Richard E. Kronauer

Sensitivity of the human circadian pacemaker to nocturnal light: melatonin phase resetting and suppression

1 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. 2 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. 3 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. 4 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.

Exposure to bright light and darkness to treat physiologic maladaptation to night work.

Working at night results in a misalignment between the sleep-wake cycle and the output of the hypothalamic pacemaker that regulates the circadian rhythms of certain physiologic and behavioral variables. We evaluated whether such physiologic maladaptation to nighttime work could be prevented effectively by a treatment regimen of exposure to bright light during the night and darkness during the day. We assessed the functioning of the circadian pacemaker in five control and five treatment studies in order to assess the extent of adaptation in eight normal young men to a week of night work. In the control studies, on the sixth consecutive night of sedentary work in ordinary light (approximately 150 lux), the mean (+/- SEM) nadir of the endogenous temperature cycle continued to occur during the night (at 3:31 +/- 0:56 hours), indicating a lack of circadian adaptation to the nighttime work schedule. In contrast, the subjects in the treatment studies were exposed to bright light (7000 to 12,000 lux) at night and to nearly complete darkness during the day, and the temperature nadir shifted after four days of treatment to a significantly later, midafternoon hour (14:53 +/- 0:32; P less than 0.0001), indicating a successful circadian adaptation to daytime sleep and nighttime work. There were concomitant shifts in the 24-hour patterns of plasma cortisol concentration, urinary excretion rate, subjective assessment of alertness, and cognitive performance in the treatment studies. These shifts resulted in a significant improvement in both alertness and cognitive performance in the treatment group during the night-shift hours. We conclude that maladaptation of the human circadian system to night work, with its associated decline in alertness, performance, and quality of daytime sleep, can be treated effectively with scheduled exposure to bright light at night and darkness during the day.

Tree structures: deducing the principle of mechanical design.

Abstract A statistical description of the branching patterns of trees is proposed in the context of a power-law tapered beam model. Depending on the exponent which describes tapering of the depth of the beam, the model either preserves geometric, elastic, or static stress similarity. A detailed study of the morphometry of three oak, one poplar, one cherry, and one white pine corroborates the stationarity of these branching structures and fits the elastically similar model. A separate study of the natural frequencies of branch segments and whole trees within four species also agrees with the predictions of the elastically similar model.

Comparisons of the variability of three markers of the human circadian pacemaker

A circadian pacemaker within the central nervous system regulates the approximately 24-h physiologic rhythms in sleep cycles, hormone secretion, and other physiologic functions. Because the pacemaker cannot be examined directly in humans, markers of pacemaker function must be used to study the pacemaker and its response to environmental stimuli. Core body temperature (CBT), plasma cortisol, and plasma melatonin are three marker variables frequently used to estimate the phase of the human pacemaker. Measurements of circadian phase using markers can contain variability due to the circadian pacemaker itself, the intrinsic variability of the marker relative to the pacemaker, the method of analysis of the marker, and the marker assay. For this report, we compared the mathematical variability of a number of methods of identifying circadian phase from CBT, plasma cortisol, and plasma melatonin data collected in a protocol in which pacemaker variability was minimized using low light levels and regular timing of both the light pattern and the rest/activity schedule. We hoped to assess the relative variabilities of the different physiological markers and the analysis methods. Methods were based on the crossing of an absolute threshold, on the crossing of a relative threshold, or on fitting a curve to all data points. All methods of calculating circadian phase from plasma melatonin data were less variable than those calculated using CBT or cortisol data. The standard deviation for the phase estimates using CBT data was 0.78 h, using cortisol data was 0.65 h, and for the eight analysis methods using melatonin data was 0.23 to 0.35 h. While the variability for these markers might be different for other subject populations and/or less stringent study conditions, assessment of the intrinsic variability of the different calculations of circadian phase can be applied to allow inference of the statistical significance of phase and phase shift calculations, as well as estimation of sample size or statistical power for the number of subjects within an experimental protocol.

