Chronobiology and Sleep. Prolonged Interval From Body Temperature Nadir to Sleep Offset in Patients With Delayed Sleep Phase Syndrome

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1 Sleep, 19(1): American Sleep Disorders Association and Sleep Research Society Chronobiology and Sleep Prolonged Interval From Body Temperature Nadir to Sleep Offset in Patients With Delayed Sleep Phase Syndrome Shigeru Ozaki, Makoto Uchiyama, Shuichiro Shirakawa and Masako Okawa Department of Psychophysiology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Ichikawa, Japan Summary: In order to clarify the relationship between sleep-wake and core body temperature rhythms in the delayed sleep phase syndrome (DSPS), we conducted simultaneous monitoring of these rhythms in seven patients with DSPS and nine healthy control subjects for 6-10 days during their conventional sleep-wake schedules. The sleep onset and offset times were determined visually from sleep logs, and the temperature data were fitted to 24- hour cosinor curves by the least squares method. The sleep onset and offset times and temperature nadir were delayed significantly in patients with DSPS compared with the control subjects (p = 0.01,0.003 and 0.02, respectively). We also found that sleep length and the temperature nadir to sleep offset interval were significantly longer in the DSPS than the control group (p = 0.03 and 0.02, respectively). The latter finding suggests that the inability of the patients with DSPS to normally phase-advance their circadian rhythm may be a consequence of masking of the advance portion of their phase-response curve by the last hours of their prolonged sleep episodes. Key Words: Delayed sleep phase syndrome (DSPS)-Circadian rhythms-core body temperature-phase-response curve Bright light pulse. The delayed sleep phase syndrome (DSPS) was first described by Weitzman et al. as a chronic sleep disorder characterized by chronic difficulty in falling asleep at the desired clock time of night and inability to be aroused easily in the morning (1,2). Conventional polysomnographic studies have revealed that sleep structure is not disturbed in patients with DSPS once sleep has been initiated and is permitted to continue until it ends spontaneously (2-5). Only chronobiological interventions, such as chronotherapy, bright light therapy and orally administered vitamin B 12 or melatonin, have been reported to be effective against sleep onset insomnia in DSPS patients, whereas conventional hypnotic drugs have little effect (6-12). These unique features have led DSPS to be classified as a circadian sleep-wake rhythm disorder (13). The core body temperature rhythm, which has been reported to represent circadian oscillation of the human Accepted for publication August Address correspondence to and reprint requests to Makoto Uchiyama, M.D., Department of Psychophysiology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kohnodai 1-7-3, Ichikawa-City, Chiba 272, Japan. 36 endogenous clock, is believed to be delayed in patients with DSPS (14-16). Effective therapeutic interventions, such as morning bright light and chronotherapy, were reported to phaseadvance the core body temperature rhythm as well as the sleep phase in patients with DSPS (10,12,14). These findings suggested that the sleep-wake and core body temperature rhythms are both phase-delayed in DSPS sufferers, but could not explain their difficulty in phase-advancing their delayed sleep phase. Weitzman et al. (1) and Czeis1er et al. (7) postulated that the advance portions of the phase-response curves of patients with DSPS are abnormally small and that this abnormality explains the etiology, especially of the difficulty in phase-advancing their sleep. However, to our knowledge, no studies presenting pathophysiological evidence to support this hypothesis have been published. Simultaneous monitoring of core body temperature and sleep-wake rhythms helps in an effort to understand the human circadian rhythm. The endogenous temperature oscillation phase may explain the changes in customary sleep timings that occur with age (17).

