The two‐process model of sleep regulation: a reappraisal

In 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.

[1]  B. Pflug,et al.  [Therapy of endogenous depressions using sleep deprivation. Practical and theoretical consequences]. , 1971, Der Nervenarzt.

[2]  K. Svendsen Sleep deprivation therapy in depression , 1976, Acta psychiatrica Scandinavica.

[3]  R. Krauss,et al.  INFERTILITY IN MALE PESTICIDE WORKERS , 1977, The Lancet.

[4]  C. Sisk,et al.  Entrainment of circadian rhythms by feeding schedules in rats with suprachiasmatic lesions. , 1979, Behavioral and neural biology.

[5]  A. Borbély A two process model of sleep regulation. , 1982, Human neurobiology.

[6]  A. Borbély,et al.  Sleep, sleep deprivation and depression. A hypothesis derived from a model of sleep regulation. , 1982, Human neurobiology.

[7]  A. Borbély,et al.  The effect of sleep deprivation on sleep in rats with suprachiasmatic lesions , 1983, Neuroscience Letters.

[8]  Irene Tobler,et al.  Effect of forced locomotion on the rest-activity cycle of the cockroach , 1983, Behavioural Brain Research.

[9]  F. Goodwin,et al.  Seasonal affective disorder. A description of the syndrome and preliminary findings with light therapy. , 1984, Archives of general psychiatry.

[10]  D. Kupfer,et al.  All-night spectral analysis of the sleep EEG in untreated depressives and normal controls , 1984, Psychiatry Research.

[11]  H. Kawamura,et al.  Circadian rhythms in multiple unit activity inside and outside the suprachiasmatic nucleus in the diurnal chipmunk (Eutamias sibiricus) , 1984, Neuroscience Research.

[12]  S. Daan,et al.  Timing of human sleep: recovery process gated by a circadian pacemaker. , 1984, The American journal of physiology.

[13]  A. Dolphin,et al.  Pertussis toxin reverses adenosine inhibition of neuronal glutamate release , 1985, Nature.

[14]  J. Aschoff,et al.  Meal Timing in Humans during Isolation without Time Cues , 1986, Journal of biological rhythms.

[15]  Larry F. Lacey,et al.  Long-term effects of on , 1987 .

[16]  S. Daan,et al.  EEG Power Density during Nap Sleep: Reflection of an Hourglass Measuring the Duration of Prior Wakefulness , 1987, Journal of biological rhythms.

[17]  C. Pollak,et al.  Meal size and intermeal interval in human subjects in time isolation , 1987, Physiology & Behavior.

[18]  R. F. Johnson,et al.  Loss of entrainment and anatomical plasticity after lesions of the hamster retinohypothalamic tract , 1988, Brain Research.

[19]  C. Milne AUTONOMIC NERVOUS SYSTEM , 1957, Nursing standard (Royal College of Nursing (Great Britain) : 1987).

[20]  S. Honma,et al.  Methamphetamine induced locomotor rhythm entrains to restricted daily feeding in SCN lesioned rats , 1989, Physiology & Behavior.

[21]  D. Dijk,et al.  Effects of SWS deprivation on subsequent EEG power density and spontaneous sleep , 2002 .

[22]  S. Daan,et al.  Bright morning light advances the human circadian system without affecting NREM sleep homeostasis. , 1989, The American journal of physiology.

[23]  A A Borbély,et al.  Time course of EEG power density during long sleep in humans. , 1990, The American journal of physiology.

[24]  U. Lahaie,et al.  Seasonal Affective Disorder , 1986, British Journal of Psychiatry.

[25]  Alexander A. Borbély,et al.  Sleep homeostasis in the rat: Simulation of the time course of EEG slow-wave activity , 1991, Neuroscience Letters.

[26]  I Tobler,et al.  Sleep deprivation in rats: effects on EEG power spectra, vigilance states, and cortical temperature. , 1991, The American journal of physiology.

[27]  H. Heller,et al.  Sleep homeostasis in suprachiasmatic nuclei-lesioned rats: effects of sleep deprivation and triazolam administration , 1992, Brain Research.

