Fibromyalgia: Chronobiological Aspects

The primary fibromyalgia syndrome (Weichteilrheumatismus) shows a circadian rhythm of the symptoms and, moreover, a seasonality of pain severeness. Although the pathophysiologic mechanisms are unknown, the circadian variations are well documented in the literature; the seasonality of pain is sometimes clinically reported. In a study on “healthy” workers, the seasonality of this disease is reported.     

Effects of genetic variants of ST8SIA2 and NCAM1 genes on seasonal mood changes and circadian preference in the general population

ST8SIA2 and NCAM1 are functionally related genes forming polysialic acid (PSA) - neural cell adhesion molecule (NCAM) complex in suprachiasmatic nucleus (SCN), the regulating site of circadian biological rhythm. In this study, the relationship of ST8SIA2 and NCAM1 with circadian and seasonal rhythms of human behavior was explored. Subjects were 261 healthy Korean adults who were free of any history of clinically significant psychiatric symptoms. The phenotypes were circadian preference and seasonal change of mood and behavior (seasonality) measured by the Composite Scale of Morningness and the Seasonal Pattern Assessment Questionnaire, respectively. Thirty-four single nucleotide polymorphisms (SNPs) across the ST8SIA2 region and 15 SNPs of NCAM1 were analyzed. A nominally significant association with seasonality and circadian preference was observed in 21 variants of both genes. After corrections for multiple testing, associations of 8 SNPs of ST8SIA2 and 2 SNPs of NCAM1 with seasonality remained significant. Some of these SNPs were also associated with psychiatric disorders in previous studies. This study demonstrated a meaningful and/or suggestive evidence of association between behavioral phenotypes reflecting human biological rhythm and two interplaying genes involved in the plasticity of SCN’s neuronal network.     

Abnormality of circadian rhythm of serum melatonin and other biochemical parameters in fibromyalgia syndrome

Fibromyalgia syndrome (FMS) is a complex chronic condition causing widespread pain and variety of other symptoms. It produces pain in the soft tissues located around joints throughout the body. FMS has unknown etiology and its pathophysiology is not fully understood. However, abnormality in circadian rhythm of hormonal profiles and cytokines has been observed in this disorder. Moreover, there are reports of deficiency of serotonin, melatonin, cortisol and cytokines in FMS patients, which are fully regulated by circadian rhythm. Melatonin, the primary hormone of the pineal gland regulates the body's circadian rhythm and normally its levels begin to rise in the mid-to-late evening, remain high for most of the night, and then decrease in the early morning. FMS patients have lower melatonin secretion during the hours of darkness than the healthy subjects. This may contribute to impaired sleep at night, fatigue during the day and changed pain perception. Studies have shown blunting of normal diurnal cortisol rhythm, with elevated evening serum cortisol level in patients with FMS. Thus, due to perturbed level of cortisol secretion several symptoms of FMS may occur. Moreover, disturbed cytokine levels have also been reported in FMS patients. Therefore, circadian rhythm can be an important factor in the pathophysiology, diagnosis and treatment of FMS. This article explores the circadian pattern of abnormalities in FMS patients, as this may help in better understanding the role of variation in symptoms of FMS and its possible relationship with circadian variations of melatonin, cortisol, cytokines and serotonin levels.     

A forced desynchrony study of circadian pacemaker characteristics in seasonal affective disorder

The circadian pacemaker is an endogenous clock that regulates oscillations in most physiological and psychological processes with a near 24-h period. In many species, this pacemaker triggers seasonal changes in behavior. The seasonality of symptoms and the efficacy of light therapy suggest involvement of the circadian pacemaker in seasonal affective disorder (SAD), winter type. In this study, circadian pacemaker characteristics of SAD patients were compared with those of controls. Seven SAD patients and matched controls were subjected to a 120-h forced desynchrony protocol, in which core body temperature and melatonin secretion profiles were measured for the characterization of circadian pacemaker parameters. During this protocol, which enables the study of unmasked circadian pacemaker characteristics, subjects were exposed to six 20-h days in time isolation. Patients participated twice in winter (while depressed and while remitted after light therapy) and once in summer. Controls participated once in winter and once in summer. Between the SAD patients and controls, no significant differences were observed in the melatonin-derived period or in the phase of the endogenous circadian temperature rhythm. The amplitude of this rhythm was significantly smaller in depressed and remitted SAD patients than in controls. No abnormalities of the circadian pacemaker were observed in SAD patients. A disturbance in thermoregulatory processes might explain the smaller circadian temperature amplitude in SAD patients during winter.     

