Grasping light
Lok, Renske
DOI:
10.33612/diss.173352710
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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
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CHAPTER 1
INTRODUCTION
The importance of light for human well-being.
Light has always been of great importance for humans. Approximately 3500 years before Christ, the Egyptian ruler Akhenaten designed the theology of light, in which light was considered as an absolute reference point that makes life possible, while darkness symbolized death 1. Night and darkness were negatively characterized as
times without sunlight, during which animals and humans remain in their homes as dead until sun rise 1. The first emergence of artificial light was 400.000 year
before the current era (BCE) with the discovery of fire, which offered opportunities for activities after sunset, suggesting that even then people felt the need for light after sunset. With the discovery of the ligWht bulb (1879 and 1880), electrical lighting was a fact. This is now ubiquitous in developed countries.
With the existence of artificial light, the importance of sunlight decreased, since light is available at all times of days. This contributed to the emergence of the 24-hour society, in which day and night-time are interchangeable. Nowadays, much more is known about the health risks of artificial light after sunset on all types of bodily processes, such as glucose tolerance and diabetes 2, but also cancer 3 and
other diseases. Artificial light exposure in the evening at home is known to affect human alertness 4, and sleep quality and sleep timing 5, which might contribute
to the fact that 3.3 million (25.4%) women and 2.6 million (19.6%) men in the Netherlands alone suffer from impaired sleep quality at night 6. Taken all together,
this indicates that light has many varying functions, both related and unrelated to vision.
Light.
Light is defined as “the natural agent that stimulates sight and makes things visible”. A light beam is characterized by its spectral composition and its intensity for each wavelength. Light intensity is defined as the amount of light that is transmitted from a light source. This can be expressed in various objective measures, such as luminance and radiance (strength of the light source) and illuminance and irradiance (light received by the surface), but most often used is irradiance, which is defined as the radiant flux received by a surface per unit area 7,8. The spectral
composition is defined as a range of colours which can be made visible by the different degrees of refraction according to wavelength at the transition of various light transmitted media. Wavelength is defined as the spatial period of the wave or the distance between the wave’s shape repeats and is inversely proportional to frequency of the wave: waves with higher frequencies have shorter wavelengths. Visible light comprises of wavelengths in the range from 400 to 700 nanometres (nm), i.e. between ultraviolet and infrared.
1
Vision.
The human image forming system is located in the retina and comprises of rods and cones. Rods are photoreceptors maximally sensitive to light of 498 nm wavelength and low intensity light, with a slow and transient response, therefore particularly useful in dimly lit circumstances. Cones are less sensitive compared to rods and hence function primarily under high intensity light. There are three different subsets of cones, which respond to different wavelengths of light, with short wavelength cones (S-cones) responding strongest to light of 420 nm, intermediate wavelength cones most sensitive to light of 530 nm (M-cone), and long wavelength cones are activated most by light of 560 nm (L-cone) 8.
For light to be perceived by the eye of mammals, photons have to be absorbed and the presence of such event needs to be detected. Through opsins, a photon is converted into an electrical signal in the retina, which can be transmitted to the brain 9. In rods, the functional opsin is rhodopsin, in S-cones cyanolabe opsin,
M-cones chlorolabe opsin and L-cones erythrolabe opsin 8. The opsins of both
rods and cones are G-protein coupled receptors and contain an 11-cis retinal chromophore, which is the aldehyde of vitamin A1 and the light absorbing portion of the opsin 9. In darkness, the cyclic guanosin monophosphate keeps the
non-selective cyclic-nucleotide-gated (CNG) channels open. When a photon reaches the photoreceptor, 11-cis retinal undergoes photo-isomerization to all-trans retinal 9. This promotes a conformational change in the opsin, leading to a signal
transduction cascade via activation of phosphodiesterase (PDE) and hydroxylation of cGMP, allowing the channel to close, producing membrane hyperpolarization
10,11, leading to depolarisation in connected bipolar cells and ganglion cells which
signal to various visual and non-visual light responsive brain areas.
Non-image-forming effects of light.
