Physiology, Sleep

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Joshua Brinkman

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Sandeep Sharma

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3/16/2019 2:23:16 PM


Sleep is an extremely complicated process which consists of more than simply closing one’s eyelids and counting sheep.  It is an active state of unconsciousness produced by the body where the brain is in a relative state of rest and is reactive primarily to internal stimulus. The exact purpose of sleep has not been fully elucidated.  There are several prominent theories currently which have explored the brain and attempt to identify a purpose for why we sleep which includes the Inactivity theory, Energy conservation theory, Restoration theory, and the Brain plasticity theory.

Inactivity theory is based on the concept of evolutionary pressure where creatures that were inactive at night were less likely to die from the predation of injury in the dark, thus creating an evolutionary and reproductive benefit to be inactive at night. 

Energy conservation theory posits that the main function of sleep is to reduce a person's energy demand during part of the day and night when it is least efficient to hunt for food. This theory is supported by the fact that the body has decreased metabolism of up to 10% during sleep.

The restorative theory states that sleep allows for the body to repair and replete cellular components necessary for biological functions that become depleted throughout an awake day. This is backed by the findings many functions in the body such as muscle repair, tissue growth, protein synthesis, and release of many of the important hormones for growth occur primarily during sleep.

Brain plasticity theory is that sleep is necessary for neural reorganization and growth of the brain’s structure and function. It is clear that sleep plays a role in the development of the brain in infants and children and explains why it is necessary that infants sleep upwards of 14 hours per day.

These theories are not exhaustive or all-inclusive of the prevalent ideas; rather, they serve to frame the concept that we do not fully understand sleep yet. It is more accepted that no single theory explains it all, and a combination of these ideas is more likely to hold the key to sleep.[1][2][3][4]


Sleep functions in a relatively predictable cyclical pattern between 2 major phases: Non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. NREM sleep is subdivided into several stages numbered 1 to 3. Each phase and stage represents the relative depth of sleep and offers unique characteristics in the brain wave, muscle tones, and eye movement patterns. As the name implies, NREM is characterized by an absence of eye movements and REM is characterized by rapid eye movements.

Sleep begins with a short NREM stage 1 phase, followed by NREM stage 2, then NREM stage 3, then finally into REM. NREM accounts for approximately 75% to 80% of total sleep and REM accounts for the remaining 20% to 25% of sleep. This progression through the stages of sleep occurs in this order of events on repeat throughout the night for varying lengths of time. The initial cycle lasts 70 to 100 minutes to complete fully. However, the remaining cycles last 90 to 120 minutes each. The amount of REM in each cycle progresses throughout the night from being minimal on initiation of sleep, but eventually is up to 30% of the cycle later in the night. A total of 4 to 5 cycles through this progression is typical in a night.

NREM stage 1 is the shallow stage of sleep where a person is still easily awoken. It lasts 1 to 7 minutes. Rhythmical alpha waves characterize electroencephalogram (EEG) at a frequency of 8 to 13 cycles per second.

NREM stage 2 lasts approximately 10 to 25 minutes in the initial cycle of sleep but progresses to consume 50% of the total sleep cycle later in the night. Stage 2 is a much deeper sleep state than stage 1, but individuals are still awoken with heavy stimulation. Brainwave activity on EEG is low voltage “sleep spindles and K-complexes.” Current theories suggest that memory consolidation occurs primarily during this stage.

NREM stage 3 lasts about 20 to 40 minutes, initially. EEG characterized by high-voltage, slow wave frequency.

REM is the phase of sleep responsible for dreaming. It is characterized by total body voluntary muscle paralysis (except for the extraocular muscles). This paralysis is thought to be a mechanism to prevent neural stimulus from dreams to manifest in actual muscular impulses during sleep. EEG in REM is “Sawtooth waveforms,” theta waves, and slow, alpha waves in a desynchronized pattern set.[5][6]


The mechanism through which sleep is generated and maintained is more of a balance between two systems located within the brain: the homeostatic processes which are functionally the body’s “need for sleep” center and the circadian rhythm which is an internal clock for the sleep-wake cycle. 

Sleep Generation is initiated within the ventrolateral preoptic nucleus (VLPO) of the anterior hypothalamus and acts to inhibit the arousal regions of the brain including the tuberomammillary nucleus, lateral hypothalamus, locus coeruleus, dorsal raphe, laterodorsal tegmental nucleus, and pedunculopontine tegmental nucleus. Hypocretin (orexin) neurons in the lateral hypothalamus help to facilitate this process in a synergistic effect.

NREM sleep is a functional disconnection between the brain stem and the thalamus and cortex maintained with hyperpolarizing GABA neurons in the reticular activating center of the thalamus and the cortex. Corticothalamic neurons signal the thalamus which causes hyperpolarization of the thalamic reticular neurons.  This process produces delta waves from both thalamic reticular and cortical pyramidal sources. Thus correlating with the varying stages 1 to 3 of NREM.

