High dose melatonin increases sleep duration during nighttime and daytime sleep episodes in older adults.

Aging is associated with changes in sleep, and improving sleep may have important consequences for the health, cognition, and quality of life of older adults. Many prescription sleep aids increase the risk of nighttime falls, have adverse effects on next-day cognition, and are associated with increased mortality. Melatonin, a hormone secreted at night, increases sleep duration in young adults but only when administered during the day when endogenous levels are low. In a month-long cross-over study, we randomized 24 healthy older (age >55, mean 64.2 ± 6.3 years) participants to receive 2 weeks of placebo and 2 weeks of either a low (0.3 mg) or high (5.0 mg) dose of melatonin 30 min before lights out. Sleep was polysomnographically recorded and was scheduled during both the biological day and night using a forced desynchrony design. Although 0.3 mg melatonin had a trend towards increasing sleep efficiency (SE) overall, this was due to its effects on sleep during the biological day. In contrast, 5 mg melatonin significantly increased SE during both biological day and night, mainly by increasing the duration of Stage 2 non-rapid eye movement sleep and slightly shortening awakenings. Melatonin should be further explored as a sleep aid for older adults.

Measuring and using light in the melanopsin age.

Light is a potent stimulus for regulating circadian, hormonal, and behavioral systems. In addition, light therapy is effective for certain affective disorders, sleep problems, and circadian rhythm disruption. These biological and behavioral effects of light are influenced by a distinct photoreceptor in the eye, melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs), in addition to conventional rods and cones. We summarize the neurophysiology of this newly described sensory pathway and consider implications for the measurement, production, and application of light. A new light-measurement strategy taking account of the complex photoreceptive inputs to these non-visual responses is proposed for use by researchers, and simple suggestions for artificial/architectural lighting are provided for regulatory authorities, lighting manufacturers, designers, and engineers.

Blue light stimulates cognitive brain activity in visually blind individuals.

Light regulates multiple non-image-forming (or nonvisual) circadian, neuroendocrine, and neurobehavioral functions, via outputs from intrinsically photosensitive retinal ganglion cells (ipRGCs). Exposure to light directly enhances alertness and performance, so light is an important regulator of wakefulness and cognition. The roles of rods, cones, and ipRGCs in the impact of light on cognitive brain functions remain unclear, however. A small percentage of blind individuals retain non-image-forming photoreception and offer a unique opportunity to investigate light impacts in the absence of conscious vision, presumably through ipRGCs. Here, we show that three such patients were able to choose nonrandomly about the presence of light despite their complete lack of sight. Furthermore, 2 sec of blue light modified EEG activity when administered simultaneously to auditory stimulations. fMRI further showed that, during an auditory working memory task, less than a minute of blue light triggered the recruitment of supplemental prefrontal and thalamic brain regions involved in alertness and cognition regulation as well as key areas of the default mode network. These results, which have to be considered as a proof of concept, show that non-image-forming photoreception triggers some awareness for light and can have a more rapid impact on human cognition than previously understood, if brain processing is actively engaged. Furthermore, light stimulates higher cognitive brain activity, independently of vision, and engages supplemental brain areas to perform an ongoing cognitive process. To our knowledge, our results constitute the first indication that ipRGC signaling may rapidly affect fundamental cerebral organization, so that it could potentially participate to the regulation of numerous aspects of human brain function.

Human phase response curve to a single 6.5 h pulse of short-wavelength light.

