Ann Natl Acad Med Sci (India), 49(3&4): 81-91, 2013

Physiology of Normal : From Young to Old

V. Mohan Kumar Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala State

ABSTRACT Human sleep, defined on the basis of electroencephalogram (EEG), electromyogram (EMG) and electrooculogram (EOG), is divided into rapid eye movement (REM) sleep and four stages of non–rapid eye movement (NREM) sleep. Collective monitoring and recording of physiological data during sleep is called . Sleep which normally starts with a period of NREM alternates with REM, about 4-5 times, every night. Sleep pattern changes with increasing age. Newborns sleep for about 14-16 hours in a day of 24 hours. Although there is a wide variation among individuals, sleep of 7-8.5 hours is considered fully restorative in adults. Apart from restorative and recovery function, energy conservation could be one of the functions of sleep. The role of sleep in neurogenesis, memory consolidation and brain growth has been suggested. Though progress in medical science has vastly improved our understanding of sleep physiology, we still do not know all the functions of sleep.

Key words : electroencephalogram, electromyogram, electrooculogram, polysomnography, REM sleep, non–REM sleep, newborns, circadian rhythm, auto- regulation, sleep function

Correspondence : Dr. V. Mohan Kumar, 8-A, Heera Gate Apartments, DPI Junction, Jagathy, Trivandrum – 695014. 82 V. Mohan Kumar

Sleep is quantified and qualified stages. They are stages 1, 2, 3 and 4 of on the basis of electrophysiological NREM sleep and REM sleep (Figure 2). signals. There are definite changes T he American Academy of Sleep in electroencephalogram (EEG), Medicine (AASM) modified the staging e l e c t r o m y o g r a m ( E M G ) a n d rules in 2007(4). The major change that electrooculogram (EOG) during sleep they have introduced was combining ( Figure 1 and 2 ). Modern definition and stages 3 and 4 of NREM sleep. classification of sleep was suggested by Nathaniel Kleitman, in 1939 in his Sleep starts with a period of seminal book titled Sleep and Wakefulness NREM sleep. REM sleep takes place after (1). Unfortunately, Kleitman is a short period of NREM sleep. This remembered today by many only for his alteration between NREM and REM discovery of occurs about 4-5 times during a normal (REM sleep) in 1953 (2). Classification of night's sleep. The first REM period may be sleep is described in detail in a manual less than 10 minutes in duration, while the written by Rechtschaffen and Kales (3). last one may exceed 60 minutes. Usually, Normal human sleep, divided into REM sleep is the last phase of a full night's non–rapid eye movement (NREM) and sleep, and one usually wakes up during REM sleep, could be classified into five this stage of sleep.

FIGURE 1 : Sleep-wakefulness, defined electrophysiologically, relies on changes in electroencephalogram (EEG), electromyogram (EMG) and electrooculogram (EOG). These signals are picked up from various sites using electrodes placed on the head. Physiology of Normal Sleep: From Young to Old 83

FIGURE 2 : There are distinct changes in electroencephalogram (EEG), electromyogram (EMG) and electrooculogram (EOG) as the subject goes from wakefulness to stages I, II, III and IV of NREM sleep and REM sleep.

Polysomnography: as reference electrodes. EOG is recorded by placing one electrode above and to the Collective monitoring and outside of the right eye, and another recording of physiologic data during sleep electrode below and to the outside of the is called polysomnography. Traditionally left eye. EMG is actually recorded from three primary measures, namely EEG, two sites. In the classical recording for EMG and EOG are used to assess different classification of sleep-wakefulness three stages of sleep-wakefulness (Figure 2). EMG leads are placed on the chin (one in Six electrodes (labeled C3, C4, A1, A2, the front and center and the other two O1, and O2) and one ground electrode are underneath and on the jawbone). placed around the cranium to record EEG, using the 10-20 system of electrode In the modern polysomnography placement. Some people think that it is many variables other than EEG, EMG and sufficient to record from only four EEG EOG are recorded. They include electrodes (C3, C4, A1, A2) and one electrocardiogram (ECG), respiratory ground electrode. On the other hand, effort, nasal and/or oral airflow, oxygen others use eight EEG electrodes (labeled saturation (SpO2), body position, and limb C3, C4, F3, F4, O1, O2 , A1, and A2 ) and movements. ECG is recorded with the one ground electrode. Ear or mastoid help of two electrodes placed on the upper process (A1, and A2 ) electrodes are used chest near the right and left arms. These 84 V. Mohan Kumar

