Effects of Light on Human Circadian Rhythms, Sleep and Cognition

Effects of light on human circadian rhythms, sleep and cognition

Christian Cajochen

Centre for Chronobiology Psychiatric Hospital of the University of Basel Basel, Switzerland

17.12.2014, Tel Aviv, Israel «Light impacts on our circadian rhythms more powerfully than any drug»

Charles Czeisler «Casting light on sleep deficiency» Nature, 2013 Light effects on human circadian rhythms

Phase & Tau

Light on circadian rhythms Amplitude

Width Light and circadian phase

Induction of a Phase Delay (3.6 h) in the Human Circadian Melatonin Rhythm by Light (10’000 lux for 6.5 h)

Midpoint Midpoint 4:45 8:21

400

Light /L)

300 pMol

200

100 Plasma Melatonin ( Melatonin Plasma 0 12 24 12 24 12 24 12 24 12 Time of Day

Khalsa et al., J Physiol (London) 2003 Light and circadian amplitude

Progressive Amplitude Attenuation and Loss of Melatonin Rhythm in Response to a three-cycle Light Stimulus (9500 lux)

Subject #1238 300

200 ~ 32 h

)

100 /L

0 pMol

0:00 0:00 0:00 0:00 0:00 0:00 0:00 0:00 Time of Day (h) Shanahan et al., J Biol Rhythms, 1999

Subject #1757 250

200 Plasma Melatonin ( Melatonin Plasma 150 ~ 55 h 100

0:00 0:00 0:00 0:00 0:00 0:00 0:00 0:00 Time of Day (h) Khalsa et al., unpublished Light and circadian width

Hormone Secretion during Continuous Wakefulness after Chronic Exposure to Short and Long Photoperiods

60 16 50 40 12

30 8 Short Photoperiod 20

4 8 light/14 h dark 10

/ml) 0 0 (Winter) pg 18 8 18 8 18 8 18 8

60 50 16 12 40 Long Photoperiod 30 CortisolPlasma(µg/dl) 8 Plasma Melatonin ( Melatonin Plasma 20 8 light/14 h dark 4 10 (Summer) 0 0 24 8 24 8 24 8 24 8 Time of Day (h) Time of Day (h)

According to Wehr, Horm Res., 1998 Light has also «non-circadian» acute effects

• Light suppresses the soporific hormone melatonin within minutes (Lewy et al., 1985)

• Light inhibits sleep-promoting GABA neurons in the ventrolateral preoptic area in the hypothalamus (VLPO, Tsai et al., 2009)

• Light activates wake-promoting orexin neurons in the lateral hypothalamus (McGregor et al., 2011) New Photoreceptor (Melanopsin) SCN (circadian Pacemaker)

Eye

Rods

Retina Cones

Provencio et al., 2000, Hattar et al., 2002, Hannibal et al., 2004

Only ca. 1% of the ganglion cells express melanopsin and are photosensitive Acute sleep induction by light in nocturnal mice

Lights ON Lights OFF 60

Wildtype

Melanopsin aDTA

Response (min) Response

Sleep

0 0 1 2 3 Time elapsed from light onset (h)

According to Muindi et al., Front Syst Neurosci, 2014 Dose response relationship of the alerting action of light

Subjective Alertness

more alert more 15

120 lux !

10 100 1000 10000 Illuminance (lux) Cajochen et al., Beh Brain Res. 2000 Xenon Lamp 300 W

Non-Visual

Color Vision Filters: 460 nm (10 nm half bandwith) 550 nm (10 nm half bandwith)

12.1 mW/cm2 for 460 nm

10.05 mW/cm2 for 550 nm Superiority of Short-wavelength Light on Human Physiology Melatonin PER2 Expression

* 0.8 16 No-Light (0 lux) 550 nm 460 nm

0.4

pg/ml * DD DD Ct

0.0

8 -0.4

Subjective Sleepiness Slow Wave Sleep (Stage4)

* * 8 % of Total Sleep TimeSleep % Total of

6 6 Karolinska Sleepiness Scale (KSS) Scale Sleepiness Karolinska

Cajochen et al., J End Clin Metab. 2005, Eur J Neurosci. 2006, Münch et al., Am J Physiol. 2006

Karolinska Sleepiness Scale (KSS) 8 6 7

Monochromatic The alerting

light

response % Sleepiness Change 0 = pre-light 10 20 30 40 50 Energy 0

Saving

light Book chapter, Book Springer,2014 et alCajochen

Lamps is

blue

., Sleepiness and human impact impact assessmenthumanSleepiness and ., - shifted Karolinska Sleepiness Scale (KSS) 4 5 6

Computer Screens

Evening Light Exposure and EEG Slow-Wave Activity Dynamics across Sleep Cycles

Bright Light 2500 lux Monochromatic Light at 460 nm Blue-enriched (6500K, 40 lux) vs. 6 lux vs. dark vs. 3000 K, 40 lux 250 300 200 200 150 200 150

100 Wave Activity Wave - 100 100 50 50

* * * * *

EEG Slow EEG

0 1 2 3 6 0 1 2 3 6 0 1 2 3 6 Time of Day (h)

Cajochen et al., Sleep 1992 Münch et al., Am J Physiol. 2006 Chellappa et al., J. Sleep Res. 2013. Does light also affect higher cognitive functions?

