Grasping light
Lok, Renske
DOI:
10.33612/diss.173352710
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from
it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date:
2021
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Lok, R. (2021). Grasping light: Mental and physiological responses to illumination. University of Groningen.
https://doi.org/10.33612/diss.173352710
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
Discussion.
The goal of this thesis was to study effects of light on various subjective and
physiological processes in humans. This resulted in multiple experiments, in
which effects of light on human alertness, thermoregulation, sleep and physical
performance were studied. In Chapter 2, a literature review concerning alerting
effects of light during the night- and daytime was presented, while in Chapter 3,
an experiment assessing if light could induce alertness during the daytime in a
dose-dependent manner was described. Since many factors influence alertness,
the relationship between alertness and melatonin production was studied in
Chapter 4. In Chapter 5, the relative contribution of wake duration (process S) and
circadian variation (process C) to alerting effects of light was assessed. Additionally,
the effects of light, sleep-wake duration, and circadian variation were studied on
human thermoregulation (Chapter 6) and sleep (Chapter 7). Since time of day
played such an important role in this thesis, its effect on physical performance
was assessed in Chapter 8.
Light increases alertness independent of time awake.
In Chapters 2,3,4 and 5, it is emphasized that subjective and objective parameters
of alertness show distinctive patterns in alerting effects of light. In addition to
studies described in this thesis, others have emphasized such differences as well
137,170,430
. Although performance is defined differently than alertness (Chapter
2), many studies use mental performance (determined as reaction time) as an
objective measure of alertness. Chapters 3, 4 and especially 5 indicate clearly
that performance is a different concept then subjective alertness, and that both are
affected differently by wake duration related variation, circadian clock phase, and
light. This is in agreement with literature
137,159,160. Experiments presented here
indicate that during daytime, subjective alerting effects of light are difficult to
manifest.
Given the distribution of sleep duration in the population
6, not many individuals
sleep for 8 consecutive hours on a regular night. In the Netherlands alone, 3.3
million women and 2.6 million men report impaired sleep quality, which may
lead to elevated levels of sleep pressure and decreased measures of subjective
alertness and mental performance
6. The relationship between light and subjective
alertness might be best described by a parabolic function, in which low levels of
sleep pressure (after awakening) create a ceiling in which light cannot induce
significant improvements in alertness (time points 0.5, 2.5 and 4.5, Fig. 1, Chapter
5). As sleep pressure increases, alertness values decrease, away from a possible
ceiling of maximal alertness. This creates room for bright light to induce significant
improvements in alertness (time points 6.5 and 8.5, Fig. 1, Chapter 5). As sleep
pressure increases even more, light might not be strong enough to induce
significant improvements (time points 10.5 and 12.5, Fig. 1, Chapter 5).
9
Figure 1: eff ects of sleep pressure on subjective alertness and performance in dim (6.5 lux) and bright light (1400 lux) conditions. Data represent mean ± standard error of the mean, with 8 subjects
per group. Black dots indicate data collected in dim light, red dots follow data collected in high intensity light and blue dots represent the diff erence. The dotted line indicates absence of change in subjective sleepiness or performance. White bars indicate fl oor and ceiling eff ects with little room for light induced increases in alertness, while green bars indicate room for alertness increments.
The hypothesis that alerting eff ects of light might be best described by a parabolic
relationship is consistent with results from a recent pilot experiment that we
conducted. In a within-subject design, 6 participants were obliged to postpone
habitual sleep onset by 0, 2, 4, 6 or 8 hours, therewith increasing homeostatic
sleep pressure levels. Two hours after habitual sleep off set, subjective alertness
was tested (by completion of the Karolinska Sleepiness Scale), under dimly lit
conditions. Consecutively, subjects were exposed to 60 minutes of bright light
(polychromatic white light of 2000 lux, as has been used in Chapter 3). Depicted
is the relationship between sleep deprivation, subjective alertness (Karolinska
Sleepiness Scale) and performance (Psychomotor Vigilance Task), expressed
relative to the dim light control condition proceeding bright light exposure (Fig.
2). For this circadian clock phase, a (signifi cant) parabolic curve best describes the
relation between sleep deprivation and subjective alertness, indicating eff ects of
light depending on sleep deprivation level. Alerting eff ects of light are the greatest
after 4 hours of sleep deprivation, when alertness is similarly improved in all
subjects (Fig. 2). 4 hours of sleep deprivation, measured 2 hours after habitual
sleep off set, coincide with alerting eff ects found in the FD design, occurring after
6.5 hours of wakefulness (Fig. 1). 6 hours of sleep deprivation (Fig. 2), coincides with
alerting eff ects of light assessed after 8.5 hours of wakefulness (Fig. 1). Subjective
alertness is poorly induced by bright light when subjects slept more or less than
4-6 hours, confi rming the hypothesis that a ceiling eff ect might be present in
well-rested individuals (0 and 2 hours of sleep deprivation, Fig. 2) and that alertness
decreases beyond light-improvable limits in severely sleep deprived individuals (8
hours of sleep deprivation, Fig. 2).
Objective alertness (or performance) however, is diff erently aff ected by sleep
deprivation. Although there is a similar light induced improvement in performance
as in subjective alertness at lower levels of sleep deprivation (2 hours), light
signifi cantly impairs performance with more sleep deprivation (4-8 hours).
Although this relationship is not fully understood, it could partially be confounded
by an hour of sitting still, which may contribute to a non-vigilant, parasympathetic
active state, which is not present at baseline since participants are just seated.
Apart from this explanation, the data do indicate that performance decrements
precede subjective sleepiness increases, indicating that reduced performance
possibly signals decreased alertness, after which subjective mental awareness of
decreased alertness may follow.
Figure 2: eff ects of light on subjective alertness and performance after diff erent levels of sleep deprivation. Data (collected after 60 minutes of light exposure) represent mean ± standard error of the
mean, with 6 subjects per group. White bars indicate fl oor and ceiling eff ects, while green and red bars indicate alertness increments and decrements respectively. A signifi cant parabolic curve best describes the relationship between sleep deprivation and subjective alertness.
Alerting eff ects of light during the 24-hour day.
To get an impression whether alerting eff ects of light are present during the
(working)day, the interaction between sleep pressure levels, circadian clock time
and light induced improvements in alertness were investigated (Fig. 3, Chapter
9
5). Signifi cant interactions were found between circadian phase, time since sleep
off set, and light induced change in subjective alertness, predominantly after
DLMO, but not during the projected daily time course (Fig. 3A, Chapter 5). This
suggests that light can only induce daytime alertness at a correct combination
of wake duration related variation and internal clock time. Probably, during the
normal wake interval, wake duration related variation and internal clock time
work together in such a way that bright light cannot provide any further subjective
improvements.
