Normal Sleep-wake Cycle Research Articles

Considering the impact of shift working on health.

Shift work is necessary for the provision of health services, especially in hospitals as it is the only way to provide continuous care to patients. Working at night is inconsistent with the body's biological clock and night shift working hugely disrupts the circadian and sleep wake cycles. In 2020, the World Health Organization classified night shift working as being a 'probable' class 2A carcinogen and a number of independent cohort studies of both night workers and shift workers have observed increased incidence of certain cancers. Altered sleep timing, food timing and light exposure typical for shift workers leads to an acute circadian disruption and misalignment of regulatory hormones. This straying from synchronisation has been shown to result in individuals being more vulnerable to a number of chronic health conditions. Night shift work disrupts the normal sleep-wake cycle, often leading to shortened sleep duration and excessive fatigue and the results of this are far reaching. This article will explore the full impact of shift working, questioning if current practices employed within the NHS should continue.

Cannabidiol as a candidate pharmacotherapy for sleep disturbance in alcohol use disorder.

Among individuals with alcohol use disorder (AUD), it is estimated that the majority suffer from persistent sleep disturbances for which few candidate medications are available. Our aim wass to critically review the potential for cannabidiol (CBD) as a treatment for AUD-induced sleep disturbance. As context, notable side effects and abuse liability for existing medications for AUD-induced sleep disturbance reduce their clinical utility. CBD modulation of the endocannabinoid system and favorable safety profile have generated substantial interest in its potential therapeutic use for various medical conditions. A number of preclinical and clinical studies suggest promise for CBD in restoring the normal sleep-wake cycle and in enhancing sleep quality in patients diagnosed with AUD. Based on its pharmacology and the existing literature, albeit primarily preclinical and indirect, CBD is a credible candidate to address alcohol-induced sleep disturbance. Well-designed RCTs will be necessary to test its potential in managing this challenging feature of AUD.

Continuous electroencephalography (cEEG) in infants with congenital heart disease (CHD).

Neonates with congenital heart disease (CHD) undergoing cardiopulmonary bypass (CPB) surgery have increased risk of impaired neurodevelopmental outcomes secondary to brain injury. This study aims to characterize pre- and post-operative continuous EEG (cEEG) patterns to detect abnormal cerebral activity in infants with CHD and investigate whether an association exists between the degree of encephalopathy in pre- and post-operative cEEG. This retrospective cohort study conducted between 2010 and 2018 at a tertiary hospital in Cleveland, OH included infants with CHD with cEEG monitoring, who underwent CPB surgery within first6 months of life. Study included 77 patients, of which 61% weremales who were operated at median age 6 days. Pre-operatively, 69% and 87% had normal cEEG and sleep-wake cycles, respectively. Post-operatively, 80% had abnormal cEEG. Longer circulatory arrest time and CPB were associated with lack of continuity (p 0.011), excessive discontinuity (p 0.007) and prolonged inter-burst interval (IBI) duration (p value < 0.001). A significant association existed between severity of encephalopathy in immediate and 24-h post-operative period (p value < 0.001). More than 80% of neonates with CHD have abnormal post-operative EEG. Longer circulatory arrest time and CPB were associated with lack of continuity, excessive discontinuity, and prolonged IBI duration on post-operative EEG. This study shows that majority of neonates with congenital heart disease (CHD) have normal pre-operative EEG with a continuous background and normal sleep-wake cycles. Also, 80% of neonates had abnormal post-operative EEG. Longer duration of arrest time and bypass time was associated with lack of continuity, excessive discontinuity, and prolonged IBI duration during post-operative EEG monitoring. These findings will help clinicians when counseling parents in the intensive care unit, risk stratification, and long-term neurodevelopmental monitoring in these high-risk patients.

