Circadian Management of Travel and Jet Lag Steven W. Lockley, Ph.D.

1. Circadian Management of Travel and 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.

2. Rapid transmeridian travel induces jet-lag • 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

3. Courtesy of NASA (http://visibleearth.nasa.gov/)

4. The ‘body clock’ or circadian pacemaker is situated in suprachiasmatic nucleus (SCN) of hypothalamus It controls the timing of most 24-hour behavioral and physiological rhythms including the sleep-wake cycle, alertness and performance rhythms, hormone production, temperature regulation, and metabolism. ‘circadian’ - ‘about a day’ http://www.bioon.com/book/biology/whole/html/

5. Cajochen et al. Am J Physiol 1999

6. Onset of myocardial infarction by time of day Peak rate at 9am Muller et al., New Engl J Med 1985 24-hour circadian rhythms in real-world situations: Motor vehicle crashes and heart attacks Fatigue-related fatal crashes by time of day Peak rate at 5am Federal Motor Carrier Safety Administration 2000

7. Evidence for peripheral circadian clocks in most organs Cardiac function • pNN50; % of R-R intervals > 50 msec different from prior interval • Mean R-R interval per 5 mins Hastings et al. Nature Neurosci Rev 2003 Hilton et al Comp Cardiol 2001

8. International business travelers reported • 76% travel-related health problems • 74% have jet-lag • 45% have GIT disorders Rogers & Reilly, 2002

9. Sleep and circadian phase Consolidated sleep can only occur at the correct circadian phase Clock Time (h) 6 12 18 0 6 12 18 0 6 Dijk and Czeisler, J Neurosci 1995

10. Sleep and circadian phase 6-hour advance (Boston to Paris) places sleep in the Wake Maintenance Zone Clock Time (h) 6 12 18 0 6 12 18 0 6 Dijk and Czeisler, J Neurosci 1995

11. Sleep and circadian phase 10-hour delay (Boston to …….) Clock Time (h) 6 12 18 0 6 12 18 0 6 Dijk and Czeisler, J Neurosci 1995

12. 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

13. cognitive deficits • reduced spatial memory • amnesia Cho, Nature Neurosci 2001

14. General criteria for Circadian Rhythm Sleep Disorder International Classification of Sleep Disorders II • 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

15. Jet-lag Type (Jet-lag Disorder) • Diagnostic criteria • 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 • 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

16. 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 asleep They will wake up ‘later’ than you in absolute time Their behaviors are DELAYED relative to you You need to DELAY your clock to adapt to LA Eastward travel requires a phase advance shift People in London (5 h eastward) are having lunch They are eating lunch ‘earlier’ than you in absolute time Their behaviors are ADVANCED relative to you You need to ADVANCE your clock to adapt to London Note: 5 h eastward = 19 h westward

17. Period of the circadian pacemaker in humans Morning Type………….Evening Type Larks……….……………Owls • 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 Mean = 24.2 h Czeisler et al. Science 1999

18. 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 60 DELAYS Mins ADVANCES Czeisler et al. Science 1999

19. Circadian period determines the direction that is easiest to adapt to Larks……….………….Owls Mean = 24.2 h 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 Czeisler et al. Science 1999

20. Baseball teams beaten by jet lag Eastward 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% Recht et al., Nature 1995

21. General criteria for Circadian Rhythm Sleep Disorder International Classification of Sleep Disorders II • There is a persistent or recurrent pattern of sleep disturbance • due primarily to one of the following: • i. Alterations of the circadian timekeeping system • ii. Misalignment between the endogenous circadian rhythm & • exogenous factors that affect the timing or duration of sleep • 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.

22. U.S. Air Carrier Traffic Statistics Slide courtesy of Dr Shantha Rajaratnam

23. 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?

24. 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?

25. Circadian adaptation in oil-rig workers Barnes et al. Neurosci Letts 1998a Barnes et al. Neurosci Letts 1998b

26. Phase Response Curve (PRC) describes the effect of light timing on the magnitude and direction of the circadian phase resetting response Light after ~6:00 am advances the circadian clock (to an earlier time) Increasing advance Increasing delay Light before ~6:00 am delays the circadian clock (to a later time) Adapated from Rajaratnam & Arendt, 2001

27. Requires advance to adapt Light after 6 am INTERNAL time Requires delay to adapt Light before 6 am INTERNAL time Schematic of timing for light treatment of Jet-lag 24 6 12 18 Time (h) Light : Dark (L:D) cycle Normal entrainment Westward flight – sleep later L Eastward flight – sleep earlier L Adapted from Arendt & Skene, Sleep Med Rev, 2005

28. Phase Response Curve (PRC) Melatonin before ~1:00 am causes an advance Light after ~6:00 am causes an advance Increasing advance Increasing delay Melatonin after ~1:00 am causes a delay Light before ~6:00 am causes a delay Adapated from Rajaratnam & Arendt, 2001