Objective alertness, on the other hand, is improved at all combinations of
circadian clock phase and sleep pressure levels (Fig. 3B,C, Chapter 5). Since
light induced improvements in performance could not be detected in Chapter
3, diff erent mechanisms might play a role. Probably, bright light decrease initial
sleep inertia, which improves performance rapidly after awakening in Chapter
5. During the remainder of bright light exposure, other mechanisms may induce
better performance. In Chapter 3, bright light exposure commenced 90 minutes
after awakening, which is a time frame when sleep inertia is no longer present.
Moreover, bright light exposure in Chapter 3 lasted for 60 minutes, which possibly
might not suffi ce for other performance inducing mechanisms to occur.
Figure 3: eff ects of light on subjective alertness and performance during the projected daily time course (recap Chapter 5). Light eff ects depending on circadian clock phase and time since sleep off set in
subjective alertness (A), performance on the PVT (B), and GNG (C). Red line indicates the projected time course over a regular day. Signifi cant diff erences between light conditions (p<0.05) are indicated by colored rectangles, in which light induced improvements are represented in green.
Alerting eff ects of light at one time of day may be at the expense of
alertness at another time of day.
Subjective sleepiness simulations indicate that light increases alertness around
two time points (6.5 and 8.5 hours of wakefulness). This may very well go at
the expense of alertness at later times of day (
>
13 hours of wakefulness; Fig. 4,
Chapter 5). This suggests that bright light exposure may increase homeostatic
sleep pressure levels, measured as an increase in subjective sleepiness. In other
words, bright light can postpone the onset of subjective sleepiness at one time of
day, but this may result in a reduction of alertness at the end of the day.
Figure 4. Subjective sleepiness plotted against time awake (h; Chapter 5). N=8 individuals, with black
and red dots representing data collected under dim and bright light conditions respectively. The dotted line indicates a predicted dose response fi t, with formula
in which Smin and Smax represent the minimum and maximum subjective sleepiness scores respectively,
t time (in minutes), a the half-maximal response constant (I50), and b the slope.
To fully understand how alerting eff ects of light depend on homeostatic sleep
pressure levels, relationships between timing of light exposure and alertness
were quantifi ed by combining results of the sleep deprivation experiment (Fig.
2) and Forced Desynchrony data (Fig. 3, Chapter 5) to Fig. 4. To construct the
vertical axis, data of Fig. 2 is implemented, while the horizontal data depicts
Forced Desynchrony data (Fig. 3 and 4). The area outside the black dotted square
9
indicates extrapolated data.
Light eff ects on subjective alertness depend strongly on both time of day and time
since sleep off set, with an optimal eff ect of light after sleeping for 3 to 7 hours, and
being awake for 5 to 10 hours (Fig. 5A). Mental performance however, is always
improved by bright light exposure, but particularly after 5 to 8 hours of sleep,
shortly after sleep off set (1 to 4 hours; Fig. 5B).
The experiment described in Chapter 3 was conducted after 8 hours of sleep
duration. Although this experiment assessed alertness at various times of days
(black arrows, Fig. 5), this reconstruction indicates that no subjective alerting
eff ects of light can be achieved at those times of day. The experiment of Chapter 3
also does not describe any eff ects on mental performance, although such eff ects
should be assessed according to Fig. 5. However, in Chapter 3, the Go-NoGo task
was implemented. Since this is a more complex form of mental performance,
it is possible that a heat map generated for this task is diff erent from the one
constructed for the Psychomotor Vigilance Task, which was the only objective
performance test conducted in the sleep deprivation experiment.
Nevertheless, performance improving eff ects of light would have been likely
observed in Chapter 3, considering that these eff ects occur during the projected
daily time course. The lack of such eff ects in Chapter 3 might be the consequence
of the duration of light exposure (as previously discussed) or the type of lighting
(LED (Chapter 3) versus fl uorescent (Chapter 5)). This would off er the intriguing
possibility that alerting eff ects of a white light source may depend on its spectral
tuning. This insight deserves thorough investigation, given its wide application in
work and learning environments.
Figure 5: heat map of light eff ects on subjective alertness and performance. By combining results
of Fig. 2 and Fig. 3, a heat map with change in sleepiness and performance can be constructed. A positive score represent an improvement in alertness/performance, depicted in green. White shaded areas indicate non-signifi cant improvements, while red surfaces represent a decrement in alertness/ performance. The black dotted lines indicate actual collected data, while data outside this rectangle
The relationship between melatonin and alertness.
In Chapter 4, the relationship between (exogenous) melatonin and alertness was
investigated, while in Chapters 3 and 5 a correlational relationship between these
parameters was discussed. Indeed, many other studies already demonstrated
a relationship between melatonin suppression and alertness. Administration of
supra-pharmacological levels of melatonin resulted in a decrease in alertness, as
has also been shown by others
228,265. In Chapter 5, high intensity light exposure
lead to significant melatonin suppression whether studied as a function of time
since sleep offset or internal clock phase. Although both processes displayed
different patterns in subjective alertness and melatonin, it was noteworthy that
at internal clock times when usually melatonin production occurs, subjective
sleepiness was lower in high intensity light compared to dim light exposure.
Taken together, the studies presented in Chapters 3,4 and 5 show a relationship
between melatonin and alertness, in which absence or suppression of melatonin
production is associated with increased (subjective) alertness, while presence of
the nocturnal hormone induces sleepiness.
Light effects on non-image forming responses depend on the
spectral composition of the light.
Studies described in this thesis indicate that general implications of light exposure
to induce (subjective) alertness are relatively limited. It is possible that light
sources employed during these experiments contributed to this conclusion.
In all experiments, a polychromatic white light source, (either from a LED or TL
light source) was used, which is known to activate all classes of photoreceptors.
However, pupillary light responses suggests that some of the photoreceptors
(S- and M-cones) inhibit the pupillary control system when selectively activated,
whereas L-cones and melanopsin response exert an excitatory role
166,167. This
may also account for other systems, indicating that opponent signals between
photoreceptors may influence processes such as alertness. Broadband white light
exposure might therefore be less efficient in provoking alerting effects of light in
comparison to monochromatic light.
Another study indicated that 1 second alternating duty cycles of light elicit stronger
circadian responses as compared to continuous light. These types of paradigms
particularly induce strong cone responses
431,432, which possibly also contribute
to alerting effects of light. Due to bi-stability of melanopsin, it may even be more
efficient to use intermittent long and short wavelength stimulation to optimally
activate the NIF-system
21. For these reasons, we cannot exclude the possibility
that specific color combinations and monochromatic temporal exposure profiles
influence subjective alertness and performance to a larger extent than constant,
long exposure duration, polychromatic white light as used in the studies presented
here.
9
The relationship between alertness and thermoregulation.