1146 SLEEP DEPRIVATION INDUCES AGEING-LIKE CHANGES IN ANTIGRAVITY MUSCLES OF YOUNG ADULT MALE WISTAR RATS

Abstract Introduction Poor muscle health is associated with a series of chronic and metabolic conditions that are prevalent in individuals who chronically experience poor-quality sleep. But there is no study deciphering the role of sleep deprivation on muscle ageing. Therefore, in the present study we have measured the ultrastructure, histopathology, and oxidative stressors in soleus muscle of wistar rat after sleep deprivation and recovery sleep. Material and Methods The experiments were conducted in 18 rats of three groups. Group I rats had normal sleep wake cycle, Group II rats were subjected to 24 h sleep deprivation (SD) by gentle handling method1 and Group III rats had recovery sleep after 24 h SD. At the end of the sleep, sleep deprivation and recovery period, soleus muscle tissue was collected for ultrastructural, histological and oxidative stress markers. Oxidative damage was assessed by lipid peroxidation, catalase activity, reduced glutathione and nuclear labelling of 8-OHdG. The study was conducted as per the guidelines of the Institutional Animal Ethics Committee (960/IAEC/16). Results The data demonstrated that SD leads to ultrastructural changes in soleus muscle which includes sarcolemmal and mitochondrial alterations. In case of histopathological and histomorphological changes there was signs of tissue degeneration, inflammatory infiltrate in type I fibres and muscle atrophy was observed in soleus muscles. There was significant increase in level of 8-OHdG (p=0.02) and malondialdehyde in 24h SD (p=0.02) than control and recovery sleep groups. Moreover, the catalase activity and reduced glutathione level was significantly decreased in 24h SD group (p≤0.02) than control and recovery sleep. Conclusion 24hr sleep deprivation leads to an ageing like state in the skeletal muscle, which was recovered after sleep rebound.

VP.49 Total sleep deprivation leads to changes in neuromuscular junction of soleus muscle in male wistar rats

Skeletal muscle atonia is a prominent feature of rapid eye movement sleep. Neuromuscular junction exhibits high morphological and functional plasticity. Sleep deprivation (SD) may influence NMJ morphology at presynaptic and postsynaptic terminals levels. In the present study, we have looked into the ultrastructural changes in the rat soleus muscle NMJ after sleep, sleep deprivation and recovery sleep. A total of 18 rats were divided into three groups. Group I rats had normal sleep wake cycle, group II rats were subjected to 24 h SD by running wheel method and group III rats had 24h recovery sleep. At the end of the study, soleus muscles were collected for electron microscopic and neurochemical study. Morphometry was performed and neurotransmitters were measured by ELISA. The study was conducted as per the guidelines of the Institutional Animal Ethics Committee (960/IAEC/16). Electron microscopic observation revealed a significant increase in mitochondrial density in 24h SD (p<0.01) as compared to control in presynaptic terminal. Further, in post synapse we found similar increase in SD (p<0.0002). Within group comparison of intact versus altered mitochondria exhibited a significant increase in the diameter of altered mitochondria in all the experimental groups (p≤0.0001). Moreover, within group comparison of area of intact versus altered mitochondria showed significant increase in area of altered mitochondria only in control (p= 0.01) and 24h SD (p= 0.02). Synaptic vesicle density we found to be significantly increased in 24h SD as compared to control (p=0.002), but not in recovery sleep at presynaptic terminal. Interestingly, the number of junctional folds per synapse profile was significantly increased in the 24h SD group as compared to control, (p= 0.002). Also, there was a significant difference between 24hr SD and recovery group (p= 0.002). Concentration of acetylcholine in 24 h sleep deprivation was decreased (p=0.02). In addition, but acetylcholine esterase activity was significantly increased (p= 0.02). The acetylcholine esterase activity did not come back to control level even after 24h of recovery sleep. Pearson correlation between acetylcholine and vesicular density showed found a negative correlation (r= 0.07, p<0.05) in 24h SD. These findings suggest that there are significant changes in neuromuscular junction of soleus muscle after24hr SD. We conclude that sleep plays a key role in NMJ homeostasis.

