Sleep, Rhythms and Performance

Transcription

1 Sleep, Rhythms and Performance

2 Conceptual Framework Daytime functioning Individual Light-Dark Cycle Circadian Photoreception Sleep-Wake Cycle Circadian Homeostat Social Factors Genetic variation Biological time Sleep-wake history Modified from: Dijk and Lockley 2002

3 Days Circadian sleep-wake rhythms Natural situations Free running in an isolated situation Sleep wake cycles: Persist in the absence of external 24-hour light dark and social cycles Are generated by an internal circadian clock Entrained to a 24-hour day Sleep episode Wake episode Core body temperature nadir 3 Midnight Noon Midnight Time of day Noon Midnight Aschoff J. Science 1965; 148:

4 Daily variation Physiology of circadian rhythms SLEEP Suprachiasmatic nucleus Hypothalamus Retina Light Time of day (h) Melatonin Cortisol Temperature 20 Optic nerve Signals to the body Pineal gland 4 Abbott A. Nature 2003;425:

5 Circadian rhythms: hierarchical organisation of a multi-oscillator system Principles and Practice of Sleep Medicine, 5 th Edition; Elsevier/Saunders 2010

6 Circadian rhythmicity, spaceflight and performance Microgravity Consequences for Amplitude of circadian rhythms? Altered light-dark cycles Consequences for Phase angle of entrainment? Amplitude of rhythms? Altered sleep-wake cycles Consequences for Performance? Health?

7 Circadian rhythmicity, spaceflight and performance Low Earth orbit periodicity of orbit much shorter than 24-h (~90 min) Ultra-short light-dark cycle consequences for entrainment? rest-activity cycle determined by mission requirements, launch and landing opportunities sleep shifting during mission sleep shifting and circadian adaptation prior to mission

8 Consequences of circadian rhythmicity for spaceflight Interplanetary missions travel to planet no external light-dark cycle which one to choose living on planet non 24-h light-dark cycle on planet (e.g. Mars=24.6) consequences for entrainment: Can we entrain to this day length? What happens to the phase angle between sleep-wake and the LD cycle?

9 Sleep-Wake Schedule on STS90 (Neurolab) Scheduled PSG Actigraphy throughout Dijk et al. Sleep, performance, circadian rhythms, and light-dark cycles during two space shuttle flights. Am J Physiol 2001; 281:R

10 Light-Dark Cycles on STS90 Iluminance (Lux) STS90 FlightDeck Frequency (%) 02:010:018:0 02:010:018:0 02: ScheduledSlep ScheduledWakefulnes Iluminance (Lux) Iluminance (Lux) Mideck Spacelab Frequency (%) 02:0 10:018:002:010:018:0 02:0 Frequency (%) 02:0 10:0 18:0 02:0 10:0 18:0 02:0 04/24/98 04/24/98 04/24/98 04/25/98 04/25/98 04/25/98 04/26/98 Timeof Day(GMT) ScheduledSlep ScheduledSlep ScheduledWakefulnes ScheduledWakefulnes Iluminance(Lux) Dijk et al. Sleep, performance, circadian rhythms, and light-dark cycles during two space shuttle flights. Am J Physiol 2001; 281:R

11 Pharmaceutical use by U.S. astronauts on space shuttle missions. Putcha L, Berens KL, Marshburn TH, Ortega HJ, Billica RD Life Sciences Research Laboratories, NASA-Johnson Space Center, Houston, TX, USA. Aviat Space Environ Med 1999 Jul;70(7):705-8 From the 219 records obtained (each representing one personflight), 94% included some medication being taken during flight; of that number, 47% were for space motion sickness, 45% for sleep disturbances, and smaller percentages for headache, backache, and sinus congestion Drugs for space motion sickness were taken mostly during the first 2 d of flight, drugs for pain during the first 4 d, and drugs for sleeplessness and sinus congestion were taken consistently for 9 flight days.

12 A few ground-based studies Effects of gravity on circadian amplitude Effects of light and sleep schedules on entrainment and amplitude Effects of sleep restriction on performance Individual differences What is happening in space?

13 Feedback of changes in posture and sleep deprivation in dim light (< 13 Lux) on rhythms 6:00 12:00 18:00 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 Day h - SD: Condition 1 or 2 40 h - SD: Condition 1 or 2 Condition 1: Condition 2: Sleep (0.03 lux) Wakefulness (~13 lux) 6:00 12:00 18:00 Time of Day Cajochen, Jewett, Dijk; J Pineal Res, 2003

14 KSS MOOD PP PR ADD DSST PEERS KDT Protocol to assess feedback effects of vigilance state and posture on circadian rhythms Elapsed Time Awake Continuous EEG + ECG 20 min 40 min Cond 1 } Cond 2 MediumTest Long Test Time of Day Long Test Battery KDT: Karolinska Drowsiness Test (4 min eyes open & 1 min eyes closed) PVT 28 Minutes KSS: Karolinska Sleepiness Scale (30s) PP: Probed Recall Memory (Presentation) (30s) PVT: Psychomotor Vigilance (10min) ADD: Calculation Performance Task (4min) DSST: Digit Symbol Substitution Task (2 min) PEERS: Performance Evaluation and Effort Rating Scale (1 min) MOOD: Mood Rating Scale (2 min) Cajochen, Dijk; Unpublished

15 (% of recording time) 100 Relative Clock Time (h) Wakefulness without Slow Eye Movements Feedback: Amplitude of observed circadian rhythms of correlates of sleepiness depends on posture Supine Sitting / Standing Unscheduled Sleep Episodes 4 2 Incidence of Slow Eye Movements during Waking Cajochen, Dijk; Unpublished Elapsed Time Awake (h)

16 More Sleepy 8 Relative Clock Time (h) * * * 6 Feedback: Amplitude of observed circadian rhythms of sleepiness and performance depend on posture * * * Supine * * * * Sitting / Standing Karolinska Sleepiness Scale Psychomotor Vigilance Performance Mean Reaction Time (msec) 20 * * # of Lapses (>500 ms) 10 Cajochen, Dijk; Unpublished Elapsed Time Awake (h)

17 Conclusion I Magnitude of performance deterioration during sleep loss may be exacerbated in the absence of physiological changes associated with postural changes, as is the case in microgravity.