Does light make you bright? Background

• We spent more and more time in front of computer and/or multimedia screens

• Displays are becoming larger in size

• Many displays are equipped with LED background light

• The light of the diplay is rather close and directed towards the eyes Effects of LED-backlit computer screens on salivary melatonin, alertness and cognitive performance in the evening

Displays: 24 inch 1920x1200 pixel

Cold Cathode Fluorescent Lamp (CCFL)

Light Emitting Diode (LED ) Salivary Melatonin

Non-LED Screen

Baseline  ~ 60 min Dark Dark Adaptation

pg/ml 4

2 LED Screen

0 * * * * 18:15 19:15 20:15 21:15 22:15 23:15 00:15 Time of Day (h)

* p<0.04; Duncans‘ multiple range test

Cajochen et al., J Appl Physiol. 2011 Electrophysiological Correlates of Subjective Sleepiness

Slow Rolling Eye Movements Frontal EEG Activity (1-7 Hz)

1.50 Non-LED Screen

Non-LED Screen

/Hz]

V μ

1.40 Baseline

20 Baseline

Dark Adaptation Dark

Dark Adaptation Dark # Per Hour Per #

1.30 EEG Power Density [ Density Power EEG LED Screen LED Screen 0

18:15 19:15 20:15 21:15 22:15 23:15 00:15 18:15 19:15 20:15 21:15 22:15 23:15 00:15 Time of Day (h) Time of Day (h)

Monitor: F1,11=26.2; p<0.0004 Time of day: F11,44=7.8; p<0.0001 Cajochen et al., J Appl Physiol. 2011 Monitor x Time: n.s. Sustained Attention and Response Control (Go/noGo Task)

Letter „W“: go

Letter „M“ : no-go

faster

LED Screen Baseline

100 Dark Adaptation

105

Relative Reaction Time (%) Time Reaction Relative

* Non-LED* Screen

slower 110 * P <0.05 18:15 19:15 20:15 21:15 22:15 23:15 00:15

Monitor: F1,11=12.2; p<0.04 Time of day: F11,44=7.8; p<0.02 Time of Day (h) Monitor x Time: F12,132=3.0; p=0.041 Cajochen et al., J Appl Physiol. 2011 Declarative Learning (Word pairs)

Correctly identified word pairs Correctly identified new word pairs

70 70 * 65 65

60 60

% 55 55

50 50

45 45

LED Screen * P <0.05 Non-LED Cajochen et al., J Appl Physiol. 2011 Light is not just for vision

Cortex Thalamus Hypothalamus Brainstem - Locus coeruleus

Limbic system - Amygdala - Hippocampus

Modified from Vandewalle et al. Trends Cogn Sci, 2009 Increase in media use in adolescents

Multiscreen Society: 53 hours per week in 8-18 year old kids/adolescents, particularly in the evening in front of LED sources

Generation M2: Media in the lives of 8- to 18-years old. Kaiser Foundation 2010 “Ipad” versus “Blue-blockers” Absorption Spectrum

1.0

0.8

0.6

0.4

0.2 Relative Amplitude Relative

0 400 450 500 550 600 650 700 Wavelength iPad Orange-tinted glasses (blue blockers) Evening melatonin secretion in adolescents

Dim Dark LED/glasses Dim

* Blue Blockers for one week 16 Clear Lenses for one week 14 * * 12

pg/ml Sleep 6

Time of day

van der Lely et al., J Adolesc Health, 2014 Subjective Sleepiness (KSS) more sleepy 2 3 4 5 6 7 8

Subjectivein Adolescents Sleepiness Dim

Dark

LED/glasses Time of of day Time *

* Sleep Sleep Dim van Lely etJ der al.,

Clear Clear Blue Blockers Blue Lenses

Adolesc for for

Health

one one

week week , 2014

PVT Performance in Adolescents (10% fastest RTs)