Human thermoregulation has been studied throughout this thesis, either as a
possible indicator of alertness (Chapter 3) or to assess its alertness influencing
potency (Chapter 4). Multiple studies have suggested correlations between
human thermoregulation and alertness, especially between alertness and distal
skin temperature (T
distal) and the distal-proximal gradient (T
DPG)
4. In Chapter 3,
light effects on human thermoregulation could not be detected, which coincided
with the lack of alerting effects of light. Exogenous melatonin administration in
Chapter 4 resulted in increased T
distaland T
DPG, which coincides with decreased
alertness. Although exact mechanisms still remain unknown, there seems to be a
relationship between thermoregulation and alertness. Possibly, thermoregulation
parameters correlate here with alertness because they both depend on internal
clock time.
Thermoregulatory changes have also been detected without changes in alertness,
indicating that thermoregulatory can vary without affecting alertness (Chapters
4 and 6). Moreover, these light effects on thermoregulation are relatively quick,
suggesting that such effects are independent of the SCN, and may even be direct.
How these pathways exactly work, remains to be elucidated.
The classical view of the thermoregulatory system is that heat production occurs
in the core, and this is reflected in proximal skin temperature (T
proximal; such as
subclavicularly or navel temperature) measurements. T
distalon the other hand
(measured at the hands or feet), reflects heat dissipation, and therefore shows
an opposite pattern. While bright light exposure decreases almost all T
distalparameters, T
proximalmeasures are less consistent (Chapter 6). Although T
naveland
T
subclavicularboth increase during bright light exposure, T
foreheadindicates a strong
light induced decrease, mimicking T
distal.Possibly, light effects on these areas of
the body are more controlled by arterial blood temperature. As expected, with
varying internal clock time, all T
proximalparameters do cycle in phase with CBT, while
all parameters of T
distalcycle in anti-phase.
Light effects on human sleep.
Previous experiments have indicated effects of daytime light exposure and
subsequent sleep
199,376. Therefore, human sleep measurements were included
in our Forced desynchrony experiment (Chapter 7). Results indicated that light
exposure alters both sleep architecture and sleep quality, as bright light exposure
resulted in more deep sleep (more time spend in NREM sleep) and increased the
depth of deep sleep (higher NREM power density). These effects were particularly
observed when the circadian system promotes wakefulness. Likewise, a subjective
measure of sleep quality indicated higher sleep quality after bright light exposure
at those circadian clock phases. Since light effects on subjective and objective
measures of sleep occurred particularly during the circadian wake phase, these
effects might be more sleep pressure (as opposed to circadian regulated) driven.
However, effects of light exposure on sleep intensity and time in deep sleep were
also found during the circadian sleep maintenance zone (when the circadian
system promotes sleep), but only when an additional sleep opportunity (longer
than 5 hours) was offered. This suggests that deep sleep inducing effects of light
occur especially in the latter part of sleep (which is possibly the consequence
of NREM-REM balance), and that a sleep opportunity should therefore be long
enough for light effects on sleep to occur.
Increased intensity and amounts of NREM sleep can both indicate more efficient
sleep pressure dissipation (sleep pressure decreases quicker and therefore sleep
is more intense) or an increase in sleep pressure (since this is known to induce
increased intensity and amounts of subsequent NREM sleep). Subjective alertness
scores seem to indicate that homeostatic sleep pressure levels increase during
bright light exposure (Fig. 4, Chapter 5), at least suggesting that the increase in
NREM sleep might be the consequence of elevated levels of homeostatic sleep
pressure. To identify whether light induces higher sleep efficacy of increased
sleep pressure, light effects should be studied when circadian clock phase
remains unaltered by light exposure and spontaneous sleep on- and offset
times are monitored. Moreover, such effects should be assessed in participants
with varying sleep quality (as opposed to subjects that only report good sleep
quality). If successful, bright light exposure may offer an healthy alternative for
the pharmaceutical treatment of reduced sleep quality and its wide range of
associated health problems.
Physical performance depends on time of day.
In Chapter 8, effects of time of day on physical performance were assessed.
Analyses of 1722 finish times of Olympic swim races, indicates that even Olympic
athletes are affected by time of day. Worst performance was assessed in the
early morning, while best performance was determined in the late afternoon.
Time of day effects on physical performance were strong: the time-of-day effect
is large, and exceeds the time difference between gold and silver medal in 40%,
silver and bronze medal in 64%, and bronze or no medal in 61% of the finals.
To optimize physical performance during an important race or game, individuals
need to align their circadian rhythms (internal clock time) with the timing of a race
or game (external clock time). An athlete’s circadian clock can be shifted such that
if a race is scheduled in the early morning (external clock time), the body (internal
clock time) can behave as if the race were in the late afternoon. This adjustment
is called “phase advancing.” Minimization of evening light, and maximization of
morning light exposure will cause a shift of circadian rhythms (and the sleep-wake
cycle) earlier. Alternatively, if the race occurs in the late evening, the individual
9
may choose to phase delay their circadian rhythms and sleep by opposite rules,
minimizing morning light exposure and maximizing evening light exposure.
Therefore, by adjusting internal clock time to match a different external clock time
than is normal for you, you can optimize your physical performance for critical
events, like a morning race. Plan to begin shifting the light pattern days ahead of
the event to reach a stable, optimized performance level, and meet the challenge
to the best of your ability.
Time of day matters.
One of the important themes throughout this thesis is time of day. In Chapters 2
and 3, the differences between daytime and nighttime alerting effects of light are
discussed, Chapters 5, 6, and 7 indicate differences in sleep pressure levels and
internal clock phase depending on time of day for a multitude of parameters, and
Chapter 8 discusses the importance of time of day for physical performance. It
can therefore be concluded that time of day and internal clock time are extremely
important for feelings of alertness, thermoregulation, mental- and physical
performance. Alerting effects of light depend on the timing of light exposure, while
mental performance can be improved throughout the day. Physical performance
is worst during the early morning, probably due to low levels in CBT. Such time of
day effects are so strong that they can even influence who will end first or second
in 37% of the races. Moreover, timing of light exposure can alter thermoregulatory
parameters, possibly influencing both physical performance and (subjective)
alertness. Since time of day has such extensive effects on a multitude of
physiological and mental parameters, it should always be taken into account when
planning or conducting experiments, regardless of the field of science.
Light effects after different exposure durations.
Light effects on various measures have been studied. However, the duration of
light exposure after which significant effects on parameters were determined,
varied both within and between parameters. Effects of light have been detected
relatively quickly after 60 minutes (Fig. 2), but also after longer exposure duration
(
>
60 minutes, Fig. 1, Chapter 5). Performance increments on both the Psychomotor
Vigilance Task and Go-NoGo task occurred after merely 30 minutes of light
exposure, and light effects on mental performance occurred in a similar time span
(Fig. 1, Chapter 5). Thermoregulation was affected by bright light exposure within
30 or 60 minutes of light exposure, depending on type of (skin temperature)
parameter and light intensity (Chapter 4, 2000 lux and Chapter 6, 1500 lux).
Since effects of light on various parameters occur after different exposure
durations, this suggests that there might be different mechanisms involved in
these processes. Some effects, especially those occurring after longer amounts
of time, may be SCN dependent, although some studies indicate alerting effects
of light to be quick and transient
109. Based on findings of this thesis, effects of
light on mental performance and electroencephalography may arise from other
connections compared to subjective alertness. Similar conclusions account for
light effects on thermoregulation. Such effects might even be direct, through
possible functional photoreceptors in the skin
433.
