II. State of sleep chacterized by slow cortical activity slow sleep
C. Structures and Mechanisms Responsible for Slow Sleep
It is difficult to study the mechanisms of sleep without briefly recalling the classical conception of the wakefulness system, which has been the basis for some years of the passive theory of sleep. Later results in some ways explained but also complicated our interpretation of the mechanisms responsible both for fast cortical activity (arousal reaction) and for behavioral wakefulness.
Passive theory activating reticular system and reticular hypothesis of sleep
An outline of the classical conception of the arousal system (163, 164, 30l, 326, 386, 402). Since 1949 (332) it has appeared that the brain-stem RF (see 71) is responsible for cortical arousal through the ascending reticular activating system (ARAS) as well as for behavioral arousal (either through the ARAS and then by a second ary corticofugal effect or by a simultaneous action on the descending reticular facilitatory system) (301, 302). According to the pioneer work of Moruzzi and Magoun (332), the ARAS occupies the brain-stem tegmentum from the medulla to the rostral part of the mesencephalon, and its corticopetal projections take either a thalamic or an extrathalamic route (409). The ARAS, a nonspecific for mation, receives collaterals from various specific pathways (301) as well as corticofugal projections that may converge at the level of the same neurons (70, 165, 325). Having an automatic unit activity (61), the "activating tone" of the ARAS is maintained by sensory inputs as well as by humoral factors. Among the latter, adrenaline would come first (116). The tonic and phasic ascending or descending reticular activity appears to be "catholic" (301). It may, however, be controlled by the cortex via a reticulo-cortico-reticular feedback mechanism (219-221). The hypothesis of a "reticular homeostasis" was recently documented in detail (115, 117). It is not our purpose to discuss this further in this review, for the "time constant" of the damping cortical action over the ARAS (shown in acute experi ment) is too short (a few msec) to explain the phenomena concerning falling asleep.
Passive theory of sleep and reticular hypothesis of sleep. The historical roots of the passive theory of sleep may be traced back quite far (see 330). Kleitman, one of the supporters of this theory, clearly explains its bases "to fall asleep" or "to be unable to remain awake" have not the same meaning. The "first term implies an active onset of sleep, while the other implies a cessation of an active condition of wakefulness" (277), i.e. a passive mechanism. If so, it is not sleep that needs to be explained, but wakefulness. Bremer's experiments (64,66) attributing the "sleep telencephalic syndrome" of the "cerveau isole" preparation to the "suppression, by interruption of the corticopetal paths, of the steady flow of excitatory impulses which are essential for the maintainance of the waking state" (67) advanced a very important electrophysiological argument in favor of Kleitman's concept. Sleep seemed then the result of a specific deafferentation of the telencephalon.
The discovery of the ARAS allowed us to alter this hypothesis slightly without, however, changing its essential meaning. Physiological sleep was then interpreted as the expression of a functional deafferentation of the ARAS "eliminating the waking influence of the ARAS" (332) and so as an absence of wakefulness. This reticular hypothesis of sleep (291) was founded on the extrapolation of the main following results.
Coma resulting from the extensive destruction of the mesencephalic tegmentum (166, 292, 293) or from barbiturate narcosis (whose depressive influence over the ARAS had been shown) (19, 167) was attributed to the interruption of an ascending flow of reticular impulse. Physiological sleep, as compared with coma, was then explained by a functional, passive reduction of the tone of the ARAS. So according to the reticular hypothesis, sleep would be due to the "desactivation en avalanche" of ascending impulses of the ARAS. This deactivation would be initiated by a slowly developing process of neuronal fatigue, precipitated at a given moment by a reduction of sensory input (66, 67).
Numerous criticisms have been raised against the passive theory and the reticular hypothesis of sleep (328).
I) The "desactivation en avalanche" explains neither why sleep may be induced by central or peripheral stimulation (see below), nor why, if it is a question of "neuronal fatigue," sleep may be obtained for such a long time (60 % of the day in the caged cat).