Associations between chronotype,sleep disturbances and seasonality with fatigue and inflammatory bowel disease symptoms

Growing number of studies suggests link between circadian rhythms and inflammatory bowel diseases (IBD) manifestation. We hypothesize that: 1) IBD are associated with increased eveningness and sleep disturbances; 2) eveningness and sleep disturbances are related to more severe IBD symptoms. In total, 129 participants were enrolled to this study, divided into three groups: 34 Crohn’s disease (CD) patients, 38 ulcerative colitis (UC) patients and 57 healthy controls (HC) group. They all fulfilled a questionnaire, consisting of the Composite Scale of Morningness (CSM), Seasonal Pattern Assessment Questionnaire (SPAQ), Pittsburgh Sleep Quality Index, Inflammatory Bowel Disease Questionnaire (IBDQ) and Multidimensional Fatigue Inventory (MFI). Multiple regression models controlled for age and sex revealed that in CD group higher eveningness measured with CSM was associated with higher general fatigue, physical fatigue, mental fatigue and reduced motivation measured by MFI. Lower CSM morning affect is associated with greater general fatigue, physical fatigue and more reduced activity. Greater seasonality scores are associated with increased physical fatigue and more reduced activity and motivation. Lower sleep quality measured with PSQI is associated with higher physical fatigue and more reduced activity. Correlational analysis revealed that higher seasonality and lower sleep quality are associated with increased systemic and bowel symptoms and decreased emotional and social functions measured with IBDQ. In UC group, eveningness is associated with greater general fatigue, physical fatigue and more reduced activity. Higher CSM morning affect is associated with decreased general fatigue, physical fatigue and less reduced activity. Higher CSM circadian preference scores are associated with decreased general and physical fatigue, and less reduced activity. Increased seasonality is associated with more physical fatigue. Lower sleep quality is associated with greater general and physical fatigue. To our best knowledge this is the first study evaluating associations between chronotype and sleep disturbances with IBD symptoms. We have found that chronotype preferences, whose role in IBD has been until now overlooked, may be one of the important factors contributing to fatigue in this clinical group.     

Adult Emergence Rhythm of Fruit Flies Drosophila melanogaster under Seminatural Conditions

In insects, the role of circadian clocks in the temporal regulation of adult emergence rhythm under natural conditions has not previously been reported. Here we present the results of a study aimed at examining the time course and waveform of emergence rhythm in the fruit fly Drosophila melanogaster under seminatural condition (SN). We studied this rhythm in wild-type and clock mutant flies under SN in parallel with laboratory condition (LAB) to examine (1) how the rhythm differs between SN and LAB, (2) what roles the circadian clock protein PERIOD and the circadian photoreceptor CRYPTOCHROME (CRY) play in the regulation of emergence rhythm under SN, and (3) whether there is seasonality in the rhythm. Under SN, wild-type flies displayed tightly gated emergence, peaking at "dawn" and gradually tapering down toward the evening, with little or no emergence by night, while in LAB, flies emerged throughout the light phase of light-dark (LD) cycles. The period loss-of-function mutant (per ( 0 )) flies were arrhythmic in LAB but displayed weak rhythmic emergence under SN. Under SN, cry mutants displayed less robust rhythm with wider gates, greater variance in peak timing, and enhanced nighttime emergence compared to controls. Furthermore, flies showed seasonal variation in emergence rhythm, coupled either to light or to humidity/temperature depending on the severity of environmental conditions. These results suggest that adult emergence rhythm of Drosophila is more robust in nature, is coupled to environmental cycles, and shows seasonal variations.     