18 Effects of a gradual shift of the sleep-wake cycle, with or without bright light Day 2 Day 9 Dijk et al. Amplitude reduction and phase shifts of melatonin, cortisol and other circadian rhythms after a gradual advance of sleep and light exposure in humans. PLoS One 2012;7(2):e30037

19 Phase shifting 1110v Bright Light 1262v Room Light Day 2 Plasma Melatonin (pmol/l) :00 00:00 12:00 00:00 Day 2 Plasma Melatonin (pmol/l) 12:00 00:00 12:00 00: Advance: 9.0 h Advance: 2.5 h Day 9 CR Plasma Melatonin (pmol\l) :00 00:00 12:00 Clock Time 00:00 Day 9 CR Plasma melatonin (pmol\l) :00 00:00 12:00 Clock Time 00:00 Dijk et al PLoS One 2012

20 Phase shifting Room Light Bright Light 02:00 02:00 Melatonin Onset (Clock Time) 22:00 18:00 14:00 22:00 18:00 14:00 10:00 10: Study Day 2 9 Study Day Dijk et al. PLoS One 2012

21 Room Light Bright Light Subjective Alertness (mm) Hours since start of Constant Routine Plasma Cortisol (ug/dl) Plasma Melatonin (pmol/l) Clock time Core body temperatrue (degrees Celcius) Dijk et al. PLoS One :00 10:00 22:00 10:00 22:00 22:00 10:00 22:00 10:00 22:00 Clock time Clock Time

22 Amplitude reduction 1134v2t2v Bright Light 1141v Room Light Day 2 SP2 Plasma Melatonin (pmol/l) 12:00 00:00 12:00 00:00 12:00 00:00 12:00 00: Day 2 SP2 Plasma Melatonin (pmol/l) Day 9 CR Plasma Melatonin (pmol\l) :00 00:00 12:00 00:00 Clock Time Day 9 CR Plasma melatonin (pmol\l) :00 00:00 12:00 00:00 Clock Time Dijk et al. PLoS One 2012

23 Alertness Subjective Alertness (mm) Cortisol Body temperature Melatonin Dijk et al. PLoS One 2012 Plasma Cortisol (ug/dl) Body Temperature (deviation from mean; C) Plasma Melatonin (pmol/l) Time (Hours relative to nadir of body temperature rhythm)

24 Light: Interim Conclusion conclusion II Non-24 hour sleep and light-dark schedules may lead to Light can be used to accelerate re-entrainment Individual Misalignment differences in reduction in overt circadian amplitude in Inappropriate timing of alertness/performance Melatonin rhythms Body Reduced temperature amplitude Light Cortisol can be used to improve maintenance Alertness of appropriate phase relationships while on non-24-h schedules Individual differences

25 What happens if we don t sleep long enough? (a ground-based study)

26 Sleep Restriction/Extension and Total Sleep Deprivation N = 36 Sleep Extension Day 1 (Adaptation day) Day 2 (Baseline 1) Day 3 (Baseline 2) Day 4 (Extension 1) Day 5 (Extension 2) Day 6 (Extension 3) Day 7 (Extension 4) Day 8 (Extension 5) Day 9 (Extension 6) Day 10 (CR) Day 11 (CR) Session starts 00:00 06:00 12:00 18:00 00:00 06:00 12:00 18:00 00:00 8hr SLEEP 8hr SLEEP 10hr SLEEP 10hr SLEEP 10hr SLEEP 10hr SLEEP 10hr SLEEP 10hr SLEEP 10hr SLEEP 12hr RECOVERY SLEEP Session ends Effects of total sleep deprivation following manipulation of sleep history Sleep Restriction Day 1 (Adaptation day) Day 2 (Baseline 1) Day 3 (Baseline 2) Day 4 (Restriction 1) Day 5 (Restriction 2) Day 6 (Restriction 3) Day 7 (Restriction 4) Day 8 (Restriction 5) Day 9 (Restriction 6) Day 10 (CR) Day 11 (CR) Session starts 8hr SLEEP 8hr SLEEP 6hr SLEEP 6hr SLEEP 6hr SLEEP 6hr SLEEP 6hr SLEEP 6hr SLEEP 6hr SLEEP 12hr RECOVERY SLEEP Session ends

27 We become sleepy KSS score at the beginning of the test battery h KSS score *** *** *** *** *** *** 6 h *** *** 7 8 Constant Routine B D1 D2 D3 D4 D5 D6 D1N1D Day N=36 Sleep extension (10h) Lo et al. PLoS One 2012