Spectral Responses of the Human Circadian System Depend on the Irradiance and Duration of Exposure to Light

Light resets the circadian clock through a non–image-forming receptor system—or so it was thought; now, cone photoreceptors are shown to also participate. Retinal Receptors Conspire to Keep Us Awake Even without an intervening miracle, some blind people can see. When confronted by light, their pupils can constrict, their circadian clocks remain in rhythm, and their blood melatonin is suppressed. Although these people do not detect images of their surroundings—usually conveyed through their missing rods and cones—light still falls on their remaining retina, including special cells that contain a pigment (melanopsin) that receives and transfers blue light, allowing some light-regulated processes to function normally. But new evidence collected by Gooley et al. shows that the distinction between image-forming and non–image-forming sight is more complicated than we have appreciated. The authors carefully examined the light sensitivity of two functions: melatonin suppression and circadian phase control. To this end, they exposed normal individuals to two different wavelengths of light, one designed to be detected by the visual image-forming system and the other by the blue-light receptor melanopsin system. Rather than the expected result—that the non–image-forming responses were induced only by blue-light melanopsin cells—they saw that, at the beginning of the illumination period and at low light levels, the visual system could also drive the non–image-forming endpoints. These findings fit with neuroanatomy; cells that contain the blue-light receptors receive input from cones, which are integral parts of the image-forming system. Furthermore, these findings suggest that we have more to learn about how to optimally activate our light receptors. Indeed, advocates of blue-light therapy for sleep disorders or other ailments will need to rethink their views, as white light may work just as well. And technology addicts beware: The authors suggest that low-light exposure from our computers or indoor lighting late at night may be interfering with our circadian rhythms, making it even harder to get up in the morning. 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 (λmax = 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.

Intrinsic near-24-h pacemaker period determines limits of circadian entrainment to a weak synchronizer in humans

Endogenous circadian clocks are robust regulators of physiology and behavior. Synchronization or entrainment of biological clocks to environmental time is adaptive and important for physiological homeostasis and for the proper timing of species-specific behaviors. We studied subjects in the laboratory for up to 55 days each to determine the ability to entrain the human clock to a weak circadian synchronizing stimulus [scheduled activity–rest cycle in very dim (≈1.5 lux in the angle of gaze) light–dark cycle] at three ≈24-h periods: 23.5, 24.0, and 24.6 h. These studies allowed us to test two competing hypotheses as to whether the period of the human circadian pacemaker is near to or much longer than 24 h. We report here that imposition of a sleep–wake schedule with exposure to the equivalent of candlelight during wakefulness and darkness during sleep is usually sufficient to maintain circadian entrainment to the 24-h day but not to a 23.5- or 24.6-h day. Our results demonstrate functionally that, in normally entrained sighted adults, the average intrinsic circadian period of the human biological clock is very close to 24 h. Either exposure to very dim light and/or the scheduled sleep–wake cycle itself can entrain this near-24-h intrinsic period of the human circadian pacemaker to the 24-h day.

Phase-shifting human circadian rhythms: influence of sleep timing, social contact and light exposure

1. Both the timing of behavioural events (activity, sleep and social interactions) and the environmental light‐dark cycle have been reported to contribute to entrainment of human circadian rhythms to the 24 h day. Yet, the relative contribution of those putative behavioural synchronizers to that of light exposure remains unclear. 2. To investigate this, we inverted the schedule of rest, sedentary activity and social contact of thirty‐two young men either with or without exposure to bright light. 3. On this inverted schedule, the endogenous component of the core temperature rhythm of subjects who were exposed to bright light showed a significant phase shift, demonstrating that they were adapting to the new schedule. In contrast, the core temperature rhythm of subjects who were not exposed to bright light moved on average 0.2 h later per day and after 10 days had not significantly adapted to the new schedule. 4. The direction of phase shift in the groups exposed to bright light was dependent on the time of bright light exposure, while control subjects drifted to a later hour regardless of the timing of their schedule of sleep timing, social contact and meals. 5. These results support the concept that the light‐dark cycle is the most important synchronizer of the human circadian system. They suggest that inversion of the sleep‐wake, rest‐activity and social contact cycles provides relatively minimal drive for resetting the human circadian pacemaker. 6. These data indicate that interventions designed to phase shift human circadian rhythms for adjustment to time zone changes or altered work schedules should focus on properly timed light exposure.