Birth seasonality in cotton-top tamarins (saguinus oedipus) despite constant food supply and body weight

Goldizen et al. (1988) reported that wild saddle-back tamarins (Saguinus fuscicollis, Callitrichidae) show birth seasonality that is correlated with food supply and body weight. They suggested a sequence of ultimate causality in which shortage of food leads to reduced body weight which leads to timing of weaning and lactation when resources are more abundant. Cotton-top tamarins in captivity show birth seasonality despite constant food supply and body weight. Although natural availability of fruit and insects (which are key foods for tamarins) is related to rainfall, birth seasonality and body weight in captive cotton-top tamarins are unrelated to rainfall. The most likely proximate mechanism for seasonality of births in tamarins is photo-period, given existing data on populations living in natural and artificial lighting.     

Characterization of circadian function in Djungarian hamsters insensitive to short day photoperiod

Summary Djungarian hamsters (Phodopus sungorus sungorus) depend mainly on day length to cue seasonal adjustments. However, not all individuals respond to short day conditions. A previous study from this laboratory proposed that nonresponsiveness to short day conditions rests with a defect in the circadian organization of these hamsters.In this study we found pronounced differences between responsive and nonresponsive hamsters in the expression of circadian rhythmicity under constant darkness and under constant illumination. While responsive hamsters showed a free-running activity pattern with a period of 23.86+0.04 h and responded to brief light pulses with the expected phase delays and phase advances, nonresponsive hamsters exhibited a period of 24.04+0.05 h and responded to light pulses with phase advances. Furthermore, 9 out of 15 responsive hamsters showed a clear split in the activity pattern within 8 weeks under constant light (80–100 lux), while only 1 of the 7 nonresponsive hamsters exhibited a split activity pattern. As a result of these differences in circadian function, nonresponsive Djungarian hamsters are incapable of proper photoperiod time measurement and photoperiod-induced seasonality.Abbreviations PRC phase response curve - ct circadian time - DD constant dark - LL constant light     

The neurobiology of adaptation to seasons: Relevance and correlations in bipolar disorders

ABSTRACT

Bipolar disorders (BDs) are severe and common psychiatric disorders. BD pathogenesis, clinical manifestations and relapses are associated with numerous circadian rhythm abnormalities. In addition, infradian fluctuations of mood, social activity, weight and sleep patterns are very frequent in BD. Disease course with a seasonal pattern (SP) occurs in approximately 25% of depressive and 15% of manic episodes, which is coupled to a more severe disease symptomatology. The pathophysiological mechanisms of seasonal effects in BD await clarification, with likely important clinical consequences. This review aims at synthesizing available data regarding the underlying pathophysiological mechanisms of seasonality in BD patients, with implications for future research directions in the study of seasonality in BD. Three factors are suggested to play significant roles in BD with SP, namely the suprachiasmatic nuclei, as well as the melatonergic and photoperiodism systems. It is proposed that BD with SP may be considered as a complex disorder resulting from the interaction of clock gene vulnerabilities and biological clock neuroplasticity, with environmental factors, such as the response to light. Light seems to play a key role in BD with SP, mainly due to two seasonal signaling pathways: a light to cortex serotonin transporter pathway, as well as a pathway connecting light to melatonin synthesis. This provides a theoretical framework for BD with SP, including for future research and clinical management. The review proposes that future research should explore markers of seasonality in BD, such as plasma melatonin, sleep–wake rhythms (with actigraphy) and genetic or epigenetic variants within the melatonin synthesis pathway. The role of light in driving BD with SP is an active area of research. Seasonality may also be intimately linked to wider aspects of BD, including via interactions with the gut microbiome, the gut–liver axis, cholesterol regulation, aspects of metabolic syndrome, vitamin D, decreased longevity, suicide risk and medication treatment targets. Further research on the role of seasonality in BD is likely to clarify the etiology, course and treatment of BD more widely.     

