Grasping light
Lok, Renske
DOI:
10.33612/diss.173352710
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Publication date:
2021
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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 4
DAYTIME MELATONIN AND
LIGHT INDEPENDENTLY
AFFECT HUMAN
ALERTNESS AND BODY
TEMPERATURE
Renske Lok
1,2, Minke J. van Koningsveld
1, Marijke C.M.
Gordijn
1,3, Domien G.M. Beersma
1, Roelof A. Hut
11University of Groningen, Chronobiology unit, Groningen Institute for
Evolutionary Life Sciences, PO box 11103, 9700CC, Groningen, the Netherlands.
2University of Groningen, Campus Fryslân, Wirdumerdijk 34, 8911 CE,
Leeuwarden, the Netherlands.
3Chrono@Work B.V. Friesestraatweg 213, 9743 AD Groningen, The
Netherlands
Abstract.
Light significantly improves alertness during the night 81,86, but results are less conclusive at daytime 197. In addition to differences in sleep pressure, differences in melatonin and core body temperature levels at those times of day might evoke different responses in alerting effects of light. In this experiment, the combined effect of daytime exogenous melatonin administration and light intensity on alertness, body- and skin temperature was studied. The goal was to assess whether (1) alerting effects of light are melatonin dependent, (2) soporific effects of melatonin are mediated via the thermoregulatory system, and (3) if light can improve alertness after melatonin-induced sleepiness levels during daytime. 10 participants participated in a within-subjected design (lasting from 12:00-16:00), comprising of 5 mg melatonin administration under dim (10 lux) and bright light (2000 lux) conditions and a placebo control under these light conditions. Melatonin concentrations were determined in saliva. Alertness (subjective and performance) was assessed half hourly. Body- and skin temperature were measured continuously. Melatonin administration increased salivary melatonin concentrations in all subjects. Subjective sleepiness and distal skin temperature increased after melatonin ingestion. Bright light exposure after melatonin administration did not change melatonin concentrations nor subjective alertness scores, but body and proximal skin temperature increased, while distal skin temperature decreased. Light exposure did not significantly affect these parameters in the placebo condition. These results indicate that (1) exogenous melatonin administration during daytime increases subjective sleepiness, implicating a role for melatonin in sleepiness regulation. (2) Bright light exposure after melatonin ingestion significantly affected thermoregulatory parameters without altering subjective sleepiness scores, therefore temperature changes are non-essential for sleepiness induced by melatonin. (3) Subjective sleepiness was increased by melatonin ingestion, but bright light administration was not able to improve melatonin induced subjective feelings of sleepiness nor performance. Other (physiological) factors may therefore contribute to differences in alerting effects of light during day- and nighttime.
Keywords: Human, Melatonin, Placebo, Alertness, Performance, Body
Daytime melatonin and light independently affect human alertness and body temperature
4
Introduction.
The suprachiasmatic nucleus (SCN) is the pacemaker of the mammalian circadian timing system. Many physiological rhythms are regulated by the SCN, like melatonin secretion and core body temperature 232,233. Concentrations of melatonin rise during the evening and peak at night, while concentrations are virtually zero during daytime in most people 234. Core body temperature (CBT) peaks in the evening and has its nadir in the early morning 28. Daily melatonin and core body temperature patterns show day to day stability. Strong correlations between the rhythm of melatonin production and CBT fluctuations have been shown 28,235. Alertness, which is associated with high levels of environmental awareness, also fluctuates in a circadian manner 175, with decreasing levels during the evening and night, lowest levels in the early morning, and high levels during daytime. Since melatonin, CBT and alertness follow circadian patterns in a stable relationship, mutual regulatory relationships have been suggested 28. Light induced melatonin suppression is associated with decreased sleepiness 81,107, although probably not at intermediate indoor light levels 86,177. Melatonin ingestion increases subjective sleepiness and lowers CBT 4. Moreover, CBT manipulations through heating or cooling, affect subjective sleepiness at times of day when melatonin is virtually absent, suggesting a relationship between CBT and sleepiness independent of melatonin 195.
