Delayed circadian rhythms and substance abuse: dopamine transmission’s time has come

Disrupted sleep and circadian rhythms are linked with substance abuse risk. Human studies that investigate relationships between sleep, circadian rhythm, and substance use reward generally rely on indirect means to infer dopaminergic function, such as functional magnetic resonance imaging. In this issue of the JCI, Zhang and colleagues used positron emission tomography (PET) to image striatal dopamine D1 (D1R) and D2/3 receptor (D/3R) availability in healthy adults. The authors assessed rest-activity rhythms, then conducted PET scans using radioligand antagonists selective for D1 receptors or D2/D3 receptors to measure D1R and D2/3R availability. They also measured the subjective drug effects of oral methylphenidate. Higher D1R availability in caudate and a greater methylphenidate reward sensitivity were associated with delayed rest-activity rhythms. Unexpectedly, lower overall activity was associated with higher D2/3R availability in the nucleus accumbens, which coincided with greater methylphenidate reward score. These findings may inform personalized prevention and/or treatment interventions.     

Methodological issues for studying the rest-activity cycle and sleep disturbances: a chronobiological approach using actigraphy data

Shift work schedules, intensive physical exercise late in the day, psychological stress, or a busy lifestyle might induce disorders of the circadian structure, which can affect health on both the physiological and neurobehavioral levels. Rest-activity rhythm is strongly connected with an organism's circadian structure, and irregular sleep-wake patterns can lead to a disruption of entrainment, resulting in physiological and neurobehavioral dysfunction. Shift nurses are often subject to disturbances in the quality and duration of their sleep, raising the possibility of negative impacts on their health and their patients' safety. Researchers have used actigraphy in a number of studies to assess sleep patterns. Because of the close connection between sleep and circadian structure, it may be useful to extend the evaluation of actigraphy data to the analysis of the rest-activity rhythm with rhythmometric procedures to provide a better understanding of possible sleep disorders in relation to entrainment. Actigraphy is an easy and reliable way to study these rhythms and identify possible circadian-rhythm disorders. In this article, the authors discuss methodological issues concerning the evaluation of the rest-activity rhythm, with a focus on actigraphy.     

Reducing disruption of circadian temperature rhythm following surgery

Temperature and other circadian rhythms are disrupted following surgery and other traumatic events. During recovery, coordination between temperature rhythms and other rhythmic physiologic processes is reduced. Studies of animals and humans have shown that return of synchrony is not immediate, but that it is important in the recovery process. The purpose of this study was to test a combination of cues that have been shown to adjust the timing of circadian temperature rhythm. The combined cues consisted of timed ingestion of caffeine and protein foods and adjustment of the sleep/wake cycle. The intervention was tested in 26 age- and gender-matched maxillofacial surgery patients. Patients were randomly assigned to control or experimental groups. Circadian temperature rhythm was measured by continuous monitoring with axillary probes and miniature recorders before and after surgery. Following surgery, both experimental and control subjects displayed 24-hour circadian temperature rhythms; however, the peak-to-trough difference was decreased more following surgery in the control subjects than in the subjects who had prepared for surgery by practicing the intervention. Control subjects also had less day-to-day stability in the phase of their rhythms following surgery. These results suggest that the intervention reduced circadian disruption following surgery and provides a way for patients to prepare themselves to resist rhythm changes.     

Biological rhythms and sleep

Sleep is regulated by dual oscillatory processes, one is the hierarchical multi oscillatory circadian system and the other is the ultradian rest-activity cycle. The circadian system is composed of the central clock located in the suprachiasmatic nucleus and the peripheral clocks in a variety of tissues which express overt rhythms. The peripheral clock(s) for sleep and wakefulness in nocturnal rodents are strongly regulated by the central clock. By contract, the peripheral clock(s) in humans is more independent of and easily desynchronized from the central clock. Nocturnal sleep is characterized by REM and nonREM cycles which appear alternatively at 1.5 to 2 hour intervals. The origin of ultradian rhythm is not known. We propose an integrated model for the regulation of sleep and wakefulness by two different oscillatory systems.     

