"Blue" Light and Its Effect on Circadian

Rhythms, Sleep, Alertness and Cognition

Presented by:
"Blue" Light and Its Effect on Circadian
Rhythms, Sleep, Alertness and Cognition

Christian Cajochen

Centre for Chronobiology

Psychiatric Hospital of the University of Basel,
Transfaculty Research Platform Molecular and Cognitive Neurosciences (MCN)
University of Basel, Switzerland

Webinar OSA Technical Group

08.04.2020

06.04.2020 1
Two «rice grains» in the brain
Light is the most important Zeitgeber !

Buttgereit, Smolen, Coogan, Cajochen, Nat Rev Rheumatol, 2015

 Light and circadian rhythms
Melatonin the best marker for human circadian phase (hands of the clock)

Midpoint Midpoint
4:45 8:21
Plasma Melatonin (pMol/L)

400 Light

300

200

100

0
12 24 12 24 12 24 12 24 12
Time of Day
Sleep
Khalsa, Cajochen et al., J Physiol (London) 2003
 Light and circadian phase
Phase-Response Curve

Corresponding Time of day (h)

6 9 12 15 18 21 0 3 6 9 12 15 18
4

2
Phase shift (h)

-1

-2
6.7 hours 10’000 lux
-3
polychromatic white light
Retina

-4
-18 -15 -12 -9 -6 -3 0 3 6 9 12 15 18
Initial Phase (time relative to DLMO=0)
Khalsa, Cajochen et al., J Physiol (London) 2003
 Non-classical Photoreceptors
intrinsically photosensitive retinal ganglion cells SCN
(iPRGs, Melanopsin) (circadian Pacemaker)

Eye
A dual sensory organ

Rods
Retina
Cones

Hattar et al. Science, 2002

Berson et al. Science, 2002
 Light and circadian phase
Phase-Response Curve

Corresponding Time of day (h)

6 9 12 15 18 21 0 3 6 9 12 15 18
4

2
Phase shift (h)

0 75 % of the
-1 resetting
response
-2

-3 6.7 hours 10’000 lux

polychromatic white light
Retina

-4 6.5 hours blue light (480 nm)

11.8 μWcm−2, 11.2 lux)
-18 -15 -12 -9 -6 -3 0 3 6 9 12 15 18
Initial Phase (time relative to DLMO=0)
Khalsa, Cajochen et al., J Physiol (London) 2003
Rüger, et al., J Physiol (London) 2013
Suppression of melatonin in a totally blind person with bright light

Sighted Person
300

200
Plasma Melatonin
100 (pmol/liter)

12 18 24 6 12 18 24 6 12
Time of Day (h)
Blind Person
300

200
Plasma Melatonin
100 (pmol/liter)

12 18 24 6 12 18 24 6 12
Time of Day (h)

Czeisler et al., New Engl Med 1995

There are at least five subtypes of ipRGCs (M1–M5)

LeGate et al., Nature Reviews Neuroscience, 2014

Light affects mood and learning through distinct retina-brain pathways

Fernandez et al., Cell 2018

Brain circuits underlying the effects of light on non-image-forming visual functions

MOOD

LeGate et al., Nature Reviews Neuroscience, 2014

SLEEP/WAKE
Light evoked sleep induction and sleep maintenance across different genotypes (mice)

Lights ON Lights OFF

60
Wildtype
Melanopsin knockout

Sleep Response (min)

Rodless/coneless
Selective ablation of melanopsin
30
containing ipRCGs by aDTA

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

This suggests that these cells serve as an exclusive pathway for mediating the acute effects of light

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

Acute alerting effects of light in diurnal humans

Subjective
Alertness
5

10
more alert

15

20

120 lux !

25

Cajochen et al., Beh Brain Res. 2000

10 100 1000 10000

Illuminance (lux)
 Carry-over effect of the light’s alerting in the evening

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
EEG Slow-Wave Activity

200
150
200 150
100
100
100
50
50
* * * * *
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
Wavelength-dependent sleep induction in a nocturnal animal

Pilorz et al., Plos Biol 2016

Polychromatic light and diur-/nocturnality

Bourgin and Hubbard, Plos Biol 2016

Blue- vs. green enriched light

Cajochen and Chellappa, Front Neural Circuits. 2016

Molecular responses to light in SCN and VLP are wavelength-dependent

Pilorz et al., Plos Biol 2016

Is this relevant to everyday life ?

http://journal.media-culture.org.au/index.php/mcjournal/article/view/1009
MOTIVATION FOR BETTER LIGHTING SOLUTIONS

We spend more than 90% of our time indoors The world gets brighter at night
 Artificial outdoor light levels correlate with human sleep-wake behavior in the US
(n=19’136)

Distribution of nocturnal outdoor illuminance

Sleep duration Bedtime Wake Up Time

More Light Outside

Ohayon and Miles, Sleep, 2016

 Light exposure and urinary melatonin levels across shift work schedules

Light (n=148) Melatonin (n=148)

Day shift
600

Urinary aMT6 (ng/mg-creatinine)

