Social defeat stress affects resident's clock gene and bdnf expression in the brain.

Social defeat stress affects behavior and changes the expression of the genes underlying neuronal plasticity in the brain. The circadian clock regulates most neuronal processes in the brain, which results in daily variations of complex behavior, and any disturbance in circadian clock oscillations increases the risk of mood and cognitive disbalance. In this study, we assessed the effect of acute and repeated social defeat stress on Per2 and Nr1d1 expression in prefrontal cortexes, hippocampi, pineal glands, olfactory bulbs, cerebella, and pituitary glands. We also evaluated the effect of our experimental setting on levels of Bdnf and plasma corticosterone, two markers widely used to asses the impact of stress on mammalian physiology. Our data show that single and repeated social defeat stress upregulates the expression of both clock genes and Bdnf in all brain structures, and corticosterone in the blood. While the general pattern of Bdnf upregulation suggests higher sensitivity in the intruder group, the clock genes are induced more significantly in residents, especially by repeated stress sessions. Our work thus suggests that the model of stress-induced anxiety and depression should consider a group of residents because, for some parameters, they may respond more distinctively than intruders.LAY SUMMARYThe resident/intruder experimental paradigm affects the expression of clock genes Per2, Nr1d1and Bdnf in the brain structures and plasma corticosterone level. The induction of clock genes is evident in both experimental groups; however, it is more marked in residents. Together with the significant increase in Bdnf levels in the majority of brain structures and plasma corticosterone in residents, our data suggest that in the model of social defeat stress, the utility of an experimental group of residents could be contributive.

Comorbidities and Subgroups of Patients Surviving Severe Acute Hypercapnic Respiratory Failure in the Intensive Care Unit.

RATIONALE: No methodical assessment of the lung, cardiac, and sleep function of patients surviving an acute hypercapnic respiratory failure episode requiring admission to the intensive care unit (ICU) has been reported in the literature. OBJECTIVES: To prospectively investigate the prevalence and impact of comorbidities in patients treated by mechanical ventilator support (invasive or noninvasive) for acute hypercapnic respiratory failure in the ICU. METHODS: Seventy-eight consecutive patients admitted for an episode of acute hypercapnic respiratory failure underwent an assessment of lung, cardiac, and sleep function by pulmonary function tests, transthoracic echocardiography, and polysomnography 3 months after ICU discharge. MEASUREMENTS AND MAIN RESULTS: Sixty-seven percent (52 of 78) of patients exhibited chronic obstructive pulmonary disease (COPD), although only 19 had been previously diagnosed. Patients without COPD were primarily obese. Prevalence of severe obstructive sleep apnea was 51% (95% confidence interval, 34-69) in patients with COPD and 81% (95% confidence interval, 54-96) in patients without COPD. Previously undiagnosed cardiac dysfunction with preserved ejection fraction was highly prevalent (44%), as was hypertension (67%). More than half of the population demonstrated at least three major comorbidities known to precipitate acute hypercapnic respiratory failure. Multimorbidity was associated with longer time to hospital discharge. Hospital readmission or death occurred in 46% of patients over an average of 3.5 months after discharge. CONCLUSIONS: Severe hypercapnic respiratory failure requiring ICU admission resulted primarily from COPD or obesity. Major comorbidities are highly prevalent in both cases and most often ignored. Surviving acute hypercapnic respiratory failure should be an opportunity to systematically evaluate lung, heart, and sleep functions to improve poor outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT 02111876).

Identification of STAT3 and STAT5 proteins in the rat suprachiasmatic nucleus and the Day/Night difference in astrocytic STAT3 phosphorylation in response to lipopolysaccharide.

Signal transducers and activators of transcription (STAT) proteins regulate many aspects of cellular physiology from growth and differentiations to immune responses. Using immunohistochemistry, we show the daily rhythm of STAT3 protein in the rat suprachiasmatic nucleus (SCN), with low but significant amplitude peaking in the morning. We also reveal the strong expression of STAT5A in astrocytes of the SCN and the STAT5B signal in nonastrocytic cells. Administration of lipopolysaccharide (LPS) acutely induced phosphorylation of STAT3 on Tyr705 during both the day and the night and induced phosphorylation on Ser727 but only after the daytime application. The LPS-induced phospho-STAT3 (Tyr705) remained elevated for 24 hr after the daytime application but declined within 8 hr when LPS was applied at night.

