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Toward optimizing lighting as a countermeasure to sleep and circadian disruption in space flight
Acta Astronautica 56 (2005) 1017 – 1024 www.elsevier.com/locate/actaastro
Toward optimizing lighting as a countermeasure to sleep and circadian disruption in space flight Robert L. Fucci, James Gardner, John P. Hanifin, Samar Jasser, Brenda Byrne, Edward Gerner, Mark Rollag, George C. Brainard∗ Thomas Jefferson University, Philadelphia, Pennsylvania, USA Available online 8 March 2005
Abstract Light is being used as a pre-launch countermeasure to circadian and sleep disruption in astronauts. The effect of light on the circadian system is readily monitored by measurement of plasma melatonin. Our group has established an action spectrum for human melatonin regulation and determined the region of 446–477 nm to be the most potent for suppressing plasma melatonin. The aim of this study was to compare the efficacy of 460 and 555 nm for suppressing melatonin using a within-subjects design. Subjects (N = 12) were exposed to equal photon densities (7.18 × 1012 photons/cm2 /s) at 460 and 555 nm. Melatonin suppression was significantly stronger at 460 nm (p < 0.02). An extension to the action spectrum showed that 420 nm light at 16 and 32 W/cm2 significantly suppressed melatonin (p < 0.04 and p < 0.002). These studies will help optimize lighting countermeasures to circadian and sleep disruption during spaceflight. © 2005 Elsevier Ltd. All rights reserved. Keywords: Pineal; Melatonin; Circadian; Light; Countermeasure; Astronauts
1. Introduction Circadian disruption and sleep loss have been documented in astronauts on missions in space as short as 10 and 16 days. The resulting diminishment in alertness, cognitive ability, and psychomotor performance can pose a serious threat to the safety of the crew and the vehicle, as well as the overall success of the mission [1]. The long-term goal of our research is to ∗ Corresponding author.
E-mail address: [email protected] (R.L. Fucci). 0094-5765/$ - see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.actaastro.2005.01.029
determine the most effective spectra of light for use as a countermeasure to sleep and circadian disruption in astronauts. Specifically, we measure circulating levels of the pineal gland hormone melatonin, which has been used extensively as a marker for photic input to the retinohypothalamic tract (RHT) [2–4]. Ambient light is the primary stimulus for the regulation of the circadian system [2,3,5,6]. In humans, detection of light for circadian regulation appears to be mediated by ocular photoreceptors [2–7]. The specific photoreceptor (or photoreceptors) responsible for transducing light stimuli for circadian regulation,
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however, is currently unknown. Several human and animal studies suggest that neither rods nor cones are required for circadian and melatonin regulation [8–14]. Furthermore, removal of the eyes in rodless, coneless transgenic mice abolishes previous circadian entrainment capability, suggesting that the novel photoreceptor lies within the structure of the eye [10]. Also, studies on people with visual blindness or color vision deficiencies suggest that neither rods nor cones are the only mediator of melatonin regulation in humans [12,13]. Of the various photopigments which have been implicated in circadian phototransduction, melanopsin is a strong candidate. Melanopsin is an opsin-based molecule that has been localized in a subset of ganglion cells in both the rodent and human retina [15–17]. It is possible, however, that there are redundant photic inputs for circadian regulation [18–20]. More studies are needed to determine the exact role of melanopsin and other photopigments in mediating circadian photoreception. A well-established neural pathway, the RHT, transduces light stimuli for the circadian system and is distinct from the pathway for optical vision [2,21]. The RHT projects from a subset of directly photosensitive, melanopsin containing ganglion cells in the retina to the suprachiasmatic nuclei (SCN), located in the hypothalamus [16,17,22–24]. The SCN are the principal circadian pacemaker and project to the pineal gland via a multi-synaptic pathway to regulate melatonin production [2,21]. In the circadian rhythms of humans and most animals, melatonin secretion is high at night and low during the day [3,25]. Given its potent effects on human circadian physiology [6,26–29], light has been used effectively in a number of therapies, including the treatment of Seasonal Affective Disorder (SAD), circadian sleep disorders, and circadian disruption due to jet-lag and shift work [6,26,30–32]. It has also been used effectively as a countermeasure for NASA astronauts and ground-control workers to position their sleep/wake cycles better in tandem with the necessary changes in work schedules before a launch [1,33–35]. Clarifying how ambient light regulates melatonin will open the door to optimizing the lighting spectrum for use as a countermeasure to circadian and sleep disruption. Exposure to light at night suppresses melatonin production in varying degrees depending on the intensity and spectral characteristics of the light.
