Circadian Management of Traveland Jet Lag
Steven W. Lockley, Ph.D.Division of Sleep Medicine, Brigham and Women’s Hospital, Boston
Division of Sleep Medicine, Harvard Medical School, Boston
DISCLOSURE: Dr. Lockley has received lecture fees from Takeda Pharmacueticals North America, consulting fees and conference travel support from Apollo Lighting, and equipment for use in Investigator-initiated and federal research studies from Philips Lighting and ResMed. Dr Lockley has received Investigator-initiated research grants from Apollo Lighting, Philips Lighting, and Alcon Inc. Dr. Lockley holds a process patent for use of short-wavelength light for resetting the human circadian pacemaker, assigned to Brigham and Women's Hospital.
• Internal circadian system cannot keep up with rapid light-dark change• Readjusts at a slow rate (~ 1h/day) causing chronic desynchronisation• Social and behavioural factors greatly influence readaptation rates
• Symptoms include- insomnia- fatigue- GIT disorders- poor performance, memory and concentration
Courtesy of NASA (http://visibleearth.nasa.gov/)
http://www.bioon.com/book/biology/whole/html/
The ‘body clock’ or circadian pacemaker is situated in suprachiasmatic nucleus(SCN) of hypothalamus
It controls the timing of most 24-hourbehavioral and physiological rhythmsincluding the sleep-wake cycle, alertnessand performance rhythms, hormoneproduction, temperature regulation,and metabolism.
‘circadian’ - ‘about a day’
Cajochen et al. Am J Physiol 1999
24-hour circadian rhythms in real-world situations:Motor vehicle crashes and heart attacks
Federal Motor Carrier Safety Administration 2000
Fatigue-related fatal crashesby time of day
Peak rate at 5am
Muller et al., New Engl J Med 1985
Onset of myocardial infarctionby time of day
Peak rate at 9am
Hastings et al. Nature Neurosci Rev 2003
Evidence for peripheral circadian clocks in most organs
Cardiac function
Hilton et al Comp Cardiol 2001
• pNN50; % of R-R intervals > 50 msec different from prior interval• Mean R-R interval per 5 mins
International business travelers reported
• 76% travel-related health problems• 74% have jet-lag• 45% have GIT disorders
Rogers & Reilly, 2002
Consolidated sleep can only occur at the correct circadian phase
Dijk and Czeisler, J Neurosci 1995
Sleep and circadian phase
Clock Time (h)
6 12 18 0 6 12 18 0 6
6-hour advance (Boston to Paris) places sleep in theWake Maintenance Zone
Sleep and circadian phase
Dijk and Czeisler, J Neurosci 1995
Clock Time (h)
6 12 18 0 6 12 18 0 6
10-hour delay (Boston to …….)
Sleep and circadian phase
Dijk and Czeisler, J Neurosci 1995
Clock Time (h)
6 12 18 0 6 12 18 0 6
Consequences of circadian misalignment
• Sleep disturbance
• Increased day-time sleepiness
• Deterioration in performance and cognition
• Disturbance in metabolic function
• Increased risk of accidents and injuries
Cho, Nature Neurosci 2001
• cognitive deficits• reduced spatial memory• amnesia
• Jet-lag type• Shift work type• Delayed sleep phase type (DSPS)• Advanced sleep phase type (ASPS)• Free-Running (Non-entrained) type (e.g. blind)
• Irregular sleep-wake type• Medical condition-related• Drug or substance-related• Non-specific
General criteria for Circadian Rhythm Sleep DisorderInternational Classification of Sleep Disorders II
Jet-lag Type(Jet-lag Disorder)
Diagnostic criteria
A. Insomnia or excessive sleepiness associated with transmeridian travel across 2 time zones
B. Associated impairment of daytime function, general malaise or somatic symptoms such as GI disturbance within 1-2 days of travel
C. Sleep disturbance not better explained by another sleep, medical, neurological, or mental disorder, medication or substance use
