of electrodes was implanted in the brain of 5 of the animals for local coagulation of the surrounding area. (This s e r i e s of experiments
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was carried out jointly with Dr. Koltsova). The following subcortical structures were investigated: (a) nuclei of
the thalamus: dorsomedial, posterolateral, reticular, anteroventral, pulvinar; (b) a r e a s of the hypothalamus: dorsal, lateral preoptic, supramammillary, ventromedial nucleus; (c) optic chiasma. The electrical activity of the hippocampus was also recorded. In analyzing the results, we were aware that the effect observed after stimulation of one of the subcortical structures is not necessarily connected directly with the activation of the particular structure because other nerve structures are also activated due to numerous connections. For example, in the hypothalamic area, an aftereffect in the form of intensified activity may occur after stimulation of about 30 structures (Niemer et al., 1960). We concentrated on the time intervals in which two stages of intensified infraslow activity would a r i s e in the brain. The following struck u s as particularly significant. When an experiment was performed on an animal for the first time, the agent did not produce the two-stage change in brain activity. Two stages were only evident when the agent was presented on the days preceding the experiment. We shall now describe the repeated experiments of this kind. The "C-fluctuations" of electrical activity that arise after introduction of a disturbance (in the form of the above-described agent) have the following characteristics. Electrical activity is markedly intensified in the stimulated nucleus and certain other nuclei after a latency period of some tens of minutes. This intensification lasts several minutes. The first cycle of "excitation" in these structures is followed by a "rest" period reflecting the original state of the electrical activity. However, 10-20 min later a new wave of "excitation" arises in the same nuclei, despite the absence of additional stimulations; this wave, in turn, gives way to another "rest" period. Such cycles of "excitation" (with a similar type of electrical pattern) a r e periodically repeated as often as five times within 2 h. They are comparable to an oscillatory process of damped nature. Thereupon, temporary, more or less sustained relaxation of activity occurs in all the nuclei. A second stage of "fluctuations" of electrical activity starts after this pause, 2-3 h from the time of the initial disturbance without the presentation of new stimulations. This stage is likewise characterized by several cycles of intensified and inhibited activity, but the electrical pattern is no longer the same as that observed a t the first stage of the "C-fluctuations". The electrical pattern of the first stage has oscillations with a frequency of 5-7 c/s giving way to oscillations with a frequency of 10-16 c/s in the periods of intensified activity. During the second stage these periods a r e marked by high-amplitude and high-frequency discharges with a frequency of up to 28 c/s. The burst or spindle-shaped form of activity takes place during this stage. Cyclic excitations of the second stage last for 1-1.5 h and cease 3-5 h from the first disturbance. However, in some instances the activity of the brain structures halts after the end of the second stage of the oscillatory process at a certain level, which then persists for several days thereafter. It will be observed that recording of the electrical pattern of the
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149 nuclei in these experiments was started only 2-5 min after stimulation s o that the earlier reactions could not be observed. Fig. 73 i s a schematic representation of the phenomenon of "Cfluctuations" in different subcortical structures with examples of the electrograms during the first and second stages of the "fluctuations". The second stage began 130 min after introduction of a disturbance. At this time infraslow activity became intensified in the cortex. This experiment was performed on August 13. On July 14, the reticular nucleus of the thalamus was stimulated for the first time and no I
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Fig. 73. llC-fluctuationsltof electrical activity in the rabbit hypothalamus and thalamus. Top, electrical pattern of the nuclei: dorsomedial thalamic (A) and dorsal hypothalamic a r e a (B) after stimulation of the latter and after stimulation of the lateral hypothalamic area (C). I = first stage; I1 = second stage. Bottom, graphic representation of the lYluctuationslt of electrical activity in the same brain structures; x = time of recording. The rise in the curve on the graph reflects increase in activity. Y-axis: amplitude of electrical oscillations (in pV); X-axis:time (in min) elapsing since presentation of the disturbance; second stage crosshatched.
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"fluctuations" could be recorded. On July 19, the same nucleus was stimulated again with no "fluctuations". On July 21, the reticular nucleus was stimulated for the third time, resulting in only one stage of "fluctuation" of electrical activity between the 16th and 190th min. The "fluctuations" resembled damped oscillations. During the periods of intensified activity that occurred at the 16th, IlOth, 120th, 130th, 160th, and 190th min, the electrical pattern of the dorsomedial thalamus revealed potential oscillations with a frequency of about 16 c/s. "Fluctuations" occurred in the sensorimotor cortex reciprocally with "fluctuations" in the subcortical structures and consisted of synchronized oscillations alternating with periods of desynchronization. During the period of "fluctuations" ISPO's appeared in the dorsomedial thalamus at the r a t e of 8 per min, in the dorsal hypothalamus 10 per min. No ISPO appeared in the reticular nucleus. A total of 8 "fluctuation" cycles were noted; no burst-like activity arose anywhere. On July 27, after an interruption of a week, the dorsal area of the hypothalamus w a s stimulated. In response "fluctuations" arose in the cortex and 100 min later damped out. Repeated stimulations on the same day evoked "fluctuations" in the dorsomedial nucleus of the thalamus and a hint that the second stage was setting in. The next day, July 28, the effect recurred in the cortex. On August 8, after an interruption of 8 days, the reticular nucleus of the thalamus was stimulated but no "fluctuations" were evident anywhere. On August 10, the reticular nucleus was stimulated again, r e sulting this time in a pronounced effect. The first stage of "fluctuations", which arose after a latent period of 28 min, and the second stage, which a r o s e 120 min after the start of stimulation and was characterized by a burst-like activity in all the structures (except the reticular nucleus of the thalamus), were observed at all the leads. ISPO too failed to appear in the reticular nucleus. The first and second stages included 3 and 4 cycles of excitation, respectively. The "fluctuations" occurred reciprocally in the cortex and subcortical nuclei. On the next day, August 11, "fluctuations" were not evoked by stimulation of the dorsal hypothalamus. On August 13 (cf. Fig. 73), the dorsal a r e a of the hypothalamus was stimulated. The first stage of "fluctuations" arose after 28 min. There was only one stage in the reticular nucleus of the thalamus which developed damped oscillations. A maximum of activity with bursts occurring in this nucleus was noted at the 35th min; ISPO's were recorded there at the same time. The second stage of "fluctuations" occurred after 120 min in the dorsomedial nucleus of the thalamus and in the dorsal a r e a of the hypothalamus. High frequencies initially predominated in the electrical pattern. These were followed by spindle-shaped activity. W e gave this day-by-day account of the experiment in order to show that the two stages of "fluctuations" occur only after systematic actions. The "fluctuation" effect was not observed in experiments on other animals the first day after the introduction of a disturbance. Repeated disturbances produced "fluctuations" similar to damped oscillations. Systematic stimulation gave rise to two stages of "fluctuations".