Alertness is known to affect many functions, such as performance, psychological and physiological well-being, caloric intake and pain sensitivity 95,96,101,102. Thus, displaying optimal alertness is beneficial and many studies have attempted to improve alertness using monochromatic or polychromatic light (for review, see 170,197. Exposure to light (of various spectral compositions, light intensities and exposure durations), improves alertness during nighttime, when melatonin concentrations are usually high and CBT decreases 81,86,227,95,107,116,163,171,177,225,22 6. However, several studies report absence of light induced alertness during daytime, when alertness and CBT levels are high and melatonin is absent (87,89,185– 187,189,193–195,197,90,109,163,179,180,182–184 , but for contradictory data see 86,188). Since alertness decreases during the night, but remains high during daytime, maximal alertness may reach a ceiling during daytime, preventing light to further increase alertness. Differences in melatonin- and CBT levels might contribute to these dissimilarities in light induced alertness.
In the Netherlands, melatonin is sold over the counter up until 5 mg units for self-treatment of sleep and jet-lag problems 236,237 and to induce circadian phase shifts 238. Administration of exogenous, supra-pharmacological, levels of melatonin have resulted in increased levels of subjective sleepiness 228. Sleepiness inducing effects of melatonin have been established at varying concentrations and are accompanied by changes in CBT, which are possibly posture dependent
228. Sleepiness inducing effects of melatonin have been attributed to its highly permeable characteristics 239, which facilitates passing the blood brain barrier and allows to affect hypothalamic CBT regulation.
Effects of melatonin administration alertness have been studied before 228, but not in relation to light during daytime. Exogenous melatonin decreases alertness, but its concentration is unaffected by light. By studying the combined effects of melatonin and light on alertness and CBT and skin temperature regulation, it can be assessed whether (1) alerting effects of light are melatonin suppression dependent, (2) soporific effects of melatonin are mediated via the thermoregulatory system, and (3) if light induced alertness depends on melatonin-induced sleepiness level during daytime. The goal of this experiment was therefore to investigate these underlying relationships using exogenous melatonin and bright light exposure.
Materials and Methods.
Participants. Subjects (5 female, 5 male), aged 20-30 years all gave written informed
consent and received financial compensation for participation. The study protocol, screening questionnaires and consent forms were approved by the medical ethics committee of the University Medical Center Groningen (NL61863.042) and were in agreement with the Declaration of Helsinki (2013). Participants reported no health problems (assessed via an in-house developed general health questionnaire), were intermediate chronotypes (Munich Chronotype Questionnaire 203, mid-sleep on free days corrected for sleep debt on work days (MSFsc ) between 3.88 - 6.17) and did not report sleep problems (Pittsburgh Sleep Quality Index
<
6; 204). Exclusion criteria were: 1) chronic medical conditions or the need for (sleep)medication use, including melatonin, 2) shift work three months before participation, 3) having travelled over multiple time-zones within two months before participation, 4) smoking, 5) excessive use of alcohol (>
3 consumptions per day), 6) use of recreational drugs in the last year, 7) a body mass index outside the range of 18 to 27, 8) inability to complete the Ishihara color blindness test 205 without errors. Participant characteristics can be found in table S1.Protocol. The experiment was conducted in April and May 2018. Local time is
expressed as GMT+2. Subjects arrived at the human isolation facility of the University of Groningen at 11:30 AM, where they stayed in individual rooms under dim light (DL) conditions (Fig. 1). Participants were equipped with DS1922L Ibuttons® (Thermochron, Australia) for measuring skin temperature on the forehead (Tforehead), navel (Tnavel), right and left subclavicular regions (Tsubclavicular), hand palms (Thands), underneath the feet (Tfeet) and in the pulp of the first toe (Ttoe). An Actiheart monitor (CamNTech, United Kingdom) was attached to the left chest to measure heartrate. Participants were seated at a desk in a semi-recumbent position. The protocol started with one hour of habituation. At 01:00 PM, participants were
Daytime melatonin and light independently affect human alertness and body temperature
4
given either a placebo (empty gelatin capsule) or melatonin pill (identical gelatin capsule filled with 5 mg time release melatonin, Melatomatine®, Vemedia, the Netherlands). 90 minutes after placebo or melatonin intervention, participants either completed the experiment under DL conditions or were exposed to bright light (BL), lasting for 90 minutes. Test sessions to assess alertness were completed half hourly from 12:00 AM onwards until the end of the paradigm. Heartrate and skin temperature were measured continuously. Each participant received both placebo and melatonin in the DL and BL condition. Participation was separated by at least one week, and subjects participated on the same day of the week. They were blinded to the melatonin or placebo intervention, therefore rendering a balanced, single blind within-subject design.
