Circadian and Diurnal Regulation of Cerebral Blood Flow.

Circadian and diurnal variation in cerebral blood flow directly contributes to the diurnal variation in the risk of stroke, either through factors that trigger stroke or due to impaired compensatory mechanisms. Cerebral blood flow results from the integration of systemic hemodynamics, including heart rate, cardiac output, and blood pressure, with cerebrovascular regulatory mechanisms, including cerebrovascular reactivity, autoregulation, and neurovascular coupling. We review the evidence for the circadian and diurnal variation in each of these mechanisms and their integration, from the detailed evidence for mechanisms underlying the nocturnal nadir and morning surge in blood pressure to identifying limited available evidence for circadian and diurnal variation in cerebrovascular compensatory mechanisms. We, thus, identify key systemic hemodynamic factors related to the diurnal variation in the risk of stroke but particularly identify the need for further research focused on cerebrovascular regulatory mechanisms.

Estimating Community Disruption from Nighttime Gunshots in 6 U.S. Cities, 2015 to 2021.

BACKGROUND: Gunshots affect those directly involved in an incident and those in the surrounding community. The community-level impact of nighttime gunshots, which may be particularly disruptive to the sleep of nearby community members, is unknown. OBJECTIVE: Our aim is to estimate the number of people potentially affected by nighttime gunshots and the relationship between nighttime gunshots and median household income in the USA. DESIGN: We collected publicly available data on the timing and location of gunshots in six U.S. cities (Baltimore, MD; Boston, MA; Washington, D.C.; New York, NY; Philadelphia, PA; and Portland, OR) from 2015 to 2021. We then analyzed the data by computing rate ratios (RRs) to compare the frequency of gunshots during nighttime hours (6:00 pm to 5:59 am) versus daytime hours (6:00 am to 5:59 pm). Additionally, we used geospatial mapping to create choropleth maps to visualize the variation in nighttime gunshot density across cities. We estimated, using city-wide population, person-nights potentially impacted by the sound of gunshots within areas of 0.2- (low) and 0.5-mile (high) radius. Finally, for five of six cities where data on median household income were available by census tract, we built nonlinear regression models to estimate the relationship between the number of nighttime gunshots and median household income. KEY RESULTS: We analyzed 72,236 gunshots. Gunshots were more common during the nighttime than daytime (overall RR = 2.5). Analyses demonstrated that the low estimates for the mean annual number of person-nights impacted by nighttime gunshots were 0.4 million in Baltimore and Portland, 1.3 million in Philadelphia, 1.6 million in Boston, 2.9 million in New York City, and 5.9 million in Washington. The number of nighttime gunshots was inversely related to median household income. CONCLUSIONS: Nighttime gunshots are prevalent, particularly in low-income neighborhoods, and may have under-recognized effects on the surrounding community.

Preoperative decreased physical activity is associated with greater postoperative pain: the mediating role of preoperative sleep disturbance.

PURPOSE: Engagement in physical activity (PA) is often associated with better sleep quality and less pain severity among patients diagnosed with breast cancer. However, less research has focused on whether patients' PA prior to breast surgery, including their perceived decrease in PA level, is associated with worse preoperative sleep quality, and subsequently, greater postoperative pain. This longitudinal study investigated whether patients' preoperative PA was associated with their postoperative pain. We also explored whether preoperative sleep disturbance partially mediated the relationship between preoperative PA and postoperative pain. METHODS: Prior to breast surgery, patients self-reported both their overall level of PA and whether they perceived a decrease in their PA since the diagnosis/onset of treatment for cancer. Patients also completed a measure of preoperative sleep disturbance. Two weeks after surgery, patients completed a measure of postoperative surgical-area pain severity. RESULTS: Our results showed that preoperatively perceiving a decrease in PA level was significantly associated with greater preoperative sleep disturbance and postoperative pain. A mediation analysis revealed that the association between preoperative decreased PA and postoperative pain was partially mediated by preoperative sleep disturbance. Notably, patients' overall preoperative level of PA was not related to preoperative sleep disturbance or postoperative pain. CONCLUSION: These findings suggest that maintaining, or even increasing, PA after diagnosis/treatment may be more important than the absolute amount of PA that women engage in during the preoperative period. Potentially, some patients with breast cancer may benefit from a preoperative intervention focused on both maintaining PA and bolstering sleep quality.

