Benita Middleton

Efficacy of melatonin treatment in jet lag, shift work, and blindness.

Melatonin has chronobiotic properties in humans. It is able to phase shift strongly endogenous rhythms, such as core temperature and its own endogenous rhythm, together with the sleep-wake cycle. Its ability to synchronize free-running rhythms has not been fully investigated in humans. There is evidence for synchronization of the sleep-wake cycle, but the available data suggest that it is less effective with regard to endogenous melatonin and core temperature rhythms. When suitably timed, most studies indicate that fast release preparations are able to hasten adaptation to phase shift in both field and simulation studies of jet lag and shift work. Both subjective and objective measures support this statement. However, not all studies have been successful. Careful evaluation of the effects on work-related performance is required. When used to alleviate the non-24-h sleep-wake disorder in blind subjects, again most studies report a successful outcome using behavioral measures, albeit in a small number of individuals. The pres suggest, however, that although leep-wake can be stabilized to 24 h, entrainment of other rhythms is exceptionally rare.

Effect of sleep deprivation on the human metabolome

Significance Sleep restriction and circadian clock disruption are associated with metabolic disorders including obesity and diabetes; this association can be studied by using the powerful tool of metabolomics. By using liquid chromatography/MS metabolomics, we have characterized plasma metabolites that were significantly affected by acute sleep deprivation (mainly lipids and acylcarnitines), all increasing during sleep deprivation. Observed increased levels of serotonin, tryptophan, and taurine may explain the antidepressive effect of sleep deprivation and deserve further study. Clear daily rhythms were observed in most metabolites, with 24 h wakefulness mainly reducing the amplitude of these rhythms. Our results further the understanding of sleep/wake regulation and the associated metabolic processes, and will be vital when using metabolic profiling to identify robust biomarkers for disease states and drug efficacy. Sleep restriction and circadian clock disruption are associated with metabolic disorders such as obesity, insulin resistance, and diabetes. The metabolic pathways involved in human sleep, however, have yet to be investigated with the use of a metabolomics approach. Here we have used untargeted and targeted liquid chromatography (LC)/MS metabolomics to examine the effect of acute sleep deprivation on plasma metabolite rhythms. Twelve healthy young male subjects remained in controlled laboratory conditions with respect to environmental light, sleep, meals, and posture during a 24-h wake/sleep cycle, followed by 24 h of wakefulness. Two-hourly plasma samples collected over the 48 h period were analyzed by LC/MS. Principal component analysis revealed a clear time of day variation with a significant cosine fit during the wake/sleep cycle and during 24 h of wakefulness in untargeted and targeted analysis. Of 171 metabolites quantified, daily rhythms were observed in the majority (n = 109), with 78 of these maintaining their rhythmicity during 24 h of wakefulness, most with reduced amplitude (n = 66). During sleep deprivation, 27 metabolites (tryptophan, serotonin, taurine, 8 acylcarnitines, 13 glycerophospholipids, and 3 sphingolipids) exhibited significantly increased levels compared with during sleep. The increased levels of serotonin, tryptophan, and taurine may explain the antidepressive effect of acute sleep deprivation and deserve further study. This report, to our knowledge the first of metabolic profiling during sleep and sleep deprivation and characterization of 24 h rhythms under these conditions, offers a novel view of human sleep/wake regulation.

Melatonin advances the circadian timing of EEG sleep and directly facilitates sleep without altering its duration in extended sleep opportunities in humans.

The rhythm of plasma melatonin originating from the pineal gland and driven by the circadian pacemaker located in the suprachiasmatic nucleus is closely associated with the circadian (approximately 24 h) variation in sleep propensity and sleep spindle activity in humans. We investigated the contribution of melatonin to variation in sleep propensity, structure, duration and EEG activity in a protocol in which sleep was scheduled to begin during the biological day, i.e. when endogenous melatonin concentrations are low. The two 14 day trials were conducted in an environmental scheduling facility. Each trial included two circadian phase assessments, baseline sleep and nine 16 h sleep opportunities (16.00–08.00 h) in near darkness. Eight healthy male volunteers (24.4 ± 4.4 years) without sleep complaints were recruited, and melatonin (1.5 mg) or placebo was administered at the start of the first eight 16 h sleep opportunities. During melatonin treatment, sleep in the first 8 h of the 16 h sleep opportunities was increased by 2 h. Sleep per 16 h was not significantly different and approached asymptotic values of 8.7 h in both conditions. The percentage of rapid eye movement (REM) sleep was not affected by melatonin, but the percentage of stage 2 sleep and sleep spindle activity increased, and the percentage of stage 3 sleep decreased. During the washout night, the melatonin‐induced advance in sleep timing persisted, but was smaller than on the preceding treatment night and was consistent with the advance in the endogenous melatonin rhythm. These data demonstrate robust, direct sleep‐facilitating and circadian effects of melatonin without concomitant changes in sleep duration, and support the use of melatonin in the treatment of sleep disorders in which the circadian melatonin rhythm is delayed relative to desired sleep time.

