Sleep physiology
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Sleep Physiology
Definition
Sleep is an active, reversible state of unconsciousness in which the brain is relatively more responsive to internal than external stimuli. It is not passive rest - the brain remains highly active, with distinct patterns of neural firing, hormone secretion, and metabolic activity across its stages.
- Miller's Anesthesia, 10e
1. Measurement: Polysomnography (PSG)
The standard method for defining sleep is polysomnography, the continuous recording of:
- EEG (electroencephalogram) - brain electrical activity
- EOG (electrooculogram) - eye movements
- EMG (electromyogram) - muscle tone (chin and legs)
Supplemented clinically by nasal airflow sensors, pulse oximetry, respiratory effort bands, and body position sensors.
PSG defines two fundamental sleep states: REM and NREM sleep.
- Harrison's Principles of Internal Medicine, 22e
2. Sleep Stages
NREM Sleep
NREM is divided into three stages of progressively deepening sleep:
| Stage | Old Name | EEG Features | Characteristics |
|---|---|---|---|
| N1 | Stage 1 | Low-voltage, mixed frequency; loss of alpha waves | Light sleep; slow, roving eye movements; easy arousal |
| N2 | Stage 2 | Sleep spindles (12-14 Hz bursts, 0.5-2 s); K-complexes (vertex waves) | Majority of total sleep time |
| N3 | Stages 3/4 (slow-wave sleep) | Delta waves predominate (high-amplitude, low-frequency) | Deepest NREM; hardest to arouse; most restorative |
N3 ("slow-wave sleep" or SWS) is the most restorative stage and predominates in the first third of the night.
REM Sleep
-
EEG: low-amplitude, mixed-frequency (resembles N1 or even wakefulness)
-
Rapid, saccadic eye movements in bursts
-
Skeletal muscle atonia (brainstem-mediated paralysis of all muscles except respiratory muscles)
-
Associated with vivid dreaming and phasic muscle twitches
-
Predominates in the last third of the night
-
Harrison's Principles of Internal Medicine, 22e; Adams and Victor's Principles of Neurology, 12e
3. Sleep Architecture (Hypnogram)
Normal adult sleep shows a consistent nightly pattern:
FIGURE: Wake-sleep hypnogram comparing a 23-year-old (top) and 68-year-old (bottom). Note the prominent N3 slow-wave sleep early in the night in the young adult, and the REM periods (dark blocks) lengthening toward morning. The older adult shows absent N3, frequent awakenings, and fragmented architecture. - Harrison's Principles of Internal Medicine, 22e
Key features:
- Sleep onset: Rapid descent through N1 → N2 → N3 within 45-60 minutes
- N3 dominates the first third of the night
- First REM episode appears in the second hour of sleep
- NREM/REM cycle ("ultradian cycle") repeats every 60-160 minutes
- 4-6 cycles per night in a typical 7-8 hour sleep
- REM episodes lengthen toward morning; N3 progressively shortens
Proportions in healthy young adults:
- N1 + N2: ~50-60% of total sleep
- N3: ~15-25%
- REM: ~20-25%
4. Circadian Regulation and the Two-Process Model
Sleep timing is governed by two interacting systems:
Process C - Circadian Drive
The suprachiasmatic nucleus (SCN) of the hypothalamus is the master biological clock. It:
- Generates an intrinsic ~24-25 hour rhythm independent of environment
- Is entrained to the 24-hour day by light input from retinal photoreceptors
- Integrates light/dark signals to synchronize activity, temperature, hormone secretion, and gene expression
- About 15% of all human genes show daily circadian expression rhythms
Melatonin, secreted by the pineal gland at night and suppressed by retinal light stimulation, is a key output signal of the SCN. Chronotype (morning vs. evening preference) reflects individual variation in the circadian clock.
Process S - Homeostatic Sleep Pressure
During wakefulness, adenosine and other sleep-promoting substances progressively accumulate in the brain, building "sleep pressure." This pressure is discharged during sleep. The SCN circadian wake drive offsets Process S during daytime hours; as it diminishes in the evening, sleep pressure becomes irresistible.
- Miller's Anesthesia, 10e; Adams and Victor's Principles of Neurology, 12e
5. Neural Control of Sleep and Wakefulness
The Ascending Arousal System (Wakefulness)
Multiple brainstem nuclei release wake-promoting neurotransmitters:
- Locus coeruleus - norepinephrine
- Raphe nuclei - serotonin
- Tuberomammillary nucleus (TMN) - histamine (major source of brain histamine; H1 antihistamines cause sedation by blocking this)
- Pedunculopontine/laterodorsal tegmental nuclei - acetylcholine
- Basal forebrain - acetylcholine
These project to the thalamus, basal forebrain, and cortex to maintain arousal.
