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FIGURE 8.1 The four basic mechanisms of sleep regulation. The clock time is reported on the x-axis. In homeostatic and circadian (W, wakefulness; S, sleep). In ultradian (SWA, slow-wave activity). In cyclic alternating pattern (CAP) SI, stage 1; REM, rapid eye movement sleep; S2, stage 2; S3, stage 3; S4, stage 4).

duration of sleep episodes is strongly influenced by the phase of the body temperature rhythm. Decreasing temperature, as occurs in the nocturnal hours, is combined with longer sleep episodes, while increasing temperature, as occurs in the morning hours, is associated with shorter sleep episodes (for a review, see Murphy and Campbell, 1996).

A 12-h-centered regulation of sleep propensity (i.e., a circa-semidian rhythm) was proposed more than 20 years ago (Broughton, 1975). In the last decade, the increasing attention to the circadian rhythm sleep disorders has expanded knowledge on the 24-h sleep propensity function, allowing identification of a total of four phases of sleep propensity (two peaks and two troughs) throughout the day. Laboratory studies (free-running, constant, and ultradian routine) have demonstrated that the timing of peaks and troughs is highly correlated with the thermal curve. In addition to the high sleep propensity during the nocturnal hours (primary sleep gate concomitant to the descending branch of deep body temperature), a less prominent peak of sleep propensity is observed in the midafternoon (secondary sleep gate), about 10 h after the temperature minimum clock time. By contrast, in addition to the trough of sleep propensity in the late morning (ascending branch of deep body temperature), there is a period of low sleep propensity in the early evening (forbidden zones for sleep), about 8 h before the temperature minimum time (Lavie, 1986; Lack and Lushington, 1996).

sleep intensity and slow-wave sleep

The variations of sleep propensity over time not only are affected by the biological clock but also are influenced by the subject's prior sleep-wake history. Extensive studies on sleep deprivation have ascertained an increase of sleep propensity after a certain number of hours of wakefulness. Moreover, there is a positive relationship between the duration of presleep wakefulness and the spectral energy enhancement of slow-wave activities (.5-4 Hz). In effect, sleep stages 3 and 4 are mostly concentrated in the early portions of sleep, while they are practically absent in the final hours. The priority of recuperation of stages 3 and 4 after sleep onset and the progressive decline of deep sleep along the night suggest the involvement of a compensatory mechanism based on the accumulation while awake of some unknown factor, which undergoes a sort of dissipa-tive process during sleep. If we skip a night of sleep, the cumulative evolution continues until the next sleep episode (either nocturnal or diurnal) that is basically characterized by a short sleep latency and by an increased amount of stages 3 and 4, still mostly represented in the early hours of sleep. In short, prolonged wakefulness hastens sleep onset and proportionally potentiates slow-wave activities, regardless of the circadian phase (Dijk et al., 1990). The increased intensity of sleep after prolonged wakefulness indicates that the characteristics of sleep recovery respond to mechanisms of homeostatic regulation (see Fig. 8.1).

The interaction between sleep-wake-dependent and sleep-wake-independent mechanisms has been determined in a number of observations. In the two-process model (Borbely, 1982), sleep regulation is viewed in terms of the interaction of a homeostatic process (S) and a circadian process (C). The displacement of the sleeping hours in inadequate periods in relation to the process C, as occurs in the jet-lag syndrome, in shift work, and in morning recovery after sleep deprivation, alters sleep in the absence of other disturbing factors.

nonrapid eye movement/rapid eye movement sleep cycle

A third mechanism of sleep regulation is the NREM-REM cyclicity characterized by periods of sustained high-voltage, slow-wave synchronized EEG patterns (NREM sleep) that are periodically replaced by sustained periods of low-voltage, fast-wave desynchronized EEG rhythms (REM sleep). The NREM/REM cycle (also referred to as the sleep cycle) is conventionally composed of a descending branch (from light to deep NREM sleep), a trough (the deepest stage of the sleep cycle), and an ascending branch (from the deepest NREM stage to REM sleep). This ultradian rhythmicity of about 90-120 min has been viewed now as an intrinsic phenomenon of sleep, now as an independent manifestation of the basic rest activity cycle (BRAC), expressed in sleep by the NREM and REM alternation and in wakefulness by periodic changes in the vigilance level and in spontaneous motility (Kleitman, 1963).