VP.37 Sleep deprivation induces aging like changes in antigravity muscles of young adult male wistar rats

Sleep is essential for the cellular, organic and systemic functions of an organism. Sleep deprivation is associated with metabolic dysfunction and ageing is so. Muscle health at elderly age is one of the major risk factor. Poor muscle health is associated with a series of chronic and metabolic conditions that are prevalent in individuals who chronically experience poor-quality sleep. But there is no study deciphering the role of sleep deprivation on muscle ageing. Therefore, in the present study we have measured the ultrastructure, histopathology, and oxidative stressors in soleus muscle of wistar rat after sleep deprivation and recovery sleep. The experiments were conducted in18 rats of three groups. Group I rats had normal sleep wake cycle, Group II rats were subjected to 24 h sleep deprivation (SD) by gentle handling method1 and Group III rats had recovery sleep after 24 h SD. At the end of the sleep, sleep deprivation and recovery period, soleus muscle tissue was collected for ultrastructural, histological and oxidative stress markers. Oxidative damage was assessed by lipid peroxidation, catalase activity, reduced glutathione and nuclear labelling of 8-OHdG. The study was conducted as per the guidelines of the Institutional Animal Ethics Committee (960/IAEC/16). The data demonstrated that SD leads to ultrastructural changes in soleus muscle which includes sarcolemmal and mitochondrial alterations. In case of histopathological and histomorphological changes there was signs of tissue degeneration, inflammatory infiltrate in type I fibers and muscle atrophy was observed in soleus muscles. There was significant increase in level of 8-OHdG (p=0.02) and malondialdehyde in 24h SD (p=0.02) than control and recovery sleep groups. Moreover, the catalase activity and reduced glutathione level was significantly decreased in 24h SD group (p≤0.02) than control and recovery sleep. Therefore, we conclude that 24hr sleep deprivation leads to an ageing like state in the skeletal muscle, which was recovered after sleep rebound.

Sleep Disorder and Cocaine Abuse Impact Purine and Pyrimidine Nucleotide Metabolic Signatures.

Disturbances in the circadian rhythm alter the normal sleep-wake cycle, which increases vulnerability to drug abuse. Drug abuse can disrupt several homeostatic processes regulated by the circadian rhythm and influence addiction paradigms, including cravings for cocaine. The relationship between circadian rhythm and cocaine abuse is complex and bidirectional, and disruption impacts both brain function and metabolic profiles. Therefore, elucidating the impact of circadian rhythm changes and cocaine abuse on the human metabolome may provide new insights into identifying potential biomarkers. We examine the effect of cocaine administration with and without circadian rhythm sleep disruption (CRSD) on metabolite levels and compare these to healthy controls in an in vivo study. A metabolomics analysis is performed on the control, CRSD, cocaine, and CRSD with cocaine groups. Plasma metabolite concentrations are analyzed using a liquid chromatography electrochemical array platform. We identify 242 known metabolites compared to the control; 26 in the CRSD with cocaine group, 4 in the CRSD group, and 22 in the cocaine group are significantly differentially expressed. Intriguingly, in the CRSD with cocaine treatment group, the expression levels of uridine monophosphate (p < 0.008), adenosine 5′-diphosphate (p < 0.044), and inosine (p < 0.019) are significantly altered compared with those in the cocaine group. In summary, alterations in purine and pyrimidine metabolism provide clues regarding changes in the energy profile and metabolic pathways associated with chronic exposure to cocaine and CRSD.

Cortical waste clearance in normal and restricted sleep with potential runaway tau buildup in Alzheimer’s disease

Accumulation of waste in cortical tissue and glymphatic waste clearance via extracellular voids partly drives the sleep-wake cycle and modeling has reproduced much of its dynamics. Here, new modeling incorporates higher void volume and clearance in sleep, multiple waste compounds, and clearance obstruction by waste. This model reproduces normal sleep-wake cycles, sleep deprivation effects, and performance decreases under chronic sleep restriction (CSR). Once fitted to calibration data, it successfully predicts dynamics in further experiments on sleep deprivation, intermittent CSR, and recovery after restricted sleep. The results imply a central role for waste products with lifetimes similar to tau protein. Strong tau buildup is predicted if pathologically enhanced production or impaired clearance occur, with runaway buildup above a critical threshold. Predicted tau accumulation has timescales consistent with the development of Alzheimer’s disease. The model unifies a wide sweep of phenomena, clarifying the role of glymphatic clearance and targets for interventions against waste buildup.