Consensus Recommendations for Standardized Data Elements, Scales, and Time Segmentations in Studies of Human Circadian/Diurnal Biology and Stroke.

Increasing evidence indicates that circadian and diurnal rhythms robustly influence stroke onset, mechanism, progression, recovery, and response to therapy in human patients. Pioneering initial investigations yielded important insights but were often single-center series, used basic imaging approaches, and used conflicting definitions of key data elements, including what constitutes daytime versus nighttime. Contemporary methodologic advances in human neurovascular investigation have the potential to substantially increase understanding, including the use of large multicenter and national data registries, detailed clinical trial data sets, analysis guided by individual patient chronotype, and multimodal computed tomographic and magnetic resonance imaging. To fully harness the power of these approaches to enhance pathophysiologic knowledge, an important foundational step is to develop standardized definitions and coding guides for data collection, permitting rapid aggregation of data acquired in different studies, and ensuring a common framework for analysis. To meet this need, the Leducq Consortium International pour la Recherche Circadienne sur l'AVC (CIRCA) convened a Consensus Statement Working Group of leading international researchers in cerebrovascular and circadian/diurnal biology. Using an iterative, mixed-methods process, the working group developed 79 data standards, including 48 common data elements (23 new and 25 modified/unmodified from existing common data elements), 14 intervals for time-anchored analyses of different granularity, and 7 formal, validated scales. This portfolio of standardized data structures is now available to assist researchers in the design, implementation, aggregation, and interpretation of clinical, imaging, and population research related to the influence of human circadian/diurnal biology upon ischemic and hemorrhagic stroke.

Altered sleep architecture in children and adolescents with Down syndrome.

OBJECTIVE: Children with Down syndrome (DS) may experience changes in sleep architecture (i.e., different sleep stages) that then affect waketime functioning, including learning, mood, and disruptive behavior. For designing and testing interventions, it is important to document any differences in sleep architecture in children with DS with and without co-occurring diagnoses, including neuropsychiatric diagnoses and obstructive sleep apnea (OSA). METHODS: A retrospective cohort study was performed at Massachusetts General Hospital for children and adolescents with DS who underwent polysomnography (PSG) between August 2016 and July 2022. Patient data collected from the electronic medical record included diagnoses, age at PSG, and PSG report. Statistical analysis included unpaired T tests to test hypotheses about differences in sleep architecture within age groups, and differences between children with DS and a co-occurring diagnosis. One way ANOVA was used to determine statistical significance of OSA severity within patients with DS. RESULTS: When compared by age group, those with DS had negative changes in sleep architecture (e.g., less sleep and more wake) when compared to normative data. Within this cohort, having a co-occurring diagnosis of autism resulted in further, negative effects on sleep architecture. 89% of those with DS had diagnosed OSA but only those with severe OSA experienced negative effects on sleep architecture. CONCLUSION: Age is an important covariate when studying the sleep of children with DS and neurotypical children. Studies are needed to test whether minimizing the observed differences in sleep architecture will translate to improved learning, mood, and behavioral outcomes, and how treating OSA affects sleep architecture.

Sleep Problems in Patients With Psoriatic Arthritis: A Systematic Literature Review and Metaanalysis.