Likelihood of acute coronary syndrome in emergency department chest pain patients varies with time of presentation

ABSTRACT: BACKGROUND: There is a circadian and circaseptal (weekly) variation in the onset of acute coronary syndrome (ACS). The aim of this study was to elucidate whether the likelihood of ACS among emergency department (ED) chest pain patients varies with the time of presentation. METHODS: All patients presenting to the Lund ED at Skane University Hospital with chest pain or discomfort during 2006 and 2007 were retrospectively included. Age, sex, arrival time at the ED and discharge diagnose (ACS or not) were obtained from the electronic medical records. RESULTS: There was a clear but moderate circadian variation in the likelihood of ACS among presenting chest pain patients, the likelihood between 8 and 10 am being almost twice as high as between 6 and 8 pm. This was mainly explained by a variation in the ACS likelihood in females and patients under 65 years, with no significant variation in males and patients over 65 years. There was no significant circaseptal variation in the ACS likelihood. CONCLUSIONS: Our results indicate that there is a circadian variation in the likelihood of ACS among ED chest pain patients, and suggest that physicians should consider the time of presentation to the ED when determining the likelihood of ACS.     

The influence of women’s attachment style on the chronobiology of labour pain,analgesic consumption and pharmacological effect

Circadian variation in biological rhythms has been identified as affecting both labour pain and the pharmacological properties of analgesics. In the context of pain, there is also a growing body of evidence suggesting the importance of adult attachment. The purpose of this study was to examine whether labour pain, analgesic consumption and pharmacological effect are significantly affected by the time of day and to analyse whether this circadian variation is influenced by women’s attachment style. This prospective observational study included a sample of 81 pregnant women receiving patient-controlled epidural analgesia (PCEA). Attachment was assessed with the Adult Attachment Scale – Revised. The perceived intensity of labour pain in the early stage of labour (3?cm of cervical dilatation and before the administration of PCEA) was measured using a visual analogue scale (VAS). Pain was also indirectly assessed by measuring the consumption of anaesthetics. The latency period and the duration of effect were recorded for a chronopharmacology characterisation. Pain, as assessed with the VAS, was significantly higher in the night-time group than in the daytime group. An insecure attachment style was significantly associated with greater labour pain at 3?cm of cervical dilatation (p?<?0.001) and before the beginning of analgesia (p?<?0.001) as well as with higher analgesic consumption and lower pharmacological efficacy (p?<?0.05). The time of day was significantly associated with the pharmacological effect: the latency period was longer at night, and the duration of the pharmacological effect was longer during the daytime. The interaction between time of day and attachment style was not significant for any of the study variables. Our results provide evidence of the importance of circadian variation in studying labour pain and the pharmacological effect of labour analgesia involving epidural blockage with a PCEA regimen. Moreover, although there was no evidence that attachment style influenced the circadian variation, these data emphasise that insecure attachment patterns are a risk factor for greater labour pain and analgesic consumption, which should be considered in pain management approaches.     

Spinal astrocytes contribute to the circadian oscillation of glutamine synthase, cyclooxygenase-1 and clock genes in the lumbar spinal cord of mice

Spinal astrocytes have key roles in the regulation of pain transmission. However, the relationship between astrocytes and the circadian system in the spinal cord remains poorly defined. In the current study, the circadian variations in the expression of several clock genes in the lumbar spinal cord of mice were examined by using real-time PCR. The expression of Period1, Period2 and Cryptochrome1 showed significant circadian oscillations, each gene peaking in the early evening. The expression of Bmal1 mRNA also exhibited a circadian pattern, peaking from around midnight to early morning. The mRNA levels of Cryptochrome2 were slightly, but not significantly altered. Molecules related to pain transmission were also investigated. The mRNA expression of glutamine synthase (GS), and cyclooxygenases (COXs), known to be involved in various spinal sensory functions, showed rhythmicity with a peak in the early evening, although the expression of the neurokinin-1 receptor, subunits of the N-methyl-d-aspartate receptor, and glutamate transporters did not change. In addition, we found that protein levels of GS and COX-1 were also high at midnight compared with midday. Furthermore, we examined the effect of intrathecal fluorocitrate (100pmol), an inhibitor of astrocytic metabolism, on the expression of oscillating genes in lumbar spinal cord. Fluorocitrate significantly suppressed astrocyte function. Furthermore, the circadian oscillation of clock gene expression and GS and COX-1 expression were suppressed. Together, these results suggest that a significant circadian rhythmicity of the expression of clock genes is present in the spinal cord and that the components of the circadian clock timed by astrocytes might contribute to spinal functions, including nociceptive processes.     

