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Sleep Medicine

Sleep Medicine

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Sleep Medicine

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Apr 1, 2017


Sleep is an activity that is exhibited by virtually all animal species, but our understanding of its true function remains unclear. What is better understood are the effects on a range of human and animal biological systems when sleep is degraded or curtailed. These effects are observed in the form of sleep loss and sleep disorders.

This textbook will describe the basic physiology of sleep and the range of sleep disorders and their consequences. Importantly, an overview of the impact of sleep and its disorders on human functioning across organs, systems, and physiological states will be provided. These often prove to be bi-directional interactions that obscure direct cause and effect relationships and challenge our ability to understand the consequences of sleep decrements. Despite an explosion of knowledge and emerging respect for the importance of sleep to human health, much remains to be understood about it and the full effects of its derangements.

Although much of the material presented will be internationally applicable, the book will be written from an Australasian perspective. Over the last thirty years in particular, significant contributions to sleep medicine have come from Australia and New Zealand; achievements from these countries in physiology, clinical research, and biotechnology, will feature prominently. Public health and community prevalence of sleep disorders will similarly be focused on Australasia, with relevant comparisons to the international setting.

Those seeking a broad understanding of sleep medicine - emerging sleep clinicians, tertiary students in health sciences and psychology - will find the book invaluable. Chapters will convey essential concepts and principles without exhaustive detail. Where appropriate, further reading will be referenced. In several chapters – on neurobiology of sleep, genetics, functions of sleep, and disorders of breathing during sleep – an expert overview will be provided of more complex areas that will challenge those already proficient in sleep medicine.
Apr 1, 2017

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  • If you say the words ‘circadian rhythm’, one of the first things that comes to mind is the daily rhythm of sleep and wakefulness. Sleep and wake, however, are easily dissociated from the circadian clock.

  • There may be brief awakening or arousals in between cycles of sleep that normally do not disrupt sleep, and one is usually not aware of these arousals.

  • The wavelength or colour of light is also important. It has long been known that short wavelength light (blue in appearance) causes the greatest shifts in circadian phase.

  • Though human sleep/wake rhythms can easily be desynchronised from the 24-hour clock, the circadian timing of sleep is critical for sleep quality and sleep length.

  • A key feature of circadian rhythms in any organism is that they are endogenously generated, occurring in the absence of external input.

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Sleep Medicine - DoctorZed Publishing



History of sleep medicine: a narrative with an Australasian perspective

Matthew T. Naughton


Three distinct phases of research have brought sleep medicine to a contemporary and thriving specialty that spans many aspects of healthcare and society. Originally, the fields of psychiatry and neurology ‘discovered’ sleep and the techniques that allowed it to be monitored. This was followed by a veterinary research phase that led to the discovery of melatonin and its role in the human circadian rhythm. The third and most prominent phase was the era of sleep-related breathing disorders, in particular obstructive sleep apnoea. This third and major impetus to the field of sleep medicine emerged from the discovery of the modern sleep apnoea therapy, the positive airway pressure device. This in turn had historical connections to the early management of a number of sleep-related breathing disorders, including polio, rheumatic heart disease, lung disease associated with premature infancy, and the adult respiratory distress syndrome.

During these three distinct phases, Australians and New Zealanders have been prominent in research and clinical care. This has resulted in the development of several successful commercial enterprises that, in combination, have had a major influence on healthcare worldwide.


Modern sleep monitoring draws from technical advances over the past 150 years and is a clinical investigation tool that has enjoyed widespread utility in recent decades. Sleep was thought to be a passive process, until in 1875 the Scottish physiologist Richard Caton observed electrical activity in animal brains. Fifty years later, the electroencephalogram (EEG) was developed by Hans Berger, a German psychiatrist, enabling researchers to discern differences between awake and sleep brain activity in humans. In the late 1930s, groups in Harvard and Chicago observed different EEG patterns during the various stages of human sleep. By 1953 Nathaniel Kleitman and Eugene Aserinsky discovered ‘rapid eye movements’ during human sleep. This landmark observation led to the description of ‘sleep architecture’ by William Dement and Daniel Kleitman in 1957, who observed the cyclic nature of rapid eye movement (REM) and non-REM sleep. Finally, in 1968, Allan Rechtschaffen and Anthony Kales described the normal human sleep stages based on the progressive slowing and synchronisation of the EEG frequency into non-REM stages 1 to 4 and the paradoxically high frequency activity of REM, a system of scoring we continue to use today.¹

The combined monitoring of sleep with respiratory function evolved in response to the observed prevalence of breathing disorders during sleep, especially obstructive sleep apnoea (OSA). Essential to this was the oximeter, a device using colorimetry measurements of blood to calculate oxygen concentration from the blue hue of desaturated haemoglobin. The first oximeter was developed in 1935 by the German physician Dr Karl Matthes and used the absorption of red and green light. In 1964, a cumbersome eight-wavelength device was developed at Hewlett Packard, and about 10 years later a simple dual light source ‘pulse’ oximeter was crafted by Takuo Aoyagi and Michio Kishi at Nihon Kohden. Soon thereafter, oximetry became widespread and eventually was recognised as the fifth standard ‘vital sign’ in healthcare (after blood pressure, heart rate, respiratory rate, and temperature).

Cardiac electrical activity was discovered by Alexander Muirhead and John Burdon-Sanderson in Britain in 1872, and 40 years later the PQRS waveform on the electrocardiogram was described by German physician Willem Einthoven. Combining measurement of sleep and respiration and their cardiac influences set the stage for polysomnography.

During the 1960s, psychology and psychiatry maintained their lead role in sleep research. Depression was shown to be associated with a short REM latency, narcolepsy was diagnosed by the sleep onset REM, and benzodiazepines had recently been developed. A psychologist from Edinburgh, Ian Oswald, moved to Perth, Western Australia, for three years in the late 1960s, where he undertook Australia’s first sleep studies.² Oswald also assisted the newly appointed Scottish academic surgeons, Hugh Dudley and John Masterton, at Monash University’s recently established Medical School. Having experienced the extremes of circadian dys-synchrony while he served in the Royal Navy in the Arctic Circle, Masterton developed an interest in the impact of sleep upon wound healing. Masterton and Oswald set up a sleep laboratory within Melbourne’s Alfred Hospital Department of Surgery to study the impact of sleep upon postoperative delirium. This initiative was most noted for attracting junior medical officer Dr Murray Johns to join this team and embark on his PhD. While they wrote seminal papers that focused on the impact of changes in REM and endocrine function upon postoperative delirium,³,⁴,⁵ it was Johns who in later years went on to describe one of the most frequently used clinical tools in sleep medicine worldwide, the Epworth Sleepiness Scale.⁶ Johns’ capacity for innovation continued, establishing the first computerised sleep monitoring system across the mid 1980s. leading to the development of one of the major international sleep monitoring companies, Compumedics Ltd.