Measuring the relative efficacy of different monochromatic wavelengths at various intensities, defined as establishing an action spectrum, is a fundamental step towards understanding the input physiology of the circadian system [36–39]. A previous long-term study by our group showed univariance among eight different fluence–response curves for wavelengths between 440 and 600 nm [14,40]. The region of 446–477 nm proved to be the most effective for melatonin suppression. Another study independently demonstrated that monochromatic light in this same wavelength region was the most potent for melatonin suppression in humans [41]. By necessity, both of these studies were conducted using a between-subjects experimental design. One aim of this study was to establish that melatonin suppression using a within-subjects design is the same as using a between-subjects design for two different wavelengths. In our previous study, the fluence–response curves were established using a different set of subjects for each wavelength, while the present study uses the same subjects to measure suppression at two different wavelengths, 460 and 555 nm (half-peak bandwidths of 10 nm), with an equal photon density of 7.18 × 1012 photons/cm2 /s. It should be noted that equal photon densities are used, as opposed to equal irradiances, because according to photobiological convention all lightdriven biological responses ultimately derive from the absorption of a photon by an organic molecule [38,39]. These two wavelengths are particularly useful for comparison since the peak sensitivity of the three-cone photopic visual system is generally accepted as 555 nm, while the transduction of light for human melatonin regulation appears to have the highest sensitivity in the 446–477 nm range. A second aim was to extend the action spectrum to the region below 440 nm by working to establish a fluence–response curve at 420 nm (half-peak bandwidth of 12 nm), and determining if it is univariant with the data from 440 to 600 nm. So far, two irradiances and a control night have been completed for eight subjects at this wavelength. This region of the spectrum has particular importance to astronauts since exposure to short wavelength visible light and ultraviolet radiation is significantly increased outside the Earth’s atmosphere.
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2. Methods and materials Both aims of this study were investigated using the methods and materials described below. The only difference in protocol between these two experiments was the selection of wavelength and/or intensity of the monochromatic light exposure. This model has been used extensively, and the times chosen for plasma collection have proven reliable for high circulating levels of melatonin [4,13,14,40,42]. 2.1. Subjects Twelve healthy male and female volunteers were recruited for the 460 nm vs. 555 nm study (mean age 23.4 ± 0.8 yr). Eight healthy male and female volunteers were recruited for the 420 nm study (mean age 24.5 ± 0.3 yr). Race and ethnic background were not considered during selection. Subjects were free from prescription medications or oral melatonin use, and reported normal and consistent sleeping patterns. Subjects passed a color vision test (Ishihara, 24-plate edition), and ocular health was confirmed by the study ophthalmologist. Participating subjects all reviewed and signed an IRB consent form. 2.2. Experimental protocol On study nights, subjects arrived and were seated in a dimly lit room. At 12:00 AM midnight, one drop of 0.5% Cyclopentolate HCl was placed in each eye to dilate the pupils. Subjects were then blindfolded. From 12:00 to 2:00 AM subjects remained in a seated, upright position in a dark room and were allowed to converse or listen to music. At 2:00 AM, while still blindfolded, the first blood sample was taken via antecubital venipuncture. Immediately following this blood sample, the blindfold was removed and light exposure began. Each subject’s head was held steady in an ophthalmologic head-holder facing a ganzfeld dome. This type of dome provides an even, patternless exposure to light and encompasses the full visual field. From 2:00 to 3:30 AM, subjects sat with their eyes open, gazing into the back of the dome. A miniature camera mounted in the back of the dome monitored eye position and wakefulness. At 3:30 AM
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the final blood sample was taken before the subject was allowed to withdraw from the light exposure. Each subject was also studied on a control night with pupils dilated and blood taken at the same time-intervals, but while remaining blindfolded and receiving no light exposure. There was always at least a week between study nights for each volunteer. 2.3. Light generation and measurement High-pressure xenon arc lamps of up to 1000 W were used to generate the light stimulus (Photon Technology International, Lawrenceville NJ). Each lamp was enclosed in a light-proof housing and was cooled by fans and circulating water. The exit beam of white light was reduced to a selected monochromatic wavelength by a grating monochromator and the relative intensity was controlled by a manual diaphragm. Adjustments were also made for the half-peak bandwidth of the resulting beam. The light beam was then reflected into a ganzfeld dome coated with a white, highly reflective surface (Spectralite) with a 95–99% reflective efficiency across the visible spectrum. Measurements of the resulting irradiance in the dome were taken with a IL1400 A radiometer/photometer with a SEL033 irradiance probe (International Light, Newburyport MA). On study nights, irradiance measurements were taken just before and just after the 90 min light exposure. During the exposure, spot measurements were taken every 30 min with a Minolta nt-1◦ luminance meter (Minolta, Osaka, Japan) to help ascertain whether light levels remained stable. 2.4. Plasma extraction and assay Blood samples were collected in glass vacutainers with EDTA anti-coagulant. Plasma was immediately separated by refrigerated centrifugation at 2000 rpm for 15 min, and then aliquoted into cryogenic vials for storage at −20 ◦ C until assay. Samples were assayed for melatonin by a modification of the radioimmunoassay described by Rollag and Niswender [40,43]. The minimum detection limit of the assay is 0.5–2.0 pg/mL.
