G.A. Kerkhof

Inter-individual differences in the human circadian system: A review

Measurements of physiological, biochemical and psychological variables at two or more different times of day reveal substantial inter-individual differences. This paper reviews studies which have dealt with these differences in terms of the morningness-eveningness, personality (introversion-extraversion), age or sex of their subjects. Studies of individual differences in the response of the circadian system to disturbance (e.g. shift work) are also discussed. The most reliable differences were observed in association with the morningness-eveningness factor. From the studies reviewed here it appeared that several rhythm parameters covaried consistently as a function of morningness-eveningness, suggesting underlying differences in the intrinsic period of the circadian system. It is argued that the differences in rhythm parameters associated with the personality dimension of introversion-extraversion are the result of exogenous influences. The results with regard to age-related and sex-related differences were not sufficient to allow conclusions to be made.

Morning-type and evening-type individuals differ in the phase position of their endogenous circadian oscillator

In dealing with inter-individual phase differences in overt circadian rhythms, it is often difficult to distinguish the impact of the endogenous circadian oscillator from that of an individuals habitual lifestyle. In an attempt to resolve this uncertainty about the role of masking influences, two groups of subjects, morning-type and evening-types, were selected and monitored during entrained, habitual sleep-wake conditions and during 24 h of controlled wakefulness in a laboratory-based constant-routine procedure. Under both conditions significant differences were observed in the circadian phases of body temperature and subjective alertness. During constant routine mean between-group differences for these two variables were 2.21 and 4.28 h, respectively. Thus, evidence is provided for the endogenous nature of morningness-eveningness.

Delayed sleep phase syndrome: A placebo‐controlled cross‐over study on the effects of melatonin administered five hours before the individual dim light melatonin onset

In a double‐blind placebo‐controlled cross‐over study, 30 patients with Delayed Sleep Phase Syndrome (DSPS) were included, of whom 25 finished the study. Melatonin 5 mg was administered during two weeks in a double‐blind setting and two weeks in an open setting successively or interrupted by two weeks of placebo. The studys impact was assessed by measurements of the 24‐h curves of endogenous melatonin production and rectal temperature (n=14), polysomnography (n=22), actigraphy (n=13), sleep log (n=22), and subjective sleep quality (n=25). Mean dim light melatonin onset (DLMO) (±SD), before treatment, occurred at 23.17 hours (±138 min). Melatonin was administered five hours before the individual DLMO. After treatment, the onset of the nocturnal melatonin profile was significantly advanced by approximately 1.5 hour. Body temperature trough did not advance significantly. During melatonin use, actigraphy showed a significant advance of sleep onset and polysomnography, a significant decreased sleep latency. Sleep architecture was not influenced. During melatonin treatment patients felt significantly more refreshed in the morning. These results show that analysis of DLMO of patients suffering from DSPS is important both for diagnosis and therapy. These results are discussed in terms of the biochemistry of the pineal.

GENETIC ANALYSIS OF MORNINGNESS AND EVENINGNESS

We studied the influence of genetic factors on individual differences in morningness-eveningness in a sample of Dutch twin families. Data were collected from adolescent twins (mean age 17.8 yr) and their parents (mean age of fathers 48.0 yr and of mothers 46.0 yr) and a sample of older twins (mean age 46.5 yr). Scores on morningness-eveningness were rated on a 5-point scale. Parents were more morning oriented than their children, and women were more morning oriented than men. With a twin-family study, separation of genetic and environmental influences on variation in morningness-eveningness is possible. Including parents and older twins in the study makes it possible to explore generation differences in these effects. The correlation between monozygotic twins was more than twice the correlation between dizygotic twins. This indicates that genetic effects may not operate in an additive manner. Therefore, a model that included genetic dominance was explored. Biometrical model fitting showed no sex differences for the magnitude of genetic and environmental factors. The total heritability—the sum of additive and nonadditive genetic influences—for morningness-eveningness was 44% for the younger generation and 47% for the older generation. However, the genetic correlation between the generations turned out to be lower than 0.5, suggesting that different genes for morningness-eveningness are expressed in both generations. (Chronobiology International, 18(5), 809–822, 2001)