In humans, it was shown that rod-less and cone-less individuals without conscious light perception still showed strong synchronization to the natural light-dark cycle (called circadian entrainment). The phase angle of entrainment shifted its timing in response to light 12. This was the first evidence for functions of light not related
to vision, but so called non-visual functions of light. Moreover, genetically modified mice, lacking the classical rod- and cone photoreceptors also showed shifted phase angle of entrainment, especially in response to light of approximately 460 nm 13,14.
These findings implied the existence of another photoreceptor, in addition to rods and cones. The discovery of a new photo pigment in the skin of Xenopus laevis, called melanopsin 15, was evidence for such a photoreceptor. Moreover, melanopsin was
found in a group of retinal ganglion cells (RGCs) 15,16, and it was suggested that light
synchronized internal circadian rhythms to external light-dark cycles by excitatory input to the neurons of the internal circadian pacemaker, the SCN, without input from rods or cones 16. These cells proved to be intrinsically photosensitive and
depolarize in response to light 16. The intrinsically photosensitive retinal ganglion
cells (ipRGC’s) turned out to contain melanopsin 17 and are primarily sensitive to
light of wavelengths around 460 nm (blue range). Later, it was shown that the classical photoreceptors also are involved in circadian entrainment 18,19
In ipRGCs, the first step of photoreception is also 11-cis-retinal conversion into all-trans-retinal. However, due to the conformational change, phospholipase C is activated 10,11. The subsequent steps are not clear yet, but protein kinase C
seems to trigger Calcium influx, producing depolarization 20. A fundamental
difference between ipRGC and the classical photo pigments is the bi-stability of melanopsin. While the functional opsin of the rods (rhodopsin) requires an intricate machinery in the retinal pigment epithelium to recover from the all-trans to the cis conformation, melanopsin is able to recover to the active conformation by absorbing a second, longer wavelength photon 21–23.
Suprachiasmatic Nucleus (SCN).
Circadian rhythms are endogenous rhythms in physiology and behaviour that persist even in the absence of any external time-cues. The term ‘circadian’ originates from Latin, in which ‘circa’ means approximately and ‘dies’ day. Circadian rhythms are therefore rhythms that persist with a cycle of approximately 24 hours. The circadian timing system consists of (1) input pathways that convey information to the circadian pacemaker, (2) the circadian pacemaker itself, and (3) the mechanism leading to expression of rhythmic outputs.
The suprachiasmatic nuclei (SCN) of the anterior hypothalamus is the site of the master circadian pacemaker in mammals (Moore & Eichler, 1972; Ralph, Foster, Davis, & Menaker, 1990; Stephan & Zucker, 1972). The SCN is a group of approximately 10.000 neurons that fire with the same period, and signal internal time to the rest of the body. Circadian rhythms can be found in behavioral and physiological processes, such as (core) body temperature, hormone production, alertness and sleep-wake cycles 27–29. Animal studies indicate that SCN ablation
results in absence of rhythmicity 25,26,30.
In 1960, it was shown for the first time that volunteers, who lived in an isolated bunker without natural light, clocks or other time cues, nevertheless maintained a roughly normal sleep-wake cycle of approximately 25 hours 31 . More recently,
it was found that the human free running circadian rhythm under dim light is actually closer to 24 hours, on average 24.18 hours 32. The Greek letter
τ
(tau)is commonly used to denote the period of this intrinsic rhythm. Together with responses of the circadian system to the imposed light-dark cycle,
τ
contributes to human behavior (such as the sleep-wake cycle). This contributes to the chronotype of humans. A chronotype is the behavioral manifestation of underlying circadian1
rhythms of myriad physical processes and is defined as the propensity to sleep ata particular time during a 24-hour period. Chronotype has both been defined by actual bedtimes 33 or preferred bed times 34. Earlier chronotypes, with a shorter
τ
are prone to go to bed early and wake up more early in comparison to late chronotypes with longerτ
33,34. Chronotype, based on actual bed times is definedas mid-sleep on free days corrected for sleep debt on work days (midpoint of sleep on work-free days, sleep-corrected, MSFsc) 33.
