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Phase advance of sleep and temperature circadian rhythms in the middle years of life in humans
Neuroscience Letters 320 (2002) 1–4 www.elsevier.com/locate/neulet
Phase advance of sleep and temperature circadian rhythms in the middle years of life in humans Julie Carrier*, Jean Paquet, Jocelyn Morettini, E´velyne Touchette Centre du Sommeil et des Rythmes Biologiques, Hoˆpital du Sacre´-Cœur de Montre´al, Department of Psychology, Universite´ de Montre´al, 5400 Boulevard Gouin Ouest, Montreal H4J 1C5, QC, Canada Received 11 October 2001; received in revised form 6 December 2001; accepted 6 December 2001
Abstract Age-related changes in sleep may be linked to modifications in the circadian timing system. This study compared sleep patterns and unmasked circadian temperature parameters between a group of young subjects and a group of middle-aged subjects. Habitual bedtime and waketime were earlier in the middle-aged than in the young. In addition, middle-aged subjects reported a greater orientation toward morningness and they showed an earlier phase of temperature rhythm. No differences were found in amplitude of temperature rhythm or in habitual phase angle between sleep and the temperature rhythm. In conclusion, a phase advance of sleep and temperature circadian rhythm is already apparent in people in their forties and fifties. These changes precede modifications in amplitude or in habitual phase angle. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Sleep; Circadian rhythms; Body temperature; Aging; Middle age; Constant routine; Morningness; Eveningness
According to contemporary models of sleep–wake cycle regulation, the interaction of homeostatic and circadian processes regulates the sleep–wake cycle [9]. The homeostatic process represents the accumulation of sleep need with increasing time awake and its dissipation during the sleep episode. The circadian process represents the rhythmic variations of sleep and wake propensity over 24 h. It has been suggested that age-related changes in sleep may be linked to modifications to the circadian timing system (CTS; see for review [2]). Studies that controlled for masking effects confirmed that young and elderly subjects differ on a number of characteristics of temperature circadian rhythm. Compared with the young, elderly subjects show a phase advance of their temperature circadian rhythm which is associated with earlier sleep timing [5,8,12], and they have a smaller amplitude of their temperature circadian rhythm [8,10]. There is still some controversy surrounding age-related differences in phase angle between the circadian temperature rhythm and the sleep–wake cycle. Some authors have reported that young and elderly subjects sleep at the same circadian phase, whereas others have found that elderly subjects wake up closer to the minimum * Corresponding author. Tel.: 11-514-338-2222x3124; fax: 11514-338-2531. E-mail address: [email protected] (J. Carrier).
of their temperature circadian rhythm [5,12]. The observation that elderly subjects awaken closer to the minimum of their temperature circadian rhythm has been interpreted as a reflection of a reduced ability to maintain sleep on the ascending limb of the temperature circadian rhythm. In fact, studies have shown that the sleep of elderly subjects is particularly vulnerable to circadian phases of lower sleep propensity [4,11], i.e. elderly subjects have more difficulty than young subjects maintaining sleep when the biological clock promotes wakefulness. Studies comparing the sleep of young and middle-aged subjects have shown that almost all sleep parameters show significant effects of age between the ages of 20 and 60 years [6,17]. Furthermore, we have shown recently that people in their forties and fifties already have more difficulty than young people maintaining sleep when they have to recuperate during the daytime following a 25-h sleep deprivation [13]. The aim of the present paper is to evaluate whether middle-aged subjects, who already show a reduced ability to maintain sleep at a circadian phase of low sleep propensity, also demonstrate modifications in the output signal from the CTS compared with the young. Temperature data were available for 27 subjects between the ages of 25 and 58 years who participated in a larger study on sleep and circadian rhythms. Subjects were separated into two groups according to their age: young (six
0304-3940/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 0 2) 00 03 8- 1
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J. Carrier et al. / Neuroscience Letters 320 (2002) 1–4
