Non-24-Hour Disorder in Blind Individuals Revisited: Variability and the Influence of Environmental Time Cues.

STUDY OBJECTIVES: To assess the interindividual and intraindividual variability in the circadian rhythms of blind individuals with non-24-h disorder and to quantify the influence of environmental time cues in blind subjects lacking entrainment (non-24-h individuals or N-24s). DESIGN: An observational study of 21 N-24s (11 females and 10 males, age 9-78 years) who kept a sleep/wake schedule of their choosing. Circadian phase was determined using the melatonin onset (MO) from plasma or saliva samples that were collected every 2 weeks. Melatonin concentrations were measured by radioimmunoassay. A total of 469 MO assessments were conducted over 5,536 days of study. The rate of drift of circadian phase was calculated using a series of MOs (total number of hours the MO drifted divided by the total number of days studied). Stability of the rest/activity rhythm was calculated using chi-squared periodogram analysis of wrist actigraphy data in 19 subjects. SETTING: Academic medical center. PARTICIPANTS: Paid volunteers. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Subjects lacked entrainment such that circadian phase drifted an average (± standard deviation) of 0.39 ± 0.29 h later per day; however, there was notable intersubject and intrasubject variability in the rate of drift including relative coordination and periods of transient entrainment during which there was little to no drift in the circadian phase. A regular, reproducible, and significant oscillation in the rate of drift was detected in 14 of the 21 subjects. A significant non-24-h rest/activity rhythm was detected in 18 of 19 subjects. There was a strong correlation (r = 0.793, P = 0.0001) between the non-24-h rest/activity rhythm and the rate of drift of the circadian phase. CONCLUSIONS: Most N-24s are influenced by unidentified environmental time cues and the non-entrained biological clock in such N-24s is reflected in their rest/activity rhythms. These findings may have diagnostic and treatment implications: this disorder might be diagnosed with actigraphy alone, relative coordination and transient entrainment may result in misdiagnosis and responsiveness to environmental time cues may influence treatment success with oral melatonin. CITATION: Emens JS; Laurie AL; Songer JB; Lewy AJ. Non-24-hour disorder in blind individuals revisited: variability and the influence of environmental time cues. SLEEP 2013;36(7):1091-1100.

Rest-activity cycle and melatonin rhythm in blind free-runners have similar periods.

In the absence of the entraining light-dark cycle, most totally blind humans free-run, albeit with relative coordination to nonphotic zeitgebers. Such blind free-runners (BFRs) often attempt to maintain a 24-h sleep-wake schedule and consequently suffer from recurrent sleep disruption and daytime somnolence. This study was conducted to determine the periods of the free-running melatonin rhythm and of the rest-activity cycle in 16 BFRs. It was found that the non-24-h component of the rest-activity rhythm correlated with the observed period of the circadian pacemaker.

Winter Depression: Integrating mood, circadian rhythms, and the sleep/wake and light/dark cycles into a bio-psycho-social-environmental model.

The phase shift hypothesis (PSH) states that most patients with SAD become depressed in the winter because of a delay in circadian rhythms with respect to the sleep/wake cycle: According to the PSH, these patients should preferentially respond to the antidepressant effects of bright light exposure when it is scheduled in the morning so as to provide a corrective phase advance and restore optimum alignment between the circadian rhythms tightly coupled to the endogenous circadian pacemaker and those rhythms that are related to the sleep/wake cycle. Recent support for the PSH has come from studies in which symptom severity was shown to correlate with the degree of circadian misalignment: it appears that a subgroup of patients are phase advanced, not phase delayed; however, the phase-delayed type is predominant in SAD and perhaps in other disorders as well, such as non-seasonal unipolar depression. It is expected that during the next few years the PSH will be tested in these and other conditions, particularly since healthy subjects appear to have more severe symptoms of sub-clinical dysphoria correlating with phase-delayed circadian misalignment; critically important will be the undertaking of treatment trials to investigate the therapeutic efficacy of morning bright light or afternoon/evening low-dose melatonin in these disorders in which symptoms are more severe as the dim light melatonin onset (DLMO) is delayed with respect to the sleep/wake cycle (non-restorative sleep should also be evaluated, as well as bipolar disorder). The possibility that some individuals (and disorders) will be of the phase-advanced type should be considered, taking into account that the correct timing of phase-resetting agents for them will be bright light scheduled in the evening and/or low-dose melatonin taken in the morning. While sleep researchers and clinicians are accustomed to phase-typing patients with circadian-rhythm sleep disorders according to the timing of sleep, phase typing based on the DLMO with respect to the sleep/wake cycle may lead to quite different recommendations for the optimal scheduling of phase-resetting agents, particularly for the above disorders and conditions.