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The reticular nucleus of the thalamus invariably had only one stage and it was of the damped oscillations type. The phenomenon of "C-fluctuations" of electrical activity in our experiments was also evoked by stimu1.ation of the lateral a r e a of the hypothalamus, lateral preoptic area, ventromedial nucleus of the hypothalamus, perichiasmal area, and sensorimotor cortex. The latent period was shortest (from 5 to 28 min) after stimulation of the cortex and perichiasmal area; it lasted 30-50 min after stimulation of the hypothalamic areas. The longest latent period (40-60 min) followed stimulation of the preoptic area. The time when the "fluctuations" ceased also varied from structure to structure. The most prolonged "Cfluctuations" were observed after stimulation of the hypothalamic and neurosecretory areas; they lasted 5 h. Since periodic intensification of the ISPO and electrical activity may also occur in isolated cortex after stimulation of the hypothalamus (cf. Chapter IV), the question a r i s e s whether there is a relationship between the phenomenon of "C-fluctuations" and the mechanism of neurohumoral regulation. Involvement of the pituitary in the origin of the phenomenon is doubtful because coagulation of the gland o r the pathways leading to it from the preoptic areas failed to prevent the "fluctuations" from appearing. Moreover, 1 o r 2 weeks after these actions, the stages of the "fluctuations" became more intense and they appeared in nuclei where they had not been observed prilor to coagulation. For example, prior to coagulation, the second stage of the "fluctuations" was seen only in the lateral preoptic area (after it was stimulated). Within a week of electrocoagulationi of the pituitary (with histological confirmation) stimulation of the lateral preoptic areawzoked intense "C-fluctuations" of activity in the same a r e a as well as in the supramammillary area and ventromedial nucleus of the hypothalamus, the latent periods being 37, 51, and 76 min, respectively. The "fluctuations" had a second stage and they were ended by the occurrence of specific activity with a frequency of about 5 c,/s at all the leads. In another case, two stages of "C-fluctuations" arose in the lateral a r e a of the hypothalamus in response to stimulation thereof, but the phenomenon was absent in the thalami5 nuclei (lateral and dorsomedial). Unilateral coagulation was then carried out in the area of the arcuate nucleus of the hypothalamus, injuring the connections between the infundibulum of the hypophysis and supraoptic area of the hypothalamus. The background activity became intensified 10 days after coagulation in the cortex, lateral and medial nuclei of the thalamus. The lateral hypothalamic area was stimulated against this background (on the coagulated side). Two distinct stages of the "C-fluctuations" arose in response in the hypothalamic area where only the second stage, which appeared 130 min after stimulation, was pronounced. The effect was repeated after 4 days. The intensification of the "fluctuations'' observed in these experiments may have been due to the fact that coagulation by itself is a highly potent stimulus which can activate many regulatory mechanisms of the brain, a peculiar kind of "stressor" capable of causing additional disturbances in the regulatory system.