In the same era of Masterton and Dudley’s work linking sleep to pathology, two international neurologists with an interest in sleep, Henri Gastaut (French) and Elio Lugaresi (Italian), organised an EEG symposium at the University of Bologna in 1967. From this traditional physiology format emerged for the first time descriptions of sleep pathologies, published in a book The Abnormalities of Sleep in Man (Auto Gaggi; 1968), one of the earliest modern textbooks of sleep disorders.⁷

During the 1970s, this shift from physiology to clinical sleep research gathered speed, aided by technological innovations in the monitoring of sleep. In 1970, Bill Dement set up a clinical sleep laboratory at Stanford University. Post-doctoral student Christian Guilleminault, a French neurologist and psychiatrist, arrived at Stanford University and soon became the clinical service head with Jerome Holland. They coined the term ‘the apnea hypopnea index’ as a metric of obstructive sleep apnoea (OSA) severity. Before long, the monitoring of clinical sleep disorders was turned from overnight testing to the specific investigation of daytime sleepiness and related symptoms by Mary Carskadon’s development of the multiple sleep latency test (Chapter 7). Mary Carskadon is now an honorary professor at the University of Adelaide.


Australian research interest in chronobiology began in the 1970s with Dr George Singer at Melbourne’s La Trobe University. Singer studied the hypothalamic mechanisms controlling hunger, thirst, and satiety in rats. Noradrenaline injected into the hypothalamus could elicit hunger during the light phase and satiety in the dark phase of the light–dark cycle, introducing the concept of circadian effect upon hunger to his student Stuart Armstrong. At that time, melatonin was known to be released from the pineal gland; however, it was thought to be important in animals only during their mating season. In humans, the pineal gland was believed to be vestigial and melatonin ‘inactive’. Armstrong and colleague Dr Jenny Redman, at La Trobe University, were the first to report that exogenous melatonin could entrain (synchronise) free-running circadian rhythms in rats who were held in constant darkness.⁸ ProfessorRoger Short, an eminent reproductive biologist at Monash University, met with Armstrong, and both collected data through self-experiment to determine whether there was a similar effect in humans. Armstrong underwent a simulated shift work regimen in the basement of one of the university colleges while Short tested circadian misalignment on himself during overseas trips. Both collected core temperature, sleep charts, and scales to record fatigue and mood, thereby describing circadian rhythm and the role of melatonin. This led to the discovery that exogenous melatonin could shift the body clock in humans and thus a treatment was found for shift work and jet lag.


The first ‘popularised’ description of the obesity hypoventilation syndrome was made by Charles Dickens in his Pickwick Papers (1837), with his account of a somnolent fat boy named Joe. Nearly 120 years later, Sidney Burwell described the clinical syndrome of obesity with awake hypercapnia and, in acknowledgement of Dickens’ original description, the term ‘Pickwickian syndrome’ gained traction in denoting the obesity hypoventilation syndrome (OHS).⁹ Soon thereafter, Gastaut and colleagues¹⁰ and R. Jung and W. Kuhlo in Germany¹¹ performed the first physiological recordings in patients with obesity hypoventilation, measuring continuous oximetry, ventilation, and electroencephalography during sleep.

From the description of hypoventilation syndromes, attention was turned to the most frequent of breathing disorders during sleep, obstructive sleep apnoea (OSA). In 1972, Elio Lugaresi presented work at the Symposium of Rimini, Italy, that described a link between sleep apnoea, snoring, and cardiovascular disease.¹² The significant prevalence of OSA was further confirmed when Christian Guilleminault, Ara Tilkian, and William Dement reported a review of sleep apnoea syndromes. At the time 350 patients had been studied and sleep apnoea identified in as many as 18%.¹³ In California in 1977, an international conference for sudden infant death syndrome (SIDS) research was funded by the Kroc Foundation (Ray Kroc was founder of fast-food giant McDonalds), and organised by Robert Kroc (son of Ray), who was a neonatal physiologist.¹⁴ At the time, there was a suspected link between sleep, ventilation, and SIDS. The meeting attracted the ‘who’s who’ across the whole of sleep and respiratory medicine. In attendance were the pioneering researchers Lugaresi, Dement, and Guilleminault, as well as others who would go on to make major contributions, including Eliot Phillipson and two Australians, David Henderson Smart and David Read. Although not appreciated by attendees at the time, nor today, the historic link between OSA and fast food has an ironic beginning.

During the 1970s, Eliot Phillipson at University of Toronto had ‘accidentally’ discovered that CO2 controlled ventilation. Initially studying the impact of exertional dyspnoea in tracheostomised dogs, he identified that post-exercise hypocapnia resulted in central apnoeas. This spurred Phillipson to study the relationship between sleep and ventilation. He took on two Australian post-doctoral respiratory physicians, Colin Sullivan and Glenn Bowes. Between 1977 and 1979, Sullivan worked with Phillipson studying the effects of hypoxia, hypercapnia, and arousals in non-REM and REM in a canine model to further understand the link between SIDS, OSA, and the OHS. Bowes followed with further canine experiments and with Phillipson wrote the acclaimed Control of Ventilation chapter in the Handbook of Physiology.¹⁵

Although we now regard upper airway collapse as the cause of most OSA, this was not known in the 1970s. Using multiple pharyngeal pressure recordings, the first to formally demonstrate upper airway collapse as the cause of OSA was John Remmers at the University of Texas, in 1978.¹⁶ This knowledge saw the incorporation of tracheostomy as a standard of treatment for OSA between 1979 and 1981.

In March 1980, Colin Sullivan (having returned from Toronto) organised the First International Workshop on the Control of Breathing, held in Sydney and attended by similar luminaries from the Kroc-sponsored meeting plus a number of key local and international prominent contributors (Figure 0.1). This event was significant for the proceedings of this meeting were first published in the first supplement of the journal Sleep,¹⁷ which was to become the key international journal for the field of sleep medicine.

Figure 0.1: International Workshop on the Control of Breathing During Sleep, Sydney, 1980.¹⁷ Back row (left to right): Faiq Issa, Hans Schulte, David Read, Michael Berthon-Jones, Charles Bryan, Gaby Bernd Duron, Colin Sullivan, Dan Shannon, John Maloney, David Henderson-Smart. Second row (L to R): Shirley Tonkin, Jacques Mouret, Richard Harding, Michael Hensley, Barry Sterman, Christian Guilleminault, Nick Saunders, John Remmers, James Dick, Heather Jeffrey and Tom Roth, Ron Hagan, John Orem. Front row seated (L to R): Bernard Burieky, Eliot Weitzman, Harvey Moldovsky, Elio Lugaresi (courtesy Colin Sullivan)

The end of the era of tracheostomy therapy for OSA began with two major publications in 1981. One was the description of uvulopalatopharyngoplasty by Japanese surgeon S. Fujita,¹⁸ beginning the surgical treatment journey for OSA (Chapter 19). The other was Sullivan’s paper describing use of continuous positive airway pressure (CPAP) as treatment for eight adult patients with severe OSA¹⁹. Sullivan describes his account of this historic achievement in Chapter 17.