Rotating:day/off shift 50
Rotating:night shift

450 40
Light (lux)

30
300

20

150
10

0 0

Time of day (h)

Razavi et al. Cancer Epidemiol Biomarkers Prev 2019
 Light at Night and Cancer
Women living in areas with high levels of ambient light at Both prostate and breast cancer were associated with high estimated
night may be at an increased risk of breast cancer exposure to outdoor light at night in the blue-enriched light spectrum

Adjusted Hazard Ratio

5 53.4-175.2

Outdoor Light-at-Night Estimates (nW/cm2 /sr)

4 37.5-53.3
Quintiles

3 26.5-37.4

2 14.3-26.4

1 0-14.2

0.8 1.0 1.2 1.4

Hazard Ratio (HR)

Risk of Invasive Breast Cancer Associated with Outdoor Estimates of Light at
Night Among 106,731 Study Participants: Adjusted HRs and 95% CIs
Estimated from Cox Proportional Hazard Models
Outdoor Light-at-Night estimates in the blue spectrum

Hurley et al., Epidemiology, 2014 Garcia-Saenz et al., Env Health Persp, 2018
 Relativer Anteil
Wellenlänge (nm)

Relativer Anteil
Wellenlänge (nm)
Smartphone use in adolescents (14-20 years)
Use of smartphones Where do you keep your smartphone during night?
1 hour prior bedtime
somewhere
irgendwo in der in the appartment
Wohnung
14% somewhere
irgendwo in the bedroom
im Zimmer
23%
99 %
Jayes
ondem
auf theNachttisch
bedside table
notbeantwortet
nicht answered
iminBett
bed
60%
notbeantwortet
nicht answered

99% yes 97% in bedroom

How often do you use your smartphone after «Lights off»

10%
never
nie
15% sporadically
selten
49% occasionally
gelegentlich 74% occasionally-often
often
häufig
25% not beantwortet
nicht answered

Strube et al. Somnologie, 2016

 Daylight-LED vs. conventional LED
100 Lux, 3700 Kelvin
Intensity [normalized]

Colour rendering, Ra different:

conLED 79,12

0.0025 dayLED 98,81

Ee [W/(sqm*nm)]
0.002

0.0015

0.001

0.0005

0
http://www.toshiba-tmat.co.jp/eng/case_tri_r/index.htm 350 450 550 650 750 850

Wavelength [nm]

Farbtemperatur von 3700K = sonniger Tag kurz nach Sonnenaufgang während "goldener Stunde” gemessen in der Sonne
https://www.nrel.gov/ grid/solar-resource/smarts.html
 Conventional LED vs. daylight LED

Which one is which?

Room equipped Room equipped

with daylight LED with conventional LED
 Daylight LED vs. conventional LED

Baseline Treatment
Night Night Conventional LED

18 22 24 8 10 14 18 22 24 8 10 14 18 22
Time of day
Baseline Treatment
Night Cognitive Test Battery
Night Daylight LED

18 22 24 8 10 14 18 22 24 8 10 14 18 22

Cognitive Performance Testing

Night sleep between

± 1 hours of usual bedtime

Within participant design with a counterbalanced order of the light conditions:

• Each participant reported two times to the lab for two light conditions (conLED and dayLED)
• The order of the light conditions was balanced among the study participants
 Conventional LED vs. daylight LED

Visual comfort ratings Sleep

Subjective Rating of Light Quality Dynamics of delta-EEG activity during sleep

250
(Brightness and Colour Temperature)

5.0

* 200
better

Relative EEG Delta Activity

4.5

(% of Baseline)
150
Light Quality

4.0
100

3.5 50 * * *
worse

DayLED
DayLED
ConLED ConLED
3.0 0 * * *
0.0 1.3 2.5 3.9 5.1 6.4 7.7

Time of Day (h)

Cajochen et al. Lighting Res. Technol., 2019

Dynamic “Daylight” LED impacts on melatonin secretion and sleep

Arousal
Sleep

vs. Sleep
Arousal

30

Dynamic light:
25 38% reduction in latency to sleep stage 1
20

15

Time (Min)
10 Static light
Dynamic light
5

0
SL1 SL2 SL3 SL2_3

Sleep Latency
Stefani et al., in prep.
 Rods
Processing of light in the human eye takes Cones
Macula
place through five photoreceptors.
Lens

These photoreceptors integrate light

according to their spectral sensitivity.

Because of this integration, information about White-LED

the light spectrum is lost.