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By way of verification, we coagulated an area which can scarcely be said to have any direct relationship to the connections of the hypothalamus with the pituitary, namely, the lamina terminalis, the upper end of which abuts the anterior commissure of the hemispheres while the lower end abuts the upper margin of the chiasma. No visible changes were observed in background electrical activity of the brain after 10 days, and the initial stimulation of the dorsal hypothalamus did not evoke "fluctuations". The second stimulation a day later evoked two stages of "fluctuations", which were somewhat more intense than they were before coagulation. On the following days the response to stimulation was weak, but after a 2 day interruption two-stage "fluctuations" were clearly evident in the thalamic and hypothalamic areas. Although coagulation of the hypophyseal t r a c t caused a much sharper difference in the intensity of the "C-fluctuations", coagulation of the lamina terminalis likewise exerted a "facilitating" influence on the appearance of the two stages of "fluctuations". The problem of "C-fluctuations" of electrical activity is still in the experimental stage so that premature conclusions must be avoided. Moreover, in our experiments we observed only one aspect of the phenomenon, i.e., that manifested in changes in the electrical activity of certain areas of the brain. No doubt other processes about which we have no information take place in the intervals between these cycles of excitation. We are now concerned solely with the fact that "fluctuations" may occur reciprocally in the cortex and hypothalamic area. We should like to begin the discussion with a few thoughts about the significance of the "C-fluctuations". The existence of "C-fluctuations" in brain structures and the way the phenomenon is manifested make it possible to analyze the work of the slow control system of the brain by comparing it with a model of a regulatory system whose initial state (equilibrium) is temporarily disrupted and then left alone. The element regulated in this model meanwhile strives to regain the original equilibrium by executing around it a s e r i e s of f r e e damped oscillations. This principle of regulation in its external manifestations resembles the phenomenon of "C-fluctuations" in the first stage of the process, where emergence from the state of homeostasis is indicated by the appearance of a rhythm. The same law of restoration of the equilibrium of the regulatable element is operative in the regulation of certain autonomic functions of the body, e . g . , in a change in the blood sugar level in response to the ingestion of glucose. The former equilibrium or a new one is achieved as a result of a damped oscillatory process (Drishel, 1960). Periodic changes were recorded by Latash (1961) in the EEG of healthy subjects and patients with injuries to the hypothalamus. The changes involved an alternation of phases of synchronization and desynchronization of potential oscillations in response to the subcutaneous injection of low doses of epinephrine. The latent period for the development of desynchronization in the EEG and marked autonomic reactions like the sympathoadrenaline c r i s i s usually lasted 15-60 min, z.e., the effect did not occur in response to the direct action of the epinephrine; rather, according to the author, it was a reflection of regulatory changes
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proceeding in opposite directions that might (under optimal conditions) end in damped oscillations, although they sometimes became intensified periodically. EEG "fluctuations" in response to the injection of epinephrine can usefully be compared with "fluctuations" in the electrical pattern of the subcortical structures in our experiments. The principle of damped oscillations does not provide for the second stage of "C-fluctuations". The existence of the second stage supports the assumption that the function of the slow control system of the brain is not solely to adjust automatically the body to the preservation of homeostasis. The regulatory process includes mechanisms that markedly influence the activity of different structures and result in fixation at a new level. By this criterion the slow control system of the brain s h a r e s .the characteristics of a model of an ultrastable system, i.e., a system capable of selectively choosing the necessary values of the parameters, rejecting unstable states, and preserving those which create the stability needed to ensure adaptability to new environmental conditions (Ashby, 1954). The second stage of "C-fluctuations" may well reflect the active reorganization of the system on a new level of operation with allowance for the effect of a new factor (a unique kind of "foresight"). This view is supported by the following facts. Experiments on the same animal showed that introduction of a disturbance did not at first elicit the "fluctuations" reaction. When reintroduced (on the second or third day), the disturbance elicited only the first stage of the "fluctuations" comparable to damped oscillations (one stage). After the experiment was repeated several times a week, the disturbance would result in the complete picture of "C-fluctuations" in two stages. If these "fluctuations" ended in a shift to a new level of activity, the introduction of new disturbances during the new few days had no further effect, i . e . , they did not evoke "fluctuations". However, after an interruption of 7-10 days the entire sequence of the "fluctuations" reappeared, suggesting the existence of "forgetting" processes in the system. The above-described pattern resembles a model in which regulation by the ultrastability principle is included when a disturbance becomes a repeated factor and the system "foresees" further repetitions, choosing the necessary "field" that will ensure the most efficient operation in the new situation. If, however, the organism is subjected to an additional trauma (coagulation of certain brain structures), the second stage becomes pronounced, even, at times, to the point of exaggeration. The change in activity of the structures may then assume a pathological form and lose its regulatory influence. One has the impression that the second stage of activity is caused both by systematic actions and by the p r e s ence of "stress" stimuli in the recent past. The facts examined in this section justify our assumption that the existence of rhythmic processes are even slower than the ISPO and have a period of several tens of minutes. These "C-fluctuations" seem to "regulate" the infraslow activity. Some dynamic characteristics of the system can be found by creating nonstationary processes in the control system by the introduction of artificial disturbances. For example, this approach enabled us to discover that a rhythmic process based on a
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logarithmic law can arise in the posterolateral nucleus of the thalamus under certain conditions. Bursts of impulses a r e generalized in this structure and eventually spread by logarithmic law with repetitions every 20 min (the process is saw-like in nature). The significance of this rhythm is not immediately apparent but, by analogy with radio engineering circuits, the process may act as a time scanner. CONCLUSIONS
Infraslow activity of the cerebral cortex changes after the formation of a conditioned defense reflex in relation to the stage in which temporary connections a r e established. It accelerates at the time when the first closures appear. It increases in amplitude, but slows at the time of generalization and almost disappears as the conditioned reflex is being fixed. Intensification of infraslow activity in the cortex is paralleled by intensification of electrical activity in certain subcortical structures: supraoptic a r e a of the hypothalamus, paraventricular nuclei, dorsomedial nucleus of the thalamus, and hippocampus. W e believe that the activity of these structures is connected with neurosecretory processes and hormonal factors. During fixation of the conditioned reflex, activity in these structures and infraslow activity are weakened simultaneously. Thus, the ISPO's reflect the results of higher cortical functiOns being combined with metabolic (hormonal) factors by the mechanisms responsible for hypothalamic integration. On the other hand, the ISPO mechanisms are closely associated with the activity of the slow control system of the brain. One of the characteristics of this system is that it does not r e a c t to a slight, one-time (accidental) external disturbance. Its reaction to an environmental factor that acts more or less systematically persists for several hours and it may be directed not only at overcoming the changes brought about in the internal environment but at reconstructing the level of activity with due regard for the possible effect of the new factor. The aetivity of the slow control system may be modeled in this respect by a system operating on the ultrastability principle. Another characteristic of the system is the long latency period of the response and the hours-long period of regulation that includes a variety of mechanisms. One way of discovering the control mechanisms may be by tieing into the system a nonstationary transitional process involving a temporary disturbance and then letting the system alone. Under these conditions the electrical activity of certain brain structures undergoes rhythmic "fluctuations" with a period of 20-30 min. There may be one o r two stages of these "fluctuations" lasting 2-3 h each, with a different kind of activity in each. Infraslow activity becomes intensified in the two stages. A rhythmic process occurs during the nonstationary interval with the same period (20-30 min). The discovery of these rhythms will enable u s to investigate the unknown mechanisms of regulation, whose
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manifestation under the conditions of an equilibrium we do not know. A preliminary examination suggests that a chemical code underlies the activity of certain links in the control process.