Forced desynchrony in bright light; a novel tool to study non-image
forming responses.
Human Forced Desynchrony designs have only been conducted under dim light
conditions (
<
10 lux), since light is known to entrain the SCN, and free-running
of the internal rhythm is imperative to obtain multiple combinations of internal
clock time and sleep pressure levels. Here, we show for the first time, that with
correctly, fast timed sleep-wake (dark-light) cycles, a (short) forced desynchrony
design under high intensity light can be performed, since there we measured
uniform phase progression of cortisol concentrations, indicating a stable free
running rhythm of the SCN (Chapter 5, Fig. 2, Fig. S5). FD designs can therefore be
used to study the interaction between light and the sleep-wake cycle and circadian
contributions on various physiological and behavioral parameters. Our high light
intensity forced desynchrony protocol is therefore a useful tool to investigate
other light effects on non-image forming responses.
However, in high intensity lighting, it is likely that only short FD designs can be
conducted, since bright light does elongate the internal period (measured in
melatonin rhythms). In a short FD design, these effects are relatively modest
(a couple of minutes per light cycle), but in longer FD designs, tau elongations
will most likely become more significant with every progressing light cycle. This
may prevent the occurrence of multiple combinations of internal clock time and
homeostatic sleep pressure levels. Such elongations will also complicate the
comparison between dim and bright light conditions, since internal clock phases
will differ between both light conditions. This should be taken into account when
using an FD design to investigate other non-image forming responses of light. This
could be considered a limitation to bright light FD designs, since longer sleep-wake
period FD designs offer more combinations of sleep pressure levels and internal
clock time combinations.
An overview.
Throughout the chapters in this thesis, relationships between time of day, light,
alertness, mental and physical performance, sleep, thermoregulation, wake
duration related effects and circadian control were studied. Combining findings
discovered by others and data generated by experiments presented in this thesis,
the following relationships between light and these parameters are suggested.
Black arrows indicate determined relationships, while red arrows indicate effects
that require further investigation (Fig. 6 and 7).
9
Light eff ects on alertness, physical performance and sleep.
With progressing time awake, subjective alertness decreases signifi cantly (Fig.
6). Eff ects of elapsed time awake on performance have been demonstrated in
literature, but this could not be replicated in this thesis. With progressing time
awake, light signifi cantly increases subjective alertness and performance. Direct
eff ects of light on both parameters have also been established. Possibly, light
also alters physical performance through wake duration related processes.
Internal clock time both stimulates and suppresses melatonin production,
subjective alertness, mental and physical performance and sleep quality. Bright
light exposure dampens internal clock amplitude, therewith infl uencing eff ects of
the circadian clock on both melatonin and subjective alertness, but not mental
performance and sleep quality. Although eff ects of internal clock time on physical
performance have been shown in this thesis, it is yet to be determined if and
how light could alter sport performance. Light signifi cantly improves subjective
and objective sleep quality, particularly when the circadian clock is promoting
wakefulness (Fig. 6).
Figure 6: Relationship between light, alertness, sleep pressure and melatonin. Dotted arrows
indicate relationships that remain to be elucidated, while black arrows indicate established relationships (thesis or elsewhere). To depict circadian infl uence, light eff ects on internal clock time are depicted in red, while dim light eff ects are represented in black.
Light eff ects on thermoregulation
Clear eff ects of melatonin on core body temperature (T
tongue), but also skin
temperature (T
head, T
distal, T
proximaland T
DPG) have been assessed. However,
light counteracts these eff ects of melatonin, even independent of melatonin
suppression (Fig. 7). Light decreases T
headan T
distalthrough wake duration related
variation, while it increases T
proximaland T
navel. The circadian clock both increases
and decreases skin temperature parameters, but light always dampens internal
clock phase, therewith minimizing thermoregulatory fl uctuations measured in
T
head, T
proximalproximal, T
naveland T
distal.
Figure 7. Relationship between light, melatonin and thermoregulation. Dotted arrows indicate
relationships that remain to be elucidated, while black arrows indicate established relationships (this thesis or elsewhere). For optimal clarity of light induces thermoregulatory eff ects, the relationship between Core Body Temperature and skin temperature is not depicted. To depict circadian infl uence, light eff ects on internal clock time are depicted in red, while dim light eff ects are represented in black. The box in the lower right indicates a small simplifi cation of the schematic.
Conclusion.
In conclusion, bright light exposure might be useful during the working day,
particularly tBo improve mental performance, while the increase in performance
might not be perceived as such given the minor eff ects on subjective alertness.
9
Light exposure in the evening should be minimized, as this suppresses melatonin
production and reduces heat loss, while the presence of melatonin and increased
heat loss facilitate sleep onset. Bright light exposure during the light phase might
be beneficial for objective and subjective subsequent sleep quality, but may also
result in higher amounts of sleep pressure. Physical performance is influenced by
time of day, and optimal performance is reached in the late afternoon.
Summary.
In the current 24 hour society, it is important to function at optimal capacity at
all times of day. Light exposure during the evening can increase alertness and
performance, which has been shown in multiple studies
4,84,91,95,226,434. However, since
humans are primarily active during daytime, it is important to determine alerting
effects of light during this time of day as well. Multiple studies have investigated
effects of polychromatic white light during daytime and found positive, mixed and
negative results (Chapter 2). A systematic experiment, in which effects of different
intensities of light on alertness were studied during various times of day, was
lacking. In Chapter 3, a dose-response curve for alerting effects of light during the
day was determined, in addition to the already existing dose-response curve for
alerting effects of light during nighttime existed
78. However, the dose-response
curve was flat: no significant effects of daytime light exposure on alertness could
be found, which significantly differed from reported effects during the night.
There are many differences between night and day, such as (1) baseline alertness
scores (with higher levels reported during daytime) and (2) absence of the
nocturnal hormone melatonin in the blood circulation. The goal of Chapter 4 was
to investigate which factors would significantly contribute to alerting effects of
light. Therefore, it was examined whether alertness levels during daytime would
reach ceiling values which would cause the absence of alerting effects of light. This
was done by administration of exogenous melatonin at a time of day during which
there was no endogenous production (Chapter 4). Results indicated that indeed,
administration of exogenous melatonin resulted in decreased subjective alertness,
suggesting that there is a relationship between melatonin and alertness. Moreover,
such effects coincided with a decrease in temperature measured underneath the
tongue, while skin temperature measured at distal regions significantly increased.
Although alertness scores were significantly worse after melatonin administration,
additional light exposure did not improve alertness. A ceiling effect may therefore
not fully explain differences in alerting effects between night and day. Bright
light administration did reverse thermoregulatory effects of melatonin ingestion,
indicating that there might be effects of light on thermoregulation independent of
alertness inducing effects.
