Search PubMed⌕ Search

Biomedical subjects

A J Lewy

Publications and source records attributed to A J Lewy.

At least 37 records · Page 2Linked to original sources
PubMed1997

Melatonin as a chronobiotic: treatment of circadian desynchrony in night workers and the blind.

Although the causes are different, totally blind people (without light perception) and night shift workers have in common recurrent bouts of insomnia and wake-time sleepiness that occur when their preferred (or mandated) sleep and wake times are out of synchrony with their endogenous circadian rhythms. In this article, the patterns of circadian desynchrony in these two populations are briefly reviewed with special emphasis on longitudinal studies in individual subjects that used the timing of melatonin secretion as a circadian marker. In totally blind people, the most commonly observed pattern is a free-running rhythm with a stable non-24-h circadian period (24.2-24.5 h), although some subjectively blind people are normally entrained, perhaps by residually intact retinoypothalamic photic pathways. Experiments at the cellular and behavioral levels have shown that melatonin can produce time dependent circadian phase shifts. With this in mind, melatonin has been administered to blind people in an attempt to entrain abnormal circadian rhythms, and substantial phase shifts have been accomplished; however, it remains to be demonstrated unequivocally that normal long-term entrainment can be produced. In untreated night shift workers, the degree and direction of phase shifting in response to an inverted sleep-wake schedule appears to be quite variable. When given at the optimal circadian time, melatonin treatment appears to facilitate phase shifting in the desired direction. Melatonin given prior to a night worker's daytime sleep also may attenuate interference from the circadian alerting process. Because melatonin has both phase-shifting and sleep-promoting actions, night shift workers, who number in the millions, may be the most likely group to benefit from treatment.

Blindness↗
PubMed1996

Phase shifting the human circadian clock using melatonin.

Melatonin is produced only during nighttime darkness. Its onset during the evening is a useful marker for circadian phase position, when melatonin levels are sampled frequently and under conditions of dim light or darkness. This marker is termed the dim light melatonin onset (DLMO). Recently, we have described a phase response curve (PRC) to melatonin in humans that is about 12 h out of phase with the PRC to light. Exogenous melatonin administration and bright light exposure can be used to shift circadian rhythms according to their respective PRCs. These phase-resetting agents can be used alone or together to treat circadian phase disorders, which include advanced and delayed sleep phase syndrome, shift work maladaptation, jet lag and winter depression. Endogenous melatonin may function to augment entrainment of circadian rhythms by the light-dark cycle.

Biomarkers↗
PubMed1996

Non-24-hour sleep-wake syndrome in a sighted man: circadian rhythm studies and efficacy of melatonin treatment.

The case of a 41-year-old sighted man with non-24-hour sleep-wake syndrome is presented. A 7-week baseline assessment confirmed that the patient expressed endogenous melatonin and sleep-wake rhythms with a period of 25.1 hours. We sought to investigate the underlying pathology and to entrain the patient to a normal sleep-wake schedule. No deficiency in melatonin synthesis was found. Furthermore, normal coupling between the melatonin and sleep propensity rhythms was documented using an "ultrashort" sleep-wake protocol. Environmental light exposure was monitored for 41 days, and the circadian timing was calculated. Sensitivity to photic input was determined with light-induced melatonin-suppression tests. Three intensities (500, 1,000, and 2,500 lux) were examined during three separate trials. The 2,500-lux trial resulted in 78% suppression, but the lesser intensity exposures were without substantial effect. Thus, the patient appeared to be subsensitive to bright light. A 4-week trial of daily melatonin administration (0.5 mg at 2100 hours) stabilized the endogenous melatonin and sleep rhythms to a period of 24.1 hours, albeit at a somewhat delayed phase. A 14-month follow-up interview revealed that the patient continued to take melatonin daily, and his sleep-wake schedule was stable to a near 24-hour schedule.

Adult↗
PubMed1995

Melatonin marks circadian phase position and resets the endogenous circadian pacemaker in humans.

Measuring the dim light melatonin onset (DLMO) is a useful and practical way to assess circadian phase position in humans. As a marker for the phase and period of the endogenous circadian pacemaker, the DLMO has been shown to advance with exposure to bright light in the morning and to delay with exposure to bright light in the evening. This 'phase response curve' (PRC) to light has been applied in the treatment of winter depression, jet lag and shift work, as well as circadian phase sleep disorders. Exogenous melatonin has phase-shifting effects described by a PRC that is about 12 h out of phase with the PRC to light. That is, melatonin administration in the morning causes phase delays and in the afternoon causes phase advances. All of the circadian phase disorders that have been successfully treated with appropriately timed exposure to bright light can be treated with appropriately scheduled melatonin administration. Melatonin administration is more convenient and therefore may be the preferred treatment.