28 Poor performance Alertness, Sustained Attention and Working Memory Deteriorate 2 Subjective alertness KSS KSS score at the beginning of the test battery PVT 1/RT of the slowest 10% responses(lsmeans) PVT Sustained attention 1.00 SART A' SART KSS score E *** ** *** *** *** *** *** *** TSD B D1 D2 D3 D4 D5 D6 TD1 TD2 Day TN Working memory Verbal 1-back A' (LSMEANS) PVT speed (ms -1 ) ** *** ** *** ** *** *** *** *** TSD B D1 D2 D3 D4 D5 D6 TD1 TD2 Day TN Sleep extension Verbal (10h) 2-back A' (LSMEANS) Sleep restriction (6h) SART A' * * *** *** *** TSD B D1 D2 D3 D4 D5 D6 TD1 TD2 Day TN Verbal 3-back A' (LSMEANS) Verbal 1-back Verbal 2-back Verbal 3-back Verbal 1-back - A' * ** ** *** Verbal 2-back - A' *** *** Verbal3-back - A' * ** ** 0.7 TSD 0.7 TSD 0.7 TSD B D1 D2 D3 D4 D5 D6 TD1 TD2 Day TN B D1 D2 D3 D4 D5 D6 TD1 TD2 Day TN B D1 D2 D3 D4 D5 D6 TD1 TD2 Day TN Lo et al. PLoS One 2012

29 Lo et al. PLoS One 2012

30 Effect Size of Repeated Partial Sleep Deprivation on Alertness, Sustained Attention and Working Memory Sleep restriction B D1 D2 D3 D4 D5 D6 TD1 TN1 TD2 Effect size (f 2 ) of chronic (condition effect on D5 and D6 combined) Control B D1 D2 D3 D4 D5 D6 TD1 TN1 TD2 Implied effect size (Cohen, 1988; van Dongen, Maislin, & Kerkhof, 2001) f Subjective Sustained alertness attention Working memory Large Medium 0.1 Small 0.0 KSS PVT speed SART A' Task V1-bk A' V2-bk A' V3-bk A' Lo et al. PLoS One 2012

31 Effect size of acute total sleep deprivation on performance Sleep restriction B D1 D2 D3 D4 D5 D6 TD1 TN1 TD2 Effect size (f 2 ) of (CRD1 vs CRN1) Control f B D1 D2 D3 D4 D5 D6 TD1 TN1 TD2 Subjective Sustained alertness attention KSS PVT speed SART A' Task V1-bk A' Working memory V2-bk A' V3-bk A' Large Lo et al. PLoS One 2012

32 Conclusion (III) Effects of partial sleep deprivation and acute total sleep deprivation on cognitive domains Many statistically significant effects Large effect on sleepiness, subjective effort and sustained attention Smaller (but still considerable) effects on working memory Working memory tasks with a high executive load do not suffer more No qualitative difference between partial and total sleep deprivation

33 What happens in space?

34 Actigraphic recording of sleep in space Dijk et al. Fig 2 Dijk et al. Sleep, performance, circadian rhythms, and light-dark cycles during two space shuttle flights. Am J Physiol 2001; 281:R

35 Polysomnography in Space John Glenn during a space mission in 1998

36 Sleep Timing and Duration Flight Day SlepOnset (relativetoscheduledbedtime) (min) (relativetoscheduledwaketime) SlepOfset (min) 8.0 SPT 7.0 SlepDuration (h) TST Flight Day Dijk et al. Fig 6 Dijk et al. Sleep, performance, circadian rhythms, and light-dark cycles during two space shuttle flights. Am J Physiol 2001; 281:R

37 REM sleep Inflight Postflight REMSlep (%of TST) Early Flight Late Flight Night-2Night-4Night-5 80 REMLatency (minutes) Early Flight Late Flight Night-2Night-4Night-5 Dijk et al. Sleep, performance, circadian rhythms, and light-dark cycles during two space shuttle flights. Am J Physiol 2001; 281:R

38 slep slep 1.0 Cortisol (microgram/min) secretion 0.5 Preflight 0.0 slep slep Cortisol (microgram/min) secretion slep slep Earlyflight Changes in Cortisol Rhythms 1.0 Cortisol (microgram/min) secretion 0.5 Lateflight 0.0 slep slep 1.0 Cortisol (microgram/min) secretion Time (Hourssincestart of first slepepisode) Postflight n=4 Dijk et al. Sleep, performance, circadian rhythms, and light-dark cycles during two space shuttle flights. Am J Physiol 2001; 281:R Dijk et al. Fig11

39 djd 4 Preflight-60 Preflight-30Preflight-7Early-flightLate-flight Postflight-1 Postflight-2Postflight-3 Number (RepsonseTime of Lapses >50ms) ReactionTime (Median;ms) PVT PVT Changes Performance 5 PRM Number of WordsRecaled Recal Time (s) PRM Preflight-60 Preflight-30Preflight-7Early-flightLate-flight Postflight-1 Postflight-2Postflight-3 Dijk et al. Fig 7 Dijk et al. Sleep, performance, circadian rhythms, and light-dark cycles during two space shuttle flights. Am J Physiol 2001; 281:R cog

40 Conclusion: low orbit Changes in sleep, circadian rhythms and performance Related to low light and non-24-h sleep-wake cycles

41

42 Basner et al. Non-24 h rest-activity

43 Individual differences in circadian period Predictor of Sleep timing? Sleep quality? Diurnal preference? Social jet lag?

44 In vivo period predicts melatonin phase Hasan et al. FASEB 2012 Timing of melatonin onset relative to bed time (h) In vivo Circadian period (h) n = 31 r s = p =

45 In vivo circadian period correlates with the increase in sleep during free days Increase in time in bed during free days (h) n=31 r s =0.5 p=0.002 Lazar et al. under review 2012 Circadian Period (h)

46 Consideration of Conclusions circadian rhythmicity sleep homeostasis in operational environments may prevent performance decrements Individual circadian characteristics may predict adaptation to particular environmental conditions.