29. Requires advance to adapt Light after 6am INTERNAL time Requires delay to adapt Light before 6am INTERNAL time Schematic of timing for light treatment of Jet-lag 24 6 12 18 Time (h) Light : Dark (L:D) cycle Normal entrainment Westward flight – sleep later L M Mel after 1am INTERNAL time Eastward flight – sleep earlier M L Mel before 1am INTERNAL time Adapted from Arendt & Skene, Sleep Med Rev, 2005

30. 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 asleep They will wake up ‘later’ than you in absolute time Their behaviors are DELAYED relative to you You need to DELAY your clock to adapt to LA Eastward travel requires a phase advance shift People in London (5 h eastward) are having lunch They are eating lunch ‘earlier’ than you in absolute time Their behaviors are ADVANCED relative to you You need to ADVANCE your clock to adapt to London Note: 5 h eastward = 19 h westward

31. Sleep Light BOS to LHR Depart 19:00, 7 h flight To adapt eastwards, you need to phase advance (5 h) Depart BOS 19:00 Arrive LHR 7:00 Increasing advance Increasing delay  BOS LHR 2300 0200 0500 0800 1100 1400 1700 2000 2300

32. Light until bedtime Sleep BOS to LHR Depart 19:00, 7 h flight To adapt eastwards, you need to phase advance (5 h) Depart BOS 19:00 Arrive LHR 7:00 Increasing advance Increasing delay BOS LHR 2300 0200 0500 0800 1100 1400 1700 2000 2300

33. Sleep BOS to LHR Depart 19:00, 7 h flight To adapt eastwards, you need to phase advance (5 h) Depart BOS 19:00 Arrive LHR 7:00 Melatonin before ~1:00 am causes an advance Increasing advance Melatonin after ~1:00 am causes a delay Increasing delay Melatonin administration - shifts the circadian clock - facilitates sleep BOS LHR 2300 0200 0500 0800 1100 1400 1700 2000 2300

34. LHR to BOS Depart 15:00, 7 h flight To adapt westwards, you need to phase delay (5 h) Sleep Light Light Depart LHR 15:00 Arrive BOS 17:00 Increasing advance Increasing delay LHR BOS 1300 1600 1900 2200 0100 0400 0700 1000 1300

35. LHR to BOS Depart 15:00, 7 h flight To adapt westwards, you need to phase delay (5 h) Sleep Depart LHR 15:00 Arrive BOS 17:00 Increasing advance Increasing delay LHR BOS 1300 1600 1900 2200 0100 0400 0700 1000 1300

36. Jet-lag travel clinic example #1 New York to Spain

37. Jet-lag travel clinic example #2: Boston to Asia • Caffeine • Naps • Hypnotics / Stimulants • Important target times

38. Courtesy Dr Laura Barger

39. Treatment of pre-mission adaptation for Shuttle Astronauts Slide courtesy of Dr Smith Johnston, NASA

40. Postprandial response during circadian misalignment (28-h day) 4 time zones West per day Scheer et al., PNAS 2009

41. Breast Cancer Risk Factors • 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 Moser et al., Cancer Causes Control 2006

42. 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 • 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 probably carcinogenic to humans (Group 2A)’ WHO International Agency for Research on Cancer Monograph Working Group Straif et al., Lancet Oncol 8, 2007 Filipski et al., Cancer Res 2004 Hastings et al. Nature Neurosci Rev 2003

43. Circadian Disruption and Cancer- Making the Connection New York Academy of Sciences and The Mushett Family Foundation June 9, 2009 http://www.nyas.org/

44. 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

45. www.understandingsleep.org www.sleep.med.harvard.edu

46. Metabolic impact of sleep- and circadian disruption Postprandial response of shift-workers in Antarctica Postprandial response to chronic partial sleep deprivation 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. 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 taken at 1330 h Lund et al., J Endocrinol, 2001 Speigel et al., Lancet 1999

47. RHT How important is the 24-hour light-dark cycle in human circadian regulation? 24.0 h 24.2 h RHT - Retinohypothalamic tract SCN – Suprachiasmatic nuclei Adapted from Arendt, 1995

48. Pineal melatonin response Entrainment by light 30 Daily 24-hour Light-dark cycle 25 20 15 Plasma melatonin (pg/ml)  10 5 0 24-hour light-dark cycle resets the circadian clock on a daily basis 30 25 20 15 10 Neuroanatomy of the circadian system 5 0 22 0 2 4 6 8 10 12 14 16 18 20

49. Pineal melatonin response Pineal melatonin response Total blindness 30 25 20 15 Plasma melatonin (pg/ml) 10 5 0 Tetraplegia (C6 lesion) 30 Circadian period range 23.6 - 25.1 h (Example shown ~24.5 h) 25 20 15 10 Neuroanatomy of the circadian system 5 0 22 0 2 4 6 8 10 12 14 16 18 20

50. Sleep and circadian rhythm disorders in Space Shuttle mission scheduled 23.5 h day STS-90 Dijk et al. Am J Physiol 2001