Disrupted nocturnal melatonin in autism: Association with tumor necrosis factor and sleep disturbances.

Sleep disturbances, abnormal melatonin secretion, and increased inflammation are aspects of autism spectrum disorder (ASD) pathophysiology. The present study evaluated the daily urinary 6-sulfatoxymelatonin (aMT6s) excretion profile and the salivary levels of tumor necrosis factor (TNF) and interleukin-6 (IL-6) in 20 controls and 20 ASD participants, as well as correlating these measures with sleep disturbances. Although 60% of ASD participants showed a significant night-time rise in aMT6s excretion, this rise was significantly attenuated, compared to controls (P < .05). The remaining 40% of ASD individuals showed no significant increase in nocturnal aMT6s. ASD individuals showed higher nocturnal levels of saliva TNF, but not IL-6. Dysfunction in the initiation and maintenance of sleep, as indicated by the Sleep Disturbance Scale for Children, correlated with night-time aMT6s excretion (r = -.28, P < .05). Dysfunction in sleep breathing was inversely correlated with aMT6s (r = -.31, P < .05) and positively associated with TNF level (r = .42, P < .01). Overall such data indicate immune-pineal axis activation, with elevated TNF but not IL-6 levels associated with disrupted pineal melatonin release and sleep dysfunction in ASD. It is proposed that circadian dysregulation in ASD is intimately linked to heightened immune-inflammatory activity. Such two-way interactions of the immune-pineal axis may underpin many aspects of ASD pathophysiology, including sleep disturbances, as well as cognitive and behavioral alterations.

Continuous intrathecal orexin delivery inhibits cataplexy in a murine model of narcolepsy.

Narcolepsy-cataplexy is a chronic neurological disorder caused by loss of orexin (hypocretin)-producing neurons, associated with excessive daytime sleepiness, sleep attacks, cataplexy, sleep paralysis, hypnagogic hallucinations, and fragmentation of nighttime sleep. Currently, human narcolepsy is treated by providing symptomatic therapies, which can be associated with an array of side effects. Although peripherally administered orexin does not efficiently penetrate the blood-brain barrier, centrally delivered orexin can effectively alleviate narcoleptic symptoms in animal models. Chronic intrathecal drug infusion through an implantable pump is a clinically available strategy to treat a number of neurological diseases. Here we demonstrate that the narcoleptic symptoms of orexin knockout mice can be reversed by lumbar-level intrathecal orexin delivery. Orexin was delivered via a chronically implanted intrathecal catheter at the upper lumbar level. The computed tomographic scan confirmed that intrathecally administered contrast agent rapidly moved from the spinal cord to the brain. Intrathecally delivered orexin was detected in the brain by radioimmunoassay at levels comparable to endogenous orexin levels. Cataplexy and sleep-onset REM sleep were significantly decreased in orexin knockout mice during and long after slow infusion of orexin (1 nmol/1 µL/h). Sleep/wake states remained unchanged both quantitatively as well as qualitatively. Intrathecal orexin failed to induce any changes in double orexin receptor-1 and -2 knockout mice. This study supports the concept of intrathecal orexin delivery as a potential therapy for narcolepsy-cataplexy to improve the well-being of patients.

Metabolism and the circadian clock converge.

Circadian rhythms occur in almost all species and control vital aspects of our physiology, from sleeping and waking to neurotransmitter secretion and cellular metabolism. Epidemiological studies from recent decades have supported a unique role for circadian rhythm in metabolism. As evidenced by individuals working night or rotating shifts, but also by rodent models of circadian arrhythmia, disruption of the circadian cycle is strongly associated with metabolic imbalance. Some genetically engineered mouse models of circadian rhythmicity are obese and show hallmark signs of the metabolic syndrome. Whether these phenotypes are due to the loss of distinct circadian clock genes within a specific tissue versus the disruption of rhythmic physiological activities (such as eating and sleeping) remains a cynosure within the fields of chronobiology and metabolism. Becoming more apparent is that from metabolites to transcription factors, the circadian clock interfaces with metabolism in numerous ways that are essential for maintaining metabolic homeostasis.

The impact of stress on sleep: Pathogenic sleep reactivity as a vulnerability to insomnia and circadian disorders.

