Disruptions in sleep–wake cycles in community-dwelling cancer patients receiving palliative care and their correlates

Significant disruptions in sleep–wake cycles have been found in advanced cancer patients in prior research. However, much remains to be known about specific sleep–wake cycle variables that are impaired in patients with a significantly altered performance status. More studies are also needed to explore the extent to which disrupted sleep–wake cycles are related to physical and psychological symptoms, time to death, maladaptive sleep behaviors, quality of life and 24-h light exposure. This study conducted in palliative cancer patients was aimed at characterizing patients’ sleep–wake cycles using various circadian parameters (i.e. amplitude, acrophase, mesor, up-mesor, down-mesor, rhythmicity coefficient). It also aimed to compare rest–activity rhythm variables of participants with a performance status of 2 vs. 3 on the Eastern Cooperative Oncology Group scale (ECOG) and to evaluate the relationships of sleep–wake cycle parameters with several possible correlates. The sample was composed of 55 community-dwelling cancer patients receiving palliative care with an ECOG of 2 or 3. Circadian parameters were assessed using an actigraphic device for seven consecutive 24-h periods. A light recording and a daily pain diary were completed for the same period. A battery of self-report scales was also administered. A dampened circadian rhythm, a low mean activity level, an early mean time of peak activity during the day, a late starting time of activity during the morning and an early time of decline of activity during the evening were observed. In addition, a less rhythmic sleep–wake cycle was associated with a shorter time to death (from the first home visit) and with a lower 24-h light exposure. Sleep–wake cycles are markedly disrupted in palliative cancer patients, especially, near the end of life. Effective non-pharmacological interventions are needed to improve patients’ circadian rhythms, including perhaps bright light therapy.     

The use of melatonin for the treatment of insomnia

The pineal product melatonin is involved in the regulation of the sleep/wake cycle in humans. In blind individuals and in people travelling through time zones, melatonin rhythms are sometimes unsynchronized with the diel cycle, and nocturnal sleep may be disturbed. Low or distorted melatonin rhythms have repeatedly been reported in middle aged and elderly insomniacs. Melatonin administration effectively synchronized the sleep wake cycle in blind individuals and in subjects suffering from jet lag and advanced sleep onset in subjects suffering from delayed sleep phase syndrome. In elderly insomniacs, melatonin replacement therapy significantly decreased sleep latency, and/or increased sleep efficiency and decreased wake time after sleep onset. In addition, melatonin substitution facilitated benzodiazepine discontinuation in chronic users. These data show an association between melatonin rhythm disturbances and difficulties to promote or maintain sleep at night. Specific melatonin formulations may be useful to treat circadian-rhythm-related sleep disorders and age-related insomnia.     

CIRCADIAN RHYTHMS AND SLEEP IN HUMAN AGING

This issue of Chronobiology International is dedicated to the age-related changes in circadian rhythms as they occur in humans. It seems timely to give an overview of the knowledge and hypotheses on these changes now that we enter a century in which the number and percentage of elderly in the population will be unprecedented. Although we should take care not to follow the current tendency to think of old age as a disease—ignoring the fine aspects of being old—there is definitely an age-related increase in the risk of a number of conditions that are at least uncomfortable.

Circadian rhythms have been attributed adaptive values that usually go unnoticed, but can surface painfully clear when derangements occur. Alterations in the regulation of circadian rhythms are thought to contribute to the symptoms of a number of conditions for which the risk is increased in old age (e.g., sleep disturbances, dementia, and depression). A multidisciplinary approach to investigate the mechanisms of age-related changes in circadian regulation eventually may result in treatment strategies that will improve the quality of life of the growing number of elderly.