The photic resetting response of the human circadian pacemaker depends on the timing of exposure, and the direction and magnitude of the resulting shift is described by a phase response curve (PRC). Previous PRCs in humans have utilized high-intensity polychromatic white light. Given that the circadian photoreception system is maximally sensitive to short-wavelength visible light, the aim of the current study was to construct a PRC to blue (480 nm) light and compare it to a 10,000 lux white light PRC constructed previously using a similar protocol. Eighteen young healthy participants (18-30 years) were studied for 9-10 days in a time-free environment. The protocol included three baseline days followed by a constant routine (CR) to assess initial circadian phase. Following this CR, participants were exposed to a 6.5 h 480 nm light exposure (11.8 µW cm(-2), 11.2 lux) following mydriasis via a modified Ganzfeld dome. A second CR was conducted following the light exposure to re-assess circadian phase. Phase shifts were calculated from the difference in dim light melatonin onset (DLMO) between CRs. Exposure to 6.5 h of 480 nm light resets the circadian pacemaker according to a conventional type 1 PRC with fitted maximum delays and advances of -2.6 h and 1.3 h, respectively. The 480 nm PRC induced ∼75% of the response of the 10,000 lux white light PRC. These results may contribute to a re-evaluation of dosing guidelines for clinical light therapy and the use of light as a fatigue countermeasure.

Amplitude reduction and phase shifts of melatonin, cortisol and other circadian rhythms after a gradual advance of sleep and light exposure in humans.

BACKGROUND: The phase and amplitude of rhythms in physiology and behavior are generated by circadian oscillators and entrained to the 24-h day by exposure to the light-dark cycle and feedback from the sleep-wake cycle. The extent to which the phase and amplitude of multiple rhythms are similarly affected during altered timing of light exposure and the sleep-wake cycle has not been fully characterized. METHODOLOGY/PRINCIPAL FINDINGS: We assessed the phase and amplitude of the rhythms of melatonin, core body temperature, cortisol, alertness, performance and sleep after a perturbation of entrainment by a gradual advance of the sleep-wake schedule (10 h in 5 days) and associated light-dark cycle in 14 healthy men. The light-dark cycle consisted either of moderate intensity 'room' light (∼90-150 lux) or moderate light supplemented with bright light (∼10,000 lux) for 5 to 8 hours following sleep. After the advance of the sleep-wake schedule in moderate light, no significant advance of the melatonin rhythm was observed whereas, after bright light supplementation the phase advance was 8.1 h (SEM 0.7 h). Individual differences in phase shifts correlated across variables. The amplitude of the melatonin rhythm assessed under constant conditions was reduced after moderate light by 54% (17-94%) and after bright light by 52% (range 12-84%), as compared to the amplitude at baseline in the presence of a sleep-wake cycle. Individual differences in amplitude reduction of the melatonin rhythm correlated with the amplitude of body temperature, cortisol and alertness. CONCLUSIONS/SIGNIFICANCE: Alterations in the timing of the sleep-wake cycle and associated bright or moderate light exposure can lead to changes in phase and reduction of circadian amplitude which are consistent across multiple variables but differ between individuals. These data have implications for our understanding of circadian organization and the negative health outcomes associated with shift-work, jet-lag and exposure to artificial light.

Revisiting spontaneous internal desynchrony using a quantitative model of sleep physiology.

Early attempts to characterize free-running human circadian rhythms generated three notable results: 1) observed circadian periods of 25 hours (considerably longer than the now established 24.1- to 24.2-hour average intrinsic circadian period) with sleep delayed to later circadian phases than during entrainment; 2) spontaneous internal desynchrony of circadian rhythms and sleep/wake cycles--the former with an approximately 24.9-hour period, and the latter with a longer (28-68 hour) or shorter (12-20 hour) period; and 3) bicircadian (48-50 hour) sleep/wake cycles. All three results are reproduced by Kronauer et al.'s (1982) coupled oscillator model, but the physiological basis for that phenomenological model is unclear. We use a physiologically based model of hypothalamic and brain stem nuclei to investigate alternative physiological mechanisms that could underlie internal desynchrony. We demonstrate that experimental observations can be reproduced by changes in two pathways: promotion of orexinergic (Orx) wake signals, and attenuation of the circadian signal reaching hypothalamic nuclei. We reason that delayed sleep is indicative of an additional wake-promoting drive, which may be of behavioral origin, associated with removal of daily schedules and instructions given to participants. We model this by increasing Orx tone during wake, which reproduces the observed period lengthening and delayed sleep. Weakening circadian input to the ventrolateral preoptic nucleus (possibly mediated by the dorsomedial hypothalamus) causes desynchrony, with observed sleep/wake cycle period determined by degree of Orx up-regulation. During desynchrony, sleep/wake cycles are driven by sleep homeostasis, yet sleep bout length maintains circadian phase dependence. The model predicts sleep episodes are shortest when started near the temperature minimum, consistent with experimental findings. The model also correctly predicts that it is possible to transition to bicircadian rhythms from either a synchronized or desynchronized state. Our findings suggest that feedback from behavioral choices to physiology could play an important role in spontaneous internal desynchrony.

