EEG delta activity during undisturbed sleep in the squirrel monkey.

The squirrel monkey (Saimiri sciureus) exhibits a robust daily rhythm of sleep-wakefulness that is under circadian control, but the nature of homeostatic sleep regulation in this diurnal primate is poorly understood. Since delta frequency (0.5-2.0 Hz) activity in the electroencephalogram (EEG) during non-Rapid Eye Movement (NREM) sleep is thought to reflect homeostatic factors contributing to sleep tendency, we measured EEG delta power density and slow wave incidence and amplitude during NREM sleep during spontaneous sleep, occurring when monkeys were housed undisturbed in a 24-hour light-dark (LD) cycle and in constant light (LL). In LD and LL conditions, monkeys exhibited circadian rhythms in delta power density, wave incidence and wave amplitude that peaked in the middle of the subjective night, several hours after consolidated sleep onset. These results differ from predictions of a purely homeostatic model of sleep that would include maximal levels of delta activity at sleep onset.

Circadian and homeostatic influences on sleep in the squirrel monkey: sleep after sleep deprivation.

A series of sleep deprivation (SD) experiments were performed to examine the relative influence of circadian and homeostatic factors on the timing of sleep in squirrel monkeys free-running in constant illumination. All SDs started at the beginning of subjective night and lasted 0, 1/4, 1/2, 1, 1 1/4, or 1 1/2 circadian cycles. These six lengths represented three pairs: (0.1), (1/4, 1 1/4), (1/2, 1 1/2). Within each pair, SD ended at the same circadian phase but differed by one circadian cycle in duration. Both before and after SD, consolidated sleep (CS) episodes occurred predominantly during subjective night, even after long SDs ending at the beginning of subjective day. CS duration was strongly influenced by circadian phase but had no overall correlation with prior wake duration. Sleep loss incurred during SDs longer than 1/4 cycle was only partially recovered over the next two circadian cycles, though total sleep duration was closer to baseline levels after the second circadian cycle after SD. There was a trend toward a positive correlation between prior wake duration and the amount of NREM and delta activity measures during subjective day. Delta activity was not increased in the first 2 hours of CS after the SD. Relatively high levels of delta activity occurred immediately after the SD ended and again at the time of baseline CS onset. These data indicate that the amount of sleep and delta activity after SD in squirrel monkeys is weakly dependent on prior wake duration. Circadian factors appear to dominate homeostatic processes in determining the timing, duration and content of sleep in these diurnal primates.

Effects of twilights on circadian entrainment patterns and reentrainment rates in squirrel monkeys.

Entrainment patterns of the circadian rhythms of body temperature and locomotor activity were compared in 6 squirrel monkeys (Saimiri sciureus) exposed to daily illumination cycles with abrupt transitions between light and darkness (LD-rectangular) or with gradual dawn and dusk transitions simulating natural twilights at the equator (LD-twilight). Daytime light intensity was 500 lux, and the total amount of light emitted per day was the same in the two conditions. Mean daytime body temperature levels were stable in LD-rectangular but increased gradually in LD-twilight, reaching peak levels during the dusk twilight. Locomotor activity showed a similar pattern, but with an additional, secondary peak near the end of dawn. Activity duration was about 0.5 h longer in LD-twilight than in LD-rectangular, but the time of activity midpoint was similar in the two conditions. Reentrainment of the body temperature rhythm was faster following an 8-h advance of the LD cycle than following an 8-h delay, but did not differ significantly between the two LD conditions. These results provide no evidence that the inclusion of twilight transitions affected the strength of the LD zeitgeber, and suggest that the observed differences in the daily patterns reflected direct effects of light intensity on locomotor activity and body temperature rather than an effect of twilights on circadian entrainment mechanisms.

Circadian phase-response curves for simulated dawn and dusk twilights in hamsters.