Circadian regulation of human sleep and age-related changes in its timing, consolidation and EEG characteristics.

The light-entrainable circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus regulates the timing and consolidation of sleep by generating a paradoxical rhythm of sleep propensity; the circadian drive for wakefulness peaks at the end of the day spent awake, ie close to the onset of melatonin secretion at 21.00-22.00 h and the circadian drive for sleep crests shortly before habitual waking-up time. With advancing age, ie after early adulthood, sleep consolidation declines, and time of awakening and the rhythms of body temperature, plasma melatonin and cortisol shift to an earlier clock hour. The variability of the phase relationship between the sleep-wake cycle and circadian rhythms increases, and in old age sleep is more susceptible to internal arousing stimuli associated with circadian misalignment. The propensity to awaken from sleep advances relative to the body temperature nadir in older people, a change that is opposite to the phase delay of awakening relative to internal circadian rhythms associated with morningness in young people. Age-related changes do not appear to be associated with a shortening of the circadian period or a reduction of the circadian drive for wake maintenance. These changes may be related to changes in the sleep process itself, such as reductions in slow-wave sleep and sleep spindles as well as a reduced strength of the circadian signal promoting sleep in the early morning hours. Putative mediators and modulators of circadian sleep regulation are discussed.     

Characteristics of infradian and circadian rhythms in the persistent vegetative state

This retrospective study investigated the circadian and infradian characteristics of blood pressure and heart rate in 26 patients with traumatic head injury in a persistent vegetative state (PVS). Systolic and diastolic blood pressures and heart rate were measured every hour for the first 240 h (10 days) following hospital admission. These data were analysed for the presence of circadian and infradian rhythms using the least-squares fit of the cosine function with the single cosinor method. Infradian rhythms were defined as biological rhythms with a period of approximately 7 days (circaseptan rhythms). All the patients studied had circadian and circaseptan rhythms of systolic and diastolic blood pressures and heart rate. The amplitudes of all the circaseptan rhythms were significantly greater than those of the corresponding circadian rhythms. It was concluded that there was an altered association between circadian and infradian blood pressure and heart rate rhythms in patients in a PVS. Circadian and infradian rhythms were present, but the infradian rhythm had a greater amplitude than the circadian rhythm.     

Circadian rhythms in drug action and drug metabolism in the mouse.

The relationship between circadian rhythms in the pharmacological actions of meperidine and hexobarbital and similar rhythms in the hepatic metabolism of these drugs was examined in mice under a variety of environmental alterations to determine whether such rhythms may be causally related. The rate of metabolism of p-nitroanisole and hexobarbital by hepatic 9000 X g supernatant fractions was found to be higher at 2400 hours (middark phase) compared to 1200 hours (midlight phase). The rhythms in in vitro hexobarbital and in vivo merperidine metabolism were inversely related in time with similar rhythms in duration of hexobarbital sleep time and meperidine analgesia. Exposure of mice to continuous lighting abolished the rhythms in metabolism and response to meperidine and hexobarbital. Reversal of the usual lighting cycle inverted the rhythm in hexobarbital metablism while abolishing the rhythm in pharmacological response to hexobarbital; meperidine was similarly affected. Adrenalectomy abolished the rhythm in hexobarbital metabolism, diminished the amplitude of the circadian variation in meperidine metabolism and abolished the rhythm in hexobarbital hypnosis and meperidine analgesia. These results indicate that circadian rhythms in the action of hexobarbital and meperidine are well correlated with similar rhythms in the disposition of these drugs.     