Although diverse topics are addressed in this issue, the possible mechanisms by which a deranged circadian timing system may be involved in sleep disturbances receives the most attention. This seems appropriate in view of the numerous studies that have addressed this relation in the last decade and also because of the high frequency and strong impact of sleep disturbances in the elderly. This introduction to the special issue first briefly addresses the impact of disturbed sleep in the elderly to show that the development of therapeutic methods other than the currently available pharmacological treatments should be given high priority. I believe that chronobiological insights may play an important role in the development of rational therapeutical methods.(Chronobiology International, 17(3), 233–243, 2000)     

Circadian rhythms and sleep in human aging

This issue of Chronobiology International is dedicated to the age-related changes in circadian rhythms as they occur in humans. It seems timely to give an overview of the knowledge and hypotheses on these changes now that we enter a century in which the number and percentage of elderly in the population will be unprecedented. Although we should take care not to follow the current tendency to think of old age as a disease—ignoring the fine aspects of being old—there is definitely an age-related increase in the risk of a number of conditions that are at least uncomfortable.

Circadian rhythms have been attributed adaptive values that usually go unnoticed, but can surface painfully clear when derangements occur. Alterations in the regulation of circadian rhythms are thought to contribute to the symptoms of a number of conditions for which the risk is increased in old age (e.g., sleep disturbances, dementia, and depression). A multidisciplinary approach to investigate the mechanisms of age-related changes in circadian regulation eventually may result in treatment strategies that will improve the quality of life of the growing number of elderly.

Although diverse topics are addressed in this issue, the possible mechanisms by which a deranged circadian timing system may be involved in sleep disturbances receives the most attention. This seems appropriate in view of the numerous studies that have addressed this relation in the last decade and also because of the high frequency and strong impact of sleep disturbances in the elderly. This introduction to the special issue first briefly addresses the impact of disturbed sleep in the elderly to show that the development of therapeutic methods other than the currently available pharmacological treatments should be given high priority. I believe that chronobiological insights may play an important role in the development of rational therapeutical methods.(Chronobiology International, 17(3), 233-243, 2000)     

Rhythms,rhythmicity and aggression

The relationships between biological rhythms and human aggressive behavior are addressed and discussed in this article: First, circadian rhythms and aggression are considered. Studies of sleep/waking cycle disturbances in aggression are reported. Severe aggression is associated with profound changes in sleep architecture. Causal link is difficult to establish given that sleep disturbance and aggressive behavior could be the symptoms of the same disorder. Specific aggressive behavior developed during sleep is also described. In addition, hormonal circadian rhythm studies are reported. Thus, low cortisol levels, in particular low cortisol variability, are associated with aggressive behavior, suggesting an inhibitory role of cortisol. Testosterone has daily and seasonal fluctuations, but no link with aggression has been established. Neurophysiological underlying mechanisms are discussed in the last part of this article, with a focus on the relationship between brain rhythm and aggression. Increase of slow-wave EEG activities is observed in individuals with aggressive behavior. Epilepsy, as a disease of brain rhythm could be associated with aggressive behavior, in pre, post and inter ictal periodes. Incidence of aggression is not likely more prevalent in epileptic individuals compared to those with other neurological conditions. Ictal changes take the form of profound behavioral changes, including aggressive behavior which has been interpreted as the emergence of “archeical” or innate motor patterns. In this multidisciplinary approach, the main difficulty is the categorization of the differents types of aggression. Finally, taken together, these studies suggest that biological rhythms, especially circadian rhythms, could provide therapeutic benefits to human aggressive behavior. Biological rhythymicity seems to be a necessary permanent training offering interesting perspectives for the adaptation to changes in the field of aggression.     

Human sleep‐wake cycles in the high arctic: Effects of unusual photoperiodicity in a natural setting

Abstract

Studies of human circadian rhythms are typically conducted in artificial environments that are low in ecological validity. In the current study, six subjects and the field director lived in temporal isolation in a completely natural environment with constant daylight (a high Arctic research camp) for six weeks. Detailed daily sleep logs were kept. In keeping with past findings, five of the six subjects developed a free‐running sleep‐wake cycle longer than 24 hours. Unlike past results, the isolated subjects did not exhibit any synchronicity in their rhythms. There was a high degree of intersubject variability in circadian patterns. The findings have important implications for the comparison of the results of laboratory and field investigations of sleep‐wake cycles.     

