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. 2013 Jul 1;36(7):1091-1100.
doi: 10.5665/sleep.2818.

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

Jonathan S Emens  1 , Amber L Laurie, Jeannie B Songer, Alfred J Lewy
Affiliations

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

Jonathan S Emens et al. Sleep. .

Abstract

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.

Keywords: Blind; circadian; melatonin; non-24-h disorder.

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Figures

Figure 1
Figure 1
(A) Twenty-one nonentrained blind individuals. Symbols represent an assessment of circadian phase (melatonin onset, MO) assessed using the time that plasma or salivary melatonin levels cross a threshold of 10 or 3 pg/mL, respectively. Women are plotted in red and men in black and gray. Subject numbers are displayed across the top of the figure. Not all data are plotted for Subjects 5 and 18. The data are plotted in a raster format where the day of study is plotted on the y-axis with successive days plotted beneath each other and the clock hour of the MOs are plotted on a repeating 24-h x-axis. The data for each subject are plotted next to each other with overall drift rate generally increasing from left to right so that all of the data can be visualized in one figure. (B) The complete dataset for Subjects 5 and 18.
Figure 2
Figure 2
Illustration of the bisection technique for quantification of relative coordination. Data are presented for Subject 5. (A) Representative section of data from study days 100 to 210 with symbols and format as in Figure 1. The average drift rate for this portion of the dataset is 0.22 h/per day (24.5 h over 110 days). This is similar to the 0.23 h/day for all 1,547 days of study). The two-point drift rate between the melatonin onset (MO) occurring at 07:16 and the MO occurring at 14:00 is 0.48 h/day. The average MO (MOavg) between these two is 10:38 (green circle). (B) The average MO from Figure 2A (10:38) is plotted against the corresponding deviation (DEV, in hours) of the two-point drift rate (0.48 h/day) from the average drift rate (0.23 h/day). The data are plotted 1.5 times. (C) The clock hour of each MOavg is plotted against all corresponding DEVs. The data are again plotted 1.5 times. The data point circled in green is the MOavg that resulted in the largest difference in average DEV between two corresponding 12-h zones. The vertical dashed lines denote the boundaries of the zones with fast and slow drift rates.
Figure 3
Figure 3
Correlation between age and average drift rate of circadian phase. Symbols are as in Figure 1.
Figure 4
Figure 4
Plot of drift rate of circadian phase versus clock hour of circadian phase for the 14 subjects who demonstrated statistically significant relative coordination. The deviation of each two-point drift rate from the average drift rate is plotted versus the corresponding average melatonin onset (MOavg) for every subject. The data are plotted 1.5 times.
Figure 5
Figure 5
Data from subject 15, who was restudied at a later date. Symbols and format are as in Figure 1. The subject demonstrated 345 days of spontaneous transient entrainment (days 809-1,154) during which her average drift rate was only 0.01 h/day (4.1 hours of drift over 345 days, the linear regression drift rate was 0.00 ± 0.01 h/day). She then spontaneously resumed a nonentrained pattern (days 1,168-1,245) with an average drift rate of 0.31 h/day (23.86 h of drift over 77 days, linear regression drift rate of 0.33 ± 0.06 h/day).
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