2) The comparison of the coma produced by extensive lesion of the mesencephalic tegmentum with physiological sleep is not allowable. As a matter of fact, in case of coma, the loops between diencephalon and brain stem are interrupted and the extrapyramidal movements that accompany behavioral arousal are no longer possible. On the other hand, it is not certain that a reversible coma tose state (by extensive lesion of the mesencephalic tegmentum in the animal) (3) might not be accompanied by a certain state of "cerebral wakefulness." It is important in this connection to report the anatomoclinical observation of Lhermitte et al. (290) a patient who had a total softening of the mesencephalic reticular formation, and whose behavior was similar to a comatose state (bilateral ptosis and akinetic mutism), was indeed able to answer precisely, through discrete flexion of the forearm, very complicated questions. Thus, this case shows that it is extremely difficult to estimate the "vigilance" level of an animal that is no longer able to manifest behavioral responses after the destruction of the extra pyramidal pathways of its tegmentum. Man alone can use adequate means to express that he can still understand (and hence that he is indeed "awake").
3) The unit exploration of the ARAS has not always revealed a reduction of the unit activity during physiological sleep (224). This argument, however, is not definitive, since there may be a reduction of the general reticular activity level during spindle activity in the animal under curare (399). Nevertheless, such a reduction in activity may be induced by an active mechanism. So the passive theory of sleep does not allow us to explain satisfactorily the processes of falling asleep and gives way now to "active" theories, which are developed below. It is still necessary to examine some recent developments of the physiology of arousal, for other structures than the ARAS may be responsible for cortical or behavioral states of arousal.
Recent aspects of the physiology of wakefulness. Two types of results have recently caused us to modify the general opinion that the mesencephalic reticular formation is the only one responsible for cortical and behavioral waking.
STRUCTURES RESPONSIBLE FOR CORTICAL ACTIVATION (AROUSAL).
The topography of the neurons activating the cerebral cortex (within the ARAS) appears to be more limited than had been first thought, since neither the bulbar RF nor the pontine RF is necessary for the occurrence of a cortical fast low-voltage ac tivity. Indeed, a midpontine section causes an increase of cerebral wakefulness (see below). The most crucial area of the ARAS responsible for cortical arousal seems to belong mainly to the anterior zone of the nucleus reticularis pontis oralis (RPO) and to the posterior zone of the mesencephalic tegmentum, since coagulations only at these levels induce a slow electrical record lasting for several days (29), whereas stimulations at these same levels involve the most tonic ac tivations (62). This region may also be responsible for the cortical activation triggered by cortical stimulation (316) or by ether anesthesia (387), which is well known to be impossible after a brain-stem intercollicular transection (a section anterior to nucleus RPO).
In addition to the ARAS neurons, however, there is another extrareticular system situated in front of the mesencephalon that may be responsible for cortical tonic desynchronization, since the slow cortical activity of the cerveau isole (which is no longer under the influence of the ARAS) yields to "spontaneous" cortical desynchronization, progressively prevalent when the animal survives for more than 8 days (32, 33, 176, 206, 273, 329, 427). The meaning and mechanisms of this desynchronization are still imprecise. It cannot be the manifestation of a telencephalic paradoxical sleep (PS), for the activation is not synchronous with the PS behavioral signs (triggered from the pons) (206). In some cases, this desynchronized cortical activity was even accompanied by ocular signs of wake fulness (tracking ocular movements) (273). The facilitatory role of hypothermia in the occurrence of desynchronization in the cerveau isole first suggests the hypothalamus might be the activating structure, but there is as yet no definite evidence for this point of view (32, 206). It is a matter for chronic, long-lasting experiments, and these observations pose once more the problem of suppression of a possible diaschisis or of a hypersensitivity of denervation whose neurohumoral bases are still unknown.
STRUCTURES RESPONSIBLE FOR BEHAVIORAL AROUSAL.
