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Chronobiology Staying in sync across the lifespan

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Title: Chronobiology Staying in sync across the lifespan


1
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Chronobiology Staying in sync across the lifespan
  • Chad Hagen M.D.
  • Sleep Medicine Fellow
  • Stanford University Sleep Medicine
  • April 4, 2007

3
Introduction
  • Biology
  • Terminology
  • Anatomy/Physiology
  • Spectrum of disorders
  • Blind Free Runners
  • Jet lag
  • Shift work
  • DSPS/ASPS
  • 3. Examples
  • Adolescent
  • Mid-lifer
  • Retiree

4
Chronobiology language
  • Melatonin (The biological night)
  • Circadian rhythm Occurs about every 24 hours
  • Ultraradian Rhythms faster than 24 h
  • Infradian Rhythms slower than 24 h
  • Zeitgebers time givers
  • Light, exercise, sleep, sound, melatonin pills
  • Biological night
  • Sleep phase
  • In, out, advanced, delayed

5
Early Circadian Studies
de Mairan (1729) as shown in Moore-Ede, Sulzman,
Fuller, 1982
6
What is this?
7
Pineal Gland -Resets the clock-Orchestrate
s circadian functions sleep-wake cycle,
endocrine fluctuations, other timed functions
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Light information transmitted to the brain by
non-visual neurons originating in the back of the
eye
11
Is it really a clock?
  • Wrist watch
  • Driven with a pre-determined period (nearly 24h)
  • Has error
  • Able to re-set
  • Free will
  • We act in accordance or defiance of the clock
  • Can give to others
  • SCN (biological clock)
  • Driven by a genetic program with a pre-determined
    period (24.1h)
  • Has error
  • Able to re-set
  • Free will
  • We act in accordance or defiance of the clock
  • Can give to others!

12
Single SCN explants generate a circadian rhythm
From Reppert, S.M.AND Weaver, D.R. Nature 418,
935 - 941 (2002)
13
SCN transplant
14
Non-believers?
  • Anyone not believe that there is a clock in the
    brain signaling the biological night.

15
The opponent process model
Sleep Academic Award 15
16
Actigram Heterozygote Clock Mutant MouseRaster
Plot
17
Circadian rhythm sleep disorders
  • Essential problem
  • Misalignment internal sleep/wake rhythm and the
    desired (or required) time for sleep
  • Results in
  • sleep and/or wake (or desire for sleep and wake)
    at inappropriate times
  • Some types of insomnia
  • Excessive sleepiness

18
If I have these problems (insomnia or sleepiness)
does it mean I have a circadian problem?
  • No
  • Sleep quantity problems
  • Inadequate sleep
  • Limit setting sleep disorder
  • Sleep state misperception
  • Other forms of insomnia
  • Sleep quality problems
  • Environment
  • Breathing problems
  • Movement problems

19
Circadian disorders
  • Delayed Sleep Phase Syndrome
  • Advanced Sleep Phase Syndrome
  • Shift work
  • Jet lag
  • Blind Free Runners

20
Delayed Sleep Phase Syndrome/Preference (Night
Owls)
  • Major sleep episode is delayed in relation to the
    desired clock time (gt 3 hours from norms)
  • Sleep onset insomnia
  • Difficulty awakening at the desired time
  • Tendency increases in adolescents
  • gt 7 of adolescents and 0.7 of middle aged
    adults
  • Significant social consequences, appear as lazy
    in the mornings, difficulty getting to work or
    school.

21
Behaviorally Induced Delayed Sleep Phase
(extrinsic)
  • Highly prevalent among high school and college
    students
  • Increased light or activity in evening
  • Minimized light and activity in morning
  • The average bedtime at Brown University
    dormitories is 2 a.m
  • Week-end late night socializing and sleeping- in
    reinforces the delay resulting in Sunday night
    insomnia

22
Treatment of DSPS
  • Stabilize the time of sleep (keep diary or wear
    actigraph) KEY constant wake time
  • Advance rhythms with
  • Light exposure/exercise in the morning
  • 6-8AM 2,000 to 2,500 lux
  • Melatonin (0.5 mg) in the evening about 3 hours
    before the desired bedtime
  • With a physician, could consider a hypnotic
  • Chronotherapy Shift entire schedule 15 to 30
    minutes per day (Difficult, and often not
    effective)

23
Advanced Sleep Phase Syndrome (Morning Larks)
  • Main sleep time advanced in relation to clock
    time
  • Symptoms
  • Compelling early evening sleepiness
  • Early sleep onset
  • Early morning awakening

24
Advanced Sleep Phase Syndrome
  • Pure syndrome uncommon.
  • Familial (inherited) form described.
  • Less social stigma and conflict (helpful trait,
    appearance of resilience, promotes easier AM
    awakening).
  • Tendency is common with aging.
  • 1 of middle aged adults, but increases with age
  • under-reported if not identified as a problem
    or conflicting with social obligations as we age.

25
  • SHIFT WORK SLEEP DISORDER

26
Evidence suggests that excessive sleepiness was
associated with which of the following?
  • Exxon Valdez oil spill
  • Destruction of the space shuttle Challenger
  • Nuclear accident at Chernobyl
  • 13.4 billion dollars in work related accidents in
    1988
  • Janet Jackson wardrobe malfunction during the
    Super Bowl Half-Time Show

27
Shift work
  • 15.2 million Americans work outside the standard
    daytime work schedule
  • Schedules vary widely
  • Occasional night duty
  • Rotating shift
  • Regular night work (or early starts or commutes)
  • Trend extended duty (10 12 hours)
  • Not often formulated as a medical problem.
  • Privacy concerns
  • I might get fired if they find out I am sleepy on
    the job
  • Labor-management conflicts.