women and five men; 25–38 years; mean age, 31.0 years; SEM ¼ 1:4); and middle-aged (ten women and six men; 40– 58 years; mean age, 49.9 years; SEM ¼ 1:3). Participants were screened beforehand to ensure that they were in good physical health and not taking any medications. The presence of sleep disorders was also an exclusion criterion. Peri-menopausal women and women using hormonal contraceptives or receiving hormonal replacement therapy were excluded. The ethical committee of the hospital approved this project. Subjects signed a consent form and were paid for their participation. In the young group (n ¼ 11), four subjects were students, five were employed (daytime schedules), and two were unemployed. In the middle-aged group (n ¼ 16), six subjects were employed (daytime schedules), eight were unemployed or retired, and two were working on contracts at home. The study was run across the entire year. Young and middle-aged subjects were studied in every season (nine subjects were studied in the winter, five subjects in spring, eight subjects in summer, five subjects in fall). About half of the young subjects (6/11) and half of the middle-aged subjects (8/16) were studied during winter/spring. Before the laboratory study, subjects completed a French version of the Horne-Ostberg questionnaire (1976) to assess morningness–eveningness [14], and 2 weeks of a sleep diary. During these 14 days, subjects were instructed to adopt their usual sleep–wake cycle. Mean values from the 14-day sleep diary were calculated for each subject to estimate habitual waketime, habitual bedtime, habitual time spent in bed and habitual subjective sleep quality (visual analog scale). After two adaptation nights, subjects were admitted in the evening for their baseline sleep evaluation and they remained at the laboratory for the next 48 h. Subjects were following their habitual sleep–wake cycle in the laboratory. Immediately after habitual wake-up time after their baseline sleep, participants were subject to a mini-constant routine for the next 25 h. Temperature was measured continuously by a disposable sensor (Yellowspring Inst.) inserted 10 cm into the rectum. During the mini-constant routine, subjects remained awake in bed in a semi-recumbent position with ambient lighting kept below 15 lux. They were given small snacks on a regular basis. A research assistant was present at all times to make sure subjects were not falling asleep. The mini-constant routine ended in the morning, 1 h after habitual wake time, and a daytime recovery sleep episode was recorded. Subjects had to stay in bed for the habitual sleep length indicated in their sleep diaries. Sleep was recorded and scored according to standard criteria (see [13] for a detailed description). Estimates of phase and amplitude were derived from the two-harmonic regression model (HARMREG), applied to each subject’s temperature rhythm recorded during the mini-constant routine [3]. Estimated clock time of the fitted minimum of temperature circadian rhythm served as the principal phase marker. As the temperature minimum was very close to the end of the constant routine, we also used
midrange crossing time of rising body temperature (from its minimum value during the baseline sleep episode that preceded the mini-constant routine to its maximum value during the mini-constant routine) as a secondary phase marker [15]. To determine midrange crossing time, each subject’s body temperature curve was first smoothed with a 60-min moving average. Second, the minimum and the maximum values of body temperature for each curve were averaged (midrange temperature value). Finally, the time of occurrence of the midrange temperature value was evaluated for each subject (midrange crossing time). Habitual phase angle was defined as the time interval between clock time occurrence of the fitted minimum (HARMREG) and habitual wake time (mean of 14-day sleep diaries). Polysomnographic phase angle was defined as the time interval between clock time occurrence of the fitted minimum (HARMREG) and electroencephalogram (EEG) wake time during baseline sleep. Detailed results on sleep have been published elsewhere [13]. To verify that the present sub-samples of young and middle-aged subjects were showing a significant difference in their ability to maintain sleep during daytime recovery sleep, a two-way analysis of variance with one independent factor (Age group: young; middle-aged) and one repeated measure (Sleep episode: baseline; recovery) was performed on sleep efficiency ((number of minutes asleep/number of minutes between sleep latency and final awakening)*100). One middle-aged woman was not included in the sleep analysis because she decided to withdraw from the experiment after only 2 h of daytime recovery sleep because she could not sleep. Both age groups showed a decrease in sleep efficiency during daytime recovery sleep despite the sleep deprivation, but the middle-aged subjects had a more abrupt decline than did the young (Age Group £ Night interaction: Fð1;24Þ ¼ 7:8; P ¼ 0:01). Contrast analyses indicated no significant difference in sleep efficiency between the two age groups during baseline sleep (Young ¼ 92.9%, SEM ¼ 1:8; Middle-aged ¼ 90.9%, SEM ¼ 1:5; P ¼ 0:4). However, during daytime recovery sleep, contrast analyses revealed that compared