Physiology, Sleep Stages

Issues of Concern

Sleep quality and time spent in each sleep stage may be altered by depression, aging, traumatic brain injuries, medications, and circadian rhythm disorders. See the "Pathophysiology" section for the physiological processes associated with each comorbidity. 

Cellular Level

Sleep-Promoting Activity

Gamma-aminobutyric acid (GABA) acts as the primary inhibitory neurotransmitter of the central nervous system (CNS). GABA binds with GABA-A receptors in the brain, promoting sleep.[2] Sleep-promoting neurons in the anterior hypothalamus release GABA, which inhibits wake-promoting regions in the hypothalamus and brainstem.[3] Adenosine also promotes sleep by inhibiting hypocretin/orexin neurons localized in the basal forebrain, lateral hypothalamus, and tuberomammillary nucleus and activating neurons in the preoptic/anterior hypothalamic area and ventrolateral preoptic area.[4]

Wakefulness-Promoting Activity

Neurochemicals, such as acetylcholine (ACh), dopamine, norepinephrine, serotonin, histamine, and the hypocretin peptides work together to maintain the waking state.[3] Cortical ACh release is highest during waking and REM sleep and lowest during NREM sleep.[5] Serotonin is released from serotonin-containing neurons of the dorsal raphe nucleus. Norepinephrine is released from norepinephrine-containing neurons of the locus coeruleus. The noradrenergic cells of the locus coeruleus inhibit REM sleep, promote wakefulness, and communicate with various other arousal-regulating brain regions, including the thalamus, hypothalamus, basal forebrain, and cortex. Histamine is released from histamine-containing neurons of the tuberomammillary nucleus of the posterior thalamus. The cell bodies of hypocretin-producing neurons are localized to the dorsolateral hypothalamus and communicate with all the major brain regions that regulate arousal.[4]

Development

The duration spent in each sleep stage evolves as individuals age, often reflecting a decline in the overall biological necessity for sleep in individuals over time.

Newborns and Infants (Birth to 1 Year)

Sleep timing in newborns is distributed evenly across day and night for the first few weeks of life, with irregular sleeping and waking patterns. Newborns sleep approximately 16 to 18 hours per day discontinuously, with the longest continuous sleep episode typically lasting 2.5 to 4 hours. Newborns have 3 different types of sleep: quiet sleep (similar to NREM), active sleep (similar to REM), and indeterminate sleep. In contrast to children and adults, newborn sleep onset occurs through REM, not NREM, with each sleep episode consisting of only 1 or 2 cycles. These sleep and sleep stages differences occur as circadian rhythms have not been elucidated.

Circadian rhythms develop around 2 to 3 months of age, with greater durations of waking hours during the day and longer periods of sleep at night. At 2 months of age, the progression of nocturnal sleeping begins. By 3 months of age, the cycling of melatonin and cortisol in a circadian rhythm occurs, and sleep onset begins with NREM. REM sleep decreases and shifts to the later part of the sleep cycle. The total NREM and REM sleep cycle is typically 50 minutes instead of the adult 90-minute cycle. At 6 months of age, the longest continuous sleep episode lengthens to 6 hours. At 12 months, infants typically sleep 14 to 15 hours daily, with most sleep occurring in the evening and only 1 to 2 naps needed during the day.[6]

Toddlers (Ages 1 to 3) and Children (Ages 3 to 9)

Around 2 to 5 years of age, the total sleep time needed each day decreases by 2 hours, from 13 to 11 hours. By 6 years of age, children manifest circadian sleep phase preferences and tend toward being night owls or early risers. One study found that children appear to have longer REM sleep latencies than adolescents and thus spend more time in stage N3.[7]

Adolescents (Age 10 to 18)

The total sleep time required for adolescents is 9 to 10 hours each night. Due to various pubertal and hormonal changes accompanying puberty's onset, slow-wave-sleep and sleep latency time declines, and time in stage N2 increases. Around mid-puberty, daytime sleepiness occurs more frequently than at earlier puberty stages.[8]

Adults (Age 18+)

