All of the bilaterally enucleated subjects (n=12) exhibited free running rhythms with periods ranging from 24.13 to 24.81 h. Although abnormal timing of hormonal patterns can confirm the presence of a circadian rhythm disorder, patients complain about the resultant circadian rhythm sleep disorder, and disturbed sleep is the most commonly reported symptom associated with misaligned circadian rhythms (Figure 3). and (Figure 4).62,67 Irregularities of sleep and its timing were previously related to an Inhibitors,research,lifescience,medical abnormal phase of the rectal temperature

rhythm37,38 and in 1990, Martens et al reported that 71% of NPL subjects (n=16) complained of a chronic sleep disorder associated with increased sleep episodes

and increased Inhibitors,research,lifescience,medical daytime sleep.68 We have extended these findings and showed that sleep depends on clrcadlan phase,69 even under real-world conditions.62 In entrained subjects, the timing of sleep was highly correlated with the timing of the aMT6s rhythm such that subjects with advanced aMT6s rhythms had a relatively earlier sleep time Inhibitors,research,lifescience,medical and subjects with delayed aMT6s rhythms had a later sleep time (Figure 4),62 In ”free-running“ subjects, a more complicated pattern emerges where sleep exhibits a non-24-hour pattern that cycles in and out of synchrony with the 24-hour social day on which most subjects try to live (Figure 3B). Inhibitors,research,lifescience,medical The episode of poor sleep is characterized by short duration night-time sleep and a high propensity for daytime naps the timing of which coincides with the aMT6s peak as the clrcadlan system drives sleepiness during the biological (but not social) night.62,70 The cyclic

sleep-wake pattern, formally termed “non-24-hour sleepwake disorder,”50 Inhibitors,research,lifescience,medical persists ad Infinitum and can be extremely table 1 disruptive and debilitating, especially In Individuals with periods very close to 24 hours, when sleep can remain misaligned from the clrcadlan cycle for many months. Figure 3. Circadian rhythms of sleep and melatonin in two blind subjects. The left-hand panels show subjective sleep times (■) over 4 to 5 weeks, double-plotted according to time of day AV-951 (abscissa) and study day (ordinate). Subjects also collected sequential … Figure 4. Relationship between sleep timing and circadian phase in entrained blind subjects. Panel A shows subjective sleep (■) and urinary 6-sulphatoxymelatonin rhythm (○) timing over 4 weeks (study day on ordinate axis, clock time on abscissa) … In addition to affecting sleep, circadian rhythm disorders also Impact waking function. In addition to the high propensity for naps during the day,70 subjects also rate themselves more sleepy and more miserable and perform worst when they are awake at an adverse circadian phase.