Dopamine D1 and D2 receptors are distinctly associated with rest-activity rhythms and drug reward

BACKGROUNDCertain components of rest-activity rhythms such as greater eveningness (delayed phase), physical inactivity (blunted amplitude), and shift work (irregularity) are associated with increased risk for drug use. Dopaminergic (DA) signaling has been hypothesized to mediate the associations, though clinical evidence is lacking.METHODSWe examined associations between rhythm components and striatal D1 (D1R) and D2/3 receptor (D2/3R) availability in 32 healthy adults (12 female, 20 male; age 42.40 ± 12.22 years) and its relationship to drug reward. Rest-activity rhythms were assessed by 1-week actigraphy combined with self-reports. [¹¹C]NNC112 and [¹¹C]raclopride positron emission tomography (PET) scans were conducted to measure D1R and D2/3R availability, respectively. Additionally, self-reported drug-rewarding effects of 60 mg oral methylphenidate were assessed.RESULTSWe found that delayed rhythm was associated with higher D1R availability in caudate, which was not attributable to sleep loss or so-called social jet lag, whereas physical inactivity was associated with higher D2/3R availability in nucleus accumbens (NAc). Delayed rest-activity rhythm, higher caudate D1R, and NAc D2/3R availability were associated with greater sensitivity to the rewarding effects of methylphenidate.CONCLUSIONThese findings reveal specific components of rest-activity rhythms associated with striatal D1R, D2/3R availability, and drug-rewarding effects. Personalized interventions that target rest-activity rhythms may help prevent and treat substance use disorders.TRIAL REGISTRATIONClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT03190954","term_id":"NCT03190954"}}NCT03190954.FUNDINGNational Institute on Alcohol Abuse and Alcoholism (ZIAAA000550).     

Melatonin: possible implications for the postoperative and critically ill patient

There is increasing interest in the hormone melatonin in postoperative and critically ill patients. The roles of melatonin in the regulation of the sleep-wake cycle, resetting of circadian rhythm disturbances and its extensive antioxidant activity have potential applications in these patient groups. The interaction between melatonin and the stresses of surgery and critical illness are explored in the context of circadian rhythms, sleep disorders and delirium. The antioxidant activity is discussed in terms of the reduction of ischaemic reperfusion injury, prevention of multi-organ failure and treatment of sepsis. Unfortunately, there is currently insufficient evidence that exogenous melatonin is effective in preventing or treating postoperative delirium. Similarly, in the critically ill patient, sleep disorders are associated with disrupted melatonin circadian secretion, but there is a paucity of data to support routine exogenous melatonin supplementation. More clinical evidence to confirm the potential benefits of melatonin therapy is required before it can be routinely used in the postoperative or critically ill patient.     

睡眠节律紊乱导致阿尔兹海默病相关机制的研究进展

认知功能损害患者睡眠障碍患病率高,表现形式多样,主要包括失眠、日间过度思睡、睡眠呼吸障碍、异态睡、不宁腿综合征、睡眠节律紊乱等。阿尔茨海默病(Alzheimer disease,AD)是最常见的认知损害类型。73%的中国汉族AD患者伴有睡眠障碍,其中53%伴有不同程度的睡眠节律紊乱。AD患者睡眠障碍在病程后期较为突出,因此睡眠节律紊乱一直被认为是AD相关神经退行性变的结果,如"日落现象"。但近期研究表明,睡眠节律紊乱很可能参与AD发生的始动环节。国外前瞻性随访研究发现,认知正常老年人群睡眠节律紊乱发生5年后更易发生AD。目前,关于睡眠节律紊乱通过何种途径促使神经系统退行性变发生的研究尚不深入。本文对睡眠节律紊乱引发AD相关病理、生物标志物变化进而导致AD发生的机制作一综述。     

Comparison between fatigue, sleep disturbance, and circadian rhythm in cancer inpatients and healthy volunteers: evaluation of diagnostic criteria for cancer-related fatigue

The aim of this study was to evaluate whether diagnostic criteria for cancer-related fatigue syndrome (CRFS) could be rigorously applied to cancer inpatients, and to explore the relationship between subjective fatigue and objective measures of physical activity, sleep, and circadian rhythm. Female cancer patients (n=25) and a comparison group of subjects without cancer (n=25) were studied. Study participants completed a structured interview for CRFS and questionnaires relating to fatigue, psychological symptoms, and quality of life (QoL). Wrist actigraphs worn for 72 hours were used as an objective measure of activity, sleep, and circadian rhythm. Compared to controls, cancer patients were more fatigued, had worse sleep quality, more disrupted circadian rhythms, lower daytime activity levels, and worse QoL. After exclusion of subjects with "probable" mood disorders, the prevalence of CRFS was 56%. Fatigue severity among the cancer patients was significantly correlated with low QoL, depression, constipation, and decreased self-reported physical functioning. It can be concluded that the diagnostic criteria for CRFS can be applied to cancer inpatients but strict application requires a rigorous assessment of psychiatric comorbidity. Despite cancer inpatients having greater impairments of sleep and circadian rhythm, it was found that fatigue severity did not appear to be related to these impairments.     