Negative pressure ventilation

Outbreaks of polio were epidemic in the late 1920s. The infectious disease affected neuromuscular function and targeted mainly children aged under 14 years, many of whom died of hypercapnic respiratory failure. This condition was known to produce significant morbidity during wakefulness, but the role of sleep and sleep-related hypoventilation in disease progression was not appreciated at the time (see Chapter 26). The negative pressure ‘iron lung’ was developed in the United States in 1928 by Drinker and Shaw as a supportive device for polio patients. An iron case within which one would ‘live’ was connected to two motorised vacuums pumps that created a cyclic negative pressure around the chest to assist ventilation. When trialled at the Boston Children’s Hospital, an 8-year-old girl survived near death with polio and respiratory failure. These devices were large and heavy and as expensive as the average home in the United States at the time.

When a polio outbreak occurred in Australia in 1937, the South Australian Department of Health asked two Adelaide-born ‘backyard’ inventors, Edward and Don Both, to develop a negative pressure ventilator that was less expensive, lighter, and transportable. Don Both was a designer and translator. Edward, the older brother, was a ‘genius without a university degree’. When asked why he had no degree, Edward stated, ‘I never got around to it!’ Edward and Don’s combined capacity for innovation was exemplified by their design of a three-wheeled electric car for use during the petrol rationing era of World War 2. Other inventions included an early fax machine, humidicribs, pen recorders, and the electric score board used at the Melbourne Cricket Ground for the 1956 Olympic Games.

In 1938 Edward left for England, where he studied the ‘iron’ lung; he then designed a cheaper ‘wooden’ lung (also known as the Both Ventilator). He met with William Morris of Oxford (Morris Garage [MG] fame), later Lord Nuffield, a British automotive manufacturer and philanthropist. Nuffield, intrigued by the wooden lung design, financed production of approximately 1700 machines at his car factory in Cowley, and donated them to hospitals throughout Britain and the British Empire. The cost of the ‘wooden’ lung was about one-tenth of the ‘iron’ lung.

In 1937–38, Professor Aubrey Burstall, an engineer at The University of Melbourne, and Dr John Forbes, a physician at Fairfield Infectious Diseases Hospital in Melbourne, were confronted by a two-year polio epidemic that saw 1275 new cases arriving at the Fairfield Hospital. Burstall made 29 wooden negative pressure lungs, which were used to treat 106 patients with respiratory failure. At the peak of this epidemic, 47 patients were sharing the 30 hospital ventilators. Seventy-seven patients died, and many more were left with permanent disabilities. Two further polio epidemics occurred (1947–48 and 1951–52) with patients continuing to require adaptations of this form of negative pressure ventilation.

Although the development of the Salk and Sabin vaccines in 1952 and 1957 respectively brought an end to polio epidemics in Australia and many developed countries, Drs Hugh Newton-John and Bryan Speed, infectious disease physicians, continued to run the long-term ventilator program at Fairfield Hospital until 1996, when the service was transferred to the Austin Hospital under the care of the late Professor Rob Pierce. On 30 October 2009, long-term Fairfield and Austin hospital patient June Middleton died, aged 83 years. Middleton had been entered in the Guinness Book of Records as the person who spent the longest time (60 years) in an iron lung.

The iron lung and the ‘wooden’ versions were large and cumbersome, and limited the patient’s mobility. Moreover, older patients using iron lungs were often unable to maintain upper airway patency due to non-physiological negative thoracic pressure swings. This caused an iatrogenic form of OSA that sometimes required nasal CPAP. Slowly, both the iron and wooden lungs fell out of regular use.

Positive pressure ventilation

While the medical profession was focused on negative pressure ventilators, positive pressure ventilators were being developed. Electricity was developed in the 1890s and the vacuum cleaner in the early 1900s; in 1936, English physician Dr Poulton described 22 patients with dyspnoea due to left-sided heart failure and pulmonary oedema who were treated successfully with the ‘pulmonary plus pressure machine’ – essentially the reverse end of a vacuum with a positive end expiratory pressure valve and mask.²⁰

During World War 2, high levels of CPAP were studied in healthy young pilots to assist flying at extremes of altitude to avoid detection by the enemy. In 1948²¹ a series of experiments by Andre Cournand described a fall in cardiac output with high levels (>20 mmHg) of positive airway pressure by mask, creating the view that positive airway pressure was unsafe for humans. However, by 1952 Danish polio patients were managed with positive pressure ventilators without ill effect. During the Vietnam War, Ashbaugh in 1967 described the efficacy of low level CPAP in adult respiratory distress syndrome in battle-scarred soldiers, renewing interest in CPAP.²² Clinical applications for CPAP diversified, and in the same year Australian neonatologist Michael Adamson, working in England, reported an improved survival in premature infants with lung disease when they were treated with CPAP.²³

In 1981, Colin Sullivan’s landmark paper was published in which eight adult patients with severe OSA who had refused tracheostomy improved with CPAP applied via a moulded nasal fibreglass mask (see Chapter 17, Figure 17.1).¹⁹ The patients felt so much better that they requested to be able to use the equipment at home. Within 12 months of Sullivan’s report, David Rapoport and colleagues from New York published similar favourable results.²⁴ The key to success was the mask incorporating an exhalation valve. Various versions of the exhalation (or PEEP) valve were trialled, including underwater seals to create CPAP, but were found to be impractical.²⁵ CPAP pumps in the early days were Hitachi LTD motors that were noisy, weighed about 7 kg, and were designed to clean and filter pools and spas. Between 1981 and 1986, patient numbers coming through Sullivan’s Sydney laboratory increased from 5 to 140 per annum. Lighter and quieter pumps with a broad variety of masks were developed. By 1989, about 1000 patients in Sydney were on CPAP. By now, Sullivan had developed an expansive research team covering animal, human physiological, and epidemiological research (Figure 0.2).