[28]  D. Dijk,et al.  Circadian and sleep/wake dependent aspects of subjective alertness and cognitive performance , 1992, Journal of sleep research.

[29]  D. Nicholls,et al.  Adenosine A1 Receptor Inhibition of Glutamate Exocytosis and Protein Kinase C‐Mediated Decoupling , 1993, Journal of neurochemistry.

[30]  J. Krueger,et al.  A neuronal group theory of sleep function , 1993, Journal of sleep research.

[31]  J. Aschoff On the Relationship between Motor Activity and the Sleep-Wake Cycle in Humans during Temporal Isolation , 1993, Journal of biological rhythms.

[32]  Peter Achermann,et al.  A model of human sleep homeostasis based on EEG slow-wave activity: Quantitative comparison of data and simulations , 1993, Brain Research Bulletin.

[33]  D. Dijk,et al.  Effect of unilateral somatosensory stimulation prior to sleep on the sleep EEG in humans , 1994, Journal of sleep research.

[34]  M. Gillette,et al.  Resetting the biological clock: mediation of nocturnal circadian shifts by glutamate and NO. , 1994, Science.

[35]  D.G.M. Dijk,et al.  Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[36]  G. Leonhardt,et al.  Circadian rhythms and sleep regulation in seasonal affective disorder , 1995, Acta Neuropsychiatrica.

[37]  P. Achermann,et al.  Dynamics of the sleep EEG after an early evening nap: experimental data and simulations. , 1996, The American journal of physiology.

[38]  A A Borbély,et al.  Brain topography of the human sleep EEG: antero‐posterior shifts of spectral power , 1996, Neuroreport.

[39]  D. Dijk,et al.  Sleep electroencephalogram in seasonal affective disorder and in control women: Effects of midday light treatment and sleep deprivation , 1996, Biological Psychiatry.

[40]  A. Wirz-Justice,et al.  A schizophrenic patient with an arrhythmic circadian rest-activity cycle , 1997, Psychiatry Research.

[41]  R. McCarley,et al.  Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. , 1997, Science.

[42]  S Folkard,et al.  Complex interaction of the sleep-wake cycle and circadian phase modulates mood in healthy subjects. , 1997, Archives of general psychiatry.

[43]  R. Mistlberger,et al.  Sleep deprivation can attenuate light-induced phase shifts of circadian rhythms in hamsters , 1997, Neuroscience Letters.

[44]  J. Meijer,et al.  Light Responsiveness of the Suprachiasmatic Nucleus: Long-Term Multiunit and Single-Unit Recordings in Freely Moving Rats , 1998, The Journal of Neuroscience.

[45]  P. Achermann,et al.  Sleep homeostasis and models of sleep regulation. , 1999, Journal of biological rhythms.

[46]  S. Oliet,et al.  Adenosine‐induced presynaptic inhibition of IPSCs and EPSCs in rat hypothalamic supraoptic nucleus neurones , 1999, The Journal of physiology.

[47]  T. Åkerstedt,et al.  Beyond the Three-Process Model of Alertness: Estimating Phase, Time on Shift, and Successive Night Effects , 1999, Journal of biological rhythms.

[48]  D. Dijk,et al.  Circadian temperature and melatonin rhythms, sleep, and neurobehavioral function in humans living on a 20-h day. , 1999, The American journal of physiology.

[49]  R. Kronauer,et al.  Interactive Mathematical Models of Subjective Alertness and Cognitive Throughput in Humans , 1999, Journal of biological rhythms.

[50]  Anna Wirz-Justice,et al.  Sleep deprivation in depression: what do we know, where do we go? , 1999, Biological Psychiatry.

[51]  P. Achermann Technical Note: A Problem with Identifying Nonlinear Interactions of Circadian and Homeostatic Processes , 1999, Journal of biological rhythms.

[52]  D. Edgar,et al.  CIRCADIAN AND HOMEOSTATIC CONTROL OF WAKEFULNESS AND SLEEP , 1999 .

[53]  P. Achermann,et al.  Sleep Homeostasis and Models of Sleep Regulation , 1999 .

[54]  M. Kas,et al.  Photic phase response curve in Octodon degus: assessment as a function of activity phase preference. , 2000, American journal of physiology. Regulatory, integrative and comparative physiology.

