Wk 7: Circadian Rhythm Disorders

  1. Conceptual model of sleep-wake regulation- two process model
    Image Upload 1
  2. Homeostatic sleep pressure and phase angle changes in adolescents
    • Younger people tend to have more homeostatic sleep pressure (fast accumulation of homeostatic sleep pressure)
    • Max homeostatic pressure is reached earlier for young adolescents
    • At the time when melatonin is released (melatonin onset), is when we have the strongest signal for wake.
    • Sleep 1-2 hours after
  3. Changes in the response of the clock to light in adolescents
    • Image Upload 2
    • Looked at ability of light to suppress melatonin.
    • Looked at changes in the clock's responsiveness to light before and after puberty
    • Found: the younger people are the more sensitive their clock is to light
    • Prepubescent were more sensitive.
    • Part of why adolescents are more at risk for delayed sleep disorder
  4. Melatonin and sleep timing in clinically-diagnosed ‘Delayed Sleep Phase Syndrome’
    • Image Upload 3
    • Square is temp
    • Triangle is melatonin onset
    • There is great variability of melatonin onset on people with the same diagnosis of delayed sleep phase syndrome
  5. Functional impairments associated with
    Delayed Sleep Wake Phase Disorder symptoms
    • Reduced productivity
    • Disrupted work/school/social/family life
    • Mood goes way down
    • Depression and DPSD are highly comorbid
    • Looked at how melatonin can help for DSPD
    • 57% circadian misalignment (required bed time 30min before DLMO)-melatonin
    • 43% No circadian misalignment (required bedtime at least 30min after DLMO).
    • They only studied people with misalignment
    • Melatonin helped compared to placebo
    • Significant difference in sleep onset time
  7. Two phenotypes for DPSD
    • One has misalignment in circadian timing (late melatonin onset)
    • One has no misalignment (Behavioural DSPD)
    • Melatonin will not help with no misalignment
  8. Circadian misalignment
    and depressive symptoms in DSPD
    32% of those with circadian misalignment (delayed clock) showed mild/moderate/severe depression compared to 9% of those without circadian misalignment
  9. Increased sensitivity of the circadian system to light in delayed sleep-wake phase disorder
    • Understanding of disease vulnerability
    • Hypothesis: people with DSPD are probably hypersensitive to light at night (and thus delays the clock)
    • Only studied people with delayed timing
    • Found that delayed and non delayed DPSD people are actually opposites- delayed are hypersensitive, non delayed are hyposensitive relative to healthy controls

    • Preliminary results:
    • Pupil constriction also more sensitive in DPSD and continue to have smaller pupil size even after exposure
    • Suggests that avoiding light at night may be the most important intervention
  10. Sleep Diagnosis using ..the pupil?
    • The pupillary light reflex distinguishes between circadian and non-circadian DSPD phenotypes in young adults
    • 87% accurate
  11. Non 24h sleep disorder
    • Tends to happen in visually blind but can happen to anyone
    • Image Upload 4In the image, waking up later and later everyday
    • Melatonin onset is later and later every day
    • Image Upload 5Stars are melatonin
    • Generally humans have longer than 24h
  12. Shift work disorder
    • There is report of insomnia and/or excessive sleepiness, accompanied by a reduction of total sleep time, which is associated with a recurring work schedule that overlaps the usual time for sleep.
    • Image Upload 6
  13. Health effects of shift work
    • Mental health: stress, anxiety, depression, neuroticism, reduced vigilance, burnout syndrome
    • Circadian rhythm disruptions: body temp, respiratory rate, hormonal production, menstrual cycle, cell division
    • Brain: sleep loss, reduced brain volume
    • Increased cancer: breast cancer, colorectal cancer
    • Cardiovascular disorders: eg. hypertention
    • Reproductive effects: low birth weight, prematurity, spontaneous abortion
    • Gastrointestinal disorders: heartburn, abdominal pains, flatulence
  14. Background
    • Sleep timing and chronotype are often not accurate measures of circadian phase, and are influenced by factors including social constraints, individual preferences, and homeostatic sleep pressure.
    • Circadian phase misalignment is associated with adverse health (and safety) outcomes.
    • Failure to measure circadian phase may result in mistiming of circadian treatments such as light therapy.
    • Circadian medicine approach requires accurate measurement of circadian phase.
  15. Markers for assessing circadian phase
    • Melatonin; plasma, saliva, urine
    • • Cortisol; plasma, saliva, urine
    • • Temperature; rectal, tympanic, oral, skin
    • • Rest-activity
    • • Sleep; PSG, diaries, actigraphy
  16. Markers of the melatonin rhythm used to characterise the timing of the circadian clock
    • Image Upload 7
    • Onset of melatonin is the start of 'biological night'
  17. Suppression of melatonin by room light
    • Showed that melatonin onset is delayed even in regular room light
    • Pretty much any light is probs delaying melatonin onset
  18. Circadian therapeutic approaches- exogenous melatonin
    • There are melatonin receptors in the SCN
    • Melatonin shifts timing 
    • It also quietens the electrical activity of the clock (ie. when it's supposed to give the big signal to stay awake, it quietens it)
    • Which makes it easier to fall asleep around melatonin onset time when taking melatonin
  19. Properties of exogenous melatonin
    • Phase resetting effect
    • early evening – phase advance
    • early morning – phase delay (by extending your biological night and starting your biological day later)
  20. Effects of exogenous melatonin (1.5 mg) on sleep timing and circadian rhythms
    • Image Upload 8
    • Changes time and it makes you sleepy
  21. Melatonin agonist (tasimelteon) improves
    ‘transient insomnia’ after phase-advance of the sleep/wake cycle
    • (something that mimics melatonin by binding to melatonin receptors)
    • Increasing doses, the more sleep
    • First approved circadian rhythms drug
    • Approved for synchronising blind people
  22. Light Phase Response Curve (PRC)
    Image Upload 9
  23. Responses to light and melatonin depend on the time of administration
    • Image Upload 10
    • After midpoint, melatonin causes delay
  24. How to solve different sleep phase problems
    • Image Upload 11
    • M= melatonin
    • L= light
  25. The human phase response curve (PRC) to melatonin
    Image Upload 12
  26. Clinical guidelines: Management
    • 1. Regular physicals (sleep-related and other comorbidities)
    • 2. Determine if removal from shift work is appropriate or
    • practically feasible
    • 3. Determine patient-specific therapeutic approach
    • A. Circadian adaptation
    • B. Symptom management (insomnia, excessive sleepiness)
    • 4. Address additional work, social, and domestic factors
    • A. Social/family/psychological
    • B. Health and safety
    • C. Work-related
Card Set
Wk 7: Circadian Rhythm Disorders
Wk 7: Circadian Rhythm Disorders