Figure 0.2: Sleep Research Team, Royal Prince Alfred Hospital & University of Sydney (1986). Back, left to right: Desiree Seagel, Mike Berthon-Jones, Roberta Thomson, unknown, Victoria Keena, Jenny Duncan, Jim Bruderer, Shu Chan, unknown, Janet Bevan, Helen Bearpark, Wes Green, Mark Hersh, Thanh Bui, Colin Sullivan, Des Lauff, Steve Burrows, Jenny Peat, Cheryl Sedgwick, Cheryl Salome, Lucy Costas, Elizabeth Ellis, Farida Bolano, Peter Edwards, Pete Donnelly, Sandy Anderson, Faiq Issa (Courtesy Ron Grunstein)

Figure 0.3: Colin Sullivan and David Rapoport at American Thoracic Society 2010 annual scientific meeting New Orleans on 30th anniversary of the 1981 Lancet publication.¹⁹

As the number of research papers in support of CPAP for OSA grew exponentially, and clinical activity in the area was well established, a British epidemiologist, Dr Wright, was asked on behalf of the UK healthcare service to evaluate the evidence that CPAP improved healthcare outcomes.²⁶ He concluded that the evidence was poor and the sleep field lacked robust clinical research. This spurred an avalanche of randomised controlled trials in the United Kingdom, Spain, Canada, Australia, and other countries to complement the basic physiological experiments (animal and human) and rapidly expanding epidemiological data bases (e.g. Wisconsin Sleep Cohort, Sleep Health Heart Study, Busselton Sleep Cohort (see Chapter 12]). Today we have compelling evidence around the prevalence, mechanisms, and repercussions of untreated OSA and associated disease and quality of life. Furthermore, we have an array of effective treatments that provide significant improvements in quality and possibly quantity of life, with increasing evidence of a positive societal impact.


In contrast to adult sleep medicine, which followed the path of psychiatry, neurology, and then respiratory medicine, the process in neonatology had different origins. It was well known that infants born prematurely died of respiratory failure and that CPAP played a major therapeutic role.²³ In addition, SIDS was a common disorder of unknown cause in children aged 6–12 months. Several explanatory theories existed at the time, such as excessive heating, lack of breast milk, and developmental delay. Many neonatologists believed SIDS to be a form of apnoea.

Figure 0.4: Australasian Sleep Association annual scientific meeting, Christchurch, New Zealand, 2010: ASA presidents from L to R: Craig Hukins, Peter Cistulli, Matthew Naughton, David Hillman, John Wheatley, Colin Sullivan, Doug McEvoy, Ron Grunstein, Shantha Rajaratnam. (Courtesy of Stephanie Blower, Australasian Sleep Association)

Table 0.1: Australasian sleep-related industry achievements

In Melbourne, the common thread of SIDS, neonatal CPAP, and control of ventilation brought Australians Michael Adamson (paediatrician) and Blair Ritchie and John Maloney (both respiratory physiologists) together in the hope of understanding and preventing SIDS. The Ritchie Institute of Baby Health was set up with a generous donation from the Ritchie family (Blair was the son of wealthy Ballarat supermarket chain owners). Karen Fitzgerald, mother of a SIDS patient, devoted her life to the SIDS Foundation, which funded one of Australia’s first paediatric sleep research centres at the Queen Victoria Hospital, Melbourne. In Sydney, John Reid, David Reed, and David Henderson Smart were leading academics in respiratory medicine at the time, with a similar interest in control of ventilation and SIDS. Their PhD student was Colin Sullivan (Figure 0.3).

In New Zealand in the 1980s, a large cohort study directed by E.A. Mitchell identified four contributory factors to SIDS: parental smoking, lower socioeconomic status, lack of breast feeding, and prone positioning. The first recommendation of ‘prone position avoidance’ to reduce SIDS was later confirmed by a large New Zealand study which resulted in a huge reduction in rates of SIDS from 6 to 1 per 1000 from 1980 to 1990.²⁷


The Australasian Sleep Association was formed in 1987 to share research between clinicians, physiologists, psychologists, and technologists, with the late Helen Bearpark driving its development. Its first annual scientific meeting was held in 1988 in Sydney, and thereafter meetings were held in each state of Australia and New Zealand, attracting high calibre local and international invited guest speakers (Figure 0.4). The ASA has played a critical role in the Australasian sleep research collaborations, along with industry development, which have remained extremely strong (Table 0.1). In 2005, it was estimated that Australia was the second most prolific research nation for our given population pertaining to sleep.²⁸ Australasia has led in many fields of sleep research, including sleep monitoring, circadian dys-synchrony, and the involvement of sleep disordered breathing across an array of diseases and treatments.


1Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Washington, DC: Public Health Service, US Government Printing Office; 1968.

2Jones HS, Oswald I. Two cases of healthy insomnia. Electroencephalogr Clin Neurophysiol. 1968;24:378–80.

3Johns MW, Egan P, Gay TGA, Masterton JP. Sleep habits and symptoms in male medical and surgical patients. BMJ. 1970;2:509–12.

4Johns MW, Gay TJA, Masterton JP, Bruce DW. Relationship between sleep habits, adrenocortical activity and personality. Psychosom Med. 1971;33(6):490–508.

5Johns MW: Methods for assessing human sleep. Arch Intern Med 1971;127:484-491.

6Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14(6):540–5.

7Gastaut H, Lugaresi E, Berti-Ceroni G, Coccagna G, editors. The abnormalities of sleep in man. Proceedings of the XVth European meeting on electroencephalography. Bologna: Aulo Gaggi Editore; 1967.

8Redman J, Armstrong S, Ng KT. Free-running activity rhythms in the rat: entrainment by melatonin. Science. 1983 Mar 4;219(4588):1089–91.

9Burwell CS, Robin ED, Whaley Bickelman AG. Extreme obesity associated with alveolar hypoventilation: a Pickwickian syndrome. Am J Med. 1956;21:811–18.

10 Gastaut H, Tassinari C, Duron B. Etude polygraphique des manifestations episodiques du syndrome de pickwick. Rev Neurol. 1965;112:568–79.

11 Jung R, Kuhlo W. Neurophysiological studies of abnormal night sleep and the Pickwician syndrome. Prog Brain Res. 1965;18:140–59.

12 Lugaresi E. Snoring. Electroencephalogr Clin Neurophysiol. 1975;39:59–64.

13 Guilleminault C, Tilkian A, Dement WC. The sleep apnea syndromes. Annu Rev Med. 1976;27:465–84.

14 Guilleminault C, Dement WC, editors. The sleep apnea syndromes. Kroc Foundation Series, vol 11. New York: Alan R Liss Inc; 1978.

15 Phillipson EA, Bowes G. Control of breathing during sleep. In: Cherniack NS, Widdicombe JG, editors. Comprehensive physiology. Supplement 11: Handbook of physiology, The respiratory system. Control of breathing. . Wiley-Blackwell for American Physiological Society; 2011. p. 649–89. First published in print 1986.

16 Remmers JE, DeGroot WJ, Sauerland EK, Anch AM. Pathogenesis of upper airway occlusion during sleep. J Appl Physiol. 1978;44:931–8.

17 Sullivan CE, Henderson-Smart DJ, Read DJC, editors. The control of breathing during sleep (alternative title: Sleep). Symposium on Sleep and Breathing; 1980 March 1–3, Sydney, Australia. New York: Raven Press; 1980.

