Publications by authors named "Melissa A St Hilaire"

31 Publications

Endogenous circadian regulation and phase resetting of clinical metabolic biomarkers.

J Pineal Res 2021 Jun 12:e12752. Epub 2021 Jun 12.

Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA, USA.

Shiftwork and circadian disruption are associated with adverse metabolic effects. Therefore, we examined whether clinical biomarkers of metabolic health are under endogenous circadian regulation using a 40 hours constant routine protocol (CR; constant environmental and behavioral conditions) and evaluated the impact of typical daily conditions with periodic sleep and meals (baseline; 8 hours sleep at night, four meals during a 16 hour wake episode) on the phase and amplitude of these rhythms. Additionally, we tested whether these circadian rhythms are reset during simulated shiftwork. Under CR (n = 16 males, mean age ± SD = 23.4 ± 2.3 years), we found endogenous circadian rhythms in cholesterol, HDL and LDL, albumin and total protein, and VLDL and triglyceride. The rhythms were masked under baseline conditions except for cholesterol, which had near-identical phases under both conditions. Resetting of the cholesterol rhythm and Dim Light Melatonin Onset (DLMO) was then tested in a study of simulated shiftwork (n = 25, 14 females, 36.3 ± 8.9 years) across four protocols; two with abrupt 8 hour delay shifts and exposure to either blue-enriched or standard white light; and either an abrupt or gradual 8 hour advance (1.6 hours/day over 5 days) both with exposure to blue-enriched white light. In the delay protocols, the cholesterol rhythm shifted later by -3.7 hours and -4.2 hours, respectively, compared to -6.6 hours and -4.7 hours, for DLMO. There was a significant advance in cholesterol in the abrupt (+5.1 hours) but not the gradual (+2.1 hours) protocol, compared to +3.1 hours and +2.8 hours in DLMO, respectively. Exploratory group analysis comparing the phases of all metabolic biomarkers under both studies showed evidence of phase shifts due to simulated shiftwork. These results show that clinical biomarkers of metabolic health are under endogenous circadian regulation but that the expression of these rhythms is substantially influenced by environmental factors. These rhythms can also be reset, which has implications for understanding how both behavioral changes and circadian shifts due to shiftwork may disrupt metabolic function.
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http://dx.doi.org/10.1111/jpi.12752DOI Listing
June 2021

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

J Pineal Res 2021 Aug 20;71(1):e12745. Epub 2021 Jun 20.

Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.

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.
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http://dx.doi.org/10.1111/jpi.12745DOI Listing
August 2021

Extended Work Shifts and Neurobehavioral Performance in Resident-Physicians.

Pediatrics 2021 03 22;147(3). Epub 2021 Feb 22.

Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, Massachusetts.

Objectives: Extended-duration work rosters (EDWRs) with shifts of 24+ hours impair performance compared with rapid cycling work rosters (RCWRs) that limit shifts to 16 hours in postgraduate year (PGY) 1 resident-physicians. We examined the impact of a RCWR on PGY 2 and PGY 3 resident-physicians.

Methods: Data from 294 resident-physicians were analyzed from a multicenter clinical trial of 6 US PICUs. Resident-physicians worked 4-week EDWRs with shifts of 24+ hours every third or fourth shift, or an RCWR in which most shifts were ≤16 consecutive hours. Participants completed a daily sleep and work log and the 10-minute Psychomotor Vigilance Task and Karolinska Sleepiness Scale 2 to 5 times per shift approximately once per week as operational demands allowed.

Results: Overall, the mean (± SE) number of attentional failures was significantly higher ( =.01) on the EDWR (6.8 ± 1.0) compared with RCWR (2.9 ± 0.7). Reaction time and subjective alertness were also significantly higher, by ∼18% and ∼9%, respectively (both <.0001). These differences were sustained across the 4-week rotation. Moreover, attentional failures were associated with resident-physician-related serious medical errors (SMEs) ( =.04). Although a higher rate of SMEs was observed under the RCWR, after adjusting for workload, RCWR had a protective effect on the rate of SMEs (rate ratio 0.48 [95% confidence interval: 0.30-0.77]).

Conclusions: Performance impairment due to EDWR is improved by limiting shift duration. These data and their correlation with SME rates highlight the impairment of neurobehavioral performance due to extended-duration shifts and have important implications for patient safety.
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http://dx.doi.org/10.1542/peds.2020-009936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919117PMC
March 2021

An ensemble mixed effects model of sleep loss and performance.

J Theor Biol 2021 01 20;509:110497. Epub 2020 Sep 20.

Department of Medicine Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA. Electronic address:

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).
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http://dx.doi.org/10.1016/j.jtbi.2020.110497DOI Listing
January 2021

Prediction of individual differences in circadian adaptation to night work among older adults: application of a mathematical model using individual sleep-wake and light exposure data.

Chronobiol Int 2020 Sep-Oct;37(9-10):1404-1411. Epub 2020 Sep 6.

Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital and Division of Sleep Medicine, Harvard Medical School, Boston, Massachusetts, USA.