Adults tend to demonstrate earlier sleep time, wake time, and reduced sleep consolidation. Adults aged 65 and older awaken approximately 1.5 hours earlier and sleep an hour earlier than adults aged 20 to 30.[9]

Gender Differences

Men tend to spend a greater amount of time in stage N1 sleep and experience more nighttime awakenings, so there is a greater propensity for daytime sleepiness. Women maintain slow-wave sleep longer than men and tend to complain more often of difficulty falling asleep. Additionally, daytime sleepiness increases during pregnancy and the first few months postpartum.[10]

Organ Systems Involved

The circadian rhythm regulates the sleep cycle, which is driven by the suprachiasmatic nucleus (SCN) of the hypothalamus. GABAergic sleep-promoting nuclei are found in the brainstem, lateral hypothalamus, and preoptic area.[11]

Transitions between sleep and wake states are influenced by multiple brain structures, including:

Hypothalamus: controls onset of sleep

Hippocampus: memory region active during dreaming

Amygdala: emotion center active during dreaming

Thalamus: prevents sensory signals from reaching the cortex

Reticular formation: regulates the transition between sleep and wakefulness

Pons: helps initiate REM sleep. The extraocular movements that occur during REM are due to the activity of PPRF (paramedian pontine reticular formation/conjugate gaze center).

Function

The sleep cycle is regulated by the circadian rhythm, which is driven by the SCN. The circadian rhythm also controls the nocturnal release of adrenocorticotropic hormone (ACTH), prolactin, melatonin, and norepinephrine (NE).[12]

Although it is apparent that humans need sleep, the current understanding of why sleep is an essential part of life is still yet to be determined. We might extrapolate that the primary value of sleep is to restore natural balance among neuronal centers, which is necessary for overall health. However, the physiological functions of sleep remain a mystery and are the subject of much research. The current hypotheses as to the function of sleep include:

1. Neural maturation
2. Facilitation of learning or memory
3. Targeted erasure of synapses to "forget" unimportant information that might clutter the synaptic network
4. Cognition
5. Clearance of metabolic waste products generated by neural activity in the awake brain
6. Conservation of metabolic energy[13]

Mechanism

Sleep occurs in five stages: wake, N1, N2, N3, and REM. Stages N1 to N3 are considered non-rapid eye movement (NREM) sleep, with each stage leading to progressively deeper sleep. Approximately 75% of sleep is spent in the NREM stages, with the majority spent in the N2 stage.[14] A typical night's sleep consists of 4 to 5 sleep cycles, with the progression of sleep stages in the following order: N1, N2, N3, N2, REM.[15] A complete sleep cycle takes roughly 90 to 110 minutes. The first REM period is short, and as the night progresses, longer periods of REM and decreased time in deep sleep (NREM) occur.

Wake/Alert

EEG recording: beta waves - highest frequency, lowest amplitude (alpha waves are seen during quiet/relaxed wakefulness)

The first stage is the wake stage or stage W, which further depends on whether the eyes are open or closed. During eye-open wakefulness, beta waves predominate. Alpha waves become the predominant pattern as individuals become drowsy and close their eyes.[16]

N1 (Stage 1) - Light Sleep (5%)

EEG recording: theta waves - low voltage

This is the lightest stage of sleep and begins when more than 50% of the alpha waves are replaced with low-amplitude mixed-frequency (LAMF) activity. Muscle tone is present in the skeletal muscle, and breathing occurs regularly. This stage lasts around 1 to 5 minutes, comprising 5% of total sleep time.

N2 (Stage 2) - Deeper Sleep (45%)

EEG recording: sleep spindles and K complexes

This stage represents deeper sleep as the heart rate and body temperature drop. The presence of sleep spindles, K-complexes, or both characterizes it. Sleep spindles are brief, powerful bursts of neuronal firing in the superior temporal gyri, anterior cingulate, insular cortices, and thalamus, inducing calcium influx into cortical pyramidal cells. This mechanism is believed to be integral to synaptic plasticity. Numerous studies suggest that sleep spindles are essential in memory consolidation, specifically procedural and declarative memory.[17] 

K-complexes are long delta waves that last approximately one second and are known to be the longest and most distinct of all brain waves. K-complexes are shown to function in maintaining sleep and memory consolidation.[18] Stage 2 sleep lasts around 25 minutes in the first cycle and lengthens with each successive cycle, eventually comprising about 45% of total sleep. This stage of sleep is when bruxism (teeth grinding) occurs.