with the young, middle-aged subjects showed lower sleep efficiency (Young ¼ 85.2%, SEM ¼ 4:8; Middle-aged ¼ 71.1%, SEM ¼ 3:0; P ¼ 0:01). Table 1 presents habitual sleep parameters derived from the sleep diary and circadian characteristics (means and SEM) in young and middle-aged subjects. Sleep onset time and wake onset time in the laboratory were also derived from the polysomnographic sleep. Habitual sleep parameters and circadian parameters were compared between the two groups using t-tests. Mean habitual bedtime and mean habitual wake time were approximately 45 min earlier in the middle-aged subjects than they were in the young subjects as were mean sleep onset time and wake onset time during baseline polysomnographic sleep recording. Young and middle-aged subjects showed no difference in either mean subjective evaluation of sleep quality or mean habitual time spent in bed. Middle-aged subjects
J. Carrier et al. / Neuroscience Letters 320 (2002) 1–4
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Table 1 Parameters a derived from the sleep diary, polysomnographic sleep onset and wake onset time, and circadian characteristics b in young and middle-aged subjects c
Mean habitual bedtime Mean habitual wake time Mean habitual time in bed (min) Mean subjective sleep quality (mm) Mean EEG sleep onset (baseline) Mean EEG wake onset (baseline) Morningness–eveningness score Clock time of the minimum (HARMREG) Amplitude (8C, HARMREG) Midrange crossing time Phase angle (HARMREG) with habitual waketime Phase angle (HARMREG) with EEG wake onset a b c
Young (n ¼ 11)
Middle-aged (n ¼ 16)
P values
23:42 (0:15) 07:54 (0:15) 510.5 (19.0) 76.9 (2.8) 23:52 (0:09) 07:44 (0:17) 55.8 (2.0) 06:19 (0:40) 0.29 (0.02) 09:50 (0:49) 1:34 (0:40) 1:24 (0:38)
23:02 (0:14) 07:04 (0:14) 500.5 (8.0) 76.2 (2.2) 23:09 (0:13) 07:03 (0:10) 65.4 (2.5) 04:49 (0:22) 0.33 (0.02) 07:55 (0:27) 2:15 (0:14) 2:14 (0:17)
0.06 0.02 n.s. n.s. 0.03 0.04 0.01 0.04 n.s. 0.04 n.s. n.s.
Fourteen-day means. Means and SEM. P values of t-tests for independent groups are also presented.
reported greater orientation toward morningness than did the young subjects. The mean score of the middle-aged subjects was in the ‘moderate morning type’ range; it was in the ‘neither morning type nor evening type’ range for the young subjects. Clock time occurrence of the fitted minimum of the temperature circadian rhythm during the miniconstant routine was significantly earlier in the middle-aged group than in the young group (see Fig. 1). Accordingly, middle-aged subjects showed earlier midrange crossing time of rising body temperature from its minimum to its maximum value during the sleep episode preceding the mini-constant routine. There was no significant difference among the groups in amplitude of the temperature circadian rhythm or in phase angle between sleep and the fitted minimum of temperature circadian rhythm. To our knowledge, this is the first study that compares unmasked temperature circadian rhythm characteristics between young and middle-aged subjects. A phase advance of both sleep and temperature circadian rhythms is already apparent in people in their forties and fifties who show a reduced ability to maintain sleep during daytime compared with young subjects. No differences in amplitude of temperature circadian rhythm or in phase angle between the sleep episode and the circadian temperature rhythm were found between young and middle-aged subjects. Important changes in the timing of sleep and circadian rhythms take place throughout the life span. Puberty has been associated with a phase delay of both sleep–wake cycle and melatonin circadian rhythms [7]. A recent study by our group has shown that young adults (18–31 years) still show melatonin circadian phase characteristics similar to those of adolescent subjects (14–17 years) [16]. Interestingly, a negative correlation between age and ambulatory temperature minimum has been reported between the ages of 18 and 41 years, which suggests that the phase of the temperature circadian rhythm comes earlier during adulthood [1]. Our results reveal that the difference in phase
between young and middle-aged subjects is already of the same magnitude as the difference previously reported between young and elderly subjects [5,12]. As illustrated by Fig. 1, the phase advance of the middleaged subjects seems more strongly related to the rising limb of the body temperature curve. Nevertheless, midrange crossing time of the temperature decline (from its maximum value to its minimum value during the mini-constant routine) was also advanced by more than an hour in the middle-aged subjects compared with the young (Young: mean ¼ 00:36 h;
Fig. 1. Ten-minute means (and SEM) of body temperature recorded during 25 h in constant conditions for the young (black circles) and the middle-aged (white circles). Rectangles represent the mean usual sleep period for the young (black rectangle) and the middle-aged subjects (white rectangle).