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2.5. Statistics Two-tailed, paired Student’s t tests were used to assess the statistical significance of raw melatonin change scores between pre- and post-light exposure, and on control nights with no light exposure. Melatonin levels for exposure nights are given a percentchange score as follows: 100 ×
3: 30 AM level − 2: 00 AM level 2: 00 AM level
Percent change scores were then control-adjusted by subtracting the percent-change of the control night for each exposure score. This takes into account the relative levels of melatonin secretion among different individuals. Pre-exposure samples and percent-change scores were assessed by one-way repeated ANOVA.
3. Results 3.1. Equal photon densities at 460 and 555 nm Both intensities and a control night were completed for 12 subjects for a total of 36 subject study nights. As observed in previous studies [4,14,40], raw melatonin values at 2:00 AM did not vary significantly (p = 0.57). As shown in Figs. 1a and b, a significant increase in raw plasma melatonin was seen on the control night, consistent with normal nighttime secretion, as well as after exposure to 555 nm. However, the same subjects at the same exposure length (90 min) to monochromatic light at 460 nm exhibited a strong decrease in raw plasma melatonin levels. Photon densities were equal (7.18 × 1012 photons/cm2 /s) at both wavelengths. Fig. 1c, illustrating percent controladjusted scores, shows that 460 nm light elicited a 40% greater plasma melatonin suppression than 555 nm light (p < 0.02). 3.2. Melatonin suppression at 420 nm Two different intensities and a control night were completed for eight different subjects, for a total of 24 subject study nights. As observed in previous studies [4,14,40], raw melatonin values at 2:00 AM did not vary significantly (p = 0.26). Both irradiances
Fig. 1. (a) This figure shows raw plasma melatonin values before and after the two equal photon density (7.18×1012 photons/cm2 /s) light exposures at 460 and 555 nm and the dark exposure control night. Each bar represents mean melatonin + SEM. Pre-values were consistent for all three conditions (F = 0.57, p = 0.57). Pre- versus post-exposure comparisons are indicated above each set of bars. (b) Each bar represents mean + SEM percent plasma melatonin change score. Melatonin secretion increased on both the control night and after exposure to 555 nm light, but was suppressed after exposure to 460 nm at an equal photon density (7.18×1012 photons/cm2 /s). (c) In this figure, each bar represents mean + SEM percent control-adjusted plasma melatonin change score. These scores show that 460 nm light can suppress melatonin approximately 40% more effectively than 555 nm light. This difference is statistically significant (p < 0.02).
(16 and 32 W/cm2 ) elicited a significant suppression of melatonin, with a greater suppression observed at the higher intensity. See Figs. 2a and b.
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Fig. 2. (a) This diagram illustrates mean + SEM raw plasma melatonin values for exposure to 420 nm light at two different corneal irradiances and a dark-exposed control night. ANOVA showed no significant differences among pre-exposure scores (F = 1.47, p = 0.26). Suppression was statistically significant at both intensities (p < 0.04 and p < 0.002). (b) In this illustration, each bar shows mean + SEM percent plasma melatonin change scores. For the two intensities tested, exposure to 420 nm light elicited a stronger suppression at the higher irradiance. Further testing will allow for the completion of a full fluence–response function.
4. Discussion To optimize light as a countermeasure for circadian and sleep disruption during space travel, it is critical to clarify the relative potency of different wavelengths to regulate circadian and neuroendocrine responses in humans. The experiments reported here demonstrate that short wavelength light (460 nm) in the blue portion of the visible spectrum is more potent than longer wavelength light (555 nm) in the green portion of the spectrum for suppressing melatonin. Furthermore, preliminary work on a 420 nm fluence–response curve shows that this wavelength can also actively suppress high nighttime levels of plasma melatonin.