Melatonin production is regulated by the Suprachiasmatic nucleus.
The SCN is connected to many other brain regions, such as the pineal gland, which is the most important brain region involved in the production of the nocturnal hormone melatonin 35. Melatonin is produced in pinealocytes from
L-tryptophan, which can be converted to serotonin (Fig. 1) and subsequently to melatonin. Melatonin signals both time of day (a ‘clock’ function) and time of year (a ‘calendar’ function) to all tissues of the body 36,37. In humans, plasma levels of
melatonin start to rise approximately 2 hours before habitual bedtime and remain elevated during darkness (clock function). In winter, melatonin secretion occurs slightly earlier compared to the summer 38. Light exposure can alter melatonin
secretion, via an indirect pathway from the SCN to the Paraventricular Nucleus (PVN) and sympathetic nervous system 39. A group of PVN neurons that project
to spinal preganglionic sympathetic neurons are also directly inhibited by the SCN. Immediate increase in neuronal SCN activity during light stimulation results therefore in decreased PVN activation of the sympathetic output to the pineal gland, resulting in decreased melatonin secretion 40,41. The melatonin rhythm
in darkness or dim light is often used as indicator of the timing of the human circadian pacemaker 40, as it is easily and reliably detected in human blood,
saliva and urine and melatonin production is not substantially masked by other influence with the exception of light exposure 42. Central and peripheral effects of
melatonin are mediated by MT1 and MT2 receptors 43. Overall, MT1 receptors are
more prevalent than MT2 receptors, with these receptors centrally expressed in the cerebral cortex, thalamus, hippocampus, cerebellum, cornea and retina, while MT2 receptors are expressed in the retina, hippocampus, SCN and cerebellum 44,45.
Peripherally, MT1 and MT2 receptors are expressed in various tissues, including blood vessels, arteries and skin. Central effects of melatonin include sleep promotion, and decreased body temperature through peripheral blood vessel vasodilation.
Figure 1. Neuronal projection and biochemical synthesis pathways involved in melatonin production. Presented pathways involve retina, intrinsically photosensitive retinal ganglion cells,
suprachiasmatic nucleus, paraventricular nucleus and pinealocytes in the pineal gland 46.
Processes that are influenced by the SCN: Sleep and wakefulness.
One of the most influential models in Chronobiology states that there is an interplay between internal clock time and time awake; the two process model of sleep regulation 47 suggests that sleep is regulated by homeostatic and circadian
influences. The homeostatic factor comprises of sleep pressure, which increases with prolonged time awake and reflects sleep propensity, which dissipates during sleep (Fig. 2). The circadian process is a reflection of SCN activity, which alternates between intervals with high- and low sleep propensity. This is independent of prior sleep and wake periods 48,49. The SCN might affect sleep via multiple brain
regions, such as the ventro-lateral preoptic nucleus (VLPO). The VLPO is primarily active during sleep 50–52 and cell-specific lesions of the VLPO reduce sleep by more
than 50% 53. Other brain regions of importance include the sub-paraventricular
zone (SPZ), since lesions in this region disrupt circadian rhythms of sleep and wakefulness 54 and dorsal medial hypothalamus (DMH lesions lead to diminished
rhythms of sleep and wakefulness 54,55. The DMH is thought to be essential for
conveying information of the SCN regarding sleep propensity to the sleep-wake-regulatory system 54,55. Complex interplays between these systems might regulate
1
Figure 2: Schematic representation of the two-process model of sleep. Graph A depicts the original
model, with bold line representing sleep pressure build-up during wakefulness and dissipation during sleep, while the dotted line indicates circadian fl uctuations 47. Graph B depicts the continuous interaction
model, in which sleep pressure and internal clock time are represented by orange and yellow arrows respectively 56.
Processes that are infl uenced by the SCN: Thermoregulation.