Phase shifts of the circadian rhythm of wheel-running activity were compared in Syrian hamsters maintained in constant darkness and exposed to 1-h naturalistic dawn or dusk twilight ramps (0.003-10 lx), or to 1-h rectangular light pulses (1 lx) providing equal photon exposure. The phase-response curves (PRCs) for dusk and rectangular pulses were virtually identical and resembled the PRC for dawn pulses, except that the mean phase advance caused by dawn pulses at circadian time 19 (CT 19) was approximately 1 h smaller. This difference could not be accounted for by differences in the amount of wheel-running observed during light pulse exposure, because the animals ran more during dusk pulses than during either of the other two pulse types. In a second experiment, 15-min rectangular light pulses (1 lx) immediately preceded by a 47-min dawn ramp caused smaller phase delays at CT 13 than rectangular pulses alone, despite a 40% increase in total photon exposure, but phase advances at CT 19 did not differ between the two light treatments. These results indicate that phase shifts of the circadian pacemaker in hamsters are determined primarily, though not entirely, by total photon exposure. They also indicate that dawn pulses may be less effective than dusk or rectangular pulses at certain circadian phases, possibly due to light adaptation during the early portion of the dawn twilight.

Twilight transitions promote circadian entrainment to lengthening light-dark cycles.

The upper limits of entrainment of the circadian activity rhythm were compared in hamsters initially exposed to daily light-dark (LD) cycles with either abrupt (LD-rectangular) or simulated twilight (LD-twilight) transitions. Daytime illuminance (10 lx) and the total amount of light emitted per day were the same under the two LD cycles. One-half of the animals in each condition had access to dark nest boxes. The period of the LD cycles was then increased from 24 to 26 h, by 5 min per day. All animals in LD-twilight remained entrained to the lengthening cycle, whereas 60% of those in LD-rectangular began to free run well before the period of the cycle reached 26 h. These effects were independent of nest box availability. The lengthening LD cycles exerted clear aftereffects on the period of the rhythms in constant darkness, the magnitude of which was related to the efficacy of prior entrainment. The results indicate that twilight transitions raise the upper limit of entrainment to LD cycles, suggesting that their inclusion increases the strength of the LD zeitgeber.

Photic entrainment in hamsters: effects of simulated twilights and nest box availability.

Entrainment of wheel-running activity rhythms was compared in hamsters exposed to daily light-dark (LD) cycles with abrupt transitions between 0 and 10 lux or with artificial twilights simulating summer solstice conditions at 41 degrees N latitude but truncated at 10 lux. The photoperiod in LD-rectangular was set at 16.24 h, equating the total light (in lux.min) emitted under the two schedules. The LD cycles were maintained for 35 days and were followed by 14 days of constant darkness (DD). Half the animals in each condition had access to a dark nest box connected to the outer compartment by a tunnel, the remaining animals being confined to a single compartment. Body temperature and locomotor activity inside the nest boxes were recorded by telemetry. Movements between the nest box and the outer compartment were monitored and the data were used to calculate light exposure at different times of the day. In all groups, the phase angle difference between wheel-running onset and dusk was more positive than that between activity offset and dawn. Hamsters with access to nest boxes, however, had later onsets, earlier offsets, and shorter activity durations (alpha s) than those without. These effects could be accounted for by the difference in light exposure between the nest and no-nest animals, particularly light exposure in the morning. The inclusion of twilights also resulted in later onsets and shorter alpha s, but the differences were relatively small and were only observed in the nest animals. The day-to-day variability in activity onset was negatively correlated with onset time and was smaller in the twilight/nest animals than in the other three groups. Most animals showed an expansion of alpha during the first few days of DD, resulting from a rapid advance of activity onsets relative to offsets. The period of the rhythms, determined from the first five activity onsets in DD, was negatively correlated with the balance of evening and morning light exposure. These results are discussed in the context of nonparametric entrainment of compound pacemakers.

MidnightSun: software for determining light exposure and phase-shifting schedules during global travel.

