Physiology of Sleep

Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4–5 cycles a night, and generally divided into non–rapid eye movement (NREM) sleep and REM sleep stages. NREM sleep, consisting of 3 stages, represents the period of transition from wakefulness, somnolence, and then deep sleep. REM sleep is characterized by rapid irregular eye movement, but with voluntary muscle atonia. The sleep stages and associated disorders are studied through the use of polysomnography, a multimodal test evaluating the brain waves, along with ocular and motor activities. Sleep disorders can be primary (which do not stem from any health problem) or can be attributable to underlying conditions or medications.

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Overview

Sleep

Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. The purpose of sleep is poorly understood; however, there are multiple theories:

  • Survival theory: 
    • Humans are diurnal by nature (creatures of the day). 
    • Awake during the day because there is better vision and fewer predators
  • Restorative theory: 
    • Sleep allows the body to heal and repair tissue, including brain reorganization, consolidation, and storage of memories. 
    • Sleep also functions as stress relief. 
  • Growth theory
    • During sleep, the pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland releases growth hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview.

Physiology

  • Characteristics of sleep in healthy persons include:
    • Closed eyes
    • Reduced brain responsiveness to stimuli
    • Differences in heart rate, BP, and respiration depending on the stage of sleep
  • Circadian rhythm: physiologic changes (including physical, mental, and behavioral) that follow a 24-hour cycle, primarily responding to light and dark
  • Suprachiasmatic nucleus (SCN, the body’s master clock):
    • Found in the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus
    • Responsible for controlling circadian rhythms and the sleep cycle
    • Regulated by the environment, receiving input from the eyes (light)
    • Decrease in light → stimulation of SCN → release of norepinephrine → stimulation of pineal gland → release of melatonin → sleep 
    • The influence of circadian rhythm is also seen in hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview (with predominant nocturnal secretion) such as:
      •  Prolactin
      • Testosterone
      • Growth hormone

Stages of Sleep

  • Typically 4–5 cycles in an 8-hour period (1 sleep cycle: 90–120 minutes)
  • Divided into non–rapid eye movement (NREM) and REM sleep stages
  • The amount of sleep as well as duration of each stage of sleep change as humans age.

Non–rapid eye movement (NREM) sleep

  • Further divided into:
    • Stage N1 (5%–10% of total sleep cycle)
    • Stage N2 (45%–55% of total sleep cycle)
    • Stage N3 (10%–20% of total sleep cycle)
  • Physiologic changes:
    • ↑ Parasympathetic tone
    • Low BP, slow heart rate, ↓ respiratory rate
    • Less vivid dreams
    • Muscle tone similar to wakefulness

REM sleep

  • Stage R sleep
  • Usually begins 90 minutes after onset of sleep and averages 4–5 episodes/night
  • Duration increases throughout the night, with increased percentage during the latter half of the night.
  • Constitutes 20%–25% of the total sleep duration
  • Believed to have a role in memory consolidation
  • Physiologic changes:
    • Surges of sympathetic and parasympathetic activity
    • Rapid irregular eye movement occurs because of activity of paramedian pontine reticular formation (PPRF), which is the conjugate gaze center.
    • Transient increase in BP and respiration
    • Variability in heart rate 
    • Penile/clitoral erection (due to increased blood flow)
    • Vivid dreams
    • Absent muscle tone
Stages of healthy sleep

Stages of healthy sleep:
Sleep is divided into non–rapid eye movement (NREM; blue bars) and REM (orange bars) stages in each sleep cycle. Around 4–5 sleep cycles occur throughout the night, with each cycle averaging 90–120 minutes.

Image by Lecturio.