[55]  Anna Wirz-Justice,et al.  Circadian Clues to Sleep Onset Mechanisms , 2001, Neuropsychopharmacology.

[56]  F. Turek,et al.  Sleep deprivation decreases phase-shift responses of circadian rhythms to light in the mouse: role of serotonergic and metabolic signals , 2001, Brain Research.

[57]  R. H. van den Hoofdakker,et al.  Sleep in seasonal affective disorder patients in forced desynchrony: an explorative study , 2002, Journal of sleep research.

[58]  R. H. van den Hoofdakker,et al.  A Forced Desynchrony Study of Circadian Pacemaker Characteristics in Seasonal Affective Disorder , 2002, Journal of biological rhythms.

[59]  P. Achermann,et al.  Mathematical models of sleep regulation. , 2003, Frontiers in bioscience : a journal and virtual library.

[60]  M. Okawa,et al.  [Sleep deprivation therapy]. , 2003, Ryoikibetsu shokogun shirizu.

[61]  Mariska J Vansteensel,et al.  Sleep states alter activity of suprachiasmatic nucleus neurons , 2003, Nature Neuroscience.

[62]  S. Daan,et al.  Quantitative analysis of the effects of slow wave sleep deprivation during the first 3 h of sleep on subsequent EEG power density , 2004, European archives of psychiatry and neurological sciences.

[63]  Giulio Tononi,et al.  Sleep homeostasis in Drosophila melanogaster. , 2004, Sleep.

[64]  Irene Tobler,et al.  Rest in the scorpion — a sleep-like state? , 1988, Journal of Comparative Physiology A.

[65]  Non-photic entrainment of human rest-activity cycle independent of circadian pacemaker , 2004 .

[66]  M. Terman,et al.  Controlled trial of naturalistic dawn simulation and negative air ionization for seasonal affective disorder. , 2006, The American journal of psychiatry.

[67]  G. Tononi,et al.  Sleep function and synaptic homeostasis. , 2006, Sleep medicine reviews.

[68]  T. Deboer,et al.  Technologies of sleep research , 2007, Cellular and Molecular Life Sciences.

[69]  Johanna H Meijer,et al.  Long term effects of sleep deprivation on the mammalian circadian pacemaker. , 2007, Sleep.

[70]  P. Achermann,et al.  Sleep homeostasis in the rat in the light and dark period , 2007, Brain Research Bulletin.

[71]  T. Dayan,et al.  The Relationship between the Golden Spiny Mouse Circadian System and Its Diurnal Activity: An Experimental Field Enclosures and Laboratory Study , 2007, Chronobiology international.

[72]  M. Vansteensel,et al.  Organization of cell and tissue circadian pacemakers: A comparison among species , 2008, Brain Research Reviews.

[73]  H. Landolt Sleep homeostasis: a role for adenosine in humans? , 2008, Biochemical pharmacology.

[74]  R. Johnston,et al.  Golden hamsters are nocturnal in captivity but diurnal in nature , 2008, Biology Letters.

[75]  Circadian Behavioral Rhythms in Cry1/Cry2 Double-Deficient Mice Induced by Methamphetamine , 2008, Journal of biological rhythms.

[76]  S. Daan,et al.  Evidence for differential human slow‐wave activity regulation across the brain , 2009, Journal of sleep research.

[77]  T. Deboer Sleep and sleep homeostasis in constant darkness in the rat , 2009, Journal of sleep research.

[78]  M. Menaker,et al.  The methamphetamine-sensitive circadian oscillator does not employ canonical clock genes , 2009, Proceedings of the National Academy of Sciences.

[79]  Manuel Schabus,et al.  Homeostatic Sleep Pressure and Responses to Sustained Attention in the Suprachiasmatic Area , 2009, Science.

[80]  S. Honma,et al.  The SCN‐independent clocks, methamphetamine and food restriction , 2009, The European journal of neuroscience.

[81]  S. Potkin,et al.  Rapid and Sustained Antidepressant Response with Sleep Deprivation and Chronotherapy in Bipolar Disorder , 2009, Biological Psychiatry.