Post-H1N1 Flu Vaccination Narcolepsy in Switzerland: A Retrospective Survey in the 30 Sleep-Certified Swiss Centers.

Narcolepsy-cataplexy is a sleep-wake disorder and suggested to be immune-mediated, involving genetic and environmental factors. The autoimmune process eventually leads to a loss of hypocretin neurons in the lateral hypothalamus. Epidemiological studies in several countries proved an increased incidence of narcolepsy after H1N1 flu vaccination and infection. This survey in 30 sleep centers in Switzerland led to the identification of 9 H1N1-vaccinated children and adults as newly diagnosed narcolepsy. Clinical features included the abrupt and severe onset of sleepiness, cataplexy and sleep fragmentation.

Baclofen-Associated Onset of Central Sleep Apnea in Alcohol Use Disorder: A Case Report.

A 61-year-old patient with alcohol use disorder (AUD) was referred for suspicion of sleep apnea syndrome (SAS). He had incurred three road accidents attributed to sleepiness over the previous year, shortly after initiation of high-dose (100 mg b.i.d.) treatment with baclofen, a molecule increasingly used in the management of AUD. Polysomnography revealed a severe central SAS (CSAS) with an apnea-hypopnea index (AHI) of 81.6/h. Baclofen was suggested as a possible cause of the CSAS, and after its withdrawal, a second polysomnography was done, showing the disappearance of the central apneas and a shift to severe obstructive SAS (AHI 43.9/h), for which a positive airway pressure (CPAP) treatment was initiated. A third polysomnography was performed under CPAP after reintroduction of baclofen (50 mg b.i.d.) by the patient, showing reappearance of the CSAS (AHI 42.1/h). This case report illustrates the deleterious effect of baclofen on breathing physiology during sleep. Since it is typically prescribed off label at high doses to a population of patients potentially using other substances that inhibit the ventilatory drive, this possible adverse effect is a major concern. When considering the use of baclofen in patients with AUD, the potential for sleep-disordered breathing should be weighed and carefully monitored.

The journey through the world of adolescent sleep.

Sleep-wake patterns and the electroencephalogram (EEG) during sleep undergo fundamental changes during adolescence. Scientific evidence indicates that these changes represent components of an extensive maturational brain remodeling process. Sleep during periods of brain maturation appears to be particularly important for health and behavior. Adolescents' sleep problems affect their cognitive and psychobehavioral functioning, making insufficient sleep during this developmental stage a significant international health concern. In this review, we summarize some key data concerning developmental changes in sleep behavior and regulation, and the association between sleep EEG changes and brain maturation. This review extends our understanding of adolescent sleep and highlights its significance for healthy development. We discuss the possibility to follow brain maturation and to detect errors in this maturational process by monitoring the developmental sleep EEG changes.

The impact of sleep education, light intervention and relaxation on sleep and mood in the elderly.

Sleep and light education (SLE) combined with relaxation is a potential method of addressing sleep and affective problems in older people. 47 participants took part in a four-week sleep education program. SLE was conducted once a week for 60-90 minutes. Participants were instructed on sleep and light hygiene, sleep processes, and practiced relaxation techniques. Participants were wearing actigraphs for 6 weeks, completed daily sleep diaries, and wore blue light-blocking glasses 120 minutes before bedtime. Measures included scores of the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Insomnia Severity Index (ISS), Beck Depression Inventory-II (BDI-II), State-Trait Anxiety Inventory (STAI) and actigraphy measurements of sleep latency, sleep efficiency, and sleep fragmentation. Sleep quality increased after SLE based on the subjective assessment and in the objective measurement with actigraphy. PSQI scores were statistically reduced indicating better sleep. Scores after the intervention significantly decreased in ESS and ISS. Sleep latency significantly decreased, whereas sleep efficiency and fragmentation index (%), did not improve. Mood significantly improved after SLE, with lower scores on the BDI-II and STAI. SLE combined with relaxation proved to be an effective method to reduce sleep problems and the incidence of depressive and anxiety symptoms.