2 LONGER SLEEP AFTER BODY TEMPERATURE NADIR IN DSPS 37 TABLE 1. Summary of the clinical features of seven patients with DSPS Age at Age at Case Sex study onset Social problems Education 1 M Educational difficulties High school 2 M Poor work schedule High school 3 M Loss of employment, social isolation College 4 M 53 48" Loss of employment, social isolation College 5 M Occupational difficulties College 6 F Occupational difficulties College 7 F Poor housekeeping College " The case 4 reported that he had had difficulties in attending morning classes in his early twenties, Thereafter he had been engaged in jobs that did not require him to attend in the morning, A job change at 48 years of age manifested his difficulty in falling asleep and waking up at desired times. Only a few studies into the relationship between sleepwake and core body temperature rhythms in patients with DSPS have been reported. In this study, we conducted simultaneous monitoring of the core body temperature and sleep-wake rhythms of DSPS sufferers during their habitually delayed sleep-wake schedules and investigated the relationship between these parameters. METHODS We studied seven patients with DSPS and nine agematched healthy controls subjects. The patient group comprised five men and two women, aged years (mean 30.9), in whom DSPS was diagnosed according to International Classification of Sleep Disorders (ICSD) criteria (13). We carried out the study before making any therapeutic interventions. No patient had been given any medication, had the habit of drinking alcohol before bedtime or abused alcohol or other psychotropic drugs. The two female patients reported no remarkable fluctuations in mood or sleep schedules during the menstrual cycle. The clinical features of the patients are shown in Table 1. We conducted a semistructured psychiatric interview that included DSM III-R criteria (18) of mood disorders, global assessment scale (19) and Hamilton's rating scale for depression (20), and we found that no patient had medical or psychiatric disorders or a history of developmental problems or severe somatic diseases. They all reported that they had had frequent difficulties in attending school at a regular time in childhood, even before the onset of DSPS. Occupational or educational difficulties had occurred in all of the patients. Because of their inability to keep to desired sleep-wake schedules, two of the seven patients had lost their jobs, and three (cases 2,5 and 6) could attend their office only during the afternoon. The control subjects were healthy male volunteers, aged years (mean 24.6), without sleep disorders or any history of using psychoactive drugs. The control subjects had regular sleep-wake habits, no remarkable weekday-weekend difference of sleep length «90 minutes) and no remarkable irregularity due to work schedule. None of the control subjects had difficulty in waking up at the desired wake time. We asked all of the subjects to keep a sleep log for 4 weeks before entering the study, and we confirmed that no marked day-by-day variations in their sleepwake schedules occurred and that their own sleep schedules were not markedly constrained by their work schedules. According to the sleep logs, we calculated subjects' average bedtimes and wake times and asked them to keep to these sleep schedules during the investigation period. No subject had traveled across time zones or performed night shift work within the previous 6 months. A rectal or vaginal temperature was recorded for 6- lo days in the subjects' home environments. We instructed them to maintain their normal schedules. During the investigation period, the subjects were not allowed to take any medication or alcoholic beverages. They recorded their bedtimes, waking times and the times of events such as meals, exercise or bathing. In three patients and six control subjects, we carried out activity measurements during the investigation period using wrist-worn activity recorders (Actigraph, Ambulatory Monitoring, Inc., Ardsley, NY; sampling time, 1 minute). The core body temperature was measured with a thermal sensor inserted in the rectum (five male patients and control subjects) or vagina (two female patients). We used an ambulatory temperature monitoring system (Ambulatory Temperature Logger, Kohden Medical Co., Tokyo, Japan), which digitized the temperature data every 5 minutes using a 12-bit analogto-digital converter and stored them in a 16-bit computer. Sleep onset and sleep offset times were determined visually from the sleep logs by an investigator who was unaware of the conditions of the SUbjects. The actigram data from the nine subjects (three patients and six controls) confirmed the reliability of the sleep log data. The core body temperature data were ob- Sleep, Vol. 19, No.1, 1996

3 38 S. OZAKI ET AL. C 38.0 Normal (37 yr male) 9 days TABLE 2. Sleep onset and offset times and lengths in DSPS patients and control subjects :: % 50 Sleep onset (hours) 2.71 ::+: ::+: Sleep offset (hours) ::+: ::+: Sleep length (hours) 8.35 ::+: ::+: U test DSPS (29 yr male) o 12 days = % --.--,--,---l hour FIG. 1. Records of simultaneous monitoring of rectal temperature and sleep phase from a control subject and a patient with DSPS under their habitual sleep-wake schedules. Mean values per 60-minute-interval are averaged time-locked to temperature minima for 9 days in the control subject (above) and for 12 days in the patient with DSPS (below). Error bars represent standard error. Histograms represent occurrence of sleep episodes per 60-minute interval. The sleep episodes in the patient occurred more frequently after the temperature minima, whereas the sleep in the control subject occurred more frequently before the temperature minima. tained each day by adding the values for the prior and subsequent 6-hour intervals ( hours, hours) to those during 24 hours. These 36-hour data were fitted to a 24-hour cosinor curve by the least squares method, using a data-analysis package (Kaleidagraph version 3.0.2, 1993, Synergy Software Co.). We used the mesor, amplitude and nadir as chronobiological temperature parameters. The median of each parameter during the investigation period of each subject was used for analysis. The Mann-Whitney U test was used to compare the data. The temperature minimum during sleep was determined by inspection of the temperature curve, and the average temperature during sleep was calculated by averaging the raw temperature data for each sleep period. Before entering the study, all the participants gave their written informed consent. RESULTS Figure 1 shows the sleep-wake records and simultaneous core body temperature monitoring data for a representative patient with DSPS (29-year-old male, Sleep, Vol. 19. No. I, case 3) and a control subject (37-year-old male). Mean sleep onset and offset times for the patient were 4.05 ::': 0.19 and ::': 0.26, whereas those for the control were 0.50 ::': 0.26 and 7.67 ::': 0.12, respectively. The sleep phase was delayed in the DSPS patient compared to the control subject. The difference in the distribution of sleep between the patient and the control subject was noted; the sleep of the patient occurred more frequently after the temperature minima, whereas the sleep of the control subject occurred more frequently before the temperature minima. The sleep onset and offset times were delayed significantly in the DSPS patients compared with the control subjects (p = 0.01 and 0.003, respectively), and sleep length was significantly longer in the former (p = 0.03, Table 2). The circadian parameters of both the DSPS patients and control subjects, together with the between-group comparison, are shown in Table 3. The temperature nadir in the DSPS patients was delayed significantly compared with the control subjects (p = 0.02). The temperature mesor, amplitude, mean and minimum values during sleep episodes in the DSPS and the control groups did not differ significantly. In order to investigate the relationship between the temperature nadir and sleep episodes, we calculated the intervals between sleep onset and the temperature nadir and the nadir to sleep offset (Table 4). The sleep onset to temperature nadir intervals of the groups did not differ significantly, but the temperature nadir to sleep offset interval was significantly longer in the DSPS than the control group (p = 0.02). TABLE 3. Circadian parameters in DSPS patients and control subjects Mesor CC) 37.02::+: ::+: 0.05 NS Amplitude CC) 0.54::+: ::+: 0.03 NS Nadir time (hours) 7.29::+: ::+: Mean temperature during sleep (0C) 36.56::+: ::+: 0.05 NS Minimum temperature during sleep (0C) 36.29::+: ::+: 0.05 NS U test. NS, not significant (p 20: 0.05).