Sleep reactivity is the trait-like degree to which stress exposure disrupts sleep, resulting in difficulty falling and staying asleep. Individuals with highly reactive sleep systems experience drastic deterioration of sleep when stressed, whereas those with low sleep reactivity proceed largely unperturbed during stress. Research shows that genetics, familial history of insomnia, female gender and environmental stress influence how the sleep system responds to stress. Further work has identified neurobiological underpinnings for sleep reactivity involving disrupted cortical networks and dysregulation in the autonomic nervous system and hypothalamic-pituitary-adrenal axis. Sleep reactivity is most pathologically and clinically pertinent when in excess, such that high sleep reactivity predicts risk for future insomnia disorder, with early evidence suggesting high sleep reactivity corresponds to severe insomnia phenotypes (sleep onset insomnia and short sleep insomnia). High sleep reactivity is also linked to risk of shift-work disorder, depression and anxiety. Importantly, stress-related worry and rumination may exploit sensitive sleep systems, thereby augmenting the pathogenicity of sleep reactivity. With the development of cost-effective assessment of sleep reactivity, we can now identify individuals at risk of future insomnia, shift-work disorder and mental illness, thus identifying a target population for preventive intervention. Given that insomniacs with high sleep reactivity tend to present with severe insomnia phenotypes, patient sleep reactivity may inform triaging to different levels of treatment. Future research on sleep reactivity is needed to clarify its neurobiology, characterize its long-term prospective associations with insomnia and shift-work disorder phenotypes, and establish its prognostic value for mental illness and other non-sleep disorders.

[Sleep-wake rhythm after extracorporeal circulation in New Zealand rabbits].

OBJECTIVE: To evaluate the change of sleep-wake rhythm after extracorporeal circulation (ECC) in New Zealand rabbits, and to explore the role of clock genes in sleep-wake rhythm disorder by ECC.
 Methods: A total of 54 New Zealand rabbits were randomly divided into 3 groups: a normal group (Group N), a sham group (Group S) and a model group (Group ECC). Electrocorticogram (ECOG), electroophthalmogram (EOG) and electromyogram (EMG) were respectively recorded by multipurpose EEG recorder, and the sleep-wake rhythm was also recorded. The mRNA and protein expressions of period1 (Per1) and cryptochrome1 (Cry1) were detected by semi-quantitative reverse transcriptase PCR (RT-PCR) and Western blot in pineal gland of rabbits. The differences between the 3 groups were compared.
 Results: 1) Compared with the Group N and Group S at 24, 48 h respectively, the total amount of sleep (TAS), light time, slow wave sleep (SWS) in the Group ECC at 24, 48 h were significantly reduced (all P<0.05), and the proportion of light sleep increased (all P<0.05), the proportion of SWS decreased (all P<0.05); 2) Compared with the Group N and Group S, the expression of Per1 mRNA in the Group ECC at 24, 48 h and Cry1 mRNA at 24 h significantly increased (all P<0.05); 3) Compared with the Group N and Group S, the expression of Per1 protein in the Group ECC at 48 h and Cry1 protein at 24 h significantly increased (all P<0.05); 4) In the Group ECC, the sleep-wake rhythm disorder and clock genes expression were ameliorated at 72 h after surgery.
 Conclusion: ECC can cause sleep-wake rhythm disorder in New Zealand rabbits, which may be related to the abnormal expression of Per1 and Cry1, and their transcription proteins.

Sleep and circadian rhythm disturbance in bipolar disorder.

BACKGROUND: Subjective reports of insomnia and hypersomnia are common in bipolar disorder (BD). It is unclear to what extent these relate to underlying circadian rhythm disturbance (CRD). In this study we aimed to objectively assess sleep and circadian rhythm in a cohort of patients with BD compared to matched controls. METHOD: Forty-six patients with BD and 42 controls had comprehensive sleep/circadian rhythm assessment with respiratory sleep studies, prolonged accelerometry over 3 weeks, sleep questionnaires and diaries, melatonin levels, alongside mood, psychosocial functioning and quality of life (QoL) questionnaires. RESULTS: Twenty-three (50%) patients with BD had abnormal sleep, of whom 12 (52%) had CRD and 29% had obstructive sleep apnoea. Patients with abnormal sleep had lower 24-h melatonin secretion compared to controls and patients with normal sleep. Abnormal sleep/CRD in BD was associated with impaired functioning and worse QoL. CONCLUSIONS: BD is associated with high rates of abnormal sleep and CRD. The association between these disorders, mood and functioning, and the direction of causality, warrants further investigation.