Sleep, excessive daytime sleepiness and fatigue in Parkinson's disease

SummaryThe objective of this questionnaire-based survey was to evaluate the prevalence and causes of sleep disturbances in 90 nondepressive patients with Parkinsons disease (PD) and 71 age-matched healthy subjects. We also assessed the prevalence and characteristics of excessive daytime sleepiness (both groups) and excessive fatigue (PD patients).A high prevalence of sleep disturbances in PD patients was found; this is to a large extent probably the result of aging. As compared with controls, patients had a more severely disturbed sleep maintenance because of nycturia, pain, stiffness, and problems with turning in bed. The prevalence of excessive dreaming is similar in both groups, but altered dream experiences almost exclusively occurred in PD.Patients rated themselves more often to be morning-types than controls. This finding may account for the reported adaptation effects in experimental settings and the reduced REM latency in PD patients.The prevalence of daytime sleepiness was similar in both groups. Excessive daytime sleepiness showed a clear diurnal pattern with a peak in the early afternoon. As for excessive fatigue, the majority of the patients did not report a preferential time for this symptom. Our findings further argue against an association of fatigue with any circadian factor, and instead suggest a relationship with the motor deficits of PD.

Melatonin for chronic sleep onset insomnia in children: a randomized placebo-controlled trial.

To establish the efficacy of melatonin treatment in childhood sleep onset insomnia, 40 elementary school children, 6 to 12 years of age, who suffered more than 1 year from chronic sleep onset insomnia, were studied in a double-blind, placebo-controlled study. The children were randomly assigned to receive either 5-mg melatonin or placebo. The study consisted of a 1-week baseline, consecutively followed by a 4-week treatment period. After that period, treatment was continued if the parents wished so. The studys impact was assessed by measurements of lights-off time, sleep onset, and wake-up time, recorded in a diary (n = 33). Sleep onset was also recorded with an actigraph (n = 25). Endogenous dim light melatonin onset was measured in saliva (n = 27). Sustained attention was evaluated with the Bourdon-Vos reaction time test (n = 36). In the melatonin group, mean (95% CI) lights-off time advanced 34 (6-63) minutes, diary sleep onset 63 (32-94) minutes, actigraphic sleep onset 75 (36-114) minutes, and melatonin onset 57 (24 to 89) minutes; total sleep time increased 41 (19-62) minutes. In the placebo group, these parameters did not shift significantly. The change during the 4-week treatment period differed between the treatment groups significantly as to lights-off time, diary and actigraphic sleep onset, sleep duration, and melatonin onset. There were no significant differences between the treatment groups in the change of sleep latency, wake-up time, and sustained attention reaction times. Mild headache occurred in 2 children during the first 2 days of the melatonin treatment. Eighteen months after the start of the trial, in 13 of the 38 children who could be followed up, melatonin treatment was stopped because their sleep problem was solved and in 1 child because sleep was not improved. Twelve children used melatonin 5 mg, the other 1.0 to 2.5 mg. One child developed mild generalized epilepsy 4 months after the start of the trial. The results show that melatonin, 5 mg at 6 PM, was relatively safe to take in the short term and significantly more effective than placebo in advancing sleep onset and dim light melatonin onset and increasing sleep duration in elementary school children with chronic sleep onset insomnia. Sustained attention was not affected. (J Child Neurol 2001;16:86-92).

Chronic insomnia and performance in a 24-h constant routine study

Insomniacs report daytime functioning problems, but studies of neurobehavioral functioning in insomniacs have shown little objective evidence of impairment. In addition, very little is known about the influence of the circadian clock on performance in chronic insomniacs. In the present study, we investigated whether chronic insomnia is associated with an overall performance deficit, and what the effect is of circadian rhythmicity, under strictly controlled laboratory conditions. A 24‐h experiment was carried out under constant routine conditions. Psychomotor performance, body temperature, and subjective functioning of 11 insomniacs and 13 healthy subjects were assessed. The insomniacs showed significant overall performance impairments in vigilance, working memory, and motor control. In addition, body temperature, performance and subjective functioning showed a circadian pattern similar to healthy subjects, with trough values in the late night/early morning and peak values in the early evening. Self‐reported functioning among the insomniacs indicated mood disturbances, concentration problems, elevated fatigue and elevated sleepiness. The results indicated that chronic insomnia is associated with a substantial lowering of the 24‐h level of performance and subjective functioning, irrespective of the type of task and/or the particular parameter, and without differential effects of circadian rhythmicity. Apparently, chronic insomnia has a negative impact upon performance as measured under strictly controlled, unmasked conditions.