Study of Sleep

Polysomnography

  • Also known as a sleep study, a multimodal test evaluating processes in sleep:
    • EEG: measures brain electrical activity
    • Electro-oculography (EOG): measures eye movements
    • Electromyography (EMG): measures muscle movements 
  • Important parameters:
    • Sleep latency: period of time to transition from “lights out,” or initiation of sleep, to onset of sleep 
    • REM latency: period of time from initiation of sleep to reaching 1st REM stage
    • Total sleep time: amount of sleep time during the recording time
    • Sleep efficiency: percentage of total sleep time over total time in bed 
    • Wake after sleep onset: period of wakefulness after onset of sleep
    • Wake after sleep offset: period of wakefulness after sleep offset (i.e., long wakeful time after an atypical early morning awakening may be a sign of depression)
    • Apnea index: measures apneic episodes ≥ 10 seconds per 1 hour of sleep
    • Nocturnal myoclonus index: measures number of periodic leg Leg The lower leg, or just "leg" in anatomical terms, is the part of the lower limb between the knee and the ankle joint. The bony structure is composed of the tibia and fibula bones, and the muscles of the leg are grouped into the anterior, lateral, and posterior compartments by extensions of fascia. Leg movements per hour

Awake and sleep stages

Generally, an adult is awake for ⅔ of the day. The body relaxes before going through different stages of sleep.

Table: Stages of sleep
Stage Description EEG wave
Awake Eyes open Person is alert and active. Beta waves
Eyes closed
  • Decrease in level of alertness
  • Relaxation
Alpha waves
NREM sleep Stage N1
  • Transition from wakefulness
  • Somnolent/drowsy
  • Light sleep
Theta waves
Stage N2
  • Less responsive, deeper sleep
  • Heart rate and temperature decrease
  • Longest stage by total duration
  • Theta waves
  • Sleep spindles (bursts of monomorphic 12- to 14-Hz waves)
  • K complexes (negative sharp waves, followed by positive component)
Stage N3
(deep sleep, or slow-wave sleep)
  • Restful sleep, deepest NREM stage
  • More difficult to arouse
  • Body/tissue growth and repair occurs.
  • Decreases with age
Delta waves
REM sleep
(stage R)
REM sleep
(dream state)
EEG:
  • Mixed, low-voltage pattern
  • Sawtooth waves
EOG:
  • REM
  • Irregular, sharply peaked eye movements
EMG:
  • Atonia of voluntary muscles (except eye and diaphragm Diaphragm The diaphragm is a large, dome-shaped muscle that separates the thoracic cavity from the abdominal cavity. The diaphragm consists of muscle fibers and a large central tendon, which is divided into right and left parts. As the primary muscle of inspiration, the diaphragm contributes 75% of the total inspiratory muscle force. Diaphragm)
  • Inactivity due to inhibited alpha motor neurons
Beta waves
(similar wave to awake state, but with atonia)

Mnemonic

The following mnemonic summarizes the sleep waves in the different stages of sleep:
“At night, BATS Drink Blood”

  • B: beta (awake, eyes open)
  • A: alpha (awake, eyes closed)
  • T: theta (stages N1 and N2)
  • S: sleep spindles (stage N2)
  • D: delta (stage N3)
  • B: beta (REM)
Sleep stages and eeg waves

Sleep stages and EEG waves:
Stage N1 shows theta waves.
Stage N2 also has theta frequency but has distinct features: sleep spindles and K complexes.
Stage N3 (deep sleep) is characterized by delta waves.
During REM sleep, sawtooth waves (beta waves similar to wakeful state) are seen, with electromyogram exhibiting atonia.

Image by Lecturio.

Sleep and Associated Disorders

Sleep-associated disorders

NREM sleep:

  • Related disorders:
    • Sleepwalking
    • Night terrors
    • Confusional arousals
    • Sleep-related eating disorder (sleep eating)
  • Bedwetting ( enuresis Enuresis The elimination disorders that most commonly occur in childhood are enuresis (urinary incontinence) and encopresis (fecal incontinence in inappropriate situations). Enuresis is usually diagnosed when children > 5 years of age continue to wet the bed. Enuresis can occur both in the daytime (diurnal) and at night (nocturnal). Elimination Disorders

REM sleep:

  • Related disorders:
    • Narcolepsy Narcolepsy Narcolepsy is a neurological sleep disorder marked by daytime sleepiness and associated with cataplexy, hypnagogic hallucinations, and sleep paralysis. There are 2 types of narcolepsy: type 1 is associated with cataplexy and type 2 has no association with cataplexy. Narcolepsy
    • Nightmares
    • REM sleep behavior disorder
  • Bedwetting ( enuresis Enuresis The elimination disorders that most commonly occur in childhood are enuresis (urinary incontinence) and encopresis (fecal incontinence in inappropriate situations). Enuresis is usually diagnosed when children > 5 years of age continue to wet the bed. Enuresis can occur both in the daytime (diurnal) and at night (nocturnal). Elimination Disorders)

Conditions associated with sleep problems

  • Depression:
    • Increased REM sleep
    • Decreased REM sleep latency
    • Decreased N3
    • Repeated nighttime awakenings
    • Early morning awakening (terminal insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia)
  • Pulmonary disease and obstructive sleep apnea Obstructive sleep apnea Obstructive sleep apnea (OSA) is a disorder characterized by recurrent obstruction of the upper airway during sleep, causing hypoxia and fragmented sleep. Obstructive sleep apnea is due to a partial or complete collapse of the upper airway and is associated with snoring, restlessness, sleep interruption, and daytime somnolence. Obstructive Sleep Apnea ( OSA OSA Obstructive sleep apnea (OSA) is a disorder characterized by recurrent obstruction of the upper airway during sleep, causing hypoxia and fragmented sleep. Obstructive sleep apnea is due to a partial or complete collapse of the upper airway and is associated with snoring, restlessness, sleep interruption, and daytime somnolence. Obstructive Sleep Apnea):
    • Reduced N3 in OSA OSA Obstructive sleep apnea (OSA) is a disorder characterized by recurrent obstruction of the upper airway during sleep, causing hypoxia and fragmented sleep. Obstructive sleep apnea is due to a partial or complete collapse of the upper airway and is associated with snoring, restlessness, sleep interruption, and daytime somnolence. Obstructive Sleep Apnea
    • REM (with atonia) affects those dependent on intercostal and accessory respiratory muscles for ventilation → hypoventilation and desaturation

Substances and associated sleep changes

Table: Substances and associated sleep changes
Substances Findings
Selective serotonin reuptake inhibitors Serotonin Reuptake Inhibitors Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications
  • Increased N1
  • Reduced total sleep
Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines
  • Increased N2
  • Reduced REM sleep
Carbamazepine
  • Increased N3
  • Reduced REM sleep
Barbiturates
  • Reduced N3
  • Reduced REM sleep
Monoamine oxidase inhibitors Monoamine oxidase inhibitors Monoamine oxidase inhibitors are a class of antidepressants that inhibit the activity of monoamine oxidase (MAO), thereby increasing the amount of monoamine neurotransmitters (particularly serotonin, norepinephrine, and dopamine). The increase of these neurotransmitters can help in alleviating the symptoms of depression. Monoamine Oxidase Inhibitors
  • Reduced N3
  • Reduced REM sleep
Tricyclic antidepressants Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants
  • Reduced N3
  • Reduced REM sleep
Alcohol
  • Reduced N3
  • Reduced REM sleep