Social jetlag, obesity and metabolic disorder: investigation in a cohort study.

BACKGROUND: Obesity is one of the leading causes of preventable death worldwide. Circadian rhythms are known to control both sleep timing and energy homeostasis, and disruptions in circadian rhythms have been linked with metabolic dysfunction and obesity-associated disease. In previous research, social jetlag, a measure of chronic circadian disruption caused by the discrepancy between our internal versus social clocks, was associated with elevated self-reported body mass index, possibly indicative of a more generalized association with obesity and metabolic dysfunction. METHODS: We studied participants from the population-representative Dunedin Longitudinal Study (N=1037) to determine whether social jetlag was associated with clinically assessed measurements of metabolic phenotypes and disease indicators for obesity-related disease, specifically, indicators of inflammation and diabetes. RESULTS: Our analysis was restricted to N=815 non-shift workers in our cohort. Among these participants, we found that social jetlag was associated with numerous clinically assessed measures of metabolic dysfunction and obesity. We distinguished between obese individuals who were metabolically healthy versus unhealthy, and found higher social jetlag levels in metabolically unhealthy obese individuals. Among metabolically unhealthy obese individuals, social jetlag was additionally associated with elevated glycated hemoglobin and an indicator of inflammation. CONCLUSIONS: The findings are consistent with the possibility that 'living against our internal clock' may contribute to metabolic dysfunction and its consequences. Further research aimed at understanding that the physiology and social features of social jetlag may inform obesity prevention and have ramifications for policies and practices that contribute to increased social jetlag, such as work schedules and daylight savings time.

Sleep-wake abnormalities in patients with cirrhosis.

A considerable proportion of patients with cirrhosis exhibit insomnia, delayed sleep habits, and excessive daytime sleepiness. These have been variously attributed to hepatic encephalopathy and impaired hepatic melatonin metabolism, but the understanding of their pathophysiology remains limited and their treatment problematic. Sleep is regulated by the interaction of a homeostatic and a circadian process. The homeostatic process determines sleep propensity in relation to sleep-wake history, thus the need to sleep increases with the duration of the waking period. The circadian process, which is marked by the 24-hour rhythm of the hormone melatonin, is responsible for the alternation of high/low sleep propensity in relation to dark/light cues. Circadian sleep regulation has been studied in some depth in patients with cirrhosis, who show delays in the 24-hour melatonin rhythm, most likely in relation to reduced sensitivity to light cues. However, while melatonin abnormalities are associated with delayed sleep habits, they do not seem to offer a comprehensive explanation to the insomnia exhibited by these patients. Fewer data are available on homeostatic sleep control: it has been recently hypothesized that patients with cirrhosis and hepatic encephalopathy might be unable, due to excessive daytime sleepiness, to accumulate the need/ability to produce restorative sleep. This review will describe in some detail the features of sleep-wake disturbances in patients with cirrhosis, their mutual relationships, and those, if any, with hepatic failure/hepatic encephalopathy. A separate section will cover the available information on their pathophysiology. Finally, etiological treatment will be briefly discussed.

Disruption of behavioral circadian rhythms induced by psychophysiological stress affects plasma free amino acid profiles without affecting peripheral clock gene expression in mice.

Disordered circadian rhythms are associated with various psychiatric conditions and metabolic diseases. We recently established a mouse model of a psychophysiological stress-induced chronic sleep disorder (CSD) characterized by reduced amplitude of circadian wheel-running activity and sleep-wake cycles, sleep fragmentation and hyperphagia. Here, we evaluate day-night fluctuations in plasma concentrations of free amino acids (FAA), appetite hormones and prolactin as well as the hepatic expression of circadian clock-related genes in mice with CSD (CSD mice). Nocturnal increases in wheel-running activity and circadian rhythms of plasma prolactin concentrations were significantly disrupted in CSD mice. Hyperphagia with a decreased leptin/ghrelin ratio was found in CSD mice. Day-night fluctuations in plasma FAA contents were severely disrupted without affecting total FAA levels in CSD mice. Nocturnal increases in branched-chain amino acids such as Ile, Leu, and Val were further augmented in CSD mice, while daytime increases in Gly, Ala, Ser, Thr, Lys, Arg, His, Tyr, Met, Cys, Glu, and Asn were significantly attenuated. Importantly, the circadian expression of hepatic clock genes was completely unaffected in CSD mice. These findings suggest that circadian clock gene expression does not always reflect disordered behavior and sleep rhythms and that plasma FFA profiles could serve as a potential biomarker of circadian rhythm disorders.