Interactive Mathematical Models of Subjective Alertness and Cognitive Throughput in Humans

The authors present here mathematical models in which levels of subjective alertness and cognitive throughput are predicted by three components that interact with one another in a nonlinear manner. These components are (1) a homeostatic component (H) that falls in a sigmoidal manner during wake and rises in a saturating exponential manner at a rate that is determined by circadian phase during sleep; (2) a circadian component (C) that is a function of the output of our mathematical model of the effect of light on the circadian pacemaker, with the amplitude further regulated by the level of H; and (3) a sleep inertia component (W) that rises in a saturating exponential manner after waketime. The authors first construct initial models of subjective alertness and cognitive throughput based on the results of sleep inertia studies, sleep deprivation studies initiated across all circadian phases, 28-h forced desynchrony studies, and alertness and performance dose response curves to sleep. These initial models are then refined using data from nearly one hundred fifty 30- to 50-h sleep deprivation studies in which subjects woke at their habitual times. The interactive three-component models presented here are able to predict even the fine details of neurobehavioral data from sleep deprivation studies and, after further validation, may provide a powerful tool for the design of safe shift work and travel schedules, including those in which people are exposed to unusual patterns of light.

The formation of vortex streets

The formation of vortex streets in the wake of two-dimensional bluff bodies can be explained by considering the non-linear interaction of two infinite vortex sheets, initially a fixed distance, h , apart, in an inviscid incompressible fluid. The interaction of such sheets (represented in the calculation by rows of point-vortices) is examined in detail for various ratios of h to the wavelength, a , of the initial disturbance. The number and strength of the concentrated regions of vorticity formed in the interaction depend very strongly on h / a . The non-linear interaction of the two vortex sheets explains both the cancellation of vorticity and vortex-street broadening observed in the wakes of bluff bodies.

Visual interactions with luminance and chromatic stimuli

The visibility of a 1 degree, 200-msec flash on a large yellow field was measured as a function of the intensity of a coincident pedestal flash (a flash that was the same in both temporal intervals of a two-alternative forced-choice trial). The various flashes were incremental (+Lum) or decremental (-Lum) yellow luminance flashes or green (+Chr) or red (-Chr) isoluminant chromatic flashes. With uncrossed conditions (Lum tests on Lum pedestals or Chr tests on Chr pedestals), we obtained the conventional dipper function, that is, the function of threshold test intensity was highly asymmetric about zero pedestal intensity, and strong pedestals induced strong masking. Crossed conditions produced neither effect: for example, with Chr tests on Lum pedestals, there was no dipper function: the function of threshold test intensity was symmetric about zero pedestal intensity, and strong pedestals produced no masking. Instead, the suprathreshold luminance pedestals facilitated chromatic detection by as much as 2-3X and also linearized the chromatic psychometric function, further enhancing sensitivity to weak chromatic stimuli. (Chromatic sensitivity on the suprathreshold luminance pedestal was approximately 25X higher than luminance sensitivity on the uniform field.) A pedestal consisting of a thin luminance ring that surrounded the chromatic test produced facilitation equal to that of the uniform-luminance pedestal: the pedestal may thus act to demarcate the test spatially and promote chromatic comparison with the surround. Removing the uniform yellow surround eliminated this crossed facilitation but did not eliminate the uncrossed facilitation (the dipper function), suggesting that different mechanisms mediate the crossed and uncrossed facilitations.