Infradian rhythmicity in sleep/wake ratio in developing infants

Although there are several reports on ultradian and circadian rhythms in newborns, we found only one report in which infradian periodicities are described for heart-rate measurements in the early stages of human development. Here, we report infradian rhythms in the monthly range in the sleep/wake cycle of four infants studied along 24 consecutive weeks. Our procedure was applied to sleep diary records from four healthy newborns. The data were arranged in binary time series representing sleep (-1) or wake (1) states. These time series were integrated in order to obtain the cumulative sleep/wake time. A measure of the sleep/wake ratio (SWR) was obtained by computing the average slope of the cumulative sleep/wake time. To extract periodicities we applied the Fourier periodogram to the temporal course of the SWR. We found a notorious difference in the SWR pattern among infants. In two infants the SWR showed a marked linear decay, spending more time asleep than awake, while in the two other infants oscillated near zero. We found robust oscillations in all children. In all cases the Fourier periodogram results present significant power in the infradian range. From these results, we suggest that sleep and wake durations are probably modulated by some internal stimuli.     

Infradian Rhythmicity in Sleep/Wake Ratio in Developing Infants

Although there are several reports on ultradian and circadian rhythms in newborns, we found only one report in which infradian periodicities are described for heart-rate measurements in the early stages of human development. Here, we report infradian rhythms in the monthly range in the sleep/wake cycle of four infants studied along 24 consecutive weeks. Our procedure was applied to sleep diary records from four healthy newborns. The data were arranged in binary time series representing sleep (?1) or wake (1) states. These time series were integrated in order to obtain the cumulative sleep/wake time. A measure of the sleep/wake ratio (SWR) was obtained by computing the average slope of the cumulative sleep/wake time. To extract periodicities we applied the Fourier periodogram to the temporal course of the SWR. We found a notorious difference in the SWR pattern among infants. In two infants the SWR showed a marked linear decay, spending more time asleep than awake, while in the two other infants oscillated near zero. We found robust oscillations in all children. In all cases the Fourier periodogram results present significant power in the infradian range. From these results, we suggest that sleep and wake durations are probably modulated by some internal stimuli.     

When brain clocks lose track of time: cause or consequence of neuropsychiatric disorders

Patients suffering from neuropsychiatric disorders often exhibit a loss of regulation of their biological rhythms which leads to altered sleep/wake cycle, body temperature rhythm and hormonal rhythms. Whereas these symptoms have long been considered to result from the pathology of the underlying disease, increasing evidence now indicates that the circadian system may be more directly involved in the etiology of psychiatric disorders. This emerging view originated with the discovery that the genes involved in the generation of biological rhythms are expressed in many brain structures where clocks function-and perhaps malfunction. It is also due to the interesting phenotypes of clock mutant mice. Here we summarize recent reports showing that alteration of circadian clocks within key brain regions associated with neuropsychiatric disorders may be an underlying cause of the development of mental illness. We discuss how these alterations take place at both systems and molecular levels.     

A history of recent advancements on <Emphasis Type="Italic">Nephrops norvegicus</Emphasis> behavioral and physiological rhythms

Biological rhythms are a widespread feature of living organisms, being expressed at any level of their organization. Behavioral and physiological rhythms can affect the results on species stock assessment when the timing of sampling is not taken into account. That timing is of importance since animals may be present or not in a certain area of sampling depending on their activity cycle. As an example of this, the rhythmic behavior and physiology of one of the most commercially important European decapods, the Norway lobster (Nephrops norvegicus) was studied. These rhythms affect its commercial catchability at a diel and at a seasonal scale. Nephrops inhabits muddy bottoms where animals dig burrows that save them from the trawl tow capture when occupied. Catch patterns have been widely used as proxy of activity rhythms of populations of different depths. Catches show a modulation upon the day-night cycle since animals emerge under optimum environmental illumination in order to feed. Emergence is also affected in a not fully clarified manner by other variables of environmental and demographic nature (e.g. food presence, hunger state, sex, size, reproductive stage, territorialism and mating). All these features make Nephrops a good model of reference for studies on biological rhythms of other commercially important deep water decapods in relation to their ecological context. In this review, we summarize the actual knowledge on Nephrops behavioral and physiological rhythms. We will compare data obtained from laboratory tests on single individuals with data obtained from trawling of populations of different depths. We will also describe some new hypotheses on the rhythmic regulation of the species behaviour, as well as potential scenarios for future research.     