Figure 1: Schematic representation of the experimental design. The protocol lasted from 12:00 AM
till 04:00 PM and comprised of an hour of habituation, followed by the placebo or melatonin intervention and subsequent dim or bright light exposure.
Test session. At the start of a test session, saliva was collected using Sarstedt
Salivettes with a cotton swab (Sarstedt BV, Etten-Leur, the Netherlands). Subsequently, participants placed a core body temperature (CBT) pill (e-CELSIUS performance, BodyCap, France, 60 second sampling interval with ±0.2ºC accuracy and 0.1ºC variability level) under the tongue to measure temperature underneath the tongue (Ttongue). Participants completed the Karolinska Sleepiness Scale (KSS; 139), which was followed by a 5-min auditory Psychomotor Vigilance task (PVT 240, E-prime version EP2Pro2.0.10.242). After completion, participants were allowed to remove the CBT-pill. Skin temperature (60 sec sampling interval, 0.0625ºC resolution, 0.5ºC accuracy) and heartrate (15 seconds sampling interval) were measured continuously throughout the experiment.
Light exposure. DL and BL polychromatic white light was delivered by a modified
Philips Energy Up light (HF3419/02, Philips, Drachten, the Netherlands)(Fig. S1 and Table S2). The light was placed at a distance of 20 cm, generating 2000 lux (BL) or 10 lux (DL, by covering the lamp with neutral density filters) at eye level.
Data pre-processing: PVT. For every individual, errors of omission were defined
as average of all test sessions + two standard deviations, anticipation errors as average of all test sessions - two standard deviations and commission errors as responding to non-target stimuli.
Data pre-processing: Skin temperature. Outliers with absolute consecutive
temperature change exceeding 2ºC were omitted. Distal (Tdistal) and proximal (Tproximal) skin temperature was calculated as the average temperature of Thands and Tfeet, and of Tsubclacivular, respectively. The distal-proximal gradient (TDPG) was calculated as the distal minus proximal skin temperature (Kräuchi et al., 1997).
Data analysis: general. Data of heartrate measurement was analyzed using
Actiheart software (version 4.0.116) and can be found in Fig. S2. Results of Ttongue measurements were averaged per test session when temperatures reached the asymptote after placement underneath the tongue. To correct for between-subject variations, all data was z-transformed at an individual level. To assess effects of melatonin administration on alertness, data after melatonin or placebo administration was expressed relative to alertness assessed at 01:00 PM. To determine effects of the light intervention, data collected during the last three test session was expressed relative to data collected at 2:30 PM. Skin temperature data was averaged over 5 minutes prior to both interventions for normalization. A 5-minute running average was calculated to smooth short-term fluctuations.
Data analysis: melatonin. Saliva samples were stored at -20ºC until analysis.
Samples were defrosted and diluted, ranging from 0 to 500 times, resulting in values within the range of the standard curve. Dilution curves were tested for linearity. Radioimmunassay (RIA) analysis (RK-DSM2; Bühlmann Laboratories AG, Schönenbuch, Switzerland) was used to determine melatonin concentrations. The limit of detection was 0.5 pg/mL, with 13.1% intra-essay variation.