REM sleep is generated by "REM-on neurons" in the mesencephalic and pontine cholinergic neurons. The pedunculopontine tegmental nucleus and the lateral dorsal tegmental neurons trigger desynchronized cortical waveforms. The tonic component of REM sleep is parasympathetically medicated, and the phasic component is sympathetically mediated.

Circadian rhythm is the body’s cyclical nature for the desire for sleep. The hypothalamus controls it via the suprachiasmatic nucleus with sensory input from the retinohypothalamic tract based on light levels detected from the retina. The circadian rhythm is approximately 24.2 hours per cycle. Melatonin, produced in the pineal gland, has also been shown to be a modulator of the circadian rhythm that has concentrations varied based on light level. Melatonin levels are greatest in the night and decreased during the daytime. Finally, body temperature has been associated as part of the circadian rhythm. The exact set point varies among different people, but it is expected to have generally lower temperatures in the morning and higher temperatures in the evening.[5][7]

Related Testing

The primary testing modality used to study sleep is polysomnography. This is a multifaceted test that includes an electrocardiogram (ECG), electroencephalography (EEG), electrooculography (EOG), electromyography (EMG), and oxygen saturation. Polysomnography should not be routinely used as a screening test. The results of all testing modalities are coordinated to paint a full picture of the sleeping status of a patient.

ECG testing is the measurement of electrical current through the myocardium of the breath and is used to diagnose cardiac aberrations including rate and rhythm.

EEG includes non-invasively placing electrodes across the scalp to measure voltage fluctuations and current of electrical activity within the brain. The exact number of electrodes used varies.  The waveforms of the brain are recorded and used to interpret the stage of sleep a person is in and detect any neurological abnormalities during sleep.

EOG is used to measure extraocular muscle function during sleep.  During NREM there should be no eye movement. Therefore eye movement is indicative of REM.

EMG is used to measure muscle function of respiration as well as peripheral limbs and can detect excessive movement or increased tension during sleep.

Oxygen saturation is used to verify that respiration is being performed as expected during sleep without any halts in breathing.[6][8]

Clinical Significance


This is the generic term for any illness that causes difficulty falling asleep and staying asleep. This is the most common of sleep illnesses and is commonly related to psychological stressors, poor sleeping environments, irregular sleep schedule, or excessive mental, physical, or chemical stimulation.

Obstructive Sleep Apnea

This is an illness where major pauses in breathing occur during sleep secondary to an obstructive process, such as the collapse of the airway secondary to obesity or weak pharyngeal musculature. When the airway collapses, breathing stops and hypoxia drives the body to awaken out of deep sleep to breathe again. When this occurs regularly in the night, restful sleep is not possible. There are 3 degrees of illness with obstructive sleep apnea Mild, Moderate, and Severe. Mild OSA is when there are 5 to 14 episodes of apnea in an hour. Moderate is when there are 15 to 30 apnea episodes in an hour. Severe OSA is when there are 30 or more episodes of OSA in an hour. Positive airway pressure therapy characterizes the treatment of OSA: Continuous Positive Airway Pressure (CPAP) and Bilevel Positive Airway Pressure (BiPAP). CPAP is constant pressure supplementation that causes the airway to splint open allowing for airflow. BiPAP is when the positive pressure supplementation is altered between 2 pressures allowing for the splinting benefit of positive pressure, but also allowing for better ventilation of the lung compared to CPAP. Also used as therapy are mandibular advancement devices and surgical therapy such as Uvulopalatopharyngoplasty, adenotonsillectomy, and maxillomandibular advancement. Mainstream therapy is positive airway supplementation, not surgical.[9]

Central sleep apnea

This illness is similar to obstructive sleep apnea. However, its etiology is related to intrinsic diminution and ultimately failure of the breathing drive or mechanisms during sleep.  Such illnesses include congenital central hypoventilation syndrome (Ondine’s curse) or congestive heart failure.  When breathing does not occur effectively, the body will awaken from deep sleep to correct hypoxia. Treatment consists of CPAP therapy, BiPAP therapy, Adaptive-servo-ventilation, or medical therapy with acetazolamide or theophylline.[10]

Mixed Sleep Apnea

Also known as Complex Sleep Apnea) is a combination of both obstructive sleep apnea and central sleep apnea symptoms. This is an illness where patients with symptoms of obstructive sleep apnea develop symptoms of central sleep apnea upon treatment with CPAP therapy during a sleep study. Treatment is typically very low-pressure CPAP therapy.[11]

