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Circadian rhythms and human medicine

In the Literature.

Here GNN posts five abstracts of articles on circadian rhythms and human medicine related to the feature story Beyond Insomnia: Strategies of Circadian Genomics.


A single dose of melatonin prevents the phase delay associated with a delayed weekend sleep pattern.

This study was designed to test the hypotheses that a delayed weekend sleep pattern may lead to a phase delay of the endogenous circadian rhythm, and that melatonin administration can counteract the phase delay and prevent the sleep and functional impairments associated with this sleep pattern. DESIGN: A within-subject, counterbalanced design was used in which each subject participated in both placebo and melatonin conditions. Subjects' sleep-wake schedules were delayed by two hours on Friday and Saturday to simulate the delayed weekend sleep pattern. Six mg of melatonin or a placebo pill was administered double blind on Sunday late afternoon. SETTING: N/A. PARTICIPANTS: Ten healthy volunteers (mean age = 22.1 years old). MEASUREMENTS and RESULTS: Salivary dim-light melatonin onset (DLMO) was measured on Friday and Monday nights. Subject's sleep was recorded with polysomnography on Sunday night and their levels of sleepiness, cognitive functioning and mood were assessed on Sunday night and Monday morning. Results show that the delayed weekend sleep pattern caused a 31.6 min delay of the endogenous melatonin rhythm. Melatonin administration counteracted the phase delay of endogenous melatonin onset. On Sunday, melatonin administration increased the sleepiness throughout the evening and reduced sleep onset latency at bedtime. On Monday morning, subjective sleepiness was decreased in the melatonin condition. CONCLUSION: A delayed weekend sleep pattern did show a mild phase-delay effect on the endogenous circadian rhythm. A single dose of melatonin can acutely reverse the weekend drift.

Sleep 2001 May 1;24(3):272-81.

Differential circadian rhythm disturbances in men with alzheimer disease and frontotemporal degeneration.

Caregiver exhaustion is a frequent consequence of sleep disturbance and rest-activity rhythm disruption that occurs in dementia. This exhaustion is the causal factor most frequently cited by caregivers in making the decision to institutionalize patients with dementia. Recent studies have implicated dysfunction of the circadian pacemaker in the etiology of these disturbances in dementia. METHODS: We studied the activity and core-body temperature rhythms in a cohort of 38 male patients with a clinical diagnosis of probable Alzheimer disease (AD) approximately 2 years before death. These patients were later given a confirmed diagnosis of AD (n = 23), frontotemporal degeneration (FTD) (n = 9), or diffuse Lewy body disease (DLB) with mixed AD or FTD pathologies (n = 6) after autopsy and neuropathological examination. Physiological rhythms of patients with AD and FTD were then compared with a group of normal, elderly men (n = 8) from the community. RESULTS: Alzheimer patients showed increased nocturnal activity and a significant phase-delay in their rhythms of core-body temperature and activity compared with patients with FTD and controls. The activity rhythm of FTD patients was highly fragmented and phase-advanced in comparison with controls and apparently uncoupled from the rhythm of core-body temperature. CONCLUSIONS: Patients with AD and patients with FTD show different disturbances in their rhythms of activity and temperature compared with each other and with normal elderly patients.

Arch Gen Psychiatry 2001 Apr;58(4):353-60.

Circadian phase resetting in older people by ocular bright light exposure.

