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All sourcesNASA NTRSDOE OSTI
NASA NTRS2003

A phase response curve to single bright light pulses in human subjects

The circadian pacemaker is differentially sensitive to the resetting effects of retinal light exposure, depending upon the circadian phase at which the light exposure occurs. Previously reported human phase response curves (PRCs) to single bright light exposures have employed small sample sizes, and were often based on relatively imprecise estimates of circadian phase and phase resetting. In the present study, 21 healthy, entrained subjects underwent pre- and post-stimulus constant routines (CRs) in dim light (approximately 2-7 lx) with maintained wakefulness in a semi-recumbent posture. The 6.7 h bright light exposure stimulus consisted of alternating 6 min fixed gaze (approximately 10 000 lx) and free gaze (approximately 5000-9000 lx) exposures. Light exposures were scheduled across the circadian cycle in different subjects so as to derive a PRC. Plasma melatonin was used to determine the phase of the onset, offset, and midpoint of the melatonin profiles during the CRs. Phase shifts were calculated as the difference in phase between the pre- and post-stimulus CRs. The resultant PRC of the midpoint of the melatonin rhythm revealed a characteristic type 1 PRC with a significant peak-to-trough amplitude of 5.02 h. Phase delays occurred when the light stimulus was centred prior to the critical phase at the core body temperature minimum, phase advances occurred when the light stimulus was centred after the critical phase, and no phase shift occurred at the critical phase. During the subjective day, no prolonged 'dead zone' of photic insensitivity was apparent. Phase shifts derived using the melatonin onsets showed larger magnitudes than those derived from the melatonin offsets. These data provide a comprehensive characterization of the human PRC under highly controlled laboratory conditions.

Randomized Controlled Trial↗
NASA NTRS2017

Circadian and Fatigue Effects on the Dynamics of the Pupillary Light Reflex

The pupillary light reflex (PLR) is known to be driven by the photo-entrainment of intrinsically-photosensitive retinal ganglion cells. These ganglion cells are known to have retino-hypothalamic projections to the suprachiasmatic nuclei (SCN), which regulates circadian rhythms, and bilateral retinal projections to the pretectal area, which mediates the PLR (Dacey et al., 2005; Hattar et al., 2002, 2006). The magnitude of the PLR has previously been shown to show circadian variation (Mnch et al., 2012). In this study, we used a constant routine protocol (Mills et al., 1978) to examine circadian and fatigue effects on the dynamics of the PLR. We characterized the PLR (pupil size as a function of time) in response to a square-wave change in the luminance of a white display background, at ten different times over a single circadian cycle. Twelve subjects participated in three daytime baseline runs followed by 7 nighttime runs each separated by an hour (17 23 hours after awakening). The constriction and dilation phases of the PLR waveform were fit separately with a single exponential model (Longtin Milton, 1988; Milton Longtin, 1990) with time constants estimated using a least-squares method. The dilation time constant exhibited a distinct sinusoidal modulation across the circadian cycle and, after 23 hours of wakefulness, decreased on average by 82 ms (paired t-test, p 0.05) relative to baseline (mean: 543 ms). The constriction time constant however, did not show an overall decrease with increased wakefulness. We conclude that the dynamics of the PLR show circadian variation and that, in addition, the briskness of the dilation response to a step-decrease in luminance shows a homeostatic enhancement with increased wakefulness.

human performance↗
NASA NTRS1976

The effect of low light intensity on the maintenance of circadian synchrony in human subjects

Experiments were conducted on six healthy male subjects aged 20-23 yr and exposed for 21 days in a confined regulated environment to 16L:8D light:dark cycle with a view toward determining whether the light environment of 16L:8D at the relatively low light intensity of 15 ft.c. is adequate for the maintenance of circadian synchrony in man. The light intensity was 100 ft.c. during the first seven days, reduced to 15 ft.c. during the next seven days, and increased again to 100 ft.c. during the last seven days. Rectal temperature (RT) and heart rate (HR) were recorded throughout the three phases. In the 100 ft.c. regime, the RT and HR rhythms remained stable and circadian throughout. It is shown that 15 ft.c. light intensity is at or below threshold for maintaining circadian synchrony of human physiologic rhythms marked by instability and internal desynchronization with degradation of performance and well-being.