Ghrelin-Leptin Abnormalities

Sleep duration has been found to play a significant role in maintaining body weight. The theory here is that an imbalance in the two essential hormones related to hunger (Leptin and Ghrelin) are aberrant with altered sleep habits. Leptin is made by adipose cells and functions to regulate energy balance by inhibiting hunger drive. Ghrelin is the counter-regulatory hormone to leptin produced by produced by cholinergic cells in the gastrointestinal tract and is responsible for increasing appetite thus encouraging the hunger drive. Shorter nights of sleep are associated with reduced leptin and elevated ghrelin. These differences in leptin and ghrelin likely lead to increased appetite, possibly explaining the increased BMI observed with sleepless nights.   This aberration is commonly associated with OSA, because of the fact that increased BMI is directly related to the development of OSA. The treatment here is to sleep consistently 7 to 8 hours per night.[12]


The exact cause of narcolepsy is unknown, and this is a diagnosis of exclusion. Essentially the normal, progression of sleep from NREM 1 to 3 into REM is faulty. When a person falls asleep, they skip NREM and progress straight into REM. This it is characterized by episodes of daytime somnolence, cataplexy, and occasionally hallucinations throughout the day that may be triggered by extreme emotions.  Many people with narcolepsy also suffer from insomnia.[13]


A state of combined sleep and wakefulness that leads to sleep-walking.  Sleepwalking is when a person ambulates of performs actions without consciously controlling the movement or having a memory of the event.  This illness is not fully understood but it has been associated with increased slow-wave sleep and sleep deprivation, and there is evidence that there is a genetic component of inheritance. Mainstay therapy consists of benzodiazepines.[6][14]

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Physiology, Sleep - Questions

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A 45-year-old male complains of daytime sleepiness that is impacting his work performance. He reports no caffeine intake or tobacco use. He has been married for 1 year and awakens easily when she turns over in bed. She reports that he occasionally snores, but it is mild. During which phase of the sleep cycle is a person most easily arousable?

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A 17-year-old female is brought in by her parents who are concerned about her sleep. The patient stays up until one or two o'clock every morning on the computer or texting. She gets up at 7:30 in the morning on weekdays to go to school but sleeps later on weekends. She admits she is tired during the day. Her parents have made rules about not using the phone or computer after 11:00 at night, but she still stays up late. Which of the following is true?

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Which of the following is not true in regard to deep sleep?

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Which stage of sleep is responsible for dreaming?

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Physiology, Sleep - References


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Clues to the functions of mammalian sleep., Siegel JM,, Nature, 2005 Oct 27     [PubMed]
A brief history of hypocretin/orexin and narcolepsy., Siegel JM,Moore R,Thannickal T,Nienhuis R,, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2001 Nov     [PubMed]
Sleep Disorders in Pregnancy., Bazalakova M,, Seminars in neurology, 2017 Dec     [PubMed]
Neuropeptidergic control of sleep and wakefulness., Richter C,Woods IG,Schier AF,, Annual review of neuroscience, 2014     [PubMed]
Sleep-dependent memory consolidation in healthy aging and mild cognitive impairment., Pace-Schott EF,Spencer RM,, Current topics in behavioral neurosciences, 2015     [PubMed]
Circadian clocks: from stem cells to tissue homeostasis and regeneration., Dierickx P,Van Laake LW,Geijsen N,, EMBO reports, 2017 Dec 19     [PubMed]
Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index., Taheri S,Lin L,Austin D,Young T,Mignot E,, PLoS medicine, 2004 Dec     [PubMed]
de Zambotti M,Cellini N,Goldstone A,Colrain IM,Baker FC, Wearable Sleep Technology in Clinical and Research Settings. Medicine and science in sports and exercise. 2019 Feb 15;     [PubMed]
Jin L,Shi L,Zhang Y,Chen BB,Wang XL,Liu YH, Antidepressants for the treatment of narcolepsy: A prospective study of 148 patients in northern China. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2019 Mar 2;     [PubMed]
Doneda D,Lopes AL,Teixeira BC,Mittelstadt SD,Moulin CC,Schwartz IV, Ghrelin, leptin and adiponectin levels in Gaucher disease type I patients on enzyme replacement therapy. Clinical nutrition (Edinburgh, Scotland). 2015 Aug;     [PubMed]
Lee SY,Kim JW, Nasopharyngeal Width and Its Association With Sleep-Disordered Breathing Symptoms in Children. Clinical and experimental otorhinolaryngology. 2019 Mar 6;     [PubMed]
Holley L, Obstructive Sleep Apnea, Insomnia, and Snoring: Evolutionary Adaptations to Increase Alertness During Sleep? Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine. 2019 Mar 5;     [PubMed]
Hsieh ST,Woo AS, Pierre Robin Sequence. Clinics in plastic surgery. 2019 Apr;     [PubMed]


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