Diurnal and seasonal differences in cardiopulmonary response to exercise in morning and evening chronotypes.

Circadian clocks regulate multiple physiological domains from molecular to behavioral levels and adjust bodily physiology to seasonal changes in day length. Circadian regulation of cellular bioenergy and immunity in the cardiovascular and muscle systems may underpin the individual diurnal differences in performance capacity during exercise. Several studies have shown diurnal differences in cardiopulmonary parameters at maximal and submaximal workloads in morning and evening circadian human phenotypes. However, the effect of seasons on these changes was not elucidated. In this study, we recruited subjects with Morningness-Eveningness Questionnaire scores corresponding to morning and evening types. Subjects underwent morning (7:00-9:00) and evening (20:00-22:00) maximal workload spiroergometry in both winter and summer seasons. We analyzed their performance time, anaerobic threshold, heart rate, and respiratory parameters. Our results suggest that evening types manifest diurnal variations in physical performance, particularly in winter. They also have slower heart rate recovery than morning types, irrespective of the time of day or season. Compared to winter, the chronotype effect on the magnitude of morning-evening differences in performance time, maximal heart rate, and anaerobic threshold onset was more significant in summer. Our data are in concordance with previous observations and confirm the difference between morning and evening types in the timing of maximum performance capacity.

Functional interactions in hierarchically organized neural networks studied with spatiotemporal firing patterns and phase-coupling frequencies.

A scalable hardware/software hybrid module--called Ubidule--endowed with bio-inspired ontogenetic and epigenetic features is configured to run a neural networks simulation with developmental and evolvable capabilities. We simulated the activity of hierarchically organized spiking neural networks characterized by an initial developmental phase featuring cell death followed by spike timing dependent synaptic plasticity in presence of background noise. An upstream 'sensory' network received a spatiotemporally organized external input and downstream networks were activated only via the upstream network. Precise firing sequences, formed by recurrent patterns of spikes intervals above chance levels, were observed in all recording conditions, thus suggesting the build-up of a connectivity able to sustain temporal information processing. The activity of a Ubinet--a network of Ubidules--is analyzed by means of virtual electrodes that recorded neural signals similar to EEG. The analysis of these signals was compared with a small set of human recordings and revealed common patterns of shift in quadratic phase coupling. The results suggest some interpretations of changes and plasticity of functional interactions between cortical areas driven by external stimuli and by learning/cognitive

The effect of the cannabinoid receptor agonist and antagonist on the light-induced changes in the suprachiasmatic nucleus of rats.

The CB1 cannabinoid receptors have been found in the rodent suprachiasmatic nucleus, and their activation suppresses the light-induced phase shift in locomotor rhythmicity of mice and hamsters. Here, we show that the CB1 receptor agonist CP55940 significantly attenuates the light-induced phase delay in rats as well. Furthermore, it blocks the light induction of c-Fos and light-induced downregulation of pERK1/2 in the SCN, and the CB1 antagonist AM251 prevents the photic induction of pERK1/2 and reduces pGSK3ß after photic stimulation. Our data suggest that the modulation of the cannabinoid receptor activity may affect the photic entrainment via the setting of the SCN sensitivity to light.

Relationship between Sleep Disorders and Health Related Quality of Life-Results from the Georgia SOMNUS Study.