Biomarkers↗
PubMed1995

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.

Brain↗
PubMed1995

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.

Body Temperature↗
PubMed1995

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.

Arousal↗
PubMed1995

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.

Circadian Rhythm↗
PubMed1995

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.

Age Factors↗
PubMed1995

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.

Circadian Rhythm↗
PubMed1995

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.

Circadian Rhythm↗
PubMed1993

Dim light melatonin onset and circadian temperature during a constant routine in hypersomnic winter depression.

The onset of melatonin secretion under dim light conditions (DLMO) and the circadian temperature rhythm during a constant routine were assessed in 6 female controls and 6 female patients with winter depression (seasonal affective disorder, SAD) before and after bright light treatment. After sleep was standardized for 6 days, the subjects were sleep-deprived and at bedrest for 27 h while core temperature and evening melatonin levels were determined. The DLMO of the SAD patients was phase-delayed compared with controls (2310 vs 2138); with bright light treatment, the DLMO advanced (2310 to 2135). The minimum of the fitted rectal temperature rhythm was phase-delayed in the SAD group compared with the controls (0542 vs 0316); with bright light treatment, the minimum advanced (0542 vs 0336).

Adult↗
PubMed1992

Sleep propensity free-runs with the temperature, melatonin and cortisol rhythms in a totally blind person.

In previous studies, we found that many totally blind people have free-running melatonin rhythms, but that free-running melatonin rhythms were not necessarily associated with periodic insomnia and daytime sleepiness. Thus, it was not clear if the circadian sleep propensity rhythm was free-running with the other circadian rhythms. In the present study, we report that the sleep propensity rhythm (as defined by an ultrashort sleep-wake schedule) free-ran with the melatonin, temperature and cortisol rhythms in a 44-year-old totally blind man even though he maintained a conventional sleep schedule and did not complain of clinically significant insomnia or excessive daytime sleepiness.

Adult↗
PubMed1992

Melatonin rhythms in night shift workers.

For some time, it has remained uncertain whether the circadian rhythms of permanent night shift workers are adapted to their night-active schedule. Previous studies of this question have often been limited by "masking" (evoked) effects of sleep and activity on body temperature and cortisol, used as marker rhythms. In this study, the problem of masking was minimized by measuring the timing of melatonin production under dim light conditions. Nine permanent night shift workers were admitted to the Clinical Research Center (CRC) directly from their last work shift of the week and remained in dim light while blood samples were obtained hourly for 24 hours. Melatonin concentrations were measured in these samples using a gas-chromatographic mass-spectrometric method. Sleep diaries were completed for two weeks prior to the admission to the CRC. Overall, the onset of the melatonin rhythm was about 7.2 hours earlier (or 16.8 hours later) in the night workers compared to day-active controls. It was not possible to know whether the phase of the melatonin rhythm was the result of advances or delays. In night shift workers, sleep was initiated (on average) about three hours prior to the onset of melatonin production. In contrast, day-active subjects initiated sleep (on average) about three hours after their melatonin onset. Thus, the sleep times selected by night shift workers may not be well-synchronized to their melatonin rhythm, assumed to mark the phase of their underlying circadian pacemaker.

Adult↗
PubMed1992

Circadian rhythm abnormalities in totally blind people: incidence and clinical significance.

When people are completely isolated from environmental time cues, their circadian rhythms free run with a nearly 24-h cycle, generated by an internal body clock. Free-running temperature, cortisol, and melatonin rhythms have also been described in totally blind people, even though they were living in normal society and had access to abundant time cues; thus an intact visual system may be essential for synchronization of the circadian system. However, because of the small numbers of subjects studied, the incidence and clinical significance of circadian rhythm abnormalities among the blind has remained uncertain. In this study, plasma melatonin (n = 20), cortisol (n = 4), and sleep propensity (n = 1) were measured in serial samples taken from totally blind subjects for 24 h. Most totally blind subjects had circadian rhythm abnormalities. In about half of the subjects, the rhythms were free-running. Some blind subjects suffered recurrent insomnia and daytime sleepiness that were maximal when the internal rhythms were out of phase with the preferred sleep times. The high incidence of abnormal circadian rhythms in blind people underscores the importance of the light-dark cycle as an important environmental synchronizer for the human circadian system.

Biological Clocks↗