It is possible, too, to dissociate, by circumscribed lesions, the activating ascending action of the ARAS responsible for cortical arousal and the descending intervention of other structures responsible for behavioral arousal. On the one hand, chronic lesions of the mesencephalic tegmentum may suppress cortical desynchronization after a nociceptive stimulus, though the animal is behaviorally awake (159, 240); on the other hand, limited coagulations of the posterior hypothalamus induce a comatose behavior, without behavioral arousal after nociceptive stimulus, whereas a tonic cortical activation may still occur (159). This corroborates the classical experiments of Ranson (225, 364, 365; see also 338) and the clinical observations of von Economo (135), which suggested that the structures responsible for behavioral arousal were situated at the level of the hypothalamus. It is also at this level that local coolings may provoke the occurrence of sleep behavior (336, 337).
Thus the integrity of the posterior hypothalamus seems to be necessary to waking behavior. The reticular descending system would then appear more like a relay or a servomechanism (128) by comparison with hypothalamic struc tures, since it would be unable by itself to achieve the complex motor integrations of the waking state. This short summary of the evolution of ideas concerning arousal systems allows us to conclude that the ARAS is not the only structure essential to a tonic cortical desynchronization and that the reticular descending system does not itself appear to be sufficient to induce a true behavioral arousal. Moreover, it seems very likely there are structures at the diencephalic level that can themselves induce the occurrence of fast cortical activity, and that the integrity of these structures is necessary for the appearance of a behavioral arousal.
PHYSIOLOGICAL EVIDENGE. After a complete midpontine pretrigeminal section (midpontine pretrigeminal preparation MPP (28-3I)) the cortical EEG shows a very definitive predominance of fast activity (78% instead of 37%). Moreover, the oculomotor reactions of this preparation (depending on the IIIrd and IVth nerves) undeniably evoke a true alertness the midpontine cat follows with vertical eye movements any object passing across its visual field (271). There is a mydriatic response to darkness (272) and a pupillary dilatation may occur at presentation of significant visual stimuli (mice) (29), which may be conditioned by hypothalamic stimulation (9,10), whereas visual accommodation persists to near objects. Other experiments allow us to eliminate an eventual irritative action on the ARAS (persistence of alertness for several days), as well as the possible role of certain humoral disturbances (28). Thiopentone injection into the vertebral artery after clamping the basilar artery causes the appearance of a fast cortical activity, whereas injection into the carotid artery is followed by cortical synchronization (298). But a cerveau isole transection, frontal to (or destroying) the anterior part of nucleus RPO, induces a synchronized cortical EEG during the first few days, without there being any ocular sign of wakefulness (10, 11, 29). Since the encephale isole preparation still presents alternate wakefulness and slow sleep (65, 66), it may be concluded that tonically active EEG synchronizing structures, located in the lower brain stem, are able to dampen the arousing activity of the ARAS.
LOCALIZATION OF THESE STRUCTURES. Some experiments favor a bulbar localization.
2) Local coagulation of the solitary tract nucleus area involves increased activity at the level of the short ciliary nerves (responsible for pupillary dilatation), induced after reticular stimulation (59, 63) in the encephale isole preparation.
3) Local reversible cooling of the bulbar floor of the 4th ventricle in the cat encephale isole preparation produces EEG and behavioral arousal, attributed to the inactivation of the bulbar synchronizing structures (whereas cooling of the pontine floor, on the contrary, produces EEG and behavioral sleep signs) (44, 45)
To these results we may add the observation, in the rat, of an increase in unit activity at the solitary tract level at the onset of slow sleep (97). So, there is much evidence (often obtained in acute conditions) suggesting that the tonically active EEG synchronizing structures, which counteract the ARAS tonic activity, are situated at the level of the medulla. However, other experiments, usually chronic, support a posterior pontine localization.