睡眠节律紊乱与阿尔兹海默病研究进展

认知功能损害患者睡眠障碍患病率高,表现形式多样,主要包括：失眠、日间过度思睡、睡眠呼吸障碍、异态睡、不宁腿综合征、睡眠节律紊乱等。阿尔茨海默病(Alzheimer"s disease,AD)是最常见的认知损害类型,73%的中国汉族AD患者伴有睡眠障碍,其中53%伴有不同程度的睡眠节律紊乱。AD患者睡眠障碍在病程中后期较为突出,所以一直以来睡眠节律紊乱都被认为是AD相关神经退行性变的结果,例如“日落现象”,患者一到傍晚就焦虑不安、难以入睡,而白天则睡眠过多。但近期研究表明,睡眠节律紊乱很可能参与AD发生的始动环节。国外前瞻性的随访研究发现,睡眠节律紊乱的认知正常老年人群,在5-10年后更容易发生AD。目前,关于睡眠节律紊乱究竟通过何种途径促使神经系统退行性变发生的研究尚不深入,本文将回顾睡眠节律紊乱引发AD相关病理、生物标记物变化的研究报道。     

How to use light and dark to produce circadian adaptation to night shift work.

The circadian rhythms of night shift workers do not usually adjust to their unusual work and sleep schedules, reducing their quality of life and producing potentially dangerous health and safety problems. This paper reviews field studies of simulated night work in which shifted light-dark cycles were constructed with artificial bright or medium-intensity light to produce circadian adaptation, ie the shifting of circadian rhythms to align with night work and day sleep schedules. By using these studies we describe fundamental principles of human circadian rhythms relevant to producing circadian adaptation to night shift work at a level designed for the reader with only a basic knowledge of circadian rhythms. These principles should enable the reader to start designing work/sleep-light/dark schedules for producing circadian adaptation in night shift workers. One specific schedule is presented as an example. Finally, we discuss phase-response curves to light and clarify common misconceptions about the production of circadian rhythm phase shifts.     

Rest/activity rhythm is related to the coexistence of pain and sleep disturbance among advanced cancer patients with pain

Purpose

This study aimed to explore the relationships among pain, sleep disturbance, and circadian rhythms in advanced cancer patients.

Methods

This cross-sectional study was conducted in 68 cancer patients from the oncology inpatient unit of a teaching hospital. Their demographic and medical characteristics, questionnaire surveys, including Brief Pain Inventory-Chinese version and Pittsburgh Sleep Quality Index Taiwanese version, and sleep logs and actigraphic recordings in consecutive 3 days and nights were collected and analyzed.

Results

The mean (SD) scores for autocorrelation coefficient at 24 h (r24) and dichotomy index (I<O) were 0.19 (0.16) and 85.29 % (0.13 %), respectively, indicating dampened circadian rhythms in participants. The mean (SD) worst pain score was 5.47 (2.70). The sleep quality global score ranged 4?～?19 with a mean (SD) of 11.19 (4.05). The worst pain levels, the Pittsburgh Sleep Quality Index (PSQI) global score, and most sleep parameters measured by actigraphy were significantly correlated with r24 and I<O. The worst pain score was significantly correlated with the PSQI global score (r?=?0.69, p?<?0.01). The Goodman version of the Sobel test further demonstrated that 45.77 % of the total effect was mediated by pain intensity (t?=?2.76, p?=?0.005). Pain was a complete mediator between circadian rhythms and sleep quality.

Conclusions

The rest/activity rhythm influences the coexisting pain and sleep disturbances. Pain functions as a complete mediator in their relationship. Interventions that improve rest/activity rhythms may improve the management of pain and sleep disturbances in cancer patients.     