N3 (Stage 3) - Deepest Non-REM Sleep (25%)

EEG recording: delta waves - lowest frequency, highest amplitude

N3 is also known as slow-wave sleep (SWS). This is considered the deepest stage of sleep and is characterized by signals with lower frequencies and higher amplitudes, known as delta waves. This stage is the most difficult to awaken from; for some people, loud noises (> 100 decibels) will not lead to an awake state. As people age, they spend less time in this slow, delta-wave sleep and more time in stage N2 sleep. Although this stage has the greatest arousal threshold, if someone is awoken during this stage, they will have a transient phase of mental fogginess, known as sleep inertia. Cognitive testing shows that individuals awakened during this stage tend to have moderately impaired mental performance for 30 minutes to 1 hour.[19] This is the stage when the body repairs and regrows tissues, builds bone and muscle, and strengthens the immune system. This is also the stage when sleepwalking, night terrors, and bedwetting occur.[20]

REM (25%)

EEG recording: beta waves - similar to brain waves during wakefulness

REM is associated with dreaming and is not considered a restful sleep stage. While the EEG is similar to an awake individual, the skeletal muscles are atonic and without movement, except for the eyes and diaphragmatic muscles, which remain active. However, the breathing rate is more erratic and irregular. This stage usually starts 90 minutes after the sleep state, with each REM cycle increasing throughout the night. The first cycle typically lasts 10 minutes, with the final cycle lasting up to 1 hour.[21] REM is when dreaming, nightmares, and penile/clitoral tumescence occur.  

Important characteristics of REM:

• Associated with dreaming and irregular muscle movements as well as rapid movements of the eyes
• People tend to awaken spontaneously in the morning during an episode of REM sleep
• Loss of motor tone, increased brain O₂ use, increased and variable pulse and blood pressure
• Increased levels of ACh
• The brain is highly active throughout REM sleep, increasing brain metabolism by up to 20%[22]

Related Testing

The clinical evaluation of sleep is performed using a polysomnogram, a procedure that utilizes an electroencephalogram (EEG), electrooculogram, electromyogram, electrocardiogram, pulse oximetry, airflow, and respiratory effort. These tests are performed overnight and usually require a minimum of 6 hours of monitoring. Specifically, an EEG records brain wave patterns via small electrodes placed on the scalp. A polysomnogram is the gold standard test for diagnosing sleep-related breathing disorders such as obstructive sleep apnea, central sleep apnea, and sleep-related hypoventilation or hypoxia. A polysomnogram may also be used to evaluate nocturnal seizures, periodic limb movement disorder, narcolepsy, and REM sleep behavior disorder.[23]

Pathophysiology

Sleep Apnea

Individuals with sleep apnea experience airway collapse in deeper sleep states, causing them to experience reduced time in stage N3 and REM sleep. This leads to excessive daytime drowsiness as proper, efficient sleep is not obtained throughout the night. There are two types of sleep apnea: central and obstructive. Central sleep apnea occurs when the brain fails to signal respiratory muscles during sleep. In contrast, obstructive sleep apnea is a mechanical problem in which there is a partial or complete blockage of the upper airway.[24]

REM Sleep Disorder

During REM, we are typically atonic, meaning we do not move due to temporary muscle paralysis. If the temporary atonia of REM sleep is disturbed, it may be possible to physically act out (often unpleasant) dreams with vocalizations and sudden limb movements. This is called rapid eye movement (REM) sleep disorder. The cause of this disorder is not entirely known but may be associated with degenerative neurological conditions such as Parkinson disease or Lewy body dementia.[25] Antidepressant use has also been shown to cause REM sleep disorder.[26]

