ChronoPhysiology and Therapy

Many of the physiological and psychological qualities that influence an athlete’s performance show diurnal variation. Humans present with a temporal phenotype, their chronotype that affects their preference for morning or evening activity. There is considerable interindividual variation in the phase relationship of physiological processes, hormones and core body temperature to external time due to chronotype. This can lead to differences in the times of peaks of physical performance within a day. Chronotype is thus an important variable in determining optimal times for training and competition and may affect an athlete’s choice of sport or his/her success in it. We review the evidence that chronotype influences athletic performance and speculate about how athletes might overcome the effects of chronotype when their schedule is out of phase with their circadian rhythm. Keywords: chronotype, circadian, athletes, training, training time-of-day, individual sports

php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). ChronoPhysiology and Therapy 2017:7 33–45 ChronoPhysiology and Therapy Dovepress

php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). ChronoPhysiology and Therapy 2017:7 19–31 ChronoPhysiology and Therapy Dovepress

php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). ChronoPhysiology and Therapy 2017:7 47–57 ChronoPhysiology and Therapy Dovepress

Circadian rhythms and clocks in adipose tissues: current insights Jana-Thabea Kiehn,* Christiane E Koch,* Marina Walter, Alexandra Brod, Henrik Oster Chronophysiology Group, Medical Department I, University of Lübeck, Lübeck, Germany *These authors contributed equally to this work Abstract: Endogenous circadian timekeepers are found in most cells and organs of the body, including the different types of adipose tissues. This clock network orchestrates 24-hour rhythms of physiology and behavior to adapt the organism to daily recurring changes in the environment. Energy intake and expenditure as well as adipose physiology are under circadian control and, therefore, energy homeostasis and circadian clock function are closely linked. In this review, we summarize the current knowledge about the regulation and targets of adipocyte circadian clocks and how circadian rhythm disruption affects energy homeostasis and adipose tissue function. We provide a more detailed overview of metabolic phenotypes of different mouse models of circadian clock dysfunction and discuss the implications of (adipose) clock disruption on adipocyte–brain cross talk and metabolic homeostasis. Keywords: food intake, metaflammation, clock genes, adipocyte–brain cross talk, adipokines

The full terms of the License are available at http://creativecommons.org/licenses/by/4.0/. The license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 2016 Cissé and Nelson. This work is published and licensed by D Medical Press Limited. The full terms of this license are availabl at https://www.dovepress.com/terms. p p and incorporate the Creative Commons Attribution – Non Commercial (unp rted, v3.0) Licen e (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). ChronoPhysiology and Therapy 2016:6 55–63 ChronoPhysiology and Therapy Dovepress

Rheumatoid arthritis (RA) is an autoimmune disorder of unknown etiology. Morning stiffness, a characteristic feature of RA, shows a 24-hour rhythm. Cytokines, which are considered to play an important role in the pathogenesis of RA, also exhibit a 24-hour rhythm, with a peak in the early morning. These rhythms have been attributed to the endogenous hormone balance and changes in expression levels of clock-related genes. Chronotherapy based on the 24-hour rhythm of RA has been performed using glucocorticoids and disease-modifying antirheumatic drugs. In a previous study, it was reported that modified-release prednisone tablets were administered to patients with RA at night, which demonstrated that the severity of morning stiffness was markedly less than that in patients receiving the standard treatment. Methotrexate (MTX) is the most frequently used RA drug worldwide. In a basic study, cytokines and inflammatory responses in RA model animals showed 24-hour rhythms, based on which MTX was administered and exerted dosing time-dependent antirheumatic effects. Plasma C-reactive protein and cytokine levels also exhibit 24-hour rhythms in patients with RA, with peaks occurring in the early morning. MTX has been shown to markedly inhibit the exacerbation of arthritis in patients with RA when it is administered as inflammatory responses and tumor necrosis factor-α levels begin to increase. Tacrolimus (TAC) is an immunosuppressive agent that is administered to patients who undergo organ transplants. Since one of the mechanisms of action of TAC is the inhibition of inflammatory cytokine production, it is used as an RA therapeutic drug. When TAC was previously administered in the early light or early dark phase to RA model animals, the group treated in the early light phase had notably inhibited increase in arthritis scores compared with that in the early dark phase. The selection of an optimal dosing time associated with 24-hour rhythms in RA symptoms may lead to more effective and safer treatments for RA using glucocorticoids and disease-modifying antirheumatic drugs. Keywords: methotrexate, steroid, circadian rhythm, cytokines