1) A brain-stem hemisection at midpontine level leads to the oc currence of a desynchronized activity at the level of the homolateral hemisphere, and a hemisection made a few millimeters in front induces a synchronized cortical activity; the former is made by suppression of the ascending synchronizing in fluence, the latter by suppression of the ARAS tonic activation. A hemisection situated a few millimeters behind the midpontine section does not cause cortical asymmetry (107, 108) (though logically it should suppress the bulbar ascending synchronizing influences). Rossi et al. (384) agree that retropontine hemisections do not produce any cortical EEG asymmetry and hence attribute an important part in the triggering of cortical synchronization to the posterior zone of the pons. However, subtotal lesions of the posterior part of the pontine RF do not prevent behavioral and EEG slow sleep (240) although they may increase the duration of desynchronized cortical activity in chronic preparations (89).
Possible role of serotonergic neurons in slow sleep. Recently, using the new fluorescent techniques of Falck et al. ( 146, 147), Dahlstrom and Fuxe ( 114, 169) have described two systems of monoaminergic neurons in the brain stem. The catecholaminergic neurons (mostly noradrenergic) with green fluorescence are located mostly in 12 groups (A1-A12) in the lateral part of the medulla, pons, and mesencephalon, whereas serotonergic cell bodies with yellow fluorescence (which is increased after injection of a potent inhibitor of mono-amino-oxidase) are almost exclusively located in 9 groups in the raphe nuclei of the brain stem. Serotonergic terminals from these cell bodies have been located in the spinal cord, the brain stem, and the rostral part of the brain.
Destruction of the raphe nuclei of the brain stem in chronic cats leads to a state of almost permanent wakefulness (244), and there is a decrease of 80-90 % in both slow sleep and paradoxical sleep during the first 2 weeks after the operation. A state of permanent EEG and behavioral wakefulness is obtained during the first 4 or 5 days. Destruction of either the anterior or the posterior half of the raphe system decreases slow sleep but less (50-60 %) than does total destruction. These experiments, together with the results of neuropharmacological alterations of brain monoamines on sleep (see below), have led to the hypothesis that "monoaminergic" neurons could be involved in sleep mechanisms.
There are thus many concordant experimental data in favor of synchronizing and sleep-inducing structures in the lower brain stem. Nevertheless more experi ments are needed in order to delineate precisely these structures and to determine whether they belong to some specific nuclei located in the medulla or the pons or whether they belong to a monoaminergic system composed of serotonergic neurons occupying the raphe nuclei from the medulla caudally to the caudal mesencephalon rostrally.
MODE OF ACTION OF EEG SYNCHRONIZING CAUDAL STRUCTURES. The mode of action of these structures, located either at the level of the posterior part of the pons or at the level of the medulla, is still unknown. They may act directly on the ARAS (296, 328, 331), but there is no electrical synchronization (recorded with macroelectrode) to corroborate this hypothesis in decorticate animals. Actually, no synchronization (spindles or slow waves) appears during behavioral sleep at the midbrain tegmentum level in chronic decorticate preparations (240). In posterior mesencephalic or chronic pontine preparations (which have no behavioral sleep comparable to slow sleep) a wide exploration of the brain stem in chronic conditions has not yet allowed us to record reticular synchronizing phenomena during periods preceding PS (240, 242).
Consequently, if tonic synchronizing structures do exist in the lower brain stem, there is no evidence their synchronizing activity acts directly on the ARAS; in fact, it may act on more rostral structures, diencephalic or cortical. There is no evidence that ARAS is only "inhibited from behind," for other facts are in favor of deactivation "from in front."
Descending hypothesis. PHYSIOLOGICAL EVIDENCE. On the one hand, the thalamus appears to be necessary for the occurrence of spindles, since its destruction by coagulation (293), section (109), or aspiration (337) abolishes cortical spindles during onset of sleep while cortical slow waves persist.
