Chapter 028. Sleep Disorders (Part 2) Stages of REM sleep (solid bars), the four stages of NREM sleep, and wakefulness over the course of the entire night for representative young and older adult men. Characteristic features of sleep in older people include reduction of slow-wave sleep, frequent spontaneous awakenings, early sleep onset, and early morning awakening. (From the Division of Sleep Medicine, Brigham and Women's Hospital.) The first REM sleep episode usually occurs in the second hour of sleep. More rapid onset of REM sleep in a young adult (particularly if <30 min) may suggest pathology such as endogenous depression, narcolepsy, circadian rhythm disorders, or drug withdrawal. NREM and REM alternate through the night with an average period of 90–110 min (the "ultradian" sleep cycle). Overall, REM sleep constitutes 20–25% of total sleep, and NREM stages 1 and 2 are 50–60%. Age has a profound impact on sleep state organization (Fig. 28-1). Slow- wave sleep is most intense and prominent during childhood, decreasing sharply at puberty and across the second and third decades of life. After age 30, there is a progressive decline in the amount of slow-wave sleep, and the amplitude of delta EEG activity comprising slow-wave sleep is profoundly reduced. The depth of slow-wave sleep, as measured by the arousal threshold to auditory stimulation, also decreases with age. In the otherwise healthy older person, slow-wave sleep may be completely absent, particularly in males. A different age profile exists for REM sleep than for slow-wave sleep. In infancy, REM sleep may comprise 50% of total sleep time, and the percentage is inversely proportional to developmental age. The amount of REM sleep falls off sharply over the first postnatal year as a mature REM-NREM cycle develops; thereafter, REM sleep occupies a relatively constant percentage of total sleep time. Neuroanatomy of Sleep Experimental studies in animals have variously implicated the medullary reticular formation, the thalamus, and the basal forebrain in the generation of sleep, while the brainstem reticular formation, the midbrain, the subthalamus, the thalamus, and the basal forebrain have all been suggested to play a role in the generation of wakefulness or EEG arousal. Current models suggest that the capacity for sleep and wakefulness generation is distributed along an axial "core" of neurons extending from the brainstem rostrally to the basal forebrain. A cluster of γ-aminobutyric acid (GABA) and galaninergic neurons in the ventrolateral preoptic (VLPO) hypothalamus is selectively activated coincident with sleep onset. These neurons project to and inhibit multiple distinct wakefulness centers including the tuberomammilary (histaminergic) nucleus that are important to the ascending arousal system, indicating that the hypothalamic VLPO neurons play a key executive role in sleep regulation. Specific regions in the pons are associated with the neurophysiologic correlates of REM sleep. Small lesions in the dorsal pons result in the loss of the descending muscle inhibition normally associated with REM sleep; microinjections of the cholinergic agonist carbachol into the pontine reticular formation appear to produce a state with all of the features of REM sleep. These experimental manipulations are mimicked by pathologic conditions in humans and animals. In narcolepsy, for example, abrupt, complete, or partial paralysis (cataplexy) occurs in response to a variety of stimuli. In dogs with this condition, physostigmine, a central cholinesterase inhibitor, increases the frequency of cataplectic attacks, while atropine decreases their frequency. Conversely, in REM sleep behavior disorder (see below), patients suffer from incomplete motor inhibition during REM sleep, resulting in involuntary, occasionally violent movement during REM sleep. Neurochemistry of Sleep Early experimental studies that focused on the raphe nuclei of the brainstem appeared to implicate serotonin as the primary sleep-promoting neurotransmitter, while catecholamines were considered to be responsible for wakefulness. Simple neurochemical models have given way to more complex formulations involving multiple parallel waking systems. Pharmacologic studies suggest that histamine, acetylcholine, dopamine, serotonin, and noradrenaline are all involved in wake promotion. In addition, pontine cholinergic neurotransmission is known to play a role in REM sleep generation. The alerting influence of caffeine implicates adenosine, whereas the hypnotic effect of benzodiazepines and barbiturates suggests a role for endogenous ligands of the GABA A receptor complex. A newly characterized neuropeptide, hypocretin (orexin), has recently been implicated in the pathophysiology of narcolepsy (see below), but its role in normal sleep regulation remains to be defined. A variety of sleep-promoting substances have been identified, although it is not known whether they are involved in the endogenous sleep-wake regulatory process. These include prostaglandin D 2 , delta sleep–inducing peptide, muramyl dipeptide, interleukin 1, fatty acid primary amides, and melatonin. The hypnotic effect of these substances is commonly limited to NREM or slow-wave sleep, although peptides that increase REM sleep have also been reported. Many putative "sleep factors," including interleukin 1 and prostaglandin D 2 , are immunologically active as well, suggesting a link between immune function and sleep-wake states. . Chapter 028. Sleep Disorders (Part 2) Stages of REM sleep (solid bars), the four stages of NREM sleep, and wakefulness over the course of the. slow-wave sleep may be completely absent, particularly in males. A different age profile exists for REM sleep than for slow-wave sleep. In infancy, REM sleep may comprise 50% of total sleep time,. and Women's Hospital.) The first REM sleep episode usually occurs in the second hour of sleep. More rapid onset of REM sleep in a young adult (particularly if <30 min) may suggest pathology