One of the bodily processes that is under strong circadian regulation, is human thermoregulation. Thermoregulation can be seen to consist of two compartments, the heat producing core and heat-loss regulating shell. As a consequence, core body temperature (CBT) and skin temperature show very diff erent temporal profi les 57–59. Highest CBT levels usually occur in the late evening (before sleep),
while the minimum occurs in the early morning (before waking up) 60,61. These
rhythmic fl uctuations in CBT occur due to changes in heat production and heat loss, with heat production depending mainly on activity of metabolic active organs such as brain, kidneys and liver. This accounts for approximately 70% of the entire resting metabolic rate 62. Parts of the skin with a high surface to volume ratio, such
as fi ngertips and toes (distal skin temperature, Tdistal), are most effi cient in heat transferal to the environment 63, but other parts like checks, hand palms, and feet
play also an important role in heat transfer. Proximal skin temperature (Tproximal) is
thought to refl ect Core Body Temperature and is regularly measured underneath the clavicles. Core body temperature is strictly regulated in the hypothalamus, with a set-point fl uctuating in a circadian manner around 37 °C. A stable CBT is of importance for many physiological and enzymatic processes.
The circadian rhythm of core body temperature fl uctuation is in phase with levels of Tproximal, while Tdistal rhythms show an inverse pattern 64. Heat (re)distribution
from the core to extremities occurs largely through blood transport. Proximal skin regions contain solely capillaries which, due to the small diameter, cause relatively slow blood fl ow and therefore slow heat exchange. Distal regions, especially in the hands and feet contain, in addition to capillaries, arteriovenous anastomoses
(AVAs), which are thick-walled vessels between arterioles and venules with a relatively large diameter, allowing significant circulation in local blood flow and heat transfer to the environment upon dilation 65.
Multiple parameters that are independently regulated by the SCN, also influence each other. For example, melatonin receptors are located in the preoptic area of the hypothalamus, primarily responsible for CBT regulation. Production of the nocturnal melatonin hormone is therefore associated with a drop in CBT, although there is also variation in CBT due to SCN activity, 4,66. Moreover, MT-1
melatonin receptors are located in precapillary smooth muscles in both proximal and distal skin regions, while MT2-receptors, with vasodilatory properties, are located in AVAs in distal skin regions 45,64,67. This indicates that melatonin can affect
CBT through heat loss regulation by the AVAs in a circadian and direct manner through light suppression. Norepinephrine binding sites located in arteries are
also functional melatonin receptors and can affect the tone of these arteries, adjusting blood circulation and therewith heat distribution 68. Melatonin agonists,
working via MT1- and MT2 receptors, induce significant decreases in CBT and proximal temperature, while increasing distal skin temperature.
Sleep onset is mainly triggered by a strong decline in CBT, while this is also associated with melatonin production. Warm feet, associated with the decrease in CBT caused by melatonin, also promote sleep onset 69,70, while temperature
manipulations during sleep can alter sleep quality 71. Moreover, sleeping at times
of day when the circadian system promotes wakefulness and alertness is difficult, indicating that there is a complex interplay between several parameters that are regulated by the SCN.
How to study circadian rhythms in humans?
To study phenomena that are under circadian regulation is relatively complex, since sleep pressure levels and circadian clock phase vary in opposite direction as a function of time of day. For example, immediately after awakening, the circadian system will promote wakefulness while sleep pressure is relatively low (Fig. 3, green circle). In the late evening, the circadian system will promote sleep, and sleep pressure levels are high due to accumulated sleep need (Fig. 3, red circle). For disentangling the role of these two major influences on parameters under circadian control, measurements need to be performed at multiple clock times and the two major processes need to be varied in time relative to each other.
1
Figure 3. The two process model of sleep with two diff erent times of day highlighted. Internal clock
time and sleep pressure levels immediately after awakening (green) or just before sleep onset (red). Depicted are the two process model of sleep (A; 47) and continuous interaction model (B; 56).