Statistics. Linear models were constructed in RStudio (version 1.0.136) and used
to determine intervention effects on subjective sleepiness, PVT performance, Ttongue, skin temperature and heartrate measurements, as dependent variables. Continuous data was grouped into half hourly bins. Independent variables were time of day and intervention. Fixed effects consisted of time of day (as categorical variable), intervention and the interaction term. Critical two-sided significance level alpha was kept at 0.05 for all statistical tests.
Results.
Administration of exogenous melatonin resulted in increased salivary melatonin concentrations (F1,114=11.55, p=1.26e-6)(Fig. 2). Approximately 1.5 hours after melatonin administration, concentrations peaked (Fig. 2C and D). Bright light
Daytime melatonin and light independently affect human alertness and body temperature
4
exposure did not alter melatonin concentrations, neither after placebo (F1,49=0.63, p=0.43) nor melatonin (F1,49=0.042, p=0.84) administration. Individual data can be found in graph S3. Melatonin levels had decreased to pre-administration levels during the dim light intervention in one subject, therefore this subject was excluded from further analysis.
Figure 2: Time course of melatonin concentrations. Concentrations were determined by half hourly
saliva samples, before and after placebo/melatonin administration. All data represent mean (black dots)
± standard error of the mean (grey), N=10 per group.
In the first 90 minutes after melatonin administration, there was a significant increase in subjective sleepiness, without a significant change in Ttongue (Fig. 3C). 10% slowest reaction times on the PVT were unaffected by melatonin ingestion. Light level exposure did not affect subjective sleepiness after placebo or melatonin ingestion, nor did it affect Ttongue after placebo ingestion. After melatonin administration however, BL exposure significantly increased Ttongue (Fig. 3D). Slowest performance was unaffected by light exposure, both after placebo and melatonin ingestion. There were no significant effects of melatonin or light administration on other output measures of performance, such as the 10% fastest reaction times, anticipation errors or lapses (p
>
0.05).Figure 3: Effects of melatonin and light on sleepiness, Ttongue and slowest reaction times. A) Original
data. B) Z-transformed data. C) Effects of melatonin in the dim and bright light group. D) Effects of light during the interval after placebo or melatonin administration. Data in C and D data are expressed relative to values at 13:00. E and F data are expressed relative to values at 14:30. DL data are depicted in orange (placebo) and dark blue (melatonin), BL data are yellow (placebo) and light blue (melatonin). All data represent mean ± standard error of the mean, N=10 per group, except for panel D, in which N=9 per group.
Table 1: Statics of melatonin and light effects on sleepiness, Ttongue and performance. Values from
linear mixed models on z-transformed data.
Effect of
melatonin Effect of light after placebo
ingestion Effect of light after melatonin ingestion Df F p Df F p F p Subjective sleepiness 1,114 114
<
0.001 1,49 0.94 0.33 0.10 0.75 Ttongue 1,114 1.27 0.29 1,49 0.22 0.64 0.32 0.003 Performance 1,114 0.42 0.73 1,49 1.99 0.30 1.10 0.30 Melatonin administration increased temperature measured in Thands and TDPG (Fig.4C). Other skin temperature parameters, such as Ttoes, Tfeet, Tsubclaviarular, Tnavel and Tforehead were unaffected by melatonin administration. BL exposure after placebo ingestion significantly increased Thands and TDPG, while other parameters were unaffected (Fig. 4D). BL administration after melatonin ingestion significantly decreased Tdistal and TDPG, while Tproximal increased.Daytime melatonin and light independently aff ect human alertness and body temperature
4
Figure 4: Eff ects of melatonin and light on skin temperatures. A) Original data. B) Z-transformed
data. C) Eff ects of melatonin in the dim and bright light group. D) Eff ects of light during the interval after placebo or melatonin administration. Data in C and D data are expressed relative to values at 13:00. E and F data are expressed relative to values at 14:30. DL data are depicted in orange (placebo) and dark blue (melatonin), BL data are in yellow (placebo) and light blue (melatonin). All data represent mean ± standard error of the mean, N=10 per group, except for panel D, which includes N=9 subjects.