47 Acknowledgements June Lo John Groeger Simon Archer Alpar Lazar Nayantara Santhi Malcolm von Schantz Sibah Hasan Antoine Viola Elizabeth Klerman Gilles Vandewalle Pierre Maquet Jon Johnston Clinical Research Centre Statisticians Sig Johnsen Patrick McGabe Nurses Research Physicians Research Staff

48

49 Sleep in Space Sleep duration in space: 5-6 hours Sleep duration on the ground: 7-8 hours Sleep loss: mission 2 hours per day 32 hours on a 16 day Santy et al. Aviat Space Environ Med 1988; 59:

50 Brain disorders cost Europe almost 800 billion (US$1 trillion) a year more than cancer, cardiovascular disease and diabetes put together 1 Since then, Bulgaria and Romania have joined the European Union and seven more categories of disorder have been added to the assessment, including eating disorders, sleep disorders, mental retardation, and childhood and developmental disorders such as autism Smith, Nature 478, 15;2011

51 What happens in space?

52 ScheduledLightsOut ScheduledLightsOn 10 Flight Deck Flight Deck Iluminance(Lux) Mideck TimeIntoScheduledSlepEpisode (Minutes) Mideck 10 Iluminance(Lux) TimeIntoScheduledWakeEpisode (Minutes) Dijk et al. Fig 9

53 Individual differences in circadian period Plasma melatonin Fibroblasts In vivo 14 In vitro Number of individuals Number of individuals Circadian period (h) Circadian period Hasan et al. FASEB 2012

54 37.5 Sp1 L-60 Sp2 BodyTemperature (Celsius) :0 06:0 12:0 18:0 0:0 06:0 12:0 2/4/98 2/5/98 EarlyFlight 37.5 Sp5 Sp6 BodyTemperature (Celsius) :0 06:0 12:0 18:0 0:0 06:0 12:0 4/2/98 4/23/ Sp14 LateFlight Sp15 BodyTemperature (Celsius) :0 06:0 12:0 18:0 0:0 06:0 12:0 5/1/98 5/2/98 Dijk et al. Fig10 Timeof Day(GMT)

55 A market for developing novel sleep/wake compounds Abbott, Nature 2011

56 A need to better understand sleep, waking performance & their interdependencies

57 Why do we sleep so late? 50 Percentage of total number of observations Percentage of total number of observations Week Days Weekend Get-up times (hours) Modified from Groeger et al. J Sleep Res 2004

58 How much sleep do I get? How much sleep do I need? Percentage of total number of observations 35 Men Women Average (men & women): h; SD 1.55 h Sleep duration (hours) Groeger, Zijlstra and Dijk; J Sleep Res 2004; 13:

59 Protocol to assess circadian characteristics 1. Assessment of habitual sleep-wake timing 2. N=36, 19 F; y 3. Biopsy 4. Forced desynchrony with plasma melatonin sampling Hasan et al. FASEB 2012

60 Synchronization by light Effects of light on the circadian clock depend on time of day Light in the morning Advances the clock Light in the evening delays the clock If period > 24 h: need to see morning light If period < 24 h: need to see evening light

61 Month Annual Pattern of Timing of Dawn, Day, Dusk, Night in Manchester Bedtime Waketime Local Time 80%; 65%; Groeger, Zijlstra,Dijk, J Sleep Res 2004

62 Circadian Regulation of Human Sleep Why Do We Sleep So Late? Thursday, 6 December 2012

63 Before the advent of artificial light, the rotation of the Earth dictated light and darkness, and the timing of our biological clocks,

64 Does artificial light at night influence our circadian and sleep physiology?

65 Light exposure 'at home' Wake time Bedtime Dawn Dusk 100 SLEEP WAKE SLEEP WAKE Irradiance ( w/cm 2 ) :00 12:00 00:00 12:00 00:00 Clock Time Blue Green Red Dawn Dusk Santhi et al, 2011;J Pineal Research N=22 (male=15) aged ± 4.67

66 Artificial light of an intensity we are exposed to at home suppresses melatonin 4 Hrs 8 Hrs Polysomnography LIGHT EXPOSURE SLEEP Relative Clock Time Irradiance ( w/cm 2 ) Home Near-Darkness Blue-Depleted Blue-Intermediate Santhi et al, 2011; J Pineal Research Blue-Enhanced Bright Blue-Enhanced Melatonin Concentration (pg/ml) Bed 19:30 20:30 21:30 22:30 23:30 Time Time Relative to Bed Time (minutes) N=

67 Why does this matter?

68 Role of melatonin in sleep regulation (in dim light) Day 1 Day 6 Clock time (h) h S-W Cycle Sleep episode Day 11 Melatonin Day 16 Day 21 Modified from Dijk DJ, Duffy JF. Ann Med 1999; 31 (2):

69 Circadian rhythm of sleep propensity associates with melatonin rhythm wake maintenance zone 40 CORRESPONDING TIME OF DAY WAKEFULNESS IN SLEEP EPISODES (% OF RT) 20 PLASMA MELATONIN (Z-SCORES) sleep opening of sleep gate CIRCADIAN PHASE (degrees) 0 degrees = melatonin maximum Modified from Dijk et al. J Physiol 1997

70 Circadian Mechanisms: Effects of melatonin on sleep in an extended sleep opportunity protocol Treatment time Study day W W (<300lux) W (<300lux) W (<300lux) W (<300lux) W (<300lux) W (<300lux) W (<300lux) W (<300lux) W W (<300lux) Sleep (<5 lux) CR No 1 (< 5 lux) Sleep (<5 lux) Sleep (<5 lux) Sleep (<5 lux) Sleep (<5 lux) Sleep (<5 lux) Sleep (<5 lux) Sleep (<5 lux) Sleep (<5 lux) Sleep (<5 lux) CR No 2 (< 5 lux) Sleep (<5 lux) W (<300lux) W (<300lux) W (<300lux) W (<300lux) W (<300lux) W (<300lux) W (<300lux) W (<300lux) mel/plac mel/plac mel/plac mel/plac mel/plac mel/plac mel/plac mel/plac plac Plasma melatonin (pg/ml) 1000 Melatonin Placebo Clock time (h) Clock time (h) 78 Rajaratnam, Dijk, Middleton, Stone, Arendt; J Clin Endocr Metab 2003

