Phase-shifting response to light in older adults.

Age-related changes in circadian rhythms may contribute to the sleep disruption observed in older adults. A reduction in responsiveness to photic stimuli in the circadian timing system has been hypothesized as a possible reason for the advanced circadian phase in older adults. This project compared phase-shifting responses to 2 h of broad-spectrum white light at moderate and high intensities in younger and older adults. Subjects included 29 healthy young (25.1 ± 4.1 years; male to female ratio: 8: 21) and 16 healthy older (66.5 ± 6.0 years; male to female ratio: 5: 11) subjects, who participated in two 4-night and 3-day laboratory stays, separated by at least 3 weeks. Subjects were randomly assigned to one of three different time-points, 8 h before (-8), 3 h before (-3) or 3 h after (+3) the core body temperature minimum (CBTmin) measured on the baseline night. For each condition, subjects were exposed in a randomized order to 2 h light pulses of two intensities (2000 lux and 8000 lux) during the two different laboratory stays. Phase shifts were analysed according to the time of melatonin midpoint on the nights before and after light exposure. Older subjects in this study showed an earlier baseline phase and lower amplitude of melatonin rhythm compared to younger subjects, but there was no evidence of age-related changes in the magnitude or direction of phase shifts of melatonin midpoint in response to 2 h of light at either 2000 lux or 8000 lux. These results indicate that the acute phase-shifting response to moderate- or high-intensity broad spectrum light is not significantly affected by age.

Light-induced changes of the circadian clock of humans: increasing duration is more effective than increasing light intensity.

STUDY OBJECTIVES: To evaluate the effect of increasing the intensity and/or duration of exposure on light-induced changes in the timing of the circadian clock of humans. DESIGN: Multifactorial randomized controlled trial, between and within subject design SETTING: General Clinical Research Center (GCRC) of an academic medical center PARTICIPANTS: 56 healthy young subjects (20-40 years of age) INTERVENTIONS: Research subjects were admitted for 2 independent stays of 4 nights/3 days for treatment with bright or dim-light (randomized order) at a time known to induce phase delays in circadian timing. The intensity and duration of the bright light were determined by random assignment to one of 9 treatment conditions (duration of 1, 2, or 3 hours at 2000, 4000, or 8000 lux). MEASUREMENTS AND RESULTS: Treatment-induced changes in the dim light melatonin onset (DLMO) and dim light melatonin offset (DLMOff) were measured from blood samples collected every 20-30 min throughout baseline and post-treatment nights. Comparison by multi-factor analysis of variance (ANOVA) of light-induced changes in the time of the circadian melatonin rhythm for the 9 conditions revealed that changing the duration of the light exposure from 1 to 3 h increased the magnitude of light-induced delays. In contrast, increasing from moderate (2,000 lux) to high (8,000 lux) intensity light did not alter the magnitude of phase delays of the circadian melatonin rhythm. CONCLUSIONS: Results from the present study suggest that for phototherapy of circadian rhythm sleep disorders in humans, a longer period of moderate intensity light may be more effective than a shorter exposure period of high intensity light.

Microtubules modulate melatonin receptors involved in phase-shifting circadian activity rhythms: in vitro and in vivo evidence.

MT1 melatonin receptors expressed in Chinese hamster ovary (CHO) cells remain sensitive to a melatonin re-challenge even following chronic melatonin exposure when microtubules are depolymerized in the cell, an exposure that normally results in MT1 receptor desensitization. We extended our findings to MT2 melatonin receptors using both in vitro and in vivo approaches. Using CHO cells expressing human MT2 melatonin receptors, microtubule depolymerization prevents the loss in the number of high potency states of the receptor when compared to melatonin-treated cells. In addition, microtubule depolymerization increases melatonin-induced PKC activity but not PI hydrolysis via Gi proteins similar to that shown for MT1Rs. Furthermore, microtubule depolymerization in MT2-CHO cells enhances the exchange of GTP on Gi-proteins using a photoaffinity analog of GTP. To test whether microtubules are capable of modulating melatonin-induced phase-shifts, microtubules are depolymerized specifically within the suprachiasmatic nucleus of the hypothalamus (SCN) of the Long Evans rat and the efficacy of melatonin to phase shift their circadian activity rhythms was assessed and compared to animals with intact SCN microtubules. We find that microtubule depolymerization in the SCN using either Colcemid or nocodazole enhances the efficacy of 10 pm melatonin to phase-shift the activity rhythms of the Long Evans rat. No enhancement occurs in the presence of beta-lumicolchicine, the inactive analog of Colcemid. Taken together, these data suggest that microtubule dynamics can modulate melatonin-induced phase shifts of circadian activity rhythms which may explain, in part, why circadian disturbances occur in individuals afflicted with diseases associated with microtubule disturbances.

Measuring melatonin in humans.