OBJECTIVE: The aim of this systematic review and metaanalysis is to summarize evidence regarding the relationship between psoriatic arthritis (PsA) and sleep problems. METHODS: We identified 36 eligible studies-26 cross-sectional, 7 cohort, and 3 interventional studies-in PubMed and Embase. RESULTS: The prevalence of self-reported sleep problems in patients with PsA ranged from 30% to 85%. A metaanalysis of 6 studies that used the Pittsburgh Sleep Quality Index revealed a prevalence of poor sleep quality for patients with PsA of 72.9% (95% CI 63-81.8; I2 = 78%), which was statistically higher than in healthy controls (26.9%, 95% CI 11.7-45.4; I2 = 81%) but not significantly different than in patients with psoriasis (59.8%, 95% CI 46.9-72.1; I2 = 51%). Sleep disturbance was ranked in the top 4 health-related quality of life domains affected by PsA. One study suggested a bidirectional relationship between PsA and obstructive sleep apnea. Predictors of sleep problems included anxiety, pain, erythrocyte sedimentation rate, depression, fatigue, physical function, and tender or swollen joint count. Tumor necrosis factor inhibitors, guselkumab, and filgotinib (a Janus kinase inhibitor) were associated with improved sleep outcomes. CONCLUSION: Poor sleep quality is prevalent in patients with PsA. Objective sleep measures (ie, actigraphy and polysomnography) have not been used in PsA studies, and evidence on the validity of patient-reported sleep measures in PsA is lacking. Future studies should validate self-reported sleep measures in PsA, explore how sleep quality relates to PsA disease activity and symptoms using both objective and subjective sleep measures, assess the efficacy of strategies to manage sleep problems, and assess the effects of such management on symptoms and disease signs in patients with PsA.

Uncovering circadian rhythms in metabolic longitudinal data: A Bayesian latent class modeling approach.

Researchers in biology and medicine have increasingly focused on characterizing circadian rhythms and their potential impact on disease. Understanding circadian variation in metabolomics, the study of chemical processes involving metabolites may provide insight into important aspects of biological mechanism. Of scientific importance is developing a statistical rigorous approach for characterizing different types of 24-hour patterns among high dimensional longitudinal metabolites. We develop a latent class approach to incorporate variation in 24-hour patterns across metabolites where profiles are modeled with finite mixtures of distinct shape-invariant circadian curves that themselves incorporate variation in amplitude and phase across metabolites. An efficient Markov chain Monte Carlo sampling is used to carry out Bayesian posterior computation. When the model was fit separately by individual to the data from a small group of participants, two distinct 24-hour rhythms were identified, with one being sinusoidal and the other being more complex with multiple peaks. Interestingly, the latent pattern associated with circadian variation (simple sinusoidal curve) had a similar phase across the three participants, while the more complex latent pattern reflecting diurnal variation differed across individual. The results suggested that this modeling framework can be used to separate 24-hour rhythms into an endogenous circadian and one or more exogenous diurnal patterns in describing human metabolism.

The circadian system, sleep, and the health/disease balance: a conceptual review.

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.

Dynamic lighting schedules to facilitate circadian adaptation to shifted timing of sleep and wake.

Circadian adaptation to shifted sleep/wake schedules may be facilitated by optimizing the timing, intensity and spectral characteristics of light exposure, which is the principal time cue for mammalian circadian pacemaker, and possibly by strategically timing nonphotic time cues such as exercise. Therefore, circadian phase resetting by light and exercise was assessed in 44 healthy participants (22 females, mean age [±SD] 36.2 ± 9.2 years), who completed 8-day inpatient experiments simulating night shiftwork, which included either an 8 h advance or 8 h delay in sleep/wake schedules. In the advance protocol (n = 18), schedules were shifted either gradually (1.6 h/day across 5 days) or abruptly (slam shift, 8 h in 1 day and maintained across 5 days). Both advance protocols included a dynamic lighting schedule (DLS) with 6.5 h exposure of blue-enriched white light (704 melanopic equivalent daylight illuminance [melEDI] lux) during the day and dimmer blue-depleted light (26 melEDI lux) for 2 h immediately before sleep on the shifted schedule. In the delay protocol (n = 26), schedules were only abruptly delayed but included four different lighting conditions: (1) 8 h continuous room-light control; (2) 8 h continuous blue-enriched light; (3) intermittent (7 × 15 min pulses/8 h) blue-enriched light; (4) 8 h continuous blue-enriched light plus moderate intensity exercise. In the room-light control, participants received dimmer white light for 30 min before bedtime, whereas in the other three delay protocols participants received dimmer blue-depleted light for 30 min before bedtime. Both the slam and gradual advance protocols induced similar shifts in circadian phase (3.28 h ± 0.37 vs. 2.88 h ± 0.31, respectively, p = .43) estimated by the change in the timing of timing of dim light melatonin onset. In the delay protocol, the continuous 8 h blue-enriched exposure induced significantly larger shifts than the room light control (-6.59 h ± 0.43 vs. -4.74 h ± 0.62, respectively, p = .02). The intermittent exposure induced ~60% of the shift (-3.90 h ± 0.62) compared with 8 h blue-enriched continuous light with only 25% of the exposure duration. The addition of exercise to the 8 h continuous blue-enriched light did not result in significantly larger phase shifts (-6.59 h ± 0.43 vs. -6.41 h ± 0.69, p = .80). Collectively, our results demonstrate that, when attempting to adapt to an 8 h overnight work shift, delay shifts are more successful, particularly when accompanied by a DLS with high-melanopic irradiance light stimulus during wake.