Human circadian rhythms in constant dim light (8 lux) with knowledge of clock time

The light/dark (L/D) cycle is a major synchronizer of human circadian rhythms. In the absence of a strong L/D cycle, synchrony with 24 hours can nevertheless be maintained in a socially structured environment, as shown in Polar regions (Broadway et al. 1987) and by some blind subjects (Czeisler et al. 1995a). The relative contribution of other time cues to entrainment in dim light has not been fully explored. The present study investigated the behaviour of melatonin (assessed as 6‐sulphatoxymelatonin); rectal temperature; activity and sleep (actigraphy and logs) in constant dim light (L/L) with access to a digital clock. 6 normal healthy males were maintained as a group in partial temporal isolation with attenuated sound and ambient temperature for 21 days. All 6 subjects showed free‐running periodicity for 6‐sulphatoxymelatonin and 5/6 subjects for temperature, activity and sleep offset. The average period (tau) was 24.26±0.049, substantially shorter than in previous experiments with a self selected L/D cycle but similar to a recent study conducted in very dim light. One subject maintained a rigid sleep/wake cycle throughout whilst his 6‐sulphatoxymelatonin rhythm free‐ran. Total sleep time, from actigraph data, did not change but sleep efficiency decreased during the experiment. The subjects did not show group synchronization. These results confirm previous data indicating the importance of the L/D cycle in human entrainment and underline the lesser role of social cues and knowledge of clock time. This particular approach will permit the administration of timed medication to sighted humans under free‐running conditions.

Light-induced melatonin suppression: age-related reduction in response to short wavelength light

One of the possible causes of disturbed circadian rhythms and sleep in the elderly may be impaired photic input to the circadian clock. Age-related changes in lens density are known to reduce the transmission of short wavelength light, which has been shown to be most effective in suppressing nocturnal melatonin. The aim of the study therefore was to investigate age-related changes in melatonin suppression in response to short and medium wavelength light. Young premenopausal (n=13) and postmenopausal (n=21) women were exposed to 30 min of monochromatic light at two different wavelengths and irradiances (lambda(max) 456 nm: 3.8 and 9.8 microW/cm(2); lambda(max) 548 nm: 28 and 62 microW/cm(2)). Melatonin suppression was compared across light treatments and between age groups. Significantly reduced melatonin suppression was noted in the elderly subjects following exposure to short wavelength (456 nm) light compared to the young subjects. These results are likely to reflect age-related changes in lens density.

Nonvisual responses to light exposure in the human brain during the circadian night

The brain processes light information to visually represent the environment but also to detect changes in ambient light level. The latter information induces non-image-forming responses and exerts powerful effects on physiology such as synchronization of the circadian clock and suppression of melatonin. In rodents, irradiance information is transduced from a discrete subset of photosensitive retinal ganglion cells via the retinohypothalamic tract to various hypothalamic and brainstem regulatory structures including the hypothalamic suprachiasmatic nuclei, the master circadian pacemaker. In humans, light also acutely modulates alertness, but the cerebral correlates of this effect are unknown. We assessed regional cerebral blood flow in 13 subjects attending to auditory and visual stimuli in near darkness following light exposures (>8000 lux) of different durations (0.5, 17, 16.5, and 0 min) during the biological night. The bright broadband polychromatic light suppressed melatonin and enhanced alertness. Functional imaging revealed that a large-scale occipito-parietal attention network, including the right intraparietal sulcus, was more active in proportion to the duration of light exposures preceding the scans. Activity in the hypothalamus decreased in proportion to previous illumination. These findings have important implications for understanding the effects of light on human behavior.