Fluorescent lamp
Lights with different spectra can look the
same.
Incandescent lamp

Slide kindly provided by Manuel Spitschan

 Metameric light stimuli

Scalar output

Goal:
2 lights with spectral power
E1 E2 E3 distributions
that do not differ in the amount they
activate the cones, but
the amount they activate melanopsin
E1 E2

“stimulated” “silent”

Spitschan and Woelders, Front in Neurol, 2018

Exploiting metamerism to regulate the impact of a visual display on alertness and melatonin suppression
independent of visual appearance

Allen et al., Sleep 2018

No evidence for an S cone contribution to the human circadian response to light

Spitschan et al. Curr Biol, 2019

Using a visual display controlling melanopic irradiance to regulate sleep
Laboratory
 Evolutionary adaptation to natural light
22.25 hours per day in
buildings 1

200.000 150 years

Slide kindly provided Oliver Stefani

1 Schweizer et al. 2007
1/ Theoretical background 2/ Objectives 4/ Results 5/ Summary 6/ Conclusion
Impact of blue- and non-blue enriched white light on circadian physiology and alertness during sustained
wakefulness in young and older individuals

BN RN

8h 40h light exposure 8h

250 lux 250 lux
Virginie Gabel, PhD
Blue - enriched
White Light
white Light
(2800K)
▪ 26 healthy participants: 20-35 years (mean ± SE: 24.96 ± 0.58 y) (9000K)
▪ 12 older: 55-75years (mean ± SE: 63.58 ± 1.27 y)

▪ Variables:

❖ Sleepiness: every hour

❖ Cognitive tests: every 2.5 hours

❖ Salivary melatonin and cortisol sample: every hour

❖ Polysomnography: continuously Control Dim Light (<8 lux)

Evidence that homeostatic sleep regulation is modulated by prior light intensity
2
Young Melanopic irriadiance ( V/cm )
0.4 12.1 32.6
180
Dim light (<8 lux, 2800K)
0.3 White light (250 lux, 2800K)
Blue Light (250 lux, 9000K) 160

0.2
140

0.1
120

Percentage of EEG Delta Activity (0.75-4.5 Hz)

0.0 100

Relative EEG Power density

[log (Recovery/Baseline Night)]

after 40-h of sustained wakefulness

-0.1 80
0 2 4 6 8 10 12 14 16 18 20 3 92 246
Hz

Older 0.4 12.1 32.6

180
0.3
160

0.2
140

0.1
120

0.0 100

-0.1 80
0 2 4 6 8 10 12 14 16 18 20 3 92 246
Hz Melanopic equivalent
daylight illuminance (lux) Cajochen et al., Clocks&Sleep, 2019
 More light during daytime increases sleep pressure (deep sleep)
Young Older
Melanopic irriadiance (mV/cm2 ) Melanopic irriadiance (mV/cm2 )
0.4 12.1 32.6 0.4 12.1 32.6
180 180

160 160

% increase after 40-h of sustained wakefulness

EEG Delta Activity (0.75-4.5 Hz)
140 140

120 120

100 100

80 80
3 92 246 3 92 246
Melanopic equivalent daylight illuminance (lux) Melanopic equivalent daylight illuminance (lux)

Cajochen et al., Clocks&Sleep, 2019

Intraocular cataract lens replacement improves circadian rhythms, cognitive function and sleep
in older adults
UV only blocking IOL‘s
100

Two frequently implanted IOLs 80

Transmission (%)
60
50 % Reduction
40

20 Blue blocking IOL‘s

Clear Lenses BlueBlockers
(UV block only) 0

-20
300 350 400 450 500 550 600 650 700

Wavelength (nm)

Chellappa et al., Jama Ophthalmology, 2019

 Summary
• Non-visual forming effects of light are ipRCGs driven and light’s effect on mood, learning and sleep are separate from
a pacemaker dependent role of the suprachiasmatic nucleus

• There are wavelength-dependent effects of light on sleep in both: nocturnal animals and diurnal humans, with
alerting short-wave length light in both

• The quality of artificial lighting, as indexed by its spectral and dynamic similarity to daylight has beneficial effects on
human sleep

• The impact of light on alertness and melatonin production can be controlled independently of visual experience
(metameric displays)

• Experienced illuminance levels during wakefulness impact on homeostatic sleep regulation in humans (i.e. deep sleep)

• Non-blue blocking IOLs may be useful in older cataract patients as a "stimulant" to increase delta-EEG activity in
nonREM sleep (i.e. deep sleep)
 Thank you
Centre for Chronobiology

•
Transfaculty Research Platform Molecular and
Dr. Carolin Reichert, Psychologist Cognitive Neurosciences (MCN)

• Dr. Ruta Lasauskaite, Psychologist

• Dr. Oliver Stefani, Engineer
• Dr. Manuel Spitschan, Psychologist www.chronobiology.ch
• Dr. Christine Blume, Psychologist

• Franziska Rudzik, Psychol., PhD student

• Laurie Thiesse, Biol., PhD student
• Dr. med. Corrado Garbazza, Psychiatrist, PhD student
• Janine Weibel, Psychol., PhD student
• Yu-Shiuan Lin, Psychol., PhD student
• Michael Strumberger, Psychol., PhD student
• Tamara Aderneuer, Physicist, PhD student

• Currently 6 Master students in Psychology

• Béa Anderlohr-Streule, Assistant
• Claudia Renz, technician

• Dr. med. Martin Meyer, Psychiatrist

• Dr. med. Helen Slawik, Psychiatrist

• Prof. em. Anna Wirz-Justice, Biochemist