t has been known for some 40 years that waking and consciousness depend upon the activity of neurons within the brainstem reticular formation (Figure 1). These neurons form the ascending reticular activating system. They project into the thalamus and excite cells which project to widespread areas of the cerebral cortex to produce the cerebral cortical activation that occurs during wakefulness.
In addition, brainstem reticular neurons project into the hypothalamus and basal forebrain where neurons are located that also project to the cerebral cortex and participate in the maintenance of an "alert" cerebral cortex.
The reticular activating system of the human brain. Various sensory inputs send nonspecific impulses into the reticular formation via collaterals as well as to specific sensory areas of the cerebral cortex (shaded). In turn, the reticular formation sends nonspecific impulses throughout the cortex (curved dashed lines) to "awaken" the entire brain.
As may be inferred from the title of this section, there are also specific brain mechanisms that promote NREM sleep and others that are responsible for REM sleep. The old notion that sleep occurs as a result of the withdrawal of activity in systems that promote wakefulness is simply not true. Sleep is not a passively occurring state, but one that is actively generated by activity in specific brain regions.
Lesions of the anterior hypothalamus and adjacent forebrain areas, which have been termed the basal forebrain (Figure 2), produce a long lasting insomnia. There is consistent damage to this area in Alzheimer's disease, which may contribute to the insomnia that characterizes this disorder.
Electrical and chemical stimulation of the basal forebrain produces NREM sleep. Indeed this is the most effective site in the brain for the induction of NREM sleep. Recently, several investigators have described neurons in this region which discharge during sleep. These cells discharge maximally during NREM sleep, with relatively little activity during REM sleep and wakefulness. This discharge pattern is unique to this brain area. Thus, stimulation, recording and lesion data implicate the basal forebrain in the control of NREM sleep.
Several lines of evidence indicate that the nucleus of the solitary tract (NTS) is involved in sleep generation. Distention of the carotid sinus, a powerful stimulus for the NTS region, induces behavioral sleep. Low frequency stimulation of the vago-aortic nerve or of the NTS also produces slow waves in the EEG. Inactivation of the lower brainstem regions, including the NTS, produces a profound arousal.
There is some evidence that certain NTS neurons increase their discharge during NREM sleep and that these neurons are reciprocally interconnected with cells in the midbrain EEG arousal region. Thus, these data suggest that the NTS region may constitute a second "center" for the regulation of NREM sleep. However, on balance there has been relatively little recent research in this area and the evidence for an NTS role in NREM sleep control is weaker than that for the basal forebrain region.
It is likely that several widely separated brain regions are sufficient to generate NREM sleep, and that all normally interact in NREM sleep triggering. This conclusion is supported by the transection studies described below, which show that while transection of the brainstem produces an animal which has REM sleep either above or below the transection, NREM sleep-like states are often present on both sides of the transection. This observation can most parsimoniously be explained by hypothesizing the existence of several NREM sleep "centers."
It is clear that a given state may not always be complete or persistent, which may perhaps occur when the activity of its "centers" are not properly coordinated. Rapid oscillations between states of wakefulness and NREM sleep likely explain many features of night terrors and sleepwalking.
A very powerful technique for localizing function is to divide the brain from the front to the back and ask "which half has the function of interest." If this question can be clearly answered, one can repeat the process, continuing the "half split technique" until the critical area is localized. One might suspect that because brain systems are so thoroughly interconnected, any major subdivision of the brain would so disorganize brain function that REM sleep-like activity would not be present in either half. This is clearly not the case. To an astounding degree, the REM sleep generator mechanisms can survive disconnection from well over 95% of the rest of the central nervous system. Conversely, destruction of a very small region of the brainstem can permanently prevent REM sleep, even if the rest of the brain's connections are intact. This characteristic of REM sleep has allowed us to achieve a relatively precise localization of the neurons critical to this state.
NREM Sleep
Localization of Brain Mechanisms for REM Sleep
Transection studies. One can cut through the midbrain (Figure 2A) in the coronal plane so as to separate the brainstem from the diencephalon and telencephalic structures. Animals with such lesions can survive for weeks or months. They manifest a striking dissociation between polygraphically defined states in the forebrain and brainstem, i.e, by transecting the neuraxis, two independent generators of behavioral state are created, one rostral and one caudal to the transection. When transections are placed at levels A or B in Figure 2, all the brainstem signs of REM sleep can be recorded caudal to the cut. Thus, atonia and rapid eye movements, as well as a REM sleep-like activation of reticular formation units, occur with a regular ultradian rhythm.