The rhythms of life: what your body clock means to you!

Until we turned our nights into days and began to travel in aircraft across multiple time zones, we were largely unaware that we possess a 'day within' driven by an internal body clock. Yet the striking impairment of our abilities in the early hours of the morning soon reminds us that we are slaves to our biology. Our ability to perform mathematical calculations or other intellectual tasks between 04.00 and 06.00 h is worse than if we had consumed several shots of whisky and would be classified as legally drunk. Biological clocks drive or alter our sleep patterns, alertness, mood, physical strength, blood pressure and every other aspect of our physiology and behaviour. Our emerging understanding of how these 24 h rhythms are generated and regulated is not only one of the great success stories of modern biology, but is also informing many areas of human health. Sleep and circadian rhythm disruption (SCRD) is a feature shared by some of the most challenging diseases of our time, including neuropsychiatric illness and serious disorders of the eye. Sleep and circadian rhythm disruption is also commonly seen across many sectors of society, from teenagers to shift workers. We also now appreciate that SCRD is far more than feeling sleepy at an inappropriate time. It promotes multiple illnesses ranging across abnormal metabolism, heart disease, reduced immunity, increased stress and abnormal cognition and mood states. This short review considers how 24 h rhythms are generated and regulated, the consequences of working against our body clock and the emerging relationship between SCRD and mental illness.

Delayed circadian phase is linked to glutamatergic functions in young people with affective disorders: a proton magnetic resonance spectroscopy study.

BACKGROUND: While the association between affective disorders and sleep and circadian disturbance is well established, little is known about the neurobiology underpinning these relationships. In this study, we sought to determine the relationship between a marker of circadian rhythm and neuronal integrity (N-Acetyl Aspartate, NAA), oxidative stress (glutathione, GSH) and neuronal-glial dysfunction (Glutamate + Glutamine, Glx). METHODS: Fifty-three young adults (age range 15-33 years, mean = 21.8, sd = 4.3) with emerging affective disorders were recruited from a specialized tertiary referral service. Participants underwent clinical assessment and actigraphy monitoring, from which sleep midpoint was calculated as a marker of circadian rhythm. Proton magnetic resonance spectroscopy was performed in the anterior cingulate cortex (ACC). The metabolites NAA, GSH and Glx were obtained, and expressed as a ratio to Creatine. RESULTS: Neither NAA or GSH were associated with sleep midpoint. However, higher levels of ACC Glx were associated with later sleep midpoints (rho = 0.35, p = 0.013). This relationship appeared to be independent of age and depression severity. CONCLUSIONS: This study is the first to demonstrate that delayed circadian phase is related to altered glutamatergic processes. It is aligned with animal research linking circadian rhythms with glutamatergic neurotransmission as well as clinical studies showing changes in glutamate with sleep interventions. Further studies may seek to examine the role of glutamate modulators for circadian misalignment.

[Light pollution, desynchronosis and aging: the state of problem and solutions].

The effect of different light conditions (constant illumination, light deprivation, the standard regime of lighting and natural for Northwest Russia lighting in different seasons of the annual cycle) on indicators of biological age and homeostasis, the development of age-related pathology, oncogenesis and longevity of rats was investigated. Exposure to constant light on the studied parameters was evaluated at different ages--antenatal, early and late postnatal period. The data about influences of substances and hormones of pineal gland on biomarkers of aging, homeostasis, spontaneous oncogenesis and longevity in experimental animals was obtained. It has been established that the light pollution and disturbance of photoperiod lead to desynchronosys and as a result to premature aging of the organism and age associated diseases. Ways of preventing accelerated aging were outlined.

[Role of hormonal regulation and stress in the interaction of sleep and biorhythms in aging].