INFRASLOW PROCESSES IN THE BRAIN AS PART OF ITS INTEGRATIVE ACTIVITY CHANGE IN THE INFRASLOW RHYTHM IN FORMATION O F THE CONDITIONED DEFENSE REFLEX
A major indication of the significance of the infraslow rhythmic processes in the integrative activity of the brain is that they a r e included during certain phases in the formation of temporary connections. The continuous cyclic interaction of the hypothalamus and neocortex through the hippocampus (cf. Chapter V) constitutes one of the substrates of cortical-subcortical integration, This "hippocampal circuit" is found only in mammals and it has evolved as a "mechanism to coordinate the high levels of cortical activity with those integral apparatuses of the emotions which are localized mostly in the subcortical structures" ( h o k h i n , 1958a, p. 309). Since infraslow activity of the brain is associated, in its origin, with the structures involved in the "hippocampal circuit", we thought it would be useful to trace the dynamics of the ISPO in the formation of conditioned reflexes. We (together with Dr. Kol'tsova) recorded ISPO and ECoG in the motor and visual areas of the rabbit cortex and in the deep brain structures, including those forming p a r t of the hippocampal circuit of the same animals. Electrodes were implanted in the hippocampus, thalamus (medial, lateral, and anterior nuclei), and hypothalamus (anterior and posterior) of 7 rabbits. The conditioned defense reflex was formed by combining a light signal with electrical stimulation of a paw. The conditioned reflex (flashes of light at a frequency of 8 c/s) w a s given for 10-15 s e c ; in the last second, reinforcement w a s supplied in the f o r m of an electrical shock applied to a front paw. Some 8-10 combinations at 5 min intervals were presented in each experiment. Paw movement and respiration were recorded on a kymograph. The procedure was carried out every other day on two rabbits. The effect on the ISPO in these cases was weak. W e therefore performed the experiments daily on the other 5 animals; the results were clear-cut. The findings can be most conveniently analyzed by dividing each experiment into four parts: (1) initial period (first 2-3 days) of forming the conditioned reflex; (2) generalization period, from 3 to 7-9 days during which the conditioned reflex could be elicited by several stimuli with occasional closures between signals; (3) fixation period during which there were 5-6 out of 8 possible manifestations of a conditioned reflex; (4) extinction period during which the conditioned stimulus was presented without any reinforcement. During the initial period, infraslow activity became intensified in all a r e a s of the cortex (visual and motor regions of both hemispheres), and the frequency of the rhythm increased from 8 to 11 per min (Fig. 69). At this time the following changes took place in the subcortical structures and hippocampus. A rhythm of about 5 c/s appeared or
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Fig. 69. Change in ISPO in different areas of the rabbit cerebral cortex during formation and extinction of the conditioned defense reflex. (I) left visual cortex; (11) sensorimotor cortex of the left hemisphere; (111) sensorimotor cortex of the right hemisphere. 0 = background before the start of formation of the conditioned reflex; 1 = initial period of formation; 2 = generalization period; 3 = fixation period; 4 = extinction period (the recordings in this and the following figures ,were made before the next presentation of the stimulus).
became intensified in the dorsomedial nucleus of the thalamus (Fig. 70), premammillary area of the hypothalamus (Fig. 71), and hippocampus (Fig. 70). Bursts of more rapid oscillations arose in the supraoptic area. Electrical activity became intensified in the dorsomedial nucleus of the hypothalamus (Fig. 70) and in the anterior thalamus. The activity remained unchanged in the lateral ventral and ventromedial nuclei of the thalamus (Fig. 72). During the generalization period, the amplitude of the ISPO increased markedly in the cortex while the frequency decreased. A rhythm of 3-5 osc/min appeared in some rabbits, "B-waves" (2-3 osc/min) in others. The ISPO's were unstable in thesubcortical structures and indistinct.
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Fig. 70. Changes in the electrical pattern of different subcortical structures of the rabbit brain during formation and extinction of the conditioned defense reflex. 0 = before the start of formation of the conditioned reflex; 1 = initial period of formation; 2 = generalization period; 3 = fixation period; 4 = extinction period. Recording (A) from the supraoptic nucleus of the hypothalamus; (B) from the dorsomedial nucleus of the hypothalamus; (C) from the dorsomedial nucleus of the thalamus; (D) from the hippocampus.
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Fig. 71. Changes in the electrical pattern of different subcortical structures of the rabbit brain during formation and extinction of the conditioned defense reflex. 0 = before the start of formation of the conditioned reflex; 1 = initial period of formation; 2 = generalization period; 3 = fixation period; 4 = extinction period. Recording: (A) from the anteromedial nucleus of the thalamus; (B) from the .anteroventral nucleus of the thalamus; (C) from the premammillary a r e a of the hypothalamus.
The recording of the dorsomedial and ventromedial nuclei of the thalamus and the hippocampus at this time exhibited synchronous oscillations with a frequency of 4-5 c/s (Fig. 70). Activity decreased at the base of the hypothalamus and in the anteroventral nucleus of the
thalamus.
During the period when the conditioned reflex was being fixed, the ISPO disappeared. Electrical activity decreased in the subcortical
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Fig. 72. Changes in the electrical pattern of different subcortical structures of the rabbit brain during formation and extinction of the conditioned defense reflex. 0 = before the start of formation of the conditioned reflex; 1 = initial period of formation; 2 = generalization period; 3 = fixation period; 4 = extinction period. Recording (A) from the dorsomedial nucleus of the thalamus; (B) from the ventromedial nucleus of the thalamus; (C) from the lateral ventral nucleus of the thalamus.