The extent to which sleep disorders are associated with impairment of health-related quality of life (HRQoL) is poorly described in the developing world. We investigated the prevalence and severity of various sleep disorders and their associations with HRQoL in an urban Georgian population. 395 volunteers (20⁻60 years) completed Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, STOP-Bang questionnaire, Insomnia Severity Index, Beck Depression Inventory-Short Form, and Short Form Health Survey (SF-12). Socio-demographic data and body mass index (BMI) were obtained. The prevalence of sleep disorders and their association with HRQoL was considerable. All SF-12 components and physical and mental component summaries (PCS, MCS) were significantly lower in poor sleepers, subjects with daytime sleepiness, apnea risk, or insomnia. Insomnia and apnea severity were also associated with lower scores on most SF-12 dimensions. The effect of insomnia severity was more pronounced on MCS, while apnea severity-on PCS. Hierarchical analyses showed that after controlling for potential confounding factors (demographics, depression, BMI), sleep quality significantly increased model's predictive power with an R² change (ΔR²) by 3.5% for PCS (adjusted R² = 0.27) and by 2.9% for MCS (adjusted R² = 0.48); for the other SF-12 components ΔR² ranged between 1.4% and 4.6%. ESS, STOP-Bang, ISI scores, all exerted clear effects on PCS and MCS in an individual regression models. Our results confirm and extend the findings of studies from Western societies and strongly support the importance of sleep for HRQoL. Elaboration of intervention programs designed to strengthen sleep-related health care and thereof HRQoL is especially important in the developing world.

Circadian rhythms of melatonin and peripheral clock gene expression in idiopathic REM sleep behavior disorder.

OBJECTIVE: To evaluate changes in the expression of clock genes and melatonin levels in patients with idiopathic REM sleep behavior disorder (RBD) as a potential early stage of synucleinopathies. METHODS: We assessed the rhythmicity of circadian clock genes using real time-quantitative polymerase chain reaction and 24-h blood melatonin profiles using radio-immunoassay in 10 RBD patients and nine age-matched controls. RESULTS: The RBD patients did not show circadian rhythmicity for clock genes Per2, Bmal1, and Nr1d1 but the rhythmicity of Per 1 remained, and the amplitude of Per3 was diminished. The 24-h melatonin rhythm did not differ between RBD patients and healthy control subjects. Melatonin profile in RBD patients was delayed by 2 h compared to controls, the habitual sleep phases were phase delayed by about 1 h, however no phase shift occurred in any of the clock genes studied. The control group had stable acrophases of melatonin rhythms of approximately 5 h whereas the RBD patients had a more dispersed range over 11 h. CONCLUSIONS: Our results suggest that RBD could be associated with altered expression of clock genes and delayed melatonin secretion. Thus, we argue that circadian system dysregulation could play a role in RBD.

Cardiac variability and heart-rate increment as a marker of sleep fragmentation in patients with a sleep disorder: a preliminary study.

STUDY OBJECTIVES: The ratio between the heart-rate increment to total power spectral density (%VLFI) has been introduced as a sensitive measure of sleep-related breathing disorders (SRBD). Since a complex interaction is present between sleep disorders and occurrence of arousals, we hypothesized that %VLFI and other indexes of heart-rate variability (HRV) measures reflect the degree of sleep fragmentation. METHODS: The high- and low-frequency peaks from spectral analysis (FFT) of R-R intervals, the HRV changes using wavelet transform (WT), the geometric and time domain HRV, and the %VLFI were measured in 336 sleep studies performed in patients with insomnia, SRBD and restless legs syndrome/periodic limb movement disorder (RLS/PLMD). The ability of HRV measures to assess sleep fragmentation was examined by correlation analysis and from the area under the receiver operating characteristic (ROC) curve. RESULTS: The ratio of low frequency to high frequency (LF/HF ratio) at the FFT and WT and the %VLFI were higher in patients with SRBD and RLS/PLMD, compared with patients with insomnia. These measures were related to the arousal (MA) index as well as to the apnea-hypopnea index, oxygen desaturations, and periodic leg movement index (p < .001). The presence of a sleep fragmentation defined as an MA index > 20 was well detected by the %VLFI (ROC area: 0.66 +/- 0.03) and the LF/HF ratio at WT (ROC area: 0.66 +/- 0.03). CONCLUSION: The %VLFI and LF/HF ratio provide indirect measures of sleep fragmentation, suggesting that HRV measures during sleep assess more the associated sleep fragmentation than the presence of a specific sleep disorder.