Circadian misalignment remains a distinct challenge for night shift workers. Variability in individual sleep-wake/light-dark patterns might contribute to individual differences in circadian alignment in night shift workers. In this simulation study, we compared the predicted phase shift from a mathematical model of the effect of light on the human circadian pacemaker to the observed melatonin phase shift among individuals who completed one of four interventions during simulated night shift work. Two inputs to the model were used to simulate circadian phase: sleep-wake/light-dark patterns measured from a wrist monitor (Simulation 1) and sleep-wake/light-dark patterns measured from a wrist monitor enhanced by known light levels measured at the level of the eye during simulated night shifts (Simulation 2). The estimated phase shift from the model was within 2 hours of the observed phase shift in ~80% of night shift workers for both simulations; none of the model-predicted phase shifts was more than ~3 hours from the observed phase shift. Overall, the root-mean-square error between observed and predicted phase shifts was better for Simulation 1. The light input from the wrist monitor informed by actual light level measured at the eye performed better in the sub-group exposed to bright light during their night shifts. The findings from this simulation study suggest that using a mathematical model combined with sleep-wake and light exposure data from a wrist monitor can facilitate the design of shift work schedules to enhance circadian alignment, which is expected to improve sleep, alertness, and performance.
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http://dx.doi.org/10.1080/07420528.2020.1813153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936005PMC
July 2021

Effect on Patient Safety of a Resident Physician Schedule without 24-Hour Shifts.

N Engl J Med 2020 06;382(26):2514-2523

From the Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital (C.P.L., S.A.R., J.P.S., L.K.B., C.S.O., S.Q., M.A.S.H., S.W.L., C.A.C.), the Division of Sleep Medicine, Harvard Medical School (C.P.L., S.A.R., L.K.B., M.A.S.H., S.W.L., C.A.C.), and the Division of General Pediatrics, Department of Pediatrics (C.P.L.), and the Division of Critical Care Medicine, Department of Anesthesiology, Critical Care, and Pain Medicine (A.L.S.), Boston Children's Hospital - all in Boston; the University of California, San Francisco (E.V., K.L.S.), and California Pacific Medical Center Research Institute (K.L.S.), San Francisco; the Sleep and Chronobiology Laboratory, Department of Integrative Physiology, University of Colorado Boulder, Boulder (K.P.W.), and Children's Hospital Colorado, University of Colorado School of Medicine, Aurora (A.C.H.); the University of Iowa Stead Family Children's Hospital, Iowa City (J.L.S.); Seattle Children's Hospital (J.K.M.) and the University of Washington (M.V.V., H.O.I.), Seattle; Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati (S.E.P.); University of Virginia Children's Hospital, Charlottesville (P.L.Y.); and the Department of Neurology and Center for Circadian and Sleep Medicine, Northwestern University, Feinberg School of Medicine, Chicago (P.C.Z.).

Background: The effects on patient safety of eliminating extended-duration work shifts for resident physicians remain controversial.

Methods: We conducted a multicenter, cluster-randomized, crossover trial comparing two schedules for pediatric resident physicians during their intensive care unit (ICU) rotations: extended-duration work schedules that included shifts of 24 hours or more (control schedules) and schedules that eliminated extended shifts and cycled resident physicians through day and night shifts of 16 hours or less (intervention schedules). The primary outcome was serious medical errors made by resident physicians, assessed by intensive surveillance, including direct observation and chart review.

Results: The characteristics of ICU patients during the two work schedules were similar, but resident physician workload, described as the mean (±SD) number of ICU patients per resident physician, was higher during the intervention schedules than during the control schedules (8.8±2.8 vs. 6.7±2.2). Resident physicians made more serious errors during the intervention schedules than during the control schedules (97.1 vs. 79.0 per 1000 patient-days; relative risk, 1.53; 95% confidence interval [CI], 1.37 to 1.72; P<0.001). The number of serious errors unitwide were likewise higher during the intervention schedules (181.3 vs. 131.5 per 1000 patient-days; relative risk, 1.56; 95% CI, 1.43 to 1.71). There was wide variability among sites, however; errors were lower during intervention schedules than during control schedules at one site, rates were similar during the two schedules at two sites, and rates were higher during intervention schedules than during control schedules at three sites. In a secondary analysis that was adjusted for the number of patients per resident physician as a potential confounder, intervention schedules were no longer associated with an increase in errors.

Conclusions: Contrary to our hypothesis, resident physicians who were randomly assigned to schedules that eliminated extended shifts made more serious errors than resident physicians assigned to schedules with extended shifts, although the effect varied by site. The number of ICU patients cared for by each resident physician was higher during schedules that eliminated extended shifts. (Funded by the National Heart, Lung, and Blood Institute; ROSTERS ClinicalTrials.gov number, NCT02134847.).
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http://dx.doi.org/10.1056/NEJMoa1900669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405505PMC
June 2020

What time is it? A tale of three clocks, with implications for personalized medicine.

J Pineal Res 2020 05 25;68(4):e12646. Epub 2020 Mar 25.

Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.

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http://dx.doi.org/10.1111/jpi.12646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285860PMC
May 2020

Using a Single Daytime Performance Test to Identify Most Individuals at High-Risk for Performance Impairment during Extended Wake.

Sci Rep 2019 11 13;9(1):16681. Epub 2019 Nov 13.

Division of Sleep and Circadian Disorders, Brigham & Women's Hospital, 221 Longwood Avenue, Boston, MA, 02115, USA.

We explored the predictive value of a neurobehavioral performance assessment under rested baseline conditions (evaluated at 8 hours awake following 8 hours of sleep) on neurobehavioral response to moderate sleep loss (evaluated at 20 hours awake two days later) in 151 healthy young participants (18-30 years). We defined each participant's response-to-sleep-loss phenotype based on the number of attentional failures on a 10-min visual psychomotor vigilance task taken at 20 hours awake (resilient: less than 6 attentional failures, n = 26 participants; non-resilient: 6 or more attentional failures, n = 125 participants). We observed that 97% of rested participants with 2 or more attentional failures (n = 73 of 151) and 100% of rested participants with 3 or more attentional failures (n = 57 of 151) were non-resilient after moderate sleep loss. Our approach can accurately identify a significant proportion of individuals who are at high risk for neurobehavioral performance impairment from staying up late with a single neurobehavioral performance assessment conducted during rested conditions. Additional methods are needed to predict the future performance of individuals who are not identified as high risk during baseline.
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http://dx.doi.org/10.1038/s41598-019-52930-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853981PMC
November 2019

Menstrual phase-dependent differences in neurobehavioral performance: the role of temperature and the progesterone/estradiol ratio.

