2 Neuroscience2.7 Neural circuits
2.7.1.2 Sleep and arousal
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Written by Resident Doctor Committee · Published
Biological rhythms
Rhythm | Period | Example |
|---|---|---|
Ultradian | Shorter than 24 hours, several a day | Sleep cycles |
Circadian | About 24 hours | Sleep-wake cycle |
Infradian | Longer than 24 hours, fewer than one a day | Winter recurrence of seasonal depression |
Circadian timing (Process C)
Process C is circadian timing, set by the suprachiasmatic nucleus (SCN) of the anterior hypothalamus, above the optic chiasm.
The SCN is the master circadian pacemaker, generating daily rhythms of sleep, feeding and hormones; light from melanopsin retinal ganglion cells resets it through the retinohypothalamic tract.
The SCN is not the supraoptic nucleus; neighbouring hypothalamic nuclei serve appetite, fluid balance, stress hormones and parturition.
Melatonin
The SCN times melatonin through a sympathetic pathway to the pineal gland, which makes melatonin in darkness.
Melatonin is low by day, rises after dark and peaks in the middle of the night, helping to promote sleep.
In non-24-hour sleep-wake rhythm disorder the circadian clock free-runs, and melatonin given at a fixed evening time entrains it to the 24-hour day.
Sleep pressure (Process S)
Process S is homeostatic sleep pressure, which builds during wakefulness and falls during sleep.
Caffeine promotes wakefulness by antagonising adenosine A2A receptors, blocking the adenosine that builds up as the signal of sleep pressure.
Arousal systems and the sleep-wake switch
The ascending arousal system maintains wakefulness: brainstem, hypothalamic and basal forebrain neurons act on thalamus and cortex, and motor-coordination structures lie outside it.
Its neurons are noradrenergic (locus coeruleus), serotonergic (raphe nuclei), histaminergic (tuberomammillary nucleus), cholinergic (basal forebrain and pontine tegmentum), dopaminergic and orexinergic (lateral hypothalamus).
In the flip-flop switch, preoptic GABA (gamma-aminobutyric acid) and galanin neurons and the arousal systems inhibit each other, giving stable states and rapid transitions.
Cholinergic activity is lowest in slow wave sleep and highest in rapid eye movement (REM) sleep; monoaminergic and other arousal systems slow in non-REM (NREM) sleep and fall quiet in REM.
Sleep stages
Stages are scored on the electroencephalogram (EEG).
Stage | EEG | Share of adult sleep |
|---|---|---|
N1 | Low-voltage theta, vertex sharp waves | About 5%; transition from waking, hypnic jerks |
N2 | Sleep spindles, K complexes | About half, the largest share |
N3 (slow wave sleep) | High-amplitude delta waves | 15 to 20% |
REM | Low-voltage mixed frequency, sawtooth waves | 20 to 25% |
Sleep spindles are brief waxing and waning bursts of about 12 to 14 Hz from thalamic and cortical circuits; with K complexes they define N2 and are absent from REM.
N3 absorbed the older stages 3 and 4, so current scoring has no stage 4.
The REM EEG resembles the waking record; high-voltage synchronised slow waves belong to N3.
Adult sleep cycles last about 90 minutes; slow wave sleep dominates early in the night and REM periods lengthen towards morning.
The main nocturnal growth hormone pulse depends on sleep and comes with the first N3 episode early in the night.
REM sleep
REM brings skeletal muscle atonia, with the lowest chin electromyogram of the night, while breathing and eye movements continue.
Autonomic activity is raised and irregular, cerebral blood flow rises, and waking from REM gives vivid dream recall far more often than waking from NREM.
REM is the predominant stage in the newborn, taking about half of 16 to 18 hours of daily sleep.
REM, with its theta activity, helps consolidate the emotional component of memory, whereas N3 slow oscillations support declarative memory.
Sleep measures
Measure | Runs from | Normal adult value |
|---|---|---|
Sleep onset latency | Lights out to the first epoch of sleep, normally N1 | 10 to 20 minutes |
REM latency | Sleep onset to the first REM period | About 90 minutes, closing the first cycle |
Wake after sleep onset (WASO) | First sleep onset to final waking, summing time awake | Under about 20 to 30 minutes |
A sleep onset latency over 30 minutes marks sleep-onset insomnia, and very short latencies mark pathological sleepiness.