18 Fujita S, Conway W, Zorick F, Roth T. Surgical correction of anatomic abnormalities in obstructive sleep apnea syndrome: uvulopalatopharyngoplasty. Otolaryngol Head Neck Surg. 1981;89:923–34.

19 Sullivan CE, Issa FG, Berthon Jones M, Eves L. Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet. 1981;317(8225):862–5.

20 Poulton EP. Left sided heart failure with pulmonary oedema; its treatment with the pulmonary plus pressure machine. Lancet. 1936;228(5894):981–3.

21 Cournand A, Motley HL, Werko L, Richards DW. Physiological studies of the effects of intermittent positive airway pressure breathing on cardiac output in man. Am J Physiol. 1948;152:162–74.

22 Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet. 1967;290(7511):319–23.

23 Adamson TM, Collins LM, Dehan M, Hawker JM, et al. Mechanical ventilation in newborn infants with respiratory failure. Lancet. 1968;292(7562): 227–31.

24 Rapoport DM, Sorken B, Garay SM, Goldring RM. Reversal of the ‘Pickwickian syndrome’ by long-term use of nocturnal positive airway pressure. N Engl J Med. 1982;307:931–3.

25 Wagner DR, Pollack CP, Weitzman ED. Nocturnal nasal airway pressure for sleep apnea. N Engl J Med. 1983;308:461–2.

26 Wright J, Dye R, Watt I, Melville A, Sheldon T. Health effects of obstructive sleep apnoea and the effectiveness of continuous positive airways pressure: a systematic review of the evidence. BMJ. 1997;314:851–60.

27 Mitchell EA, Scragg R, Stewart AW, Becroft DM, et al. Results from the first year of the New Zealand cot death study. N Z Med J. 1991;104:71–6.

28 Rippon I, Lewison G, Partridge MR. Research outputs in respiratory medicine. Thorax. 2005;60:63–7.

Part 1

Physiology of Sleep

This section describes the basic characteristics of sleep and the mechanisms that underpin them. As this part will demonstrate, our understanding of sleep – its regulation, neurobiology, and genetics – has been greatly enhanced over recent decades. Yet, as Chapter 5 describes, the basic purpose of sleep steadfastly remains within the realm of theoretical constructs. This group of chapters will provide an up to date account of the key aspects of the physiology of sleep that a practitioner in this field will require.

Chapter 1

Normal human sleep: infancy to adulthood

Arthur Teng & Sandra Chuang


A health professional working closely with parents and infants and adolescents often needs to address important questions on normal sleep duration and pattern, sleep hygiene, and safe sleep practices from infancy through to adulthood.¹–⁵ This chapter will overview the important physiological aspects of sleep and their transitions into maturity.


Sleep can be divided into two main stages: non rapid eye movement sleep (non-REM), and rapid eye movement (REM) sleep. Each stage is defined by distinctive levels of arousal, autonomic response, brain activity, and muscle tone. Based on characteristic electroencephalogram (EEG) activity, non-REM sleep is further categorised into three main stages, with stage 1 (N1) being the lightest, and stage 3 (N3) being the deepest sleep stage. Features of the sleep stages are depicted in Figure 1.1. Stage 1 sleep is considered to be a transitional state between awake and asleep, characterised by drowsiness, slow rolling eye movements, and reduced responsiveness. Alpha waves (8–12 Hz) measured from the EEG are present in the awake relaxed state with the eyes closed. These transit to a slower theta (4–8 Hz) rhythm as light sleep is entered. Stage 2 sleep is considered to be the onset of true sleep, with decreased eye movements, reduced muscle tone, and deceleration of respiratory and heart rate. Stage 2 sleep is characterised by K-complexes and spindles (Figure 1.2). K-complexes are characterised by a fast negative (upward) component and a slower positive (downward) component. Spindles are often seen within the complex. The peak-to-peak amplitude is ≥75 μV. Stage 3 sleep is also known as deep or slow-wave sleep. More detailed explanations of these characteristics are given in Chapter 6. Stage 3 sleep is characterised by rhythmic breathing, decreased heart rate, and delta waves on EEG (Figure 1.1). Delta waves are usually ≤2 Hz or less and measure ≥75 μV from peak to peak.

Figure 1.1: Diagram depicting the major sleep stages. Wakefulness demonstrates alpha rhythm. Stage 1 sleep demonstrates theta wave activity. Stage 2 sleep demonstrates theta wave activity with a sleep spindle and K complex. Stage N3 sleep shows delta waves. REM sleep shows low muscle tone, rapid eye movements, and an active EEG. Left axis: EMG is electromyogram measuring muscle tone; EOG1 and EOG2 are electro-oculogram recording eye movements. Frontal (F4-M1), central (C4 M1), and occipital (O2-M1) EEG leads depict the cortical activity.

Figure 1.2: A 30-second epoch of a polysomnogram from a 7-year-old child in Stage 2 sleep. Note the spindles as marked (12–14 Hz) followed by a K-complex in the box. K-complexes are characterised by a fast negative (upward) component and a slower positive (downward) component. Spindles are often seen within the complex. The peak-to-peak amplitude is ≥75 μV. Each vertical dotted line in the box is 0.5 seconds.

In comparison, REM sleep is characterised by bursts of rapid eye movements on electro-oculogram (EOG), muscle paralysis and low muscle tone, varied respiratory pattern and dreaming (Figure 1.1). Intense EEG activity during REM sleep similar to that of the awake state suggests higher brain functioning is actively involved in REM sleep. The REM sleep EEG is characterised by low-voltage, mixed-frequency activity, with so-called saw-tooth waves. It is also easier to wake up from REM sleep than from non-REM sleep if disturbed.

In children and adults, sleep moves through repeated cycles of non-REM and REM sleep throughout the night. There may be brief awakening or arousals in between cycles of sleep that normally do not disrupt sleep, and one is usually not aware of these arousals. Typically, in the first part of the night, most sleep is non-REM sleep. As the night progress, REM becomes the more predominant stage of sleep.

Figure 1.3: Typical trace alternans in an infant polysomnogram. Note the intermittent bursts of slow waves (a) with intervening periods of extremely low amplitude EEG activity (b).


In the newborn, three stages of sleep are recognised: quiet sleep (like deep non-REM sleep), active or REM sleep, and indeterminate sleep (where no criteria are met for quiet sleep and REM). For premature infants, the separation between active and quiet sleep becomes clearer by 30 weeks of corrected age. This evolves into well-defined REM and non-REM sleep as the infant brain matures. Hence in active or REM sleep, respiration can vary in rate and amplitude, with occasional myoclonic jerks of the arms or legs. Babies can enter REM sleep directly from wakefulness, unlike older children and adults.

Specific characteristics of infant sleep:

•There are no sleep spindles until 4–6 weeks of age

•Delta waves develop at roughly the same time as sleep spindles

•K-complexes arrive at 3–6 months of age ( Figure 1.2 )

•Behavioural and observational criteria are more significant than state definitions in this age group.