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As described in the introduction, a within-subjects experimental design was used for each of the fluence–response curves at each of the eight wavelengths in the original action spectrum study. This design is known to produce the most reliable results. However, using the same set of subjects to establish fluence–response curves for all eight wavelengths was not feasible. That study spanned four years and the potential for subject dropout precluded a complete within-subjects design for the whole action spectrum [14,40]. The measurement of two different wavelengths (460 and 555 nm) at equal photon densities (7.18 × 1012 photons/cm2 /s) showed a statistically stronger melatonin suppression at 460 nm. This finding supports the expectation that a within-subjects design yields results consistent with a betweensubjects design, since the peak sensitivity of the action spectrum in the original study was in the range of 446–477 nm. This comparison is significant in that 555 nm is the generally accepted peak of sensitivity for the three-cone photopic visual system [44], and appears distinct from the peak sensitivity for input to the human RHT [40,41]. Relative to illuminating spacecraft interiors, it is important to be aware that current lighting designs are configured to serve only one function, i.e. to support astronaut vision, not circadian regulation. For optimum astronaut health and safety, future lighting designs need to support both vision and circadian entrainment. In some cases, strong light stimuli will be needed to circadian phase-shift astronauts when there are alterations in work schedules. Furthermore, bright light has an acute alerting effect [45–51] which may be useful when work schedules are unexpectedly extended. There will also be circumstances in which lighting should support vision but provide less circadian impact, such as when astronauts read before sleeping. In considering the benefits of bright light for entraining and phase-shifting astronauts’ circadian rhythms as well as increasing alertness, it is also important to consider electrical energy consumption. In general, production of bright white light requires more energy. By optimizing the lighting spectrum to emphasize the most potent wavelengths, an energy saving can be realized. This concept has been well demonstrated by recent studies [40,52]. Previously, the eight melatonin suppression fluence–response curves between 440 and 600 nm
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were all shown to be univariant with high coefficients of correlation [40]. This suggests, but does not prove, that the suppression of melatonin is regulated by a single photoreceptor type [37,38]. It is important to test for the presence of a fluence–response curve at 420 nm as well. At this time only two intensities have been tested. Further studies at 420 nm will clarify the sensitivity of melatonin regulation in the shorter wavelengths, and determine if univariance can be found with the fluence–response curves of the other eight wavelengths. This could prove especially helpful in the eventual identification or rejection of potential candidates for the circadian photopigment(s). It is important to note that the present studies did not measure effects of light exposure on circadian phaseshifting or entrainment. The experiments specifically measured the effects of light exposure on acute melatonin suppression during one time of night. Although some investigators consider melatonin suppression to be only a surrogate measure for circadian input, there is strong evidence that light-intensity thresholds for melatonin suppression and phase-shifting are very similar in humans [53]. Furthermore, a recent study demonstrated a strong parallel in terms of wavelength sensitivity between melatonin suppression and circadian phase-shifting in humans [52]. It thus remains reasonable to hypothesize that a common, shared photoreceptor system is responsible for both melatonin suppression and other circadian effects. Given that light is a powerful regulator of the human circadian system, elucidating the action spectrum for melatonin suppression is important not only for determining the circadian photopigment(s) and related circadian physiology, but also for a practical understanding of how the human circadian system responds to different lighting situations. Only then can the most effective photic countermeasures to circadian disruption be developed and implemented. This is especially relevant for longer duration space flight, such as the 5–6 month stays currently required on the International Space Station, as well as any future deep space endeavors such as manned missions to Mars or a return to the Moon. Ultimately, the data from these studies can be used to (1) improve light treatment as a countermeasure for circadian and sleep-wake disruption during space flight, (2) identify the best spectral transmission for spacesuit visors and the windows used in space vehicles and habitats, and (3) engineer the ideal
spectral distribution for illumination of general living quarters during space exploration. Optimizing the lighting spectrum also has the potential for widespread applications on Earth. A US Congressional report estimates that the 20 million Americans who are full-time shift workers show a demonstrable increase in health problems, including cardiovascular disease, cognitive problems, and emotional distress [30]. It is hoped that the lighting countermeasures developed for spaceflight can also be used on Earth for a variety of therapeutic and architectural applications.
Acknowledgements The authors would like to thank our skilled phlebotomists Christine Glasgow and Patricia Becerra, as well as Ben Warfield, Bill Coyle, Gena Glickman, Stephanie Tavener, Julie Francos, and Rob Hanifin for their technical assistance. This work was supported in part by grants from the National Space Biomedical Research Institute under NASA Cooperative Agreement NCC-58, the National Institute of Neurological Disorders and Stroke NIH RO1NS36590, and the Philadelphia Section of the Illuminating Engineering Society. Reprint requests should be addressed to George C. Brainard, Ph.D. (Light Research Program, Thomas Jefferson University, 1025 Walnut St., Room 507, Philadelphia PA, 19107; fax: (215) 923-7588; email: [email protected]).