Additional features: more severe during eastward travel for majority of population, GI disturbance may persist longer than sleep problems, circadian adaptation takes ~1 h/day, may be exacerbated by inappropriate light exposure
To remember the required direction of shift to adapt,think about what people are doing right now at the destination
Westward travel requires a phase delay shift
People in LA (3 h westward) are still asleepThey will wake up ‘later’ than you in absolute timeTheir behaviors are DELAYED relative to youYou need to DELAY your clock to adapt to LA
Eastward travel requires a phase advance shift
People in London (5 h eastward) are having lunchThey are eating lunch ‘earlier’ than you in absolute timeTheir behaviors are ADVANCED relative to youYou need to ADVANCE your clock to adapt to London
Note: 5 h eastward = 19 h westward
Period of the circadian pacemaker in humans
• Average ~24.2 h (23.6-25.0 h)
• Determines direction and extent of daily shift required to entrain to 24 h
- phase angle of entrainment- diurnal preference or ‘owl vs lark’- adaptation to jet-lag or shift-work
• Genetic basis
Czeisler et al. Science 1999
Morning Type………….Evening Type Larks……….……………Owls
Mean = 24.2 h
Period determines direction and extent of daily adjustment to remain entrained to the 24-hour day
-60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60DELAYS ADVANCESMins Czeisler et al. Science 1999
Circadian period determines the directionthat is easiest to adapt to
Czeisler et al. Science 1999
75% naturally delay (‘westward’) - require phase advance to correct their clock each day
25% naturally advance (‘eastward’) - require phase delay to correct their clock each day
Larks……….………….Owls
Mean = 24.2 h
Recht et al., Nature 1995
Baseball teams beaten by jet lagEastward travel by the visitors is a disadvantage for them
When visiting team flies from West Coast to East Coast, East home team wins 63%When visiting team flies from East Coast to West Coast, West home team wins 56%
General criteria for Circadian Rhythm Sleep DisorderInternational Classification of Sleep Disorders II
A. There is a persistent or recurrent pattern of sleep disturbancedue primarily to one of the following:
i. Alterations of the circadian timekeeping systemii. Misalignment between the endogenous circadian rhythm &
exogenous factors that affect the timing or duration of sleep
B. The circadian related sleep disruption leads to insomnia,excessive daytime sleepiness or both.
C. The sleep disturbance is associated with impairment of social,occupational or other areas of functioning.
U.S. Air Carrier Traffic Statistics
International Passenger Revenue Passenger Enplanements (1996 - 2007)
(passenger services)
Year
1996 1998 2000 2002 2004 2006 2008
tota
l nu
mb
er o
f p
asse
ng
ers
bo
ard
ing
an
air
craf
t (0
00s)
0
20000
40000
60000
80000
100000
Source: US Bureau of Transportation Statistics, T-100 Market and Segment
Slide courtesy of Dr Shantha Rajaratnam
Treatment options for jet-lag(insomnia and excessive sleepiness)
• Prescription medication- Hypnotics- Stimulants- Melatonin agonists (hypnotic and chronobiotic?)
• Over-the-counter medication- Melatonin (hypnotic?)- Caffeine (stimulant)
• Circadian re-adaptation- Melatonin (chronobiotic)- Light-dark control (chronobiotic and stimulant)
• Prophylactic naps• Meal timing?
Treatment options for jet-lag(insomnia and excessive sleepiness)
• Prescription medication- Hypnotics- Stimulants- Melatonin agonists (hypnotic and chronobiotic?)
• Over-the-counter medication- Melatonin (hypnotic?)- Caffeine (stimulant)
• Circadian re-adaptation- Melatonin (chronobiotic)- Light-dark control (chronobiotic and stimulant)
• Prophylactic naps• Meal timing?