Sleep quality among internally displaced Georgian adolescents and population-based controls.

Sleep problems in children and adolescents are a significant public health concern and may be linked to a variety of psychoemotional difficulties. This study aimed to evaluate sleep quality and associated factors in conflict-affected Georgian adolescents after 9 months of forced displacement. Thirty-three internally displaced adolescents (mean age 11.4 years) and 33 adolescents (mean age 10.8 years) from the general population completed the Epworth Sleepiness Scale and the Children's Depression Inventory (CDI). Parents completed the Children's Sleep-Wake Scale and provided information on their socioeconomic status (SES) and the adolescents' sleep behavior, academic performance, and peer social relationships. The groups differed significantly in sleep quality, peer relationships, SES, and CDI scores. In the internally displaced group, the only significant predictor of sleep quality was SES, which increased the predictive capacity of the model (demographic and psychosocial variables) by 20% in the hierarchical analyses. The most significant predictor in the non-internally displaced group was CDI. This research indicates that displacement may affect sleep quality and psychosocial functioning. The importance of family SES as a contributing factor to displaced adolescents' poor sleep quality is highlighted. An integrated approach designed to improve the psychosocial environment of internally displaced adolescents is needed for their protection.

Sleep-wake patterns and sleep quality in urban Georgia.

OBJECTIVES: Sleep problems represent a worldwide health concern but their prevalence and impacts are unknown in most non-European/North American countries. This study aimed to evaluate sleep-wake patterns, sleep quality and potential correlates of poor sleep in a sample of the urban Georgian population. METHODS: Analyses are based on 395 volunteers (267 females, 128 males, aged 20-60 years) of the Georgia Somnus Study. Subjects completed the Pittsburgh Sleep Quality Index (PSQI) and the Beck Depression Inventory-Short Form. Sociodemographic information and self-reported height and weight were collected. RESULTS: 43% of subjects had poor sleep quality (PSQI > 5). Further, 41% had low sleep efficiency, 27.6% slept 6 hours or less, 32.4% went to bed after midnight, 27.6% snored, 10.6% were taking sleep medication, and 26.8% had sleep maintenance problems as occurring three or more times a week. The latest bedtime, rise time, and gender effect on these variables were found in the age group 20-29 years. PSQI global score showed a significant age but not gender difference. The economic status and the depression score were two significant predictors of sleep quality. CONCLUSIONS: Poor sleep quality has a high prevalence and is strongly linked to the economic status. Study findings call for a global assessment of sleep problems in countries where sleep disturbances represent an insufficiently recognized public health issue.

Circadian Dexras1 in rats: Development, location and responsiveness to light.

Dexras1 has been shown to exhibit clock-dependent rhythm in mice suprachiasmatic nucleus (SCN), and its genetic deletion modulates circadian responses to photic and nonphotic cues. We show that the rhythmic expression of Dexras1 mRNA and protein in rat SCN already oscillates with low amplitude at postnatal day 3 and can be detected as early as embryonic day 20. In contrast, its expression in peripheral tissues is not rhythmic in adult rats either. The Dexras1 protein is expressed predominantly in the dorsomedial part of the SCN and the light pulse has only a limited effect on its expression. Our data provide the descriptive basis for speculation about the Dexras1 involvement in the rat circadian physiology.

Sleep disturbances in patients treated for panic disorder.

BACKGROUND AND PURPOSE: Disturbed night sleep is a common complaint of patients with panic disorder. The aim of the present study was to demonstrate whether the sleep disturbances can be successively influenced by the standard therapy for treating panic disorder. PATIENTS AND METHODS: Psychiatric examinations of 20 outpatients with panic disorder were supplemented with a study of sleep quality using standardised interviews, sleep logs and polysomnographic recordings. RESULTS: A statistical comparison of data showed that reduced anxiety after successful treatment of panic disorder was not necessarily followed by improved sleep parameters. CONCLUSION: The results suggest that the conventional therapy applied to these patients is not sufficient to treat the co-existing insomnia. Consequently, it seems to be of importance to supplement the treatment of panic disorders with specific treatment of the sleep disturbance.

