Abstract
Study Objectives
Sleep regularity predicts many health-related outcomes. Currently, however, there is no systematic approach to measuring sleep regularity. Traditionally, metrics have ...assessed deviations in sleep patterns from an individual’s average; these traditional metrics include intra-individual standard deviation (StDev), interdaily stability (IS), and social jet lag (SJL). Two metrics were recently proposed that instead measure variability between consecutive days: composite phase deviation (CPD) and sleep regularity index (SRI). Using large-scale simulations, we investigated the theoretical properties of these five metrics.
Methods
Multiple sleep–wake patterns were systematically simulated, including variability in daily sleep timing and/or duration. Average estimates and 95% confidence intervals were calculated for six scenarios that affect the measurement of sleep regularity: “scrambling” the order of days; daily vs. weekly variation; naps; awakenings; “all-nighters”; and length of study.
Results
SJL measured weekly but not daily changes. Scrambling did not affect StDev or IS, but did affect CPD and SRI; these metrics, therefore, measure sleep regularity on multi-day and day-to-day timescales, respectively. StDev and CPD did not capture sleep fragmentation. IS and SRI behaved similarly in response to naps and awakenings but differed markedly for all-nighters. StDev and IS required over a week of sleep–wake data for unbiased estimates, whereas CPD and SRI required larger sample sizes to detect group differences.
Conclusions
Deciding which sleep regularity metric is most appropriate for a given study depends on a combination of the type of data gathered, the study length and sample size, and which aspects of sleep regularity are most pertinent to the research question.
IMPORTANCE: Impaired sleep and alertness are some of the most common nonmotor manifestations of Parkinson disease (PD) and currently have only limited treatment options. Light therapy (LT), a widely ...available treatment modality in sleep medicine, has not been systematically studied in the PD population. OBJECTIVE: To determine the safety and efficacy of LT on excessive daytime sleepiness (EDS) associated with PD. DESIGN, SETTINGS, AND PARTICIPANTS: This randomized, placebo-controlled, clinical intervention study was set in PD centers at Northwestern University and Rush University. Participants were 31 patients with PD receiving stable dopaminergic therapy with coexistent EDS, as assessed by an Epworth Sleepiness Scale score of 12 or greater, and without cognitive impairment or primary sleep disorder. Participants were randomized 1:1 to receive bright LT or dim-red LT (controlled condition) twice daily in 1-hour intervals for 14 days. This trial was conducted between March 1, 2007, and October 31, 2012. Data analysis of the intention-to-treat population was conducted from November 1, 2012, through April 30, 2016. MAIN OUTCOMES AND MEASURES: The primary outcome measure was the change in the Epworth Sleepiness Scale score comparing the bright LT with the dim-red LT. Secondary outcome measures included the Pittsburgh Sleep Quality Index score, the Parkinson’s Disease Sleep Scale score, the visual analog scale score for daytime sleepiness, and sleep log–derived and actigraphy-derived metrics. RESULTS: Among the 31 patients (13 males and 18 females; mean SD disease duration, 5.9 3.6 years), bright LT resulted in significant improvements in EDS, as assessed by the Epworth Sleepiness Scale score (mean SD, 15.81 3.10 at baseline vs 11.19 3.31 after the intervention). Both bright LT and dim-red LT were associated with improvements in sleep quality as captured by mean (SD) scores on the Pittsburg Sleep Quality Index (7.88 4.11 at baseline vs 6.25 4.27 after bright LT, and 8.87 2.83 at baseline vs 7.33 3.52 after dim-red LT) and the Parkinson’s Disease Sleep Scale (97.24 22.49 at baseline vs 106.98 19.37 after bright LT, and 95.11 19.86 at baseline vs 99.28 16.94 after dim-red LT). Bright LT improved several self-reported mean (SD) sleep metrics, including sleep fragmentation (number of overnight awakenings, 1.51 1.03 at baseline vs 0.92 0.97 after the intervention), sleep quality (sleep diary score, 3.03 1.01 at baseline vs 3.53 0.91 after the intervention), and ease of falling asleep (sleep diary score, 2.32 0.89 at baseline vs 1.83 0.88 after the intervention). Light therapy was associated with increased daily physical activity as assessed by actigraphy (average activity SD counts, 165.01 66.87 at baseline vs 194.59 87.81 after the intervention). CONCLUSIONS AND RELEVANCE: Light therapy was well tolerated and may be a feasible intervention for improving the sleep-wake cycles in patients with PD. Further studies are required to determine optimal parameters of LT for PD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01338649
Many regions and countries are reconsidering their use of Daylight Saving Time (DST) but their approaches differ. Some, like Japan, that have not used DST over the past decades are thinking about ...introducing this twice-a-year change in clock time, while others want to abolish the switch between DST and Standard Time, but don't agree which to use: California has proposed keeping
DST (i.e., all year round), and the EU debates between
Standard Time and
DST. Related to the discussion about DST is the discussion to which time zone a country, state or region should belong: the state of Massachusetts in the United States is considering switching to Atlantic Standard Time, i.e., moving the timing of its
(local time) 1 h further east (which is equivalent to perennial DST), and Spain is considering leaving the Central European Time to join Greenwich Mean Time (GMT), i.e., moving its social timing 1 h further west. A wave of DST discussions seems to periodically sweep across the world. Although DST has always been a political issue, we need to discuss the biology associated with these decisions because the circadian clock plays a crucial role in how the outcome of these discussions potentially impacts our health and performance. Here, we give the necessary background to understand how the
,
,
, time zones, and DST interact. We address numerous fallacies that are propagated by lay people, politicians, and scientists, and we make suggestions of how problems associated with DST and time-zones can be solved based on circadian biology.