Table 2: Statics of melatonin and light effects on skin temperatures. Values from linear mixed
models on z-transformed data.
Effect of melatonin Effect of light after
placebo ingestion Effect of light after melatonin ingestion
Df F p Df F p F p TToes 1,114 0.51 0.67 1,49 0.55 0.46 8.30 0.005 TFeet 1,114 0.64 0.56 1,49 0.17 0.68 0.00 0.98 THands 1,114 4.83 0.004 1,49 10.22 0.002 3.94 0.04 Tsubclavicular 1,114 1.99 0.12 1,49 2.21 0.14 9.93 0.002 TNavel 1,114 0.14 0.94 1,49 0.00 0.95 0.02 0.88 TForehead 1,114 0.00 0.99 1,49 2.25 0.14 1.52 0.22 TDPG 1,114 7.00 <0.001 1,49 6.30 0.01 6.75 0.01
Discussion.
Our results indicate that exogenous melatonin administration during daytime increases salivary melatonin concentrations to supra-pharmacological levels and that this coincides with a decrease in subjective alertness, implicating a possible role for the nocturnal hormone in alertness regulation. This decrease in alertness was accompanied by an increase in Tdistal and TDPG, leaving a possible role for the thermoregulatory system in sleepiness inducing effects of melatonin. Bright light administration after melatonin ingestion however, did not alter melatonin concentrations, but did increase Tproximal, Ttongue and did decrease Tdistal, indicating that light is able to counteract thermoregulatory effects of exogenous melatonin. Importantly, subjective sleepiness was not significantly altered by bright light exposure. Since thermoregulatory changes due to the light intervention occurred without affecting subjective sleepiness, thermoregulatory processes seem not directly related to alerting effects of light under high melatonin levels. It has been described that light can increase alertness at night, but results are less conclusive during daytime, possibly due to relatively high levels of alertness during the day. Since subjective sleepiness was increased by melatonin ingestion, but bright light administration did not affect subjective feelings of sleepiness nor performance, light cannot restore melatonin induced sleepiness.
Studying underlying relationships using elevated melatonin levels. A possible
disadvantage of using exogenous melatonin to study underlying relationships between melatonin, sleepiness and temperature, is that detected concentrations are far above endogenous levels (for a review, see 241). Underlying relationships suggested here may therefore not reflect regulatory relationships under natural circumstances. In our local population, 5 mg melatonin administration resulted in
Daytime melatonin and light independently affect human alertness and body temperature
4
higher compared to endogenous concentrations 242. Soporific and thermoregulatory effects of melatonin have however been reported when exogenous melatonin intake increases circulating melatonin levels within the nocturnal physiological range 243. Moreover, endogenous brain melatonin concentrations are estimated to be 6 to 20 fold higher than in serum 244–247. It is possible that concentrations reaching the brain after exogenous melatonin administration, especially since melatonin is highly lipophilic and can easily pass the blood-brain barrier, are comparable to endogenously produced levels during darkness. Therefore, effects reported in this study might approximate effects determined after endogenous production. Furthermore, subjective sleepiness levels reported during endogenous melatonin production, are comparable to those reported here after exogenous melatonin ingestion 115, as do the relative changes in T
DPG 248. This supports the notion that brain melatonin levels after exogenous ingestion might approximate those during endogenous production.