Compression Coating Technique and its Formulation in Circadian Rhythm Activity with Chronotherapeutic Drug Delivery System

Background: Circadian rhythms is a natural process that regulates the sleep wake cycle which is associated with several physiological, biochemical, endocrine, behavioural processes in humans and entrainment to light-dark cycle. The activity of Ramelteon is believed to contribute to its sleep-promoting properties and thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle. A tablet can be given before 2 hr of bed time, so the Ramelteon drug shows its effect throughout the night by releasing the active content with lag time followed by sustained action to promote the sleep. Materials and Methods: Chronotherapeutic drug delivery system were prepared by compression coating technology using pH independent, hydrophilic and hydrophobic polymers. Results: Drug excipient compatibility indicated that the Ramelteon Active pharmaceutical ingredient (API) is compatibility with the excipients proposed. The X-ray Diffraction (XRD) studies indicated that the crystalline form of the Ramelteon API existed in the finished formulation. Conclusion: The core tablets containing Eudragit RSPO 10mg/tablet and ratio of Ethyl cellulose: Hydroxy propyl methyl cellulose (HPMC) of 70:30 in the outer coating material yielded a desired lag time of 2 hr and drug release for a period of 4 hr to achieve a chronotherapeutic drug delivery system. Ramelteon is an excellent candidate in designing chronotherapeutic drug delivery systems and further in vivo studies can be explored in the treatment of circadian rhythm with sleep wake cycle disorders.

Sepsis triggered oxidative stress-inflammatory axis: the pathobiology of reprogramming in the normal sleep-wake cycle.

In individuals with sepsis-related neurodegenerative illness, sleep and circadian rhythm disturbance are common. The alteration in genomic expression linked with the immune-directed oxidative stress-inflammatory axis is thought to cause these individuals' abnormal sleep. On the other hand, sleep is linked to normal brain activity through common neurotransmitter systems and regulatory mechanisms. Ailments (ranging from cognitive to metabolic abnormalities) are seldom related to aberrant sleep that is made worse by sleep disturbance, which throws off the body's sleep-wake cycle. PubMed/Springer link /Public library of science/ScienceDirect/ Mendeley/Medline and Google Scholar were used to find possibly relevant studies. For the literature search, many keywords were considered, both individually and in combination. 'Sepsis,' 'Epidemiology of sepsis,' 'Sepsis-related hyper inflammation,' 'Relationship of sepsis-associated clock gene expression and relationship of inflammation with the reprogramming of genetic alterations' were some of the key terms utilized in the literature search. Our main objective is to understand better how traumatic infections during sepsis affect CNS processes, particularly sleep, by investigating the pathobiology of circadian reprogramming associated with immune-directed oxidative stress-inflammatory pathway responsive gene expression and sleep-wake behaviour in this study.

Designing the formulations in circadian rhythm activity with chronotherapeutic drug delivery system using ramelteon

Ramelteon is an orally sleep promoting agent that is chemically designated as (S)- N- [2-(1,6,7,8-Tetrahydro-2H-indeno-[5,4b] furan-8-yl) ethyl] propionamide and contains one chiral centre. Ramelteon is a neutral compound with no acid or base functional groups, and as such, its aqueous solubility is independent of pH. The activity of Ramelteon at the MT1and MT2 receptors is believed to contribute to its sleep-promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle. These maintenance of circadian rhythm can be well controlled by designing the formulations with chronotherapeutic drug delivery system. This article summarizes to design, develop and evaluate the chronotherapeutic drug delivery system with various approaches using control release polymers like Eudragit RSPO, Hydroxy propyl methyl cellulose (HPMC), Ethyl cellulose etc., the approaches like compression coating technique, pulsatile drug delivery system and coating technique. The main objective of controlling the drug release pattern is to achieve the lag time of 2 hours followed by drug release profile for 4 hours. Also an attempt has been made to conclude on various approaches studied which can be used in the treatment of circadian rhythm using Ramelteon API.