On the other hand, after complete removal of the neocortex (240, 251, 418), there appears an immediate permanent disappearance, lasting several months, of the synchronized or slow activity at the subcortical structures (thalamus or reticular formation) level, even after pentobarbitone injection (251, 404). How ever, the recruiting response (RR) obtained by medial thalamic stimulation may persist at the RF level after decortication (396, 400, 401), but it is likely that the RR is induced by mechanisms different from those provoking the sleep spindles, since it is not accompanied by pyramidal responses typical of spindles (72). On the contrary, if even a small part of the gyrus orbItal.is and coronalis anterior is left undamaged, reticular slow waves may persist during sleep (240) in subtotally decorticate chronic cats (240). This fact suggests that the basal part of the cortex is essential for the subcortical synchronization of slow sleep. This hypothesis has found support in the recent experiments of Velasco and Lindsley (424). In acute conditions, ablation of the entire dorsal convexity and of the medial and cingulate regions of the cortex failed to interfere with the spindle bursts whereas ablations confined to the orbItal. cortex alone abolished completely these potentials in both cortex and thalamus. Therefore the orbItal. cortex appears to be the only region of the neocortex to play a crucial role in the regulation of the thalamo-cortical synchronizing function.
Other experiments are also in favor of a descending cortical synchronizing influence on the brain stem but they do not permit us to localize a specific cortical region.
The functional depression of the cortex (by local application of KCl), which involves the "spreading depression of Lao" suppressing the cortical EEG, abolishes the reticular spindles and slow waves (54, 432, 434).
Unilateral, only cortical, interventions (removing of the dura mater) involve cortical homolateral synchronizing phenomena (419).
These data permit us to infer that the synchronized slow activity observed at the brain-stem level during slow sleep necessitates the presence of the cortex, and most probably the orbItal. cortex, and therefore that there are synchronizing but not obligatory sleep-inducing structures at a rostral level.
MODE OF ACTION. The activating influence of the cortex on the ARAS has been repeatedly demonstrated in acute (70) as well as in chronic conditions (403) and has been confirmed by the demonstration of postsynaptic excitatory potentials by cortical stimulation at the level of the reticulospinal neurons (299). On the other hand, the mechanisms of inhibitory action of the cortex on the ARAS are still almost unknown. To date, it has not been possible to elicit postsynaptic inhibitory potential (by intracellular recording at the ARAS level in acute experiments) after cortical stimulation (299, 300). However, there is some evidence suggesting that the cortex may have an inhibitory descending influence, either on the ARAS or on the facilitatory descending reticular system.
On one hand, gamma activity is depressed during cortical spindles (76, 214); on the other, cortical stimulation can inhibit, in a lasting and cumulative way, the unitary activity at thalamic level (282), but no direct proof of this action has been yet found at the hypothalamic or mesencephalic tegmentum level. According to Krnjevic et al. (283), this cortical inhibition would be the expression of an eventual noncholinergic chemical agent.
DESCENDING PATHWAYS. The descending pathways responsible for synchronizing phenomena at the brain-stem level still remain largely unknown. Nevertheless, we know the part of the pyramidal tract that transmits the spindles of cortical origin (8, 437). Pyramidal projections have also been described at the pontobulbar RF level (190, 297). The limbic midbrain circuit (339), and particularly the medial forebrain bundle, may constitute a descending pathway, receiving inhibitory influences from the neo- and paleocortex. The impingement point of the limbic midbrain circuit with the ARAS would then be located at the level of the limbic midbrain area described by Nauta (339); it must be admitted, however, that lesions at this level do not suppress slow sleep (95, 206).
SUBCORTICAL SYNCHRONIZATION AND SLEEP. In the neodecorticate animal, the presence of behavioral sleep phases (240), preceding PS, was established, apart from any synchronizing phenomenon at the thalamic or mesencephalic tegmentum level. Therefore we must conclude that ARAS synchronization is not a necessary condition for the occurrence of a sleep behavior. Nevertheless, the existence of high-voltage spikes at the rhinencephalon during this state (240) suggests the eventual role of a paleocorticofugal descending influence normally added to the neocorticofugal synchronizing influence, thus accounting for sleep in de corticate animals. The inhibitory (but not synchronizing) action of the rhinen cephalon at the ARAS level has been described in acute experiments (6). How ever, there is as yet no proof that the high-voltage spikes observed either at the level of the rhinencephalon or in its efferent pathways (240) exert an inhibitory activity acting on the hypothalamo-reticular arousal system.
