Non REM sleep

Figure 22.4 Idealised EEG-like patterns in sleep and waking. When we are awake and aroused the EEG is desynchronised (a). As we become drowsy and pass into sleep the EEG waves become more synchronised with 8-12 Hz alpha waves (b), sleep spindles then appear (c) before the EEG becomes even more synchronised with slow (about 1-2 Hz) high-voltage waves characteristic of deep slow-wave sleep (SWS). About every 90 min this pattern is disrupted and the EEG becomes more like that in arousal (d) except that the subject remains asleep. This phase of sleep is also characterised by rolling, rapid eye movements, the so-called REM sleep. SWS is consequently also known as non-REM sleep. These tracings have been drawn to show the main features of the different EEG phases of sleep and as such are much simpler than those that are actually recorded...

Augment, or more probably, break up thalamic-cortico synchrony and its tendency to promote slow-wave EEG activity and non-REM sleep. Whether this results in full arousal, or merely a temporary disruption of sleep to give REM periods without full awaking, will depend on the balance of inputs and the overall state of cortical activity. 

Complicated processes govern wakefulness, sleep, and the transitions leading to sleep initiation and maintenance. Although the neurophysiology of sleep is complex, certain neurotransmitters promote sleep and wakefulness in different areas of the central nervous system (CNS). Serotonin is thought to control non-REM sleep, whereas cholinergic and adrenergic transmitters mediate REM sleep. Dopamine, norepinephrine, hypocretin, substance P, and histamine all play a role in wakefulness. Perturbations of various neurotransmitters are responsible for some sleep disorders and explain why various treatment modalities are beneficial. 

Non-REM parasomnias usually do not require treatment. If needed, low-dose benzodiazepines such as clonazepam can be prescribed for bothersome episodes. Clonazepam reduces the amount of sleep time spent in stages 3 and 4 of non-REM sleep, where most non-REM parasomnias occur. For treating RBD, clonazepam 0.5 to 2 mg at bedtime is the drug of choice, although melatonin 3 to 12 mg at bedtime also may be effective. Patients with RBD also should have dangerous objects removed from the bedroom and cushions placed on the floor to reduce the chance of injury from breakthrough episodes. 

Non-REM sleep A state of usually dreamless sleep that occurs regularly during a normal period of sleep with intervening periods of rapid eye movement (REM) sleep and that consists of four distinct substages and low levels of autonomic physiologic activity. 

The contribution of the 5-HT2c receptor to sleep expression has been studied also in 5-HT2c receptor knockout mice. Compared with wild-type animals, mice lacking the 5-HT2c receptor have greater amounts and longer episodes of W, less non-REM sleep, and fewer non-REM to REMS transitions (Frank et al, 2002). 

Immunohistochemical and electrophysiological studies of the hypothalamic preoptic area (POA), which plays a major role in sleep promotion, have identified a subset of sleep-active ventrolateral POA (VLPO) neurons (Sherin et al. 1996 Szymusiak et al. 1998). A tightly clustered group of VLPO neurons appears to promote non-REM sleep, by suppression of the histaminergic arousal system, which... 

Figure 14.2 Hypocretinergic activity dependent on the states of vigilance. During wakefulness, metabolic, circadian, and behavioral inputs converge on hypocretin neurons, which activate noradrenergic neurons in the locus coeruleus and promote arousal. During non-REM sleep, the activity of hypocretin neurons decreases, but the inhibitory influence of REM-off neurons on REM-on cells is still effective. During REM sleep, hypocretin and REM-off cells are silent, disinhibiting REM-on cells. Reprinted with permission from Sutcliffe de Lecea (2002). (See also Plate 7.)...

Figure 15.3 EEG/EMG recordings showing the differences between cataplexy (A) in an orexin l mouse, and a sleep attack (B) in an OX-jR mouse. Note how cataplexy (i.e. an abrupt arrest) is associated with a transition to REM sleep, but the sleep attack (i.e. a gradual arrest) shows the characteristics of non-REM sleep after the transition. In fact, based only on these EEG/EMG records, the sleep attack would not appear unusual, and it is the associated behavior, as revealed on the concurrent video recordings (i.e. the collapse into sleep without the typical preparatory behaviors), that reveals how this type of attack is similar to the overwhelming sleepiness experienced by the narcoleptic patient. Vertical arrows denote the times at which an arrest is behaviorally evident. Scale bar is 10 sec. Adapted from Willie et al. (2003).

The second constellation of narcoleptic symptoms can be summarized under the rubric of excessive daytime sleepiness, or an inability to regulate wakefulness. As recently reviewed by Mochizuki et al. (2004), at least four explanations have to date been proposed for this sleepiness a deficit in arousal, an impaired circadian alertness signal, abnormal homeostatic regulation of non-REM sleep, and excessive vigilance state fragmentation. These mechanisms are not mutually exclusive, and there are possible roles for orexin signaling in each of them, as we review in the following sections. 

Orexin deficiency and abnormal regulation of non-REM sleep homeostasis... 

Sleepiness in narcolepsy has also been considered a subjective phenomenon associated with the instability of boundaries between behavioral states and the constant intrusion of sleep episodes into wakefulness. Under baseline conditions, 0X2R, orexin , and orexin/ataxin-3 transgenic mice have normal amounts of wakefulness and non-REM sleep during the light and dark phases and over 24 h (Chemelli et al, 1999 Hara et al, 2001 Mochizuki et al, 2004 Willie... 

This belief was further supported by the evidence of a correlation between the clinical response and REM sleep suppression as well as a temporal relationship between the onset of clinical response and REM sleep suppression. However, some of the later studies suggested that REM sleep suppression is not necessary for the antidepressant action (Gillin 1983). For example, some studies show evidence of no change or even an increase in REM sleep with the treatment of depression (Gillin et al. 2001). Recently, Landolt Gillin (Landolt and Gillin 2002) have also demonstrated that the antidepressant response to phenelzine treatment does not depend on elimination of REM sleep or inhibition of slow wave activity in non-REM sleep. However, the generalization of some of these studies is limited because of their small sample size. 

Electroencephalogram (EEG) sleep studies on the use of antidepressants in depressed patients have not produced clear evidence of the involvement of REM or non-REM sleep in the mechanisms underlying clinical change. Furthermore, the role of the physiological mechanisms of sleep during treatment with antidepressants is still unclear. Further basic sleep research is necessary (Gillin 1983) to interpret the effects of antidepressants on EEG sleep in terms of the physiological processes of sleep. 

In rats, cocaine (6 mg/kg, i.p. or p.o.) has been shown to induce a significant increase in sleep latency and a reduction in total sleep time, including a decrease in both non-REM sleep and REM sleep (Schwartz 2004). In humans, cocaine, amphetamines, and methylphenidate also produce decreases in sleepiness, an increased latency to sleep, and a marked decrease in REM sleep associated with an increased latency to the onset of this state. Amphetamine, methylphenidate, and cocaine are known to act by enhancing the amount of the monoamines available within the synaptic cleft of synapses in the CNS. 

Hypocretin neurons also send excitatory projections to regions of the brain that synthesize DA and NE, both of which also play a role in arousal (Kaslin et al. 2004). The central noradrenergic system is involved in the control of arousal (Mallick et al. 2002). LC neurons fire fastest during wakefulness, slow down during non-REM sleep, and stop firing almost completely during REM sleep (Aston-Jones et al. 1991). 

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