Evidence for widespread alterations in cortical microstructure after 32\u2009h of sleep deprivation

Cortical microstructure is influenced by circadian rhythm and sleep deprivation, yet the precise underpinnings of these effects remain unclear. The ratio between T1-weighted and T2-weighted magnetic resonance images (T1w/T2w ratio) has been linked to myelin levels and dendrite density and may offer novel insight into the intracortical microstructure of the sleep deprived brain. Here, we examined intracortical T1w/T2w ratio in 41 healthy young adults (26 women) before and after 32 h of either sleep deprivation (n = 18) or a normal sleep-wake cycle (n = 23). Linear models revealed significant group differences in T1w/T2w ratio change after 32 h in four clusters, including bilateral effects in the insular, cingulate, and superior temporal cortices, comprising regions involved in attentional, auditory and pain processing. Across clusters, the sleep deprived group showed an increased T1w/T2w ratio, while the normal sleep-wake group exhibited a reduced ratio. These changes were not explained by in-scanner head movement, and 95% of the effects across clusters remained significant after adjusting for cortical thickness and hydration. Compared with a normal sleep-wake cycle, 32 h of sleep deprivation yields intracortical T1w/T2w ratio increases. While the intracortical changes detected by this study could reflect alterations in myelin or dendritic density, or both, histological analyses are needed to clarify the precise underlying cortical processes.

Cerebellar malfunction and postoperative sleep disturbances after general anesthesia: a narrative review.

The cerebellum is widely regarded as a brain region involved in motor processing, non-motor processing, and even sleep-wake cycles. Cerebellar dysfunction may cause changes in the sleep-wake cycle, leading to sleep disturbances. At present, there is limited research on its effect on postoperative sleep after general anesthesia, despite the suspicion of its implication in postoperative sleep disturbances. With this review, we aim to provide a clear and comprehensive review of the cerebellar activity during the normal sleep-wake cycle, the correlation between cerebellar dysfunction and postoperative sleep disturbances, and the effects of general anesthesia on cerebellar dysfunction. Future large-scale multicenter trials are needed to objectively support the present results, identify the initial cerebellar dysfunction to prevent postoperative sleep disturbances, and develop new therapeutic measures targeting sleep disturbances with possible far-reaching implications for neurodegenerative diseases in general.

Prognostic Value of Amplitude-Integrated Electroencephalography in Term Neonates With Encephalopathy

To evaluate the prognostic value of amplitude-integrated EEG in term neonates with encephalopathy. In this prospective observational study we enrolled 58 term neonates with encephalopathy from March, 2019 to March, 2020. Level of alertness was ascertained as per Volpe's classification and tone as per Amiel-Tison scale of tone assessment. Abnormal aEEG was defined as background activity other than continuous normal voltage, or immature or absent sleep-wake cycle, or presence of electrical seizure. Primary outcome was abnormal neurological examination at discharge and/or death prior to discharge. Out of 58 neonates, aEEG was abnormal for 50 (86.2%). There was a statistically significant association between abnormal aEEG findings and primary outcome (P=0.04). The aEEG score cut-off of >2 had satisfactory sensitivity (88.8%) and specificity (79.5%) to predict primary outcome. Abnormal aEEG had good sensitivity but low specificity to predict the primary outcome in term neonates with encephalopathy.

Shift Work and Breast Cancer.

The rates of shift work outside of daylight hours have increased in recent years, and nighttime shift work is now considered a potential carcinogenic occupational exposure. Light at night exposure, lower melatonin production, and the production of stress-related mediators disrupt normal sleep–wake cycles. Women who work lower-wage jobs and part-time workers whose shifts are determined entirely by their supervisors (rotating shifts) may be subject to stress related to efforts to align childcare and other needs with the unpredictable nature of rotating shift work. The causal link between breast cancer and the sleep cycle or circadian disruption are yet to be established; however, disruption of the circadian cycles by light at night exposure or chronic exposure to stress-related mediators have all been linked to the increased risk of breast cancer. We review the existing literature on shift work and breast cancer, identify knowledge gaps, and suggest future directions for research.