are recorded merely to note the heart rate polysomnogram, and EEG in particular, is and rhythm, and for alerting the technician essential for any sleep-wake analysis, to a possible emergency situation. They scoring of about 1400 pages (i.e. a also demonstrate whether desaturation patient's one night record) is time during apnea leads to arrhythmias or not. consuming. So, people often resort to Airflow is monitored with the help of a computer scoring to come to a conclusion, thermistor or thermocouple sensor. This which is not a healthy practice. But device looks similar to a nasal cannula and automation is superior to manual scoring is secured just under the patient's nose. It in some ways, as the computer can use a senses the amount of air moving into and lot of parameters, such as alpha rhythm, out of the airways and sends signals to the sleep spindles, delta waves, rapid eye physiological recorder. This tracing is movements or tonic chin EMG levels to used to determine the presence and extent make a hypnogram (Figure 3). of apneic episodes. Respiratory effort is assessed using a piezo crystal. Two Velcro Sleep stages : bands, one placed around the chest under The most important parameter the breasts and one around the abdomen, required for sleep analysis is EEG. The serve to determine chest wall and different EEG waves found during sleep abdominal movements during breathing. and wakefulness could be classified as Each band has a piezo crystal transducer. delta ( 4Hz, 150-250V), theta (4 - 8 Hz, The force of chest or abdominal expansion 100-200V), alpha (8-13 Hz, 50 -100V), on the bands stretches the transducer and beta (13Hz, 50V) on the basis of their alters the signals to the physiological frequencies and amplitudes. During the recorder. These leads, combined with the wakeful stage, the EEG alternates airflow sensor, help to detect apnea. Limb between beta and alpha activity. Alpha movements are assessed by recording activity is observed when the subject is EMG. For that purpose two EMG leads relaxed and the eyes are closed. Beta are placed on the inside of each calf activity appears when the subject is alert muscle, about 2-4cm apart. Oxygen with eyes open and scanning the visual saturation of blood is measured by a pulse environment. The amount of visual oximeter probe placed on the finger, or scanning would be reflected in the EOG, earlobe of the patient. either as abundant or as scarce activity. Video cameras are used to monitor The EMG may be high or moderate, the patient. If the patient's activity is tape depending on the degree of muscle recorded while sleeping, the technician tension. can review the tape at any time during the The alpha activity decreases analysis. It helps to verify whether during stage 1 of NREM sleep (Figure 2). strange-looking waveforms were caused The EEG consists mostly of low voltage, by the patient's movement, or due to any mixed frequency activity, with much of it other reason. Though visual assessment of in 3-7 Hz range. The EOG activity is Physiology of Normal Sleep: From Young to Old 85

FIGURE 3 : Computer assisted scoring of sleep-wakefulness is shown in the upper

graph. Simultaneous recording of heart rate, SaO2 and body position are shown below that. W- wake stage; R- REM sleep; 1, 2, 3 and 4 are NREM sleep stages 1, 2, 3 and 4 mostly absent, but slow rolling eye and decreasing frequency. Muscles are movements would be present. The EMG is progressively relaxed during the deeper moderate to low during this period. stages of sleep. Though muscle activity is Against the background of low voltage, reduced, the sleeper makes postural mixed frequency EEG (of stage 1), sleep adjustments after about every 20 minutes. spindles (12-14 Hz sinusoidal waves) During NREM sleep, the heart rate and BP appear as the person enters stage 2 of decline, but the gastrointestinal motility NREM sleep. Eye movements (EOG) are and parasympathetic activity increase. rare, and EMG is low to moderate during stage 2. During stage 3, delta waves NREM sleep alternates with REM appear in the EEG, but the EOG and EMG sleep. Human REM sleep is marked by the continue to remain as before. There is a EEG reverting to a low voltage, mixed quantitative increase in delta waves frequency pattern, similar to that of during stage 4, so that they come to NREM stage 1 sleep. The eyeballs show dominate the EEG tracing. The EOG rolling movement, with superimposed continues as before, and EMG shows bursts of rapid eye movements during this slight reduction. In a nutshell, as the sleep phase of sleep. So bursts of prominent progresses to deeper stages, i.e. from stage REMs appear in EOG.The REM sleep is 1 to 4, the EEG shows increasing voltage also called “paradoxical sleep”, as the 86 V. Mohan Kumar