Sleep 2020 02;43(2)

Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA.

Study Objectives: Women in the luteal phase of the menstrual cycle exhibit better cognitive performance overnight than women in the follicular phase, although the mechanism is unknown. Given the link between core body temperature (CBT) and performance, one potential mechanism is the thermoregulatory role of progesterone (P4), estradiol (E2), and their ratio (P4/E2), which change across the menstrual cycle. We examined the role of P4/E2 in modulating performance during extended wake in premenopausal women. Additionally, we compared the acute effects of nighttime light exposure on performance, CBT, and hormones between the menstrual phases.

Methods: Participants were studied during a 50 h constant routine and a 6.5 h monochromatic nighttime light exposure. Participants were 16 healthy, naturally cycling women (eight follicular; eight luteal). Outcome measures included reaction time, attentional failures, self-reported sleepiness, CBT, melatonin, P4, and E2.

Results: As compared to women in the luteal phase, women in the follicular phase exhibited worse performance overnight. CBT was significantly associated with performance, P4, and P4/E2 but not with other sex hormones. Sex hormones were not directly related to performance. Light exposure that suppressed melatonin improved performance in the follicular phase (n = 4 per group) to levels observed during the luteal phase and increased CBT but without concomitant changes in P4/E2.

Conclusions: Our results underscore the importance of considering menstrual phase when assessing cognitive performance during sleep loss in women and indicate that these changes are driven predominantly by CBT. Furthermore, this study shows that vulnerability to sleep loss during the follicular phase may be resolved by exposure to light.
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http://dx.doi.org/10.1093/sleep/zsz227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457328PMC
February 2020

An Exploration of the Temporal Dynamics of Circadian Resetting Responses to Short- and Long-Duration Light Exposures: Cross-Species Consistencies and Differences.

J Biol Rhythms 2019 10 1;34(5):497-514. Epub 2019 Aug 1.

Division of Sleep Medicine, Harvard Medical School, Boston, Massachusetts.

Light is the most effective environmental stimulus for shifting the mammalian circadian pacemaker. Numerous studies have been conducted across multiple species to delineate wavelength, intensity, duration, and timing contributions to the response of the circadian pacemaker to light. Recent studies have revealed a surprising sensitivity of the human circadian pacemaker to short pulses of light. Such responses have challenged photon counting-based theories of the temporal dynamics of the mammalian circadian system to both short- and long-duration light stimuli. Here, we collate published light exposure data from multiple species, including gerbil, hamster, mouse, and human, to investigate these temporal dynamics and explore how the circadian system integrates light information at both short- and long-duration time scales to produce phase shifts. Based on our investigation of these data sets, we propose 3 new interpretations: (1) intensity and duration are independent factors of total phase shift magnitude, (2) the possibility of a linear/log temporal function of light duration that is universal for all intensities for durations less than approximately 12 min, and (3) a potential universal minimum light duration of ~0.7 sec that describes a "dead zone" of light stimulus. We show that these properties appear to be consistent across mammalian species. These interpretations, if confirmed by further experiments, have important practical implications in terms of understanding the underlying physiology and for the design of lighting regimens to reset the mammalian circadian pacemaker.
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http://dx.doi.org/10.1177/0748730419862702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363039PMC
October 2019

Effects on resident work hours, sleep duration, and work experience in a randomized order safety trial evaluating resident-physician schedules (ROSTERS).

Sleep 2019 08;42(8)

Department of Medicine and Neurology, Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA.

Study Objectives: We compared resident physician work hours and sleep in a multicenter clustered-randomized crossover clinical trial that randomized resident physicians to an Extended Duration Work Roster (EDWR) with extended-duration (≥24 hr) shifts or a Rapidly Cycling Work Roster (RCWR), in which scheduled shift lengths were limited to 16 or fewer consecutive hours.

Methods: Three hundred two resident physicians were enrolled and completed 370 1 month pediatric intensive care unit rotations in six US academic medical centers. Sleep was objectively estimated with wrist-worn actigraphs. Work hours and subjective sleep data were collected via daily electronic diary.

Results: Resident physicians worked fewer total hours per week during the RCWR compared with the EDWR (61.9 ± 4.8 versus 68.4 ± 7.4, respectively; p < 0.0001). During the RCWR, 73% of work hours occurred within shifts of ≤16 consecutive hours. In contrast, during the EDWR, 38% of work hours occurred on shifts of ≤16 consecutive hours. Resident physicians obtained significantly more sleep per week on the RCWR (52.9 ± 6.0 hr) compared with the EDWR (49.1 ± 5.8 hr, p < 0.0001). The percentage of 24 hr intervals with less than 4 hr of actigraphically measured sleep was 9% on the RCWR and 25% on the EDWR (p < 0.0001).

Conclusions: RCWRs were effective in reducing weekly work hours and the occurrence of >16 consecutive hour shifts, and improving sleep duration of resident physicians. Although inclusion of the six operational healthcare sites increases the generalizability of these findings, there was heterogeneity in schedule implementation. Additional research is needed to optimize scheduling practices allowing for sufficient sleep prior to all work shifts.Clinical Trial: Multicenter Clinical Trial of Limiting Resident Work Hours on ICU Patient Safety (ROSTERS), https://clinicaltrials.gov/ct2/show/NCT02134847.
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http://dx.doi.org/10.1093/sleep/zsz110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685326PMC
August 2019

Brief (<4 hr) sleep episodes are insufficient for restoring performance in first-year resident physicians working overnight extended-duration work shifts.