One of the ways to disentangle the eff ects of internal clock time from homeostatic sleep pressure is in a forced desynchrony design (FD, Fig. 4). The principle of a FD design is to enforce a sleep-wake cycle on subjects which is signifi cantly shorter or longer than 24 hours. This cycle deviates so strongly from the usual 24-h light-dark cycle, that the human internal pacemaker can no longer entrain, resulting in free running of internal rhythms, i.e. the clock will cycle according to its own internal period. Since forced sleep and wake periods are scheduled, diff erent combinations of internal clock time and sleep pressure levels will occur (Fig. 4). After completion of the protocol, it is possible to mathematically disentangle eff ects of sleep pressure and circadian clock time.
Figure 4. The principle of a forced desynchrony design represented in a double plot. In this example,
a sleep-wake cycle of 28 h is imposed with sleep occurring in darkness and wakefulness in dim light. This 28-h dark-dim light dark cycle is outside of the range of entrainment for the humans circadian system and as a result, sleep will occur at diff erent phases of the circadian cycle, allowing to disentangle circadian infl uences from eff ects of sleep and wake state (homeostatic infl uences). If testing a parameter of interest at 24:00 (dotted line), then internal time would be the same throughout every calendar day of the protocol (under the presumption that the SCN does not alter its intrinsic period). Due to scheduled sleep-wake times however, the duration that an individual is awake will diff er on every FD day (blue arrows).
Circadian rhythms and non-image forming eff ects of light.
In the absence of time cues, internal rhythms usually cycle with a period longer than 24 hours 31,32. One solar day lasts approximately 24 hours, since that is the
time it takes for the earth to rotate so that the sun appears at the same place in the sky the next day. However, the earth rotates in an elliptical orbit around the sun, resulting in a day length slightly longer (in the order of 10 seconds) during winter compared to summer. Nevertheless, this day-night cycle enables synchronisation of non-24h internal circadian rhythms to the 24-h rhythms in the environment. Disturbances to the solar light-dark cycle by artifi cial lighting has made it increasingly more diffi cult to synchronize internal and external rhythms with an optimal phase angle of entrainment. Moreover, the amount of time that humans spend outdoors in full daylight as opposed to (lower light intensity) indoor light is very limited or absent in modern societies. Taken together, these two aspects result in blunted entrainment signals to the internal clock, with less daylight exposure and longer periods of artifi cial light exposure, as opposed to before the emergence of electrical lighting. That this truly infl uences circadian rhythms has been demonstrated by studying traditional hunter-gatherer tribes, who do not have electrical lighting, resulting in earlier bed- and rise times 72,73.
Even in western countries, absence of electrical lighting has indicated earlier sleep and rise times. Relative to regular in-home electrical lighting, a weekend camping
1
Thesis overview.
The introduction presented here raises important questions about effects of (artificial) light on the internal clock and therewith on various facets of everyday life. In this thesis, effects of artificial light on multiple psychological and physiological factors, including alertness, melatonin and cortisol production, thermoregulation, physical performance, sleep, appetite and metabolism are studied. Moreover, it is assessed how these effects depend on time of day and internal clock time. Chapter 2 provides a detailed overview on the concept of alertness, how this is influenced by the SCN, and how to assess human alertness. It also describes previously published literature reporting light effects on alertness during daytime. In Chapter 3, effects of various intensities of artificial light on alertness during daytime are presented. The goals of this study were (1) to design a dose-response curve between light intensity and alertness, and (2) to determine whether human alertness can be improved during daytime by increased light exposure. To gain further insight into underlying mechanisms of alerting effects of light, first the underlying relationship between melatonin, thermoregulation and light was investigated (Chapter 4), while second, a forced desynchrony design was conducted to investigate effects of homeostatic sleep pressure and internal clock time on alertness (Chapter 5). Chapters 6 and 7 cover other data collected during a forced desynchrony design, in which Chapter 6 discusses light effects on human thermoregulation and Chapter 7 describes effects of high intensity lighting on subsequent subjective and objective sleep quality as a function of internal clock time. Time of day effects on physical (in addition to mental) performance are studied in professional athletes (Chapter 8).
Figure 5. Overview of effects of the central pacemaker and light-dark cycle on sleep-wake rhythmicity, alertness, melatonin production, and core body temperature.