Experimental investigation has ascertained that the intrinsic alternation between NREM and REM sleep is under the control of an oscillatory process generated by a particular rhythmicity of neurotransmission and by the reciprocal interaction between two neuronal groups with REM-on and REM-off activities. Cholinergic neurons localized preferably in the laterodorsal and peduncular nuclei of the pontine tegmentum promote REM sleep (REM-on cells). In contrast, aminergic neuronal complexes (norepinephrine, epinephrine, and serotonin) localized in the locus ceruleus, in the dorsal nuclei of the raphe, and in the peribrachial region of the pons are very active during the NREM stages and silent during NREM sleep (REM-off cells). The relation between these neuronal assemblies is regulated by the mathematical model of the reciprocal induction defined by Lotka and Volterra (McCarley and Hobson, 1975). Similar to the struggle between preys and predators, their action is always on the move. The slowing of the firing activity of the REM-off cells facilitates the REM-on population that becomes progressively more active and triggers a REM episode. The activity of these cells then declines for the rebound activation of the REM-off cells that block the REM episode and promote a new period of NREM sleep. The nocturnal succession of the NREM/REM cycles originates from this sequence of reciprocally induced effects (see Fig. 8.1). The competitive interaction between these centers appears as an intrinsic chronometric mechanism that follows an ordinate sequence and that can be quantitatively described by the limit cycle reciprocal interaction model of REM cycle control (McCarley and Massaquoi, 1986).

dynamics of thalamic neurons during sleep

A further pivotal mechanism involved in sleep regulation concerns the transmission of information through the thalamocortical pathways. In particular, the thalamic reticular nucleus (TRN) forms an essential part of the circuits that link the thalamus to the cerebral cortex. The afferent neurons to the TRN from thalamus and cortex, together with those from brain stem and basal forebrain, play a critical role in controlling the firing patterns of thalamocortical relay cells, which can be in either a "tonic" mode or a "burst" mode. In the tonic mode, there is a relatively unmodified, linear information transfer through the thalamic relay from ascending pathways to the cortex. The burst mode has been characteristically seen during sleep or epileptic discharges and has therefore been considered to be a global mechanism that prevents the relay of information to the cortex (Steriad eetal., 1994).

The neurophysiological behavior of the TRN has been observed also in other thalamic centers. At the wake-sleep transitions, neurons of various thalamic nuclei quit the tonic firing mode (substrate of the EEG beta waves) to enter the burst or oscillatory mode. During the bursting mode, spindles, K-complexes, and delta bursts become manifest (NREM sleep). When thalamic networks are in the rhythmic bursting mode, they respond to afferent stimulation by producing a stereotyped oscillation, which is characterized by the properties of the neurons involved, but not by the properties of the afferent signal (Steriade et al., 1993). During the tonic firing mode (wakefulness and REM sleep), the transfer ratio has a value of 1.0. When the bursting mode is entered (drowsiness and light NREM sleep), the output reduces and the transfer ratio lowers to .7. This ratio further drops to about .3-.4 when the slow delta waves of deep NREM sleep appear. On awakening, the transfer ratio immediately recovers the 1.0 value (Coenen, 1995; Coenen and Vendrik, 1972).

At variance with this rigid behavior, even in the burst mode, the thalamocortical relay cells can respond to sensory stimuli. Although this transmission is nonlinear, the afferent activity is transmitted to cortex and the signal-to-noise ratio can be even higher than in the tonic mode. That is, in the burst mode, the system is primed to react to changes in input activity instead of transfering this activity reliably to the cortex for analysis. For the latter, the system needs to switch to the tonic mode. In other words, there is a capacity of the thalamic cells, when in the burst mode, to respond to novel activity patterns and then to change to the tonic mode so that the new stimuli can be accurately transferred to the cortex (Guillery et al., 1998).

In light of this, the current view of the function of the thalamus is that it produces state-dependent gating of sensory information flow to the cerebral cortex. Tonic relay cell activity, corresponding to awake, alert behavioral states, allows for faithful information transmission to the cortex. However, rhythmically bursting relay cell firing, which corresponds to sleep states, imposes spindle oscillations on the cortex and produces slow-wave EEG signals. These findings extend the view of the thalamus by replacing the idea of a "gate" with that of a "tunable temporal filter." The thalamic neurons filter the peripheral input while the tuning of the filter varies continuously with the degree of bursting in the neuronal spike train. These variations in the dynamics and the bursting of the relay cells undergo natural fluctuations in arousal and attentiveness (Mukherjee and Kaplan, 1995).

low-frequency (<1 hz) oscillations in the human sleep electroencephalogram

Falling asleep is rarely an abrupt process but instead it occurs along a gradual replacement of the faster low-voltage alpha and beta rhythms by the slower high-voltage theta and delta EEG activities. In addition to these tonic changes, the wake-sleep transition is also characterized by the appearance of transient EEG features that allow sleep maintenance through adaptive adjustments of the arousal level to internal or external inputs. In particular, K-complexes, which are physiological markers of NREM sleep but can also be triggered by sensory stimulation, on the one hand serve as momentary arousals (both spontaneous and evoked K-complexes are accompanied by increases of the sympathetic activity); on the other hand, with their ample slow biphasic wave form, reflect sleeplike qualities.