Family studies in insomnia.

OBJECTIVE: Several predisposing factors to insomnia have been hypothesized, including a familial component; however, few studies have focused on this topic. The aim of this study is to evaluate the prevalence of insomnia among first-degree relatives of chronic insomniacs and to compare the symptoms between sporadic and familial insomnia. METHODS: Two hundred fifty-six consecutive chronic insomniacs completed a clinical interview, psychometric questionnaires, a questionnaire on the family history of insomnia and, when indicated, a polysomnography. A control group was performed to estimate a base-rate incidence of insomnia in their families. RESULTS: Patients with primary (n=77) and psychiatric (n=104) insomnia were definitely included. Of those with primary insomnia, 72.7% reported familial insomnia compared with 24.1% in the noninsomnia control group. Among the psychiatric insomniacs, 43.3% reported familial insomnia. The mother was the relative most frequently affected. Comparisons between the family prevalence rates of insomnia assessed by the probands and by first-degree relatives show high concordance. A tendency to a younger age at onset was observed in familial and primary insomnia. CONCLUSION: This study reports a significant increase of familial aggregation of insomnia, warranting further genetic studies in primary insomnia with early age at onset.

Influence of personality disorder on the treatment of panic disorder--comparison study.

UNLABELLED: Most clinicians tend to believe that the occurrence of the anxiety disorder in comorbidity with a personality disorder often leads to longer treatment, worsens the prognosis, and thus increasing treatment costs. The study is designed to compare the short-term effectiveness of combination of cognitive behavioral therapy and pharmacotherapy in patient suffering with panic disorder with and without personality disorder. METHOD: We compare the efficacy of 6th week therapeutic program and 6th week follow up in patients suffering with panic disorder and/or agoraphobia and comorbid personality disorder (29 patients) and panic disorder and/or agoraphobia without comorbid personality disorder (31 patients). Diagnosis was done according to the ICD-10 research diagnostic criteria confirmed with MINI and support with psychological methods: IPDE, MCMI-III and TCI. Patients were treated with CBT and psychopharmacs. They were regularly assessed in week 0, 2, 4, 6 and 12 by an independent reviewer on the CGI (Clinical Global Improvement) for severity and change, PDSS (Panic Disorder Severity Scale), HAMA (Hamilton Anxiety Rating Scale), SDS (Sheehan Disability Scale), HDRS (Hamilton Depression Rating Scale), and in self-assessments BAI (Beck Anxiety Inventory) and BDI (Beck Depression Inventory). RESULTS: A combination of CBT and pharmacotherapy proved to be the effective treatment of patients suffering with panic disorder and/or agoraphobia with or without comorbid personality disorder. The 12th week treatment efficacy in the patients with panic disorder without personality disorder had been showed significantly better compared with the group with panic disorder comorbid with personality disorder in CGI and specific inventory for panic disorder--PDSS. Also the scores in depression inventories HDRS and BDI showed significantly higher decrease during the treatment comparing with group without personality disorder. But the treatment effect between groups did not differ in objective anxiety scale HAMA, and subjective anxiety scale BAI.

Delayed Effect of the Light Pulse on Phosphorylated ERK1/2 and GSK3ß Kinases in the Ventrolateral Suprachiasmatic Nucleus of Rat.

The intrinsic period of circadian clock in the suprachiasmatic nucleus is entrained to a 24-h cycle by external cues, mainly light. Previous studies have shown that light applied at night induces robust phosphorylation of extracellular-signal-regulated kinase that is necessary to process the light pulse into the phase shift of the clock phase. In this study, we show the persistent downregulation of phosphorylated extracellular-signal-regulated kinase and transient downregulation of phosphorylated glycogen synthase kinase-3beta in the ventrolateral part of the suprachiasmatic nucleus to photic stimuli starting at 2 h after the beginning of the light pulse. As both kinases are involved in regulation of circadian clockwork, we hypothesize that these changes may contribute to the phase-shifting effect of light at night.