The forebrain of animals with transections at levels A and B shows both synchronized and desynchronized EEG patterns which alternate spontaneously. However, the desynchronized patterns are not accompanied by spontaneous rapid eye movements. During desynchronized patterns vertical pursuit eye movements and changes in pupil diameter can be evoked by external visual stimuli. The stereotypic spontaneous rapid eye movements with myosis that characterizes REM sleep is not present. The desynchronized EEG seen in the rostral portion of these preparations closely resembles that of wakefulness.
Because of the presence of REM sleep caudal to midbrain and midpontine transections (Figure 2A and B), and the absence of REM sleep signs rostral to such transections, one may conclude that structures rostral to the midbrain are not required for REM sleep, and that structures caudal to the midbrain contain neurons which are sufficient to generate REM sleep. This same procedure can be carried one step further by transecting between the pons and medulla (Figure 2C). In this case, structures caudal to the cut do not show REM sleep, while structures rostral to the cut do show signs of REM sleep.
From the above one can see that when the pons is connected to mid- and fore-brain structures, most of the defining signs of REM sleep are observed in these rostral structures. When the pons is connected to the medulla and spinal cord, as in the midbrain transected animal, most of the defining signs of REM sleep are observed in caudal structures. When a transection is made at the junction of the spinal cord and medulla (Figure 2D), all of the signs of REM sleep occur in all rostral brain areas, i.e., in the medulla, pons, midbrain and forebrain.
One can then transect through the middle of the pons, thereby destroying pontine neurons, and again ask the question "which side has REM sleep" After this transection, REM sleep is not observed on either side of the transection. When one transects both rostral and caudal to the pons, producing an isolated pons, the pontine signs of REM sleep can be seen in the pons.
From the above we can conclude that the pons is both necessary and sufficient to generate the basic phenomena of REM sleep.
Lesion studies. In an attempt to further localize the pontine neurons generating REM sleep, a number of investigators have removed portions of the pons within the region defined as critical by transection studies (Figure 3). It is possible to block REM sleep by placing lesions within the pontine region identified by transection studies. The critical lesions occupy the lateral portion of the pontine tegmentum an area that includes the nucleus reticularis pontis oralis and a site ventral to the locus coeruleus. This small area, which comprises just a few cubic millimeters of tissue, apparently recruits the massive change in brain neuronal activity that is REM sleep. Another way of viewing the effect of such lesions is that they block both the atonia of REM sleep and, by damaging areas that control locomotion, also block the expression of motor activity during REM sleep. By blocking these two major components of REM sleep, the "state," at least as it is usually defined, ceases to exist. Lesions limited to the noradrenergic neurons of the locus coeruleus, which is adjacent to the nucleus reticularis pontis oralis, as well as chemical depletion of norepinephrine, do not block REM sleep.
Unit recording studies. Guided by lesion, stimulation and anatomical data, researchers have recorded from the pons to observe the activity of neurons that might be involved in the generation of sleep.
Lateral pontine and medial medullary reticular areas. These areas contain cells which 1) discharge at a high rate throughout REM sleep and 2) have little or no activity during NREM sleep. During waking, these cells are generally silent, even during vigorous movement; however, some are active during head lowering and related postural changes which involve reductions of tone in a number of muscles. The pontine "REM sleep-on" cells are distributed throughout the lateral pontine region implicated by lesion studies in REM sleep control (Figure 4, stippled region in top brainstem section). This distribution is significant, since it indicates that the critical lesion does not merely interrupt fibers of passage, but also removes the somas of cells which are selectively active in REM sleep. The medullary REM sleep-on cell population (Figure 4, stippled region in middle brainstem section) is thought to mediate the suppression of muscle tone in REM sleep via excitatory projections to the lower brainstem and then via inhibitory projections to spinal cord motoneurons (Figure 4). The subsequent suppression of muscle tone has now been shown to be produced by the postsynaptic inhibition of motoneurons (see Part D., NREM and REM Sleep).
Some neurons within the pons fire bursts of action potentials during REM sleep. These neurons in turn excite other neurons in the thalamus, which in turn excite neurons in the cortex. The phasic excitation that results is called PGO waves, for the pontine, lateral geniculate and occipital cortical sites from which they are most readily recorded.