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J. Carrier et al. / Neuroscience Letters 320 (2002) 1–4
SEM ¼ 0:31; middle-aged: mean ¼ 23:19 h; SEM ¼ 0:31) but the difference did not quite reach significance (P ¼ 0:1). We cannot rule out entirely the possibility that the phase advance of the rising limb of the circadian temperature rhythm may be related to the evoked effect of the preceding sleep episode on body temperature. Further studies estimating phase with other circadian rhythms (e.g. melatonin) or using a longer constant routine should be performed in young and middle-aged subjects to resolve this issue. The middle years of life are also associated with more difficulty maintaining sleep during daytime, even after a sleepless night. The mechanisms underlying this age-related lower tolerance to a phase angle misalignment are not yet understood. This lower tolerance to a phase angle misalignment cannot be easily explained solely by a malfunction of the CTS. First, aside from a phase advance of both sleep and temperature circadian rhythms, we find no other difference between young and middle-aged subjects in the output signal from the CTS, as measured with unmasked body temperature rhythm. Furthermore, the fact that the sleep of older subjects is more sensitive to this ‘unfavorable’ circadian phase would suggest that the CTS is sending a stronger waking signal during the day as we get older. Results from the present study as well as from previous studies of the elderly do not support this possibility. Studies have shown no change or even reductions in the circadian modulation of many circadian markers with increasing age [8,18–20]. It has been proposed that modification in the interaction between homeostatic and circadian sleep regulation processes may explain age-related lower tolerance to a phase angle misalignment [10]. We have shown previously that middle-aged subjects show a reduced rebound of slowwave sleep and of slow wave activity following an acute 25h sleep deprivation [13]. We suggested that the smaller homeostatic response following the acute sleep deprivation in the middle-aged subjects was not able to ‘override’ the increasing circadian wake propensity as their daytime sleep episode progressed. Future studies should evaluate the integrity of homeostatic sleep regulatory process to test this suggestion.
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This research was supported by grant MT-14999 from the Canadian Institutes of Health Research (CIHR: Carrier), CIHR Scholarship (Carrier), and a fellowship from ‘Les Fonds de Recherches en Sante´ du Que´ bec’ (Touchette). The authors are grateful to Sonia Frenette, the project coordinator; to Marie Dumont for useful comments on the manuscript; and to our technicians for day-to-day study management.
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[19] [1] Baehr, E.K., Revelle, W. and Eastman, C.I., Individual differences in the phase and amplitude of the human circadian temperature rhythm: with an emphasis on morningness– eveningness, J. Sleep Res., 9 (2000) 117–127. [2] Bliwise, D.L., Sleep and circadian rhythm disorders in aging and dementia, In F.W. Turek and P.C. Zee (Eds.), Regulation
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of Sleep and Circadian Rhythms, Marcel Dekker, New York, 1999, pp. 487–526. Brown, E.N. and Czeisler, C.A., The statistical analysis of circadian phase and amplitude in constant-routine coretemperature data, J. Biol. Rhythms, 7(3) (1992) 177–202. Campbell, S.S. and Dawson, D., Aging young sleep: a test of the phase advance hypothesis of sleep disturbance in the elderly, J. Sleep Res., 1 (1992) 205–210. Carrier, J., Monk, T.H., Reynolds, C.F.I., Buysse, D.J. and Kupfer, D.J., Are age differences in sleep due to phase differences in the output of the circadian timing system? Chronobiol. Int., 16 (1999) 79–91. Carrier, J., Land, S., Buysse, D.J., Kupfer, D.J. and Monk, T.H., The effects of age and gender on sleep EEG power spectral density in the “middle” years of life (20y–60y), Psychophysiology, 38 (2001) 232–242. Carskadon, M.A., Acebo, C., Richardson, G.S., Tate, B.A. and Seifer, R., An approach to studying circadian rhythms of adolescent humans, J. Biol. Rhythms, 12 (1997) 278–289. Czeisler, C.A., Dumont, M., Duffy, J.F., Steinberg, J.D., Richardson, G.S., Brown, E.N., Sanchez, R., Rios, C.D. and Ronda, J.M., Association of sleep–wake habits in older people with changes in output of circadian pacemaker, Lancet, 340 (1992) 933–936. Daan, S., Beersma, D.G.M. and Borbely, A.A., Timing of human sleep: recovery process gated by circadian pacemaker, Am. J. Physiol., 246 (1984) R161–R178. Dijk, D.-J. and Duffy, J.F., Circadian regulation of human sleep and age-related changes in its timing, consolidation and EEG characteristics, Ann. Med., 31 (1999) 130–140. Dijk, D.