The Four Major Concepts
Sleep, an active phenomenon. Until recently neurophysiologists had considered sleep to be a unique passive state opposed to waking. With the discovery of the ascending reticular activating system (1), waking could be explained in terms of an increase in the activity of this activating system, and sleep, in terms of the passive dampening of the system (2). This theory requires only one system to explain the succession from waking to sleep and thus obeys the law of economy according to which a living organism always selects the simplest possible means of realizing a potential function. This theory of sleep was widely accepted initially but has since been drastically challenged.
The finding that sleep could be induced by electrical stimulation of different parts of the brain was at variance with the passive theory of sleep. How ever the "passive theorists" could easily defend their position by questioning the validity of electrical stimulation. It is exceedingly difficult to conceive of a system of sleep as diffuse as that suggested by studies of stimulation; sleep can be induced by stimulation of many different parts of the brain, including those which overlap the ascending reticular activating system: cortex, thalamus, subthalamus, hypothalamus, mesencephalon, pons, cerebellum, medulla, spinal cord, sensory nerves, and so on (3). In the absence of stimulation a cat with electrodes permanently implanted in its brain may sleep "spontaneously" 60 to 70 percent of the time (4). Thus the probability that the cat will "fall asleep" spontaneously after electrical stimula tion of the brain is greater than the chance level; very few experiments deal ing with "hypnogenic" stimulation (electrical or chemical) provided conclusive and statistically significant data. Finally it was realized that sleep could be induced only by stimulation of low frequency corresponding to the frequency of the sleep spindles. In sum, the finding that sleep could be induced by stimulation was not a major proof that the passive theory of sleep was invalid.
To prove the existence of an active sleep-inducing system it was necessary to produce a state of insomnia by means of a lesion destroying this system. The first step in this direction was transection of the brain stem immediately be low the ascending reticular activating system. A mid-pontine transection was shown to produce a definite increase in waking behavior and in electroencephalographic traces characteristic of waking (5). This suggested that synchronizing or hypnogenic structures were located in the lower brain stem. However, limited lesions in many structures of the pons or the medulla (mostly in the lateral part of the lower brain stem) did not reveal a definite location of these hypnogenic structures (6). Nevertheless, in 1960 most neurophysiologists were ready to accept the hypothesis that there are sleep-inducing mechanisms which can actively dampen the activity of the ascending reticular activating system.
This concept was more readily accepted when, at about the same time, new and conclusive data indicated that sleep could not be considered a unique phenomenon opposed to waking but did in fact, at least in the mammalian and avian brain, consist of two successive states.
Sleep or sleeps. The concept of the dichotomy of sleep has very ancient roots, predating even modern physiology (7). Major advances are marked by publications that appeared in the late 1950's (8). Since this topic has been the subject of many recent reviews (9), I shall survey it very rapidly.
In brief, the mammalian sleeping brain successively passes through two states which can be recognized very easily through the application of poly graphic techniques in the study of ani mals with electrodes permanently im planted in the brain ( Fig. 1).
The first state has been called slow wave sleep (10). In this state the animal has a posture characteristic of sleep, its eyes are closed, and the pupils are myotic. A degree of postural tonus al ways remains in some muscle groups of the body (including those of the neck). The electrical activity of the cortex is characterized by spindles and slow waves.
After a time this state is succeeded by a totally different state. I have given it the name of paradoxical sleep (11) because I found that the association of a cortical activity similar to that of waking with a total absence of electromyo graphic activity associated with muscular activity of the neck appeared paradoxical. Paradoxical sleep has two different phenomenological aspects, which may be described briefly as follows.
1 ) Tonic activity. There is a fast, low-voltage cortical activity similar to that of waking, associated with a regular theta rhythm in the hippocampus and a total disappearance of electromyographic evidence of muscular activity. Tonic phenomena persist for several minutes and are accompanied by phasic behavioral and electrical phenomena which are highly characteristic of paradoxical sleep in most mammals.
2) Phasic activity. Rapid eye movements (50 to 60 per minute) occur in a rather stereotyped pattern which is different from that of waking. They are associated with a cortical and subcortical activity which has been termed pontogeniculo-occipItal. activity, or deep sleep waves (12, 13). Such phasic activity is composed of high-voltage waves which can be recorded from the reticular formation of the pons, from the lateral geniculate, and from the occipItal. cortex. They are almost identical to those recorded during visual attention (13). Apparently these "PGO" waves occur in a rather fixed pattern, since they occur at a fairly constant daily rate in the cat (14,000 + 3000 waves per day) (14). They occur transiently during slow-wave sleep, and they always precede paradoxical sleep by some 30 to 45 seconds. Their rate during paradoxical sleep is also fairly constant (0 + 5 waves per minute). The inner most mechanism of these PGO waves is a fascinating problem which has not yet been solved, despite many investigations (12, 13, 15). During paradoxical sleep a "spontaneous" activity occurs periodically which resembles the electrical activity of visual input during waking. Neurophysiological evidence suggests that, during this state of sleep, active phenomena are triggering electrical events (PGO waves) and behavioral events (rapid eye movements) which may have earlier counterparts in the waking events of visual input. This suggestion may provide a cue for understanding the function of paradoxical sleep.