Winget, C. M.↗
NASA NTRS1996

Dose-response relationships for resetting of human circadian clock by light

Since the first report in unicells, studies across diverse species have demonstrated that light is a powerful synchronizer which resets, in an intensity-dependent manner, endogenous circadian pacemakers. Although it is recognized that bright light (approximately 7,000 to 13,000 lux) is an effective circadian synchronizer in humans, it is widely believed that the human circadian pacemaker is insensitive to ordinary indoor illumination (approximately 50-300 lux). It has been proposed that the relationship between the resetting effect of light and its intensity follows a compressive nonlinear function, such that exposure to lower illuminances still exerts a robust effect. We therefore undertook a series of experiments which support this hypothesis and report here that light of even relatively low intensity (approximately 180 lux) significantly phase-shifts the human circadian pacemaker. Our results clearly demonstrate that humans are much more sensitive to light than initially suspected and support the conclusion that they are not qualitatively different from other mammals in their mechanism of circadian entrainment.

NASA Discipline Regulatory Physiology↗
NASA NTRS1994

Effects of light on brain and behavior

It is obvious that light entering the eye permits the sensory capacity of vision. The human species is highly dependent on visual perception of the environment and consequently, the scientific study of vision and visual mechanisms is a centuries old endeavor. Relatively new discoveries are now leading to an expanded understanding of the role of light entering the eye in addition to supporting vision, light has various nonvisual biological effects. Over the past thirty years, animal studies have shown that environmental light is the primary stimulus for regulating circadian rhythms, seasonal cycles, and neuroendocrine responses. As with all photobiological phenomena, the wavelength, intensity, timing and duration of a light stimulus is important in determining its regulatory influence on the circadian and neuroendocrine systems. Initially, the effects of light on rhythms and hormones were observed only in sub-human species. Research over the past decade, however, has confirmed that light entering the eyes of humans is a potent stimulus for controlling physiological rhythms. The aim of this paper is to examine three specific nonvisual responses in humans which are mediated by light entering the eye: light-induced melatonin suppression, light therapy for winter depression, and enhancement of nighttime performance. This will serve as a brief introduction to the growing database which demonstrates how light stimuli can influence physiology, mood and behavior in humans. Such information greatly expands our understanding of the human eye and will ultimately change our use of light in the human environment.

Brainard, George C.↗
NASA NTRS1993

New findings regarding light intensity and its effects as a zeitgeber in the Sprague-Dawley rat

In most mammals, the suprachiasmatic nucleus of the anterior hypothalamus has been implicated as the central driving mechanism of circadian rhythmicity. The photic input from the retina, via the retino-hypothalamic tract, and modulation from the pineal gland help regulate the clock. In this study, we investigated the effects of low light intensity on the circadian system of the Sprague-Dawley rat. A series of light intensity experiments were conducted to determine if a light level of 0.1 Lux will maintain entrained circadian rhythms of feeding, drinking, and locomotor activity.

Tischler, A. C.↗
NASA NTRS2000

Dynamic resetting of the human circadian pacemaker by intermittent bright light

In humans, experimental studies of circadian resetting typically have been limited to lengthy episodes of exposure to continuous bright light. To evaluate the time course of the human endogenous circadian pacemaker's resetting response to brief episodes of intermittent bright light, we studied 16 subjects assigned to one of two intermittent lighting conditions in which the subjects were presented with intermittent episodes of bright-light exposure at 25- or 90-min intervals. The effective duration of bright-light exposure was 31% or 63% compared with a continuous 5-h bright-light stimulus. Exposure to intermittent bright light elicited almost as great a resetting response compared with 5 h of continuous bright light. We conclude that exposure to intermittent bright light produces robust phase shifts of the endogenous circadian pacemaker. Furthermore, these results demonstrate that humans, like other species, exhibit an enhanced sensitivity to the initial minutes of bright-light exposure.

