The pathophysiology of jet lag.

Jet Lag Disorder (JLD) is a recognized circadian rhythm sleep disorder characterized by insomnia or excessive daytime sleepiness (and sometimes general malaise and somatic symptoms) associated with transmeridian jet travel. It is a consequence of circadian misalignment that occurs after crossing time zones too rapidly for the circadian system to keep pace. The thesis of this review is that a rational treatment approach for jet lag can be grounded in an understanding of the biology of the human circadian timekeeping system. An overview of circadian rhythm physiology is presented with special emphasis on the role of light exposure and melatonin secretion in the regulation of circadian timing. Both timed light exposure (or avoidance) and exogenous melatonin administration have been recruited as treatment modalities to accelerate circadian realignment, based on an understanding of their role in circadian physiology. In addition to circadian misalignment, other contributing causes to jet lag are considered including travel-related sleep deprivation and fatigue. Clinical field trials that have tested the application of circadian rhythm based interventions are then reviewed.

Circadian rhythm sleep disorders: part II, advanced sleep phase disorder, delayed sleep phase disorder, free-running disorder, and irregular sleep-wake rhythm. An American Academy of Sleep Medicine review.

OBJECTIVE: This the second of two articles reviewing the scientific literature on the evaluation and treatment of circadian rhythm sleep disorders (CRSDs), employing the methodology of evidence-based medicine. We herein report on the accumulated evidence regarding the evaluation and treatment of Advamced Sleep Phase Disorder (ASPD), Delayed Sleep Phase Disorder (DSPD), Free-Running Disorder (FRD) and Irregular Sleep-Wake Rhythm ISWR). METHODS: A set of specific questions relevant to clinical practice were formulated, a systematic literature search was performed, and relevant articles were abstracted and graded. RESULTS: A substantial body of literature has accumulated that provides a rational basis the evaluation and treatment of CRSDs. Physiological assessment has involved determination of circadian phase using core body temperature and the timing of melatonin secretion. Behavioral assessment has involved sleep logs, actigraphy and the Morningness-Eveningness Questionnaire (MEQ). Treatment interventions fall into three broad categories: 1) prescribed sleep scheduling, 2) circadian phase shifting ("resetting the clock"), and 3) symptomatic treatment using hypnotic and stimulant medications. CONCLUSION: Circadian rhythm science has also pointed the way to rational interventions for CRSDs and these treatments have been introduced into the practice of sleep medicine with varying degrees of success. More translational research is needed using subjects who meet current diagnostic criteria.

Circadian rhythm sleep disorders: part I, basic principles, shift work and jet lag disorders. An American Academy of Sleep Medicine review.

OBJECTIVE: This the first of two articles reviewing the scientific literature on the evaluation and treatment of circadian rhythm sleep disorders (CRSDs), employing the methodology of evidence-based medicine. In this first part of this paper, the general principles of circadian biology that underlie clinical evaluation and treatment are reviewed. We then report on the accumulated evidence regarding the evaluation and treatment of shift work disorder (SWD) and jet lag disorder (JLD). METHODS: A set of specific questions relevant to clinical practice were formulated, a systematic literature search was performed, and relevant articles were abstracted and graded. RESULTS: A substantial body of literature has accumulated that provides a rational basis the evaluation and treatment of SWD and JLD. Physiological assessment has involved determination of circadian phase using core body temperature and the timing of melatonin secretion. Behavioral assessment has involved sleep logs, actigraphy and the Morningness-Eveningness Questionnaire (MEQ). Treatment interventions fall into three broad categories: 1) prescribed sleep scheduling, 2) circadian phase shifting ("resetting the clock"), and 3) symptomatic treatment using hypnotic and stimulant medications. CONCLUSION: Circadian rhythm science has also pointed the way to rational interventions for the SWD and JLD, and these treatments have been introduced into the practice of sleep medicine with varying degrees of success. More translational research is needed using subjects who meet current diagnostic criteria.

Relative coordination to unknown "weak zeitgebers" in free-running blind individuals.

Light is the primary synchronizer of the human biological clock. In more than half of those blind individuals who completely lack light perception, the absence of photic input to the hypothalamic circadian pacemaker results in rhythms that free-run (blind free-runners [BFRs]) with a period typically greater than 24 h. The remainder are entrained, although sometimes at an abnormal phase angle. It is presumed that weak as-yet-to-be-identified time cues provide the necessary resetting stimulus in these entrained individuals. These weak zeitgebers might be expected to modulate the observed circadian period in blind people who are not actually entrained by them. The authors report here the results from 5 BFRs (average linear regression period +/-SD of 24.31 +/- 0.06 h) who had high-resolution (many and frequent) phase assessments. All 5 subjects demonstrated a similar and reproducible pattern of changes in observed period (period response curves) indicative of relative coordination. The precise shape of the period response curve to weak zeitgebers has implications for the entrainment of BFRs using exogenous melatonin administration or other nonphotic stimuli. Sighted individuals may also be affected by such weak zeitgebers, which may be obscured by the stronger light/dark cycle.

Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period.

In a previous report, we were unable to entrain one out of seven totally blind people with free-running endogenous melatonin rhythms to 10 mg of exogenous melatonin. This person had the longest circadian period (24.9 h) of the group. We now find that this person can be entrained to 0.5 mg of melatonin, but not to 20 mg. These results are consistent with the idea that too much melatonin may spill over onto the wrong zone of the melatonin phase-response curve.

Zeitgeber hierarchy in humans: resetting the circadian phase positions of blind people using melatonin.

Four blind individuals who were thought to be entrained at an abnormal circadian phase position were reset to a more normal phase using exogenous melatonin administration. In one instance, circadian phase was shifted later. A fifth subject who was thought to be entrained was monitored over four years and eventually was shown to have a circadian period different from 24 h. These findings have implications for treating circadian phase abnormalities in the blind, for distinguishing between abnormally entrained and free-running blind individuals, and for informing the debate over zeitgeber hierarchy in humans.

Host melatonin secretion is a timing signal for the release of W. bancrofti microfilaria into the circulation.

Infection of the lymphatic system by Wuchereria bancrofti microfilaria is the most common cause of elephantiasis, a disease that affects over 100 million people. The nightly release of microfilaria into the circulation coincides with the feeding activity of its mosquito vector, a synchronization that is presumably an evolutionary adaptation favoring survival and transmission of the parasite. During the daytime hours, the microfilaria are thought to be sequestered in the lungs, and because they are not exposed to the solar light/dark cycle, there must be some other cue that entrains their nightly release into the periphery. I hypothesize that the host's secretion of melatonin synchronizes the nocturnal release of the microfilaria. It follows that exogenous melatonin administration during the day would also trigger release of microfilaria in the blood and could be used as a provocative diagnostic test for filariasis.

Circadian rhythm sleep disorders: lessons from the blind.

As totally blind people cannot perceive the light-dark cycle (the major synchroniser of the circadian pacemaker) their circadian rhythms often "free run" on a cycle slightly longer than 24 h. When the free-running sleep propensity rhythm passes out of phase with the desired time for sleep, night-time insomnia and daytime sleepiness result. It has recently been shown that daily melatonin administration can entrain the circadian pacemaker, thereby correcting this burdensome circadian sleep disorder. The primary purpose of this review is to elevate awareness of circadian sleep disorders in totally blind people (especially free-running rhythms) and to provide some guidance for clinical management. An additional goal is to show how research on sleep and circadian rhythms in the totally blind can contribute insights into the scientific understanding of the human circadian system. 2001 Harcourt Publishers Ltd