Sleep Physiology & Sleep-Wake Disorders
From the SCN clock to the orexin switch: how each stage looks and how sleep breaks
Circadian control and the sleep–wake switch
Suprachiasmatic nucleus. The SCN of the anterior hypothalamus is the master pacemaker. Melanopsin-containing retinal ganglion cells send light information through the retinohypothalamic tract, entraining its roughly 24-hour rhythm, and the SCN in turn times daily cycles of cortisol, prolactin, core temperature and melatonin.
Melatonin. At night a sympathetic relay (SCN → paraventricular nucleus → upper thoracic intermediolateral column → superior cervical ganglion) releases norepinephrine onto pinealocytes, which convert serotonin into melatonin. Light suppresses this output, so melatonin rises in darkness.
The switch. Wakefulness is sustained by ascending arousal systems: locus coeruleus (NE), raphe (5-HT), tuberomammillary nucleus (histamine) and pontine and basal forebrain cholinergic neurons. GABAergic neurons of the ventrolateral preoptic nucleus inhibit these centers to allow sleep, and adenosine accumulating during waking builds sleep pressure (caffeine blocks its receptors). Orexin (hypocretin) neurons of the lateral hypothalamus excite the arousal nuclei and stabilize the switch so wake and sleep do not flicker into each other.
Histamine from the tuberomammillary nucleus explains why first-generation antihistamines that enter the brain cause drowsiness.
Sleep stages and architecture
| Stage | EEG | Share of adult sleep | Key features |
|---|---|---|---|
| Awake | Beta when alert; alpha when relaxed with eyes closed | — | Beta = highest frequency, lowest voltage |
| N1 | Theta | ~5% | Lightest sleep, easily roused |
| N2 | Sleep spindles, K complexes | ~45–55% | Largest share of the night |
| N3 | Delta (low frequency, high amplitude) | ~15–25% in young adults | Deepest and hardest to arouse; growth hormone peak; sleepwalking, sleep terrors, bedwetting |
| REM | Low-voltage, fast, sawtooth waves | ~20–25% | Atonia, dreams, erections, rapid eye movements, nightmares |
Cycling. A night contains 4–6 NREM–REM cycles of about 90 minutes, with the first REM period arriving about 90 minutes after sleep onset. N3 dominates the first third of the night and REM periods lengthen toward morning, so sleep terrors cluster early and nightmares late.
REM physiology. REM is "paradoxical" sleep: an awake-looking EEG in a nearly paralyzed body. Brainstem circuits inhibit spinal motor neurons while sparing the diaphragm and extraocular muscles; dreams are vivid, pulse and blood pressure fluctuate, the penis and clitoris become engorged, and the PPRF generates conjugate horizontal eye movements. Pontine cholinergic neurons switch REM on, while norepinephrine and serotonin neurons fall silent, so drugs that raise NE or 5-HT suppress REM.
Normal nocturnal erections in a man with erectile dysfunction point to a psychogenic cause; their absence suggests an organic one.
What reshapes sleep architecture
| Modifier | Effect |
|---|---|
| Newborns | About half of sleep is REM |
| Aging | Marked ↓ N3, mild ↓ REM, ↑ sleep latency and awakenings, advanced phase |
| Major depression | ↓ REM latency, ↑ REM (early, dense eye movements), ↓ N3, repeated and early-morning awakenings |
| Benzodiazepines | ↓ sleep latency, ↑ N2, ↓ N3 and REM |
| Alcohol | Early-night sedation and REM suppression, late-night fragmentation, REM rebound in withdrawal |
| Most antidepressants | Suppress REM, lengthen REM latency; may unmask REM behavior disorder |
Abruptly stopping any REM suppressant (alcohol, barbiturates, many antidepressants) produces REM rebound with vivid dreams and nightmares.
Narcolepsy
Mechanism. Type 1 narcolepsy reflects selective loss of orexin neurons in the lateral hypothalamus, probably autoimmune (strong HLA-DQB1*06:02 association), with low CSF hypocretin-1. The unstable switch lets fragments of REM break into wakefulness:
- Excessive daytime sleepiness with sleep attacks despite adequate night sleep.
- Cataplexy: brief loss of muscle tone (knee buckling, jaw sagging) triggered by laughter or strong emotion, with preserved consciousness.
- Hypnagogic (falling asleep) and hypnopompic (waking) hallucinations.
- Sleep paralysis for seconds to minutes at sleep–wake transitions.
Diagnosis. Polysomnography followed by a multiple sleep latency test showing mean sleep latency ≤8 minutes and ≥2 sleep-onset REM periods (REM within 15 minutes of falling asleep).
Treatment. Scheduled naps; modafinil or armodafinil (wake-promoting, weak dopamine reuptake inhibition) or amphetamine-type stimulants for sleepiness; sodium oxybate (GHB, a GABA-B agonist) to consolidate night sleep and reduce cataplexy; pitolisant (H3 inverse agonist that boosts histamine release) as an alternative. REM-suppressing antidepressants also reduce cataplexy.
Sodium oxybate is a potent CNS depressant; combined with alcohol or other sedatives it can cause respiratory depression.
Parasomnias, circadian disorders and restless legs
| Feature | Sleep terror | Nightmare | REM behavior disorder |
|---|---|---|---|
| Stage | N3 | REM | REM without atonia |
| Timing | First third of night | Last third of night | REM periods, later night |
| Typical patient | Child | Any age | Older man |
| Behavior | Screaming, sweating, tachycardia; inconsolable | Wakes frightened but oriented | Punches, kicks, shouts out dreams |
| Recall | None | Vivid | Recalls dream content |
REM sleep behavior disorder. Loss of REM atonia often injures a bed partner. Most idiopathic cases later develop an α-synucleinopathy (Parkinson disease, dementia with Lewy bodies, multiple system atrophy). Manage with bedroom safety plus melatonin or clonazepam; SSRIs and SNRIs can unmask it. Sleepwalking and enuresis, like sleep terrors, arise from N3.
Circadian rhythm disorders. Delayed sleep phase (adolescents) means very late sleep onset and waking; advanced phase (older adults) means early-evening sleepiness and early waking. Morning light advances the clock and evening light delays it; low-dose evening melatonin helps advance a delayed phase. Jet lag is worse flying east, shift work disorder affects night workers, and totally blind people may drift on a non-24-hour rhythm (treated with the melatonin agonist tasimelteon).
Restless legs syndrome. An urge to move the legs with unpleasant sensations, worse at rest and in the evening and relieved by movement; most patients also have periodic limb movements of sleep. It is linked to low brain iron with dopaminergic dysfunction, iron deficiency, CKD, pregnancy and neuropathy. Replete iron when ferritin is low. Dopamine agonists (pramipexole, ropinirole) help but cause augmentation over time, so α2δ ligands (gabapentin, pregabalin) are now preferred.
Insomnia pharmacology
Orexin receptor antagonists (suvorexant, lemborexant, daridorexant) block OX1 and OX2 receptors, silencing the wake signal. They are contraindicated in narcolepsy and can cause next-day somnolence and narcolepsy-like sleep paralysis or hypnagogic hallucinations.
Ramelteon is an MT1/MT2 melatonin receptor agonist for sleep-onset insomnia with no dependence or abuse liability, so it is not a controlled substance. It is cleared by CYP1A2 and must not be combined with fluvoxamine.