To further explore factors influencing alerting effects of light, these effects were
studied in a forced desynchrony (FD) design. The principle of a FD design is that the
endogenous circadian oscillations are dissociated from the imposed light-dark and
sleep-wake oscillation by altering the sleep-wake cycle period. As a result, effects
of sleep-wake related variation and circadian processes can be mathematically
disentangled. Results indicated clear differences between subjective and objective
measures of alertness. Alerting effects of light on subjective measures of alertness
depended both on progressing time awake and internal clock time, while objective
parameters (performance and EEG activity) were better throughout the normal
light phase, independent of time awake and internal clock time. This indicates that
(1) light alters subjective and objective alertness differently, and therefore (2) that
subjective and objective parameters might reflect different aspects of alertness.
Since it was noted in Chapter 4 that light can affect thermoregulation, such effects
were also studied in the FD design. In Chapter 6, it was confirmed that light has
effects on human thermoregulation, with significant dampening of the amplitude
of Core Body Temperature (CBT) and skin temperature parameters. Moreover,
CBT and proximal skin temperature cycled in phase, while distal skin temperature,
resembling heat dissipation to the environment, followed opposite patterns.
Effects of light on thermoregulation were independent of effects of melatonin
suppression and these effects were relatively quick, indicating that light has a
direct effect on human thermoregulation, possibly even independent of the SCN.
Previously conducted studies indicated light effects on sleep quality
199,376,382. To
quantify relative sleep-wake related variation and circadian factors on these
effects, light effects on sleep were also studied during the FD protocol (Chapter 7).
Results indicated that artificial bright light exposure increases NREM sleep power
and time in deep sleep. These effects were maximal during the circadian wake
maintenance zone. Subjective sleep quality variation showed similar patterns,
with increased sleep quality reported following bright light exposure when the
internal system promoted wakefulness. In a 3 hours recovery sleep opportunity
however, prior light increased the amount of deep sleep. This suggests that
when the circadian system promotes sleep, light may improve sleep quality too.
However, these effects only occur when the sleep opportunity is sufficiently long.
Lastly, time of day effects were studied on physical performance (Chapter 8). To
this end, swim times of professional athletes competing in the Olympic games of
Athens, Beijing, London and Rio de Janeiro were collected. Performance outcomes
indicated significantly worsened performance in the early morning, compared
to the late afternoon. Possibly, thermoregulation significantly moderates such
effects, since CBT is high in the evening and low during morning. Regardless
underlying mechanisms, time of day can have detrimental sport consequences;
race schedules can contribute to winning silver or gold, since time of day effects
9
are bigger than the difference between gold and silver medal in 40%, silver and
bronze medal in 64%, and bronze or no medal in 61% of the finals. Race timing
should therefore be taken into account when scheduling sports competitions,
instead of peak broadcast times.
Advice for the general public
• Light effects on human subjective alertness are relatively modest during
daytime. However, if one is slightly sleep deprived, bright light exposure
might induce subjective alertness.
• If someone is more severely sleep deprived, alternative ways of decreasing
sleep pressure should be employed (such as a nap). This will result in a
decrease of sleep pressure levels, to levels that allow alertness inducing
effects of light.
• Light effects on human mental performance are relatively profound.
Although bright light may not induce feelings of alertness, one will perform
better.
• Light can affect human thermoregulation. Sleep onset is associated with a
quick decrease in Core Body Temperature. If one wants to facilitate sleep
onset, endogenous melatonin production and the natural drop in CBT should
be facilitated. Hence, one should minimize light exposure in the evening.
• Oral melatonin usage can induce subjective feelings of sleepiness and
decrease Core Body Temperature. Both factors may facilitate shorter sleep
onset latency. However, salivary melatonin levels increase tremendously
after ingesting exogenous melatonin; one should not take 5 mg of oral
melatonin, since this induces melatonin levels 500 times higher than levels
assessed after endogenous production.
• Time of day affects physical performance, with better results in the early
evening as compared to the morning. If one has an important sports
competition and needs to perform well, try to schedule this to occur in the
early evening. If this is not possible, one may choose to shift the internal
body clock in such a way that the game occurs in the early evening according
to internal time of the athlete.
References
1. Hornung, E. (1999) Akhenaten and the Religion of Light. In Ithaca (Cornell University Press, ed), pp. 1–250
2. Morris, C.J. et al. (2015) Endogenous circadian system and circadian misalignment impact
glucose tolerance via separate mechanisms in humans. Proc. Natl. Acad. Sci., 112, 2225–2234.
3. Cordina-Duverger, E. et al. (2018) Night shift work and breast cancer: a pooled analysis of
population-based case–control studies with complete work history. Eur. J. Epidemiol., 33, 369–
379.
4. Cajochen, C. et al. (2005) High sensitivity of human melatonin, alertness, thermoregulation,
and heart rate to short wavelength light. J. Clin. Endocrinol. Metab., 90, 1311–1316.
5. Wright Jr., K.P. et al. (2014) Entrainment of the human circadian clock to the natural light-dark
cycle. Curr. Biol., 23, 1554–1558.
6. Tiemeier, H. et al. (2017) Factsheet resultaten slaaponderzoek hersenstichting.
7. Meyer-Arendt, J.R. (1968) Radiometry and photometry: units and conversion factors. Appl.
Opt., 7, 2081.
8. Lucas, R.J. et al. (2014) Measuring and using light in the melanopsin age. Trends Neurosci., 37,
1–9.
9. Baylor, D. (1996) How photons start vision. Proc. Natl. Acad. Sci., 93, 560–565.
10. Cope, K.R. et al. (2014) Photobiological interactions of blue light and photosynthetic photon
flux: Effects of monochromatic and broad-spectrum light sources. Photochem. Photobiol., 90,
574–584.
11. Fain, G.L. et al. (2010) Phototransduction and the evolution of photoreceptors. Curr. Biol., 20,
R114–R124.
12. Czeisler, C.A. et al. (1995) Suppression of melatonin secretion in some blind patient by
exposure to bright light. N. Engl. J. Med., 322, 6–11.
13. Lucas, R.J. et al. (1999) Neither functional rod photoreceptors nor rod or cone outer segments
are required for the photic inhibition of pineal melatonin. Endocrinology, 140, 1520–1524.
14. Freedman, M.S. et al. (1999) Regulation of mammalian circadian behavior by rod,
non-cone, ocular photoreceptors. Science (80-. )., 284, 502–504.
15. Provencio, I. et al. (1998) Melanopsin: an opsin in melanophores, brain, and eye. PNAS, 95,
340–345.
16. Provencio, I. et al. (2000) A novel human opsin in the inner retina. J Neurosci, 20, 600–605.
17. Berson, D.M. et al. (2002) Phototransduction by retinal ganglion cells that set the circadian
clock. Science (80-. )., 295, 1070–1073.