This brief description of the phenomenological events occurring during slow wave sleep and paradoxical sleep is certainly not sufficient to prove that these two types of sleep are associated with two different functional states of the brain. However, this association has heen well demonstrated by the finding that paradoxical sleep may be selectively suppressed without altering slow-wave sleep, through the use of various drugs and through specific lesions. These neuropharmacological and neurophysiological data favoring a dualistic theory of sleep are strongly supported by ontogenic and phylogenic studies.
Numerous investigations (16) have shown that, immediately after birth, most newborn mammals of species whose central nervous system is incompletely developed at birth (for example, the cat, rat, and rabbit) manifest only the succession from waking to paradoxical sleep. Slow-wave sleep appears later, when the maturation of the cortical network is achieved. In newborn mammals of species whose central nervous system is well developed at birth (for example, the guinea pig and lamb), slow-wave sleep and paradoxical sleep alternate in a periodic fashion immediately after birth.
Even if the phylogenetic story of sleep is far from complete, the dichotomy between slow-wave sleep and paradoxical sleep has been well demonstrated. Paradoxical sleep has been shown to be absent in fish (17), probably absent in reptiles (18), present but very short-l;ved in birds (19), and present in every mammalian form studied up to now, from the opposum (20) to the elephant (21) and, of course, man (8).
In summary, in phenomenological, neuropharmacological, neurophysiological, ontogenic, and phylogenic studies, two qualitatively different states of sleep involving two different mechanisms and probably serving two different functions are distinguishable.
Quantitative aspect of the sleep states. The first step in the study of the sleep states was description of their qualitative patterns. During this time no quantitative study of sleep was attempted, due especially to economic and technical difficulties. Recent data, however, have shown that the sleep states are, like the rectal temperature, the heart rate, and the basic metabolism, a biological constant (4). It is thus possible to consider slow-wave sleep and paradoxical sleep as a quantitative index of the innermost mechanisms of the brain. This advance has made it possible to study the sleep states in relation to quantitative alterations in brain func tion such as result from drug injection or limited brain lesion, or in relation to data obtained through biochemical analysis. It is also possible to correlate the circadian variation of the sleep states with the circadian biochemical variation in the brain (22).
Sleep is a subject of "wet" neurophysiology.
With the advent of a growing interest in the biochemistry of the nervous system, F.O. Schmidt has introduced the terms "dry" and "wet" neurophysiology, with reference, respectively, to the electrical and the neurohumoral phenomena (23). Ten years ago the passive theory of sleep could be relatively easily explained in terms of dry-neurophysiology mechanisms (for example, the reduction of afferent input to the ascending reticular activating system, neuronal fatigue, and so on) (2). When it was realized that sleep is a diffuse system, a dry-neurophysiology mechanism could no longer explain the circadian variations of the organism. The time constant of the electrical potentials of the brain is of the order of milliseconds and can therefore not be that of the circadian or ultradian rhythmicity of the sleep states. This concept is most conclusively demonstrated by the alteration in sleep states that is effected by selective deprivation of paradoxical sleep (24). Following such deprivation, a long-lasting , rebound of paradoxical sleep (increases in frequency of phase and frequency of PGO waves) (14) occurs, which usually lasts for a period approximately half the duration of the deprivation. No dry neurophysiology mechanism, however sophisticated, can explain this rebound phenomenon, which may last for several days or even weeks.
Thus any theory of sleep must depend upon the concept of wet neurophysiology for its validity.
In summary, recent major advances in the neurophysiology of sleep have led to the following concepts.
1) Sleep is an active state of the brain. Thus, it should be possible to produce insomnia through circumscribed lesion of the brain.
2) Sleep is not a single phenomenon but, instead, consists of two different states which involve two different mech anisms of the brain. Thus it should be possible to selectively suppress either slow-wave sleep or paradoxical sleep by limited lesion or by drugs.
3) The sleep states can be quantita tively measured. Thus it should be possible to correlate their quantity with any suitable quantitative biochemical, neuropharmacological, or structural alteration.
4) Biochemical mechanisms which cannot be explained exclusively in terms of short-term neuronal mechanism are involved in sleep states.
* Student's t-test values for P obtained by comparison with group A; NS; not significant. Each P column refers to the column that immediately precedes it.
Table 1. Comparison, for various groups of cats with brain lesions, of (i) the amount of sleep following surgery, expressed as a percentage of total recording time (10 to 13 days); (ii) the percentage of the raphe system left intact; and (iii) the amounts of serotonin and noradrenalin in the brain rostral to the lesion, expressed as percentages of the amounts in the brains of normal control cats. The group divisions are based on the extent of the lesion and the amount of sleep following surgery: (A) cats with insignificant destruction of the raphe system-an amount having no effect on sleep; (B and C) cats with major but less than total destruction of the raphe system; (D) cats with almost total destruction of the raphe system. The percentages are mean values for an entire group, plus standard deviation.
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