Effects of the 5HT1A agonist/antagonist BMY 7378 on light-induced phase advances in hamster circadian activity rhythms during aging

The entrainment of some circadian rhythms in rodents and humans to the environmental light-dark cycle deteriorates during aging. Recent evidence suggests that the time-keeping ability of the circadian pacemaker maintains its endogenous period in both hamsters and humans. This suggests that any changes in the coupling between environmental cues and the circadian pacemaker are not due to changes in "clock speed," but rather due to a weakened coupling between the afferent systems relaying environmental information and the circadian pacemaker located in the suprachiasmatic nucleus. The suprachiasmatic nucleus receives serotonergic input from the raphe nuclei, and serotonergic 5HT1A,7 agonists have been reported to lose their circadian phase-adjusting efficacy during aging in hamsters. In the present study, the authors report the effects of a novel serotonergic agonist BMY 7378 on light-induced phase advances during aging in the hamster. The present report demonstrates that BMY 7378 is a highly efficacious chronobiotic that more than doubles the magnitude of light-induced phase shifts in hamster wheel-running activity rhythms. Light-induced phase advances in hamster wheel-running activity of at least 6 h following a single systemic dose of BMY 7378 are routinely observed. Furthermore, BMY 7378 potentiation of phase shifts is maintained in old hamsters, suggesting that BMY 7378 has a different site of activity than previously reported 5HT1A,7 agonists that have a diminished effect on circadian phase during aging.     

Identification of an estrogen-regulated circadian mechanism necessary for breast acinar morphogenesis

Altered estrogen receptor α (ERA) signaling and altered circadian rhythms are both features of breast cancer. By using a method to entrain circadian oscillations in human cultured cells, we recently reported that the expression of key clock genes oscillates in a circadian fashion in ERA-positive breast epithelial cells but not in breast cancer cells, regardless of their ERA status. Moreover, we reported that ERA mRNA oscillates in a circadian fashion in ERA-positive breast epithelial cells, but not in ERA-positive breast cancer cells. By using ERA-positive HME1 breast epithelial cells, which can be both entrained in vitro and can form mammary gland-like acinar structures in three-dimensional (3D) culture, first we identified a circuit encompassing ERA and an estrogen-regulated loop consisting of two circadian clock genes, PER2 and BMAL1. Further, we demonstrated that this estrogen-regulated circuit is necessary for breast epithelial acinar morphogenesis. Disruption of this circuit due to ERA-knockdown, negatively affects the estrogen-sustained circadian PER2-BMAL1 mechanism as well as the formation of 3D HME1 acini. Conversely, knockdown of either PER2 or BMAL1, by hampering the PER2-BMAL1 loop of the circadian clock, negatively affects ERA circadian oscillations and 3D breast acinar morphogenesis. To our knowledge, this study provides the first evidence of the implication of an ERA-circadian clock mechanism in the breast acinar morphogenetic process.     

Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans.

Biological circadian clocks oscillate with an approximately 24-hour period, are ubiquitous, and presumably confer a selective advantage by anticipating the transitions between day and night. The circadian rhythms of sleep, melatonin secretion and body core temperature are thought to be generated by the suprachiasmatic nucleus of the hypothalamus, the anatomic locus of the mammalian circadian clock. Autosomal semi-dominant mutations in rodents with fast or slow biological clocks (that is, short or long endogenous period lengths; tau) are associated with phase-advanced or delayed sleep-wake rhythms, respectively. These models predict the existence of familial human circadian rhythm variants but none of the human circadian rhythm disorders are known to have a familial tendency. Although a slight 'morning lark' tendency is common, individuals with a large and disabling sleep phase-advance are rare. This disorder, advanced sleep-phase syndrome, is characterized by very early sleep onset and offset; only two cases are reported in young adults. Here we describe three kindreds with a profound phase advance of the sleep-wake, melatonin and temperature rhythms associated with a very short tau. The trait segregates as an autosomal dominant with high penetrance. These kindreds represent a well-characterized familial circadian rhythm variant in humans and provide a unique opportunity for genetic analysis of human circadian physiology.     