-J., Duffy, J.F., Riel, E., Shanahan, T.L. and Czeisler, C.A., Ageing and the circadian and homeostatic regulation of human sleep during forced desynchrony of rest, melatonin and temperature rhythms, J. Physiol., 516 (1999) 611–627. Duffy, J.F., Dijk, D.-J., Klerman, E.B. and Czeisler, C.A., Later endogenous circadian temperature nadir relative to an earlier wake time in older people, Am. J. Physiol., 275 (1998) R1478–R1487. Gaudreau, H., Morettini, J., Lavoie, H.B. and Carrier, J., Effects of a 25-h sleep deprivation on daytime sleep in the middle-aged, Neurobiol. Aging, 22 (2001) 461–468. Horne, J.A. and Ostberg, O., A self-assessment questionnaire to determine morningness–eveningness in human circadian rhythms, Int. J. Chronobiol., 4 (1976) 97–110. Krauchi, K., Cajochen, C., Danilenko, K.V. and Wirz-Justice, A., The hypothermic effect of late evening melatonin does not block the phase delay induced by concurrent bright light in human subjects, Neurosci. Lett., 232 (1997) 57–61. Laberge, L., Carrier, J., Lespe´ rance, P., Lambert, C., Vitaro, F., Tremblay, R.E. and Montplaisir, J., Sleep and circadian phase characteristics of adolescent and young adult males in a naturalistic summertime condition, Chronobiol. Int., 17 (2000) 1–13. Landolt, H.P., Dijk, D.J., Achermann, P. and Borbely, A.A., Effect of age on the sleep EEG: slow-wave activity and spindle frequency activity in young and middle-aged men, Brain Res., 738 (1996) 205–212. Monk, T.H., Buysse, D.J., Reynolds, C.F., Kupfer, D.J. and Houck, P.R., Circadian temperature rhythms of older people, Exp. Gerontol., 30 (1995) 455–474. Monk, T.H., Buysse, D.J., Reynolds, C.F., Kupfer, D.J. and Houck, P.R., Subjective alertness rhythms in elderly people, J. Biol. Rhythms, 11 (1996) 268–276. Zeitzer, J.M., Daniels, J.E., Duffy, J.F., Klerman, E.B., Shanahan, T.L., Dijk, D.-J. and Czeisler, C.A., Do plasma melatonin concentrations decline with age ? Am. J. Med., 107 (1999) 432–436.
Phase advance of sleep and temperature circadian rhythms in the middle years of life in humans Julie Carrier*, Jean Paquet, Jocelyn Morettini, E´velyne Touchette Centre du Sommeil et des Rythmes Biologiques, Hoˆpital du Sacre´-Cœur de Montre´al, Department of Psychology, Universite´ de Montre´al, 5400 Boulevard Gouin Ouest, Montreal H4J 1C5, QC, Canada Received 11 October 2001; received in revised form 6 December 2001; accepted 6 December 2001
Abstract Age-related changes in sleep may be linked to modifications in the circadian timing system. This study compared sleep patterns and unmasked circadian temperature parameters between a group of young subjects and a group of middle-aged subjects. Habitual bedtime and waketime were earlier in the middle-aged than in the young. In addition, middle-aged subjects reported a greater orientation toward morningness and they showed an earlier phase of temperature rhythm. No differences were found in amplitude of temperature rhythm or in habitual phase angle between sleep and the temperature rhythm. In conclusion, a phase advance of sleep and temperature circadian rhythm is already apparent in people in their forties and fifties. These changes precede modifications in amplitude or in habitual phase angle. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Sleep; Circadian rhythms; Body temperature; Aging; Middle age; Constant routine; Morningness; Eveningness
According to contemporary models of sleep–wake cycle regulation, the interaction of homeostatic and circadian processes regulates the sleep–wake cycle [9]. The homeostatic process represents the accumulation of sleep need with increasing time awake and its dissipation during the sleep episode. The circadian process represents the rhythmic variations of sleep and wake propensity over 24 h. It has been suggested that age-related changes in sleep may be linked to modifications to the circadian timing system (CTS; see for review [2]). Studies that controlled for masking effects confirmed that young and elderly subjects differ on a number of characteristics of temperature circadian rhythm. Compared with the young, elderly subjects show a phase advance of their temperature circadian rhythm which is associated with earlier sleep timing [5,8,12], and they have a smaller amplitude of their temperature circadian rhythm [8,10]. There is still some controversy surrounding age-related differences in phase angle between the circadian temperature rhythm and the sleep–wake cycle. Some authors have reported that young and elderly subjects sleep at the same circadian phase, whereas others have found that elderly subjects wake up closer to the minimum * Corresponding author. Tel.: 11-514-338-2222x3124; fax: 11514-338-2531. E-mail address: [email protected] (J. Carrier).