Sleep 2019 05;42(5)

Departments of Medicine and Neurology, Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA.

Study Objectives: The Accreditation Council for Graduate Medical Education (ACGME) recently reinstated extended-duration (24-28 hr) work shifts (EDWS) for postgraduate year 1 (PGY-1) resident physicians. This study examined the relationship between overnight sleep duration during EDWS and subsequent "post-call" performance in PGY-1 resident physicians.

Methods: Thirty-four PGY-1 resident physicians (23 males; 24-32 years) were studied between 2002 and 2004 during 3-week Q3 "on-call" rotation schedules in the Medical and Cardiac Intensive Care Units at Brigham and Women's Hospital in Boston. Daily sleep logs (validated by ambulatory polysomnography) were collected and the 10 min psychomotor vigilance task (PVT) was administered every ~6 hr during each EDWS. Generalized estimating equations were used to examine the relationship between overnight sleep duration and PVT performance "post-call" (0500-1900 hr). Postcall performance during EDWS was compared with sessions matched for time-of-day and weeks-into-schedule in the same resident physician during an intervention schedule that eliminated EDWS.

Results: Resident physicians obtained an average of 1.6 ± 1.5 hr cumulative sleep overnight during EDWS (<4 hr on 92% of nights). PVT attentional failures were significantly reduced only after >4 hr sleep (p = 0.027 versus no sleep). Despite this apparent improvement, the odds of incurring >1 attentional failure were 2.72 times higher during postcall following >4 hr sleep compared with matched sessions during non-EDWS.

Conclusions: Even with >4 hr sleep overnight (8% of EDWS), performance remained significantly impaired. These findings suggest that even "strategic napping," a recommendation recently removed from ACGME guidelines, is insufficient to mitigate severe performance impairment introduced by extending duty beyond 16 hr.
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http://dx.doi.org/10.1093/sleep/zsz041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519906PMC
May 2019

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

J Physiol 2018 06 29;596(11):2147-2157. Epub 2018 Apr 29.

Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women's Hospital, Boston, MA, USA.

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.
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http://dx.doi.org/10.1113/JP275501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983136PMC
June 2018

Relationship between melatonin and bone resorption rhythms in premenopausal women.

J Bone Miner Metab 2019 Jan 9;37(1):60-71. Epub 2018 Jan 9.

Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, 221 Longwood Avenue BLI-438, Boston, MA, 02115, USA.

Although evidence exists for a daily rhythm in bone metabolism, the contribution of factors such as melatonin levels, the light-dark cycle, and the sleep-wake cycle is difficult to differentiate given their highly correlated time courses. To examine these influences on bone resorption, we collected 48-h sequential urine samples under both ambulatory (8-h sleep:16-h wake) and constant routine (CR) (constant wake, posture, nutrition and dim light) conditions from 20 healthy premenopausal women. Urinary 6-sulphatoxymelatonin (aMT6s; ng/h) and the bone resorption marker amino-terminal cross-linked collagen I telopeptide (NTx; bone collagen equivalents nM/h) were assayed and fit by cosinor models to determine significant 24-h rhythms and acrophase. Most participants had significant 24-h aMT6s rhythms during both ambulatory and CR conditions (95 and 85%, respectively), but fewer had significant 24-h NTx rhythms (70 and 70%, respectively). Among individuals with significant rhythms, mean (± SD) aMT6s acrophase times were 3:57 ± 1:50 and 3:43 ± 1:25 h under ambulatory and CR conditions, respectively, and 23:44 ± 5:55 and 3:06 ± 5:15 h, respectively, for NTx. Mean 24-h levels of both aMT6s and NTx were significantly higher during CR compared with ambulatory conditions (p < 0.0001 and p = 0.03, respectively). Menstrual phase (follicular versus luteal) had no impact on aMT6s or NTx timing or 24-h levels. This study confirms an endogenous circadian rhythm in NTx with a night-time peak when measured under CR conditions, but also confirms that environmental factors such as the sleep-wake or light-dark cycles, posture or meal timing affects overall concentrations and peak timing under ambulatory conditions, the significance of which remains unclear.
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http://dx.doi.org/10.1007/s00774-017-0896-6DOI Listing
January 2019

Sleep patterns predictive of daytime challenging behavior in individuals with low-functioning autism.

Autism Res 2018 02 1;11(2):391-403. Epub 2017 Dec 1.

Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences, Monash University, Melbourne, Australia.

Increased severity of problematic daytime behavior has been associated with poorer sleep quality in individuals with autism spectrum disorder. In this work, we investigate whether this relationship holds in a real-time setting, such that an individual's prior sleep can be used to predict their subsequent daytime behavior. We analyzed an extensive real-world dataset containing over 20,000 nightly sleep observations matched to subsequent challenging daytime behaviors (aggression, self-injury, tantrums, property destruction and a challenging behavior index) across 67 individuals with low-functioning autism living in two U.S. residential facilities. Using support vector machine classifiers, a statistically significant predictive relationship was found in 81% of individuals studied (P < 0.05). For all five behaviors examined, prediction accuracy increased up to approximately eight nights of prior sleep used to make the prediction, indicating that the behavioral effects of sleep may manifest on extended timescales. Accurate prediction was most strongly driven by sleep variability measures, highlighting the importance of regular sleep patterns. Our findings constitute an initial step towards the development of a real-time monitoring tool to pre-empt behavioral episodes and guide prophylactic treatment for individuals with autism. Autism Res 2018, 11: 391-403. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Lay Summary: We analyzed over 20,000 nights of sleep from 67 individuals with autism to investigate whether daytime behaviors can be predicted from prior sleep patterns. Better-than-chance accuracy was obtained for 81% of individuals, with measures of night-to-night variation in sleep timing and duration most relevant for accurate prediction. Our results highlight the importance of regular sleep patterns for better daytime functioning and represent a step toward the development of 'smart sleep technologies' to pre-empt behavior in individuals with autism.
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http://dx.doi.org/10.1002/aur.1899DOI Listing
February 2018

Behaviorally-determined sleep phenotypes are robustly associated with adaptive functioning in individuals with low functioning autism.