Plasma Arginine Vasopressin and motor activity in major depression

BACKGROUND Previously, we found that mean plasma concentrations of arginine vasopressin (AVP), but not of oxytocin (OT), were higher in depressed patients than in healthy controls. Plasma AVP concentrations were positively correlated to clinically rated psychomotor retardation. To further explore this previously reported relation we studied psychomotor retardation by means of an activity monitor, which is a more fine-focused and more objective instrument to analyze motor retardation than a clinical rating scale. METHODS Plasma AVP and OT concentrations, and day- and nighttime wrist activity were measured in 48 in- and outpatients with major depression and 30 healthy controls during a period of 5 consecutive days and nights. RESULTS Principal components analysis revealed three components of motor activity: motor activity during wakefulness, motor activity during sleep, and the awake/sleep time ratio. In patients and controls an inverse relationship between plasma AVP concentrations and motor activity during wakefulness was found. Patients with elevated AVP plasma levels showed increased motor activity during sleep. CONCLUSIONS These results suggest that high plasma AVP levels are related to the clinical picture of daytime psychomotor retardation and nighttime motor activity in major depression. Mean plasma OT concentrations were not related to measures of motor activity.

REPEATED ASSESSMENT OF THE ENDOGENOUS 24-HOUR PROFILE OF BLOOD PRESSURE UNDER CONSTANT ROUTINE ∗

The impact of environmental and behavioral factors on the 24-h profile of blood pressure (BP) has been well established. Various attempts have been made to control these exogenous factors, in order to investigate a possible endogenous circadian variation of BP. Recently, we reported the results of the first environmentally and behaviorally controlled laboratory study with 24-h recordings of BP and heart rate (HR) during maintained wakefulness. In this constant-routine study, a pronounced endogenous circadian rhythm of HR was found, but circadian variation of BP was absent. This result suggested that the circadian rhythm of BP observed in earlier controlled studies, with sleep allowed, was evoked by the sleep–wake cycle as opposed to the endogenous circadian pacemaker. In order to verify our previous finding during maintained wakefulness, we repeated the experiment five times with six normotensive, healthy young subjects. Statistical analyses of the hourly measurements of BP and HR confirmed the replicable presence of an endogenous circadian rhythm of HR, as well as the consistent absence of an endogenous circadian variation of BP. Thus, this study provided additional evidence that the 24-h profile of BP—as observed under normal circumstances—is the sole result of environmental and behavioral factors such as the occurrence of sleep, and has no endogenous circadian component. (Chronobiology International, 18(1), 85–98, 2001)

Effects of repeated sleep deprivation in the dark- or light-period on sleep in rats

This study was designed to examine the differences between sleep duration and EEG when sleep was restricted to the rest- or activity-phase for 5 successive days, achieved by repeated sleep deprivation in the dark (DSD) or light-period (LSD). In the DSD-experiment the percentages of the vigilance states were comparable to the level of the baseline light period. In LSD, the amounts of all sleep states increased substantially relative to baseline dark. The sleep episodes were lengthened in DSD and LSD. The duration of NREM-sleep and the sleep episodes remained longer in the light than in the dark, indicating circadian influences. In the first hours after sleep deprivation the delta activity during NREM-sleep was enhanced in LSD and to a lesser extent in DSD. This effect diminished over the consecutive days in both experiments. The EEG energy gained during sleep and its accumulation pattern on each day in DSD and LSD were strikingly similar, thereby reflecting a homeostatic process. After the sleep deprivation days, small changes were observed in the distribution of the vigilance states, the delta activity and EEG energy over the light- and dark-period.