Seasonal Affective Disorder: An Overview

Seasonal Affective Disorder (SAD) is a condition of regularly occurring depressions in winter with a remission the following spring or summer. In addition to depressed mood, the patients tend to experience increased appetite and an increased duration of sleep during the winter. SAD is a relatively common condition, affecting 1–3% of adults in temperate climates, and it is more prevalent in women.

The pathological mechanisms underlying SAD are incompletely understood. Certain neurotransmitters have been implicated; a dysfunction in the serotonin system in particular has been demonstrated by a variety of approaches. The role of circadian rhythms in SAD needs to be clarified. The phase-delay hypothesis holds that SAD patients' circadian rhythms are delayed relative to the sleep/wake or rest/activity cycle. This hypothesis predicts that the symptoms of SAD will improve if the circadian rhythms can be phase-advanced. There is some experimental support for this.

SAD can be treated successfully with light therapy. In classical light therapy, the SAD sufferer sits in front of a light box, exposed to 2000–10,000 lux for 30–120min daily during the winter. Other forms of light treatments, pharmacotherapy, and other therapies are currently being tested for SAD.     

Sleep,daily activity rhythms and postpartum mood: A longitudinal study across the perinatal period

Women with a diagnosis of bipolar and major depressive disorders are at higher risk to develop postpartum depression. The primary objective of this longitudinal study was to determine whether daily activity rhythms and sleep parameters differ between women with and without a history of a mood disorder across the perinatal period. A secondary objective was to determine whether changes in these parameters were associated with postpartum mood. In total, 33 women were included in this study, 15 of which had a history of a mood disorder (high-risk group) and 18 who did not (low-risk group). Sleep and daily rhythms were assessed subjectively and objectively during the third trimester (≥26 weeks gestation) and again at 6–12 weeks postpartum. Mood was also assessed at both time points. Women in the high-risk group showed greater subjective daily rhythms and sleep disturbances across the perinatal period. Objective sleep efficiency was worse in the high-risk group in the postpartum period. Changes in both subjective daily rhythms and objective sleep efficiency were predictive of changes in depressive symptoms across the perinatal period. These findings encourage the development of preventative therapeutics to ensure circadian rhythm and sleep stability throughout the perinatal period.     

Thematic Review Series: Intestinal Lipid Metabolism: New Developments and Current Insights: Circadian regulators of intestinal lipid absorption

Among all the metabolites present in the plasma, lipids, mainly triacylglycerol and diacylglycerol, show extensive circadian rhythms. These lipids are transported in the plasma as part of lipoproteins. Lipoproteins are synthesized primarily in the liver and intestine and their production exhibits circadian rhythmicity. Studies have shown that various proteins involved in lipid absorption and lipoprotein biosynthesis show circadian expression. Further, intestinal epithelial cells express circadian clock genes and these genes might control circadian expression of different proteins involved in intestinal lipid absorption. Intestinal circadian clock genes are synchronized by signals emanating from the suprachiasmatic nuclei that constitute a master clock and from signals coming from other environmental factors, such as food availability. Disruptions in central clock, as happens due to disruptions in the sleep/wake cycle, affect intestinal function. Similarly, irregularities in temporal food intake affect intestinal function. These changes predispose individuals to various metabolic disorders, such as metabolic syndrome, obesity, diabetes, and atherosclerosis. Here, we summarize how circadian rhythms regulate microsomal triglyceride transfer protein, apoAIV, and nocturnin to affect diurnal regulation of lipid absorption.     