A role for melatonin in alertness regulation. Regulatory relationships between
melatonin and alertness have been suggested 81,228. Our study shows that daytime administration of 5 mg melatonin leads to a significant increase in subjective sleepiness, with a peak 60-90 minutes after melatonin ingestion, which coincides with a peak in melatonin concentration. Moreover, subjective sleepiness ratings decrease as melatonin concentrations diminish as well. This data supports the idea that exogenous melatonin plays a role in alertness regulation. Endogenous melatonin production only occurs during darkness, indicating that in diurnal animals this hormone may have a natural function in signaling the optimal time for sleep and sleepiness 249. Moreover, one of the distinct functions of melatonin in humans is priming of sleep associated brain activation patterns 244, as it provides information about environmental light conditions and therefore time of day 250. The relatively fast soporific effects of melatonin suggest that this might be a direct physiological consequence 243, independent of melatonin’s action as zeitgeber signal 251,252.
Melatonin effects on thermoregulation and alertness. The mechanisms
by which exogenous melatonin increases sleepiness are not known yet. Since melatonin is highly lipophilic, it can easily pass the blood brain barrier 239. Binding sites for melatonin have been found in hypothalamic areas associated with thermoregulatory processes as well as circadian rhythmicity 253. Projections from the SCN to the preoptic area of the hypothalamus cause circadian modulations of CBT 254 and nocturnal secretion of melatonin, also regulated by the SCN, plays an important role in CBT regulation in the evening 255. The circadian rhythm of melatonin production is in phase with levels of Tdistal, while Tproximal rhythms show an inverse pattern 64. Heat (re)distribution from the core to extremities occurs through blood transport. Proximal skin regions contain solely capillaries, which due to the small diameter, cause relatively slow blood flow. The circadian time
course of blood flow through capillaries in proximal regions follows therefore the time course of CBT. Distal regions contain, in addition to capillaries, arteriovenous anastomoses (AVAs), thick-walled vessels between arterioles and venules with a relatively large diameter, allowing significant circulation in local blood flow rates and heat transfer to the environment 65. Blood flow rate in T
distal follows the inverse pattern of CBT. Melatonin receptors, such as the vasoconstrictive MT1-receptor, are located in precapillary smooth muscles in both proximal and distal skin regions. MT2-receptors, with vasodilatory properties, are located in AVAs in distal skin regions 45,64,67. This indicates that melatonin might also affect skin temperature locally, in addition to centrally. 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 increases in DPG. A dose response relationship between melatonin and CBT has been established 256. Since melatonin affects temperature regulation on multiple levels and changes in body temperature correlate to altered alertness 257, it might be that melatonin induces alertness reduction due to changes in body and skin temperature. Our experiment indicates that melatonin administration did not result in a significant decrease in Ttongue, although subjective sleepiness did decrease. It has been indicated however, that subjective sleepiness may change due to changes in Tdistal64. In this study, the increase in Tdistal was paralled by an increase in subjective sleepiness, indicating that melatonin may indeed induce sleepiness through thermoregulatory effects. However, bright light exposure was able to counteract thermoregulatory effects of melatonin, possibly via activation of the sympathetic nervous system. Tdistal decreases, while Tproximal is heated, which ultimately leads to an increase in Ttongue. Temperature effects occurred without significantly altering subjective sleepiness scores, indicating that soporific effects of melatonin might not depend on thermoregulation after all. This has also been indicated in other studies 258. It should be noted however that thermoregulatory effects might be posture dependent, since orthostatic changes (standing up) block soporific effects, probably via sympathetic nerve activity 259. Our study, in which participants were constantly seated in a semi-recumbent position, adds to the body of literature indicating that it is not thermoregulatory alterations that induce sleepiness. However, other studies have reported decreased sleepiness due to a decrease of 1 ºC in Tdistal 64. In our study, light was able to decrease Tdistal with approximately 0.5ºC. It is possible that temperature changes were not extensive enough to induce sleepiness changes. Alternative mechanisms via which melatonin might induce sleepiness are via the GABA chloride channel complex 260 or attenuation of SCN-dependent mechanisms responsible for promoting and maintaining cortical and behavioral arousal 261 by inhibiting the wakefulness generating system in the brain 262,263.