EEG (recorded from animals) during this of the several intrinsic body rhythms phase becomes desynchronised (i.e. low modulated by the suprachiasmatic voltage fast activity), similar to the wake nucleus of the hypothalamus, and the stage. REM sleep, which appears after 30- pineal gland. They set the body clock to 9 0 m i n u t e s o f N R E M s l e e p , i s approximately 25 hours, with clues such characterised by a profound loss of muscle as environmental variables (like light tone (except eye, middle ear and exposure) and activity schedule respiratory muscles). Muscle twitches, entraining it to a 24-hour cycle. Light, respiratory changes, increased heart rate which entrains the circadian clock to a 24- and coronary blood flow are the other hour rhythm, is called a "zeitgeber," a features of this stage. The subject recalls German word meaning "time-giver". dreaming, when woken from REM sleep. Thus, the inherent circadian rhythm Though REM sleep is associated with continuously interacts with the external dream, some mental activity is associated environments. Sleep-wake cycle can with NREM sleep also. But it is less vivid continue even without external clues, but and not accompanied by full dream then the cycle length assumes a narrative. Dreams are usually visual, but periodicity of around 25 hours. the congenitally blind have auditory dreams. REM sleep is associated with Sleep changes with age: penile erection and testosterone release. The amount of sleep needed by It is a common assumption that each person is usually constant, although mammalian sleep and wake states are there is a wide variation among distinctly different. Though modern individuals and cultures. In adults, sleep science identifies waking, NREM sleep of 7-8.5 hours is considered fully and REM sleep, very objectively, by using restorative. In some cultures, total sleep physiological signs and behavioural often is divided into an overnight sleep correlates, studies have shown that each of period of 6-7.5 hours and a mid afternoon these states can intrude into the other. nap of about one hour. Sleep pattern Some components of REM sleep can, at changes with increasing age. Newborns times, appear in awake states in some show several sleep-wake cycles in a day of clinical conditions. Similarly, wakeful 24 hours. This polycyclic rhythm passes behaviour can intrude into sleep, in some through a biphasic pattern before a clinical conditions, resulting in striking monocyclic pattern is established in consequences (5). young adults. In newborns, the total duration of sleep in a day can be 14-16 Sleep-wake cycle consists of hours. Most of it is REM sleep. During old inherent rhythmic changes with 24 hour age, total sleep is not only reduced, it is (circadian) periodicity in physiological, often divided into an overnight sleep biochemical, and psychological processes period of less than 6-7.5 hours and a mid in the body. Circadian sleep rhythm is one afternoon nap of about one hour. Physiology of Normal Sleep: From Young to Old 87

Neural regulation of sleep: interactions of the pedenculo-pontine and lateral dorsal tegmental areas with the According to traditional belief, dorsal raphae nucleus and locus prolonged activity of the brain during the coeruleus, for the generation of REM day is followed by rest, at night, in the sleep (7). Unfortunately, overemphasis of form of sleep. Sleep was considered as a localization of sleep regulating areas had passive process till the 1950s (6). This led to a misunderstanding of sleep passive theory of sleep was replaced by regulation itself. The emphasis on the the active sleep genesis concept, mainly active regulation of sleep cannot overlook after the realization that brain activity is the basic fact that the passive withdrawal only slightly reduced during sleep. of wakefulness plays a role in the Findings during the next 50 years initiation of sleep. There is now growing emphasized that sleep is an active process evidence to suggest that sleep is auto- of the brain. Employing various modern regulatory and that it is not necessary to techniques, discrete areas were demarked attribute sleep genesis to either an active by various scientists who assigned them or a passive mechanism (8,9). the roles in the regulation of NREM and REM sleep (Figure 4). This led to the Functions of sleep : assertions about the roles of the preoptic and other basal forebrain areas in the The importance of sleep is evident generation of NREM sleep, and the from the health problems resulting from

