SUMMARYIn the last three decades the two-process model of sleep regulation has served as a major conceptual framework in sleep research. It has been applied widely in studies on fatigue and performance and to dissect individual differences in sleep regulation. The model posits that a homeostatic process (Process S) interacts with a process controlled by the circadian pacemaker (Process C), with time-courses derived from physiological and behavioural variables. The model simulates successfully the timing and intensity of sleep in diverse experimental protocols. Electrophysiological recordings from the suprachiasmatic nuclei (SCN) suggest that S and C interact continuously. Oscillators outside the SCN that are linked to energy metabolism are evident in SCN-lesioned arrhythmic animals subjected to restricted feeding or methamphetamine administration, as well as in human subjects during internal desynchronization. In intact animals these peripheral oscillators may dissociate from the central pacemaker rhythm. A sleep/fast and wake/feed phase segregate antagonistic anabolic and catabolic metabolic processes in peripheral tissues. A deficiency of Process S was proposed to account for both depressive sleep disturbances and the antidepressant effect of sleep deprivation. The model supported the development of novel non-pharmacological treatment paradigms in psychiatry, based on manipulating circadian phase, sleep and light exposure. In conclusion, the model remains conceptually useful for promoting the integration of sleep and circadian rhythm research. Sleep appears to have not only a short-term, use-dependent function; it also serves to enforce rest and fasting, thereby supporting the optimization of metabolic processes at the appropriate phase of the 24-h cycle. IN TROD UCTI ONThe two-process model of sleep regulation was proposed more than three decades ago. It had a large impact on sleep research and is still a prevalent conceptual model. This is reflected by the persistently high number of citations per year of the original papers. AAB and SD published the original papers of the two process model (Borb ely, 1982;Daan et al., 1984), whereas AAB and AWJ related the model to sleep in depression and the antidepressant effect of sleep deprivation (Borb ely and Wirz-Justice, 1982).

A model for the timing of human sleep is presented. It is based on a sleep-regulating variable (S)--possibly, but not necessarily, associated with a neurochemical substance--which increases during wakefulness and decreases during sleep. Sleep onset is triggered when S approaches an upper threshold (H); awakening occurs when S reaches a lower threshold (L). The thresholds show a circadian rhythm controlled by a single circadian pacemaker. Time constants of the S process were derived from rates of change of electroencephalographic (EEG) power density during regular sleep and during recovery from sleep deprivation. The waveform of the circadian threshold fluctuations was derived from spontaneous wake-up times after partial sleep deprivation. The model allows computer simulations of the main phenomena of human sleep timing, such as 1) internal desynchronization in the absence of time cues, 2) sleep fragmentation during continuous bed rest, and 3) circadian phase dependence of sleep duration during isolation from time cues, recovery from sleep deprivation, and shift work. The model shows that the experimental data are consistent with the concept of a single circadian pacemaker in humans. It has implications for the understanding of sleep as a restorative process and its timing with respect to day and night.

According to the two-process model of sleep regulation, the timing and structure of sleep are determined by the interaction of a homeostatic and a circadian process. The original qualitative model was elaborated to quantitative versions that included the ultradian dynamics of sleep in relation to the non-REM-REM sleep cycle. The time course of EEG slow-wave activity, the major marker of non-REM sleep homeostasis, as well as daytime alertness were simulated successfully for a considerable number of experimental protocols. They include sleep after partial sleep deprivation and daytime napping, sleep in habitual short and long sleepers, and alertness in a forced desynchrony protocol or during an extended photoperiod. Simulations revealed that internal desynchronization can be obtained for different shapes of the thresholds. New developments include the analysis of the waking EEG to delineate homeostatic and circadian processes, studies of REM sleep homeostasis, and recent evidence for local, use-dependent sleep processes. Moreover, nonlinear interactions between homeostatic and circadian processes were identified. In the past two decades, models have contributed considerably to conceptualizing and analyzing the major processes underlying sleep regulation, and they are likely to play an important role in future advances in the field.

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