[82]  H. Burgess Partial Sleep Deprivation Reduces Phase Advances to Light in Humans , 2010, Journal of biological rhythms.

[83]  F. Cappuccio,et al.  Quantity and Quality of Sleep and Incidence of Type 2 Diabetes A systematic review and meta-analysis , 2010 .

[84]  D. Dijk,et al.  PERIOD3, circadian phenotypes, and sleep homeostasis. , 2010, Sleep medicine reviews.

[85]  Joseph S. Takahashi,et al.  Circadian Integration of Metabolism and Energetics , 2010, Science.

[86]  Giulio Tononi,et al.  Antidepressant effects of selective slow wave sleep deprivation in major depression: a high-density EEG investigation. , 2011, Journal of psychiatric research.

[87]  A. B. Reddy,et al.  Circadian Clocks in Human Red Blood Cells , 2010, Nature.

[88]  M. Ferrara,et al.  Going local: insights from EEG and stereo-EEG studies of the human sleep-wake cycle. , 2011, Current topics in medicinal chemistry.

[89]  Serge Daan,et al.  Lab Mice in the Field: Unorthodox Daily Activity and Effects of a Dysfunctional Circadian Clock Allele , 2011, Journal of biological rhythms.

[90]  S. Daan,et al.  Working for Food Shifts Nocturnal Mouse Activity into the Day , 2011, PloS one.

[91]  Elizabeth B Klerman,et al.  Revisiting Spontaneous Internal Desynchrony Using a Quantitative Model of Sleep Physiology , 2011, Journal of biological rhythms.

[92]  G. Tononi,et al.  Local use-dependent sleep; synthesis of the new paradigm. , 2011, Current topics in medicinal chemistry.

[93]  G. Vandewalle,et al.  Abnormal Hypothalamic Response to Light in Seasonal Affective Disorder , 2011, Biological Psychiatry.

[94]  R. Armitage,et al.  Sleep homeostasis in alcohol-dependent, depressed and healthy control men , 2011, European Archives of Psychiatry and Clinical Neuroscience.

[95]  P. Achermann,et al.  Topographical aspects in the dynamics of sleep homeostasis in young men: individual patterns , 2011, BMC Neuroscience.

[96]  Ueli Schibler,et al.  Crosstalk between components of circadian and metabolic cycles in mammals. , 2011, Cell metabolism.

[97]  E. L. West,et al.  Dominant Cone-Rod Dystrophy: A Mouse Model Generated by Gene Targeting of the GCAP1/Guca1a Gene , 2011, PloS one.

[98]  Andrew J. Millar,et al.  Peroxiredoxins are conserved markers of circadian rhythms , 2012, Nature.

[99]  R. Levitan,et al.  Seasonal affective disorder. , 2012, Handbook of clinical neurology.

[100]  G. Tononi,et al.  Sex-related differences in sleep slow wave activity in major depressive disorder: a high-density EEG investigation , 2012, BMC Psychiatry.

[101]  D. E. F. L. Flôres,et al.  Field and Laboratory Studies Provide Insights into the Meaning of Day-Time Activity in a Subterranean Rodent (Ctenomys aff. knighti), the Tuco-Tuco , 2012, PloS one.

[102]  A. Wirz-Justice,et al.  Young Women With Major Depression Live on Higher Homeostatic Sleep Pressure Than Healthy Controls , 2012, Chronobiology international.

[103]  Simone Gori,et al.  Decreased Coherent Motion Discrimination in Autism Spectrum Disorder: The Role of Attentional Zoom-Out Deficit , 2012, PloS one.

[104]  P. Bech,et al.  A 9-week randomized trial comparing a chronotherapeutic intervention (wake and light therapy) to exercise in major depressive disorder patients treated with duloxetine. , 2012, The Journal of clinical psychiatry.

[105]  Rupert Lanzenberger,et al.  Light-dependent alteration of serotonin-1A receptor binding in cortical and subcortical limbic regions in the human brain , 2012, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[106]  Sunggu Yang,et al.  Aberrant light directly impairs mood and learning through melanopsin-expressing neurons , 2012, Nature.

