Aerospace Medicine Grand Rounds
University of Texas Medical Branch / Johnson Space Center
May 24, 2011
Non-visual photoreception in the human eye:
Using light to counter jetlag,
shiftwork and fatigue
Steven W. Lockley, Ph.D.
Division of Sleep Medicine, Brigham and Women’s Hospital, Boston, MA
Division of Sleep Medicine, Harvard Medical School, Boston, MA
slockley@hms.harvard.edu
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.
http://www.bioon.com/book/biology/whole/html/
‘circadian’ - ‘about a day’
Cajochen et al. Am J Physiol 1999
Sleep and circadian phase
Consolidated sleep can only occur at the correct circadian phase
Clock Time (h)
6
Dijk and Czeisler, J Neurosci 1995
12
18
0
6
12
18
0
6
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
24-hour circadian rhythms in motor vehicle crashes
and heart attacks
Fatigue-related fatal crashes
by time of day
Onset of myocardial infarction
by time of day
Peak rate at 5am
Peak rate at 9am
Federal Motor Carrier Safety Administration 2000
Muller et al., New Engl J Med 1985
Period of the circadian pacemaker in humans
Larks……….………….Owls
Morning type…………Evening type
• Average ~24.2 h (23.6-25.0 h)
• Stable in healthy aging
• 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 shiftwork
• Genetic basis, correlated with
polymorphisms in PER gene
Czeisler et al. Science 1999
Phase angle of entrainment under controlled conditions
3wks fixed 8-h sleep schedule at home
Plasma DLMO on admission <3 lux
Day 1 [~3 lux]
DLMO-Sleep onset phase angle (n=33)
Mean ( SD) = 2.15  1.03 h
Median = 2.23 h
Range = -4.5 to 0.5 h
Phase angle correlates with intrinsic
circadian period measured under
Forced Desynchrony in same subjects
For each 0.1 h difference in period, there
was a 0.4 h difference in phase angle
Adapted from Wright et al., J Biol Rhythms 2005
Pineal melatonin response
Entrainment by light
30

24-hour light-dark cycle
resets the circadian clock
on a daily basis
25
Plasma melatonin (pg/ml)
Daily 24-hour
Light-dark cycle
20
15
10
5
0
30
25
20
15
10
Neuroanatomy of the circadian system
5
0
22
0
2
4
6
8
10
12
14
16
18
20
Pineal melatonin response
Total blindness
Plasma melatonin (pg/ml)
30
25
20
15
10
5
0
Tetraplegia (C6 lesion)
30
25
20
15
10
Neuroanatomy of the circadian system
5
0
22
0
2
4
6
8
10
12
14
16
18
20
‘Circadian’ Photoreception
Multiple neuroendocrine and neurobehavioral responses
• Light is the most powerful time cue for resetting the circadian
pacemaker and ensuring correct synchronization of the internal
clock with the environment
• Failure to entrain the circadian pacemaker results in sleep
disorders, fatigue, performance problems, hormone and
metabolic disorders
• Common examples include the circadian desynchronization
caused by shift-work, jet-lag and Advanced- and Delayed Sleep
Phase Disorder
‘Circadian’ Photoreception
Multiple neuroendocrine and neurobehavioral responses
• Much like the ear has dual functions for audition and balance,
the human eye has a dual role in detecting light for a range of
behavioral and physiological responses separate and apart
from sight
• These ‘non-visual’ effects of light are mediated by a novel
non-rod, non-cone photoreceptor located in the ganglion cell
layer of the eye
• These photosensitive ganglion cell contain a novel opsin,
melanopsin, to detect light which is maximally sensitive to
short-wavelength (blue) visible light (max ~480 nm)
‘Circadian’ Photoreception
Multiple neuroendocrine and neurobehavioral responses
• Circadian entrainment
• Circadian phase shifting
• Melatonin suppression
• Subjective alertness / EEG
• Neurobehavioral performance
• Cortisol stimulation
• Cardio- and thermoregulation
• Pupillary reflex
• Stimulation of clock gene expression
• Photoperiodism and seasonality
• Solar navigation
Circadian photoreception
in non-human mammals
bilateral enucleation abolishes circadian photoreception
but not in mice that are…
• retinally degenerate rodless (rd/rd)
• retinally degenerate slow rodless (rds/rds)
• retinally degenerate transgenic rodless (rdta)
• coneless (cl), rodless/coneless (rd/cl, rdta/cl)
• cryptochrome 2-less (cry2-)
• rodless and/or cryptochrome-less (rd/cry1-/cry2-)
• rodless / vitamin A-less
A novel opsin termed melanopsin (OPN4) is cloned
Provencio et al., J Neurosci, 2000
Laminar Organization of the Retina
Melanopsin-containing
intrinsically photosensitive
retinal ganglion cells (ipRGCs)
~0.3% of all GCs
Primate
retina
Dacey et al., Nature 2005
Hattar et al., Science 2002
Action spectra demonstrate short-wavelength sensitivity (max 480 nm)
for non-rod, non-cone photoreceptor system
Melanopsin-containing intrinsically
photosensitive retinal ganglion cells
max = 484 nm
Rat ipRGC
Spectral
Primate ipRGC
Pupillary reflex to light in totally
visually blind mice and human
Rodless-coneless
mouse
Rod-cone dystrophy
No light perception
87-yr old female
max = 481 nm
Berson et al. Science 2002; Lucas et al. Nature Neurosci 2001; Dacey et al. Nature 2005; Zaidi et al., Curr Biol 2007
‘Circadian’ Photoreception
Properties of light affecting circadian photoreception
• Wavelength
• Timing
• Intensity
• Pattern
• Light history
‘Circadian’ Photoreception
What is the evidence for a novel photoreceptor system?