Infants in quiet sleep exhibit bursts of slow waves, at times intermixed with sharp waves, and intervening periods of relative quiescence with extreme low-amplitude activity. This pattern is known as trace alternans (Figure 1.3). For premature infants, this is often seen by ~37 weeks of corrected age.


Birth to preschool

At birth, the circadian rhythm or body clock is not fully developed, and hence sleep can occur throughout day and night. Sleep periods lasting one to two sleeping cycles of 40 minutes are often synchronised with feeding time.⁶ Circadian rhythm emerges at ~2–3 months of age, with increased response to light/dark cues to synchronise the sleep/wake state in infants. Another factor affecting the newborn’s sleep is the predominance of time spent in active (REM) sleep, and the shorter sleep cycles (~40 minutes) of quiet and active sleep, compared to an adult’s 90-minute cycles. Like adults, babies usually wake briefly at the end of each sleep cycle.⁶,⁷ Hence, with the shorter sleep cycles, and the predominance of active or REM sleep which are easier to wake up from than quiet sleep, babies biologically have more awakenings and sleep more lightly than adults.

Figure 1.4: Changes in total sleep and proportion of REM and non-REM in the developing child from infancy. (Modified from Roffwarg et al.⁸)

The sleep pattern matures as a child grows physically between 0–36 months, with decreasing daytime sleep, increasing night-time sleep, and increased consolidation in sleep duration and timing (Figure 1.4). The proportion of REM sleep decreases gradually from 50% of total sleep to 20–25% by the age of 5 years. REM sleep becomes concentrated in the later sleep cycles of the night and non-REM sleep in the earlier part of the night. The organisation of non-REM into the characteristic stages 1–3 becomes more evident by 6 months of age. Night-time sleep is consolidated into two long sleep periods by 12 months, with one or two distinct daytime naps. Total daily sleep requirements also decrease steadily, from 14–15 hours/day at the age of 1 year, to 11 hours by age 5. By the age of 4 years, most children no longer require a daytime nap, although considerable individual variations exist.

From childhood to adolescence

Normal, healthy pre-school-age children, school-age children, adolescents, and young adults, transition from awake into sleep through non-REM sleep. This is in clear contrast to infants, who normally transition to sleep through REM sleep. By late childhood and early adolescence all electrophysiological variables have approximated young adult values. In adolescence there is slight lengthening of the so-called circadian period (or body clock) compared to adults (approximately 24.3 hours compared to 24.2 hours).⁹,¹⁰ Another well-documented finding is that of a delay of the timing of the nocturnal sleep episode during the teenage years. This is thought to result from a combination of social, behavioural, and biological factors. There are, unlike in childhood, considerable differences between school and non-school nights. There is good evidence that there is a gradual decline of total sleep time from early to late adolescence, with objective measures suggesting that teenagers are significantly sleepier than adults and pre-teen children.


The first few weeks of life is a period of critical sleep organisation and establishment of the diurnal cycle. Sleep is initially of short duration and fragmented. Total sleep time decreases with age, and daytime sleep also decreases together with the percentage of REM sleep. Most infants at 9 months of age would be able to sleep through the night. From childhood to adolescence there is a gradual approximation of adult sleep patterns. This knowledge of normal sleep physiology will equip the health professional to address more holistically the many health issues on which sleep and its disorders may have important impacts.


1Davis KF, Parker KP, Montgomery GL. Sleep in infants and young children: Part one: normal sleep. J Pediatr Health Care. 2004;18(2):65–71.

2Wake M, Morton-Allen E, Poulakis Z, Hiscock H, et al. Prevalence, stability, and outcomes of cry-fuss and sleep problems in the first 2 years of life: prospective community-based study. Pediatrics. 2006;117(3):836–42.

3Teng A, Bartle A, Sadeh A, Mindell J. Infant and toddler sleep in Australia and New Zealand. J Paediatr Child Health. 2012;48(3):268–73.

4Lam P, Hiscock H, Wake M. Outcomes of infant sleep problems: a longitudinal study of sleep, behavior, and maternal well-being. Pediatrics. 2003;111(3):e203–7.

5Zuckerman B, Stevenson J, Bailey V. Sleep problems in early childhood: continuities, predictive factors, and behavioral correlates. Pediatrics. 1987;80(5):664–71.

6Zee PC, Turek FW. Introduction to sleep and circadian rhythms. In: Turek FW, Zee PC, editors. Regulation of sleep and circadian rhythms. New York: Marcel Dekker Inc.; 1999. p. 1–17.

7Anders TF, Sadeh A, Appareddy V. Normal sleep in neonates and children. In: Ferber R, Kryger M, editors. Principles and practice of sleep medicine in the child. Philadelphia: W.B. Saunders Company; 1995. p. 7–18.

8Roffwarg HP, Muzio JN, Dement WC. Ontogenetic development of the human sleep-dream cycle. Science. 1966;152(3722):604–19.

9Carskadon MA, Labyak SE, Acebo C, Seifer R. Intrinsic circadian period of adolescent humans measured in conditions of forced desynchrony, Neurosci Lett. 1999;260(2):129–132.

10 Czeisler CA, Duffy JF, Shanahan TL, Brown EN, et al. Stability, precision, and near-24-hour period of the human circadian pacemaker. Science. 1999;284(5423):2177–81.

Chapter 2

Biological rhythms and sleep

Sean W. Cain, Michelle Y. Coleman & Elise M. McGlashan


Whether we measure hour by hour, the number of dividing cells in any tissue, the volume of urine excreted, the reaction to a drug, or the accuracy and the speed with which arithmetical problems are solved, we usually find that there is a maximum value at one time of day and a minimum value at another.

Jurgen Aschoff, Circadian Rhythms in Man, 1965¹

Throughout evolutionary history, living organisms have been exposed to rhythmic changes in the environment. These rhythms are associated with the period of the Earth’s rotation, its movements around the Sun, and gravitational effects of the Moon. Many different rhythms with a variety of periods exist, such as ultradian rhythms (less than 20 hours), circatidal rhythms (~12 hours), circalunar rhythms (~29.5 days), and circannual rhythms (~one year). The most ubiquitous biological rhythm is the approximately 24-hour circadian rhythm. This rhythm is related to the wax and wane of light levels over the 24-hour day. Circadian rhythms have been observed in a vast range of life forms, from single-celled organisms (e.g. cyanobacterium Synechococcus spp. and the dinoflagellate alga Gonyaulax polyedra) to humans. So fundamental are circadian rhythms to life on Earth that virtually all organisms display them. Even within organisms, virtually all cells can express 24-hour rhythms. These recurrent patterns of physiology and behaviour help organisms to synchronise to the external environment and predict recurrent events, such as the presence of predators and availability of food, thereby supporting an organism’s functioning and survival.