of their temperature circadian rhythm [5,12]. The observation that elderly subjects awaken closer to the minimum of their temperature circadian rhythm has been interpreted as a reflection of a reduced ability to maintain sleep on the ascending limb of the temperature circadian rhythm. In fact, studies have shown that the sleep of elderly subjects is particularly vulnerable to circadian phases of lower sleep propensity [4,11], i.e. elderly subjects have more difficulty than young subjects maintaining sleep when the biological clock promotes wakefulness. Studies comparing the sleep of young and middle-aged subjects have shown that almost all sleep parameters show significant effects of age between the ages of 20 and 60 years [6,17]. Furthermore, we have shown recently that people in their forties and fifties already have more difficulty than young people maintaining sleep when they have to recuperate during the daytime following a 25-h sleep deprivation [13]. The aim of the present paper is to evaluate whether middle-aged subjects, who already show a reduced ability to maintain sleep at a circadian phase of low sleep propensity, also demonstrate modifications in the output signal from the CTS compared with the young. Temperature data were available for 27 subjects between the ages of 25 and 58 years who participated in a larger study on sleep and circadian rhythms. Subjects were separated into two groups according to their age: young (six
0304-3940/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 0 2) 00 03 8- 1
2
J. Carrier et al. / Neuroscience Letters 320 (2002) 1–4
women and five men; 25–38 years; mean age, 31.0 years; SEM ¼ 1:4); and middle-aged (ten women and six men; 40– 58 years; mean age, 49.9 years; SEM ¼ 1:3). Participants were screened beforehand to ensure that they were in good physical health and not taking any medications. The presence of sleep disorders was also an exclusion criterion. Peri-menopausal women and women using hormonal contraceptives or receiving hormonal replacement therapy were excluded. The ethical committee of the hospital approved this project. Subjects signed a consent form and were paid for their participation. In the young group (n ¼ 11), four subjects were students, five were employed (daytime schedules), and two were unemployed. In the middle-aged group (n ¼ 16), six subjects were employed (daytime schedules), eight were unemployed or retired, and two were working on contracts at home. The study was run across the entire year. Young and middle-aged subjects were studied in every season (nine subjects were studied in the winter, five subjects in spring, eight subjects in summer, five subjects in fall). About half of the young subjects (6/11) and half of the middle-aged subjects (8/16) were studied during winter/spring. Before the laboratory study, subjects completed a French version of the Horne-Ostberg questionnaire (1976) to assess morningness–eveningness [14], and 2 weeks of a sleep diary. During these 14 days, subjects were instructed to adopt their usual sleep–wake cycle. Mean values from the 14-day sleep diary were calculated for each subject to estimate habitual waketime, habitual bedtime, habitual time spent in bed and habitual subjective sleep quality (visual analog scale). After two adaptation nights, subjects were admitted in the evening for their baseline sleep evaluation and they remained at the laboratory for the next 48 h. Subjects were following their habitual sleep–wake cycle in the laboratory. Immediately after habitual wake-up time after their baseline sleep, participants were subject to a mini-constant routine for the next 25 h. Temperature was measured continuously by a disposable sensor (Yellowspring Inst.) inserted 10 cm into the rectum. During the mini-constant routine, subjects remained awake in bed in a semi-recumbent position with ambient lighting kept below 15 lux. They were given small snacks on a regular basis. A research assistant was present at all times to make sure subjects were not falling asleep. The mini-constant routine ended in the morning, 1 h after habitual wake time, and a daytime recovery sleep episode was recorded. Subjects had to stay in bed for the habitual sleep length indicated in their sleep diaries. Sleep was recorded and scored according to standard criteria (see [13] for a detailed description). Estimates of phase and amplitude were derived from the two-harmonic regression model (HARMREG), applied to each subject’s temperature rhythm recorded during the mini-constant routine [3]. Estimated clock time of the fitted minimum of temperature circadian rhythm served as the principal phase marker. As the temperature minimum was very close to the end of the constant routine, we also used