There are thus many concordant facts that favor the existence of behavioral and EEG sleep-inducing structures in the lower brain stem, and it is possible that these structures belong to a group of serotonergic neurons located in the raphe nuclei. On the other hand, the orbItal. cortex, which seems to play a de terminant role in the appearance of the EEG pattern of slow sleep (cortical and subcortical spindles and slow waves), is not, however, necessary for the appearance of behavioral sleep.
A possible explanation of these apparently contradictory facts would be that the sleep-inducing structures of the lower brain stem may act directly on the ARAS without generating synchronization.
The orbItal. cortex would then secondarily assume its necessary synchronizing influence, either through a direct action from the lower brain-stem structures or indirectly through the decrease of the activating effect of the ARAS.
Whatever may be the interpretation of the contradictory facts reported, supporting either of the hypotheses trying to delimit the structures responsible for behavioral drowsiness and for synchronization, other experimental results suggest that slow sleep may be actively induced by both central and peripheral stimulations. These are based on the results of stimulation and that is why they will be treated separately, for they produce no definite conclusions in favor of either the ascending or the descending hypothesis.
Results of electrical and chemical stimulations. CENTRAL TRIGGERING OF SLOW SLEEP. This field was opened by Hess' classical experiments (202, 203). In chronic experiments in cats (145) low-frequency (from 3 to 15 cycles/sec) stimulation of numerous structures in the brain may induce spindles or cortical slow waves with or without sleep behavior (as a matter of fact, we know that the presence of recruiting cortical waves by thalamic stimulation may be observed during behavioral arousal) . That is why, successively, the following have been described or suggested as "hypnogenic" structures some cortical areas frontal, somesthetic cortex; anterior and posterior suprasylvian gyrus (82), visual and motor cortex (347, 355); head of the caudate nucleus (77, 78); the internal capsule (186); the preoptic region (102, 103, 199, 412, 413, 443); dorsal (349) or ventral hippocampus (264, 349); the amygdala (280, 281); the anterior (150, 264, 349) or posterior (348) hypo thalamus; mamillary bodies (349); the thalamus massa intermedia (13, 203); diffuse thalamic system (14, 222, 317, 318); the interpeduncularis nucleus (348, 349); the mesencephalic (157, 191, 259, 257) or pontine (90, 382, 383) reticular formation; the cerebellum (448); and the medulla region of the solitary nucleus (295, 296). So almost the whole encephalon has hypnogenic capacities. That is why the localizing value of hypnogenic electric stimulations is little justified the interpretation of the results yielded by this method indeed meets numerous difficulties. The stimulation may not act on neuronal cell bodies at all but rather on their afferent or efferent axons. On the other hand, one stimulation may excite both synchronizing and activating elements, though most stimulations are of low frequency (that of spindles). Moreover, it is difficult to know whether sleep is induced by the stimulations or has been spontaneously produced, for most in vestigators agree that the occurrence of sleep is favored by stimulating a "relaxed" animal and that it is extremely difficult to induce sleep during a state of intense alertness, except with long repeated stimulations (375). In fact, a careful survey of the numerous experimental results in which EEG and/or behavioral sleep has been induced by cerebral stimulation is quickly discouraging and we have been unwilling to undertake such a difficult synthetic work, so imprecise and varied are the criteria used to define sleep. We refer the interested reader (who trusts the effect of hypnogenic cerebral stimulations) to Parmeggianl's recent paper (349), which is one of the most fully documented. Our personal experience, during which we have stimulated hundreds of chronic cats over a period of several years, has not convinced us that a cat, asleep after any stimulation (other than the painful ones), would not have gone to sleep spontaneously. Actually, if a hypnogenic intracerebral stimulation is effective, it is because the numerous bodily needs responsible for wakefulness are fulfilled heat, food, comfort, etc. It is possible that some intracerebral stimulation may induce behavioral or/and EEG sleep in a hungry, frightened female cat during estrus, exposed to a cold environment, but in such an unusual case, it would certainly not be a "physiological sleep." This methodological problem again explains why research about sleep is so protracted and yet also so fascinating.