A key feature of circadian rhythms in any organism is that they are endogenously generated, occurring in the absence of external input. Circadian rhythms are not simply a passive reaction to daily cycles in the environment. The earliest demonstration of the likely endogenous nature of circadian rhythms was made by Jean-Jacques d’Ortous de Mairan in 1729 in the Mimosa pudica plant. This plant opens its leaves during the day and closes them at night. (This plant will also close its leaves in the day in response to touch, which is why it is known as the ‘sensitive’ plant.) To test whether these daily leaf movements were a passive response to the environmental light cycle (i.e. light causing the leaves to open), d’Ortous de Mairan shielded the plants from light and demonstrated that the daily cycle in their leaf movements continued² (Figure 2.1). Though these and many other observations supported the idea that circadian rhythms are endogenous, the idea that unseen exogenous factors drove these rhythms persisted. A demonstration of the rhythms continuing in space, orbiting the Earth, left little to debate that the source of circadian rhythms was within the organism.³

In general, the demonstration of endogenous circadian rhythms has involved the observation of rhythms while attempting to eliminate exposure to daily periodic environmental changes. A typical study in rodent models involves placing animals in constant darkness and observing either running wheel activity, general locomotor activity, or measurement of body temperature. These rhythms are referred to as ‘free running,’ as they are expressed in the absence of environmental cues that could change their timing. These free-running rhythms reflect the timing of the endogenous clock and rarely have a period that exactly matches the 24-hour solar day, typically running slightly slower or faster than 24 hours.

Though the use of constant darkness is common in animal models, it is not practical in the study of human circadian rhythms. In blind humans, however, endogenous free-running rhythms can be observed in the absence of a response to the 24-hour light/dark cycle. While human rhythms are close to 24 hours, they are usually slightly longer. As such, blind people who are not able to perceive light exhibit rhythms that do not match the 24-hour light/dark cycle and become progressively misaligned.⁴ The fact that some of these blind individuals have never had light perception is strong evidence that these near-24-hour rhythms were not something learned through repeated early exposure to the 24-hour light/dark cycle. Indeed, it is evidence that experience with 24-hour cycles is not necessary for the generation and expression of circadian rhythms, and thus these rhythms are generated from within and not learned.

Figure 2.1: A representation of d’Ortous de Mairan’s experiment for studying plant leaf movements. Observation of the top plants suggests that direct exposure to light might drive the opening of the leaves. However, when isolated from sunlight, leaves continue to open in the day and close at night, though there is no direct exposure to light/dark cycles. Artist: Tayla Broekman


Unlike a broken clock, which is correct twice a day, an endogenous clock that is not aligned with the environment is almost never correct. As the period (length of timing) of endogenous clocks are rarely exactly 24 hours, these need to synchronised, or entrained, to external cues in the environment. The inability to synchronise rhythms to environmental light has serious effects on sleep and wakefulness in the blind, resulting in what is called Non-24-hour sleep-wake disorder. Here, the ability to maintain normal sleep and wake patterns is affected by the free-running rhythm of the clock periodically promoting sleep during the day and promoting wakefulness during the night. Take, for example, a blind individual with a circadian period of 24 hours and 40 minutes. Their internal timing is delayed by 40 minutes each day, taking 36 days to realign to the ideal biological time of sleep. External time cues that synchronise our circadian rhythms are known as ‘zeitgebers’ (Zeitgeber means ‘time giver’ in German), and environmental light is the primary zeitgeber,⁵ which is not surprising, as circadian rhythms developed as a means of tracking the 24-hour light/dark cycle.

Light exposure is able to entrain circadian rhythms by shifting the phase (a single point in the 24-hour day) of the endogenous clock. By changing this phase, light essentially adjusts the clock’s time of day. Light will phase shift the clock to an earlier time (phase advance), a later time (phase delay), or cause no shift at all, depending on the time of day that the exposure occurs. The relationship between light exposure and the degree and direction of phase shift is represented on a plotted phase response curve (PRC). While the PRC tends to be similar for members of the same species, each individual will have a slightly different curve, reflecting variability in sensitivity to light and its phase-shifting effects. Experimentally developed PRCs have been produced for a vast range of species, including rodents and humans (Figure 2.2).⁶,⁷ Overall, for both nocturnal (night-active) and diurnal (day-active) species, light exposure in the early night results in a phase delay of rhythms, while light exposure in the late night and early morning results in a phase advance, with the least amount of shift occurring during the day. It is useful to think of phase shifts as correcting errors in the clock’s timing. Clocks that run long (e.g. 24.5 hours) will need to have 30 minutes removed each day to keep time with the 24-hour day. This can be achieved with daily advances of the clock through morning exposure to light. Clocks that run short (e.g. 23.5 hours) will need to have 30 minutes added each day to keep time with the 24-hour day, achieved with daily delays through evening light exposure.

Figure 2.2: An illustration of the phase-shifting effects of light, or phase response curve, in humans, following a 6.7-hour white light pulse plotted across circadian time. Phase shifts are shown on the vertical axis, with positive values representing phase advances and negative values representing phase delays. The dotted horizontal line represents the anticipated average 0.54-hour drift delay of the internal clock between pre- and post-stimulus assessments (~3 days). From Khalsa et al. (2003).

Though all light PRCs have the same general shape, with delays in the early evening or night and advances in the late night or early morning, the size of the shift depends on the quality of the light to which the organism is exposed. Given the same length of exposure, brighter light will cause greater phase shifts. The relation between brightness and phase shifting magnitude is non-linear, with the half maximum response to 10 000 lux (equivalent to daylight when it is overcast) seen at only ~100 lux (near standard indoor lighting levels) in humans.⁸ Thus, even light we perceive as relatively dim can have a powerful effect on the clock’s timing.

The wavelength or colour of light is also important. It has long been known that short wavelength light (blue in appearance) causes the greatest shifts in circadian phase. This was first demonstrated over 50 years ago by Woody Hastings in the single-celled Gonyaulax polyedra⁹ and has also been demonstrated in rodents⁷ and humans.¹⁰ In humans and other mammals, it is now known that circadian photoreception takes place in a set of intrinsically photosensitive retinal ganglion cells (ipRGCs). These express the photo-pigment melanopsin, a protein that is most sensitive to blue light (~480 nm wavelength). The high sensitivity of the circadian system to light, blue light in particular, is concerning for our health, as the use of blue-enriched light-emitting devices (such as smart phones and tablets) has become so common. Exposure to this type of light, which may not appear visually bright but has a powerful impact on the clock, is likely a contributing factor for many who either have poor sleep or are unable to sleep at a ‘normal’ bed time.