Circadian adaptation in oil-rig workers
Barnes et al. Neurosci Letts 1998a Barnes et al. Neurosci Letts 1998b
Adapated from Rajaratnam & Arendt, 2001
Incr
easi
ng
ad
van
ceIn
crea
sin
g d
elay
Light after ~6:00 amadvances the circadian clock
(to an earlier time)
Light before ~6:00 amdelays the circadian clock
(to a later time)
Phase Response Curve (PRC) describes the effect of light timing onthe magnitude and direction of the circadian phase resetting response
24 126 18Time (h)
Light : Dark (L:D) cycle
Normal entrainment
Westward flight – sleep later
Requires advance to adaptLight after 6 am INTERNAL time
Eastward flight – sleep earlier
Requires delay to adaptLight before 6 am INTERNAL time
L
L
Schematic of timing for light treatment of Jet-lag
Adapted from Arendt & Skene, Sleep Med Rev, 2005
Phase Response Curve (PRC)
Adapated from Rajaratnam & Arendt, 2001
Light after ~6:00 amcauses an advance
Light before ~6:00 amcauses a delay
Melatonin before ~1:00 amcauses an advance
Melatonin after ~1:00 amcauses a delay
Incr
easi
ng
ad
van
ceIn
crea
sin
g d
elay
24 126 18Time (h)
Light : Dark (L:D) cycle
Normal entrainment
Westward flight – sleep later
Requires advance to adaptLight after 6am INTERNAL time
Eastward flight – sleep earlier
Requires delay to adaptLight before 6am INTERNAL time
L
L
Schematic of timing for light treatment of Jet-lag
Adapted from Arendt & Skene, Sleep Med Rev, 2005
M
M
Mel after 1am INTERNAL time
Mel before 1am INTERNAL time
To remember the required direction of shift to adapt,think about what people are doing right now at the destination
Westward travel requires a phase delay shift
People in LA (3 h westward) are still asleepThey will wake up ‘later’ than you in absolute timeTheir behaviors are DELAYED relative to youYou need to DELAY your clock to adapt to LA
Eastward travel requires a phase advance shift
People in London (5 h eastward) are having lunchThey are eating lunch ‘earlier’ than you in absolute timeTheir behaviors are ADVANCED relative to youYou need to ADVANCE your clock to adapt to London
Note: 5 h eastward = 19 h westward
DepartBOS 19:00
ArriveLHR 7:00
LHR 2300 0200 0500 0800 1100 1400 1700 2000 2300
BOS to LHRDepart 19:00, 7 h flightTo adapt eastwards, you
need to phase advance (5 h)In
crea
sin
g a
dva
nce
Incr
easi
ng
del
ay
Sleep Light
BOS
DepartBOS 19:00
ArriveLHR 7:00
LHR 2300 0200 0500 0800 1100 1400 1700 2000 2300
BOS to LHRDepart 19:00, 7 h flightTo adapt eastwards, you
need to phase advance (5 h)In
crea
sin
g a
dva
nce
Incr
easi
ng
del
ay
Sleep
BOS
Light until bedtime
DepartBOS 19:00
ArriveLHR 7:00
LHR 2300 0200 0500 0800 1100 1400 1700 2000 2300
BOS to LHRDepart 19:00, 7 h flightTo adapt eastwards, you
need to phase advance (5 h)
Sleep
BOS
Incr
easi
ng
ad
van
ceIn
crea
sin
g d
elay
Melatonin administration - shifts the circadian clock - facilitates sleep
Melatonin before ~1:00 amcauses an advance
Melatonin after ~1:00 amcauses a delay
DepartLHR 15:00
ArriveBOS 17:00
BOS 1300 1600 1900 2200 0100 0400 0700 1000 1300LHR
Incr
easi
ng
ad
van
ceIn
crea
sin
g d
elay
LHR to BOSDepart 15:00, 7 h flightTo adapt westwards, youneed to phase delay (5 h)
Light Light Sleep
DepartLHR 15:00
ArriveBOS 17:00
BOS 1300 1600 1900 2200 0100 0400 0700 1000 1300LHR
LHR to BOSDepart 15:00, 7 h flightTo adapt westwards, youneed to phase delay (5 h)
Incr
easi
ng
ad
van
ceIn
crea
sin
g d
elay
Sleep
Jet-lag travel clinic example #1New York to Spain
12 AM 1 AM 2 AM 3 AM 4 AM 5 AM 6 AM 7 AM 8 AM 9 AM 10 AM 11 AM 12 PM 1 PM 2 PM 3 PM 4 PM 5 PM 6 PM 7 PM 8 PM 9 PM 10 PM 11 PM
