Chronobiology Staying in sync across the lifespan

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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

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Introduction

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

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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

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Early Circadian Studies
de Mairan (1729) as shown in Moore-Ede, Sulzman,
Fuller, 1982
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What is this?
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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
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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!

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Single SCN explants generate a circadian rhythm
From Reppert, S.M.AND Weaver, D.R. Nature 418,
935 - 941 (2002)
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SCN transplant
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Non-believers?

• Anyone not believe that there is a clock in the
  brain signaling the biological night.

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The opponent process model
Sleep Academic Award 15
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Actigram Heterozygote Clock Mutant MouseRaster
Plot
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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

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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

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Circadian disorders

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

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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.

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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

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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)

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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

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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.

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• SHIFT WORK SLEEP DISORDER

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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

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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.

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Shift Work Sleep Disorder

• Insomnia when trying to sleep
• Excessive sleepiness when trying to stay awake
• Related to work schedule

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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

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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

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Summary

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

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Jet lag

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

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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.

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Treatment of Jet Lag

• Go first class!

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Treatment of Jet Lag

• If you are staying for 1 or 2 days, try to
  maintain your home schedule.

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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

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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).

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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.

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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

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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).

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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.

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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

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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.

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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?

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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)

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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?