观察右美托咪定辅助镇静对全身麻醉患者手术后睡眠质量的影响

目的:观察右美托咪定辅助镇静对全身麻醉患者手术后睡眠质量的影响。方法:选取2018年5月至2020年5月新疆克拉玛依市中心医院收治的全身麻醉患者200例作为研究对象,按随机数字表法分为观察组和对照组,每组100例。对照组给予丙泊酚全麻,观察组给予丙泊酚全麻联合右美托咪定辅助镇静。采用匹兹堡睡眠指数量表(Pittsburgh Sleep Quality Index,PSQI)对2组患者手术后睡眠质量情况进行评估比较,采用Ramsay镇静评分分析2种麻醉镇静方式对患者手术后复苏及镇静情况的影响,利用阿森斯失眠量表(Athens Insomnia Scale,AIS)对患者手术后失眠情况进行评估,同时统计2组患者不良反应发生率。结果:手术后,观察组所需苏醒时间、拔管时间与对照组比较,差异均无统计学意义(P>0.05);拔管后10 min、拔管后20 min,观察组的Ramsay镇静评分均高于对照组,2组比较差异有统计学意义(P<0.05);手术后1 d、手术后4 d、手术后7 d,观察组AIS失眠评分显著低于对照组,2组比较差异有统计学意义(P<0.05);手术前、手术当天,观察组与对照组的PSQI评分比较,差异无统计学意义(P>0.05);手术后4 d、出院前1 d,观察组的PSQI评分明显低于对照组,2组比较差异均有统计学意义(P<0.05);手术后,观察组不良反应总发生率显著低于对照组,2组比较差异均有统计学意义(P<0.05)。结论:对接受全身麻醉手术治疗的患者给予右美托咪定辅助镇静治疗,不仅能帮助患者维持术中麻醉镇静状态,还可有效改善患者手术后睡眠质量。     

Changes in the first postoperative night bispectral index of patients after thyroidectomy with different types of primary anesthetic management: a randomized controlled trial

Despite major advances in anesthesia management and developments in anesthetic agents, postoperative sleep disturbances remain dissatisfactory for many patients. We hypothesized that propofol might have a subtle influence on sleep after thyroidectomy compared to sevoflurane. A randomized, single-blinded, controlled trial was conducted at the First Hospital of China Medical University from October 2014 to October 2015. One hundred and twenty-four patients undergoing thyroidectomy were enrolled and received sevoflurane (sevoflurane group) or propofol (propofol group) as anesthesia maintenance. Major assessments were made during the operation (different types of anesthetic management) and on the first postoperative night (sleep status). The primary outcome was postoperative sleep status, measured by the BIS-Vista monitor on the first night after surgery between propofol and sevoflurane groups. A total of 105 patients (79 women, 26 men; mean age 49 years; range 18–65 years) were included in the final study sample. All patients in both groups showed one of the five sleep patterns classified by this trial. The BIS-area under the curve was decreased, the sleep efficiency index was significantly increased, and the durations of postoperative sleep and sleep stage N3 were increased by 110.5 and 36.5 min per patient, respectively, in the propofol compared to the sevoflurane group. Propofol might preserve sleep time immediately after thyroidectomy. Clinical Trials.gov identifier: NCT 02146976.     

轮班制对ICU女护士昼夜活动节律与疲倦的影响

目的 比较ICU女护士不同工作时长（8 h和12 h）昼夜活动节律相关指标与工作前后疲倦的差异,并分析疲倦程度的影响因素。 方法 采用便利抽样法选取北京市3所三级甲等综合医院228名ICU女护士,通过一般资料问卷、李氏疲倦量表（Lee's Fatigue Scale）进行调查,使用活动记录仪实施客观测量。 结果 护士昼夜活动节律相关指数中静息-活动周期（r24）和昼夜节律整体偏低,8 h轮班制护士总睡眠时间明显低于12 h轮班制护士,差异有统计学意义（P<0.001）。8 h轮班制护士在值夜班前的疲倦程度比12 h轮班制护士高,但12 h轮班制护士在值夜班后的疲倦程度比8 h轮班制护士高,差异有统计学意义（P<0.001）。多元线性回归分析显示,昼夜活动节律指标中的工作时活动水平、总睡眠时间、静息-活动周期（r24）是工作后疲倦度的显著预测因子,尤其是ICU12 h轮班制护士。 结论 通过昼夜活动节律相关指标与工作前后疲倦度相关性探讨,有助于护理管理者了解护士工作状态,为改善ICU护士轮班方式、限定夜班数量及量化工作负荷提供依据。     