WASO measures difficulty maintaining sleep (middle insomnia).
Shortened REM latency occurs in depression, schizophrenia, mania and eating disorders, so it is non-specific and does not mark depression or its subtypes.
Drugs and sleep
Drug | During use | On stopping |
|---|---|---|
Benzodiazepines, regular use | Shorter sleep onset latency, less N1, more N2, less slow wave sleep, less REM with longer REM latency | REM rebound |
Amphetamine-type stimulants | Less REM and slow wave sleep | REM rebound |
Modafinil | Promotes wakefulness | No REM rebound |
Stopping alcohol, hypnotics or other REM-suppressing substances can bring vivid dreams and insomnia.
Insomnia and hypersomnia
Insomnia is persistent sleep difficulty, often driven by hyperarousal and conditioned wakefulness.
Initial insomnia is difficulty getting to sleep, with a prolonged sleep onset latency but sleep maintained once it starts and normal final waking.
Hypersomnia is excessive sleep duration or daytime sleepiness despite adequate opportunity to sleep, with prompt onset, long unbroken nights and repeated daytime sleep episodes.
Kleine-Levin syndrome
Kleine-Levin syndrome is a recurrent hypersomnia of adolescence with relapsing episodes of behavioural change, a male excess and normal function between attacks.
Cataplexy is not a feature; it belongs to narcolepsy type 1.
During episodes, functional imaging shows reduced prefrontal association cortex activity, matching the apathy, disinhibition and slowed thinking.
The thalamus, part of the ascending arousal system, is the most consistent site of reduced perfusion or metabolism on single-photon emission computed tomography and positron emission tomography.
Hypothalamic changes in Kleine-Levin syndrome are less consistent.
Narcolepsy
Excessive daytime sleepiness is present in almost all patients and is required for diagnosis; the other classic symptoms occur in only some.
Narcolepsy is recognised from daytime sleepiness with REM-intrusion phenomena: cataplexy, sleep paralysis, and hypnagogic or hypnopompic hallucinations.
Isolated sleep paralysis lacks the daytime sleepiness, and obstructive sleep apnoea lacks the REM intrusion.
Cataplexy is abrupt loss of muscle tone triggered by emotion or startle, with awareness preserved; catalepsy is a prolonged maintained posture with tone kept.
Narcolepsy type 1 (with cataplexy) is caused by selective loss of hypocretin (orexin) neurons in the lateral, perifornical and posterior hypothalamus, which removes the input that stabilises wakefulness.
Type 1 leaves cerebrospinal fluid (CSF) orexin low and is strongly associated with human leucocyte antigen (HLA) DQB1 06:02.
The multiple sleep latency test confirms narcolepsy: after overnight polysomnography, it stages sleep and shows short sleep latency and early REM periods.
Tests of breathing, movement, subjective sleepiness or HLA type do not confirm it; CSF hypocretin helps in selected cases.
Modafinil, a wake-promoting agent, is the first drug for excessive daytime sleepiness.
In the UK modafinil is licensed only for excessive daytime sleepiness in narcolepsy, other indications having been withdrawn in the 2010 to 2011 European restriction.
Parasomnias
Feature | Nightmares | Sleep terrors and sleepwalking |
|---|---|---|
Stage | REM | NREM slow wave sleep arousal |
Timing | Late in the night | First third of the night |
Presentation | Distressing dream recalled on waking | Marked arousal, poor responsiveness, little recall |
Nightmares are common in childhood, have no consistent link with enuresis and are not by themselves a sign of psychopathology.
REM sleep behaviour disorder
REM sleep behaviour disorder is REM sleep without normal atonia, so the person acts out dreams; it can precede a synucleinopathy.
Management starts with bedroom safety, and drug choice weighs falls, cognition and breathing risks.
Clonazepam is a first-line drug.
Melatonin, acting at MT1 and MT2 receptors to help restore REM atonia, is also recommended.
Dopaminergic drugs treat the motor signs of an associated synucleinopathy but not the parasomnia.
Sleep deprivation
Sleep loss impairs sustained attention, working memory and learning, raises irritability and impulsivity, and people underestimate their impairment; severe loss can cause hallucinations.