Non-NASA Center↗
NASA NTRS1999

Effects of square-wave and simulated natural light-dark cycles on hamster circadian rhythms

Circadian rhythms of activity (Act) and body temperature (Tb) were recorded from male Syrian hamsters under square-wave (LDSq) and simulated natural (LDSN, with dawn and dusk transitions) light-dark cycles. Light intensity and data sampling were under the synchronized control of a laboratory computer. Changes in reactive and predictive onsets and offsets for the circadian rhythms of Act and Tb were examined in both lighting conditions. The reactive Act onset occurred 1.1 h earlier (P < 0.01) in LDSN than in LDSq and had a longer alpha-period (1.7 h; P < 0.05). The reactive Tb onset was 0.7 h earlier (P < 0.01) in LDSN. In LDSN, the predictive Act onset advanced by 0.3 h (P < 0.05), whereas the Tb predictive onset remained the same as in LDSq. The phase angle difference between Act and Tb predictive onsets decreased by 0.9 h (P < 0.05) in LDSN, but the offsets of both measures remained unchanged. In this study, animals exhibited different circadian entrainment characteristics under LDSq and LDSN, suggesting that gradual and abrupt transitions between light and dark may provide different temporal cues.

NASA Discipline Regulatory Physiology↗
NASA NTRS1999

Circadian Entrainment, Sleep-Wake Regulation and Neurobehavioral Performance During Extended Duration Space Flight

Long-duration manned space flight requires crew members to maintain a high level of cognitive performance and vigilance while operating and monitoring sophisticated instrumentation. However, the reduction in the strength of environmental synchronizers in the space environment leads to misalignment of circadian phase among crew members, coupled with restricted time available to sleep, results in sleep deprivation and consequent deterioration of neurobehavioral function. Crew members are provided, and presently use, long-acting benzodiazepine hypnotics on board the current, relatively brief space shuttle missions to counteract such sleep disruption, a situation that is only likely to worsen during extended duration missions. Given the known carry-over effects of such compounds on daytime performance, together with the reduction in emergency readiness associated with their use at night, NASA has recognized the need to develop effective but safe countermeasures to allow crew members to obtain an adequate amount of sleep. Over the past eight years, we have successfully implemented a new technology for shuttle crew members involving bright light exposure during the pre-launch period to facilitate adaptation of the circadian timing system to the inversions of the sleep-wake schedule often required during dual shift missions. However for long duration space station missions it will be necessary to develop effective and attainable countermeasures that can be used chronically to optimize circadian entrainment. Our current research effort is to study the effects of light-dark cycles with reduced zeitgeber strength, such as are anticipated during long-duration space flight, on the entrainment of the endogenous circadian timing system and to study the effects of a countermeasure that consists of scheduled brief exposures to bright light on the human circadian timing system. The proposed studies are designed to address the following Specific Aims: (1) test the hypothesis that synchronization of the human circadian pacemaker will be disturbed in men and women by the reduction in LD cycle strength. (2) test the hypothesis that this disturbed circadian synchronization will result in the secretion of the sleep-promoting hormone melatonin during the waking day, disturbed sleep, reduced growth hormone secretion, and impaired performance and daytime alertness; (3) as a countermeasure, test the hypothesis that brief daily exposures to bright light (10,000 lux) will reestablish normal entrained circadian phase, resulting in improved sleep consolidation, normalized sleep structure and endogenous growth hormone secretion and enhanced daytime performance. To date, we have carried out twelve experiments to address Hypotheses I and 2 and data analyses are in progress. The results of the current research may have important implications for the treatment of circadian rhythm sleep disorders, such as delayed sleep phase syndrome and shift-work dyssomnia, which are anticipated to have a high incidence and prevalence during extended duration space flight such as planned for the International Space Station and manned missions to Mars.

Czeisler, Charles A.↗
NASA NTRS2002

The plasma membrane-associated NADH oxidase of spinach leaves responds to blue light

The plasma membrane-associated NADH oxidase (NOX) of spinach leaf disks is characterized by oscillations in activity with a regular period length of ca. 24 min. Within a single population of plants exposed to light at the same time, NOX activities of all plants function synchronously. Exposure of plants transferred from darkness to blue light (495 nm, 2 min, 50 micromoles m-2 s-1) resulted in a complex response pattern but with a new maximum in the rate of NOX activity 36 (24+12) min after illumination and then with maxima in the rate of NOX activity every 24 min thereafter. Transient maxima in NOX activity were observed as well after 9.3 + /- 1.4 and 20.7 +/- 2.1 min. The blue light response differed from the response to red (650 nm, 10 min, 50 micromoles m-2 s-1) or white light where activity maxima were initiated 12 min after the light exposure followed by maxima every 24 min thereafter. Green or yellow light was ineffective. The light response was independent of the time in the 24-min NOX cycle when the light was given. The net effects of blue and red light were ultimately the same with a new maximum in the rate of NOX activity at 12+24=36 min (and every 24 min thereafter), but the mechanisms appear to be distinct.