71 Melatonin induces sleep PLACEBO CONDITION MELATONIN CONDITION Baseline CR1 Rec1/Placebo Placebo Placebo Placebo Placebo Placebo Placebo Placebo Placebo CR2 Rec2 Study day Clock time (h) Time into sleep episode (h) Clock time (h) Time into sleep episode (h) Baseline CR1 Rec1/Melatonin Melatonin Melatonin Melatonin Melatonin Melatonin Melatonin Melatonin Placebo CR2 Rec2 Sleep efficiency (%) Rajaratnam, Middleton, Stone, Arendt, Dijk; J Physiol 2004

72 Melatonin advances circadian rhythms PLACEBO CONDITION MELATONIN CONDITION Plasma melatonin (pg/ml) Post-treatment Pre-treatment 20 Plasma cortisol (nmol/l) Core body temperature ( o 37.0 C) Clock time (hr) Rajaratnam et al 2003

73 Artificial light of an intensity we are exposed to at home suppresses melatonin 4 Hrs 8 Hrs Polysomnography LIGHT EXPOSURE SLEEP Relative Clock Time Irradiance ( w/cm 2 ) Home Near-Darkness Blue-Depleted Blue-Intermediate Santhi et al, 2011; J Pineal Research Blue-Enhanced Bright Blue-Enhanced Melatonin Concentration (pg/ml) Bed 19:30 20:30 21:30 22:30 23:30 Time Time Relative to Bed Time (minutes) N=

74 Light in the evening reduces subjective sleepiness Sleepy 7 Relative Clock Time 19:30 20:30 21:30 22:30 23:30 Bed Time Subjective Sleepiness Near-Darkness Blue-Depleted Blue-Intermediate Blue-Enhanced Bright Blue-Enhanced Alert Time Relative to Bed Time (minutes)

75 and delays polysomnographically assessed sleep onset Near-Darkness (1) Blue-Depleted (2) Blue-Intermediate (3) Blue-Enhanced (4) Bright Blue-Enhanced (5) N=20-22 Santhi et al, 2012; J Pineal Research

76 Lo et al. PlosOne 2012 In addition: Sleep restriction delays the clock Timing of Melatonin Onset: After 10 h TIB: 23:28 ± 00:15 After 6 h TIB 00:13 ± 00:15 Difference= 45 minutes n=36, P <

77 But We still have to get up in the morning to Go to work Bring the children to school Go to school Sleep restriction Negative health consequences

78 Is there nothing positive to be said about (artificial) light?

79 Light Image forming effects: vision Non-image forming effects: Alters timing of biological rhythms Exerts direct effects on physiology and behaviour Spectral Sensitivity

80 Light as a modulator of cognitive brain function. Vandewalle, Maquet, Dijk Trends in Cognitive Sciences, Vol 13 no 10; 2009 Gilles Vandewalle Pierre Maquet Imaging PET fmri Light Performance and Cognition During the Night During the Day

81 Brain mechanisms involved in the lightinduced non-visual modulation of cognitive responses Response at light onset Early response within 10 sec Late response during or after prolonged exposure (16-20 min) Light as a modulator of cognitive brain function. Vandewalle, Maquet, Dijk. 2009

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83 Participants 104 Healthy volunteers, aged were recruited through a presentation of the protocol to all RS Components employees working on two floors (3 and 4). 96 volunteers completed the full study RS Components, Corby, UK

84 Hypothesis The alertness and performance of workers will be improved following exposure to 17000K (blue-enriched light), compared to 4000K (white light) 17000K 4000K

85 Effect of blue-enriched light on sleepiness in the workplace 5.5 Week 1 Week 2 Week 3 Week Sleepiness morning 1 lunch 1 evening1 morning2 lunch2 evening2 morning3 lunch3 evening3 morning4 lunch4 evening4 Viola et al. Scand J Work Environ Health. 2008

86 Effect of blue-enriched light on sleep quality, and self-reported daytime functioning < < White light Blue-light Increase Baseline 0.14 Sleep Quality Alertness Fatigue Performance Viola et al. Scand J Work Environ Health Blue light vs. White light comparison

87 Light Circadian phase shifting and 'direct' effects of light may be used to improve wakefulness and sleep Avoid light in the evening if you find it difficult to wake up in the morning

88 Back to Sleep

89 Why do some of us sleep even later? 50 Percentage of total number of observations Percentage of total number of observations Week Days Weekend Get-up times (hours) Modified from Groeger et al. J Sleep Res 2004

90 Stable individual differences in the response to 'room' light Melatonin AUC in Blue-Intermediate I (% of Near-Darkness AUC) sensitive insensitive r = Melatonin AUC in Blue-Intermediate II (% of Near-Darkness AUC) Santhi et al, 2012; J Pineal Research Intra-class correlation coefficient= 0.44

91 Melatonin phase predicts latency to sleep onset when sleeping at habitual time Latency to persistent sleep (min) n=34 r s =0.48 P= Timing of melatonin onset relative to bedtime (h) Lazar et al. under review 2012

92 In vivo circadian period correlates with diurnal preference (Horne-Ostberg) Morningness-Eveningness score 86 'evening type' 'neither' 'morning type' 16 In vivo n = 31 r s = p = Circadian period (h) Hasan et al. FASEB 2012