Circadian Biology and Stroke.

Circadian biology modulates almost all aspects of mammalian physiology, disease, and response to therapies. Emerging data suggest that circadian biology may significantly affect the mechanisms of susceptibility, injury, recovery, and the response to therapy in stroke. In this review/perspective, we survey the accumulating literature and attempt to connect molecular, cellular, and physiological pathways in circadian biology to clinical consequences in stroke. Accounting for the complex and multifactorial effects of circadian rhythm may improve translational opportunities for stroke diagnostics and therapeutics.

An ensemble mixed effects model of sleep loss and performance.

Sleep loss causes decrements in cognitive performance, which increases risks to those in safety-sensitive fields, including medicine and aviation. Mathematical models can be formulated to predict performance decrement in response to sleep loss, with the goal of identifying when an individual may be at highest risk for an accident. This work produces an Ensemble Mixed Effects Model that combines a traditional Linear Mixed Effects (LME) model with a semi-parametric, nonlinear model called Mixed Effects Random Forest (MERF). Using this model, we predict performance on the Psychomotor Vigilance Task (PVT), a test of sustained attention, using biologically motivated features extracted from a dataset containing demographic, sleep, and cognitive test data from 44 healthy participants studied during inpatient sleep loss laboratory experiments. Our Ensemble Mixed Effects Model accurately predicts an individual's trend in PVT performance, and fits the data better than prior published models. The ensemble successfully combines MERF's high rate of peak identification with LME's conservative predictions. We investigate two questions relevant to this model's potential use in operational settings: the tradeoff between additional model features versus ease of collecting these features in real-world settings, and how recent a cognitive task must have been administered to produce strong predictions. This work addresses limitations of previous approaches by developing a predictive model that accounts for interindividual differences and utilizes a nonlinear, semi-parametric method called MERF. We methodologically address the modeling decisions required for this prediction problem, including the choice of cross-validation method. This work is novel in its use of data from a highly-controlled inpatient study protocol that uncouples the influence of the sleep-wake cycle from the endogenous circadian rhythm on the cognitive task being modeled. This uncoupling provides a clearer picture of the model's real-world predictive ability for situations in which people work at different circadian times (e.g., night- or shift-work).

Robust stability of melatonin circadian phase, sleep metrics, and chronotype across months in young adults living in real-world settings.