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structures and hippocampus. An increased level of activity w a s noted in the anterior nuclei of the thalamus and in the premammillary a r e a of the hypothalamus. The ISPO reintensified in the cortex of both hemispheres the second day after the start of extinction. During the extinction period a distinct rhythm of 4-5 c/s again appeared in the pattern of the medial thalamus and in the posterior hypothalamus. There were no appreciable changes in the other nuclei of these structures during the extinction period. On the fifth day after the s t a r t of extinction, infraslow oscillations in the cortex were like those in an intact animal prior to the formation of conditioned reflexes. There is a period of ISPO intensification in the cerebral cortex during the formation of conditioned reflexes in rabbits. Electrical activity intensifies in the thalamic and hypothalamic areas, as confirmed by the findings of Trofimov et a l . (1958). Our facts show very clearly that the greatest changes in frequency of the ISPO occur during the f i r s t 2 or 3 days after the stimuli are presented. During this time the ISPO's in the cortex increase (from 8 to 12 per min); they a r e paralleled by higher amplitude activity in the electrical pattern of certain nuclei of the hypothalamus and thalamus. After 3-4 days (generalization period) the frequency of the ISPO decreases markedly (to 2 per min), but their amplitude increases. Characteristic synchronous slow oscillations with a frequency of 4-5 c/s continue to be recorded in the record of the medial nuclei of the thalamus, posterior hypothalamus, and hippocampus. The activity is considerably reduced in the lateral and ventral nuclei of the thalamus and in certain hypothalamic structures. Changes in frequency of the ISPO in different phases of the formation of temporary connections apparently signify a different degree of involvement of the slow control system of the brain in these processes. The initial phases in the formation of the conditioned defense reflex a r e presumably accompanied by high activity of the brain structures concerned with control over the hormonal level and making considerable use of the neurosecretory mechanisms of the brain. As the conditioned reflex becomes fixed, the activity of these structures diminishes and the processes in the high-speed systems of the brain gain in importance. Analysis in the light of comparative physiology reveals that at all stages of evolution the metabolic elements involved in the formation of conditioned reflexes are realized by the slow processes (Koshtoyants, 1957). As soon as the organism experiences the need to adapt to environmental conditions, these "lower self -regulatory devices, which functioned well in maintaining certain functions at a constant level, must immediately adapt to the requirements of the particular behavioral act" (Anokhin, 1958a, p. 186). An organized behavioral act undoubtedly involved the neurohormonal complex (whisksupplies the energy needed for this act) in the reaction through the connections of the cerebral cortex with the subcortical structures. Our findings illustrate this view. The intensification of electrical activity in the supraoptic area, paraventricular hypothalamus, and dorsomedial thalamic nucleus during the generalization stages indicates that these structures may be the neural mechanism of generalized hormonal reactions,
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Intensification of the ISPO in the formation of conditioned connections and in "stress" reactions (cf. Chapter 111) suggests that the ISPO's r e flect the effect of the higher functions of the cerebral cortex being combined with the autonomic influences through the region of hypothalamic integration; they may well be connected with the emotional sphere. Thus, infraslow activity reflects the processes that play a major role in the integrative activity of the brain. SLOW CONTROL SYSTEM O F THE BRAIN
In studying the control mechanisms of the brain, it is convenient to distinguish the main types of systems, the components and interrelations. Warm-blooded animals have a rapid system and a slow system. The former controls the quick reactions to stimulation, many of which have been studied in detail, e . g . , the orienting reflex. The second evaluates more or less systematically active environmental factors and r e o r ganizes the level of activity s o as to regulate resistance and homeostasis. The slow control system influences the parameters of the rapid system, changing the latter's level of activity. If the brain were to be regarded solely as the organ of adaptation, its task would be to organize the conditions required to keep the variables of the organism within normal limits. In other words, the brain in this case would function as a homeostatic regulator. In this monograph we shall not discuss the properties of the brain and mechanisms as a whole that enable it to function as a regulator. We shall focus only on a few manifestations of such activity, specifically on what we have called the "C-fluctuations" of electrical activity in brain structures. We pointed out in earlier chapters that infraslow brain activity is intensified by certain actions after a long latency period, 30-100 and 120-200 min later. We conjectured that this phenomenon reflects the activity of the slow control system of the brain, one of the functions s e e m s to be not only to automatically adjust themsystemto keeping the internal environment constant but actively to establish a new level of activity. To characterize this system, it was necessary to analyze the electrical activity of certain brain structures whose involvement in the phenomenon of intensification of infraslow activity takes place, we assume, under the conditions of directed functioning of the system. The dynamic properties of this system were investigated by introducing artificial disturbances which disrupted its equilibrium. The subsequent behavior of the system was observed for a considerable period of time. Such a disturbance, which took place in the form of a pulse function and lasted for several seconds, was electrical stimulation of one of the brain structures by pulses of current with a duration of 10 p e c , frequency of 30 and 100 c/s, and amplitude of 4 V. Experiments were performed on 15 nonanesthetized rabbits. Bipolar electrodes were implanted in the sensorimotor cortex of both hemispheres and some parts of the thalamus and hypothalamus. Additionally, a pair of electrodes was implanted in the brain of 5 of the animals for local coagulation of the surrounding area. (This s e r i e s of experiments
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was carried out jointly with Dr. Koltsova). The following subcortical structures were investigated: (a) nuclei of