5 AM 6 AM 7 AM 8 AM 9 AM 10 AM 11 AM 12 PM 1 PM 2 PM 3 PM 4 PM 5 PM 6 PM 7 PM 8 PM 9 PM 10 PM 11 PM 12 PM 1 AM 2 AM 3 AM 4 AM
Monday 27-Oct-08 MTuesday 28-Oct-08 MQ Q Q
Wednesday 29-Oct-08 Q Q Q Q Q Q Nap MThursday 30-Oct-08 M
Friday 31-Oct-08 MSaturday 1-Nov-08
Sunday 2-Nov-08 Q MQ Q Q Q Q Q Q Q Q Q Q Nap
Monday 3-Nov-08 MTuesday 4-Nov-08 M
Wednesday 5-Nov-08 MThursday 6-Nov-08
Friday 7-Nov-08
12 AM 1 AM 2 AM 3 AM 4 AM 5 AM 6 AM 7 AM 8 AM 9 AM 10 AM 11 AM 12 PM 1 PM 2 PM 3 PM 4 PM 5 PM 6 PM 7 PM 8 PM 9 PM 10 PM 11 PM
6 AM 7 AM 8 AM 9 AM 10 AM 11 AM 12 PM 1 PM 2 PM 3 PM 4 PM 5 PM 6 PM 7 PM 8 PM 9 PM 10 PM 11 PM 12 PM 1 AM 2 AM 3 AM 4 AM 5 AM
USA
SPAIN*
USA**
SPAIN
Key
SLEEP Q FLYING
TRY TO SLEEP OR NAP PRIORITIZE BRIGHT LIGHT EXPOSURE
WEAR SUNGLASSES – AVOID LIGHT DO NOT WEAR SUNGLASSES – SEE LIGHT
M TAKE MELATONIN
Jet-lag travel clinic example #2: Boston to Asia Key
SLEEP Q FLYING
TRY TO SLEEP OR NAP PRIORITIZE BRIGHT LIGHT EXPOSURE
WEAR SUNGLASSES – AVOID LIGHT DO NOT WEAR SUNGLASSES – SEE LIGHT
M TAKE MELATONIN
• Caffeine• Naps• Hypnotics / Stimulants• Important target times
Courtesy Dr Laura Barger
Treatment of pre-mission adaptationfor Shuttle Astronauts
Slide courtesy of Dr Smith Johnston, NASA
Scheer et al., PNAS 2009
Postprandial response during circadian misalignment (28-h day)4 time zones West per day
Moser et al., Cancer Causes Control 2006
• Female flight-attendants and shift-workers have >50% increased risk of breast cancer compared to non-shift-working women
• Totally blind women have ~50% reduction in breast cancer risk and risk increases with increasing visual acuity
Breast Cancer Risk Factors
Hastings et al. Nature Neurosci Rev 2003
Consequences of shift work disorder or short sleep
Circadian misalignment and sleep disruption likely underlie increased risk of accidents and injuries, heart disease, metabolic
disorders and diabetes and some cancers in shift-workers
Filipski et al., Cancer Res 2004
Mice placed in ‘jet-lag’ schedules
• 8 h advance every 2 days• Tumor growth increased vs no shift (innoculated Glasgow osteosarcoma)
‘shift-work that involves circadian disruption is probablycarcinogenic to humans (Group 2A)’
WHO International Agency for Research on Cancer Monograph Working GroupStraif et al., Lancet Oncol 8, 2007
Circadian Disruption and Cancer-Making the Connection
New York Academy of Sciences andThe Mushett Family Foundation
June 9, 2009
http://www.nyas.org/
Key considerations in managing jet-lag
• Design advice using circadian and sleep principles
• Circadian adaptation with appropriately timed - light-dark exposure - melatonin / melatonin agonists
• Direct sleepiness countermeasures- light, prophylactic naps, caffeine, stimulants
• Direct insomnia countermeasures- Melatonin / melatonin agonists, hypnotics
• Maintain good sleep practices (eye-mask, earplugs)
• Develop jet-lag education programs
Treating jet-lag will improves performance efficiency,health & safety
www.understandingsleep.org
www.sleep.med.harvard.edu
Metabolic impact of sleep- and circadian disruption
Post-prandial glucose, insulin, triacylglycerol, non-esterified fatty acids are elevated after a test meal taken at 0130 h as compared to the same meal takenat 1330 h
Lund et al., J Endocrinol, 2001
Sleep restriction (4 h/night x 6 nights) caused impaired glucose tolerance and reduced insulin response in young healthy subjects similar to that seen in non-insulin-dependent diabetics.