Cortex

NREM

Basal forebrain & caudal brainstem Thalamus

Posterior Brainstem hypothal amus

Awake Awake & REM

FIGURE 4 : The diagram shows the areas of the brain which are primarily implicated in the regulation of NREM and REM sleep and wakefulness. It also shows the major neural connections involved in the regulation of sleep-wakefulness. 88 V. Mohan Kumar

sleep disorders. Some sleep disturbances  Energy conservation could be can be described as temporary mild one function of sleep. Energy inconveniences, while others are far more consumption during sleep is less by serious with disastrous consequences. 15%. Energy intake (food intake) is Persistent and repeated interruption of increased on . Sleep sleep affects the physical and mental is more in newborns, infants and in health of the individual. Inadequate sleep small mammals with high surface causes not only misery to the sufferer, but to mass ratio. Energy cost of it also has far reaching socioeconomic thermoregulation is high in small consequences. Sleep is considered animals. Carnivores and omnivores, essential for life as it is preserved through which are generally safe when asleep, evolution. Moreover, both REM and may be using the energy-conservation NREM sleep show rebound after sleep aspects of sleep. Carnivores that eat restriction or deprivation. Sleep pressure meals with high calorific density can after sleep deprivation is so strong that one afford to have long periods of sleep. falls asleep, even at the cost of one's own life. Sleep-deprived rodents die earlier  Sleep may have a thermoregulatory than the food-deprived animals. Rats f u n c t i o n . M i l d h e a t i n g o f deprived of sleep die in 2-3 weeks, while hypothalamic sleep regulatory area & food-deprived rats may survive for 4-5 warm atmospheric temperature weeks. Almost all mammals show induce sleep in animals. Body heating NREM–REM cyclic alternation. Sleep prior to sleep increases slow wave must be having a universal functional sleep in man. Many sleep - active significance, though it is still difficult to n e u r o n s i n t h e b r a i n a r e enumerate its functions. Some of the t h e r m o s e n s i t i v e . C o o l i n g o f possible functions of sleep are listed brainstem (REM generating areas) in below (10). experimental animals produces an increase in REM sleep. Brain  Sleep may be having a restorative and temperature increases during REM recovery function, especially for the sleep, even though thermoregulation brain. Sleep is said to prevent is suppressed during this stage of metabolic brain injury. Sleep time sleep. REM sleep is maximum during may be related to defense against early morning, when the body oxidative stress. Normal metabolism temperature is at the lowest level. This produces high levels of reactive prevents the fall in brain temperature. o x y g e n s p e c i e s ( R O S ) b y mitochondria. ROS levels are reduced  The role of REM sleep in brain growth during sleep. Sleep facilitates the has been suggested for long. Sleep, synthesis of molecules that protect especially REM sleep, is more in new- brain cells from oxidative stress. borns. Premature babies have higher REM sleep. REM sleep amount is Physiology of Normal Sleep: From Young to Old 89

strongly correlated with brain memory consolidation remains maturity at birth, in the animal largely unproven. Sleep deprivation kingdom. Guinea pigs have very little and disturbed sleep certainly reduce REM sleep at birth. New-born guinea concentration and learning. Motor pigs are born with teeth, claws, fur and training and improved performance open eyes. They thermoregulate and produce increased slow waves in the make locomotor movements within parietal cortex, during sleep. So slow- an hour of birth. They eat solid food wave sleep may facilitate memory within a day of birth. As their brain is consolidation. Regions active during relatively mature at birth the new- task performance in PET imaging, are born guinea pigs have very little REM more reactivated during REM sleep. sleep. Similarly, sheep and giraffe are Several genes that are believed to relatively mature at birth, and have contribute to memory consolidation very little REM sleep. are up regulated during sleep.

 S l e e p m a y a l s o f a c i l i t a t e  Sleep is proposed to have many other neurogenesis. Protein synthesis in the functions. Discharge of emotions brain is increased during slow-wave through dreaming is an age-old sleep. Short-term (2–3-days) total function ascribed to sleep. Those s l e e p d e p r i v a t i o n , b l o c k s animals which are immature at birth proliferation of cells in the dentate benefit from the sleep-induced gyrus. Experimentally reducing light reduction in activity. Reduced activity input in neonates reduced cells in the would also lead to reduced exposure visual system. When neonates were to danger. According to some studies also REM sleep-deprived, this man shows disturbed behaviour after shrinkage in the visual system was REM deprivation. But, depressed accelerated. It is suggested that the persons show marked improvement neuronal development proceeds on REM sleep deprivation. according to genetic programmes, only when NREM sleep of neonates is Unanswered questions about sleep : interrupted by REM sleep. Sleep patterns of some animals make us doubt the validity of above  Memory consolidation during sleep mentioned statements regarding functions h a s b e e n p r o p o s e d b y m a n y of sleep. There is near absence of sleep in investigators. There has been a postpartum marine mammals (whales, manifold increase in publications on dolphins) and also their neonates do not this topic during the last few years. sleep for several days. When on land, fur Non-declarative memory (motor seals show both NREM and REM sleep. skill) is enhanced during sleep, But when they are in water, they show no probably during specific sleep stages. REM sleep. When they move back onto The role of sleep in declarative 90 V. Mohan Kumar