4 LONGER SLEEP AFTER BODY TEMPERATURE NADIR IN DSPS 39 TABLE 4. Relationship between temperature nadir and sleep phase Sleep onset-nadir interval (hours) 4.57 :!:: :!:: 0.14 NS Relative point (%) 53.1 :!:: :!:: 2.8 NS Nadir-sleep offset interval (hours) 3.78 :!:: :!:: U test. NS, not significant (p ~ 0.05). DISCUSSION In the present study, the sleep onset and offset times and body temperature (BT) nadir were significantly delayed in DSPS patients in comparison with the controls subjects, whereas their temperature mesor, amplitude, mean and minimum values during sleep did not differ significantly. These results suggest that the entire circadian rhythms were phase-delayed in the patients. Previous studies have not clarified the relationship between sleep phase and other circadian parameters, such as BT and hormonal rhythms. Wagner et al. reported that the circadian temperature rhythms in DSPS sufferers, together with sleep episodes, were entirely phase-delayed relative to the clock time during their habitual delayed sleep-wake schedules (21). Under a controlled light-dark schedule (light: hours), however, similar circadian parameters, such as plasma melatonin and urinary 6-sulphatoxymelatonin profiles, pulse duration and peak concentrations in patients with DSPS were reported to be within the normal range, but sleep episodes were delayed (8). The aim of the present study was to clarify the relationship between sleep phase and BT rhythm under home conditions in DSPS patients. With respect to the relationship between sleep phase and BT rhythm, only one group of workers has carried out a comparative study of patients with DSPS and control subjects during their habitual sleep-wake schedules, but no clear differences were found (21). In the present study, sleep length and the intervals between the BT nadir and sleep offset were found to be significantly longer in the patients with DSPS than the control subjects. These findings are, to our knowledge, the first evidence of different circadian structures in DSPS patients. Although there is a possibility that work schedule might put a constraint on sleep duration in healthy normal subjects, we considered that we could minimize such a possibility by carefully selecting the controls subjects. Czeisler et al. indicated that the duration of sleep episodes in internally synchronized free-running subjects correlated highly with the circadian phase of BT rhythm at bedtime; a sleep episode that started around the BT maximum lasted longer than one that started around the BT minimum (22). Our finding that the longer sleep duration in DSPS patients was not associated with a longer sleep onset to BT nadir interval indicates that their longer sleep episodes may not be explained by the phase angle between sleep onset and BT rhythm. Alternatively, the clinical findings that most of our patients had difficulty in awakening at a regular hour, even in their childhood when sleep onset insomnia had not emerged, may indicate that it is essential for patients with DSPS to sleep longer and that this longer sleeping tendency could be related to the etiology of this condition (23). Human isolation studies conducted in a time-cue free facility have suggested that waking occurs during the ascending portion of the circadian temperature rhythm (22). As far as we know, no study has referred to the exact circadian timing of sleep offset, whereas several workers have pointed out the relationship between sleep onset timing and length (22,24,25). Recently, several studies have demonstrated the phase-resetting effect of bright light pulses on the human circadian system. Experiments conducted in a time-cue free environment indicated that bright light pulses given slightly before the BT nadir phase-delayed the human circadian temperature and sleepwake rhythms, whereas such pulses slightly after the BT nadir phase-advanced them (26-28). Similar phase responses of the timing of sleep to bright light were observed under experimental conditions of entrainment to a 24-hour period (29,30). These findings suggest that phase-advancing of the human circadian clock may require bright light slightly after the BT nadir (morning bright light). The longer BT nadir to sleep offset interval in DSPS patients compared with control subjects suggests that their inability to phaseadvance their circadian rhythms normally might be a consequence of masking of the advance portion of their phase-response curves by the last hours of their longer sleep episodes. This postulate, obtained from our clinical study, should be worthy of further experimental human studies, including an evaluation of hormonal rhythm andlor an application of a demasking protocol such as the constant routine (31). Acknowledgement: This study was partly supported by a Research Grant (SA-lO) for Nervous and Mental Disorders from the Ministry of Health and Welfare. REFERENCES 1. Weitzman ED, Czeisler CA, Coleman RM, et a\. Delayed sleep phase syndrome: a biological rhythm disorder. Sleep Res 1979;8: Weitzman ED, Czeisler CA, Coleman RM, Spielman AJ, Zim- Sleep, Vol. 19, No.1, 1996

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