Changes in the sleep–wake rhythm,sleep quality,mood, and quality of life of patients receiving treatment for lung cancer: A longitudinal study

Studies on the diurnal sleep–wake rhythm of patients with lung cancer have mostly examined patients cross-sectionally, whereas the effects of lung cancer treatment over time have rarely been considered. Through long-term longitudinal tracking of patients with lung cancer, this study examined changes in their sleep–wake rhythm, sleep quality, anxiety, depressive symptoms, fatigue and quality of life (QoL) at various treatment stages. In addition, factors affecting their QoL were explored. Hierarchical linear modeling was adopted to analyze a convenience sample of 82 patients with lung cancer. The changes in their sleep–wake rhythm, sleep, mood (anxiety, depressive symptoms and fatigue) and QoL were observed at five time points: prior to treatment and at weeks 6, 12, 24 and 48 after the start of the treatment. The effects of sex, age, cancer stage, treatment type, comorbidities and time were controlled to determine the predictors of patients’ QoL. The results showed that patients’ sleep–wake rhythms were poor before treatments. Compared with baseline, the sleep–wake rhythms of the patients significantly improved at week 48, and anxiety significantly improved at weeks 6, 12, 24 and 48. By contrast, their fatigue became exacerbated at weeks 8 and 48. Moreover, QoL improved significantly from week 6 until the end of the treatment period. QoL was negatively affected by poor sleep quality (β = ?0.69, p = 0.00) and depressive symptoms (β = ?2.59, p < 0.001) and positively affected by regular sleep–wake rhythms (β = 0.23, p = 0.001). Therefore, clinical health-care professionals should focus more attention to the fatigue levels of patients with lung cancer before, during and after treatment. Health-care professionals may also need to provide such patients with health education regarding sleep hygiene and with emotional support to assist them in maintaining regular sleep–wake rhythms in order to improve their QoL.     

Individual Traits and Environmental Factors Influencing Sleep Timing: A Study of 225 Japanese Couples

Behavioral and physiological processes, such as sleep-wakefulness, thermoregulation, and hormone secretion, exhibit 24-h rhythms in most organisms. These biological rhythms are driven by the circadian clock system and are entrained by the external environment, which in the case of humans includes social time schedules. Couples might be ideal experimental subjects to discriminate between individual traits and environmental factors, as they share lifestyle habits but not genetic backgrounds. In this study, sleep timing was compared between married Japanese couples (n?=?225) who had lived together for 1 yr or more (mean 17 yrs). Additionally, the authors evaluated the influence of individual traits and environmental factors on an individual's sleep timing per each couple. The results reveal that the sleep timings of a couple are mainly associated with the chronotypes of the husband and wife, whereas the sleep timings are significantly influenced by certain environmental factors. The findings suggest that chronotype remains one of the major determinants of an individual's sleep onset and wake times. Understanding an individual's chronotype may help improve the quality of life issues surrounding sleep. (Author correspondence: mishima@ncnp.go.jp)     

A mathematical model of the sleep/wake cycle

We present a biologically-based mathematical model that accounts for several features of the human sleep/wake cycle. These features include the timing of sleep and wakefulness under normal and sleep-deprived conditions, ultradian rhythms, more frequent switching between sleep and wakefulness due to the loss of orexin and the circadian dependence of several sleep measures. The model demonstrates how these features depend on interactions between a circadian pacemaker and a sleep homeostat and provides a biological basis for the two-process model for sleep regulation. The model is based on previous “flip–flop” conceptual models for sleep/wake and REM/NREM and we explore whether the neuronal components in these flip–flop models, with the inclusion of a sleep-homeostatic process and the circadian pacemaker, are sufficient to account for the features of the sleep/wake cycle listed above. The model is minimal in the sense that, besides the sleep homeostat and constant cortical drives, the model includes only those nuclei described in the flip–flop models. Each of the cell groups is modeled by at most two differential equations for the evolution of the total population activity, and the synaptic connections are consistent with those described in the flip–flop models. A detailed analysis of the model leads to an understanding of the mathematical mechanisms, as well as insights into the biological mechanisms, underlying sleep/wake dynamics.     