STUDY OBJECTIVES: To provide guidelines for collecting and analyzing urinary, salivary, and plasma melatonin, thereby assisting clinicians and researchers in determining which method of measuring melatonin is most appropriate for their particular needs and facilitating the comparison of data between laboratories. METHODS: A modified RAND process was utilized to derive recommendations for methods of measuring melatonin in humans. RESULTS: Consensus-based guidelines are presented for collecting and analyzing melatonin for studies that are conducted in the natural living environment, the clinical setting, and in-patient research facilities under controlled conditions. CONCLUSIONS: The benefits and disadvantages of current methods of collecting and analyzing melatonin are summarized. Although a single method of analysis would be the most effective way to compare studies, limitations of current methods preclude this possibility. Given that the best analysis method for use under multiple conditions is not established, it is recommended to include, in any published report, one of the established low threshold measures of dim light melatonin onset to facilitate comparison between studies.

Phase-dependent treatment of delayed sleep phase syndrome with melatonin.

STUDY OBJECTIVE: Delayed sleep phase syndrome (DSPS) is a circadian-rhythm sleep disorder characterized by abnormally late sleep and wake times. Melatonin, taken in the evening, advances sleep and circadian phase in patients with DSPS. However, little is known about the most effective dose or time of administration. In the present study, we tested the effectiveness of melatonin to advance the timing of sleep and circadian phase in individuals with DSPS. DESIGN: Following baseline assessment of sleep and circadian phase, subjects were randomly assigned to 1 of 3 treatment groups. The administration of melatonin (0.3 or 3.0 mg) or placebo was double-blinded. SETTING: All procedures were conducted on an outpatient basis. PARTICIPANTS: Thirteen subjects with DSPS, recruited via flyers, advertisements, and referrals from the Sleep Clinic, completed this study. INTERVENTIONS: Melatonin (0.3 or 3.0 mg) or placebo was administered between 1.5 and 6.5 hours prior to dim light melatonin onset for a 4-week period. MEASUREMENTS AND RESULTS: Both doses of melatonin advanced the circadian phase of endogenous melatonin. The magnitude of phase advance in dim-light melatonin onset correlated strongly with the time of melatonin administration, with earlier times being more effective (r2 = 0.94, P < .0001). Similar, though weaker, relationships were obtained between the timing of melatonin administration and changes in sleep time. CONCLUSIONS: These results indicate that melatonin advances the circadian clock and sleep in patients with DSPS in a phase-dependent manner. This is the first study that reports a relationship between timing of melatonin administration and phase changes in patients with DSPS.

Morning or evening activity improves neuropsychological performance and subjective sleep quality in older adults.

STUDY OBJECTIVES: Sleep disturbances and decline in neuropsychological performance are common in older adults. Reduced social and physical activity is likely a contributing factor for these age-related changes in sleep and cognition. We previously demonstrated that a program of structured social and physical activity, with 2 daily activity sessions, 1 in the morning and 1 in the evening for a relatively short period of 2 weeks, improved sleep and neuropsychological performance in community-dwelling older adults. The goals of this pilot study were to determine whether a single daily morning or evening activity session for 2 weeks would also improve sleep and neuropsychological function and whether these effects were dependent on the timing of the activity sessions. DESIGN: We compared the effect of morning or evening structured activity sessions in a repeated-measures crossover design. Subjective mood, neuropsychological performance tasks, and subjective and objective measures of sleep were assessed at baseline and after the intervention. SETTING: All procedures took place in the participant's residence. PARTICIPANTS: Twelve older men and women (74.6 +/- 5.5 years of age). INTERVENTIONS: Subjects participated in 14 days of structured activity sessions in the morning (9:00-10:30 am) or evening (7:00-8:30 pm). Sessions consisted of stretching, low-impact aerobics, and game playing. MEASUREMENTS AND RESULTS: Exposure to either morning or evening activity significantly improved performance on a neuropsychological test battery. Morning activity sessions increased throughput on 4 of 8 performance tasks, while evening activity sessions improved throughput on 7 of the 8 performance tasks. Subjective sleep-quality ratings, measured by the Pittsburg Sleep Quality Index, improved following activity sessions in either the morning or the evening. Objective measures of sleep did not improve when measured by actigraphy or polysomnography. CONCLUSIONS: These results suggest that short-term exposure to either morning or evening social and physical activity improves objective measures of neuropsychological performance and subjective sleep quality in the elderly. Increasing exposure to social and physical activity may be a useful intervention to improve sleep quality and daytime function in older adults.

Nimodipine potentiates light-induced phase shifts of circadian activity rhythms but not c-fos expression in the suprachiasmatic nucleus of mice.

The present study assessed whether treatment with the L-type calcium channel antagonist nimodipine affects the responsiveness of the circadian pacemaker to light in C3H/HeN mice. Nimodipine (10 mg/kg, sc) increased the magnitude of light-induced phase delays (P<0.01) and c-fos mRNA expression in the paraventricular nuclei (P<0.01), but not in the suprachiasmatic nuclei (SCN). These results suggest that nimodipine may affect phase shifts of circadian activity rhythms through a mechanism independent of c-fos expression in the SCN.