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Toward optimizing lighting as a countermeasure to sleep and circadian disruption in space flight Robert L. Fucci, James Gardner, John P. Hanifin, Samar Jasser, Brenda Byrne, Edward Gerner, Mark Rollag, George C. Brainard∗ Thomas Jefferson University, Philadelphia, Pennsylvania, USA Available online 8 March 2005
Abstract Light is being used as a pre-launch countermeasure to circadian and sleep disruption in astronauts. The effect of light on the circadian system is readily monitored by measurement of plasma melatonin. Our group has established an action spectrum for human melatonin regulation and determined the region of 446–477 nm to be the most potent for suppressing plasma melatonin. The aim of this study was to compare the efficacy of 460 and 555 nm for suppressing melatonin using a within-subjects design. Subjects (N = 12) were exposed to equal photon densities (7.18 × 1012 photons/cm2 /s) at 460 and 555 nm. Melatonin suppression was significantly stronger at 460 nm (p < 0.02). An extension to the action spectrum showed that 420 nm light at 16 and 32 W/cm2 significantly suppressed melatonin (p < 0.04 and p < 0.002). These studies will help optimize lighting countermeasures to circadian and sleep disruption during spaceflight. © 2005 Elsevier Ltd. All rights reserved. Keywords: Pineal; Melatonin; Circadian; Light; Countermeasure; Astronauts
1. Introduction Circadian disruption and sleep loss have been documented in astronauts on missions in space as short as 10 and 16 days. The resulting diminishment in alertness, cognitive ability, and psychomotor performance can pose a serious threat to the safety of the crew and the vehicle, as well as the overall success of the mission [1]. The long-term goal of our research is to ∗ Corresponding author.
E-mail address: [email protected] (R.L. Fucci). 0094-5765/$ - see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.actaastro.2005.01.029
determine the most effective spectra of light for use as a countermeasure to sleep and circadian disruption in astronauts. Specifically, we measure circulating levels of the pineal gland hormone melatonin, which has been used extensively as a marker for photic input to the retinohypothalamic tract (RHT) [2–4]. Ambient light is the primary stimulus for the regulation of the circadian system [2,3,5,6]. In humans, detection of light for circadian regulation appears to be mediated by ocular photoreceptors [2–7]. The specific photoreceptor (or photoreceptors) responsible for transducing light stimuli for circadian regulation,
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however, is currently unknown. Several human and animal studies suggest that neither rods nor cones are required for circadian and melatonin regulation [8–14]. Furthermore, removal of the eyes in rodless, coneless transgenic mice abolishes previous circadian entrainment capability, suggesting that the novel photoreceptor lies within the structure of the eye [10]. Also, studies on people with visual blindness or color vision deficiencies suggest that neither rods nor cones are the only mediator of melatonin regulation in humans [12,13]. Of the various photopigments which have been implicated in circadian phototransduction, melanopsin is a strong candidate. Melanopsin is an opsin-based molecule that has been localized in a subset of ganglion cells in both the rodent and human retina [15–17]. It is possible, however, that there are redundant photic inputs for circadian regulation [18–20]. More studies are needed to determine the exact role of melanopsin and other photopigments in mediating circadian photoreception. A well-established neural pathway, the RHT, transduces light stimuli for the circadian system and is distinct from the pathway for optical vision [2,21]. The RHT projects from a subset of directly photosensitive, melanopsin containing ganglion cells in the retina to the suprachiasmatic nuclei (SCN), located in the hypothalamus [16,17,22–24]. The SCN are the principal circadian pacemaker and project to the pineal gland via a multi-synaptic pathway to regulate melatonin production [2,21]. In the circadian rhythms of humans and most animals, melatonin secretion is high at night and low during the day [3,25]. Given its potent effects on human circadian physiology [6,26–29], light has been used effectively in a number of therapies, including the treatment of Seasonal Affective Disorder (SAD), circadian sleep disorders, and circadian disruption due to jet-lag and shift work [6,26,30–32]. It has also been used effectively as a countermeasure for NASA astronauts and ground-control workers to position their sleep/wake cycles better in tandem with the necessary changes in work schedules before a launch [1,33–35]. Clarifying how ambient light regulates melatonin will open the door to optimizing the lighting spectrum for use as a countermeasure to circadian and sleep disruption. Exposure to light at night suppresses melatonin production in varying degrees depending on the intensity and spectral characteristics of the light.