There is now little doubt that disrupted day/night (circadian) time structures are involved in the initiation and promotion of neoplastic disease. It has been established that the incidence of breast cancer, colorectal cancer, and prostate cancer is increased as a result of nocturnal exposure to light and circadian function disruption and that cancer patient survival is diminished. So the question is: what public health measures can be implemented to minimize these health hazards? In addition, untreated cancer patients experience the symptom cluster of brief, interrupted, and poor nighttime sleep; depressed mood/anxiety; daytime fatigue/lethargy; and anorexia/early satiety/diminished taste sensation - each of which is virtually pathognomonic of a disrupted circadian temporal organization. Direct measurements of patients' activities and their timing and intensity using actigraphy reveal that untreated cancer patients experience severe deterioration in the robustness (amplitude) and day-to-day phase stability of their daily rest/ activity rhythms - and one of the most personal and socially destructive results of such circadian disorientation is unplanned, unwanted, and avoidable temporal isolation from family, friends, and society. Thus, therapeutic manipulation of the circadian clock is a powerful tool for improving cancer patients' quality of life (QOL), making life more worth living and perhaps prolonging higher quality survival. We herein take what we have learned to design and execute strategies shown to be beneficial and carefully measure cancer patient benefits. Outcome measures include indices that describe our ability to enhance/maintain circadian organization and orientation, diminish the above-mentioned symptoms, and improve QOL and survival prolongation. We herein implement a suite of noninvasive, riskless and costless, largely behavior-based circadian rhythm entrainment and disturbance avoidance techniques for widespread everyday use by cancer patients and survivors together with real-time actigraphic monitoring, continuous electronic feedback, and positive reinforcement of these simple temporal tuning interventions.

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In chronic obstructive pulmonary disease (COPD), there is large individual variability in the progression of the disease. Low amplitude of rest–activity rhythms has been associated with worse prognosis in a variety of diseases, but it has not been investigated in COPD. The first aim of this exploratory study was to compare disease severity and prognosis indicators between COPD patients with relatively high or low amplitude of their rest–activity cycle, as measured with actigraphy. As a second objective, 24-hour profiles of both activity levels and nighttime-sleep quality were compared between the two subgroups to assess the relative contribution of day- and night-activity levels to high and low rest–activity rhythm amplitude in this population. Rest–activity rhythms were measured with 8–14 days of wrist actigraphy in 14 patients (nine men), aged 58–79 years, suffering from moderate-to-severe COPD. Relative amplitude of 24-hour activity profiles ranged from 0.72 to 0.98. Participants were divided at the median into high-amplitude (mean ± standard deviation 0.9±0.04) and low-amplitude (0.79±0.05) subgroups. There was no significant difference between the two subgroups for pulmonary function or exercise capacity. However, the low-amplitude group had more severe symptoms of dyspnea and worse prognostic scores than the high-amplitude group ( P <0.05). The 24-hour activity profiles revealed higher levels of activity in the high-amplitude group for the 12–3 pm interval ( P <0.05). There was no significant difference between the two groups for subjective or actigraphic estimates of sleep quality, sleep duration, or proportion of daytime sleep. This exploratory study is a first step toward the identification of larger rest–activity rhythm amplitude as a marker of better prognosis in COPD and as another potential target for exercise-based rehabilitation programs in this population. Keywords: actigraphy, accelerometry, circadian rhythms, COPD, respiratory disorders, prognosis, physical activity, sleep

The immune system is composed of two arms, the innate and the adaptive immunity. While the innate response constitutes the first line of defense and is not specific for a particular pathogen, the adaptive response is highly specific and allows for long-term memory of the pathogen encounter. T lymphocytes (or T cells) are central players in the adaptive immune response. Various aspects of T cell functions vary according to the time of day. Circadian clocks located in most tissues and cell types generate 24-hour rhythms of various physiological processes. These clocks are based on a set of clock genes, and this timing mechanism controls rhythmically the expression of numerous other genes. Clock genes are expressed in cells of the immune system, including T cells. In this review, we provide an overview of the circadian control of the adaptive immune response, with emphasis on T cells, including their development, trafficking, response to antigen, and effector functions. Keywords: circadian clock, adaptive immune response, T lymphocyte, antigen, cytokine, proliferation

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This review examines biological rhythms in persons with obsessive–compulsive disorder (OCD) and their potential relevance to the pathophysiology and treatment of this disorder. In some cases of OCD, the expression of affective, cognitive, and behavioral symptoms may be influenced by circadian and seasonal rhythms, and this could possibly interact with other neurophysiological factors. Further work is required to characterize circadian profiles linked to OCD, but findings thus far highlighted delays in both the sleep–wake cycle and melatonin secretion, as well as reduced circadian rhythmicity of body temperature. It is proposed that these changes in behavioral and endogenous rhythms may increase one’s vulnerability to obsessive–compulsive symptoms. Accordingly, obsessive–compulsive symptoms appear to be more severe in individuals with lower circadian amplitude and often worsen in the afternoon and evening. An increasing number of studies reported encouraging outcomes following the integration of sleep and circadian-based treatments in the management of OCD. There is a need for larger controlled trials evaluating the efficacy of chronotherapies in the context of OCD. Keywords: chronobiology, circadian rhythms, sleep–wake cycle