Identification of an estrogen-regulated circadian mechanism necessary for breast acinar morphogenesis

Altered estrogen receptor α (ERA) signaling and altered circadian rhythms are both features of breast cancer. By using a method to entrain circadian oscillations in human cultured cells, we recently reported that the expression of key clock genes oscillates in a circadian fashion in ERA-positive breast epithelial cells but not in breast cancer cells, regardless of their ERA status. Moreover, we reported that ERA mRNA oscillates in a circadian fashion in ERA-positive breast epithelial cells, but not in ERA-positive breast cancer cells. By using ERA-positive HME1 breast epithelial cells, which can be both entrained in vitro and can form mammary gland-like acinar structures in three-dimensional (3D) culture, first we identified a circuit encompassing ERA and an estrogen-regulated loop consisting of two circadian clock genes, PER2 and BMAL1. Further, we demonstrated that this estrogen-regulated circuit is necessary for breast epithelial acinar morphogenesis. Disruption of this circuit due to ERA-knockdown, negatively affects the estrogen-sustained circadian PER2-BMAL1 mechanism as well as the formation of 3D HME1 acini. Conversely, knockdown of either PER2 or BMAL1, by hampering the PER2-BMAL1 loop of the circadian clock, negatively affects ERA circadian oscillations and 3D breast acinar morphogenesis. To our knowledge, this study provides the first evidence of the implication of an ERA-circadian clock mechanism in the breast acinar morphogenetic process.     

Significant Determinants of Mouse Pain Behaviour

Transgenic mouse behavioural analysis has furthered our understanding of the molecular and cellular mechanisms underlying damage sensing and pain. However, it is not unusual for conflicting data on the pain phenotypes of knockout mice to be generated by reputable groups. Here we focus on some technical aspects of measuring mouse pain behaviour that are often overlooked, which may help explain discrepancies in the pain literature. We examined touch perception using von Frey hairs and mechanical pain thresholds using the Randall-Selitto test. Thermal pain thresholds were measured using the Hargreaves apparatus and a thermal place preference test. Sodium channel Nav1.7 knockout mice show a mechanical deficit in the hairy skin, but not the paw, whilst shaving the abdominal hair abolished this phenotype. Nav1.7, Nav1.8 and Nav1.9 knockout mice show deficits in noxious mechanosensation in the tail, but not the paw. TRPA1 knockout mice, however, have a loss of noxious mechanosensation in the paw but not the tail. Studies of heat and cold sensitivity also show variability depending on the intensity of the stimulus. Deleting Nav1.7, Nav1.8 or Nav1.9 in Nav1.8-positive sensory neurons attenuates responses to slow noxious heat ramps, whilst responses to fast noxious heat ramps are only reduced when Nav1.7 is lost in large diameter sensory neurons. Deleting Nav1.7 from all sensory neurons attenuates responses to noxious cooling but not extreme cold. Finally, circadian rhythms dramatically influence behavioural outcome measures such as von Frey responses, which change by 80% over the day. These observations demonstrate that fully characterising the phenotype of a transgenic mouse strain requires a range of behavioural pain models. Failure to conduct behavioural tests at different anatomical locations, stimulus intensities, and at different points in the circadian cycle may lead to a pain behavioural phenotype being misinterpreted, or missed altogether.     

Rhythmic changes in pain sensitivity in teeth

In 136 healthy men, circadian variations in pain threshold have been observed in healthy front teeth, the pain being elicited by a cold stimulus, alterations in threshold then being inferred from changes in the minimum cold application time. The pain threshold is maximal in the early afternoon and at a minimum in the early morning. In previous experiments using an electrical current as the pain stimulus, a similar diurnal variation of sensitivity was also observed. These results conform with clinical experience of the time of onset of toothache, and are also in accord with known diurnal variations of pain sensitivity in other organs. Further studies were carried out on one subject. The minimum cold application time test was performed over more than 3 years on a healthy front tooth. The results suggest a circannual rhythm of the pain threshold, with a maximum in October/November and a minimum in May.