Sci Rep 2017 10 27;7(1):14228. Epub 2017 Oct 27.

Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences, Monash University, Melbourne, Australia.

Despite sleep disturbance being a common complaint in individuals with autism, specific sleep phenotypes and their relationship to adaptive functioning have yet to be identified. This study used cluster analysis to find distinct sleep patterns and relate them to independent measures of adaptive functioning in individuals with autism. Approximately 50,000 nights of care-giver sleep/wake logs were collected on school-days for 106 individuals with low functioning autism (87 boys, 14.77 ± 3.11 years) for 0.5-6 years (2.2 ± 1.5 years) from two residential schools. Using hierarchical cluster analysis, performed on summary statistics of each individual across their recording duration, two clusters of individuals with clearly distinguishable sleep phenotypes were found. The groups were summarized as 'unstable' sleepers (cluster 1, n = 41) and 'stable' sleepers (cluster 2, n = 65), with the former exhibiting reduced sleep duration, earlier sleep offset, and less stability in sleep timing. The sleep clusters displayed significant differences in properties that were not used for clustering, such as intellectual functioning, communication, and socialization, demonstrating that sleep phenotypes are associated with symptom severity in individuals with autism. This study provides foundational evidence for profiling and targeting sleep as a standard part of therapeutic intervention in individuals with autism.
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http://dx.doi.org/10.1038/s41598-017-14611-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660229PMC
October 2017

The effects of spectral tuning of evening ambient light on melatonin suppression, alertness and sleep.

Physiol Behav 2017 Aug 1;177:221-229. Epub 2017 May 1.

Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, United States; Division of Sleep and Circadian Disorders, Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, United States; Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, United States.

We compared the effects of bedroom-intensity light from a standard fluorescent and a blue- (i.e., short-wavelength) depleted LED source on melatonin suppression, alertness, and sleep. Sixteen healthy participants (8 females) completed a 4-day inpatient study. Participants were exposed to blue-depleted circadian-sensitive (C-LED) light and a standard fluorescent light (FL, 4100K) of equal illuminance (50lx) for 8h prior to a fixed bedtime on two separate days in a within-subject, randomized, cross-over design. Each light exposure day was preceded by a dim light (<3lx) control at the same time 24h earlier. Compared to the FL condition, control-adjusted melatonin suppression was significantly reduced. Although subjective sleepiness was not different between the two light conditions, auditory reaction times were significantly slower under C-LED conditions compared to FL 30min prior to bedtime. EEG-based correlates of alertness corroborated the reduced alertness under C-LED conditions as shown by significantly increased EEG spectral power in the delta-theta (0.5-8.0Hz) bands under C-LED as compared to FL exposure. There was no significant difference in total sleep time (TST), sleep efficiency (SE%), and slow-wave activity (SWA) between the two conditions. Unlike melatonin suppression and alertness, a significant order effect was observed on all three sleep variables, however. Individuals who received C-LED first and then FL had increased TST, SE% and SWA averaged across both nights compared to individuals who received FL first and then C-LED. These data show that the spectral characteristics of light can be fine-tuned to attenuate non-visual responses to light in humans.
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http://dx.doi.org/10.1016/j.physbeh.2017.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536841PMC
August 2017

Circadian phase resetting by a single short-duration light exposure.

JCI Insight 2017 04 6;2(7):e89494. Epub 2017 Apr 6.

Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

In humans, a single light exposure of 12 minutes and multiple-millisecond light exposures can shift the phase of the circadian pacemaker. We investigated the response of the human circadian pacemaker to a single 15-second or 2-minute light pulse administered during the biological night. Twenty-six healthy individuals participated in a 9-day inpatient protocol that included assessment of dim light melatonin onset time (DLMO time) before and after exposure to a single 15-second ( = 8) or 2-minute ( = 12) pulse of bright light (9,500 lux; 4,100 K fluorescent) or control background dim light (<3 lux; = 6). Phase shifts were calculated as the difference in clock time between the two phase estimates. Both 15-second and 2-minute exposures induced phase delay shifts [median (± SD)] of -34.8 ± 47.2 minutes and -45.4 ± 28.4 minutes, respectively, that were significantly ( = 0.04) greater than the control condition (advance shift: +22.3 ± 51.3 minutes) but were not significantly different from each other. Comparisons with historic data collected under the same conditions confirmed a nonlinear relationship between exposure duration and the magnitude of phase shift. Our results underscore the exquisite sensitivity of the human pacemaker to even short-duration single exposures to light. These findings may have real-world implications for circadian disruption induced by exposure to brief light stimuli at night. The study was registered as a clinical trial on www.clinicaltrials.org, NCT #01330992. Funding for this study was provided by NSBRI HFP02802 and NIH P01-AG09975, R01-HL114088 (EBK), RC2-HL101340-0 (EBK, SWL, SAR, REK), K02-HD045459 (EBK), K24-HL105664 (EBK), T32-HL07901 (MSH, SAR), HL094654 (CAC), and AG044416 (JFD). The project described was supported by NIH grant 1UL1 TR001102-01, 8UL1TR000170-05, UL1 RR 025758, Harvard Clinical and Translational Science Center, from the National Center for Advancing Translational Science.
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http://dx.doi.org/10.1172/jci.insight.89494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374060PMC
April 2017

Modeling Neurocognitive Decline and Recovery During Repeated Cycles of Extended Sleep and Chronic Sleep Deficiency.