the thalamus: dorsomedial, posterolateral, reticular, anteroventral, pulvinar; (b) a r e a s of the hypothalamus: dorsal, lateral preoptic, supramammillary, ventromedial nucleus; (c) optic chiasma. The electrical activity of the hippocampus was also recorded. In analyzing the results, we were aware that the effect observed after stimulation of one of the subcortical structures is not necessarily connected directly with the activation of the particular structure because other nerve structures are also activated due to numerous connections. For example, in the hypothalamic area, an aftereffect in the form of intensified activity may occur after stimulation of about 30 structures (Niemer et al., 1960). We concentrated on the time intervals in which two stages of intensified infraslow activity would a r i s e in the brain. The following struck u s as particularly significant. When an experiment was performed on an animal for the first time, the agent did not produce the two-stage change in brain activity. Two stages were only evident when the agent was presented on the days preceding the experiment. We shall now describe the repeated experiments of this kind. The "C-fluctuations" of electrical activity that arise after introduction of a disturbance (in the form of the above-described agent) have the following characteristics. Electrical activity is markedly intensified in the stimulated nucleus and certain other nuclei after a latency period of some tens of minutes. This intensification lasts several minutes. The first cycle of "excitation" in these structures is followed by a "rest" period reflecting the original state of the electrical activity. However, 10-20 min later a new wave of "excitation" arises in the same nuclei, despite the absence of additional stimulations; this wave, in turn, gives way to another "rest" period. Such cycles of "excitation" (with a similar type of electrical pattern) a r e periodically repeated as often as five times within 2 h. They are comparable to an oscillatory process of damped nature. Thereupon, temporary, more or less sustained relaxation of activity occurs in all the nuclei. A second stage of "fluctuations" of electrical activity starts after this pause, 2-3 h from the time of the initial disturbance without the presentation of new stimulations. This stage is likewise characterized by several cycles of intensified and inhibited activity, but the electrical pattern is no longer the same as that observed a t the first stage of the "C-fluctuations". The electrical pattern of the first stage has oscillations with a frequency of 5-7 c/s giving way to oscillations with a frequency of 10-16 c/s in the periods of intensified activity. During the second stage these periods a r e marked by high-amplitude and high-frequency discharges with a frequency of up to 28 c/s. The burst or spindle-shaped form of activity takes place during this stage. Cyclic excitations of the second stage last for 1-1.5 h and cease 3-5 h from the first disturbance. However, in some instances the activity of the brain structures halts after the end of the second stage of the oscillatory process at a certain level, which then persists for several days thereafter. It will be observed that recording of the electrical pattern of the
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149 nuclei in these experiments was started only 2-5 min after stimulation s o that the earlier reactions could not be observed. Fig. 73 i s a schematic representation of the phenomenon of "Cfluctuations" in different subcortical structures with examples of the electrograms during the first and second stages of the "fluctuations". The second stage began 130 min after introduction of a disturbance. At this time infraslow activity became intensified in the cortex. This experiment was performed on August 13. On July 14, the reticular nucleus of the thalamus was stimulated for the first time and no I
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Fig. 73. llC-fluctuationsltof electrical activity in the rabbit hypothalamus and thalamus. Top, electrical pattern of the nuclei: dorsomedial thalamic (A) and dorsal hypothalamic a r e a (B) after stimulation of the latter and after stimulation of the lateral hypothalamic area (C). I = first stage; I1 = second stage. Bottom, graphic representation of the lYluctuationslt of electrical activity in the same brain structures; x = time of recording. The rise in the curve on the graph reflects increase in activity. Y-axis: amplitude of electrical oscillations (in pV); X-axis:time (in min) elapsing since presentation of the disturbance; second stage crosshatched.
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"fluctuations" could be recorded. On July 19, the same nucleus was stimulated again with no "fluctuations". On July 21, the reticular nucleus was stimulated for the third time, resulting in only one stage of "fluctuation" of electrical activity between the 16th and 190th min. The "fluctuations" resembled damped oscillations. During the periods of intensified activity that occurred at the 16th, IlOth, 120th, 130th, 160th, and 190th min, the electrical pattern of the dorsomedial thalamus revealed potential oscillations with a frequency of about 16 c/s. "Fluctuations" occurred in the sensorimotor cortex reciprocally with "fluctuations" in the subcortical structures and consisted of synchronized oscillations alternating with periods of desynchronization. During the period of "fluctuations" ISPO's appeared in the dorsomedial thalamus at the r a t e of 8 per min, in the dorsal hypothalamus 10 per min. No ISPO appeared in the reticular nucleus. A total of 8 "fluctuation" cycles were noted; no burst-like activity arose anywhere. On July 27, after an interruption of a week, the dorsal area of the hypothalamus w a s stimulated. In response "fluctuations" arose in the cortex and 100 min later damped out. Repeated stimulations on the same day evoked "fluctuations" in the dorsomedial nucleus of the thalamus and a hint that the second stage was setting in. The next day, July 28, the effect recurred in the cortex. On August 8, after an interruption of 8 days, the reticular nucleus of the thalamus was stimulated but no "fluctuations" were evident anywhere. On August 10, the reticular nucleus was stimulated again, r e sulting this time in a pronounced effect. The first stage of "fluctuations", which arose after a latent period of 28 min, and the second stage, which a r o s e 120 min after the start of stimulation and was characterized by a burst-like activity in all the structures (except the reticular nucleus of the thalamus), were observed at all the leads. ISPO too failed to appear in the reticular nucleus. The first and second stages included 3 and 4 cycles of excitation, respectively. The "fluctuations" occurred reciprocally in the cortex and subcortical nuclei. On the next day, August 11, "fluctuations" were not evoked by stimulation of the dorsal hypothalamus. On August 13 (cf. Fig. 73), the dorsal a r e a of the hypothalamus was stimulated. The first stage of "fluctuations" arose after 28 min. There was only one stage in the reticular nucleus of the thalamus which developed damped oscillations. A maximum of activity with bursts occurring in this nucleus was noted at the 35th min; ISPO's were recorded there at the same time. The second stage of "fluctuations" occurred after 120 min in the dorsomedial nucleus of the thalamus and in the dorsal a r e a of the hypothalamus. High frequencies initially predominated in the electrical pattern. These were followed by spindle-shaped activity. W e gave this day-by-day account of the experiment in order to show that the two stages of "fluctuations" occur only after systematic actions. The "fluctuation" effect was not observed in experiments on other animals the first day after the introduction of a disturbance. Repeated disturbances produced "fluctuations" similar to damped oscillations. Systematic stimulation gave rise to two stages of "fluctuations".