The present work describes bibliographic analysis of ontogenetic changes in hormonal regulation of sleep and circadian biorhythms. It is suggested that two-stage, age-related dynamics of such changes may be related to differential occurrence registered by us earlier, of maxima of morbidity and mortality caused by a number of disorders, in middle-age and in senile period. It is proposed to concentrate future efforts on elaboration of mathematical models of ontogenetic regulation, on the basis of systems biomedicine.

CD40 activation induces NREM sleep and modulates genes associated with sleep homeostasis.

The T-cell derived cytokine CD40 ligand is overexpressed in patients with autoimmune diseases. Through activation of its receptor, CD40 ligand leads to a tumor necrosis factor (TNF) receptor 1 (TNFR1) dependent impairment of locomotor activity in mice. Here we report that this effect is explained through a promotion of sleep, which was specific to non-rapid eye movement (NREM) sleep while REM sleep was suppressed. The increase in NREM sleep was accompanied by a decrease in EEG delta power during NREM sleep and by a decrease in the expression of transcripts in the cerebral cortex known to be associated with homeostatic sleep drive, such as Homer1a, Early growth response 2, Neuronal pentraxin 2, and Fos-like antigen 2. The effect of CD40 activation was mimicked by peripheral TNF injection and prevented by the TNF blocker etanercept. Our study indicates that sleep-wake dysregulation in autoimmune diseases may result from CD40 induced TNF:TNFR1 mediated alterations of molecular pathways, which regulate sleep-wake behavior.

Discovery of a potent, selective, and orally bioavailable histamine H3 receptor antagonist SAR110068 for the treatment of sleep-wake disorders.

Previous studies have shown that compound 1 displayed high affinity towards histamine H3 receptor (H3R), (human (h-H3R), K(i)=8.6 nM, rhesus monkey (rh-H3R), K(i)=1.2 nM, and rat (r-H3R), K(i)=16.5 nM), but exhibited high affinity for hERG channel. Herein, we report the discovery of a novel, potent, and highly selective H3R antagonist/inverse agonist 5a(SS) (SAR110068) with acceptable hERG channel selectivity and desirable pharmacological and pharmacokinetic properties through lead optimization sequence. The significant awakening effects of 5a(SS) on sleep-wake cycles studied by using EEG recording in rats during their light phase support its potential therapeutic utility in human sleep-wake disorders.

Monitoring salivary melatonin concentrations in children with sleep disorders using liquid chromatography-tandem mass spectrometry.

BACKGROUND: Melatonin is synthesized in the pineal gland and is an important circadian phase marker, especially in the determination of sleep patterns. Both temporary and permanent abnormal sleep patterns occur in children; therefore, it is desirable to have methods for monitoring melatonin in biological fluids in the diagnosis and treatment of such disorders. OBJECTIVE: The objective of the study is to develop a liquid chromatography-tandem mass spectrometry method for the determination of melatonin in saliva and to apply it to monitoring salivary concentrations in children with sleep disorders. METHODS: A deuterated internal standard (d7-melatonin) was added to a diluted saliva sample (20 µL) in an autosampler vial insert, and 50 µL were injected. Plasticware was strictly avoided, and all glassware was scrupulously cleaned and then baked at 120°C for at least 48 hours to obtain satisfactory performance. Reverse-phase chromatography was performed on a C8 column using a linear gradient elution profile comprising mobile phases A (0.1% aqueous formic acid) and B (15% methanol in acetonitrile containing 0.1% formic acid), pumped at a total flow rate of 0.8 mL/min. The run time was 8 minutes. After atmospheric pressure chemical ionization, mass spectrometric detection was in positive ion mode. Mass detection was by selected reaction monitoring mode with the following mass transitions used for quantification: melatonin, m/z 233.0 → 173.8 and d7-melatonin, m/z 240.0 → 178.3. RESULTS: Linearity (r > 0.999) was established from 3.9 to 1000 pg/mL. Imprecision (coefficient of variation percent) was less than 11%, and accuracy was 100-105% (7.0-900 pg/mL). The method was selective, and the mean (range) ratio of the slopes of calibrations in water to those in daytime saliva samples collected from 10 healthy adult subjects was 0.989 (0.982-0.997), indicating negligible matrix effects. The application of the assay was demonstrated in healthy adults and in children being clinically investigated for sleep disturbances. CONCLUSIONS: A validated liquid chromatography-tandem mass spectrometry method suitable for monitoring salivary melatonin in children with circadian rhythm sleep disorders is reported. The method also has potential application to pediatric population pharmacokinetic studies using sparse sampling of saliva as the biological sample matrix.