midrange crossing time of rising body temperature (from its minimum value during the baseline sleep episode that preceded the mini-constant routine to its maximum value during the mini-constant routine) as a secondary phase marker [15]. To determine midrange crossing time, each subject’s body temperature curve was first smoothed with a 60-min moving average. Second, the minimum and the maximum values of body temperature for each curve were averaged (midrange temperature value). Finally, the time of occurrence of the midrange temperature value was evaluated for each subject (midrange crossing time). Habitual phase angle was defined as the time interval between clock time occurrence of the fitted minimum (HARMREG) and habitual wake time (mean of 14-day sleep diaries). Polysomnographic phase angle was defined as the time interval between clock time occurrence of the fitted minimum (HARMREG) and electroencephalogram (EEG) wake time during baseline sleep. Detailed results on sleep have been published elsewhere [13]. To verify that the present sub-samples of young and middle-aged subjects were showing a significant difference in their ability to maintain sleep during daytime recovery sleep, a two-way analysis of variance with one independent factor (Age group: young; middle-aged) and one repeated measure (Sleep episode: baseline; recovery) was performed on sleep efficiency ((number of minutes asleep/number of minutes between sleep latency and final awakening)*100). One middle-aged woman was not included in the sleep analysis because she decided to withdraw from the experiment after only 2 h of daytime recovery sleep because she could not sleep. Both age groups showed a decrease in sleep efficiency during daytime recovery sleep despite the sleep deprivation, but the middle-aged subjects had a more abrupt decline than did the young (Age Group £ Night interaction: Fð1;24Þ ¼ 7:8; P ¼ 0:01). Contrast analyses indicated no significant difference in sleep efficiency between the two age groups during baseline sleep (Young ¼ 92.9%, SEM ¼ 1:8; Middle-aged ¼ 90.9%, SEM ¼ 1:5; P ¼ 0:4). However, during daytime recovery sleep, contrast analyses revealed that compared with the young, middle-aged subjects showed lower sleep efficiency (Young ¼ 85.2%, SEM ¼ 4:8; Middle-aged ¼ 71.1%, SEM ¼ 3:0; P ¼ 0:01). Table 1 presents habitual sleep parameters derived from the sleep diary and circadian characteristics (means and SEM) in young and middle-aged subjects. Sleep onset time and wake onset time in the laboratory were also derived from the polysomnographic sleep. Habitual sleep parameters and circadian parameters were compared between the two groups using t-tests. Mean habitual bedtime and mean habitual wake time were approximately 45 min earlier in the middle-aged subjects than they were in the young subjects as were mean sleep onset time and wake onset time during baseline polysomnographic sleep recording. Young and middle-aged subjects showed no difference in either mean subjective evaluation of sleep quality or mean habitual time spent in bed. Middle-aged subjects
J. Carrier et al. / Neuroscience Letters 320 (2002) 1–4
3
Table 1 Parameters a derived from the sleep diary, polysomnographic sleep onset and wake onset time, and circadian characteristics b in young and middle-aged subjects c
Mean habitual bedtime Mean habitual wake time Mean habitual time in bed (min) Mean subjective sleep quality (mm) Mean EEG sleep onset (baseline) Mean EEG wake onset (baseline) Morningness–eveningness score Clock time of the minimum (HARMREG) Amplitude (8C, HARMREG) Midrange crossing time Phase angle (HARMREG) with habitual waketime Phase angle (HARMREG) with EEG wake onset a b c
Young (n ¼ 11)
Middle-aged (n ¼ 16)
P values
23:42 (0:15) 07:54 (0:15) 510.5 (19.0) 76.9 (2.8) 23:52 (0:09) 07:44 (0:17) 55.8 (2.0) 06:19 (0:40) 0.29 (0.02) 09:50 (0:49) 1:34 (0:40) 1:24 (0:38)
23:02 (0:14) 07:04 (0:14) 500.5 (8.0) 76.2 (2.2) 23:09 (0:13) 07:03 (0:10) 65.4 (2.5) 04:49 (0:22) 0.33 (0.02) 07:55 (0:27) 2:15 (0:14) 2:14 (0:17)
0.06 0.02 n.s. n.s. 0.03 0.04 0.01 0.04 n.s. 0.04 n.s. n.s.
