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Circadian Rhythm of Sleep and Associated Sleep-Wake Disorders

From Fishman's Pulmonary Diseases & Disorders + Murray & Nadel's Textbook of Respiratory Medicine

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I. DEFINITION AND BASIC CONCEPTS

• Circadian rhythm (Latin: circa = about, diem = day) refers to endogenous biological oscillations with a near-24-hour periodicity that persist even in the absence of external time cues.
• Sleep and circadian rhythm are highly coupled processes. In Borbely's two-process model, they were initially considered independent but interacting:
  • Process C (Circadian) - the biological clock with a ~24-hour rhythm
  • Process S (Homeostatic/Sleep drive) - builds progressively during wakefulness like an hourglass; resets during sleep
• The intrinsic circadian period in humans is approximately 24.3 hours, not exactly 24 hours; regular light exposure entrains it to 24 hours. (Murray & Nadel, Ch. 118)
• These two forces interact to support a regular daily sleep pattern over time. (Murray & Nadel)

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II. THE MOLECULAR CLOCK - MECHANISMS (Fishman's, Ch. 12)

• Original discovery: mutant Drosophila fruit flies with abnormal circadian periods led to identification of the first clock gene, period (per).
• Jeff Hall, Michael Rosbash, and Michael Young received the Nobel Prize for describing this molecular mechanism.
• In mammals, the main clock proteins are:
  • 3 Period proteins: PER1, PER2, PER3
  • 2 Cryptochrome proteins: CRY1, CRY2
• These form a complex in the cytoplasm, enter the nucleus, and inhibit their own transcription controlled by the CLOCK/BMAL1 complex - a classic negative feedback loop.
• PER proteins are phosphorylated by casein kinase 1e (CK1e) and CKII → ubiquitination → degradation (this sets the period).
• A second loop: orphan nuclear receptor genes Rev-Erbα/β and RORα/β: RORs activate BMAL1; REV-ERBs repress BMAL1.
• The clock is a cell-autonomous process - individual cells show circadian oscillation.

• Mutations in PER2 phosphorylation site and CK1 delta → Familial Advanced Sleep Phase Syndrome (FASPS)
  • Patients sleep at 7:30 PM and wake at 4:00 AM
• Mutations in DEC2 (BHLEH41) → Short sleeper phenotype (<6 hours) without daytime performance impairment

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III. THE SUPRACHIASMATIC NUCLEUS (SCN) - MASTER CLOCK (Fishman's, Ch. 12)

• Located in the hypothalamus, contains ~20,000 neurons
• Lesioning/destruction of SCN → animal becomes arrhythmic (no circadian period)
• Entrainment: The intrinsic period is not exactly 24 hours; entrained daily to 24 hours by light/dark signals
• Retino-hypothalamic tract (RHT): direct neural track from retina to SCN
• Light sensing for circadian entrainment uses melanopsin (in retinal ganglion cells scattered across the retina) - separate from rod/cone visual system
  • Particularly sensitive to blue light range (basis of blue-light blocking glasses, blue-light therapy boxes)
• After time-zone change, re-entrainment is slow: ~1 hour per day

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IV. PERIPHERAL CLOCKS (Fishman's, Ch. 12)

• Clock molecules are expressed in all tissues - functioning peripheral clocks exist in all organs
• ~3-10% of all mRNAs show rhythmic (diurnal) expression in different tissues
• Peripheral clocks synchronized by:
  • Signals from master SCN clock
  • Local signals: autonomic nerve activity, body temperature, glucocorticoids, feeding patterns
• Phase shifting of peripheral clocks occurs more rapidly than for SCN (e.g., altering feeding time shifts liver clocks without affecting SCN)
• Lung clock: A functioning molecular clock exists in Clara cells of bronchial epithelium
  • Genes encoding extracellular matrix, cell cycle, apoptosis, and chemokine ligands show diurnal oscillation
  • Immune response of the lung is under circadian control
  • FEV1 shows circadian variation; asthma symptoms show circadian variation
  • Lung clock is affected by hypoxia (exposure to hypoxia phase-shifts clocks in tissue-specific fashion)
  • Circadian rhythm dysfunction has implications for lung cancer (breast cancer risk also inversely associated with circadian rhythm disorders - Murray & Nadel)

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V. SLEEP-WAKE PHYSIOLOGY (Murray & Nadel, Ch. 118 + Fishman's, Ch. 12)

1. Circadian output from SCN - maintains regular daily timing for sleep/wakefulness
2. Homeostatic pressure - drive to sleep increases as time since last sleep increases

• Sleep divides into REM and NREM sleep
• NREM stages:
  • N1: Slowing of EEG frequency
  • N2: Sleep spindles + K complexes (synchronized EEG)
  • N3: Slow-wave/delta sleep (stages 3 & 4 collapsed into N3) - synchronized oscillatory cortical firing generating large slow waves on EEG
• REM sleep: Mixed frequency, low amplitude EEG (similar to wakefulness) + skeletal muscle atonia (except extraocular muscles and diaphragm)
• Ultradian cycles: 4-5 cycles of ~90 minutes each; early night = more slow-wave sleep; later cycles = progressively longer REM
• Normal morning awakening is typically out of REM sleep

• Wake-promoting neurons (increased firing in wake, reduced in NREM, virtually absent in REM):
  • Cholinergic cells - basal forebrain
  • Orexin/hypocretin cells - lateral hypothalamus (respond to positive emotions)
  • Histamine cells - posterior hypothalamus
  • Dopamine cells - peri-aqueductal grey
  • Noradrenaline cells - locus coeruleus
  • Serotonin cells - brainstem raphe nuclei
• Sleep-promoting neurons (increased firing during sleep):
  • Ventrolateral preoptic area (VLPO) of hypothalamus - called the "sleep switch"
  • Medial preoptic area (MPO)
  • Contain inhibitory neurotransmitter GABA
• REM-specific: Cholinergic neurons in pedunculopontine tegmentum (PPT) and lateral-dorsal tegmentum (LDT) - fire more in REM than NREM (REM = high cholinergic tone)