The application of circadian principles has the potential to alleviate jet-lag in global travelers, but their application is hampered by the difficulty of determining light exposure along international flight routes. Computerized tools can solve this problem algorithmically. We have developed a program for Macintosh computers, called MidnightSun, which allows researchers to display ambient lighting conditions at any geographical location at any time of the year. The program contains a data base with the latitudes and longitudes of over 3000 airports. It calculates flight paths and durations, and prints a graphical itinerary indicating times of daylight during flights and layovers. Given a travel itinerary and a user-defined phase response curve (PRC) for light, it recommends light exposure times that may accelerate the reentrainment of circadian rhythms to new time zones and reduce the deleterious effects of jet-lag (depending on the efficacy of the PRC and the compliance of the traveler). Other potential applications include determining lighting protocols for photoperiodism experiments and providing data sets for mathematical circadian simulations under naturalistic lighting conditions.

Light treatment for sleep disorders: consensus report. I. Chronology of seminal studies in humans.

Examination of the influence of the light-dark cycle on circadian rhythmicity has been a fundamental aspect of chronobiology since its inception as a scientific discipline. Beginning with Bünning's hypothetical phase response curve in 1936, the impact of timed light exposure on circadian rhythms of literally hundreds of species has been described. The view that the light-dark cycle was an important zeitgeber for the human circadian system, as well, seemed to be supported by early studies of blind and sighted subjects. Yet, by the early 1970s, based primarily on a series of studies conducted at Erling-Andechs, Germany, the notion became widely accepted that the light-dark cycle had only a weak influence on the human circadian system and that social cues played a more important role in entrainment. In 1980, investigators at the National Institute of Mental Health reported that bright light could suppress melatonin production in humans, thereby demonstrating unequivocally the powerful effects of light on the human central nervous system. This finding led directly to the use of timed bright light exposure as a tool for the study and treatment of human circadian rhythms disorders.

Light treatment for sleep disorders: consensus report. II. Basic properties of circadian physiology and sleep regulation.

The rationale for the treatment of sleep disorders by scheduled exposure to bright light in seasonal affective disorder, jet lag, shift work, delayed sleep phase syndrome, and the elderly is, in part, based on a conceptual framework developed by nonclinical circadian rhythm researchers working with humans and other species. Some of the behavioral and physiological data that contributed to these concepts are reviewed, and some pitfalls related to their application to bright light treatment of sleep disorders are discussed. In humans and other mammals the daily light-dark (LD) cycle is a major synchronizer responsible for entrainment of circadian rhythms to the 24-h day, and phase response curves (PRCs) to light have been obtained. In humans, phase delays can be induced by light exposure scheduled before the minimum of the endogenous circadian rhythm of core body temperature (CBT), whereas phase advances are induced when light exposure is scheduled after the minimum of CBT. Since in healthy young subjects the minimum of CBT is located approximately 1 to 2 h before the habitual time of awakening, the most sensitive phase of the PRC to light coincides with sleep, and the timing of the monophasic sleep-wake cycle itself is a major determinant of light input to the pacemaker. The effects of light are mediated by the retinohypothalamic tract, and excitatory amino acids play a key role in the transduction of light information to the suprachiasmatic nuclei. LD cycles have direct "masking" effects on many variables, including sleep, which complicates the assessment of endogenous circadian phase and the interpretation of the effects of light treatment on sleep disorders. In some rodents motor activity has been shown to affect circadian phase, but in humans the evidence for such a feedback of activity on the pacemaker is still preliminary. The endogenous circadian pacemaker is a major determinant of sleep propensity and sleep structure; these, however, are also strongly influenced by the prior history of sleep and wakefulness. In healthy young subjects, light exposure schedules that do not curtail sleep but induce moderate shifts of endogenous circadian phase have been shown to influence the timing of sleep and wakefulness without markedly affecting sleep structure.

Light treatment for sleep disorders: consensus report. III. Alerting and activating effects.