Appropriate synchronization of the timing of behaviors with the circadian clock and adequate sleep are both important for almost every physiological process. The timing of the circadian clock relative to social (ie, local) clock time and the timing of sleep can vary greatly among individuals. Whether the timing of these processes is stable within an individual is not well-understood. We examined the stability of circadian-controlled melatonin timing, sleep timing, and their interaction across ~ 100 days in 15 students at a single university. At three time points ~ 35-days apart, circadian timing was determined from the dim-light melatonin onset (DLMO). Sleep behaviors (timing and duration) and chronotype (ie, mid-sleep time on free days corrected for sleep loss on school/work days) were determined via actigraphy and analyzed in ~ 1-month bins. Melatonin timing was stable, with an almost perfect relationship strength as determined via intraclass correlation coefficients ([ICC]=0.85); average DLMO timing across all participants only changed from the first month by 21 minutes in month 2 and 5 minutes in month 3. Sleep behaviors also demonstrated high stability, with ICC relationship strengths ranging from substantial to almost perfect (ICCs = 0.65-0.85). Average DLMO was significantly associated with average chronotype (r2  = 0.53, P <.01), with chronotype displaying substantial stability across months (ICC = 0.61). These findings of a robust stability in melatonin timing and sleep behaviors in young adults living in real-world settings holds promise for a better understanding of the reliability of previous cross-sectional reports and for the future individualized strategies to combat circadian-associated disease and impaired safety (ie, "chronomedicine").

In-person vs home schooling during the COVID-19 pandemic: Differences in sleep, circadian timing, and mood in early adolescence.

During the COVID-19 pandemic, schools around the world rapidly transitioned from in-person to remote learning, providing an opportunity to examine the impact of in-person vs remote learning on sleep, circadian timing, and mood. We assessed sleep-wake timing using wrist actigraphy and sleep diaries over 1-2 weeks during in-person learning (n = 28) and remote learning (n = 58, where n = 27 were repeat assessments) in adolescents (age M ± SD = 12.79 ± 0.42 years). Circadian timing was measured under a single condition in each individual using salivary melatonin (Dim Light Melatonin Onset; DLMO). Online surveys assessed mood (PROMIS Pediatric Anxiety and Depressive Symptoms) and sleepiness (Epworth Sleepiness Scale - Child and Adolescent) in each condition. During remote (vs in-person) learning: (i) on school days, students went to sleep 26 minutes later and woke 49 minutes later, resulting in 22 minutes longer sleep duration (all P < .0001); (ii) DLMO time did not differ significantly between conditions, although participants woke at a later circadian phase (43 minutes, P = .03) during remote learning; and (iii) participants reported significantly lower sleepiness (P = .048) and lower anxiety symptoms (P = .006). Depressive symptoms did not differ between conditions. Changes in mood symptoms were not mediated by sleep. Although remote learning continued to have fixed school start times, removing morning commutes likely enabled adolescents to sleep longer, wake later, and to wake at a later circadian phase. These results indicate that remote learning, or later school start times, may extend sleep and improve some subjective symptoms in adolescents.

A classification approach to estimating human circadian phase under circadian alignment from actigraphy and photometry data.

The time of dim light melatonin onset (DLMO) is the gold standard for circadian phase assessment in humans, but collection of samples for DLMO is time and resource-intensive. Numerous studies have attempted to estimate circadian phase from actigraphy data, but most of these studies have involved individuals on controlled and stable sleep-wake schedules, with mean errors reported between 0.5 and 1 hour. We found that such algorithms are less successful in estimating DLMO in a population of college students with more irregular schedules: Mean errors in estimating the time of DLMO are approximately 1.5-1.6 hours. We reframed the problem as a classification problem and estimated whether an individual's current phase was before or after DLMO. Using a neural network, we found high classification accuracy of about 90%, which decreased the mean error in DLMO estimation-identifying the time at which the switch in classification occurs-to approximately 1.3 hours. To test whether this classification approach was valid when activity and circadian rhythms are decoupled, we applied the same neural network to data from inpatient forced desynchrony studies in which participants are scheduled to sleep and wake at all circadian phases (rather than their habitual schedules). In participants on forced desynchrony protocols, overall classification accuracy dropped to 55%-65% with a range of 20%-80% for a given day; this accuracy was highly dependent upon the phase angle (ie, time) between DLMO and sleep onset, with the highest accuracy at phase angles associated with nighttime sleep. Circadian patterns in activity, therefore, should be included when developing and testing actigraphy-based approaches to circadian phase estimation. Our novel algorithm may be a promising approach for estimating the onset of melatonin in some conditions and could be generalized to other hormones.