Daytime melatonin and light independently affect human alertness and body temperature
4
Lack of alerting effects of light after melatonin induced sleepiness. Our study
did not demonstrate alerting effects of light after placebo ingestion, indicating
that light under these circumstance does not induce alertness during daytime, as we have shown before 89. This emphasizes differences between night and day, since alerting effects of light during the night have been reported 170,197. A possible explanation is based on the high level of (subjective) daytime alertness, causing a possible ceiling effect 115. Exogenous melatonin ingestion was able to increase subjective sleepiness, therefore removing a potential ceiling of maximal alertness during the day and allowing for alertness improvement by light. Although subjective sleepiness feelings did decrease in parallel to decreasing melatonin levels, this was not influenced by bright light exposure. Since there was no significant effects of light on feelings of alertness, even after inducing additional sleepiness by exogenous melatonin, there are three possible explanations: (1) melatonin might not have reduced alertness sufficiently, therefore the ceiling of alertness might not have decreased enough to induce alerting effects of light, (2) a ceiling effect does not explain the lack of alerting effects of light during daytime, or (3) light cannot induce alertness when melatonin concentration are high. Since subjective sleepiness scores after melatonin administration are similar to those reported during the late evening, when alerting effects of light have been found 4, it is possible that a ceiling effect does not explain discrepancies between night and day. However, imaging studies have shown that although both melatonin and sleep deprivation increase sleep propensity and induce similar levels of sleepiness, there are clear differences in brain activity patterns 244. Melatonin administration induces changes in brain activity patterns resembling patterns seen during sleep, while sleep deprivation does not. Although melatonin administration and sleep deprivation induction have similar effects in terms of subjective sleepiness scores, underlying neuronal mechanisms might be very different. Studies investigating alerting effects of light during the day after sleep deprivation do find significant effects 188,189 while several studies that do not impose sleep deprivation do not (for a review see 170,197). Another mechanism by which melatonin could affect levels of sleepiness is by affecting the circadian regulation of sleep and sleepiness, since melatonin is also known for its phase shifting properties 264. Sleep deprivation alters sleep pressure, suggesting that an increased level of sleep pressure is important for allowing alerting effects of light 244. Positive effects of light on subjective sleepiness levels have been found after exogenous melatonin administration in the evening, indicating that light
can induce alertness when high levels of melatonin are present and supporting
the notion that other (physiological factors), such as sleep pressure, might be of importance for alerting effects of light 265. Noteworthy is the fact that although subjective measures and most physiological measures reflect a significant increase in sleepiness, performance remains unaffected by either melatonin or light intervention during daytime. This contrasts with another study where effects of different concentrations of melatonin were found to impair performance 243.
Multiple studies, including this study, suggest that cognitive performance tasks might not be an accurate indication of alertness 157,170 since performance does not correlate with validated subjective measures of alertness or any of the temperature parameters that are associated with sleepiness. Some studies even indicate that correlates between subjective alertness and physiological measures of alertness are stronger compared to performance tasks 162.
Conclusion. In conclusion, 5 mg oral melatonin ingestion causes a significant
increase in distal skin temperature and subjective sleepiness, without affecting performance. Bright light exposure after melatonin ingestion does not reduce subjective sleepiness, but does increase body temperature and proximal skin temperature, while decreasing distal skin temperature. Melatonin might not induce sleepiness via the thermoregulatory system, since temperature can be restored without affecting alertness. Through which mechanisms melatonin does induce sleepiness, remains unknown. Bright white light exposure was not able to induce significant changes in subjective alertness after melatonin induced sleepiness. As alerting effects of light after exogenous melatonin administration have been determined in the evening, dissimilarities in alerting effects of light between night and day might be caused by different mechanisms underlying feelings of sleepiness, possibly due to differences in (physiological) parameters, such as core body- and skin temperature, and/or sleep pressure levels.