Orexin (Hypocretin) - The Stabilizer
Orexinergic neurons in the lateral hypothalamus are critical for maintaining stable wakefulness. They:
- Provide excitatory input to all arousal system nuclei
- Stabilize the sleep-wake switch against unintended transitions
- Loss of orexin neurons causes narcolepsy (sudden attacks of sleep/cataplexy)
- Suvorexant and other dual orexin receptor antagonists block OX2R to promote sleep
The Sleep Switch - VLPO
The ventrolateral preoptic nucleus (VLPO) and median preoptic nucleus (MnPO) of the anterior hypothalamus are the main sleep-promoting areas. They fire at high frequency during sleep and send GABAergic/galaninergic inhibitory projections to all arousal nuclei.
The Flip-Flop Switch Model
FIGURE: The flip-flop switch model (Saper et al.). During wakefulness (A), brainstem arousal nuclei excite the thalamus and cortex while inhibiting VLPO/MnPO. Orexin reinforces this state. During sleep (B), VLPO/MnPO neurons inhibit the brainstem arousal nuclei and orexin neurons; the switch "flops" to sleep. The mutual inhibition ensures rapid, stable transitions - not gradual drifts. - Miller's Anesthesia, 10e
NREM-REM Switch
A second flip-flop switch in the pons governs NREM-REM transitions:
- REM-on neurons: Sublaterodorsal nucleus (glutamatergic + GABAergic) - promotes REM
- REM-off neurons: Ventrolateral periaqueductal gray / lateral pontine tegmentum - suppresses REM
- Mutual inhibition between these two groups generates the cycling REM/NREM switch
The muscle atonia of REM is mediated by glycinergic and GABAergic inhibition of spinal motor neurons, driven from the sublaterodorsal nucleus.
- Adams and Victor's Principles of Neurology, 12e; Miller's Anesthesia, 10e
6. Physiological Changes During Sleep
Cardiovascular
- NREM (especially N3): Reduced heart rate, reduced blood pressure, reduced sympathetic tone ("nocturnal dip")
- REM: Increased sympathetic tone; blood pressure and heart rate fluctuate. Loss of the nocturnal dip (e.g., from sleep apnea) is associated with daytime hypertension and increased cardiovascular risk
Respiratory
- Breathing slows and becomes more regular in NREM
- Respiratory rate is more irregular in REM
- Upper airway muscle tone is reduced during sleep, predisposing to obstructive sleep apnea
Renal
- Urine output decreases (increased ADH secretion); urine osmolality increases
Endocrine (Key Relationships)
| Hormone | Relationship to Sleep |
|---|---|
| Growth hormone | Major surge in first 2 hours, during N3 slow-wave sleep |
| Cortisol | Peaks in early morning; high on awakening |
| TSH (thyroid-stimulating hormone) | Peaks at sleep onset |
| Melatonin | Produced throughout night; suppressed by morning light |
| Prolactin | Rises during sleep; highest concentration shortly after sleep onset |
| LH | Sleep-associated increase in pubertal boys and girls |
| Testosterone | Circadian + sleep-stage dependent secretion |
Other
-
Penile erections occur periodically during REM sleep (basis of NPT testing)
-
Temperature regulation is impaired during REM (ectothermic state)
-
Adams and Victor's Principles of Neurology, 12e
7. Effects of Age on Sleep
| Age Group | Sleep Characteristics |
|---|---|
| Neonate | 16-20 h/day; ~50% REM sleep |
| Child | 10-12 h/day; fragmented over multiple episodes |
| Adolescent | 9-10 h; N3 decreases after puberty |
| Young adult | 7-8 h; 20-25% REM, 15-25% N3 |
| >65 years | ~6-6.5 h; N3 may be absent; frequent nocturnal awakenings; fragmented sleep |
Women tend to sleep slightly more than men from age ~35 onward. The ultradian sleep cycle matures into the adult REM-NREM pattern over the first year of life.
- Adams and Victor's Principles of Neurology, 12e; Harrison's Principles of Internal Medicine, 22e
8. Sleep Deprivation Effects
- Degrades cognitive performance, particularly sustained vigilance and reaction time
- Young adults are especially susceptible to slowed reaction times
- Sleep deprivation increases sleep pressure, leading to faster sleep onset and increased N3 intensity on recovery nights
- Chronic sleep deprivation is linked to metabolic, cardiovascular, psychiatric, and immune dysfunction
Summary Table: REM vs. NREM
| Feature | NREM (N1/N2/N3) | REM |
|---|---|---|
| EEG | Slowing; spindles, K-complexes, delta waves | Low-amplitude, mixed frequency |
| Eye movements | Slow, roving (N1); absent (N2/N3) | Rapid, saccadic |
| Muscle tone | Gradually reduced | Absent (atonia) |
| Dreams | Rare, thought-like | Vivid, narrative |
| Heart rate/BP | Reduced | Variable, fluctuating |
| Growth hormone | Secreted during N3 | Not prominent |
| % of night | ~75-80% | ~20-25% |
| Timing in night | First third | Last third |
Sources: Harrison's Principles of Internal Medicine 22e | Adams and Victor's Principles of Neurology 12e | Miller's Anesthesia 10e
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