18. Panda, S. et al. (2002) Melanopsin (Opn4) requirement for normal light-induced circadian
phase shifting. Science (80-. )., 298, 2213–2216.
19. Ruby, N.F. et al. (2002) Role of melanopsin in circadian responses to light. Science (80-. )., 298,
2211–2213.
20. Graham, D.M. et al. (2008) Melanopsin ganglion cells use a membrane-sssociated rhabdomeric
9
21. Hartwick, A.T.E. et al. (2007) Light-evoked calcium responses of isolated
melanopsin-expressing retinal ganglion cells. J. Neurosci., 27, 13468–13480.
22. Mure, L.S. et al. (2007) Melanopsin-dependent nonvisual responses: Evidence for
photopigment bistability in vivo. J. Biol. Rhythms, 22, 411–424.
23. Mure, L.S. et al. (2009) Melanopsin bistability: A fly’s eye technology in the human retina. PLoS
One, 4,
24. Ralph, M.R. et al. (1990) Transplanted suprachiasmatic nucleus determines circadian period.
Science (80-. )., 247, 975–978.
25. Stephan, F.K. et al. (1972) Circadian rhythms in drinking behavior and locomotor activity of
rats are eliminated by hypothalamic lesions. Proc. Natl. Acad. Sci. USA, 69, 1583–1586.
26. Moore, R.Y. et al. (1972) Loss of a circadian adrenal corticosterone rhythm following
suprachiasmatic lesions in the rat. Brain Res. Bull., 72, 54–56.
27. Fuller, C.A. et al. (1981) Circadian rhythm of body temperature persists after suprachiasmatic
lesions in the squirrel monkey. Am.J.Physiol, 241, R385–R391.
28. Wright Jr., K.P. et al. (2002) Relationship between alertness, performance, and body
temperature in humans. Am. J. Physiol. - Regul. Integr. Comp. Physiol., 283, 1370–1377.
29. Wright Jr., K.P. et al. (2006) Sleep and wakefulness out of phase with internal biological time
impairs learning in humans. J. Cogn. Neurosci., 18, 508–521.
30. Rusak, B. et al. (1979) Neural regulation of circadian rhythms. Physiol. Rev., 59, 449–526.
31. Aschoff, J. (1960) Exogenous and endogenous components in circadian rhythms. Cold Spring
Harb. Symp. Quant. Biol., 25, 11028.
32. Czeisler, C.A. et al. (1999) Stability, precision, and near – 24-hour period of the human circadian
pacemaker. Science (80-. )., 284, 2177–2182.
33. Roenneberg, T. et al. (2007) Entrainment of the human circadian clock. Cold Spring Harb. Symp.
Quant. Biol., 72, 293–299.
34. Horne, J.A. et al. (1976) A self-assessment questionnaire to determine
morningness-eveningness in human circadian rhythms. Int. J. Chronobiol., 4, 97–110.
35. Moore, T.A. (1996) Neural control of the pineal gland. Behav. Brain Res., 73, 125–130.
36. Hut, R.A. et al. (2011) Evolution of time-keeping mechanisms : early emergence and adaptation
to photoperiod. Philos. Trans. R. Soc. B Biol. Sci., 366, 2141–2154.
37. Hut, R.A. (2014) Photoperiodism: shall EYA compare thee to a summer’s day? Curr. Biol., 21,
22–25.
38. Paul, M.A. et al. (2015) Physiology & Behavior Sleep and the endogenous melatonin rhythm of
high arctic residents during the summer and winter. Physiol. Behav., 141, 199–206.
39. Saper, C.B. et al. (2005) The hypothalamic integrator for circadian rhythms. 28,
40. Pandi-Perumal, S.R. et al. (2006) Melatonin Nature’s most versatile biological signal? FEBS, 273,
2813–2838.
41. Maronde, E. et al. (2007) The mammalian pineal gland : known facts , unknown facets. 18,
142–149.
42. Benloucif, S. et al. (2005) Stability of melatonin and temperature as circadian phase markers
43. Ekmekcioglu, C. (2006) Melatonin receptors in humans: biological role and clinical relevance.
Biomed. Pharmacother., 60, 97–108.
44. Alarma-Estrany, R. et al. (2007) Melatonin receptors in the eye: location, second messengers
and role in ocular physiology. Pharmacol Ther, 113, 507–522.
45. Dubocovich, M.L. et al. (2000) Molecular Pharmacology and function of Melatonin Receptor
Subtypes, Kluwer Academic / Plenum Publishers.
46. Gordijn, M.C.M. (2018) Melatoninebehandeling voor slaap-waakstoornissen. Psyfar, 1, 9–17.
47. Daan, S. et al. (1984) Timing of human sleep: recovery process gated by a circadian pacemaker.
Am. J. Physiol., 246, R161–R183.
48. Borbely, A.A. (1982) A two process model of sleep regulation. Hum. Neurobiol., 1, 195–204.
49. Borbely, A.A. et al. (1999) Sleep homeostasis and models of sleep regulation. J. Biol. Rhythm.,
14, 557–568.
50. Gaus, S.E. et al. (2002) Ventrolateral preoptic nucleus contains sleep-active, galaninergic
neurons in multiple mammalian species. Neuroscience, 115, 285–294.
51. Sherin, J.E. et al. (1998) Innervation of histaminergic tuberomammillary neurons by GABAergic
and galaninergic neurons in the ventrolateral preoptic nucleus of the rat. J. Neurosci., 18,
4705–4721.
52. Szymusiak, R. et al. (1998) Sleep-waking discharge patterns of ventrolateral preoptic/anterior
hypothalamic neurons in rats. Brain Res., 803, 178–188.
53. Lu, J. et al. (2002) Selective activation of the extended ventrolateral preoptic nucleus during
rapid eye movement sleep. J. Neurosci., 22, 4568–4576.
54. Aston-Jones, G. (2005) Brain structures and receptors involved in alertness. Sleep Med., 6, 3–7.
55. Chou, T.C. et al. (2003) Critical role of dorsomedial hypothalamic nucleus in a wide range of
behavioral circadian rhythms. J. Neurosci., 23, 10691–10702.
56. Dijk, D.J. et al. (1999) Circadian and homeostatic control of wakefulness and sleep. Lung Biol
Heal. Dis, 133, 111–47.
57. Aschoff, J. (1971) Energiehaushald und Temperaturregulation. In Physiologie der Menschen pp. 43–112
58. Aschoff, J. et al. (1972) Thermal conductance in man: its dependence on time of day and ambient temperature. In Advances in climatic physiology pp. 334–48
59. Aschoff, J. (1955) The daily course of the body temperature in man. Klin Wochenschr, 33, 545–
551.
60. Aschoff, J. (1892) The circadian rhythm of body temperature as a function of body size. In A
comparison to animal physiology pp. 173–89
61. Aschoff, J. et al. (1958) Kern und schale im wärmehaushal des menschen. Naturwissenschaften,
45, 477–85.
