Sleep Structure and Its Distribution over the 24 Hours Are Regulated by Several Mechanisms Which Interact with One Another in a Rather

SLEEP STRUCTURE AND ITS DISTRIBUTION OVER THE 24 HOURS ARE REGULATED BY SEVERAL MECHANISMS WHICH INTERACT WITH ONE ANOTHER IN A RATHER regular manner. Mathematical models of sleep-wake time course and intranight dynamics of physiological human sleep have been proposed, offering a conceptual framework for the analysis and interpretation of sleep regulatory processes.1-5 Among the available models, the 2-process model of sleep regulation has been evaluated and corroborated most frequently and has been able to simulate and predict sleep behavior in different physiological and experimental conditions. In the 2-process model of sleep regulation1-5 the power density of the delta (0.5 4.5 Hz) band, called slow wave activity (SWA) and obtained by spectral analysis of sleep EEG, is supposed to reflect the variations in a homeostatic recovery process (Process S) that increases in a saturating exponential way during wakefulness. Its decrease is expressed by the exponential decline in SWA during sleep. Sleep deprivation elicits an SWA rebound in the recovery night.1,3,5 The homeostatic pressure interacts with circadian and ultradian oscillations of sleep propensity leading to the nocturnal distribution of sleep and to the NREM-REM periodic alternation during sleep.1-5 Sleep structure and sleep distribution in humans with narcolepsy differ from normal subjects. The sleep of narcoleptic patients is characterized by a polyphasic distribution over the 24 hours and by frequent occurrence of REM sleep onsets. It has been suggested6-8 that these phenotypic sleep features could be ascribed to an alteration of the strength of the homeostatic process or to a disequilibrium between homeostatic and sleep-wake regulatory rhythms (circadian and ultradian rhythms). Deprivation and bed rest study protocols have shown that the homeostatic regulation of sleep is preserved in narcoleptics.8-11 In particular, it has been shown that after 16 or 32 hours of forced wakefulness, the nocturnal sleep structure of narcoleptics becomes compact, and the SWA during sleep decays exponentially with a time-constant similar to normal subjects.8-10 However, despite the effect of sleep deprivation, narcoleptic patients still had a high frequency of REM sleep onsets and showed longer NREM-REM sleep cycles than controls, even though the amount of wakefulness during the night was similar in the 2 groups.10,11 In our preliminary work, we have tried to simulate sleep features of narcoleptic and normal subjects by combining a 2-process model of sleep regulation, describing overnight dynamics of SWA, with the reciprocal-interaction model of REM regulation suggested by McCarley and Hobson.12,13 The reciprocal interaction model proposes that REM inhibiting neurons (RemOff cells) of the dorsal raphe (DR) and locus coeruleus (LC) have an inhibitory collateral autofeedback that eventually stops their own activity and allows the neurons (RemOn cells) of the laterodorsal tegmental (LDT) and pedunculopontine (PPT) nuclei to gain acA Model-Based Approach to Homeostatic and Ultradian Aspects of Nocturnal Sleep Structure in Narcolepsy