93 Conclusion(II) Individual differences in circadian period correlate with Diurnal preference Sleep quality Melatonin phase PSG assessed sleep latency when sleeping at habitual times Change in sleep from weekdays to weekend

94 Variation in sleep timing: Morning and evening types Percentage of total number of observations Percentage of total number of observations Week Days Sleep Survey (Surrey Sleep Research Centre) Weekend Get-up times (hours)

95 PER3 VNTR genotype is associated with diurnal preference Genotype Frequency - Percent of total 20% M I E D 14 PER3 5/5 20% M I E 20 M I E % % % 0 0% 0 60% 40% PER3 4/5 7 60% 40% % 20% 20 0% 0% 0 80% 60% 40% PER3 4/4 80% 60% 40% % 20% 20 0% M I E D N=80 N=80 N=80 N=23 Total = 1590 (extremes selected) 0% M I E N=58 N=58 N=40 Total = 1089 (extremes selected) 0 M I E N=208 N=227 N=228 Total = 663 (all genotyped) Archer et al., 2003 Jones et al., 2007 Pereira et al., 2005 Lazar et al., 2012

96 PER3 VNTR also predicts reported sleep-wake timing in ~675 healthy men and women aged Genotypes * * * * * * * * * * * Bedtime Midpoint of sleep Wakeup time 23:15 23:30 23:45 00:00 03:45 04:00 04:15 08:00 08:15 08:30 Clock time (hours:minutes) PER3 4/4 PER3 4/5 PER3 5/5 Lazar et al. Chronobiology International, 2012

97 Conceptual Framework Daytime functioning Individual Light-Dark Cycle Circadian Photoreception Sleep-Wake Cycle Circadian Homeostat Social Factors Genetic variation Biological time Sleep-wake history Modified from: Dijk and Lockley 2002

98 Sleep Homeostasis

99 Short sleeper How much sleep do we need? Long sleeper 2080S HBD:6.1 hours 2059S HBD:10.0 hours MSLT MSLT 12 h 4 h Open boxes: outpatient self report Closed boxes: inpatient scheduled Klerman and Dijk, Unpublished Figure

100 Are we sleep deprived? N=17/10F; (mean 21.8) Total Sleep Time per 24 h (hours) h Baseline Extended Sleep Opportunity Day Klerman and Dijk SLEEP 2005

101 Shorter habitual sleep duration: Higher sleep propensity during daytime Multiple Sleep Latency Test (Minutes; median) Habitual Sleep Duration (Hours) Klerman and Dijk SLEEP 2005

102 Age-related reduction in the maximal capacity for sleep N=18 N= h (0.4)** 7.4 h (0.4) 2.1 h (0.1)*** 1.3 h( 0.1) 6.7 h (0.4) 6.1 h (0.3) Klerman and Dijk, Current Biology 2008

103 Age-related reduction in daytime sleep propensity 20 YOUNG: (20-30y) n=41 16 MIDDLE-AGED: (40-55y) n=31 ** OLDER: (66-83y) n=31 Sleep 12 Latency (mins) ** Young Middle-aged Elderly More Sleepy 8 4 ** *** * *** ** *** * ** 09:00 11:00 13:00 15:00 17:00 *** *** Time of Day Dijk et al Sleep 2010

104 Sleep duration, sleep need and ageing Recommended sleep duration (after controlling for age) Long Long Debt Short Young Age Older Short

105 Plasma melatonin (pg / ml) Sleep stages Spindle Activity Slow-Wave Activity Sleep Phenomenology Lights on Lights off NREM 4 NREM 3 NREM 2 NREM 1 Wake REM :00 00:00 03:00 06:00 09:00 11:00 Time of the day

106 SWA (%) Sleep-Wake Induced Changes in SWA: A Marker of Sleep Homeostasis and Regulator of Synaptic Homeostasis? Nocturnal sleep Daytime naps Time of day (h) Sleep (h) Wakefulness (h) increase in synaptic strength W decrease in synaptic strength S Dijk D-J. Behav Brain Res 1995;69: Tononi and Cirelli.Sleep Med Rev :49-62.

107 What happens if I don t get enough deep sleep?

108 Baseline SWS/SWA Deprivation and Recovery R0010 N-1 (Baseline) R0010 N 1 (SWS disruption) R0010 N 2 (SWS disruption) R0010 N 3 (Recovery)

109 Effects of two nights of SWS deprivation on sleepiness (and performance) Main comparison: Baseline (D-1) vs. D2 Time in Bed: 8 hours for 1 week prior to laboratory study (actigraphically verified) 5 Assessments per day Sleepiness and performance assessment at: 1,3,5,7, 9 h after lights on Sleep Latency Test at: 2,4,6,8,10 h after lights on 44 young subjects (21 men and 23 women), aged middle-aged subjects (15 men and 20 women), aged older subjects, (6 men and 25 women), aged 65 and over The PPS set (n=110) was used for the statistical analyses

110 Mean (units) Increased subjective sleepiness (Karolinska Sleepiness Scale) Increased sleepiness (on a 9 point scale) 5 Profile During Study 1.50 D2: Change From Baseline *** 1.00 *** D-1 D1 D2 D3 Day Control SWS/SWA Deprivation 0.00 Control SWS/SWA Deprivation Con.Est.: 0.65 Value of Cohen's d: 0.80 Dijk et al. Sleep. 2010;33:

111 Increased daytime sleep propensity following SWS disruption Sleep Latency (min) SWS disruption Control 6 *** *** C vs. D B D1 D2 R Day Dijk et al. Sleep. 2010;33:

112 More errors of commission, worse attention modulated motion sensitivity, motor tracking Day 2: Change From Baseline SART:EOC CFF: Mean Descending (Hz) MTT - Root Mean-Squared Euclidean Error Cohen's * d: 0.39 SWS leads to fewer errors ** Cohen's d: SWS enhances flicker-fusion discrimination Cohen's d: 0.41 * SWS leads to more accurate tracking Mean +/- SD Groeger et al. SLEEP 2007; 30:A134 Control SWS/SWA Deprivation SART:EOC - sustained/divided attention where non targets responded to when should not CFF: Mean descending - Attention modulated motion sensitivity? Discriminate flicker from fusion MTT: Deviation from tracking a moving target

113 Sleep latency Tiredness Quality Energy Refreshed Function Relaxed Sleepiness Mean positive affect Mean negative affect Sedation Co-ordination Depression Anxiety Mean descending Median Mean ascending Errors of commission Errors of omission Number attempted Percentage correct Slow eye movements Theta power/low alpha freq. Mean distance error Mean deviation Peripheral response time SEQUENCE (PRE) RANDOM SEQUENCE (POST) PRE-Post RAN-Pre Number incorrect Number of unique correct Accuracy Number correct 1 Back accuracy 2 Back accuracy 1 Back accuracy 2 Back accuracy Mean recognition time Mean motor transport time Mean motor transport time Mean recognition time Non-word prime difference Non-word non-prime difference Prime non-prime word difference Absolute Value of Cohen's d Sizing the effect of SWS disruption Absolute Cohen's d (contrast between treatments, D2 - D-1, baseline as co-variate, D1 and D2 in model) SLEEPINESS MOOD SUSTAINED MOTOR EXEC. WORK DECISION SLEEPINESS ATTENTION CONTROL FUNCT. MEM. TIME MSLT * + Multiple Sleep Latency Test * + * + E-diary + + PANAS KSS * + * Line Analogue Rating Scales CFF * * Sustained Attention Resp. Task Digital Symbol Substitution Karolinska Drowsiness Test large medium small Pursuit Motor Tracking Continuous Tracking Serial Reaction Task Verbal Fluency Task Paced Visual Serial Addition Task Goal Neglect Task Spatial N-Back Tasks Verbal N-Back Tasks Simple Reaction Time Task Choice Reaction Time Lexical Decision Time 0.0 Groeger et al. SLEEP 2007; 30:A134 * = Significance with 5% expected false discovery rate (JRSSB, 57, pp ) + = unadjusted p-value <0.05 Underlined measures show detrimental effect of SWS/SWA deprivation (simple difference) 8

114 Outline The past Kleitman and Cognitive Chronobiology Circadian and Homeostatic Regulation of Performance (Forced desynchrony) P= f(c,h) Today Repeated Partial Sleep Deprivation Acute Total Sleep Deprivation Effects across cognitive domains Interaction with circadian phase Effect of genotype Conclusion Outlook

115 Poor performance Interaction of Sleep History and Circadian Phase 10 h 6 h KSS score Subjective alertness KSS1 (LSMEANS; N = 36) Relative clock time (hr) ** *** * * *** *** Hours relative to DLMO D Working memory Verbal 1-back - A' * Melatonin (z) PVT speed (ms -1 ) PVT Sustained attention SART PVT slowest 10% (LSMEANS; N = 36) Relative clock time (hr) *** *** ** * Hours relative to DLMO Verbal 1-back Verbal 2-back Verbal 3-back Verbal 1-back A' (LSMEANS; N = 36) Relative clock time (hr) * * ** Hours relative to DLMO Melatonin (z) Verbal 2-back - A' *** * ** *** Verbal 2-back A' (LSMEANS; N = 36) Relative clock time (hr) ** *** Hours relative to DLMO * * ** Melatonin (z) Melatonin (z) SART A' Verbal 3-back - A' SART A' (LSMEANS; N = 36) Relative clock time (hr) ** ** *** ** ** *** Hours relative to DLMO Verbal 3-back A' (LSMEANS; N = 36) Relative clock time (hr) * ** Hours relative to DLMO Melatonin (z) Melatonin (z) Lo et al. PLoS One 2012

116 Interaction of Sleep History and Effect size (f 2 ) of condition averaged across kss1, pvt slowest 10%, sart a', verbal nbk A' during CR f Circadian Phase Relative clock time Large Medium Small Hours relative to DLMO Melatonin (z) Lo et al. PLoS One 2012

117 Wake Maintenance Zone and the Melatonin Rhythm wake maintenance zone 40 CORRESPONDING TIME OF DAY WAKEFULNESS IN SLEEP EPISODES (% OF RT) 20 PLASMA MELATONIN (Z-SCORES) sleep opening of sleep gate CIRCADIAN PHASE (degrees) 0 degrees = melatonin maximum Modified from Dijk et al. J Physiol 1997

118 Circadian Rescue and Neglect Effect and size in the (f 2 ) of morning condition averaged across kss1, pvt slowest 10%, sart a', verbal nbk A' during CR f vulnerable at night Relative clock time Large Medium Small Hours relative to DLMO Melatonin (z) resilience during wake maintenance zone Lo et al. PLoS One 2012

119 Outline The past Kleitman and Cognitive Chronobiology Circadian and Homeostatic Regulation of Performance (Forced desynchrony) P= f(c,h) Today Repeated Partial Sleep Deprivation Acute Total Sleep Deprivation Effects across cognitive domains Interaction with circadian phase Effect of PER3 VNTR genotype Conclusion Outlook