land, after spending weeks in the water, increase REM sleep in humans, with no they show no REM rebound. Cetacean rebound reduction during the subsequent mothers show no rebound increase in night. Administration of monoamine sleep after the postpartum period. oxidase inhibitors or brain lesions can Migratory birds also do not sleep during suppress REM sleep for months or years their long migration. This sleep reduction (with no detectable cognitive or during the migration is not followed by physiological symptoms). Sleep sleep rebound. Moreover, it is not possible reduction in mania is also not followed by to assert that all animals sleep, though rebound sleep. lower forms of animals show rest-activity cycles. Length of sleep also varies Conclusion : in different mammals. Giraffes and It can be concluded that sleep is elephants sleep for 4-5 hrs, whereas important for health and survival. Modern opossum, bats and giant armadillos sleep technology had made great advances in for 18 hrs. Amount of NREM and REM r e c o r d i n g a n d a n a l y z i n g s l e e p - sleep also varies in different animals. wakefulness, and also the progress in Platypus has more REM sleep than any medical science have vastly improved our other animal (about 10 hrs). Guinea pig understanding of the physiology of sleep. has only 1 hour of REM sleep per day. But, we still do not know all the functions Length of REM-NREM cycle varies from of sleep. Though some sleep disturbances less than 12 min in rats to 90 min or more are temporary mild inconveniences, in man. Variation in sleep and its duration physical and mental health of the and pattern is not restricted to animals. individual are grossly affected when there Mild body heating increases sleep, is persistent repeated interruption of sleep. with no rebound insomnia, not only in Inadequate sleep causes not only misery to animals but also in man. Heating the body, the sufferer, but it also has far reaching prior to sleep increases slow-wave sleep in socioeconomic consequences. man. Extending sleep time can slightly

REFERENCES phenomena, during sleep. Science 118: 273-274. 1. Kleitman N (1963). Sleep and wakefulness: Revised and Enlarged 3. Rechtschaffen A and Kales AA Edition. Chicago: The University of (1968). A manual of standardized Chicago Press, 550 pp. terminology: technique and scoring systems for sleep stages of human 2. Aserinsky E and Kleitman N (1953). subjects. National Institutes of Regularly occurring periods of eye Neurological Diseases and Blindness, m o t i l i t y, a n d c o n c o m i t a n t Bethesda, MD, 1–57. Physiology of Normal Sleep: From Young to Old 91

4. Iber C, Ancoli-Israel S, Chesson AL, N R E M - R E M c y c l e . and Quan SF (2007). The AASM Neuropsychopharmacology: The manual for the scoring of sleep and Fifth Generation of Progress. Edited associated events: rules, terminology, by Kenneth L. Davis, Dennis Charney, and technical specifications. Joseph T. Coyle, and Charles Westchester, IL: American Academy Nemeroff. American College of of Sleep Medicine. Neuropsychopharmacology, Chapter 128, pp1859-1877. 5. Mahowald MW and Schenck CH (2005). Insights from studying human 8. Kumar VM (2010). Sleep is neither a sleep disorders. Nature 437: 1279- passive nor an active phenomenon. 1285. Sleep and Biological Rhythms 8: 163–169. 6. G o t t e s m a n n C ( 1 9 9 9 ) . Neurophysiological support of 9. Kumar VM (2012). Sleep is an auto- consciousness during waking and regulatory global phenomenon. Front sleep. Prog Neurobiol 59: 469-508. Neurol 3: 94 (1-2). 7. Pace-Schott EF and Hobson JA 10. Siegel, JM (2005). Clues to the (2002). Basic mechanisms of sleep: functions of mammalian sleep. Nature New evidence on the neuroanatomy 437: 1264-1271. a n d n e u r o m o d u l a t i o n o f t h e