NASA Discipline Cell Biology↗
NASA NTRS2000

A statistical model of the human core-temperature circadian rhythm

We formulate a statistical model of the human core-temperature circadian rhythm in which the circadian signal is modeled as a van der Pol oscillator, the thermoregulatory response is represented as a first-order autoregressive process, and the evoked effect of activity is modeled with a function specific for each circadian protocol. The new model directly links differential equation-based simulation models and harmonic regression analysis methods and permits statistical analysis of both static and dynamical properties of the circadian pacemaker from experimental data. We estimate the model parameters by using numerically efficient maximum likelihood algorithms and analyze human core-temperature data from forced desynchrony, free-run, and constant-routine protocols. By representing explicitly the dynamical effects of ambient light input to the human circadian pacemaker, the new model can estimate with high precision the correct intrinsic period of this oscillator ( approximately 24 h) from both free-run and forced desynchrony studies. Although the van der Pol model approximates well the dynamical features of the circadian pacemaker, the optimal dynamical model of the human biological clock may have a harmonic structure different from that of the van der Pol oscillator.

NASA Discipline Regulatory Physiology↗
NASA NTRS2014

Fatigue‐Related Countermeasures for Long‐Duration Exploration Missions

The NASA Human Research Program's (HRP) Behavioral Health and Performance Element (BHP) supports and conducts research to mitigate deleterious outcomes related to fatigue, sleep loss, circadian desynchronization, and work overload. Objective evidence indicates that within the context of the International Space Station (ISS), sleep is reduced and there is circadian misalignment. Despite chronic sleep loss and high workloads; however, astronauts successfully complete their missions. Contributing to their success is not only the tremendous skills and capabilities of each astronaut, but also the collaborative team efforts amongst the crew, between flight and ground crews, and through real‐time care provided by medical personnel. It is anticipated that risks to human health and performance will increase in the context of exploration missions, where crewmembers will venture to deep space for extended durations and in small vehicles with limited communication with home. Hence, fatigue‐related countermeasures are being developed and/or validated that include unobtrusive monitoring technologies to detect fatigue‐related performance decrements, environmental countermeasures, and sleep education and training for flight and ground crews. Given that fatigue is an issue in current ISS missions, the BHP works collaboratively with Space Medicine operations to collect data in the operational environment, to validate fatigue-related countermeasures, and provide evidence‐based mitigations. Our presentation will summarize fatigue‐related operational research that is underway through NASA's BHP in partnership with its operational counterparts. Efforts include studies evaluating the effects of hypnotics, lighting protocols as countermeasures for circadian entrainment, and investigations involving education and training. This presentation will further identify, based on flight and terrestrial evidence, additional sleep and circadian countermeasures that may still be needed to support exploration missions. Lessons learned from transitioning research deliverables into ISS operations will also be discussed.

Whitmire, A.↗
NASA NTRS2000

Circadian Behavioral Study: LED vs Cool White Fluorescent - 0.1, 1, 10, 40, 80 lux

Currently, the light source most commonly used in animal habitat lighting is cool white fluorescent (CWF) light. It was the objective of this study to evaluate a novel LED light source for use in animal habitat lighting by comparing its effectiveness to CWF light in producing and maintaining a normal circadian entrainment. The LED and CWF lights had similar spectral power distributions. Sprague-Dawley rats (175-350 g) were kept individually in metabolic cages, under a strict lighting control: 4 days of acclimation at 12:12 LD, 14 days of 12:12 LD, 14 days of 24:0 LD (free-run), and finally 12:12 LD. Food and water were provided ad libitum. Three behavioral parameters were monitored continuously: gross locomotor activity, drinking, and feeding. Combined mean free run periods (tau) were (mean +/- SEM): 24.6 +/- 0.1 and 24.7 +/- 0.2 at 0.1 lux, 25.5 +/- 0.1 and 25.7 +/- 0.1 at 1.0 lux, 25.3 +/- 0.2 and 25.4 +/- 0.2 at 10 lux, 25.8 +/- 0.1 and 25.9 +/- 0.1 at 40 lux, and 25.9 +/- 0.1 and 25.9 +/- 0.1 at 80 lux, CWF and LED respectively. ANOVA found a significant effect (p < 0.05) due to light level, but no difference in tau between rats exposed to constant CWF light and rats exposed to constant LED light. This study has shown that LED light can produce the same entrainment pattern as a conventional CWT light at similar intensities (0.1, 1, 10, 40, and 80 lux). LED light sources may be a suitable replacement for conventional light sources used in animal habitat lighting while providing many mechanical and economical advantages.