120 PER3 VNTR Genotype Effects on Sleepiness 2 10 h PER3 4/4 KSS score * ** * 6 h *** *** CR B D1 D2 D3 D4 D5 D6 D1N1D Day PER3 4/5 * Genotype* Condition:p<0.001 CR B D1 D2 D3 D4 D5 D6 D1N1D Day 2 PER3 5/5 ** ** *** *** *** *** *** CR B D1 D2 D3 D4 D5 D6 D1N1D KSS score 3 Day Lo et al. PLoS One 2012

121 Effect of PER 3 VNTR on Performance during Repeated Partial Sleep Deprivation Sleep B D1 D2 D3 D4 D5 D6 TD1 TN1 TD2 Effect size (f 2 restriction ) of genotype*chronic (condition effect on D5 and D6 combined) Control B D1 D2 D3 D4 D5 D6 TD1 TN1 TD Subjective alertness Sustained attention Working memory Small f KSS PVT speed SART A' Task V1-bk A' V2-bk A' V3-bk A' Lo et al. PLoS One 2012

122 Larger Effect of PER3 VNTR on Working Memory during Total Sleep Deprivation B D1 D2 D3 D4 D5 D6 TD1 TN1 TD2 Sleep restriction Control B D1 D2 D3 D4 D5 D6 TD1 TN1 TD2 Effect size (f 2 ) of genotype*acute sleep loss (CRD1 vs CRD2) 0.05 Subjective Sustained alertness attention Working memory 0.04 Small 0.03 f KSS PVT speed SART A' Task V1-bk A' V2-bk A' V3-bk A' Lo et al. PLoS One 2012

123 Effect size (f ) of genotype*condition interaction during CR Relative clock time KSS1 KSS2 KSS2 - KSS1 PVT median RT PVT SD RT PVT (slowest 10%) PVT (fastest 10%) PVT (lapses) SART miss SART false alarm SART A' Verbal 1-back A' Spatial 1-back A' Pictorial 1-back A' Integrated 1-back A' Verbal 2-back A' Spatial 2-back A' Pictorial 2-back A' Integrated 2-back A' Verbal 3-back A' Verbal 1-back B" D Spatial 1-back B" D Pictorial 1-back B" D Integrated 1-back B" D Verbal 2-back B" D Spatial 2-back B" D Pictorial 2-back B" D Integrated 2-back B" D Verbal 3-back B" D Verbal 1-back demand30 Verbal 2-back demand31 Verbal 3-back demand32 Verbal 1-back mental effort 33 Verbal 2-back mental effort 34 Verbal 3-back mental effort 35 Verbal 1-back physical effort 36 Verbal 2-back physical effort 37 Verbal 3-back physical effort 38 Verbal 1-back energy 39 Verbal 2-back energy 40 Verbal 3-back energy 41 FIR median RT 42 FIR SD RT 43 RIR median RT 44 RIR SD RT 45 RIR-FIR median RT 46 RIR-FIR SD RT 47 PTT median ED 48 PTT SD ED 49 PTT time on target (1 0 ) 50 PANAS positive PANAS negative Hours relative to DLMO Interaction of Genotype, f f f f f f f f f f f f f 0. 6 Sleep History and Circadian Phase Effect size (f 2 ) of genotype*condition interaction averaged across all tasks (52 variables) during CR f Relative clock time Small Hours relative to DLMO Melatonin (z) Lo et al. PLoS One 2012

124 Conclusion II Effects of PER3 VNTR Small compared to the effects of acute total sleep deprivation Largest for subjective sleepiness working memory task with a high executive load Largest genotype effects in the morning hours when sleep pressure is high Small effects during wake maintenance zone

125 Conclusion III Effects of sleep history on cognitive performance during subsequent total sleep deprivation depend on cognitive domain circadian phase genotype Large effects on sleepiness, subjective effort and sustained attention Remarkable resilience during wake maintenance zone (circadian rescue) Large effects during the morning (circadian neglect) Large divergence between tasks and genotypes in the morning when sleep pressure is high

126 Outlook Implications for shift work? Brain basis of effects Wake maintenance zone; cognitive rescue? Sleepiness, Effort Why are working memory tasks with a high executive load not more affected by sleep loss? PER3 VNTR genotype?

127 Acknowledgements June Lo John Groeger Simon Archer Alpar Lazar Nayantara Santhi Malcolm von Schantz Sibah Hasan Antoine Viola Elizabeth Klerman Gilles Vandewalle Pierre Maquet Jon Johnston Clinical Research Centre Statisticians Sig Johnsen Patrick McGabe Nurses Research Physicians Research Staff

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131 SWA (μv 2 ) Regulation of Sleep: Homeostasis (I) Time course of SWA during baseline sleep and recovery sleep following sleep deprivation in human and rat Baseline Recovery from sleep deprivation Human a W N R Rat b W N R Time since sleep onset (h) a 36-h sleep deprivation (data from a single male subject) b 24-h sleep deprivation Dijk D-J, et al. Am J Physiol 1990;258:R Franken P, et al. Am J Physiol 1995;269:R

132 Sleep latency (min) SWA (%) Sleep homeostasis: Reduced sleep propensity and SWA after a nap in the early evening B N+P Baseline Post-nap Sleep N P B=Baseline N=Nap P=Post-nap N+P=Sum of Nap plus Post-nap a Wakefulness NonREM REM Study in 9 healthy male volunteers a Time course of SWA and vigilance states from a single volunteer Time of day (h) Werth E, et al. Am J Physiol Regulatory Integrative Comp Physiol 1996;271:

133 To cover The basics Circadian rhythms and homeostasis Light and entrainment Light and cognition Plos One Why do we sleep so late? What happens if we don t get enough? Or reduce SWS Ageing