Age-Related Changes in Acute and Phase-Advancing Responses to Monochromatic Light

Reduced sensitivity to short-wavelength (blue) light with age has been shown for light-induced melatonin suppression. The current research aimed to determine if a similar age-related reduction occurs in subjective alertness, mood, and circadian phase-advancing responses. Young (n = 11, 23.0 ± 2.9 years) and older (n = 15, 65.8 ± 5.0 years) healthy males participated in laboratory sessions that included a 2-h intermittent monochromatic light exposure, individually timed to begin 8.5 h after their dim light melatonin onset (DLMO) determined in a prior visit. In separate sessions, pupil-dilated subjects were exposed to short-wavelength blue (λ max 456 nm) and medium-wavelength green (λmax 548 nm) light matched for photon density (6 × 1013 photons/cm2/sec). Subjective alertness, sleepiness, and mood were verbally assessed every 15 to 30 min before, during, and up to 5 h after the light exposure. The magnitude of phase advance was assessed as the difference in plasma melatonin rhythm phase markers before and after light exposure. Following blue light exposure, responses in older men were significantly diminished compared with young men for subjective alertness (p < 0.0001), sleepiness (p < 0.0001), and mood (p < 0.05) during and after light exposure. There was no significant effect of age on these parameters following green light exposure. The phase advances to both blue and green light were larger in the young than older subjects, but did not reach statistical significance. In general, phase advances to blue light were slightly larger than to green light in both young and old, but did not reach statistical significance. The current results add to previous findings demonstrating reduced responsiveness to the acute effects of blue light in older people (melatonin suppression, alertness). However, under the study paradigm, the phase-advancing response to light does not appear to be significantly impaired with age.

The suitability of actigraphy, diary data, and urinary melatonin profiles for quantitative assessment of sleep disturbances in schizophrenia: A case report

Sleep disruption is a commonly encountered clinical feature in schizophrenic patients, and one important concern is to determine the extent of this disruption under “real” life situations. Simultaneous wrist actigraphy, diary records, and repeated urine collection for urinary 6‐sulphatoxymelatonin (aMT6s) profiles are appropriate tools to assess circadian rhythms and sleep patterns in field studies. Their suitability for long‐term recordings of schizophrenic patients living in the community has not been evaluated. In this case report, we document long‐term simultaneous wrist actigraphy, light detection, repeated urine collection, and diary records as a suitable combination of non‐invasive techniques to quantify and assess changes in sleep‐wake cycles, light exposure, and melatonin profiles in a schizophrenic patient. The actigraph was well‐tolerated by the patient, and compliance to diary records and 48 h urine collection was particularly good with assistance from family members. The data obtained by these techniques are illustrated, and the results reveal remarkable abnormal patterns of rest‐activity patterns, light exposure, and melatonin production. We observed various rest‐activity patterns, including phase‐shifts, highly delayed sleep on‐ and offsets, and irregular rest‐activity phases. The period of the rest‐activity rhythm, light‐dark cycle, and melatonin rhythm was longer than 24 h. These circadian abnormalities may reinforce the altered sleep patterns and the problems of cognitive function and social engagement associated with schizophrenic.

Robust circadian rhythm in heart rate and its variability: influence of exogenous melatonin and photoperiod

Heart rate (HR) and heart rate variability (HRV) undergo marked fluctuations over the 24‐h day. Although controversial, this 24‐h rhythm is thought to be driven by the sleep–wake/rest–activity cycle as well as by endogenous circadian rhythmicity. We quantified the endogenous circadian rhythm of HR and HRV and investigated whether this rhythm can be shifted by repeated melatonin administration while exposed to an altered photoperiod. Eight healthy males (age 24.4 ± 4.4 years) participated in a double‐blind cross‐over design study. In both conditions, volunteers were scheduled to 16 h–8 h rest : wake and dark : light cycles for nine consecutive days preceded and followed by 29‐h constant routines (CR) for assessment of endogenous circadian rhythmicity. Melatonin (1.5 mg) or placebo was administered at the beginning of the extended sleep opportunities. For all polysomnographically verified wakefulness periods of the CR, we calculated the high‐ (HF) and low‐ (LF) frequency bands of the power spectrum of the R–R interval, the standard deviation of the normal‐to‐normal (NN) intervals (SDNN) and the square root of the mean‐squared difference of successive NN intervals (rMSSD). HR and HRV variables revealed robust endogenous circadian rhythms with fitted maxima, respectively, in the afternoon (16:36 hours) and in the early morning (between 05:00 and 06:59 hours). Melatonin treatment phase‐advanced HR, HF, SDNN and rMSSD, and these shifts were significantly greater than after placebo treatment. We conclude that endogenous circadian rhythmicity influences autonomic control of HR and that the timing of these endogenous rhythms can be altered by extended sleep/rest episodes and associated changes in photoperiod as well as by melatonin treatment.

Night‐time sleep disturbance does not correlate with neuropsychiatric impairment in patients with cirrhosis

Background: Sleep–wake disturbances are common in patients with cirrhosis and are generally attributed to the presence of hepatic encephalopathy.