Finally, it must be pointed out that sleep induced by central stimulation has only been observed in animals with an intact cortex. Stimulation of the thalamus in neodecorticate animals does not induce sleep (240).
The solution expected from chemical stimulations in situ is not yet forthcoming. As there are serious criticisms as to the specificity of the action of the drugs (366), such techniques have no greater localizing value than have electric stimulations. The areas in which chemical stimulations are claimed to induce slow sleep, either EEG or electrical and behavioral, become more and more numerous, and in a few years they may cover all the places where electric stimulations induce sleep. Though adrenaline injected in situ at the brain-stem level has a clear arousing action, the proof of the arousing action of adrenaline or noradrenaline is, however, not yet definitely established (see 35); the injection of adrenaline into the carotid has no activating effect (94). On the other hand, in young birds and kittens whose blood-brain barrier is permeable, adrenaline injection induces behavioral sleep (268, 307). Likewise, a state "resembling sleep" may be obtained by injecting adrenaline at the level of the ventricles (158). Acetylcholine or serotonin (445) injected in microcrystals appears to have a real hypnogenic effect. Injected at the level of the caudate nucleus (445), the preoptic region (197, 198), the medial thalamus (445), the pontine reticular formation (109), and the limbic midbrain circuit (199), they may produce slow sleep states, though sometimes these states seem more like coma because it is so difficult to wake the animals (197).
PERIPHERAL REPLEX INDUCTION OF SLOW SLEEP. "Slow sleep" may be induced not only by cerebral stimulation but also by the stimulation of numerous afferent systems e.g. auditory stimulations (378), repetition of insignificant tones during habituation (238, 389), or the repetition of tones that have acquired an inhibitory signal value (in Pavlovian terminology) (327, 388), intermittent photic stimula tions (21), stimulation of the cutaneous (Group II) or muscular nerves (360, 361, 378). The synchronizing cortical action of pressure applied to the skin (285) has also been described. Vegetative afferent influences may also induce drowsiness vagus (118, 354) or laryngeal stimulations (369), probably acting via vagal afferents, may induce EEG, ocular, and behavioral signs of sleep. Finally, the profound sleep-like state observed by Koch (278), caused by stimulation of the depressor nerves, may also induce an EEG pattern of sleep in the encephale isole, where no change of blood pressure is produced (60). All these findings show that slow sleep may be actively induced but do not give any knowledge about these active mechanisms. On the one hand, the role of these stimulations does not appear to be exclusive, since the encephale isole animal, with buffer nerves and vagi transected (disconnected from most vegetative and muscular afferents), still exhibits "slow sleep." On the other hand, the central locus of action of external hypnogenic stimulations is still unknown. Bulbar structures on which baroceptive impulses are directly impinging do not appear to coincide with the solitary tract "synchronizing" area (295), and the synchronizing tone of the lower brain stem does not seem to be triggered by barosensitive afferents (108). The fact that EEG synchronizing afferents of Group II chiefly project at the gigantocellularis nucleus level (in decerebrate animals) (362) does not allow us to assume the intervention of synchronizing caudal brain-stem structures, for, very likely, more rostral projections might be observed in the intact animal. Finally, we must mention it is relatively easy to synchronize and induce sleep in preparations with an intact cortex, including midpontine pretrigeminal preparations (21, 304) (by flashes of light), whose level of arousal is, however, much increased. This action supports the intervention of a descending rostral synchronizing mechanism. We have still no evidence that sleep can be induced by external stimuli in decorticate or in anterior mesencephalic preparations.