Sleep 2017 Jan;40(1)

Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA.

Study Objectives: Intraindividual night-to-night sleep duration is often insufficient and variable. Here we report the effects of such chronic variable sleep deficiency on neurobehavioral performance and the ability of state-of-the-art models to predict these changes.

Methods: Eight healthy males (mean age ± SD: 23.9 ± 2.4 years) studied at our inpatient intensive physiologic monitoring unit completed an 11-day protocol with a baseline 10-hour sleep opportunity and three cycles of two 3-hour time-in-bed (TIB) and one 10-hour TIB sleep opportunities. Participants received one of three polychromatic white light interventions (200 lux 4100K, 200 or 400 lux 17000K) for 3.5 hours on the morning following the second 3-hour TIB opportunity each cycle. Neurocognitive performance was assessed using the psychomotor vigilance test (PVT) administered every 1-2 hours. PVT data were compared to predictions of five group-average mathematical models that incorporate chronic sleep loss functions.

Results: While PVT performance deteriorated cumulatively following each cycle of two 3-hour sleep opportunities, and improved following each 10-hour sleep opportunity, performance declined cumulatively throughout the protocol at a more accelerated rate than predicted by state-of-the-art group-average mathematical models. Subjective sleepiness did not reflect performance. The light interventions had minimal effect.

Conclusions: Despite apparent recovery following each extended sleep opportunity, residual performance impairment remained and deteriorated rapidly when rechallenged with subsequent sleep loss. None of the group-average models were capable of predicting both the build-up in impairment and recovery profile of performance observed at the group or individual level, raising concerns regarding their use in real-world settings to predict performance and improve safety.
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http://dx.doi.org/10.1093/sleep/zsw009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084743PMC
January 2017

Circadian Melatonin Rhythm Following Traumatic Brain Injury.

Neurorehabil Neural Repair 2016 11 23;30(10):972-977. Epub 2016 May 23.

School of Psychological Sciences and Institute for Cognitive and Clinical Neurosciences, Monash University, VIC, Australia Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, MA. USA Division of Sleep Medicine, Department of Medicine, Harvard Medical School, MA, USA

Background: Sleep-wake disturbances are highly prevalent following traumatic brain injury (TBI), impeding rehabilitaion and quality of life. However, the mechanisms underlying these sleep disturnbances are unclear, and efficacious treatments are lacking. To investigate possible mechanisms underlying sleep disturbance in TBI, we examined characteristics of the circadian rhythm of melatonin, a hormone involved in sleep-wake regulation. We compared TBI patients reporting sleep disturbance with age- and gender-matched healthy volunteers.

Methods: We conducted an overnight observational study with salivary melatonin samples collected hourly in 9 patients with severe TBI and 9 controls. Salivary dim light melatonin onset (DLMO) as well as melatonin synthesis onset (SynOn) and offset (SynOff) were used to determine circadian timing. Total overnight salivary melatonin production was calculated as the area under the curve from melatonin synthesis onset to offset.

Results: Compared with healthy individuals, TBI patients showed 42% less melatonin production overnight (d = 0.87; P = .034). The timing of DLMO was delayed by approximately 1.5 hours in patients with TBI compared with controls (d = 1.23; P = .003).

Conclusions: In patients with TBI, melatonin production was attenuated overnight, and the timing of melatonin secretion was delayed. We suggest that disruption to the circadian regulation of melatonin synthesis is a feature of severe TBI, possibly contributing to the sleep difficulties that are commonly reported in this population.
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http://dx.doi.org/10.1177/1545968316650279DOI Listing
November 2016

Impact of Common Diabetes Risk Variant in MTNR1B on Sleep, Circadian, and Melatonin Physiology.

Diabetes 2016 06 11;65(6):1741-51. Epub 2016 Feb 11.

Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA Division of Sleep Medicine, Harvard Medical School, Boston, MA.

The risk of type 2 diabetes (T2D) is increased by abnormalities in sleep quantity and quality, circadian alignment, and melatonin regulation. A common genetic variant in a receptor for the circadian-regulated hormone melatonin (MTNR1B) is associated with increased fasting blood glucose and risk of T2D, but whether sleep or circadian disruption mediates this risk is unknown. We aimed to test if MTNR1B diabetes risk variant rs10830963 associates with measures of sleep or circadian physiology in intensive in-laboratory protocols (n = 58-96) or cross-sectional studies with sleep quantity and quality and timing measures from self-report (n = 4,307-10,332), actigraphy (n = 1,513), or polysomnography (n = 3,021). In the in-laboratory studies, we found a significant association with a substantially longer duration of elevated melatonin levels (41 min) and delayed circadian phase of dim-light melatonin offset (1.37 h), partially mediated through delayed offset of melatonin synthesis. Furthermore, increased T2D risk in MTNR1B risk allele carriers was more pronounced in early risers versus late risers as determined by 7 days of actigraphy. Our results provide the surprising insight that the MTNR1B risk allele influences dynamics of melatonin secretion, generating a novel hypothesis that the MTNR1B risk allele may extend the duration of endogenous melatonin production later into the morning and that early waking may magnify the diabetes risk conferred by the risk allele.
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http://dx.doi.org/10.2337/db15-0999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878414PMC
June 2016

Caffeine does not entrain the circadian clock but improves daytime alertness in blind patients with non-24-hour rhythms.