Fourteen-day means. Means and SEM. P values of t-tests for independent groups are also presented.
reported greater orientation toward morningness than did the young subjects. The mean score of the middle-aged subjects was in the ‘moderate morning type’ range; it was in the ‘neither morning type nor evening type’ range for the young subjects. Clock time occurrence of the fitted minimum of the temperature circadian rhythm during the miniconstant routine was significantly earlier in the middle-aged group than in the young group (see Fig. 1). Accordingly, middle-aged subjects showed earlier midrange crossing time of rising body temperature from its minimum to its maximum value during the sleep episode preceding the mini-constant routine. There was no significant difference among the groups in amplitude of the temperature circadian rhythm or in phase angle between sleep and the fitted minimum of temperature circadian rhythm. To our knowledge, this is the first study that compares unmasked temperature circadian rhythm characteristics between young and middle-aged subjects. A phase advance of both sleep and temperature circadian rhythms is already apparent in people in their forties and fifties who show a reduced ability to maintain sleep during daytime compared with young subjects. No differences in amplitude of temperature circadian rhythm or in phase angle between the sleep episode and the circadian temperature rhythm were found between young and middle-aged subjects. Important changes in the timing of sleep and circadian rhythms take place throughout the life span. Puberty has been associated with a phase delay of both sleep–wake cycle and melatonin circadian rhythms [7]. A recent study by our group has shown that young adults (18–31 years) still show melatonin circadian phase characteristics similar to those of adolescent subjects (14–17 years) [16]. Interestingly, a negative correlation between age and ambulatory temperature minimum has been reported between the ages of 18 and 41 years, which suggests that the phase of the temperature circadian rhythm comes earlier during adulthood [1]. Our results reveal that the difference in phase
between young and middle-aged subjects is already of the same magnitude as the difference previously reported between young and elderly subjects [5,12]. As illustrated by Fig. 1, the phase advance of the middleaged subjects seems more strongly related to the rising limb of the body temperature curve. Nevertheless, midrange crossing time of the temperature decline (from its maximum value to its minimum value during the mini-constant routine) was also advanced by more than an hour in the middle-aged subjects compared with the young (Young: mean ¼ 00:36 h;
Fig. 1. Ten-minute means (and SEM) of body temperature recorded during 25 h in constant conditions for the young (black circles) and the middle-aged (white circles). Rectangles represent the mean usual sleep period for the young (black rectangle) and the middle-aged subjects (white rectangle).
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SEM ¼ 0:31; middle-aged: mean ¼ 23:19 h; SEM ¼ 0:31) but the difference did not quite reach significance (P ¼ 0:1). We cannot rule out entirely the possibility that the phase advance of the rising limb of the circadian temperature rhythm may be related to the evoked effect of the preceding sleep episode on body temperature. Further studies estimating phase with other circadian rhythms (e.g. melatonin) or using a longer constant routine should be performed in young and middle-aged subjects to resolve this issue. The middle years of life are also associated with more difficulty maintaining sleep during daytime, even after a sleepless night. The mechanisms underlying this age-related lower tolerance to a phase angle misalignment are not yet understood. This lower tolerance to a phase angle misalignment cannot be easily explained solely by a malfunction of the CTS. First, aside from a phase advance of both sleep and temperature circadian rhythms, we find no other difference between young and middle-aged subjects in the output signal from the CTS, as measured with unmasked body temperature rhythm. Furthermore, the fact that the sleep of older subjects is more sensitive to this ‘unfavorable’ circadian phase would suggest that the CTS is sending a stronger waking signal during the day as we get older. Results from the present study as well as from previous studies of the elderly do not support this possibility. Studies have shown no change or even reductions in the circadian modulation of many circadian markers with increasing age [8,18–20]. It has been proposed that modification in the interaction between homeostatic and circadian sleep regulation processes may explain age-related lower tolerance to a phase angle misalignment [10]. We have shown previously that middle-aged subjects show a reduced rebound of slowwave sleep and of slow wave activity following an acute 25h sleep deprivation [13]. We suggested that the smaller homeostatic response following the acute sleep deprivation in the middle-aged subjects was not able to ‘override’ the increasing circadian wake propensity as their daytime sleep episode progressed. Future studies should evaluate the integrity of homeostatic sleep regulatory process to test this suggestion.
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This research was supported by grant MT-14999 from the Canadian Institutes of Health Research (CIHR: Carrier), CIHR Scholarship (Carrier), and a fellowship from ‘Les Fonds de Recherches en Sante´ du Que´ bec’ (Touchette). The authors are grateful to Sonia Frenette, the project coordinator; to Marie Dumont for useful comments on the manuscript; and to our technicians for day-to-day study management.
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