Chronic sleep curtailment, even without extended (>16-h) wakefulness, degrades human vigilance performance.

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.

Relationship between endogenous melatonin concentrations and uterine contractions in late third trimester of human pregnancy.

In humans, circulating levels of the hormone melatonin and the initiation of spontaneous labor are both higher at night than during the day. Since activation of uterine melatonin receptors can stimulate human in vitro uterine contractions and these receptors are only expressed on the uterine tissue of women in labor, we hypothesized that circulating melatonin concentrations would affect uterine contractions in vivo. We evaluated the impact of light-induced modulation of melatonin secretion on uterine contractions in women during late third trimester (~36-39 weeks) of pregnancy in two inpatient protocols. We found a significant (P < 0.05) positive linear association between circulating melatonin concentrations and the number of uterine contractions under both protocols. On average, uterine contractions increased between 1.4 and 2.1 contractions per 30 minutes for every 10 pg/mL*h increase in melatonin concentration. These findings have both basic science and clinical implications for pregnant women, since endogenous melatonin levels and melatonin receptor activity can be altered by light and/or pharmaceutical agents.

Pharmaceutical-based entrainment of circadian phase via nonlinear model predictive control.

The widespread adoption of closed-loop control in systems biology has resulted from improvements in sensors, computing, actuation, and the discovery of alternative sites of targeted drug delivery. Most control algorithms for circadian phase resetting exploit light inputs. However, recently identified small-molecule pharmaceuticals offer advantages in terms of invasiveness and potency of actuation. Herein, we develop a systematic method to control the phase of biological oscillations motivated by the recently identified small molecule circadian pharmaceutical KL001. The model-based control architecture exploits an infinitesimal parametric phase response curve (ipPRC) that is used to predict the effect of control inputs on future phase trajectories of the oscillator. The continuous time optimal control policy is first derived for phase resetting, based on the ipPRC and Pontryagin's maximum principle. Owing to practical challenges in implementing a continuous time optimal control policy, we investigate the effect of implementing the continuous time policy in a sampled time format. Specifically, we provide bounds on the errors incurred by the physiologically tractable sampled time control law. We use these results to select directions of resetting (i.e. phase advance or delay), sampling intervals, and prediction horizons for a nonlinear model predictive control (MPC) algorithm for phase resetting. The potential of this ipPRC-informed pharmaceutical nonlinear MPC is then demonstrated in silico using real-world scenarios of jet lag or rotating shift work.

Functional decoupling of melatonin suppression and circadian phase resetting in humans.

KEY POINTS: There is assumed to be a monotonic association between melatonin suppression and circadian phase resetting induced by light exposure. We tested the association between melatonin suppression and phase resetting in humans. Sixteen young healthy participants received nocturnal bright light (∼9500 lux) exposure of continuous or intermittent patterns, and different durations ranging from 12 min to 6.5 h. Intermittent exposure patterns showed significant phase shifts with disproportionately less melatonin suppression. Each and every bright light stimulus in an intermittent exposure pattern induced a similar degree of melatonin suppression, but did not appear to cause an equal magnitude of phase shift. These results suggest that phase shifts and melatonin suppression are functionally independent such that one cannot be used as a proxy measure of the other. ABSTRACT: Continuous experimental light exposures show that, in general, the conditions that produce greater melatonin suppression also produce greater phase shift, leading to the assumption that one can be used as a proxy for the other. We tested this association in 16 healthy individuals who participated in a 9-day inpatient protocol by assessing melatonin suppression and phase resetting in response to a nocturnal light exposure (LE) of different patterns: (i) dim-light control (<3 lux; n = 6) or (ii) two 12-min intermittent bright light pulses (IBL) separated by 36 min of darkness (∼9500 lux; n = 10). We compared these results with historical data from additional LE patterns: (i) dim-light control (<3 lux; n = 11); (ii) single continuous bright light exposure of 12 min (n = 9), 1.0 h (n = 10) or 6.5 h (n = 6); or (iii) an IBL light pattern consisting of six 15-min pulses with 1.0 h dim-light recovery intervals between them during a total of 6.5 h (n = 7). All light exposure groups had significantly greater phase-delay shifts than the dim-light control condition (P < 0.0001). While a monotonic association between melatonin suppression and circadian phase shift was observed, intermittent exposure patterns showed significant phase shifts with disproportionately less melatonin suppression. Each and every IBL stimulus induced a similar degree of melatonin suppression, but did not appear to cause an equal magnitude of phase shift. These results suggest unique specificities in how light-induced phase shifts and melatonin suppression are mediated such that one cannot be used as a proxy measure of the other.