Sleep Med 2015 Jun 11;16(6):800-4. Epub 2015 Feb 11.

Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA, USA; Division of Sleep Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA; Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK. Electronic address:

Objective/background: Totally blind individuals are highly likely to suffer from Non-24-Hour Sleep-Wake Disorder due to a failure of light to reset the circadian pacemaker in the suprachiasmatic nuclei. In this outpatient case series, we investigated whether daily caffeine administration could entrain the circadian pacemaker in non-entrained blind patients to alleviate symptoms of non-24-hour sleep-wake disorder.

Patients/methods: Three totally blind males (63.0 ± 7.5 years old) were studied at home over ~4 months. Urinary 6-sulphatoxymelatonin (aMT6s) rhythms were measured for 48 h every 1-2 weeks. Participants completed daily sleep-wake logs, and rated their alertness and mood using nine-point scales every ~2-4 h while awake on urine sampling days. Caffeine capsules (150 mg per os) were self-administered daily at 10 a.m. for approximately one circadian beat cycle based on each participant's endogenous circadian period τ and compared to placebo (n = 2) or no treatment (n = 1) in a single-masked manner.

Results: Non-24-h aMT6s rhythms were confirmed in all three participants (τ range = 24.32-24.57 h). Daily administration of 150 mg caffeine did not entrain the circadian clock. Caffeine treatment significantly improved daytime alertness at adverse circadian phases (p <0.0001) but did not decrease the occurrence of daytime naps compared with placebo.

Conclusions: Although caffeine was able to improve daytime alertness acutely and may therefore provide temporary symptomatic relief, the inability of caffeine to correct the underlying circadian disorder means that an entraining agent is required to treat Non-24-Hour Sleep-Wake Disorder in the blind appropriately.
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http://dx.doi.org/10.1016/j.sleep.2015.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465963PMC
June 2015

A mathematical model of the circadian phase-shifting effects of exogenous melatonin.

J Biol Rhythms 2013 Feb;28(1):79-89

Division of Sleep Medicine, Brigham & Women's Hospital, Harvard Medical School, MA 02115, USA.

Melatonin is endogenously produced and released in humans during nighttime darkness and is suppressed by ocular light exposure. Exogenous melatonin is used to induce circadian phase shifts and sleep. The circadian phase-shifting ability of a stimulus (e.g., melatonin or light) relative to its timing may be displayed as a phase response curve (PRC). Published PRCs to exogenous melatonin show a transition from phase advances to delays approximately 1 h after dim light melatonin onset. A previously developed mathematical model simulates endogenous production and clearance of melatonin as a function of circadian phase, light-induced suppression, and resetting of circadian phase by light. We extend this model to include the pharmacokinetics of oral exogenous melatonin and phase-shifting effects via melatonin receptors in the suprachiasmatic nucleus of the mammalian hypothalamus. Model parameters are fit using 2 data sets: (1) blood melatonin concentration following a 0.3- or 5.0-mg dose, and (2) a PRC to a 3.0-mg dose of melatonin. After fitting to the 3.0-mg PRC, the model correctly predicts that, by comparison, the 0.5-mg PRC is slightly decreased in amplitude and shifted to a later circadian phase. This model also reproduces blood concentration profiles of various melatonin preparations that differ only in absorption rate and percentage degradation by first-pass hepatic metabolism. This model can simulate experimental protocols using oral melatonin, with potential application to guide dose size and timing to optimally shift and entrain circadian rhythms.
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http://dx.doi.org/10.1177/0748730412468081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733227PMC
February 2013

Human phase response curve to a single 6.5 h pulse of short-wavelength light.

J Physiol 2013 Jan 22;591(1):353-63. Epub 2012 Oct 22.

Circadian Physiology Program, Division of Sleep Medicine, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115, USA.

The photic resetting response of the human circadian pacemaker depends on the timing of exposure, and the direction and magnitude of the resulting shift is described by a phase response curve (PRC). Previous PRCs in humans have utilized high-intensity polychromatic white light. Given that the circadian photoreception system is maximally sensitive to short-wavelength visible light, the aim of the current study was to construct a PRC to blue (480 nm) light and compare it to a 10,000 lux white light PRC constructed previously using a similar protocol. Eighteen young healthy participants (18-30 years) were studied for 9-10 days in a time-free environment. The protocol included three baseline days followed by a constant routine (CR) to assess initial circadian phase. Following this CR, participants were exposed to a 6.5 h 480 nm light exposure (11.8 μW cm(-2), 11.2 lux) following mydriasis via a modified Ganzfeld dome. A second CR was conducted following the light exposure to re-assess circadian phase. Phase shifts were calculated from the difference in dim light melatonin onset (DLMO) between CRs. Exposure to 6.5 h of 480 nm light resets the circadian pacemaker according to a conventional type 1 PRC with fitted maximum delays and advances of -2.6 h and 1.3 h, respectively. The 480 nm PRC induced ∼75% of the response of the 10,000 lux white light PRC. These results may contribute to a re-evaluation of dosing guidelines for clinical light therapy and the use of light as a fatigue countermeasure.
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http://dx.doi.org/10.1113/jphysiol.2012.239046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3630790PMC
January 2013

Melanopsin and rod-cone photoreceptors play different roles in mediating pupillary light responses during exposure to continuous light in humans.