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The reticular nucleus of the thalamus invariably had only one stage and it was of the damped oscillations type. The phenomenon of "C-fluctuations" of electrical activity in our experiments was also evoked by stimu1.ation of the lateral a r e a of the hypothalamus, lateral preoptic area, ventromedial nucleus of the hypothalamus, perichiasmal area, and sensorimotor cortex. The latent period was shortest (from 5 to 28 min) after stimulation of the cortex and perichiasmal area; it lasted 30-50 min after stimulation of the hypothalamic areas. The longest latent period (40-60 min) followed stimulation of the preoptic area. The time when the "fluctuations" ceased also varied from structure to structure. The most prolonged "Cfluctuations" were observed after stimulation of the hypothalamic and neurosecretory areas; they lasted 5 h. Since periodic intensification of the ISPO and electrical activity may also occur in isolated cortex after stimulation of the hypothalamus (cf. Chapter IV), the question a r i s e s whether there is a relationship between the phenomenon of "C-fluctuations" and the mechanism of neurohumoral regulation. Involvement of the pituitary in the origin of the phenomenon is doubtful because coagulation of the gland o r the pathways leading to it from the preoptic areas failed to prevent the "fluctuations" from appearing. Moreover, 1 o r 2 weeks after these actions, the stages of the "fluctuations" became more intense and they appeared in nuclei where they had not been observed prilor to coagulation. For example, prior to coagulation, the second stage of the "fluctuations" was seen only in the lateral preoptic area (after it was stimulated). Within a week of electrocoagulationi of the pituitary (with histological confirmation) stimulation of the lateral preoptic areawzoked intense "C-fluctuations" of activity in the same a r e a as well as in the supramammillary area and ventromedial nucleus of the hypothalamus, the latent periods being 37, 51, and 76 min, respectively. The "fluctuations" had a second stage and they were ended by the occurrence of specific activity with a frequency of about 5 c,/s at all the leads. In another case, two stages of "C-fluctuations" arose in the lateral a r e a of the hypothalamus in response to stimulation thereof, but the phenomenon was absent in the thalami5 nuclei (lateral and dorsomedial). Unilateral coagulation was then carried out in the area of the arcuate nucleus of the hypothalamus, injuring the connections between the infundibulum of the hypophysis and supraoptic area of the hypothalamus. The background activity became intensified 10 days after coagulation in the cortex, lateral and medial nuclei of the thalamus. The lateral hypothalamic area was stimulated against this background (on the coagulated side). Two distinct stages of the "C-fluctuations" arose in response in the hypothalamic area where only the second stage, which appeared 130 min after stimulation, was pronounced. The effect was repeated after 4 days. The intensification of the "fluctuations'' observed in these experiments may have been due to the fact that coagulation by itself is a highly potent stimulus which can activate many regulatory mechanisms of the brain, a peculiar kind of "stressor" capable of causing additional disturbances in the regulatory system.
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By way of verification, we coagulated an area which can scarcely be said to have any direct relationship to the connections of the hypothalamus with the pituitary, namely, the lamina terminalis, the upper end of which abuts the anterior commissure of the hemispheres while the lower end abuts the upper margin of the chiasma. No visible changes were observed in background electrical activity of the brain after 10 days, and the initial stimulation of the dorsal hypothalamus did not evoke "fluctuations". The second stimulation a day later evoked two stages of "fluctuations", which were somewhat more intense than they were before coagulation. On the following days the response to stimulation was weak, but after a 2 day interruption two-stage "fluctuations" were clearly evident in the thalamic and hypothalamic areas. Although coagulation of the hypophyseal t r a c t caused a much sharper difference in the intensity of the "C-fluctuations", coagulation of the lamina terminalis likewise exerted a "facilitating" influence on the appearance of the two stages of "fluctuations". The problem of "C-fluctuations" of electrical activity is still in the experimental stage so that premature conclusions must be avoided. Moreover, in our experiments we observed only one aspect of the phenomenon, i.e., that manifested in changes in the electrical activity of certain areas of the brain. No doubt other processes about which we have no information take place in the intervals between these cycles of excitation. We are now concerned solely with the fact that "fluctuations" may occur reciprocally in the cortex and hypothalamic area. We should like to begin the discussion with a few thoughts about the significance of the "C-fluctuations". The existence of "C-fluctuations" in brain structures and the way the phenomenon is manifested make it possible to analyze the work of the slow control system of the brain by comparing it with a model of a regulatory system whose initial state (equilibrium) is temporarily disrupted and then left alone. The element regulated in this model meanwhile strives to regain the original equilibrium by executing around it a s e r i e s of f r e e damped oscillations. This principle of regulation in its external manifestations resembles the phenomenon of "C-fluctuations" in the first stage of the process, where emergence from the state of homeostasis is indicated by the appearance of a rhythm. The same law of restoration of the equilibrium of the regulatable element is operative in the regulation of certain autonomic functions of the body, e . g . , in a change in the blood sugar level in response to the ingestion of glucose. The former equilibrium or a new one is achieved as a result of a damped oscillatory process (Drishel, 1960). Periodic changes were recorded by Latash (1961) in the EEG of healthy subjects and patients with injuries to the hypothalamus. The changes involved an alternation of phases of synchronization and desynchronization of potential oscillations in response to the subcutaneous injection of low doses of epinephrine. The latent period for the development of desynchronization in the EEG and marked autonomic reactions like the sympathoadrenaline c r i s i s usually lasted 15-60 min, z.e., the effect did not occur in response to the direct action of the epinephrine; rather, according to the author, it was a reflection of regulatory changes