Postprandial response ofshift-workers in Antarctica
Postprandial response to chronicpartial sleep deprivation
Speigel et al., Lancet 1999
Adapted from Arendt, 1995
RHT
How important is the 24-hour light-dark cyclein human circadian regulation?
RHT - Retinohypothalamic tractSCN – Suprachiasmatic nuclei
24.2 h24.0 h
Plas
ma
mel
aton
in (
pg/m
l)
0
5
10
15
20
25
30
0
5
10
15
20
25
30
22 0 2 4 6 8 10 12 14 16 18 20
24-hour light-dark cycleresets the circadian clockon a daily basis
Neuroanatomy of the circadian system
Entrainment by light
Pineal melatonin response
Daily 24-hourLight-dark cycle
Pineal melatonin response
Tetraplegia (C6 lesion)
Neuroanatomy of the circadian system
Total blindness
Pineal melatonin response
Pla
sma
mel
ato
nin
(p
g/m
l)
0
5
10
15
20
25
30
0
5
10
15
20
25
30
22 0 2 4 6 8 10 12 14 16 18 20
Circadian period range 23.6 - 25.1 h(Example shown ~24.5 h)
Dijk et al. Am J Physiol 2001
Shuttle mission scheduled 23.5 h day
Sleep and circadian rhythm disorders in Space
STS-90
Phoenix Lander Mission:How to entrain to a Martian day (24.66 h)
Subjects completed daily diaries on PDAs,documenting work, sleep and naps.
Barger, Lockley et al, unpublished
Time since lights on (h)
-4 -2 0 2 4 6 8 10 12
Su
bje
ctiv
e al
ertn
ess
(mea
n +
sem
)
1
2
3
4
5
6
7
8
9
Time since lights on (h)
-4 -2 0 2 4 6 8 10 12
Au
dito
ry reaction
time
(mean
ms
+ s
em)
200
300
400
500
Time since lights on (h)
-4 -2 0 2 4 6 8 10 12
Lap
ses > 500 m
s(m
ean n
um
ber
+ s
em)
0
5
10
15
20
Subjective sleepiness
Auditory reaction time Lapses of attention > 500 ms
Short-wavelength sensitivity for the acute alerting effects of light
460 nm light is more effective at enhancingalertness and performance than 555 nm light
Sleepy
Alert
460 nm555 nm
Lockley et al., Sleep 2006
Light Applications - Clinical
• Treatment of circadian rhythm sleep disorders- Advanced-, Delayed-, Non-24-hour Sleep Disorders- Shift-work Disorder, Jet-lag- Sleep timing changes due to adolescence and aging
• Entrainment to non-24-hour ‘days’- Space flight and bases, Submariners, Antarctica
• Treatment of affective disorders- Seasonal Affective Disorder (Glickman et al., 2005; Anderson et al., 2009)
- Alzheimer's Disease (Riemersma-van der Lek et al., JAMA 2008)
- General mood, non-seasonal depression?
• Improving general sleep patterns- Hospital and institutionalized patients- Child and adolescent sleep
• Non-pharmacological sleepiness countermeasure• Safe, reversible, short-acting, inexpensive• High levels of caffeine use illustrate need
- Offices, schools, colleges, factories, control rooms…- Military, security, transport (pilots, captains, truck/car/train drivers)- Safety-sensitive occupations (physicians, nurses, nuclear…)- Anywhere where enhanced alertness and safety is important
Light Applications - General
• Challenge is to incorporate these benefits into design• Lighting design to optimize visual and non-visual effects• Flexible, ‘smart’ lighting systems with user interaction
International business travelers report
• 76% travel-related health problems• 74% have jet-lag• 45% have GIT disorders
Rogers & Reilly, 2002
Jet-lag in mice and men
Mice placed in ‘jet-lag’ schedules
• 8 h advance every 2 days• Tumor growth increased (innoculated Glasgow osteosarcoma)
Filipski et al., Cancer Res 2004