Effect on sleep of posterior hypothalamus stimulation in cluster headache

OBJECTIVE: To evaluate the structure and quality of sleep and the circadian rhythm of body core temperature (BcT degrees ) in patients with drug-resistant chronic cluster headache (CH) before and during deep brain stimulation (DBS) of the posterior hypothalamus. BACKGROUND: Chronic CH is a severe primary headache and frequently associated with disturbances in sleep. Posterior hypothalamus DBS is performed as an effective treatment of drug-resistant chronic CH. The effects of posterior hypothalamus DBS on sleep and the circadian rhythm of BcT degrees are unknown. METHODS: Three male patients with chronic drug-resistant CH underwent 48-hour consecutive polysomnography (PSG) by means of the VITAPORT system with determination of BcT degrees by means of a rectal probe. Recordings were done before electrode implantation in the posterior hypothalamus and after optimized DBS of posterior hypothalamus. RESULTS: Before electrode implantation PSG showed nocturnal CH attacks, reduced sleep efficiency, fragmented sleep and increased periodic limb movements in sleep (PLMS). During DBS nocturnal CH attacks were abolished and sleep efficiency and PLMS improved. BcT degrees circadian rhythm was normal both before and during DBS. CONCLUSIONS: Our data show that DBS of posterior hypothalamus in drug-resistant chronic CH is effective in curtailing nocturnal CH attacks, and is associated with improved sleep structure and quality. Chronic CH displays a normal circadian rhythm of BcT degrees, unchanged during hypothalamic DBS.     

Melatonin as a regulator of human sleep and circadian systems

Melatonin(N-acetyl-5-methoxytryptamine) is synthesized from tryptophan and is intensively secreted into the blood only in darkness (nighttime) by the pineal gland. Melatonin is not only the most reliable marker of internal circadian phase but also a potent sleep-promoting and circadian phase regulatory agent in humans. There is evidence that daytime administered melatonin is able to exhibit short-acting hypnagogic effect and phase-shifting of the circadian rhythms such that sleep timing and associated various physiological functions realign at a new desired phase. Under favor of these properties, melatonin and melatonin receptor agonists have been shown to be potent therapeutic agents for the treatment of circadian rhythm sleep disorders and some type of insomnia.     

Body-temperature circadian rhythm in 67 patients after heart valve replacement surgery secondary to valvular heart disease

PurposePatient body temperature was monitored after cardiac valve replacement, in order to explore the characteristics of body-temperature circadian rhythm and the factors influencing that rhythm.MethodsA cohort of 67 patients who received cardiac valve replacement in a Fuzhou, Fujian province, China, general hospital underwent temperature measurements and analysis (by cosine curve) of their body-temperature circadian rhythm. A biological rhythm model was established through principal component analysis and evaluation of biological rhythm features. Multiple circadian parameters were included through linear regression analysis.ResultsPatients' temperature after cardiac valve replacement exhibited circadian characteristics (p < 0.05), among which the scores of temperature mesor, amplitude, and acrophase were respectively (37.61 ± 0.08), (0.10 ± 0.09), and −33 (–355, –119). Body-temperature rhythms were influenced by both gender and cardiopulmonary bypass time (p < 0.05).ConclusionAlthough some patients' circadian characteristics disappeared after cardiac valve replacement, circadian rhythms remained intact for most patients. Measures that were found to mitigate body-temperature circadian rhythm disruption included building a natural rhythm of light/darkness and decreasing cardiopulmonary bypass time.