Aging is associated with frequent complaints about earlier bedtimes and waketimes. These changes in sleep timing are associated with an earlier timing of multiple endogenous rhythms, including core body temperature (CBT) and plasma melatonin, driven by the circadian pacemaker. One possible cause of the age-related shift of endogenous circadian rhythms and the timing of sleep relative to clock time is a change in the phase-shifting capacity of the circadian pacemaker in response to the environmental light-dark cycle, the principal synchronizer of the human circadian system. METHODS: We studied the response of the circadian system of 24 older men and women and 23 young men to scheduled exposure to ocular bright light stimuli. Light stimuli were 5 hours in duration, administered for 3 consecutive days at an illuminance of approximately 10,000 lux. Light stimuli were scheduled 1.5 or 3.5 hours after the CBT nadir to induce shifts of endogenous circadian pacemaker to an earlier hour (phase advances) or were scheduled 1.5 hours before the CBT nadir to induce shifts to a later hour (phase delays). The rhythms of CBT and plasma melatonin assessed under constant conditions served as markers of circadian phase. RESULTS: Bright light stimuli elicited robust responses of the circadian timing system in older people; both phase advances and phase delays were induced. The magnitude of the phase delays did not differ significantly between older and younger individuals, but the phase advances were significantly attenuated in older people. CONCLUSIONS: The attenuated response to light stimuli that induce phase advances does not explain the advanced phase of the circadian pacemaker in older people. The maintained responsiveness of the circadian pacemaker to light implies that scheduled bright light exposure can be used to treat circadian phase disturbances in older people.

J Investig Med 2001 Jan;49(1):30-40.

Circadian time of morning light administration and therapeutic response in winter depression.

We investigated a possible mechanism of action for the antidepressant response to light-phase advances of the circadian clock-by measuring the onset of melatonin secretion before and after light treatment in the morning or evening. METHODS: Plasma melatonin was sampled in 42 patients with seasonal affective disorder, in the evening or overnight while depressed and after 10 to 14 days of light therapy (10 000 lux for 30 minutes) when symptoms were reassessed. RESULTS: Morning light produced phase advances of the melatonin rhythm, while evening light produced delays, the magnitude depending on the interval between melatonin onset and light exposure, or circadian time (morning, 7.5 to 11 hours; evening, 1.5 to 3 hours). Delays were larger the later the evening light (r = 0.40), while advances were larger the earlier the morning light (r = 0.50). Although depression ratings were similar with light at either time of day, response to morning light increased with the size of phase advances up to 2.7 hours (r = 0.44) regardless of baseline phase position, while there was no such correlation for evening light. In an expanded sample (N = 80) with the sleep midpoint used as a reference anchor for circadian time, early morning light exposure was superior to late morning and to evening exposure. CONCLUSION: The antidepressant effect of light is potentiated by early-morning administration in circadian time, optimally about 8.5 hours after melatonin onset or 2.5 hours after the sleep midpoint.

Arch Gen Psychiatry 2001 Jan;58(1):69-75.

Sleep and circadian phase characteristics of adolescent and young adult males in a naturalistic summertime condition.

Our aim was to compare the circadian phase characteristics of healthy adolescent and young adult males in a naturalistic summertime condition. A total of 19 adolescents (mean age 15.7 years) and 18 young adults (mean age 24.5 years) with no sleep problems took part in this study. Two-night polysomnographic (PSG) sleep recordings and 24h secretion patterns of urinary 6-sulfatoxymelatonin were monitored in all 37 subjects. Sleep-wake patterns were initially assessed at home using a standard sleep diary. Circadian assessment included the measure of dim light melatonin offset (DLMOff) and the morningness-eveningness (M/E) questionnaire. As expected, compared to young adults, adolescents habitually spent more nocturnal time in bed and spent more time (and percentage) in delta sleep. No difference was found between adolescents and young adults on multiple sleep latency test (MSLT) sleep onset latencies, M/E, melatonin secretion measures (24h total, nighttime, daytime, and night ratio), and DLMOff. For the subjects as a whole, correlational analyses revealed a significant association between the DLMOff and M/E and between both these phase markers and habitual bedtimes, habitual rising times, and melatonin secretion measures (daytime levels and the night ratio). No association was found between phase markers and daytime sleepiness or sleep consolidation parameters such as sleep efficiency or number of microarousals. These results together indicate that adolescents and young adults investigated during summertime showed similar circadian phase characteristics, and that, in these age groups, an evening phase preference is associated with a delayed melatonin secretion pattern and delayed habitual sleep patterns without a decrease in sleep consolidation or vigilance.

Chronobiol Int 2000 Jul;17(4):489-501.

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