Holley, Daniel C.↗
NASA NTRS1999

Light masking of circadian rhythms of heat production, heat loss, and body temperature in squirrel monkeys

Whole body heat production (HP) and heat loss (HL) were examined to determine their relative contributions to light masking of the circadian rhythm in body temperature (Tb). Squirrel monkey metabolism (n = 6) was monitored by both indirect and direct calorimetry, with telemetered measurement of body temperature and activity. Feeding was also measured. Responses to an entraining light-dark (LD) cycle (LD 12:12) and a masking LD cycle (LD 2:2) were compared. HP and HL contributed to both the daily rhythm and the masking changes in Tb. All variables showed phase-dependent masking responses. Masking transients at L or D transitions were generally greater during subjective day; however, L masking resulted in sustained elevation of Tb, HP, and HL during subjective night. Parallel, apparently compensatory, changes of HL and HP suggest action by both the circadian timing system and light masking on Tb set point. Furthermore, transient HL increases during subjective night suggest that gain change may supplement set point regulation of Tb.

Non-NASA Center↗
NASA NTRS1970

Mechanisms of action of light on circadian rhythms in the monkey

Light is considered by many investigators to be the primary Zeitgeber for most physiologic rhythms. In order to study the effects on biorhythms of changing photoperiods and to provide information on the nature of the wave forms and the mechanisms of entrainment, unrestrained male monkeys (Cebus albifrons, Macaca nemestrina) were maintained in a sound-proofed environmental chamber. The Cebus was initially maintained on a 12L:12D schedule; it was subjected to a 180 degrees phase shift for 14 days, then returned to the original photoperiod. In two experiments (24 days; 27 days each) the same monkey was again maintained on a 12L:12D schedule which was gradually altered to a constant light environment. Deep body temperature (DBT) data were obtained with miniature radiotransmitters. Locomotor activity (LMA) was measured by strain gauges. Under the 12L:12D regimens the Macaca DBT cycles were uniform as to phase and wave form for over 60 weeks. These wave forms were analyzed by the use of periodogram and correlogram analyses and by fitting to the Volterra Integro-Differential Equation. Phase angle relationships between Zeitgeber and physiologic parameters were characterized. After the photoperiod phase shift the DBT cycle rephased in about 9 days. During the rephasing process the wave form changed. The shapes of the wave forms of DBT and activity were maintained with increasing light until an 18L:6D photoperiod was reached. The rhythms were entrained to the onset of darkness rather than lights on. Major and minor periods of LMA were detected. Hysteresis diagrams showed that DBT led the onset of major LA by 6 hr and the end of major activity by 2 hr.

Light↗
NASA NTRS2001

Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor

The photopigment in the human eye that transduces light for circadian and neuroendocrine regulation, is unknown. The aim of this study was to establish an action spectrum for light-induced melatonin suppression that could help elucidate the ocular photoreceptor system for regulating the human pineal gland. Subjects (37 females, 35 males, mean age of 24.5 +/- 0.3 years) were healthy and had normal color vision. Full-field, monochromatic light exposures took place between 2:00 and 3:30 A.M. while subjects' pupils were dilated. Blood samples collected before and after light exposures were quantified for melatonin. Each subject was tested with at least seven different irradiances of one wavelength with a minimum of 1 week between each nighttime exposure. Nighttime melatonin suppression tests (n = 627) were completed with wavelengths from 420 to 600 nm. The data were fit to eight univariant, sigmoidal fluence-response curves (R(2) = 0.81-0.95). The action spectrum constructed from these data fit an opsin template (R(2) = 0.91), which identifies 446-477 nm as the most potent wavelength region providing circadian input for regulating melatonin secretion. The results suggest that, in humans, a single photopigment may be primarily responsible for melatonin suppression, and its peak absorbance appears to be distinct from that of rod and cone cell photopigments for vision. The data also suggest that this new photopigment is retinaldehyde based. These findings suggest that there is a novel opsin photopigment in the human eye that mediates circadian photoreception.