Measuring the relative efficacy of different monochromatic wavelengths at various intensities, defined as establishing an action spectrum, is a fundamental step towards understanding the input physiology of the circadian system [36–39]. A previous long-term study by our group showed univariance among eight different fluence–response curves for wavelengths between 440 and 600 nm [14,40]. The region of 446–477 nm proved to be the most effective for melatonin suppression. Another study independently demonstrated that monochromatic light in this same wavelength region was the most potent for melatonin suppression in humans [41]. By necessity, both of these studies were conducted using a between-subjects experimental design. One aim of this study was to establish that melatonin suppression using a within-subjects design is the same as using a between-subjects design for two different wavelengths. In our previous study, the fluence–response curves were established using a different set of subjects for each wavelength, while the present study uses the same subjects to measure suppression at two different wavelengths, 460 and 555 nm (half-peak bandwidths of 10 nm), with an equal photon density of 7.18 × 1012 photons/cm2 /s. It should be noted that equal photon densities are used, as opposed to equal irradiances, because according to photobiological convention all lightdriven biological responses ultimately derive from the absorption of a photon by an organic molecule [38,39]. These two wavelengths are particularly useful for comparison since the peak sensitivity of the three-cone photopic visual system is generally accepted as 555 nm, while the transduction of light for human melatonin regulation appears to have the highest sensitivity in the 446–477 nm range. A second aim was to extend the action spectrum to the region below 440 nm by working to establish a fluence–response curve at 420 nm (half-peak bandwidth of 12 nm), and determining if it is univariant with the data from 440 to 600 nm. So far, two irradiances and a control night have been completed for eight subjects at this wavelength. This region of the spectrum has particular importance to astronauts since exposure to short wavelength visible light and ultraviolet radiation is significantly increased outside the Earth’s atmosphere.
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2. Methods and materials Both aims of this study were investigated using the methods and materials described below. The only difference in protocol between these two experiments was the selection of wavelength and/or intensity of the monochromatic light exposure. This model has been used extensively, and the times chosen for plasma collection have proven reliable for high circulating levels of melatonin [4,13,14,40,42]. 2.1. Subjects Twelve healthy male and female volunteers were recruited for the 460 nm vs. 555 nm study (mean age 23.4 ± 0.8 yr). Eight healthy male and female volunteers were recruited for the 420 nm study (mean age 24.5 ± 0.3 yr). Race and ethnic background were not considered during selection. Subjects were free from prescription medications or oral melatonin use, and reported normal and consistent sleeping patterns. Subjects passed a color vision test (Ishihara, 24-plate edition), and ocular health was confirmed by the study ophthalmologist. Participating subjects all reviewed and signed an IRB consent form. 2.2. Experimental protocol On study nights, subjects arrived and were seated in a dimly lit room. At 12:00 AM midnight, one drop of 0.5% Cyclopentolate HCl was placed in each eye to dilate the pupils. Subjects were then blindfolded. From 12:00 to 2:00 AM subjects remained in a seated, upright position in a dark room and were allowed to converse or listen to music. At 2:00 AM, while still blindfolded, the first blood sample was taken via antecubital venipuncture. Immediately following this blood sample, the blindfold was removed and light exposure began. Each subject’s head was held steady in an ophthalmologic head-holder facing a ganzfeld dome. This type of dome provides an even, patternless exposure to light and encompasses the full visual field. From 2:00 to 3:30 AM, subjects sat with their eyes open, gazing into the back of the dome. A miniature camera mounted in the back of the dome monitored eye position and wakefulness. At 3:30 AM
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the final blood sample was taken before the subject was allowed to withdraw from the light exposure. Each subject was also studied on a control night with pupils dilated and blood taken at the same time-intervals, but while remaining blindfolded and receiving no light exposure. There was always at least a week between study nights for each volunteer. 2.3. Light generation and measurement High-pressure xenon arc lamps of up to 1000 W were used to generate the light stimulus (Photon Technology International, Lawrenceville NJ). Each lamp was enclosed in a light-proof housing and was cooled by fans and circulating water. The exit beam of white light was reduced to a selected monochromatic wavelength by a grating monochromator and the relative intensity was controlled by a manual diaphragm. Adjustments were also made for the half-peak bandwidth of the resulting beam. The light beam was then reflected into a ganzfeld dome coated with a white, highly reflective surface (Spectralite) with a 95–99% reflective efficiency across the visible spectrum. Measurements of the resulting irradiance in the dome were taken with a IL1400 A radiometer/photometer with a SEL033 irradiance probe (International Light, Newburyport MA). On study nights, irradiance measurements were taken just before and just after the 90 min light exposure. During the exposure, spot measurements were taken every 30 min with a Minolta nt-1◦ luminance meter (Minolta, Osaka, Japan) to help ascertain whether light levels remained stable. 2.4. Plasma extraction and assay Blood samples were collected in glass vacutainers with EDTA anti-coagulant. Plasma was immediately separated by refrigerated centrifugation at 2000 rpm for 15 min, and then aliquoted into cryogenic vials for storage at −20 ◦ C until assay. Samples were assayed for melatonin by a modification of the radioimmunoassay described by Rollag and Niswender [40,43]. The minimum detection limit of the assay is 0.5–2.0 pg/mL.