Narcolepsy

Narcolepsy is a sleep cycle disorder in which individuals present with persistent daytime sleepiness and brief episodes of muscle weakness (cataplexy). In narcolepsy, sleep regulation is disturbed, and individuals tend to skip the initial phases of sleep and fall directly into REM sleep. These individuals can enter the REM phase and have dreams during short naps. This limits their amount of sleep in the N3 deep-sleep stage and thus causes an irregular sleep pattern. These individuals may experience a sudden loss of muscle strength as body muscles are atonic and paralyzed in the REM-sleep phase. These lapses into REM sleep can happen anytime during the day and usually last seconds to minutes.[27]

Somnambulism

Also known as sleepwalking, somnambulism is a common occurrence in school-aged children. These individuals tend to make purposeful movements, but they are not acting out their dreams. Dreams occur during the REM phase of the sleep cycle, in which the body is fully paralyzed. Sleepwalking occurs because the sleep cycle is still in the maturing phase, and proper sleep/wake cycles are not yet regulated. Sleepwalking is typically associated with common behaviors, such as dressing, eating, and urinating. Therefore, sleepwalking occurs in the non-rapid eye movement phases, usually in N3.[28]

Depression

Studies have demonstrated that individuals with depression have an increase in their total REM sleep but a decrease in their REM latency (i.e., the time between sleep onset and the start of the first REM period).[29] 

Aging

Difficulty initiating and maintaining sleep is cited in approximately 43% of elderly individuals. Older adults tend to experience insomnia and earlier wake times, with multiple studies hypothesizing it is due to the advanced circadian rhythm that accompanies age. This causes irregular melatonin and cortisol secretion within the circadian clock. Decreased melatonin may be due to the gradual deterioration of the hypothalamic nuclei that drive circadian rhythms. Elderly individuals sleep 36% less than children at age 5. While the ability to sleep becomes more difficult, the need does not decrease. Additional factors include a continuous increase in sleep latency and nighttime awakenings, inconsistency of external cues such as light exposure, irregular meal times, nocturia, and decreased mobility, leading to a reduction in exercise. The most notable change associated with aging is the progressive decrease in time spent in SWS.[30]

Traumatic Brain Injury

Studies have shown that individuals with a traumatic brain injury (TBI) experience prolonged sleep onset latencies, shorter total sleep time, and more nighttime awakenings than controls. TBI patients were also found to spend less time in REM sleep. These individuals report poor sleep quality, more daytime dysfunction, and the use of more sleep medication.[31]

Clinical Significance

As humans spend about one-third of their lives asleep, understanding the physiology and pathophysiology of sleep and sleep cycles remains clinically significant. Lack of sleep affects our memory and ability to think clearly, and sleep deprivation can lead to neurological dysfunction, such as mood swings and hallucinations. Those who do not get enough sleep are at higher risk of developing obesity, DM, and cardiovascular disease.[32]

Sleep difficulties are associated with adverse effects on well-being, functioning, and quality of life. Lack of or altered sleep can disrupt family life, well-being, and the ability to care for children or oneself. With 50 to 70 million Americans chronically suffering from a disorder of sleep and wakefulness, sleep quality is of clinical relevance.

Insomnia is a common condition associated with significant impairment in function and quality of life, psychiatric and physical morbidity, and accidents. As such, effective treatment must be provided in clinical practice. Insomnia is a complaint of difficulty falling or staying asleep, associated with significant distress or impairment in daytime function, and occurs despite an adequate opportunity for sleep. It is a common condition, with an approximate general population point prevalence of 10%. As it is common, it will likely be seen in a clinical setting. Available treatment options include both non-medication treatments, most notably cognitive behavioral therapy (CBT) for insomnia, and various pharmacologic therapies such as benzodiazepines, melatonin receptor agonists, selective histamine H1 antagonists, antidepressants, antipsychotics, anticonvulsants, and non-selective antihistamines.[33] 

Alcohol, benzodiazepines, and barbiturates are associated with decreased REM sleep. Benzodiazepines are a significant class of drugs used for the treatment of insomnia as these tend to increase the arousal threshold in stage N3 and REM sleep. These 2 stages are known to have the highest arousal threshold, and benzodiazepines further increase this threshold. They also tend to decrease the overall time spent in stage N3 and REM sleep and, thus, can be used for night terrors and sleepwalking as these occur in the N3 and REM sleep phases.[34]