62. Kräuchi, K. (2007) The human sleep wake cycle reconsidered from a thermoregulatory point
of view. 90, 236–245.
63. Refinetti, R. et al. (1992) The circadian rhythm of body temperature. Physiol. Behav., 51, 613–
9
64. Kräuchi, K. et al. (2006) Thermoregulatory effects of melatonin in relation to sleepiness.
Chronobiol. Int., 23, 475–484.
65. Vanggaard, L. et al. (2012) Thermal responses to whole-body cooling in air with special
reference to arteriovenous anastomoses in fingers. Clin. Physiol. Funct. Imaging, 32, 463–469.
66. Nave, R. et al. (1996) Hypnotic and hypothermic effects of melatonin on daytime sleep in
humans: Lack of antagonism by flumazenil. Neurosci. Lett., 214, 123–126.
67. Masana, M. et al. (2002) MT(2) melatonin receptors are present and functional in rat caudal
artery. J. Pharmacol. Exp. Ther., 302, 1295–1302.
68. Viswanathan, M. et al. (1990) Expression of melatonin receptors in arteries involved in
thermoregulation. Proc. Natl. Acad. Sci. U. S. A., 87, 6200–6203.
69. Kräuchi, K. et al. (1999) Warm feet promote the rapid onset of sleep. Nature, 401, 36–37.
70. Raymann, R.J.E.M. et al. (2005) Cutaneous warming promotes sleep onset. Am. J. Physiol. Regul.
Integr. Comp. Physiol., 288, R1589–R1597.
71. Ajwad, A. et al. (2018) Sleep depth enhancement through ambient temperature manipulation
in mice. Proc. Annu. Int. Conf. IEEE Eng. Med. Biol. Soc. EMBS, 2018-July, 1392–1395.
72. de la Iglesia, H.O. et al. (2015) Access to electric light is associated with shorter sleep duration
in a traditionally hunter-gatherer community. J. Biol. Rhythms, 30, 342–350.
73. Yetish, G. et al. (2015) Natural sleep and its seasonal variations in three pre-industrial societies.
Curr. Biol., 25,
74. Stothard, E.R. et al. (2017) Circadian entrainment to the natural light-dark cycle across seasons
and the weekend. Curr. Biol., 27, 1–6.
75. Golombek, D.A. et al. (2010) Physiology of circadian entrainment. Physiol. Rev, 90, 1063–1102.
76. Hughes, S. et al. (2016) Signalling by melanopsin (OPN4) expressing photosensitive retinal
ganglion cells. Eye, 30, 247–254.
77. Pittendrigh, C.S. et al. (1976) A functional analysis of circadian pacemakers in nocturnal
rodents. J. Comp. Physiol. A, 106, 333–355.
78. Cajochen, C. et al. (2000) Dose-response relationship for light intensity and ocular and
electroencephalographic correlates of human alertness. Behav. Brain Res., 115, 75–83.
79. Gooley, J.J. et al. (2011) Exposure to room light before bedtime suppresses melatonin onset
and shortens melatonin duration in humans. J. Clin. Endocrinol. Metab., 96, 463–472.
80. Zeitzer, J.M. et al. (2000) Sensitivity of the human circadian peacemaker to nocturnal light,
melatonin phase resetting and suppression. J. Physiol., 526, 695–702.
81. Cajochen, C. (2007) Alerting effects of light. Sleep Med. Rev., 11, 453–464.
82. Cajochen, C. et al. (2011) Evening exposure to a light-emitting diodes (LED)-backlit computer
screen affects circadian physiology and cognitive performance. J. Appl. Physiol., 110, 1432–
1438.
83. Chellappa, S.L. et al. (2013) Acute exposure to evening blue-enriched light impacts on human
sleep. J. Sleep Res., 22, 573–580.
84. Lavoie, S. et al. (2003) Vigilance levels during and after bright light exposure in the first half of
85. Najjar, R.P. et al. (2014) Chronic artificial blue-enriched white light is an effective
countermeasure to delayed circadian phase and neurobehavioral decrements. PLoS One, 9,
e102827.
86. Ruger, M. et al. (2005) Time-of-day-dependent effects of bright light exposure on human psychophysiology: comparison of daytime and nighttime exposure. AJP Regul. Integr. Comp.
Physiol., 290, R1413–R1420.
87. Smolders, K.C.H.J. et al. (2012) A higher illuminance induces alertness even during office hours: Findings on subjective measures, task performance and heart rate measures. Physiol.
Behav., 107, 7–16.
88. Van Der Lely, S. et al. (2015) Blue blocker glasses as a countermeasure for alerting effects of
evening light-emitting diode screen exposure in male teenagers. J. Adolesc. Heal., 56, 113–119.
89. Lok, R. et al. (2018) White light during daytime does not improve alertness in well-rested
individuals. J. Biol. Rhythms, 33, 637–648.
90. Smolders, K.C.H.J. et al. (2018) Investigation of dose-response relationships for effects of white light exposure on correlates of alertness and executive control during regular daytime
working hours. J. Biol. Rhythms, 33, 649–661.
91. Figueiro, M.G. et al. (2009) Preliminary evidence that both blue and red light can induce
alertness at night. BMC Neurosci., 10,
92. Posner, M.I. (2008) Measuring alertness. Ann. N. Y. Acad. Sci., 1129, 193–199.
93. Moller, H.J. et al. (2006) Sleepiness is not the inverse of alertness: Evidence from four sleep
disorder patient groups. Exp. Brain Res., 173, 258–266.
94. Oken, B.S. et al. (2006) Vigilance, alertness, or sustained attention: physiological basis and
measurement. Clin. Neurophysiol., 117, 1885–1901.
95. Figueiro, M.G. et al. (2015) Light at night and measures of alertness and performance:
implications for shift workers. Biol. Res. Nurs., 18, 90:100.
96. Curcio, G. et al. (2001) Sleepiness: evaluating and quantifying methods. Int. J. Psychophysiol.,
41, 251–263.
97. Van Dongen, H.P.A. et al. (2004) Systematic interindividual differences in neurobehavioral
impairment from sleep loss: evidence of trait-like differential vulnerability. Sleep, 27, 423–433.
98. Cajochen, C. et al. (2003) Role of melatonin in the regulation of human circadian rhythms and
sleep. J. Neuroendocrinol., 15, 432–437.
99. Dijk, D.J. et al. (1992) Circadian and sleep/wake dependent aspects of subjective alertness and
cognitive performance. J. Sleep Res., 1, 112–117.
100. Hull, J.T. et al. (2003) The influence of subjective alertness and motivation on human
performance independent of circadian and homeostatic regulation. J. Biol. Rhythms, 18, 329–
338.
101. Pardi, D. et al. (2016) Eating decisions based on alertness levels after a single night of sleep
manipulation: a randomized clinical trial. Sleep, 40, 1–8.
102. Alexandre, C. et al. (2017) Decreased alertness due to sleep loss increases pain sensitivity in
mice. Nat. Med., 23, 768–774.