The association of irregular sleep schedules with circadian timing and academic performance has not been systematically examined. We studied 61 undergraduates for 30 days using sleep diaries, and ...quantified sleep regularity using a novel metric, the sleep regularity index (SRI). In the most and least regular quintiles, circadian phase and light exposure were assessed using salivary dim-light melatonin onset (DLMO) and wrist-worn photometry, respectively. DLMO occurred later (00:08 ± 1:54 vs. 21:32 ± 1:48; p < 0.003); the daily sleep propensity rhythm peaked later (06:33 ± 0:19 vs. 04:45 ± 0:11; p < 0.005); and light rhythms had lower amplitude (102 ± 19 lux vs. 179 ± 29 lux; p < 0.005) in Irregular compared to Regular sleepers. A mathematical model of the circadian pacemaker and its response to light was used to demonstrate that Irregular vs. Regular group differences in circadian timing were likely primarily due to their different patterns of light exposure. A positive correlation (r = 0.37; p < 0.004) between academic performance and SRI was observed. These findings show that irregular sleep and light exposure patterns in college students are associated with delayed circadian rhythms and lower academic performance. Moreover, the modeling results reveal that light-based interventions may be therapeutically effective in improving sleep regularity in this population.
Endogenous central and peripheral circadian oscillators are key to organizing multiple aspects of mammalian physiology; this clock tracks the day-night cycle and governs behavioral and physiologic ...rhythmicity. Flexibility in the timing and duration of sleep and wakefulness, critical to the survival of species, is the result of a complex, dynamic interaction between 2 regulatory processes: the clock and a homeostatic drive that increases with wake duration and decreases during sleep. When circadian rhythmicity and sleep homeostasis are misaligned-as in shifted schedules, time zone transitions, aging, or disease-sleep, metabolic, and other disorders may ensue.
Summary
The field of “circadian medicine” is a recent addition to chronobiology and sleep research efforts. It represents a logical step arising from the increasing insights into the circadian system ...and its interactions with life in urbanised societies; applying these insights to the health/disease balance at home and in the medical practice (outpatient) and clinic (inpatient). Despite its fast expansion and proliferating research efforts, circadian medicine lacks a formal framework to categorise the many observations describing interactions among the circadian system, sleep, and the health/disease balance. A good framework allows us to categorise observations and then assign them to one or more components with hypothesised interactions. Such assignments can lead to experiments that document causal (rather than correlational) relationships and move from describing observations to discovering mechanisms. This review details such a proposed formal framework for circadian medicine and will hopefully trigger discussion among our colleagues, so that the framework can be improved and expanded. As the basis of the framework for circadian medicine, we define “circadian health” and how it links to general health. We then define interactions among the circadian system, sleep, and the health/disease balance and put the framework into the context of the literature with examples from six domains of health/disease balance: fertility, cancer, immune system, mental health, cardiovascular, and metabolism.
Millions of individuals routinely remain awake for more than 18 h daily, which causes performance decrements. It is unknown if these functional impairments are the result of that extended wakefulness ...or from the associated shortened sleep durations. We therefore examined changes in objective reaction time performance and subjective alertness in a 32-d inpatient protocol in which participants were scheduled to wakefulness durations below 16 h while on a 20-h “day,” with randomization into standard sleep:wake ratio (1:2) or chronic sleep restriction (CSR) ratio (1:3.3) conditions. This protocol allowed determination of the contribution of sleep deficiency independent of extended wakefulness, since individual episodes of wakefulness in the CSR condition were only 15.33 h in duration (less than the usual 16 h of wakefulness in a 24-h day) and sleep episodes were 4.67 h in duration each cycle. We found that chronic short sleep duration, even without extended wakefulness, doubled neurobehavioral reaction time performance and increased lapses of attention fivefold, yet did not uniformly decrease self-reported alertness. Further, these impairments in neurobehavioral performance were worsened during the circadian night and were not recovered during the circadian day, indicating that the deleterious effect from the homeostatic buildup of CSR is expressed even during the circadian promotion of daytime arousal. These findings reveal a fundamental aspect of human biology: Chronic insufficient sleep duration equivalent to 5.6 h of sleep opportunity per 24 h impairs neurobehavioral performance and self-assessment of alertness, even without extended wakefulness.