Predominance of distal skin temperature changes at sleep onset across menstrual and circadian phases

Menstrual cycle-associated changes in reproductive hormones affect body temperature in women. We aimed to characterize the interaction between the menstrual, circadian, and scheduled sleep-wake cycles on body temperature regulation. Eight females entered the laboratory during the midfollicular (MF) and midluteal (ML) phases of their menstrual cycle for an ultradian sleep-wake cycle procedure, consisting of 36 cycles of 60-minute wake episodes alternating with 60-minute nap opportunities, in constant bed-rest conditions. Core body temperature (CBT) and distal skin temperature (DT) were recorded and used to calculate a distal-core gradient (DCG). Melatonin, sleep, and subjective sleepiness were also recorded. The circadian variation of DT and DCG was not affected by menstrual phase. DT and DCG showed rapid, large nap episode-dependent increases, whereas CBT showed slower, smaller nap episode-dependent decreases. DCG values were significantly reduced for most of the wake episode in an overall 60-minute wake/60-minute nap cycle during ML compared to MF, but these differences were eliminated at the wake-to-nap lights-out transition. Nap episode-dependent decreases in CBT were further modulated as a function of both circadian and menstrual factors, with nap episode-dependent deceases occurring more prominently during the late afternoon/evening in ML, whereas nap episode-dependent DT and DCG increases were not significantly affected by menstrual phase but only circadian phase. Circadian rhythms of melatonin secretion, DT, and DCG were significantly phase-advanced relative to CBT and sleep propensity rhythms. This study explored how the thermoregulatory system is influenced by an interaction between circadian phase and vigilance state and how this is further modulated by the menstrual cycle. Current results agree with the thermophysiological cascade model of sleep and indicate that despite increased CBT during ML, heat loss mechanisms are maintained at a similar level during nap episodes, which may allow for comparable circadian sleep propensity rhythms between menstrual phases.     

Alterations of Locomotor Activity Rhythm and Sleep Parameters in Patients With Advanced Glaucoma

The aim of this study was to evaluate the effect of advanced glaucoma on locomotor activity rhythms and related sleep parameters. Nine normal subjects and nine age-matched patients with bilateral advanced primary open-angle glaucoma, >10 yrs since diagnosis, were included in this observational, prospective, case-control study. Patients were required to record the timing and duration of their sleep and daily activities, and wore an actigraph on the wrist of the nondominant arm for 20 d. Activity rhythm period, MESOR (24-h time-series mean), amplitude (one-half peak-to-trough variation), and acrophase (peak time), plus long sleep episodes during the wake state, sleep duration, efficiency, and latency, as well as mean activity score, wake minutes, and mean wake episodes during the sleep interval were assessed in controls and glaucomatous patients. Glaucomatous patients exhibited significant decrease in nighttime sleep efficiency, and significant increase in the mean activity score, wake minutes, and mean wake episode during the night. These results suggest that alterations of circadian physiology could be a risk to the quality of life of patients with glaucoma. (Author correspondence: ruthr@fmed.uba.ar)     

Alteration of Daily and Circadian Rhythms following Dopamine Depletion in MPTP Treated Non-Human Primates

Disturbances of the daily sleep/wake cycle are common non-motor symptoms of Parkinson''s disease (PD). However, the impact of dopamine (DA) depletion on circadian rhythms in PD patients or non-human primate (NHP) models of the disorder have not been investigated. We evaluated alterations of circadian rhythms in NHP following MPTP lesion of the dopaminergic nigro-striatal system. DA degeneration was assessed by in vivo PET ([¹¹C]-PE2I) and post-mortem TH and DAT quantification. In a light∶dark cycle, control and MPTP-treated NHP both exhibit rest-wake locomotor rhythms, although DA-depleted NHP show reduced amplitude, decreased stability and increased fragmentation. In all animals, 6-sulphatoxymelatonin peaks at night and cortisol in early morning. When the circadian system is challenged by exposure to constant light, controls retain locomotor rest-wake and hormonal rhythms that free-run with stable phase relationships whereas in the DA-depleted NHP, locomotor rhythms are severely disturbed or completely abolished. The amplitude and phase relations of hormonal rhythms nevertheless remain unaltered. Use of a light-dark masking paradigm shows that expression of daily rest-wake activity in MPTP monkeys requires the stimulatory and inhibitory effects of light and darkness. These results suggest that following DA lesion, the central clock in the SCN remains intact but, in the absence of environmental timing cues, is unable to drive downstream rhythmic processes of striatal clock gene and dopaminergic functions that control locomotor output. These findings suggest that the circadian component of the sleep-wake disturbances in PD is more profoundly affected than previously assumed.