28
Shift Work Sleep Disorder
  • Insomnia when trying to sleep
  • Excessive sleepiness when trying to stay awake
  • Related to work schedule

29
Management of Shift Work Intolerance
  • Optimize consistent scheduling
  • Employee support
  • Change job or shift if non-adapting
  • Planned napping
  • Alerting agents approved for shift work
  • With physician consultation, hypnotics (sleeping
    pills) may be appropriate

30
Management of Shift Work Intolerance
  • Clock resetting
  • Bright light therapy while at work
  • Melatonin prior to daytime sleep
  • Consistent sleep schedule across work and
    non-work days
  • May not apply to short runs of night work

31
Summary
  • Treatment of shift work intolerance depends on
  • Individual preference
  • Expected direction of circadian de-synchrony
  • The degree of alertness demanded by the job

32
Jet lag
  • Disturbed sleep
  • Eastward flight difficulties falling asleep
  • Westward flight difficulties staying asleep
  • Impaired daytime alertness
  • Gastrointestinal symptoms

33
Clinical Course
  • Usually a benign nuisance that is self-limited.
  • However travel time is often precious, so
    treatment may be preferred.
  • In some cases, the circadian pacemaker may shift
    in the opposite direction from travel, resulting
    in a prolonged adjustment.

34
Treatment of Jet Lag
  • Go first class!

35
Treatment of Jet Lag
  • If you are staying for 1 or 2 days, try to
    maintain your home schedule.

36
Treatment of Jet LagHypnotic medications
  • May be used to promote sleep in flight, and few
    days after arrival, while the process of
    re-synchronization is in progress.
  • Avoid concurrent use of alcohol.
  • Physician consultation
  • Avoid over the counter preperations

37
In-flight hypnotic medications Cautions
  • Global amnesia reported.
  • Odd confused behavior, fighting, or eating while
    in a sleep state.
  • Contraindicated in people with a tendency for
    deep vein thrombosis (blood clots).

38
Treatment of Jet LagLight Exposure
  • Natural light exposure after arrival will
    eventually reset the circadian system to local
    time.
  • The phase re-setting effects of light can be
    enhanced by carefully timing the light exposure.

39
Treatment of Jet LagMelatonin
  • When traveling eastward, take melatonin at
    bedtime, or earlier.
  • When traveling westward, take melatonin for early
    morning awakening.
  • Dose 0.5 to 1 mg.
  • Use as a darkness signal

40
Risks of melatonin
  • Wrong timing ? wrong shift!
  • Fertility in young women?
  • Report of potential hypertension
  • No confirmed reports of toxicity or overdose
  • Original studies with 50-100mg in elderly
    subjects with no significant adverse effects
    greater than placebo other than sedation.
  • Current recommendations see no additional benefit
    in doses greater than 3 mg.
  • 0.5 mg approximates natural melatonin
    concentration in the blood (unknown concentration
    in the brain).

41
Risks of melatonin
  • No other hormone is available in the United
    States without a prescription.
  • Contained naturally in some foods, the U.S.
    Dietary Supplement Health and Education Act of
    1994 allows it to be sold as a dietary supplement
    (e.g., vitamins and minerals).
  • Is not approved by the Food and Drug
    Administration (FDA) or controlled in the same
    way as drugs.
  • Schiff and Natures bounty used in some research
    protocols, synthesized in laboratory by rDNA so
    no longer a risk of CJD.
  • Avoid additives ie Valerian, other extracts,
    etc.

42
Light therapy
  • Risks
  • Family or personal history of retinal or eye
    tumors?
  • Wrong direction if timing incorrect
  • Mania induction in bipolar disorder
  • Use
  • 2,000 to 2,500 lux
  • 45 degrees off center
  • Timing
  • 6-8am or 8-11 pm depending on desired effect
  • Within arms reach
  • NO visors
  • NO dawn simulators
  • Natural light, outdoors preferably, direct, no
    sunglasses

43
Application of chronobiology across the lifespan
Adolescence
  • 15 year old student with difficulty waking up in
    the morning, finds his best study time is
    between 9 pm and 1 am and hasnt gone to sleep
    before 2 am for the past 4 weeks.
  • New tardiness this year, quit AM orchestra
    practice because she thinks its stupid, and is
    at a high school that begins one hour earlier
    than her junior high school did last year.

44
Adolescence (continued)
  • Delayed sleep phase (Night Owl)
  • What other sleep problem did this create?
  • Involuntary sleep restriction from the
    intersection of her sleep phase and her social
    obligations
  • Is the orchestra really stupid
  • Sleep restriction ? irritability, poor focus,
    energy
  • We cant cure the drama of adolescence
  • But, it may be unnecessarily difficult if a sleep
    disorder is present.
  • What should she and her family do?

45
Application across the lifespan Jet Lag
  • SFO to London
  • Take LOW DOSE 0.5 mg of melatonin at 300 pm for
    the three days leading to departure, then at
    London bed time after arrival.
  • May consider sleeping medication after eating
    dinner on the plane (try earlier than usual
    bedtime)

46
Application of chronobiology across the lifespan
Retirement
  • A 65 year old man retired from a career in
    finance wants to watch the late show with his
    wife and sleep-in now that hes retired, but he
    feels compelled to sleep at 830 pm and is awake
    each morning at 4 am.
  • Wife is offended that hes avoiding her at
    night.
  • What is this? What can he do about it?
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