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2.5. Statistics Two-tailed, paired Student’s t tests were used to assess the statistical significance of raw melatonin change scores between pre- and post-light exposure, and on control nights with no light exposure. Melatonin levels for exposure nights are given a percentchange score as follows: 100 ×
3: 30 AM level − 2: 00 AM level 2: 00 AM level
Percent change scores were then control-adjusted by subtracting the percent-change of the control night for each exposure score. This takes into account the relative levels of melatonin secretion among different individuals. Pre-exposure samples and percent-change scores were assessed by one-way repeated ANOVA.
3. Results 3.1. Equal photon densities at 460 and 555 nm Both intensities and a control night were completed for 12 subjects for a total of 36 subject study nights. As observed in previous studies [4,14,40], raw melatonin values at 2:00 AM did not vary significantly (p = 0.57). As shown in Figs. 1a and b, a significant increase in raw plasma melatonin was seen on the control night, consistent with normal nighttime secretion, as well as after exposure to 555 nm. However, the same subjects at the same exposure length (90 min) to monochromatic light at 460 nm exhibited a strong decrease in raw plasma melatonin levels. Photon densities were equal (7.18 × 1012 photons/cm2 /s) at both wavelengths. Fig. 1c, illustrating percent controladjusted scores, shows that 460 nm light elicited a 40% greater plasma melatonin suppression than 555 nm light (p < 0.02). 3.2. Melatonin suppression at 420 nm Two different intensities and a control night were completed for eight different subjects, for a total of 24 subject study nights. As observed in previous studies [4,14,40], raw melatonin values at 2:00 AM did not vary significantly (p = 0.26). Both irradiances
Fig. 1. (a) This figure shows raw plasma melatonin values before and after the two equal photon density (7.18×1012 photons/cm2 /s) light exposures at 460 and 555 nm and the dark exposure control night. Each bar represents mean melatonin + SEM. Pre-values were consistent for all three conditions (F = 0.57, p = 0.57). Pre- versus post-exposure comparisons are indicated above each set of bars. (b) Each bar represents mean + SEM percent plasma melatonin change score. Melatonin secretion increased on both the control night and after exposure to 555 nm light, but was suppressed after exposure to 460 nm at an equal photon density (7.18×1012 photons/cm2 /s). (c) In this figure, each bar represents mean + SEM percent control-adjusted plasma melatonin change score. These scores show that 460 nm light can suppress melatonin approximately 40% more effectively than 555 nm light. This difference is statistically significant (p < 0.02).
(16 and 32 W/cm2 ) elicited a significant suppression of melatonin, with a greater suppression observed at the higher intensity. See Figs. 2a and b.
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Fig. 2. (a) This diagram illustrates mean + SEM raw plasma melatonin values for exposure to 420 nm light at two different corneal irradiances and a dark-exposed control night. ANOVA showed no significant differences among pre-exposure scores (F = 1.47, p = 0.26). Suppression was statistically significant at both intensities (p < 0.04 and p < 0.002). (b) In this illustration, each bar shows mean + SEM percent plasma melatonin change scores. For the two intensities tested, exposure to 420 nm light elicited a stronger suppression at the higher irradiance. Further testing will allow for the completion of a full fluence–response function.
4. Discussion To optimize light as a countermeasure for circadian and sleep disruption during space travel, it is critical to clarify the relative potency of different wavelengths to regulate circadian and neuroendocrine responses in humans. The experiments reported here demonstrate that short wavelength light (460 nm) in the blue portion of the visible spectrum is more potent than longer wavelength light (555 nm) in the green portion of the spectrum for suppressing melatonin. Furthermore, preliminary work on a 420 nm fluence–response curve shows that this wavelength can also actively suppress high nighttime levels of plasma melatonin.