Analysis of K-complex densities (i.e., the number of K-complexes per minute of sleep) has been accomplished and findings indicate densities of one K-complex per minute in stage 2 (Johnson and Karpan, 1968; Johnson et al., 1976; Halasz el al., 1985). Further detailed investigation confirmed values of 1.36 ± 0.84 in stage 2, and 1.21 ± .93 in stages 3 and 4 (Paiva and Rosa, 1991). However, the K-complex densities have overnight fluctuations according to the distribution within the sleep cycle. Peaks in densities (i.e., when K-complexes can be clustered in sequences) are often observed in connection with stage transitions, independent of the direction of the shift. A study based on spectral analysis revealed that sequences of K-complexes are embedded in a slow oscillation with a period of about 1.5 s (frequency of about .6 Hz). In particular, stage 2 shows a principal peak at .5 Hz surrounded by other lower peaks; whereas in stages 3 and 4, there is a dominant peak at .7 Hz (Amzica and Steriade, 1997).

In addition to this .6-.9-Hz slow oscillation marked by the periodic recurrence of K-complexes, other distinct components below 1 Hz are also present in the human sleep EEG spectrum. All-night spectral analysis of successive .5-s epochs in NREM human sleep revealed a sharp .23-Hz peak that corresponded to a periodicity of 4 s, and a .047-Hz peak in the low-frequency range that corresponded to a 21 -32-s periodicity (Achermann and Borbely, 1997). A 3-5 s periodicity between sleep spindles has been demonstrated in human NREM sleep (Evans and Richardson, 1995), while fluctuations in the 20-35-s range have already been described in human NREM sleep by means of automatic analysis using Hjorth descriptors (Depoortere et al., 1993) and spectral analysis (Ferrillo et al., 1997; Barcaro et al., 1998; Rosa et al., 1999). This rhythm, known to occur in physiological NREM sleep, is referred to as the cyclic alternating pattern (CAP; Terzano et al., 1985, 1988).

cyclic alternating pattern as a marker of sleep instability

Cyclic alternating pattern (CAP) is a classical EEG feature of periodic activities (Gaches, 1971). It is recognized in the sleep EEG every time this presents an alternating sequence of two stereotyped EEG patterns (Fig. 8.2):

1. The repetitive element, or phase A, is identified by a set of phasic events, with a mean duration between 8 and 12 s and occupying about 40% of the entire CAP cycle. The A phase is the expression of a transient activation of the arousal level during sleep. Accordingly, it is associated with an increase of the neurovegetative activities and can be coupled with an enhancement of muscle tone.

2. The recurring interval, or phase B, is identified by the recovery of background activities, with a mean duration around 16-20 s and occupying about 60% of the CAP cycle. The B phase of CAP is the expression of a transient deepening of the arousal level during sleep. Accordingly, it is associated with an inhibition of muscle tone and neurovegetative activities (Terzano et al., 1996) that may induce a respiratory event (apnea, hypopnea) or a heart rate blockage. This condition of global inhibition can be contrasted by subwakening stimulation that reactivates immediately an A phase.

In light of this, CAP is the EEG translation of a sustained arousal oscillation between activation (phase A) and inhibition (phase B) that makes sleep as well as muscular and autonomic functions unstable. The complementary pattern, defined as non-CAP (NCAP), consisting of a rhythmic EEG background, with few, randomly distributed arousal-related phasic events, represents, on the contrary, a stable sleep condition associated with regular neurovegetative activities (Fig. 8.2). Intensive though subwakening perturbation delivered during NCAP determines the prompt appearance of a CAP sequence (Terzano and Parrino, 1991).



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100 pV 1_1 sec

FIGURE 8.2 Microstructural analysis of sleep stage 2 according to the CAP/NCAP framework. Top: portion of a cyclic alternating pattern (CAP) sequence identified by separated clusters of arousal-related phasic events against the sleep stage EEG background. Notice that the CAP sequence is not driven by any motor or respiratory disturbance. Bottom: period of noncyclic alternating pattern (NCAP), characterized by a sustained homogeneous EEG background. The specimen contains also several recurring sleep spindles. EOG, eye movements. EMG, submental muscle; EKG, heart rate; O-N PNG, oro-nasal flow; THOR PNG, thoracic pneumogram; TIB ANT R, right anterior tibialis muscle; TIB ANT L, left anterior tibialis muscle.

scoring of cyclic alternating pattern parameters

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Sleeping Sanctuary

Sleeping Sanctuary

Salvation For The Sleep Deprived The Ultimate Guide To Sleeping, Napping, Resting And  Restoring Your Energy. Of the many things that we do just instinctively and do not give much  of a thought to, sleep is probably the most prominent one. Most of us sleep only because we have to. We sleep because we cannot stay awake all 24 hours in the day.

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