Action spectra for melatonin suppression peak at ~460 nm and do
not match known rod and cone photoreceptors
scotopic
photopic
max = 446-477 nm
90 mins exposure
Brainard et al. J Neurosci 2001
max = 459 nm
30 mins exposure
Thapan et al. J Physiol 2001
Short-wavelength sensitivity for resetting the circadian pacemaker
460 nm light is nearly twice as effective at resetting the clock than 555 nm light
Phase shift  (h)
mean ± sem
1
0
-1
-1.67 ± 0.26 h
-2
-2.99 ± 0.18 h*
-3
-4
* p < 0.0006
460 nm
555 nm
photons/cm2/s 2.8 x 1013
2.8 x 1013
W/cm2
12.1
10.0
photopic lux
5.0
68.1
scotopic lux
116.6
68.7
Note: Photopic lux does not predict
The biological response to the light
Lockley et al., J Clin Endocrinol Metab 2003
Short-wavelength sensitivity for the
acute alerting effects of light
in sighted subjects
Subjective sleepiness
Subjective alertness (mean + sem)
9
Sleepy
8
7
460 nm light is more effective at enhancing
alertness and performance than 555 nm light
6
5
4
3
2
460 nm
555 nm
Alert
1
-4
-2
0
2
4
6
8
10
12
Time since lights on (h)
Auditory reaction time
Lapses of attention > 500 ms
20
Lapses > 500 ms
(mean number + sem)
Auditory reaction time
(mean ms + sem)
500
400
300
200
15
10
5
0
-4
-2
0
2
4
6
Time since lights on (h)
8
10
12
-4
-2
0
2
4
6
8
10
12
Time since lights on (h)
Lockley et al., Sleep 2006
Short-duration (<1’) blue light preferentially activates the brain
473 nm light increases activity in brain areas associated with alertness, performance
and mood during the day compared to 430 nm or 527 nm light
Transient effects at light onset
Left
Hippocampus
Memory
Right
Amygdala
Emotion
Mood
Left
thalamus
Sustained effects during
35s 2-back task
Left
Thalamus
Alertness
Cognition
Memory
Left
middle frontal
gyrus
Working memory
Right and Left
brainstem
Arousal
Cognition
Executive function
fMRI– Functional Magnetic Resonance Imaging
Vandewalle et al., PLoS One 2007
Locus
Coeruleus?
NE; arousal
Some totally blind people with
eyes maintain normal
melatonin suppression
response to light and have
normal circadian entrainment
Evidence for separation of light
detection for visual and nonvisual effects of light
Confirms the integrity
of the retina-RHT-SCNpineal pathway
Czeisler et al. New Engl J Med 1995

Adapted from Lockley & Gooley, Curr Biol 2006
Light Applications - Clinical
• Entrainment to non-24-hour ‘days’
- Space flight and bases, Submariners, Antarctica
• Treatment of circadian rhythm sleep disorders
- Advanced-, Delayed-, Non-24-hour Sleep Disorders
- Jet-Lag Disorder, Shift-work Disorder
- Sleep timing changes due to adolescence and aging
• Treatment of affective disorders
- Seasonal Affective Disorder
- Alzheimer's Disease
- General mood, non-seasonal depression?