Though light is the primary synchroniser of circadian rhythms, some nonphotic stimuli have been shown to alter the timing of the clock. These nonphotic stimuli, such as exercise¹¹ and arousal,¹² have been shown to affect the timing of the clock, but all generally have a weaker effect than light. In blind humans, 24-hour entrainment can be seen in some individuals, despite no photoreception.¹³ It is not known which are the main non-photic stimuli producing this entrainment; however, they appear to be effective only in those with circadian periods that are very close to 24 hours, indicating minor effects of non-photic stimuli in humans. Though it was once thought that the human circadian system was more responsive to non-photic than photic stimuli,¹ we now know that, like other animals, it is light that is the primary entraining agent for circadian rhythms in humans.

Of non-photic inputs to the clock, the hormone melatonin is one of the more reliable and powerful. Most people have heard of melatonin as a sleep aid that is effective in humans. In nocturnal animals, however, the onset of melatonin secretion is associated with an increase in activity rather than sleep onset. In both nocturnal or diurnal animals melatonin in produced by the pineal gland at night, and it has therefore been referred to by the ominous name ‘the hormone of darkness’. This hormone, when given at the right time of day, can produce large phase shifts. Much as light produces phase shifts primarily when it is normally absent (at night), melatonin administration produces phase shifts in the day, when it is not naturally produced. In a ground-breaking study by Jenny Redman in 1983 at La Trobe University in Australia, it was shown that melatonin injections can be as powerful as light at entraining circadian rhythms.¹⁴ Phase response curves to melatonin have generally shown melatonin to produce small delays in the morning and larger advances in the late afternoon and early evening. This potent ability to advance the clock has made melatonin useful in entraining the clocks of blind individuals. As the period of the clock in the blind is nearly always greater than 24 hours, the ability of melatonin to produce relatively large advances allows many blind individuals to entrain to the 24-hour day.¹⁵ The efficacy of melatonin in bringing stability to circadian rhythms in the blind has led to a melatonin agonist (Tasimelteon) being the first US Food and Drug Administration-approved drug to treat a circadian-based disorder.


As virtually all organisms display circadian rhythms, the source of these rhythms depends on the type of organism. In single-celled organisms, the seat of the clock is in the nucleus. In the sea slug Bulla gouldiana, it is in the eyes in a group of basal retinal neurons. In mammals, the master circadian clock is in the two small suprachiasmatic nuclei (SCN), which are located in the anterior hypothalamus of the brain. The SCN is seated directly above the optic chiasm (hence its name), where the optic nerves cross over and reform as the left and right optic tracts. This handy position of the SCN allows it to receive direct input from the eyes.

This small region of the brain was thought to be the seat of the circadian clock in mammals after lesions of the area resulted in arrhythmic hormone release and activity in rats. Though such work pointed to the role of this tissue in the expression of 24-hour rhythms, a very elegant study by Martin Ralph in 1990 demonstrated that this tissue must be the primary source of these rhythms.¹⁶ In 1988, Martin noticed that one of the hamsters he ordered from a breeder displayed very odd 22-hour rhythms. Rather than ignore this odd animal, he bred it. When he bred two hamsters with 22-hour rhythms, offspring had either 24-hour, 22-hour, or 20-hour rhythms, indicating that this was a genetic mutation. By chance, he found the first mammalian clock mutant! This became known as the tau (meaning ‘period’) mutant hamster (see Chapter 4 for a detailed description). This is an excellent lesson in not ignoring your outliers.

Around the same time that the mutant hamster was found, others had discovered that transplantation of the SCN tissue could bring back circadian activity rhythms in animals with SCN lesions. Using this new technique and the mutant hamsters, it was shown that transplantation of the mutant SCN into a wild-type hamster resulted in 20-hour mutant activity rhythms. Further, transplantation of a wild-type SCN into a mutant hamster resulted in normal approximately 24-hour rhythms. Thus, the hosts displayed the rhythms of the donor SCN tissue. The transplantation of an amount of tissue that was about the size of a pinhead could change the behaviour of the whole animal! This study clearly demonstrated that SCN tissue was not just necessary for the expression of rhythms, but must be generating the rhythms that result in circadian timing.

The SCN itself shows a rhythm in electrical activity, being most active in the day and less active at night, in both nocturnal and diurnal animals. Light inputs directly to the SCN from the retina via the retinohypothalamic tract. In response to light, the neurotransmitters glutamate and pituitary adenylate cyclase-activating polypeptide (PACAP) are released, activating the SCN and causing changes in gene expression. The SCN controls the timing of many rhythms in the brain and body, through both neural connections and diffusing factors. For example, the SCN regulates melatonin secretion by the pineal gland through a multisynaptic connection via the superior cervical ganglion. Other outputs from the SCN include the paraventricular nucleus of the hypothalamus and the dorsomedial hypothalamus, which control corticosteroid release from the adrenal cortex, as well as other regions involved in neuroendocrine signalling.

Within the SCN are individual pacemaker cells that keep their own 24-hour timing through genetic signalling. In these pacemaker cells, an autoregulatory feedback loop exists with sets of clock genes that are turned off and on in 24-hour intervals. One protein that acts to alter the cycling of this feedback loop is casein kinase 1ε,¹⁷ which acts to break down the ‘period’ protein and slow the progression of the feedback loop. It is the casein kinase 1ε gene that is mutated in the tau mutant hamster, causing a faster cycling of the clock.


If you say the words ‘circadian rhythm’, one of the first things that comes to mind is the daily rhythm of sleep and wakefulness. Sleep and wake, however, are easily dissociated from the circadian clock. In early human studies, in which people lived in isolated bunkers underground, it was found that sleep and wake rhythms would start cycling at a different rate from the underlying circadian rhythm in core body temperature.¹ This spontaneous desynchronisation resulted in sleep/wake rhythms that were often well over 30 hours long, with clock-driven rhythms remaining at ~24 hours. Though human sleep/wake rhythms can easily be desynchronised from the 24-hour clock, the circadian timing of sleep is critical for sleep quality and sleep length. As shown by Charles Czeisler in a study of individuals following self-selected sleep/wake schedules while living in a sleep laboratory for nearly 3 months, the amount of sleep recorded each day was strongly dependent on circadian time¹⁸. Subsequent studies in which individuals were placed on 28-hoursleep/wake cycles (a ‘forced desynchrony’ protocol) have shown that the amount of time it takes to fall asleep and the quality of sleep are also strongly determined by the timing of the circadian clock.¹⁹ Those who engage in night-shift work or experience jet lag become acutely aware of the importance of matching their internal rhythms with the times that they sleep and wake.


Before the invention of bright artificial light, our light/dark cycles were largely determined by the rotation of the Earth. Now, signalling to our clock that it is ‘day’ is as easy as flicking a switch. The easy control of the input to our circadian clock can result in unstable light/dark signals that may impact our health. A clear example of the negative effects of repeated circadian disruption comes from studies in shift workers, who are at increased risk for cardiovascular disease, metabolic disorders (obesity, diabetes), fertility problems, kidney, sleep and mood disorders, and

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