In addition to the well-established phase-shifting properties of timed exposure to bright light, some investigators have reported an acute alerting, or activating, effect of bright light exposure. To the extent that bright light interventions for sleep disturbance may cause subjective and/or central nervous system activation, such a property may adversely affect the efficacy of treatment. Data obtained from patient samples and from healthy subjects generally support the notion that exposure to bright light may be associated with enhanced subjective alertness, and there is limited evidence of objective changes (EEG, skin conductance levels) that are consistent with true physiological arousal. Such activation appears to be quite transient, and there is little evidence to suggest that bright light-induced activation interferes with subsequent sleep onset. Some depressed patients, however, have experienced insomnia and hypomanic activation following bright-light exposure.

Light treatment for sleep disorders: consensus report. IV. Sleep phase and duration disturbances.

Advanced and delayed sleep phase disorders, and the hypersomnia that can accompany winter depression, have been treated successfully by appropriately timed artificial bright light exposure. Under entrainment to the 24-h day-night cycle, the sleep-wake pattern may assume various phase relationships to the circadian pacemaker, as indexed, for example, by abnormally long or short intervals between the onset of melatonin production or the core body temperature minimum and wake-up time. Advanced and delayed sleep phase syndromes and non-24-h sleep-wake syndrome have been variously ascribed to abnormal intrinsic circadian periodicity, deficiency of the entrainment mechanism, or--most simply--patterns of daily light exposure insufficient for adequate phase resetting. The timing of sleep is influenced by underlying circadian phase, but psychosocial constraints also play a major role. Exposure to light early or late in the subjective night has been used therapeutically to produce corrective phase delays or advances, respectively, in both the sleep pattern and circadian rhythms. Supplemental light exposure in fall and winter can reduce the hypersomnia of winter depression, although the therapeutic effect may be less dependent on timing.

Light treatment for sleep disorders: consensus report. V. Age-related disturbances.

Sleep maintenance insomnia is a major complaint among the elderly. As a result, an inordinate proportion of sleeping pill prescriptions go to individuals over 65 y of age. Because of the substantial problems associated with use of hypnotics in older populations, efforts have been made to develop nondrug treatments for age-related sleep disturbance, including timed exposure to bright light. Such bright light treatments are based on the assumption that age-related sleep disturbance is the consequence of alterations in the usual temporal relationship between body temperature and sleep. Although studies are limited, results strongly suggest that evening bright light exposure is beneficial in alleviating sleep maintenance insomnia in healthy elderly subjects. Less consistent, but generally positive, findings have been reported with regard to bright light treatment of sleep and behavioral disturbance in demented patients. For both groups, it is likely that homeostatic factors also contribute to sleep disturbance, and these may be less influenced by bright light interventions.

Light treatment for sleep disorders: consensus report. VI. Shift work.

The unhealthy symptoms and many deleterious consequences of shift work can be explained by a mismatch between the work-sleep schedule and the internal circadian rhythms. This mismatch occurs because the 24-h zeitgebers, such as the natural light-dark cycle, keep the circadian rhythms from phase shifting to align with the night-work, day-sleep schedule. This is a review of studies in which the sleep schedule is shifted several hours, as in shift work, and bright light is used to try to phase shift circadian rhythms. Phase shifts can be produced in laboratory studies, when subjects are kept indoors, and faster phase shifting occurs with appropriately timed bright light than with ordinary indoor (dim) light. Bright light field studies, in which subjects live at home, show that the use of artificial nocturnal bright light combined with enforced daytime dark (sleep) periods can phase shift circadian rhythms despite exposure to the conflicting 24-h zeitgebers. So far, the only studies on the use of bright light for real shift workers have been conducted at National Aeronautics and Space Administration (NASA). In general, the bright light studies support the idea that the control of light and dark can be used to overcome many of the problems of shift work. However, despite ongoing practical applications (such as at NASA), much basic research is still needed.

Light treatment for sleep disorders: consensus report. VII. Jet lag.