270 Dark Dim Dark LED/glasses Dim 265

260 Blue Blockers for one week *

255 Clear Lenses for one week

)

ms 250

time time ( Sleep 245

240 Reaction 235

230

225 19.22h 21.22h 22.22h 08.52h

Time of day

van der Lely et al. 2014, in press Interindividual Differences

Age

Effects of light on human alertness Gender

Clock-Gene polymorphism (PER3) Age-related effects of moderate light (250 lux) on melatonin and alertness during 40-h of sleep loss Young Older 20 Dim Light (8 lux, 40h)

Moderate Light (250 lux, 40h)

/ml) pg 10

5 Melatonin Melatonin (

12 16 20 0 4 8 12 16 20 12 16 20 0 4 8 12 16 20

Time of day (h)

10 Young Older sleepy

4 Sleepiness

2 Ongoing study by V. Gabel and A. Viola

alert 0 12 16 20 0 4 8 12 16 20 12 16 20 0 4 8 12 16 20 Time of day (h) Gender

Number of Participants and 10 12 14 0 2 4 6 8

Light Light and gender

preference 6500 K

light 2500 temperature K

Chi - square=

9.6; p

= 0.002

Light and gender Gender and alerting response to light

) N=16 N=21 sleepy 6500K 6500K 2 2

baseline 2500K 2500K

light light

- pre

1 1

Sleepiness 0

difference 0

( KSS, KSS, ( * alert -1 -1 * 18 19 20 21 22 23 24 18 19 20 21 22 23 24 Time of day (h) Time of day (h)

Gender x Time x Light: p=0.07

Light and gender Gender and Psychomotor Vigilance Performance

N=16 N=21

150 150 6500K

2500K

175 175 *

200 200 Median Reaction time Median Reaction

225 225 Slower Slower ms Faster Dim light Dark Light exposure Dim light Dark Light exposure (8 lux) (0 lux) (40 lux) (8 lux) (0 lux) (40 lux)

Gender x Time x Light: p<0.04

Light and PER3 (i.e. clock gene)

A PER3 VNTR polymorphism is implicated:

• Chronotype: PER3 5/5 earlier types than PER3 4/4 (Archer et al. 2003; Pereira et al, 2005; Jones et al. 2007)

• “Homeotype”: PER3 5/5 more sleep pressure (EEG SWA) than PER3 4/4 (Viola et al. 2007, 2012; Goel et al. 2009)

• “Cognotype”: PER3 5/5 more vulnerable to detrimental effects of sleep deprivation and adverse circadian phase than PER3 4/4 (Viola et al. 2007; Groeger et al. 2008; VandeWalle 2009, 2011)

Could some of these effects be explained by a differential response to light in PER3 5/5 and PER3 4/4 individuals? PER3 polymorphism and response to light

PER3 4/4 6500K PER3 5/5 15 2500K 15 Light Light 60 exposure 60 exposure 12 12 40 40 *

9 20 9 20 /ml 0 0 pg 6 6

3 3 Melatonin

0 0

9 9

more 40 40

7 20 7 20 *

0 0 KSS

5 5 Sleepiness

less 3 3

0.8 0.8

0.6 0.6

Frontal EEG power density /Hz

2 0.4 15 0.4 15 during wakefulness (1-7 Hz) KDT µV 0 10 -15 0.2 0.2 5 -30

0 -45 0.0 0.0 * 18 19 20 21 22 23 24 18 19 20 21 22 23 24 Time of Day (h) Chellappa et al., J Clin End Metab., 2012 Summary

 Non-visual effects of light can be seen from genes up to complex neurobehavioral performance such as higher cognitive functions

 Evening light levels < 40 lux affect human circadian physiology, alertness and cognitive performance levels, if these light sources emit a strong blue portion of the visible spectrum

 Some of these effects are age and gender dependent

 Light sensitivity in humans may be modulated by a clock gene polymorphism implicated in sleep-wake regulation

Take home message

The selection of commercially available lamps and computer screens may play an important role because they considerably impact on circadian physiology and cognitive performance at home and in the workplace Acknowledgements

Centre for Chronobiology (www.chronobiology.ch) • Antoine Viola, PhD • Christina Schmidt, PhD • Virginie Gabel • Mirjam Münch, PhD • Sarah Chellappa, PhD • Sylvia Frey, PhD • Doreen Anders, PhD • Micheline Maire • Carolin Reichert • Jakub Späti, PhD

Fraunhofer Institute • Oliver Stefani

EU IP Swiss Federal Office for Public Health Daimler-Benz Foundation Acute sleep induction by light in nocturnal mice

Lights ON Lights OFF 60 Wildtype

Melanopsin knockout Rodless/coneless Melanopsin aDTA

Response (min) Response

Sleep

0 0 1 2 3 Time elapsed from light onset (h)

According to Muindi et al., Front Syst Neurosci, 2014