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As described in the introduction, a within-subjects experimental design was used for each of the fluence–response curves at each of the eight wavelengths in the original action spectrum study. This design is known to produce the most reliable results. However, using the same set of subjects to establish fluence–response curves for all eight wavelengths was not feasible. That study spanned four years and the potential for subject dropout precluded a complete within-subjects design for the whole action spectrum [14,40]. The measurement of two different wavelengths (460 and 555 nm) at equal photon densities (7.18 × 1012 photons/cm2 /s) showed a statistically stronger melatonin suppression at 460 nm. This finding supports the expectation that a within-subjects design yields results consistent with a betweensubjects design, since the peak sensitivity of the action spectrum in the original study was in the range of 446–477 nm. This comparison is significant in that 555 nm is the generally accepted peak of sensitivity for the three-cone photopic visual system [44], and appears distinct from the peak sensitivity for input to the human RHT [40,41]. Relative to illuminating spacecraft interiors, it is important to be aware that current lighting designs are configured to serve only one function, i.e. to support astronaut vision, not circadian regulation. For optimum astronaut health and safety, future lighting designs need to support both vision and circadian entrainment. In some cases, strong light stimuli will be needed to circadian phase-shift astronauts when there are alterations in work schedules. Furthermore, bright light has an acute alerting effect [45–51] which may be useful when work schedules are unexpectedly extended. There will also be circumstances in which lighting should support vision but provide less circadian impact, such as when astronauts read before sleeping. In considering the benefits of bright light for entraining and phase-shifting astronauts’ circadian rhythms as well as increasing alertness, it is also important to consider electrical energy consumption. In general, production of bright white light requires more energy. By optimizing the lighting spectrum to emphasize the most potent wavelengths, an energy saving can be realized. This concept has been well demonstrated by recent studies [40,52]. Previously, the eight melatonin suppression fluence–response curves between 440 and 600 nm
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were all shown to be univariant with high coefficients of correlation [40]. This suggests, but does not prove, that the suppression of melatonin is regulated by a single photoreceptor type [37,38]. It is important to test for the presence of a fluence–response curve at 420 nm as well. At this time only two intensities have been tested. Further studies at 420 nm will clarify the sensitivity of melatonin regulation in the shorter wavelengths, and determine if univariance can be found with the fluence–response curves of the other eight wavelengths. This could prove especially helpful in the eventual identification or rejection of potential candidates for the circadian photopigment(s). It is important to note that the present studies did not measure effects of light exposure on circadian phaseshifting or entrainment. The experiments specifically measured the effects of light exposure on acute melatonin suppression during one time of night. Although some investigators consider melatonin suppression to be only a surrogate measure for circadian input, there is strong evidence that light-intensity thresholds for melatonin suppression and phase-shifting are very similar in humans [53]. Furthermore, a recent study demonstrated a strong parallel in terms of wavelength sensitivity between melatonin suppression and circadian phase-shifting in humans [52]. It thus remains reasonable to hypothesize that a common, shared photoreceptor system is responsible for both melatonin suppression and other circadian effects. Given that light is a powerful regulator of the human circadian system, elucidating the action spectrum for melatonin suppression is important not only for determining the circadian photopigment(s) and related circadian physiology, but also for a practical understanding of how the human circadian system responds to different lighting situations. Only then can the most effective photic countermeasures to circadian disruption be developed and implemented. This is especially relevant for longer duration space flight, such as the 5–6 month stays currently required on the International Space Station, as well as any future deep space endeavors such as manned missions to Mars or a return to the Moon. Ultimately, the data from these studies can be used to (1) improve light treatment as a countermeasure for circadian and sleep-wake disruption during space flight, (2) identify the best spectral transmission for spacesuit visors and the windows used in space vehicles and habitats, and (3) engineer the ideal
spectral distribution for illumination of general living quarters during space exploration. Optimizing the lighting spectrum also has the potential for widespread applications on Earth. A US Congressional report estimates that the 20 million Americans who are full-time shift workers show a demonstrable increase in health problems, including cardiovascular disease, cognitive problems, and emotional distress [30]. It is hoped that the lighting countermeasures developed for spaceflight can also be used on Earth for a variety of therapeutic and architectural applications.
Acknowledgements The authors would like to thank our skilled phlebotomists Christine Glasgow and Patricia Becerra, as well as Ben Warfield, Bill Coyle, Gena Glickman, Stephanie Tavener, Julie Francos, and Rob Hanifin for their technical assistance. This work was supported in part by grants from the National Space Biomedical Research Institute under NASA Cooperative Agreement NCC-58, the National Institute of Neurological Disorders and Stroke NIH RO1NS36590, and the Philadelphia Section of the Illuminating Engineering Society. Reprint requests should be addressed to George C. Brainard, Ph.D. (Light Research Program, Thomas Jefferson University, 1025 Walnut St., Room 507, Philadelphia PA, 19107; fax: (215) 923-7588; email: [email protected]).
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