The human circadian system adapts to prior photic history.

Light is the most potent stimulus for synchronizing the endogenous circadian timing system to the 24 h day. The timing, intensity, duration, pattern and wavelength of light are known to modulate photic resetting of the circadian system and acute suppression of melatonin secretion. The effect of prior photic history on these processes, however, is not well understood. Although previous studies have shown that light history affects the suppression of melatonin in response to a subsequent light exposure, here we show for the first time that a very dim light history, as opposed to a typical indoor room illuminance, amplifies the phase-shifting response to a subsequent sub-saturating light stimulus by 60­70%. This greater efficacy provides evidence for dynamic adaptive changes in the sensitivity of circadian ocular photoreception. This plasticity has important implications for the optimization of light therapy for the treatment of circadian rhythm sleep disorders.

Spectral responses of the human circadian system depend on the irradiance and duration of exposure to light.

In humans, modulation of circadian rhythms by light is thought to be mediated primarily by melanopsin-containing retinal ganglion cells, not rods or cones. Melanopsin cells are intrinsically blue light-sensitive but also receive input from visual photoreceptors. We therefore tested in humans whether cone photoreceptors contribute to the regulation of circadian and neuroendocrine light responses. Dose-response curves for melatonin suppression and circadian phase resetting were constructed in subjects exposed to blue (460 nm) or green (555 nm) light near the onset of nocturnal melatonin secretion. At the beginning of the intervention, 555-nm light was equally effective as 460-nm light at suppressing melatonin, suggesting a significant contribution from the three-cone visual system (lambda(max) = 555 nm). During the light exposure, however, the spectral sensitivity to 555-nm light decayed exponentially relative to 460-nm light. For phase-resetting responses, the effects of exposure to low-irradiance 555-nm light were too large relative to 460-nm light to be explained solely by the activation of melanopsin. Our findings suggest that cone photoreceptors contribute substantially to nonvisual responses at the beginning of a light exposure and at low irradiances, whereas melanopsin appears to be the primary circadian photopigment in response to long-duration light exposure and at high irradiances. These results suggest that light therapy for sleep disorders and other indications might be optimized by stimulating both photoreceptor systems.

Diurnal variation in CSF orexin-A in healthy male subjects.

STUDY OBJECTIVE: Orexin-A is hypothesized to promote wakefulness, and we examined whether cerebrospinal fluid (CSF) orexin-A levels are higher during the waking period in man. DESIGN: Within-subjects, repeated-measures design with balanced ordering of sampling at approximately 5 AM and 5 PM. PARTICIPANTS: Eight healthy young males. MESUREMENTS: CSF orexin-A levels and standard polysomnography. RESULTS: Orexin-A levels during the sleep period were 4% higher than during the waking period (314.9 pg/ml versus 302.8 pg/ml, p < 0.03). Sleep period orexin-A levels were negatively correlated with REM sleep as a percentage of total sleep time (p < 0.05). The day and night levels of orexin-A were strongly correlated within subjects (r = 0.97; p < 0.0001) even though the samples were collected 1-2 weeks apart. CONCLUSIONS: Orexin-A levels in lumbar CSF are slightly higher at 5 AM than at 5 PM. Because orexin release is thought to be highest during the waking period, this observation was unexpected and may reflect a long delay between the release of orexin and its appearance in lumbar CSF. Orexin-A levels vary moderately between subjects, but are quite consistent within the same subject. Thus, for the diagnostic evaluation of narcolepsy, the time of CSF collection should have little impact.