Non-invasive Gamma ENtrainment Using Sensory stimulation (GENUS) at 40Hz reduces Alzheimer's disease (AD) pathology such as amyloid and tau levels, prevents cerebral atrophy, and improves behavioral ...testing performance in mouse models of AD. Here, we report data from (1) a Phase 1 feasibility study (NCT04042922, ClinicalTrials.gov) in cognitively normal volunteers (n = 25), patients with mild AD dementia (n = 16), and patients with epilepsy who underwent intracranial electrode monitoring (n = 2) to assess safety and feasibility of a single brief GENUS session to induce entrainment and (2) a single-blinded, randomized, placebo-controlled Phase 2A pilot study (NCT04055376) in patients with mild probable AD dementia (n = 15) to assess safety, compliance, entrainment, and exploratory clinical outcomes after chronic daily 40Hz sensory stimulation for 3 months. Our Phase 1 study showed that 40Hz GENUS was safe and effectively induced entrainment in both cortical regions and other cortical and subcortical structures such as the hippocampus, amygdala, insula, and gyrus rectus. Our Phase 2A study demonstrated that chronic daily 40Hz light and sound GENUS was well-tolerated and that compliance was equally high in both the control and active groups, with participants equally inaccurate in guessing their group assignments prior to unblinding. Electroencephalography recordings show that our 40Hz GENUS device safely and effectively induced 40Hz entrainment in participants with mild AD dementia. After 3 months of daily stimulation, the group receiving 40Hz stimulation showed (i) lesser ventricular dilation and hippocampal atrophy, (ii) increased functional connectivity in the default mode network as well as with the medial visual network, (iii) better performance on the face-name association delayed recall test, and (iv) improved measures of daily activity rhythmicity compared to the control group. These results support further evaluation of GENUS in a pivotal clinical trial to evaluate its potential as a novel disease-modifying therapeutic for patients with AD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Sleep changes markedly across the life span and complaints about insomnia are prevalent in older people
1. Whether age-related alterations in sleep are due to modifications in social factors, ...circadian physiology, homeostatic drive, or the ability to sleep remains unresolved. We assessed habitual sleep duration at home and then quantified daytime sleep propensity, sleep duration, and sleep structure in an inpatient protocol that included extended sleep opportunities covering 2/3 of the circadian cycle (12 hr at night and 4 hr in the afternoon) for 3–7 days in 18 older and 35 younger healthy men and women. At baseline, older subjects had less daytime sleep propensity than did younger subjects. Total daily sleep duration, which was initially longer than habitual sleep duration, declined during the experiment to asymptotic values that were 1.5 hr shorter in older (7.4 ± 0.4 SEM, hour) than in younger subjects (8.9 ± 0.4). Rapid-eye-movement sleep and non-rapid-eye-movement sleep contributed about equally to this reduction. Thus, in the absence of social and circadian constraints, both daytime sleep propensity and the maximal capacity for sleep are reduced in older people. These data have important implications for understanding age-related insomnia.
Weight gain and obesity have reached alarming levels. Eating at a later clock hour is a newly described risk factor for adverse metabolic health; yet, how eating at a later circadian time influences ...body composition is unknown. Using clock hour to document eating times may be misleading owing to individual differences in circadian timing relative to clock hour.
This study examined the relations between the timing of food consumption relative to clock hour and endogenous circadian time, content of food intake, and body composition.
We enrolled 110 participants, aged 18–22 y, in a 30-d cross-sectional study to document sleep and circadian behaviors within their regular daily routines. We used a time-stamped-picture mobile phone application to record all food intake across 7 consecutive days during a participant's regular daily routines and assessed their body composition and timing of melatonin release during an in-laboratory assessment.
Nonlean individuals (high body fat) consumed most of their calories 1.1 h closer to melatonin onset, which heralds the beginning of the biological night, than did lean individuals (low body fat) (log-rank P = 0.009). In contrast, there were no differences between lean and nonlean individuals in the clock hour of food consumption (P = 0.72). Multiple regression analysis showed that the timing of food intake relative to melatonin onset was significantly associated with the percentage of body fat and body mass index (both P < 0.05) while controlling for sex, whereas no relations were found between the clock hour of food intake, caloric amount, meal macronutrient composition, activity or exercise level, or sleep duration and either of these body composition measures (all P > 0.72).
These results provide evidence that the consumption of food during the circadian evening and/or night, independent of more traditional risk factors such as amount or content of food intake and activity level, plays an important role in body composition. This trial was registered at clinicaltrials.gov as NCT02846077.
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