Modeling the adenosine system as a modulator of cognitive performance and sleep patterns during sleep restriction and recovery.

Sleep loss causes profound cognitive impairments and increases the concentrations of adenosine and adenosine A1 receptors in specific regions of the brain. Time courses for performance impairment and recovery differ between acute and chronic sleep loss, but the physiological basis for these time courses is unknown. Adenosine has been implicated in pathways that generate sleepiness and cognitive impairments, but existing mathematical models of sleep and cognitive performance do not explicitly include adenosine. Here, we developed a novel receptor-ligand model of the adenosine system to test the hypothesis that changes in both adenosine and A1 receptor concentrations can capture changes in cognitive performance during acute sleep deprivation (one prolonged wake episode), chronic sleep restriction (multiple nights with insufficient sleep), and subsequent recovery. Parameter values were estimated using biochemical data and reaction time performance on the psychomotor vigilance test (PVT). The model closely fit group-average PVT data during acute sleep deprivation, chronic sleep restriction, and recovery. We tested the model's ability to reproduce timing and duration of sleep in a separate experiment where individuals were permitted to sleep for up to 14 hours per day for 28 days. The model accurately reproduced these data, and also correctly predicted the possible emergence of a split sleep pattern (two distinct sleep episodes) under these experimental conditions. Our findings provide a physiologically plausible explanation for observed changes in cognitive performance and sleep during sleep loss and recovery, as well as a new approach for predicting sleep and cognitive performance under planned schedules.

Applying mathematical models to predict resident physician performance and alertness on traditional and novel work schedules.

BACKGROUND: In 2011 the U.S. Accreditation Council for Graduate Medical Education began limiting first year resident physicians (interns) to shifts of ≤16 consecutive hours. Controversy persists regarding the effectiveness of this policy for reducing errors and accidents while promoting education and patient care. Using a mathematical model of the effects of circadian rhythms and length of time awake on objective performance and subjective alertness, we quantitatively compared predictions for traditional intern schedules to those that limit work to ≤ 16 consecutive hours. METHODS: We simulated two traditional schedules and three novel schedules using the mathematical model. The traditional schedules had extended duration work shifts (≥24 h) with overnight work shifts every second shift (including every third night, Q3) or every third shift (including every fourth night, Q4) night; the novel schedules had two different cross-cover (XC) night team schedules (XC-V1 and XC-V2) and a Rapid Cycle Rotation (RCR) schedule. Predicted objective performance and subjective alertness for each work shift were computed for each individual's schedule within a team and then combined for the team as a whole. Our primary outcome was the amount of time within a work shift during which a team's model-predicted objective performance and subjective alertness were lower than that expected after 16 or 24 h of continuous wake in an otherwise rested individual. RESULTS: The model predicted fewer hours with poor performance and alertness, especially during night-time work hours, for all three novel schedules than for either the traditional Q3 or Q4 schedules. CONCLUSIONS: Three proposed schedules that eliminate extended shifts may improve performance and alertness compared with traditional Q3 or Q4 schedules. Predicted times of worse performance and alertness were at night, which is also a time when supervision of trainees is lower. Mathematical modeling provides a quantitative comparison approach with potential to aid residency programs in schedule analysis and redesign.