103. Horvath, T.L. et al. (1999) Hypocretin (Orexin) activation and synaptic innervation of the Locus
9
104. Hattar, S. et al. (2002) Melanopsin-containing retinal ganglion cells: architecture, projections,
and intrinsic photosensitivity. Science (80-. )., 295, 1065–1070.
105. Sonoda, T. et al. (2016) Re-evaluating the role of intrinsically photosensitive retinal ganglion
cells: new roles in image-forming functions. Integr. Comp. Biol., 56, 834–841.
106. Gooley, J.J. et al. (2003) A broad role for melanopsin in nonvisual photoreception. J. Neurosci.,
23, 7093–7106.
107. Lockley, S.W. et al. (2006) Short-wavelength sensitivity for the direct effects of light on
alertness, vigilance, and the waking electroencephalogram in humans. Sleep, 29, 161–168.
108. Vandewalle, G. et al. (2007) Brain responses to violet, blue, and green monochromatic light
exposures in humans: Prominent role of blue light and the brainstem. PLoS One, 2, 1–10.
109. Vandewalle, G. et al. (2006) Report daytime light exposure dynamically enhances brain
responses. Curr. Biol., 16, 1616–1621.
110. Hattar, S. et al. (2006) Central projections of melanopsin-ex- pressing retinal ganglion cells in
the mouse. J Comp Neurol, 497, 326–349.
111. Fisk, A.S. et al. (2018) Light and cognition: Roles for circadian rhythms, sleep, and arousal.
Front. Neurol., 9, 1–18.
112. Duffy, J.F. et al. (2005) Entrainment of the human circadian system by light. J Biol Rhythm., 20,
326–338.
113. Vetter, C. et al. (2011) Blue-enriched office light competes with natural light as a zeitgeber.
Scand. J. Work. Environ. Heal., 37, 437–445.
114. Czeisler, C. et al. (1980) Human sleep: its duration and organization depend on its circadian
phase. Science (80-. )., 210, 1264–1267.
115. Åkerstedt, T. et al. (2017) Normative data on the diurnal pattern of the Karolinska Sleepiness Scale ratings and its relation to age, sex, work, stress, sleep quality and sickness absence/
illness in a large sample of daytime workers. J. Sleep Res., 26, 559–566.
116. Perrin, F. et al. (2004) Nonvisual responses to light exposure in the human brain during the
circadian night. Curr. Biol., 14, 1842–1846.
117. Vandewalle, G. et al. (2009) Light as a modulator of cognitive brain function. Trends Cogn. Sci.,
13, 429–438.
118. Sherin, J.E. et al. (1996) Activation of Ventrolateral Preoptic neurons during sleep. Science (80-.
)., 271, 216–219.
119. Gvilia, I. (2006) Preoptic area neurons and the homeostatic regulation of rapid eye movement
sleep. J. Neurosci., 26, 3037–3044.
120. Fort, P. et al. (2009) Alternating vigilance states: New insights regarding neuronal networks
and mechanisms. Eur. J. Neurosci., 29, 1741–1753.
121. Moore, J.T. et al. (2012) Direct activation of sleep-promoting VLPO neurons by volatile
anesthetics contributes to anesthetic hypnosis. Curr. Biol., 22, 2008–2016.
122. Lu, J. et al. (2000) Effect of lesions of the ventrolateral preoptic nucleus on NREM and REM
sleep. J. Neurosci., 20, 3830–3842.
123. Chou, T.C. et al. (2002) Afferents to the ventrolateral preoptic nucleus. J. Neurosci., 22, 977–
124. Foote, L. et al. (1991) Effects of Locus Coeruleus activation on electroencephalographic in
activity in Neocortex and Hippocampus. J. Neurosci., 11, 3135–3145.
125. Hagan, J.J. et al. (1999) Orexin A activates locus coeruleus cell firing and increases arousal in
the rat. Proc. Natl. Acad. Sci. U. S. A., 96, 10911–6.
126. Brown, T.M. et al. (2008) Electrophysiological actions of orexins on rat suprachiasmatic
neurons in vitro. Neurosci. Lett., 448, 273–278.
127. Klisch, C. et al. (2009) Orexin A modulates neuronal activity of the rodent suprachiasmatic
nucleus in vitro. Eur. J. Neurosci., 30, 65–75.
128. Winsky-Sommerer, R. (2004) Interaction between the corticotropin-releasing factor system
and Hypocretins (Orexins): A novel circuit mediating stress response. J. Neurosci., 24, 11439–
11448.
129. Lee, H.S. et al. (2005) Retrograde study of hypocretin-1 (orexin-A) projections to subdivisions
of the dorsal raphe nucleus in the rat. Brain Res., 1059, 35–45.
130. Mieda, M. et al. (2002) Sleep, feeding, and neuropeptides: Roles of orexins and orexin
receptors. Curr. Opin. Neurobiol., 12, 339–345.
131. Hermann, D.M. et al. (1997) Afferent projections to the rat nuclei raphe magnus, raphe
pallidus and reticularis gigantocellularis pars
α
demonstrated by iontophoretic application ofcholeratoxin (subunit b). J. Chem. Neuroanat., 13, 1–21.
132. Jacobs, B.L. et al. (2002) Activity of medullary serotonergic neurons in freely moving animals.
Brain Res. Rev., 40, 45–52.
133. Allen, G. V. et al. (1994) Serotoninergic and nonserotoninergic neurons in the medullary raphe system have axon collateral projections to autonomic and somatic cell groups in the medulla
and spinal cord. J. Comp. Neurol., 350, 357–366.
134. Pressman, M.R. et al. (1989) Relationship of autonomic nervous system activity to daytime
sleepiness and prior sleep. Sleep, 12, 239–45.
135. McGinty, D.J. et al. (1976) Dorsal raphe neurons: depression of firing during sleep in cats. Brain
Res., 101, 569–575.
136. Trulson, M.E. et al. (1979) Raphe unit activity in freely moving cats: Correlation with level of
behavioral arousal. Brain Res., 163, 135–150.
137. Zhou, X. et al. (2012) Mismatch between subjective alertness and objective performance
under sleep restriction is greatest during the biological night. J. Sleep Res., 21, 40–49.
138. Aitken, R.C. (1969) Measurement of feelings using visual analogue scales. Proc. R. Soc. Med.,
62, 989–993.
139. Åkerstedt, T. et al. (1990) Subjective and objective sleepiness in the active individual. Int. J.
Neurosci., 52, 29–37.
140. Drummond, S.P. a et al. (2005) The neural basis of the psychomotor vigilance task. Sleep, 28,
1059–1068.
141. Bokura, H. et al. (2001) Electrophysiological correlates for response inhibition in a Go/NoGo
task. Clin. Neurophysiol., 112, 2224–2232.
142. Santamaria, J. et al. The EEG of drowsiness in normal adults. , Journal of Clinical Neurophysiology, 4. (1987) , 327–382.