Schematic illustration of present hypothesis regarding atonia mechanisms during REM sleep. It is assumed that during REM sleep, neurons of the nucleus reticularis pontis oralis (stippled area in top section) exert an excitatory influence via the lateral tegmentoreticular tract on neurons in the medulla (stippled area in middle section), which in turn exert a generalized inhibition on spinal motoneurons via the ventrolateral reticulospinal tract. Abbreviations: AF, anterior funiculus; DLF, dorsolateral funiculus; FTG, gigantocellular tegmental field; Gc, n. reticularis gigantocellularis; IO, inferior olivary complex; LC, n. locus coeruleus; Mc, n. reticularis magnocellularis; Pc, n. reticularis parvocellularis; Rtp, n. reticularis tegmenti pontis; VLF, ventolateral funiculus.
Locus Coeruleus and raphe.Nonadrenergic cells of the locus coeruleus and serotonergic cells of the raphe (Figure 5) have a similar discharge pattern the sleep waking cycle (Figure 6).
A cross section of the brain stem at the pons level shows the raphe, or serotonergic neurons, right in the midline of the brainstem. The locus coeruleus cells are more lateral.
During wakefulness the discharge of these sets of cells is very regular and tonic in contrast to the burst pause discharge pattern seen in most reticular neurons. During the initial stages of NREM sleep these cells slow slightly. During the "transition" to REM sleep, discharge in both serotonergic and noradrenergic cells slows dramatically. During REM sleep these cells have their lowest discharge rates and many are completely silent.
The significance of these unit activity patterns for REM sleep control and for the "function" of REM sleep is unclear. The slowing of discharge in these cells in NREM sleep argues against the hypothesis that increased release of serotonin or norepinephrine triggers NREM sleep. The minimal discharge rate of these cells in REM sleep also argues against the hypothesis that these transmitters maintain REM sleep. The possible relation of the cessation of activity in locus coeruleus cells to the function of REM sleep will be discussed below.
The following is a description of the present state of our knowledge about the localization of the mechanisms which are responsible for generating REM sleep:
Experimental manipulations and pathological states allow us to further localize and analyze the mechanisms generating REM sleep. Lesion studies have demonstrated that atonia and EEG desynchrony can be individually dissociated from the REM sleep state, i.e., that REM sleep can exist without muscle atonia or with a synchronized EEG. Conversely, stimulation studies have demonstrated that each of these phenomena can be separately evoked. It is especially important to note that cholinergic stimulation of different regions within the pons has been shown to be able to induce each of these phenomena.
Pontine and medullary lesions can produce the syndrome of REM sleep without atonia. The critical lesions for producing this effect are much smaller than those required to block the REM sleep state. Animals with these lesions have relatively normal NREM sleep. During "REM" sleep they have periods of desynchronized EEG, rapid eye movements, and myosis as seen in normal REM sleep. However, muscle tone is present throughout these periods. Depending upon the exact placement of the lesion, the animal's motor activity during this state will range from a slight raising of the head to elaborate displays of exploratory, aggressive and other behaviors. The animal remains generally unresponsive to the environment during these displays and can be "awakened" by strong stimulation. These findings leave little doubt that REM sleep without atonia is in fact a variant of the normal REM sleep state. A clinical condition in humans of REM sleep without atonia has been described; it is called REM Behavior Disorder.
Atonia without REM sleep. Atonia without REM sleep occurs when there is a loss of muscle tone which can be evoked by injection of the cholinergic agonist carbachol or the cholinesterase inhibitor physostigmine into the dorsal pons. The region where injection produces the most immediate and complete loss of tone corresponds with the region which, when lesioned, produces REM sleep without atonia (see Figure 3).
A second area in which stimulation can elicit atonia is the medial medulla. Electrical stimulation of a rather restricted portion of this area will trigger atonia. Cholinergic stimulation of the caudal medial medulla, in the nucleus paramedianus, will also trigger atonia. Thus, two medullary and one pontine region are able to produce the complete suppression of muscle tone seen in REM sleep.
Cataplexy. Cataplexy, a symptom of narcolepsy, is the sudden loss of muscle tone during wakefulness; it is triggered by strong emotions, physical activity and other variables. Physiologically it is similar to the "atonia without REM sleep" state mentioned above. It is reasonable to hypothesize that one or more of the mechanisms that have been identified as promoting or inhibiting atonia are malfunctioning in narcoleptics, with the result being that a stimulus which would produce arousal in an intact individual produces cataplexy in narcoleptics. Cholinergic mechanisms seem to be important in cataplexy, as they are in experimental atonia. Physostigmine triggers cataplexy in narcoleptic dogs, while atropine blocks spontaneously occurring cataplexy in these animals. Narcoleptic dogs have an increased levels of cholinergic receptors in the pons and medial medulla. In summary, we can hypothesize that a hypersensitivity of cholinoceptive cells in the pons and/or medial medulla is responsible for atonia during cataplectic attacks.
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