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

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ng

ad

van

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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