• Measuring sleep latency every 2 hours over 24 hours reveals a biphasic pattern
• Two peaks of sleepiness:
  1. Nocturnal hours (primary)
  2. Early afternoon (2-4 PM) - "siesta time"
• Present in all age groups (though peak time may vary)
• Correlates with time of occurrence of car crashes attributed to driver falling asleep
• Body temperature rhythm synchronizes most closely with sleepiness: falls in late afternoon, lowest during middle of sleep period, rises before morning awakening

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VI. CIRCADIAN RHYTHM SLEEP-WAKE DISORDERS (Murray & Nadel + Fishman's)

1. Delayed Sleep-Wake Phase Disorder (DSWPD)

• Most common circadian rhythm disorder
• Characterized by: natural bedtime preference during early morning hours (commonly 2 AM or later), rise time preference = late morning or midday
• Presents with: difficulty initiating sleep, inability to awaken on time in the morning
• If allowed to follow natural schedule → few daytime symptoms; sleep is otherwise normal
• When work/school imposes conflicting schedule → sleep restriction → excessive daytime sleepiness
• Management:
  • Melatonin in the evening (shifts biological clock earlier)
  • Bright light exposure in the morning (advances circadian phase)
  • Effects may not be dramatic; patients tend to revert easily if measures not maintained
  • Some patients choose occupations compatible with delayed phase

2. Advanced Sleep-Wake Phase Disorder (ASWPD)

• Sleep begins in the early evening; terminates in the early morning
• Genetic basis: Familial form associated with PER2 phosphorylation mutation and CK1 delta mutation
• Conflicts with social/work schedules
• Management: Bright light exposure in early evenings to delay sleep onset

3. Shift Work Disorder

• Characterized by >1 month of:
  • Excessive sleepiness during scheduled work time
  • Insomnia during scheduled sleep times
• Context: nonconventional and/or rotating work schedules
• Workers with normal nocturnal sleep suddenly face a trough of sleepiness during middle of night work period - circadian influences are promoting sleep while they attempt to stay awake
• Interferes with nocturnal blood pressure dipping → elevated BP → increased risk of chronic hypertension and cardiovascular disease
• Associated with increased risk of breast cancer and musculoskeletal pain
• Management:
  • Optimize sleep environment and schedule
  • Pre-shift napping
  • Bright light exposure during night shifts
  • Avoid bright light during return home in morning (to allow sleep)
  • Melatonin to promote sleep
  • Judicious use of hypnotics to promote sleep
  • Modafinil and caffeine to promote wakefulness during work

4. Jet Lag Disorder

• Circadian misalignment due to travel across time zones
• Body's circadian rhythm is out of synchrony with clock time
• Manifests as: sleep disruption, daytime symptoms, performance impairment
• Sleeping at inappropriate times impairs sleep efficiency and sleep quality
• Re-entrainment rate: ~1 hour per day (eastward travel more difficult than westward)
• Management:
  • Sleep scheduling
  • Appropriately timed light therapy
  • Melatonin (at destination bedtime)

5. Irregular Sleep-Wake Circadian Rhythm Disorder

• Loss of the normal circadian sleep-wake cycle
• Multiple short sleep episodes across 24 hours
• Often seen in neurodegeneration, institutionalized elderly
• Management: structured light exposure, melatonin, enforced activity schedules

6. Non-24-Hour Sleep-Wake Rhythm Disorder (Free-Running)

• Circadian rhythm not entrained to 24 hours; follows intrinsic period (~24.3 hours)
• Common in totally blind individuals (lack retinal light input for SCN entrainment)

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VII. MELATONIN AND ZEITGEBERS (Murray & Nadel, Ch. 118)

• Light is the strongest zeitgeber ("time-giver"/synchronizer)
• Exposure to light during daytime + dark environment at night → physiologic secretion of melatonin in the evening → facilitates sleep initiation
• Core body temperature falls in the evening (a circadian cue for sleep initiation)
• Other zeitgebers: regular meal times, physical activity, social interactions, environment, bedtime routines
• Alcohol: lowers arousal threshold as blood levels fall → early morning awakenings; delays circadian rhythms (should be avoided 4 hours before bedtime)
• Nicotine: stimulant → delays sleep onset
• Caffeine: should be avoided at least 6 hours prior to sleep time

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VIII. CONSEQUENCES OF CIRCADIAN/SLEEP DISRUPTION (Murray & Nadel)

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IX. HEALTHY SLEEP DIMENSIONS (Murray & Nadel, Ch. 118)

1. Regularity - sleep over many days
2. Satisfaction - quality perception
3. Daytime alertness - restorative capacity
4. Timing - aligned with circadian rhythm
5. Efficiency - low awakenings; low wake-after-sleep-onset time
6. Duration - sufficient total sleep time

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X. QUICK SUMMARY TABLE: CIRCADIAN SLEEP-WAKE DISORDERS

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• Fishman's Pulmonary Diseases and Disorders (Ch. 12: Sleep and Circadian Rhythms; Ch. 100: Circadian Clocks in Cardiovascular System and Lung; Ch. 101: Circadian Rhythms and Sleep)
• Murray & Nadel's Textbook of Respiratory Medicine (Ch. 118: Sleep Disruption - Introduction, Circadian Rhythm Disorders, Primary Sleep Disorders, Treatment)