[107]  Masahiro Takeshima,et al.  Total sleep deprivation followed by sleep phase advance and bright light therapy in drug-resistant mood disorders. , 2013, Journal of affective disorders.

[108]  S. Daan,et al.  Body Temperature Predicts the Direction of Internal Desynchronization in Humans Isolated from Time Cues , 2013, Journal of biological rhythms.

[109]  P. Franken A role for clock genes in sleep homeostasis , 2013, Current Opinion in Neurobiology.

[110]  J. Meijer,et al.  Irradiance encoding in the suprachiasmatic nuclei by rod and cone photoreceptors , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[111]  W. M. Wood-Vasey,et al.  The post illumination pupil response is reduced in seasonal affective disorder , 2013, Psychiatry Research.

[112]  Carla S. Möller-Levet,et al.  Mistimed sleep disrupts circadian regulation of the human transcriptome , 2014, Proceedings of the National Academy of Sciences.

[113]  Rachel Leproult,et al.  Circadian Misalignment Augments Markers of Insulin Resistance and Inflammation, Independently of Sleep Loss , 2014, Diabetes.

[114]  M. George,et al.  Adjunctive triple chronotherapy (combined total sleep deprivation, sleep phase advance, and bright light therapy) rapidly improves mood and suicidality in suicidal depressed inpatients: an open label pilot study. , 2014, Journal of psychiatric research.

[115]  Eran Segal,et al.  Transkingdom Control of Microbiota Diurnal Oscillations Promotes Metabolic Homeostasis , 2014, Cell.

[116]  M. Frank,et al.  Sleep, clocks, and synaptic plasticity , 2014, Trends in Neurosciences.

[117]  S. Chakrabarti Chronotherapeutics for affective disorders: A clinician's manual for light and wake therapy , 2014 .

[118]  E. Smeraldi,et al.  Changes of cortical excitability as markers of antidepressant response in bipolar depression: preliminary data obtained by combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) , 2014, Bipolar disorders.

[119]  G. Vandewalle,et al.  Neuroimaging, cognition, light and circadian rhythms , 2014, Front. Syst. Neurosci..

[120]  G. Tononi,et al.  Sleep and the Price of Plasticity: From Synaptic and Cellular Homeostasis to Memory Consolidation and Integration , 2014, Neuron.

[121]  F. Benedetti,et al.  Rapid treatment response of suicidal symptoms to lithium, sleep deprivation, and light therapy (chronotherapeutics) in drug-resistant bipolar depression. , 2014, The Journal of clinical psychiatry.

[122]  S. Yooseph,et al.  Diet and feeding pattern affect the diurnal dynamics of the gut microbiome. , 2014, Cell metabolism.

[123]  A. IJzerman,et al.  Caffeine increases light responsiveness of the mouse circadian pacemaker , 2014, The European journal of neuroscience.

[124]  Serge Daan,et al.  Cold and hunger induce diurnality in a nocturnal mammal , 2014, Proceedings of the National Academy of Sciences.

[125]  B. Giros,et al.  A highly tunable dopaminergic oscillator generates ultradian rhythms of behavioral arousal , 2014, eLife.

[126]  S. Maret,et al.  In Vivo Imaging of the Central and Peripheral Effects of Sleep Deprivation and Suprachiasmatic Nuclei Lesion on PERIOD-2 Protein in Mice. , 2015, Sleep.

[127]  Derk-Jan Dijk,et al.  Circadian regulation of slow waves in human sleep: Topographical aspects , 2015, NeuroImage.

[128]  Z. W. Zhang,et al.  Corrigendum: Vacancy-controlled ultrastable nanoclusters in nanostructured ferritic alloys , 2015, Scientific Reports.

[129]  G. Goodhill,et al.  How deeply does your mutant sleep? Probing arousal to better understand sleep defects in Drosophila , 2015, Scientific Reports.

[130]  T. Deboer Behavioral and electrophysiological correlates of sleep and sleep homeostasis. , 2015, Current topics in behavioral neurosciences.

[131]  S. Maret,et al.  Title : In Vivo Imaging of the Central and Peripheral Effects of Sleep Deprivation and Suprachiasmatic Nuclei Lesion on PERIOD2 Protein in Mice , 2022 .