Sleep and sleep deprivation differentially alter white matter microstructure: A mixed model design utilising advanced diffusion modelling

Sleep deprivation influences several critical functions, yet how it affects human brain white matter (WM) is not well understood. The aim of the present work was to investigate the effect of 32 hours of sleep deprivation on WM microstructure compared to changes observed in a normal sleep-wake cycle (SWC). To this end, we utilised diffusion weighted imaging (DWI) including the diffusion tensor model, diffusion kurtosis imaging and the spherical mean technique, a novel biophysical diffusion model. 46 healthy adults (23 sleep deprived vs 23 with normal SWC) underwent DWI across four time points (morning, evening, next day morning and next day afternoon, after a total of 32 hours). Linear mixed models revealed significant group × time interaction effects, indicating that sleep deprivation and normal SWC differentially affect WM microstructure. Voxel-wise comparisons showed that these effects spanned large, bilateral WM regions. These findings provide important insight into how sleep deprivation affects the human brain.

Electroacupuncture: A New Approach for Improved Postoperative Sleep Quality After General Anesthesia.

General anesthesia produces a state of drug-induced unconsciousness that is controlled by the extent and duration of administered agents. Whether inhalation or intravenous in formulation, such agents may interfere with normal sleep–wake cycles, impairing postoperative sleep quality and creating complications. Electroacupuncture is a new approach widely applied in clinical practice during recent years. This particular technology helps regulate neurotransmitter concentrations in the brain, lowering norepinephrine and dopamine levels to improve sleep quality. It also alleviates surgical pain that degrades postoperative sleep quality after general anesthesia by downregulating immune activity (SP, NK-1, and COX-1) and upregulating serotonin receptor (5-HT1AR, 5-HT2AR) and endocannabinoid expression levels. However, large-scale, multicenter studies are still needed to determine the optimal duration, frequency, and timing of electroacupuncture for such use.

A cross-sectional study on the preponderance of stress and depression among medical students and their association with various recent factors

Background: Stress and depression among medical students are the prevalent and global concern these days. Stress is a critical risk factor for depression as it can contribute to depression through various pathways. Stress is multifactorial in causation which can be associated or attributable to depression. Aims: The aim of this study is to evaluate and elicit the levels of stress and depression in association with various recent factors, accounting and resulting to stress and depression. Subjects and Methods: This is a cross-sectional study conducted among medical students of a well-recognized medical college. Analysis sheets consisting of Beck's Depression Inventory (BDI), Perceived Stress Scale (PSS), and other criteria comprising demographic details such as gender, age, year of studying and some associated factors which include appetite, gastrointestinal (GI) problem, sleep, social feelings, body mass index (BMI), and hair fall adding to stress and depression were made to fill by 288 medical students of a medical college. Results: Majority of the study participants have moderate-or-high levels of stress but no depression. Nearly 46.5% of the study participants have normal values of BMI, and 42.7% are over the levels of their normal BMI. Nearly 59.7% of the total students have hair fall, 76.7% have normal sleep-wake cycle, 77.4% have normal social feelings, 75.6% have normal appetite, and 84.7% do not have any GI problems. When the relation between stress and these study variables was observed, the association between BMI and hair fall was found to be significant. Conclusions: First-year students feel more stressed that could be due to their recent entry into the course. Female students are more prone to these stressors and depressors. Juniors are more stressed when compared to senior students.

Embracing Different Decision-making Styles

Embracing Different Decision-making Styles

3.25 INFANT DELIRIUM: DEVELOPMENTAL CHALLENGES TO INTERPRETATION OF LEVEL OF CONSCIOUSNESS WITH BEDSIDE SCREENING

Delirium assessments in newborn infants pose specific challenges because of the pattern of their unique sleep-wake cycle and rapid developmental evolution. We review the importance of understanding normal sleep-wake cycles in infants when assessing the level of consciousness (LOC), a key aspect of delirium assessment.