Sleep disturbances are an all-too-familiar symptom of jet lag and a prime source of complaints for transmeridian travelers and flight crews alike. They are the result of a temporary loss of synchrony between an abruptly shifted sleep period, timed in accordance with the new local day-night cycle, and a gradually reentraining circadian system. Scheduled exposure to bright light can, in principle, alleviate the symptoms of jet lag by accelerating circadian reentrainment to new time zones. Laboratory simulations, in which sleep time is advanced by 6 to 8 h and the subjects exposed to bright light for 3 to 4 h during late subjective night on 2 to 4 successive days, have not all been successful. The few field studies conducted to date have had encouraging results, but their applicability to the population at large remains uncertain due to very limited sample sizes. Unresolved issues include optimal times for light exposure on the first as well as on subsequent treatment days, whether a given, fixed, light exposure time is likely to benefit a majority of travelers or whether light treatment should be scheduled instead according to some individual circadian phase marker, and if so, can such a phase marker be found that is both practical and reliable.

Wavelength dependence of light-induced phase shifts and period changes in hamsters.

The wavelength dependence of three different circadian responses to light was compared in Syrian hamsters: phase advances and phase delays induced by 15-min light pulses at CT18 (circadian time 18) and CT13, respectively, and changes in free-running period under different levels of constant illumination (LL) intensity. Fluorescent lamps with transmission maxima at 436, 514, and 658 nm were used for delivering blue, green, and red light, respectively. White fluorescent light was also used in the LL portion of the study. The magnitude of each circadian response was plotted as a function of light intensity expressed in photons cm-2 s-1, and intensity-response relationships for the different wavelengths were quantified by fitting the data with a 4-parameter sigmoidal function using a least-squares curve-fitting routine. For each response type, the curves for the different wavelengths were identical but displaced along the horizontal axis [i.e., the functions differed only in the intensity (sigma) required for producing a half-maximal response]. The values of sigma for green and blue light were similar, while that for red light was several times greater. These results indicate that a single class of photoreceptors with peak sensitivity in the blue-green region mediates light-induced phase advances, phase delays, and changes in the period of the hamster circadian pacemaker.

Failure of triazolam to alter circadian reentrainment rates in squirrel monkeys.

The short-acting benzodiazepine triazolam has been shown to cause phase-dependent phase shifts of the circadian activity rhythms of squirrel monkeys maintained in constant light. The present study sought to determine whether properly timed triazolam administration can also accelerate the reentrainment of circadian rhythms following phase shifts of the daily light-dark (LD) cycle. Circadian rhythms of telemetered body temperature and locomotor activity were recorded from squirrel monkeys exposed to an 8-h phase advance of the LD cycle, followed 16 days later by an 8-h phase delay. On the day of the phase advance, each animal received a single injection of triazolam (0.3 mg) or of vehicle alone in midsubjective day (circadian time 6 [CT6], where CT0 represents the time of light onset and the beginning of subjective day, and CT12 the time of dark onset and the beginning of subjective night]), 2 h after the new time of dark onset, while on the day of the phase delay the animals received triazolam or vehicle in late subjective night (CT20), just before dark onset. This procedure was then repeated, giving triazolam to animals that had previously received vehicle alone, and vehicle to animals that had received triazolam. The daily acrophases of the temperature and activity rhythms were calculated by cosinor analysis, and exponential functions were fitted to the acrophases that followed each of the phase shifts.(ABSTRACT TRUNCATED AT 250 WORDS)

Rats anticipate and discriminate between two daily feeding times.

Intact rats and rats bearing lesions of the suprachiasmatic nuclei (SCNX rats) were trained to obtain food by pressing either of two levers located on opposite sides of a cylindrical cage. Intact rats were maintained in constant light (LL) and under daily light-dark (LD) cycles, SCNX rats in LL only. A restricted daily feeding schedule was next imposed, such that pressing one lever provided food for a limited duration (1 or 2 hr) at one time of day while pressing the second lever provided food for the same duration at another time of day. Most rats generally showed anticipatory lever-pressing preceding both daily feeding times, and several discriminated between the two, pressing the lever appropriate for each feeding time more than the inappropriate lever. Discrimination performance was better in intact rats in LD than in intact or SCNX rats in LL. These results indicate that rats can associate different food locations with different times of day, an ability previously known only in honeybees and birds.