• Improving general sleep patterns
- Hospital and institutionalized patients
- Child and adolescent sleep
• Insomnia or excessive sleepiness following travel across  2 time zones
• Internal circadian system cannot keep up with rapid light-dark change
• Readjusts at a slow rate (~ 1h/day) causing chronic desynchronisation
• Social and behavioral factors greatly influence readaptation rates
• More severe during eastward travel for majority of population
• Symptoms include
- insomnia
- fatigue
- GIT disorders
- poor performance, memory and concentration
Sleep and circadian phase
9-hour advance (Houston to Moscow)
Clock Time (h)
6
Dijk and Czeisler, J Neurosci 1995
12
18
0
6
12
18
0
6
The circadian clock determines the direction
that is easiest to adapt to
Larks……….………….Owls
Mean = 24.2 h
75% naturally delay (‘westward’)
- require phase advance each day
25% naturally advance (‘eastward’)
- require phase delay each day
Czeisler et al. Science 1999
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
• cognitive deficits
• reduced spatial memory
• amnesia
Cho, Nature Neurosci 2001
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; Flynn-Evans et al., Cancer Causes Control 2009
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
‘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
Short sleep duration in non-shift-working populations is
associated with increased risk of hypertension, stroke and heart
attack, obesity, Type II diabetes and possibly mortality
Hastings et al. Nature Neurosci Rev 2003
Circadian oscillators in liver, heart, lung,
ovaries, stomach, esophagus, kidneys,
bladder…..etc, etc
Postprandial response during circadian misalignment (28-h day)
4 time zones West per day
Scheer et al., PNAS 2009
Treatment options for jet-lag
(insomnia and excessive sleepiness)
• Circadian re-adaptation
- Light-dark control (chronobiotic and stimulant)
• Prescription medication
- Melatonin (soporific)
- Melatonin agonists (soporific and chronobiotic)
- Hypnotics
- Stimulants
• Over-the-counter medication
-Caffeine (stimulant)
• Planned naps
• Meal timing
‘Circadian’ Photoreception
Properties of light affecting circadian photoreception
• Wavelength
• Timing
• Intensity
• Pattern
• Light history
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 (2 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 (6 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: 6 h eastward = 18 h westward
Increasing delay
Increasing advance
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)
Light before ~6:00 am
delays the circadian clock
(to a later time)
Adapated from Rajaratnam & Arendt, 2001
Schematic of timing for light treatment of Jet-lag
Time (h)
24
6
12
18
Light : Dark (L:D) cycle
Normal entrainment
Westward flight – sleep later
L
Requires delay to adapt
Light before 6 am INTERNAL time
Eastward flight – sleep earlier
L
Adapted from Arendt & Skene, Sleep Med Rev, 2005
Requires advance to adapt
Light after 6 am INTERNAL time
Increasing delay
Increasing advance
Phase Response Curve (PRC)
Melatonin before ~1:00 am
causes an advance
Light after ~6:00 am
causes an advance
Melatonin after ~1:00 am
causes a delay
Light before ~6:00 am
causes a delay
Adapated from Rajaratnam & Arendt, 2001
Schematic of timing for light treatment of Jet-lag
Time (h)
24
6
12
18
Light : Dark (L:D) cycle
Normal entrainment
Westward flight – sleep later
L
M
Requires delay to adapt
Light before 6am INTERNAL time
Mel after 1am INTERNAL time
Eastward flight – sleep earlier
M
L
Adapted from Arendt & Skene, Sleep Med Rev, 2005
Requires advance to adapt
Light after 6am INTERNAL time
Mel before 1am INTERNAL time
NASA Jet-lag travel example
Houston to Tokyo (9 hours)
Houston
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
Tokyo
3 PM
4 PM
5 PM
6 PM
7 PM
8 PM
9 PM
10 PM
11 PM
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
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Wed
17-Feb-10
Thu
18-Feb-10
Fri
19-Feb-10
Sat
20-Feb-10
Sun
21-Feb-10
Mon
22-Feb-10
Tue
23-Feb-10
Wed
24-Feb-10
Thu
25-Feb-10
Fri
26-Feb-10
Sat
27-Feb-10
Sun
28-Feb-10
Mon
1-Mar-10
Tue
2-Mar-10
Wed
3-Mar-10
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 M 
M
M
NAP
M
M
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 M 
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NAP
M
M
M
M
Key
SLEEP
M
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FLYING
TRY TO SLEEP OR NAP
PRIORITIZE BRIGHT LIGHT EXPOSURE
WEAR SUNGLASSES – AVOID LIGHT
DO NOT WEAR SUNGLASSES – SEE LIGHT
TAKE MELATONIN
Light Applications - General
• 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
• Challenge is to incorporate these benefits into design
• Lighting design to optimize visual and non-visual effects
• Flexible, ‘smart’ lighting systems with user interaction
www.understandingsleep.org
www.sleep.med.harvard.edu