Conflict of interest.
The authors have declared the following potential conflict of interest with respect to the research, authorship, and/or publication of this article: Philips Drachten has made an inkind contribution to the experiment. Dr. Gordijn reports receiving consultancy fees from Philips Consumer Lifestyle, not related to the submitted work.
Funding.
This research was funded by the University of Groningen Campus Fryslân (Grant No. 01110939; co-financed by Philips Drachten and Provincie Fryslân).
Data availability.
Original data, analyses, and R-codes can be accessed by contacting the corresponding author. The complete data-set (original and analyzed) and R-codes are also available at the data repository at the University of Groningen.
Daytime melatonin and light independently affect human alertness and body temperature
4
Supplementary information
Table S1: Participant characteristics
Characteristic Mean ± SEM
Age (y) 23.20 ± 1.08
MSFsc 4.77 ± 0.27
PSQI 3.00 ± 0.42
Caffeine (cups) 1.11 ± 0.35
BMI (kg/m2) 21.47 ± 0.37
Table S2: Photometric properties of background- and experimental light according to the Lucas file8
Type Color
temperature (K)
Illuminance
(lux) Cyanopic (lux) Melanopic (lux) Rhodopic
(lux)
Chloropic
(lux) Eyrthropic (lux)
Dim light 5800 10 10.1 9.71 9.78 10.21 9.89
Bright light 5800 2000 1744 1933 1934 1975 1925
Figure S1: Spectral composition of dim- (dashed line) and bright light (solid line). Illuminance was
measured on the vertical plane at the level of the eye. The light was generated with a modified Philips Energy Up light, in which two white LEDs had been substituted by two blue LEDs.
Figure S2: Effects of melatonin and light on heartrate and inter-beat interval. A) Original data. B)
Z-transformed data. C) Effects of melatonin in the dim and bright light group. D) Effects of light during the interval after placebo or melatonin administration. Data in C and D data are expressed relative to values at 13:00. E and F data are expressed relative to values at 14:30. DL data are depicted in orange (placebo) and dark blue (melatonin), BL data are yellow (placebo) and light blue (melatonin). All data represent mean ± standard error of the mean, N=10 per group, except for panel D, in which N=9 per group.
Table S3: Statics of melatonin and light effects on heartrate and inter-beat interval. Values from
linear mixed models on z-transformed data.
Effect of melatonin under dim light Effect of melatonin under bright light Effect of light after placebo ingestion Effect of light after melatonin ingestion Df F p F p Df F p F p Heartrate 1,55 0.15 0.70 5.49 0.02* 1,49 0.08 0.77 0.81 0.37 Inter-Beat Interval 1,55 2.13 0.15 0.07 0.79 1,49 3.23 0.08 0.41 0.53
Daytime melatonin and light independently affect human alertness and body temperature
4
Figure S3: Individual data of melatonin concentrations of placebo/melatonin interventions plotted against time of day. Placebo/melatonin and dim/bright light administration is indicated by top panels.
Figure S4. Relationship between temperature measured underneath the tongue and distal-proximal gradient. A significant positive correlation between temperature measured under the tongue
and distal-proximal gradient could be detected (p=0.0001).
Ttongue as proxy for CBT. Temperature variations were measured with skin
temperature measurements on various proximal and distal locations as well as underneath the tongue. CBT is usually measured rectally, tympanic or esophageal, and is relatively costly and/or invasive. Variation in Ttongue resembled variation in Tcollarbone and Tnavel, which are thought to be skin temperature proxies for CBT.
Furthermore, correlations between Ttongue and distal proximal gradient exist, which
reveal a similar pattern as found in literature between CBT and DPG 255. Taken
together, these are strong indications that Ttongue can be considered to resemble CBT, but more importantly might reflect the more measure of head temperature, which might be more relevant for cognitive performance.
Daytime melatonin and light independently affect human alertness and body temperature