Clinical Relevance

  • Circadian rhythm sleep–wake disorder Circadian Rhythm Sleep–Wake Disorder Circadian rhythm sleep–wake disorders are a group of conditions marked by recurrent patterns of sleep disruption. These disorders can be due to an alteration of the circadian system (intrinsic) or a misalignment between an individual’s inner circadian rhythm and the environment (extrinsic). The disruption impairs the individual’s daily activities. Circadian Rhythm Sleep–Wake Disorder: recurrent patterns of sleep disruption due to abnormalities of the circadian system or when the sleep–wake cycle is misaligned with the environment. Subtypes include delayed sleep-phase disorder, advanced sleep-phase disorder, shift-work disorder, and jet-lag disorder.
  • Parasomnias Parasomnias Parasomnias are a pattern of sleep disorders marked by unusual actions, activities, or physiological events that occur during sleep or sleep-wake transitions. Parasomnias are divided into which sleep phase the symptoms occur, either rapid eye movement (REM) or non-REM (NREM). Parasomnias: pattern of sleep disorder marked by unusual behavior, movements, or experiences that occur during sleep or sleep–wake transitions. Symptoms may include abnormal movements, emotions, dreams, and autonomic activity.
  • Restless legs syndrome Restless legs syndrome Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome (Willis-Ekbom disease): sleep-related movement disorder that is marked by an overwhelming urge to move the legs accompanied by an unpleasant sensation that is relieved with movement. Symptoms occur during the evening and are associated with sleep disturbance. 
  • Narcolepsy Narcolepsy Narcolepsy is a neurological sleep disorder marked by daytime sleepiness and associated with cataplexy, hypnagogic hallucinations, and sleep paralysis. There are 2 types of narcolepsy: type 1 is associated with cataplexy and type 2 has no association with cataplexy. Narcolepsy: sleep disorder characterized by excessive daytime sleepiness and falling asleep at inappropriate times. Narcolepsy Narcolepsy Narcolepsy is a neurological sleep disorder marked by daytime sleepiness and associated with cataplexy, hypnagogic hallucinations, and sleep paralysis. There are 2 types of narcolepsy: type 1 is associated with cataplexy and type 2 has no association with cataplexy. Narcolepsy is associated with hypnagogic hallucinations (vivid tactile/auditory or visual hallucinations), cataplexy (emotionally triggered loss of muscle tone, during laughing, for example), and sleep paralysis (inability to move after awakening).
  • Insomnia: disorder of sleep difficulty (problems with initiation and/or maintenance of sleep) marked by symptoms that interfere with duration and/or quality of sleep despite adequate opportunity for sleep.
  • Obstructive sleep apnea: episodic apnea, or cessation of breathing during sleep, in which the period of apnea lasts for ≥ 10 seconds. Obstructive sleep apnea is usually due to a partial or complete collapse of the upper airway and is associated with snoring, restlessness, daytime headache, and somnolence.

References

  1. Ganti, L, Kaufman, M., Blitzstein, S. (2016). Sleep-wake disorders. Chapter 15 of First Aid for the Psychiatry Clerkship, 4th ed.
  2. Kirsch, D. (2020). Stages and architecture of normal sleep. UpToDate. Retrieved March 27, 2021, from https://www.uptodate.com/contents/stages-and-architecture-of-normal-sleep
  3. Kotagal, S. (2021). Parasomnias Parasomnias Parasomnias are a pattern of sleep disorders marked by unusual actions, activities, or physiological events that occur during sleep or sleep-wake transitions. Parasomnias are divided into which sleep phase the symptoms occur, either rapid eye movement (REM) or non-REM (NREM). Parasomnias of children, including sleepwalking. UpToDate. Retrieved May 16, 2021, from https://www.uptodate.com/contents/parasomnias-of-childhood-including-sleepwalking
  4. Patel A.K., Reddy, V., Araujo, J.F. (2020). Physiology, Sleep Stages. https://www.ncbi.nlm.nih.gov/books/NBK526132/
  5. Roehrs, T., Roth, T. (2021). The effects of medications on sleep quality and sleep architecture. UpToDate. Retrieved May 16, 2021, from https://www.uptodate.com/contents/the-effects-of-medications-on-sleep-quality-and-sleep-architecture
  6. Sadock, B. J., Sadock, V. A., Ruiz, P. (2014). Chapter 16 of Kaplan and Sadock’s Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry, 11th ed., pp. 533–563).
  7. Shrivastava, D., Jung, S., Saadat, M., Sirohi, R., Crewson, K. (2014). How to interpret the results of a sleep study. Journal of Community Hospital Internal Medicine Perspectives 4:24983. https://doi.org/10.3402/jchimp.v4.24983

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