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proceeding in opposite directions that might (under optimal conditions) end in damped oscillations, although they sometimes became intensified periodically. EEG "fluctuations" in response to the injection of epinephrine can usefully be compared with "fluctuations" in the electrical pattern of the subcortical structures in our experiments. The principle of damped oscillations does not provide for the second stage of "C-fluctuations". The existence of the second stage supports the assumption that the function of the slow control system of the brain is not solely to adjust automatically the body to the preservation of homeostasis. The regulatory process includes mechanisms that markedly influence the activity of different structures and result in fixation at a new level. By this criterion the slow control system of the brain s h a r e s .the characteristics of a model of an ultrastable system, i.e., a system capable of selectively choosing the necessary values of the parameters, rejecting unstable states, and preserving those which create the stability needed to ensure adaptability to new environmental conditions (Ashby, 1954). The second stage of "C-fluctuations" may well reflect the active reorganization of the system on a new level of operation with allowance for the effect of a new factor (a unique kind of "foresight"). This view is supported by the following facts. Experiments on the same animal showed that introduction of a disturbance did not at first elicit the "fluctuations" reaction. When reintroduced (on the second or third day), the disturbance elicited only the first stage of the "fluctuations" comparable to damped oscillations (one stage). After the experiment was repeated several times a week, the disturbance would result in the complete picture of "C-fluctuations" in two stages. If these "fluctuations" ended in a shift to a new level of activity, the introduction of new disturbances during the new few days had no further effect, i . e . , they did not evoke "fluctuations". However, after an interruption of 7-10 days the entire sequence of the "fluctuations" reappeared, suggesting the existence of "forgetting" processes in the system. The above-described pattern resembles a model in which regulation by the ultrastability principle is included when a disturbance becomes a repeated factor and the system "foresees" further repetitions, choosing the necessary "field" that will ensure the most efficient operation in the new situation. If, however, the organism is subjected to an additional trauma (coagulation of certain brain structures), the second stage becomes pronounced, even, at times, to the point of exaggeration. The change in activity of the structures may then assume a pathological form and lose its regulatory influence. One has the impression that the second stage of activity is caused both by systematic actions and by the p r e s ence of "stress" stimuli in the recent past. The facts examined in this section justify our assumption that the existence of rhythmic processes are even slower than the ISPO and have a period of several tens of minutes. These "C-fluctuations" seem to "regulate" the infraslow activity. Some dynamic characteristics of the system can be found by creating nonstationary processes in the control system by the introduction of artificial disturbances. For example, this approach enabled us to discover that a rhythmic process based on a
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logarithmic law can arise in the posterolateral nucleus of the thalamus under certain conditions. Bursts of impulses a r e generalized in this structure and eventually spread by logarithmic law with repetitions every 20 min (the process is saw-like in nature). The significance of this rhythm is not immediately apparent but, by analogy with radio engineering circuits, the process may act as a time scanner. CONCLUSIONS
Infraslow activity of the cerebral cortex changes after the formation of a conditioned defense reflex in relation to the stage in which temporary connections a r e established. It accelerates at the time when the first closures appear. It increases in amplitude, but slows at the time of generalization and almost disappears as the conditioned reflex is being fixed. Intensification of infraslow activity in the cortex is paralleled by intensification of electrical activity in certain subcortical structures: supraoptic a r e a of the hypothalamus, paraventricular nuclei, dorsomedial nucleus of the thalamus, and hippocampus. W e believe that the activity of these structures is connected with neurosecretory processes and hormonal factors. During fixation of the conditioned reflex, activity in these structures and infraslow activity are weakened simultaneously. Thus, the ISPO's reflect the results of higher cortical functiOns being combined with metabolic (hormonal) factors by the mechanisms responsible for hypothalamic integration. On the other hand, the ISPO mechanisms are closely associated with the activity of the slow control system of the brain. One of the characteristics of this system is that it does not r e a c t to a slight, one-time (accidental) external disturbance. Its reaction to an environmental factor that acts more or less systematically persists for several hours and it may be directed not only at overcoming the changes brought about in the internal environment but at reconstructing the level of activity with due regard for the possible effect of the new factor. The aetivity of the slow control system may be modeled in this respect by a system operating on the ultrastability principle. Another characteristic of the system is the long latency period of the response and the hours-long period of regulation that includes a variety of mechanisms. One way of discovering the control mechanisms may be by tieing into the system a nonstationary transitional process involving a temporary disturbance and then letting the system alone. Under these conditions the electrical activity of certain brain structures undergoes rhythmic "fluctuations" with a period of 20-30 min. There may be one o r two stages of these "fluctuations" lasting 2-3 h each, with a different kind of activity in each. Infraslow activity becomes intensified in the two stages. A rhythmic process occurs during the nonstationary interval with the same period (20-30 min). The discovery of these rhythms will enable u s to investigate the unknown mechanisms of regulation, whose
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155
manifestation under the conditions of an equilibrium we do not know. A preliminary examination suggests that a chemical code underlies the activity of certain links in the control process.