Effects of restricted feeding schedules on circadian organization in squirrel monkeys.

Free running circadian rhythms of motor activity, food-motivated lever-pressing, and either drinking (N = 7) or body temperature (N = 3) were recorded from 10 squirrel monkeys maintained in constant illumination with unlimited access to food. Food availability was then restricted to a single unsignaled 3-hour interval each day. The feeding schedule failed to entrain the activity rhythms of 8 monkeys, which continued to free-run. Drinking was almost completely synchronized by the schedule, while body temperature showed a feeding-induced rise superimposed on a free-running rhythm. Nonreinforced lever-pressing showed both a free-running component and a 24-hour component that anticipated the time of feeding. At the termination of the schedule, all recorded variables showed free-running rhythms, but in 3 animals the initial phase of the postschedule rhythms was advanced by several hours, suggesting relative coordination. Of the remaining 2 animals, one exhibited stable entrainment of all 3 recorded rhythms, while the other appeared to entrain temporarily to the feeding schedule. These results indicate that restricted feeding schedules are only a weak zeitgeber for the circadian pacemaker generating free-running rhythms in the squirrel monkey. Such schedules, however, may entrain a separate circadian system responsible for the timing of food-anticipatory changes in behavior and physiology.

Circadian rhythms in hippocampal responsiveness to perforant path stimulation and their relation to behavioral state.

Male rats were chronically implanted with electrodes to record the monosynaptic granule cell response in the dentate gyrus of hippocampus to perforant path stimulation while the animals were unrestrained. Samples of the dentate response were collected every 15 min for up to 14 days under various lighting conditions including constant light (LL) and constant darkness (DD). Circadian rhythms in the slope of evoked population EPSPs were found in all records. EPSP rhythms reached peak values during subjective night. Circadian rhythms in the height of the population spike were found in 8 out of the 12 animals studied. Spike rhythms reached peak values during the subjective day at times when EPSPs were at a daily minimum. Rhythms were confirmed statistically by periodogram. Rhythms followed changes in the LD cycle and persisted under LL or DD. The behavioral state associated with each sample was determined by EEG and video records of 4 animals. Day-night differences in EPSPs were found within the active awake, still alert, slow-wave and paradoxical sleep states. Day-night differences in the spike were detected during the still alert and paradoxical sleep states.

Entrainment of split circadian activity rhythms in hamsters.

Hamsters that showed splitting of their circadian rhythms of wheel-running activity following long-term exposure to constant illumination (LL) were exposed to light-dark (LD) cycles with 2-hr dark segments, and with periods of 24.00, 24.23 or 24.72 hr. For comparison, hamsters showing nonsplit rhythms were also studied. In all cases of split rhythms, at least one of the two split components entrained to the LD cycles. In some animals, the second component continued to free-run until it merged with the entrained component, while in others, the second component also entrained to the LD cycle but maintained a stable phase angle of 6-14.5 hr relative to dark onset. These results were obtained in cases where the period of the LD cycle was shorter than that of the split rhythms and in cases where it was longer, implying that split components can be phase-advanced as well as phase-delayed by 2 hr of darkness. Three hamsters that showed stable entrainment of split rhythms were allowed to free-run in LL. The LD cycles were then reinstated, but instead of overlapping with the first component, as it did before, the dark segment was timed to overlap with the second. The entrainment patterns that ensued were similar to the ones obtained during the first LD exposure, indicating that the two split components respond to darkness in a qualitatively similar fashion. These results are further evidence that the pacemaker system underlying split circadian activity rhythms in hamsters is composed of two mutually coupled populations of oscillators that have similar properties, including a bidirectional phase response curve. Such a dual-oscillator organization may also underlie normal, or nonsplit, activity rhythms, as suggested by Pittendrigh and Daan (1976c), but the data are also compatible with the alternative view that the circadian pacemaker consists of a large number of coupled oscillators, which only dissociate into two separate populations in some animals under conditions of moderate LL intensity.