Non-NASA Center↗
NASA NTRS1991

Light as a chronobiologic countermeasure for long-duration space operations

Long-duration space missions require adaptation to work-rest schedules which are substantially shifted with respect to earth. Astronauts are expected to work in two-shift operations and the environmental synchronizers (zeitgebers) in a spacecraft differ significantly from those on earth. A study on circadian rhythms, sleep, and performance was conducted by exposing four subjects to 6 deg head-down tilt bedrest (to simulate the effects of the weightless condition) and imposing a 12-h shift (6 h delay per day for two days). Bright light was tested in a cross-over design as a countermeasure for achieving faster resynchronization and regaining stable conditions for sleep and circadian rhythmicity. Data collection included objective sleep recording, temperature, heart rate, and excretion of hormones and electrolytes as well as performance and responses to questionnaires. Even without a shift in the sleep-wake cycle, the sleep quantity, circadian amplitudes and 24 h means decreased in many functions under bedrest conditions. During the shift days, sleepiness and fatigue increased, and alertness decreased. However, sleep quantity was regained, and resynchronization was completed within seven days after the shift for almost all functions, irrespective of whether light was administered during day-time or night-time hours. The time of day of light exposure surprisingly appeared not to have a discriminatory effect on the resynchronization speed under shift and bedrest conditions. The results indicate that simulated weightlessness alters circadian rhythms and sleep, and that schedule changes induce additional physiological disruption with decreased subjective alertness and increased fatigue. Because of their operational implications, these phenomena deserve additional investigation.

Samel, Alexander↗
NASA NTRS2011

Molecular Mechanisms of Circadian Regulation During Spaceflight

Disruption of the regular environmental circadian cues in addition to stringent and demanding operational schedules are two main factors that undoubtedly impact sleep patterns and vigilant performance in the astronaut crews during spaceflight. Most research is focused on the behavioral aspects of the risk of circadian desynchronization, characterized by fatigue and health and performance decrement. A common countermeasure for circadian re-entrainment utilizes blue-green light to entrain the circadian clock and mitigate this risk. However, an effective countermeasure targeting the photoreceptor system requires that the basic circadian molecular machinery remains intact during spaceflight. The molecular clock consists of sets of proteins that perform different functions within the clock machinery: circadian oscillators (genes whose expression levels cycle during the day, keep the pass of cellular time and regulate downstream effector genes), the effector or output genes (those which impact the physiology of the tissue or organism), and the input genes (responsible for sensing the environmental cues that allow circadian entrainment). The main environmental cue is light. As opposed to the known photoreceptors (rods and cones), the non-visual light stimulus is received by a subset of the population of retinal ganglion cells called intrinsically photosensitive retinal ganglion cells (ipRGC) that express melanopsin (opsin 4 -Opn4-) as the photoreceptor. We hypothesize that spaceflight may affect ipRGC and melanopsin expression, which may be a contributing cause of circadian disruption during spaceflight. To answer this question, eyes from albino Balb/cJ mice aboard STS-133 were collected for histological analysis and gene expression profiling of the retina at 1 and 7 days after landing. Both vivarium and AEM (animal enclosure module) mice were used as ground controls. Opn4 expression was analyzed by real time RT/qPCR and retinal sections were stained for Opn4 immunofluorescence. Opn4 was decreased (abrogated in one case) in retinas that concurrently showed higher evidence of oxidative stress. We propose that oxidative stress can lead to a decrease in melanopsin expression, likely via ipRGC loss or impairment, and thus, it can be a contributing factor to circadian disruption during spaceflight. Countermeasures contemplating the use of light should therefore be complemented with melanopsin expression maintenance and/or reduction in oxidative stress.

Zanello, Susana↗