Update on the role of melatonin in the prevention of cancer tumorigenesis and in the management of cancer correlates, such as sleep-wake and mood disturbances: review and remarks.

The aim of this article was to perform a systematic review on the role of melatonin in the prevention of cancer tumorigenesis--in vivo and in vitro--as well as in the management of cancer correlates, such as sleep-wake and mood disturbances. The International Agency for Research on Cancer recently classified "shift-work that involves circadian disruption" as "probably carcinogenic to humans" (Group 2A) based on "limited evidence in humans for the carcinogenicity of shift-work that involves night-work", and "sufficient evidence in experimental animals for the carcinogenicity of light during the daily dark period (biological night)". The clinical implications and the potential uses of melatonin in terms of biologic clock influence (e.g. sleep and mood), immune function, cancer initiation and growth, as well as the correlation between melatonin levels and cancer risk, are hereinafter recorded and summarized. Additionally, this paper includes a description of the newly discovered effects that melatonin has on the management of sleep-wake and mood disturbances as well as with regard to cancer patients' life quality. In cancer patients depression and insomnia are frequent and serious comorbid conditions which definitely require a special attention. The data presented in this review encourage the performance of new clinical trials to investigate the possible use of melatonin in cancer patients suffering from sleep-wake and mood disturbances, also considering that melatonin registered a low toxicity in cancer patients.

Association of the Period3 clock gene length polymorphism with salivary cortisol secretion among police officers.

OBJECTIVE: This study evaluated whether measures of waking or diurnal cortisol secretion, or self-reported psychological disturbances differed among police officers with a Period3 (PER3) clock gene length polymorphism. METHODS: The cortisol awakening response was characterized via the area under the salivary cortisol curve with respect to the increase (AUCI) or total waking cortisol (AUCG). Diurnal cortisol measures included the slope of diurnal cortisol and the diurnal AUCG. Psychological disturbances were characterized using the Center for Epidemiologic Studies Depression Scale, Impact of Events Scale, and Life Events Scale. RESULTS: Officers with a 4/5 or 5/5 genotype had higher awakening AUCG and greater diurnal cortisol AUCG levels compared to officers with the 4/4 genotype. Among those working more afternoon or night shifts, waking AUCI and AUCG were greater among officers with a 4/5 or 5/5 genotype compared to the 4/4 referents. CONCLUSION: Cortisol secretion was modified among police officers with different PER3 VNTR clock gene variants.

[Circadian clock disruption and diabetes mellitus].

Recent studies have demonstrated relationships between the dysfunction of circadian clocks and the development of obesity and type 2 diabetes. In humans, both shift work and the genetic variations of clock genes increase the risk of these disorders. In mice, the light conditions which induce chronic jet lag and modifications of the clock genes cause obesity and/or type 2 diabetes. Moreover, circadian clocks in peripheral tissues are impaired in both patients with type 2 diabetes and genetically obese diabetic mice. Therefore, circadian clocks are important new therapeutic targets for preventing and treating obesity and type 2 diabetes.

[Circadian rhythm sleep disorder].

Primary pathophysiology of circadian rhythm sleep disorders(CRSDs) is a misalignment between the endogenous circadian rhythm phase and the desired or socially required sleep-wake schedule, or dysfunction of the circadian pacemaker and its afferent/efferent pathways. CRSDs consist of delayed sleep phase type, advanced sleep phase type, free-running type, irregular sleep-wake type, shift work type and jet lag type. Chronotherapy using strong zeitgebers (time cues), such as bright light and melatonin/ melatonin type 2 receptor agonist, is effective when administered with proper timing. Bright light is the strongest entraining agent of circadian rhythms. Bright light therapy (appropriately-timed exposure to bright light) for CRSDs is an effective treatment option, and can shift the sleep-wake cycle to earlier or later times, in order to correct for misalignment between the circadian system and the desired sleep-wake schedule. Timed administration of melatonin, either alone or in combination with light therapy has also been shown to be useful in the treatment of CRSDs.