The sleep electroencephalogram (EEG) provides biomarkers of depression, which may help with diagnosis, prediction of therapy response, and prognosis in the treatment of depression.In patients with depression, characteristic sleep EEG changes include impaired sleep continuity, disinhibition of rapid-eye-movement (REM) sleep, and impaired non-REM sleep.Most antidepressants suppress REM sleep in depressed patients, healthy volunteers, and in animal models.REM suppression appears to be an important, but not an absolute requirement, for antidepressive effects of a substance.Enhanced REM density, a measure for frequency of REM, characterizes high-risk probands for affective disorders.REM-sleep changes were also found in animal models of depression.Sleep-EEG variables were shown to predict the response to treatment with antidepressants.Furthermore, certain clusters of sleep EEG variables predicted the course of the disorder for several years.Some of the predicted sleep EEG markers appear to be related to hypothalamic-pituitary-adrenal system activity.

Keywords: melatonin, melatonergic system, mood disorders, depression, seasonal affective disorder, bipolar disorder

The light information pathways and their relationship with the body rhythms have generated a new insight into the neurobiology and the neurobehavioral sciences, as well as into the clinical approaches to human diseases associated with disruption of circadian cycles. Light-based strategies and/or drugs acting on the circadian rhythms have widely been used in psychiatric patients characterized by mood-related disorders, but the timing and dosage use of the various treatments, although based on international guidelines, are mainly dependent on the psychiatric experiences. Further, many efforts have been made to identify biomarkers able to disclose the circadian-related aspect of diseases, and therefore serve as diagnostic, prognostic, and therapeutic tools in clinic to assess the different mood-related symptoms, including pain, fatigue, sleep disturbance, loss of interest or pleasure, appetite, psychomotor changes, and cognitive impairments. Among the endogenous factors suggested to be involved in mood regulation, the neurotrophins, nerve growth factor, and brain-derived neurotrophic factor show anatomical and functional link with the circadian system and mediate some of light-induced effects in brain. In addition, in humans, both nerve growth factor and brain-derived neurotrophic factor have showed a daily rhythm, which correlate with the morningness–eveningness dimensions, and are influenced by light, suggesting their potential role as biomarkers for chronotypes and/or chronotherapy. The evidences of the relationship between the diverse mood-related disorders, with a specific focus on depression, and neurotrophins are reviewed and discussed herein in terms of their circadian significance, and potential translation into clinical practice. Keywords: retinal ganglional cells, mesocorticolimbic circuits, chronotherapy, ocular eye drops administration, neurotrophins

Blood pressure, like most physiological processes, exhibits a circadian pattern of variation. Disruption of the normal circadian rhythm of blood pressure is associated with end organ damage and increased risk of adverse cardiovascular outcomes. In this review, we discuss the role of the renin angiotensin aldosterone system and the molecular clock in maintaining circadian blood pressure patterns. We also consider disrupted circadian blood pressure rhythms and hypertension in distinct populations and the role of chronotherapy in the treatment of hypertension. Keywords: clock, kidney, adrenal, aldosterone, chronotherapy, sleep

Changes in the sleep–wake cycle across development from childhood to adulthood, typically involve a steady shortening of the sleep period and a delay of sleep phase, with a period of more rapid change across adolescence. Accompanying these changes is the maturation of neuroendocrine rhythms such as melatonin, cortisol, and pubertal hormones. These endogenous rhythms are closely associated with behavioral changes in rest and activity rhythms, although environmental factors such as light exposure and academic and social demands likely play an interactive role. Other behavioral aspects, such as physical activity and eating behaviors, are also associated with changes in sleep–wake rhythms, and may be mediational factors in the development of physical illnesses. The sleep–wake cycle and related factors are implicated in the development of mental illnesses. There are several potential avenues of future research that may be valuable in terms of improving interventions and treatments for both mental and physical illnesses. Keywords: circadian rhythm, developmental, adolescence, youth

The patterns of activity/sleep, eating/fasting, etc show that our lives are under the control of an internal clock. Cancer is a systemic disease that affects sleep, feeding, and metabolism. All these processes are regulated by the circadian clock on the one hand, but on the other hand, they can serve as signals to tighten up the patient's circadian clock by robust daily routine. Usually, anticancer treatments take place in hospitals, where the patient's daily rest/activity pattern is changed. However, it has been shown that oncology patients with a disturbed circadian clock have poorer survival outcomes. The administration of different anticancer therapies can disturb the circadian cycle, but many cases show that circadian rhythms in tumors are deregulated per se. This fact can be used to plan anticancer therapies in such a manner that they will be most effective in antitumor action, but least toxic for the surrounding healthy tissue. Metabolic processes are highly regulated to prevent waste of energy and to ensure sufficient detoxification; as a consequence, xenobiotic metabolism is under tight circadian control. This gives the rationale for planning the administration of anticancer therapies in a chronomodulated manner. We review some of the potentially useful clinical praxes of anticancer therapies and discuss different possible approaches to be used in drug development and design in the future. Keywords: circadian rhythms, cancer, chronotherapy, detoxification metabolism