Regulation of circadian period in humans was thought to differ from that of other species, with the period of the activity rhythm reported to range from 13 to 65 hours (median 25.2 hours) and the period of the body temperature rhythm reported to average 25 hours in adulthood, and to shorten with age. However, those observations were based on studies of humans exposed to light levels sufficient to confound circadian period estimation. Precise estimation of the periods of the endogenous circadian rhythms of melatonin, core body temperature, and cortisol in healthy young and older individuals living in carefully controlled lighting conditions has now revealed that the intrinsic period of the human circadian pacemaker averages 24.18 hours in both age groups, with a tight distribution consistent with other species. These findings have important implications for understanding the pathophysiology of disrupted sleep in older people.

Ocular exposure to early morning room light can significantly advance the timing of the human circadian pacemaker. The resetting response to such light has a non‐linear relationship to illuminance. The dose‐response relationship of the human circadian pacemaker to late evening light of dim to moderate intensity has not been well established. Twenty‐three healthy young male and female volunteers took part in a 9 day protocol in which a single experimental light exposure6.5 h in duration was given in the early biological night. The effects of the light exposure on the endogenous circadian phase of the melatonin rhythm and the acute effects of the light exposure on plasma melatonin concentration were calculated. We demonstrate that humans are highly responsive to the phase‐delaying effects of light during the early biological night and that both the phase resetting response to light and the acute suppressive effects of light on plasma melatonin follow a logistic dose‐response curve, as do many circadian responses to light in mammals. Contrary to expectations, we found that half of the maximal phase‐delaying response achieved in response to a single episode of evening bright light (≈9000 lux (lx)) can be obtained with just over 1 % of this light (dim room light of ≈100 lx). The same held true for the acute suppressive effects of light on plasma melatonin concentrations. This indicates that even small changes in ordinary light exposure during the late evening hours can significantly affect both plasma melatonin concentrations and the entrained phase of the human circadian pacemaker.

The response of the human circadian pacemaker to light was measured in 45 resetting trials. Each trial consisted of an initial endogenous circadian phase assessment, a three-cycle stimulus which included 5 hours of bright light per cycle, and a final phase assessment. The stimulus induced strong (type 0) resetting, with responses highly dependent on the initial circadian phase of light exposure. The magnitude and direction of the phase shifts were modulated by the timing of exposure to ordinary room light, previously thought to be undetectable by the human pacemaker. The data indicate that the sensitivity of the human circadian pacemaker to light is far greater than previously recognized and have important implications for the therapeutic use of light in the management of disorders of circadian regulation.

No abstract

A general model is developed to account for all kinds of periodic breathing (PB) resulting from instability in respiratory control: in normals during sleep and on acute exposure to high altitude, in sleeping infants, and in patients with cardiovascular or neurologic lesions. It is found that in almost every case the ventilatory oscillation is mediated predominantly by the peripheral controller. System stability is decreased by hypoxia, hypercapnia, increased lung washout times, prolonged lung-chemoreceptor delays, and high controller sensitivity. Stability is enhanced by large lung CO2 and O2 storage volumes but little affected by body tissue stores. Using our own measurements of lung-ear delays, the model predicts that the mean cycle time of PB decreases from about 30 s at sea level to 20 s at 14,000 ft, in excellent agreement with data from other studies. Allometric scaling of the relevant parameters also shows close agreement between model predictions and data obtained on infants.

In humans, circadian responses to light are 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 just as effective as 460 nm light at suppressing melatonin, suggesting a significant contribution from the three-cone visual system (lambdamax 555 nm). During 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 non-visual 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 are consistent with a non-redundant role for visual photoreceptors and melanopsin in mediating human non-visual photoreception and suggest that light therapy for circadian rhythm sleep disorders and other indications might be optimized by stimulating both the melanopsin- and cone-driven photoreceptor systems.

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.

Human circadian rhythms were once thought to be insensitive to light, with synchronization to the 24-hour day accomplished either through social contacts or the sleep-wake schedule. Yet the demonstration of an intensity-dependent neuroendocrine response to bright light has led to renewed consideration of light as a possible synchronizer of the human circadian pacemaker. In a laboratory study, the output of the circadian pacemaker of an elderly woman was monitored before and after exposure to 4 hours of bright light for seven consecutive evenings, and before and after a control study in ordinary room light while her sleep-wake schedule and social contacts remained unchanged. The exposure to bright light in the evening induced a 6-hour delay shift of her circadian pacemaker, as indicated by recordings of body temperature and cortisol secretion. The unexpected magnitude, rapidity, and stability of the shift challenge existing concepts regarding circadian phase-resetting capacity in man and suggest that exposure to bright light can indeed reset the human circadian pacemaker, which controls daily variations in physiologic, behavioral, and cognitive function.