J Neurosci 2012 Oct;32(41):14242-53

Program in Neuroscience and Behavioral Disorders, Duke-National University of Singapore Graduate Medical School Singapore, Singapore 169857.

In mammals, the pupillary light reflex is mediated by intrinsically photosensitive melanopsin-containing retinal ganglion cells that also receive input from rod-cone photoreceptors. To assess the relative contribution of melanopsin and rod-cone photoreceptors to the pupillary light reflex in humans, we compared pupillary light responses in normally sighted individuals (n = 24) with a blind individual lacking rod-cone function. Here, we show that visual photoreceptors are required for normal pupillary responses to continuous light exposure at low irradiance levels, and for sustained pupillary constriction during exposure to light in the long-wavelength portion of the visual spectrum. In the absence of rod-cone function, pupillomotor responses are slow and sustained, and cannot track intermittent light stimuli, suggesting that rods/cones are required for encoding fast modulations in light intensity. In sighted individuals, pupillary constriction decreased monotonically for at least 30 min during exposure to continuous low-irradiance light, indicating that steady-state pupillary responses are an order of magnitude slower than previously reported. Exposure to low-irradiance intermittent green light (543 nm; 0.1-4 Hz) for 30 min, which was given to activate cone photoreceptors repeatedly, elicited sustained pupillary constriction responses that were more than twice as great compared with exposure to continuous green light. Our findings demonstrate nonredundant roles for rod-cone photoreceptors and melanopsin in mediating pupillary responses to continuous light. Moreover, our results suggest that it might be possible to enhance nonvisual light responses to low-irradiance exposures by using intermittent light to activate cone photoreceptors repeatedly in humans.
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http://dx.doi.org/10.1523/JNEUROSCI.1321-12.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3515688PMC
October 2012

Classifying performance impairment in response to sleep loss using pattern recognition algorithms on single session testing.

Accid Anal Prev 2013 Jan 5;50:992-1002. Epub 2012 Sep 5.

Analytic and Modeling Unit, Division of Sleep Medicine, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115, USA.

There is currently no "gold standard" marker of cognitive performance impairment resulting from sleep loss. We utilized pattern recognition algorithms to determine which features of data collected under controlled laboratory conditions could most reliably identify cognitive performance impairment in response to sleep loss using data from only one testing session, such as would occur in the "real world" or field conditions. A training set for testing the pattern recognition algorithms was developed using objective Psychomotor Vigilance Task (PVT) and subjective Karolinska Sleepiness Scale (KSS) data collected from laboratory studies during which subjects were sleep deprived for 26-52h. The algorithm was then tested in data from both laboratory and field experiments. The pattern recognition algorithm was able to identify performance impairment with a single testing session in individuals studied under laboratory conditions using PVT, KSS, length of time awake and time of day information with sensitivity and specificity as high as 82%. When this algorithm was tested on data collected under real-world conditions from individuals whose data were not in the training set, accuracy of predictions for individuals categorized with low performance impairment were as high as 98%. Predictions for medium and severe performance impairment were less accurate. We conclude that pattern recognition algorithms may be a promising method for identifying performance impairment in individuals using only current information about the individual's behavior. Single testing features (e.g., number of PVT lapses) with high correlation with performance impairment in the laboratory setting may not be the best indicators of performance impairment under real-world conditions. Pattern recognition algorithms should be further tested for their ability to be used in conjunction with other assessments of sleepiness in real-world conditions to quantify performance impairment in response to sleep loss.
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http://dx.doi.org/10.1016/j.aap.2012.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3513628PMC
January 2013

Human phase response curve to a 1 h pulse of bright white light.

J Physiol 2012 Jul 30;590(13):3035-45. Epub 2012 Apr 30.

Division of Sleep Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115, USA.

The phase resetting response of the human circadian pacemaker to light depends on the timing of exposure and is described by a phase response curve (PRC). The current study aimed to construct a PRC for a 1 h exposure to bright white light (∼8000 lux) and to compare this PRC to a <3 lux dim background light PRC. These data were also compared to a previously completed 6.7 h bright white light PRC and a <15 lux dim background light PRC constructed under similar conditions. Participants were randomized for exposure to 1 h of either bright white light (n=18) or <3 lux dim background light (n=18) scheduled at 1 of 18 circadian phases. Participants completed constant routine (CR) procedures in dim light (<3 lux) before and after the light exposure to assess circadian phase. Phase shifts were calculated as the difference in timing of dim light melatonin onset (DLMO) during pre- and post-stimulus CRs. Exposure to 1 h of bright white light induced a Type 1 PRC with a fitted peak-to-trough amplitude of 2.20 h. No discernible PRC was observed in the <3 lux dim background light PRC. The fitted peak-to-trough amplitude of the 1 h bright light PRC was ∼40% of that for the 6.7 h PRC despite representing only 15% of the light exposure duration, consistent with previous studies showing a non-linear duration–response function for the effects of light on circadian resetting.
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http://dx.doi.org/10.1113/jphysiol.2012.227892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406389PMC
July 2012

Analysis method and experimental conditions affect computed circadian phase from melatonin data.

PLoS One 2012 12;7(4):e33836. Epub 2012 Apr 12.

Division of Sleep Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.

Accurate determination of circadian phase is necessary for research and clinical purposes because of the influence of the master circadian pacemaker on multiple physiologic functions. Melatonin is presently the most accurate marker of the activity of the human circadian pacemaker. Current methods of analyzing the plasma melatonin rhythm can be grouped into three categories: curve-fitting, threshold-based and physiologically-based linear differential equations. To determine which method provides the most accurate assessment of circadian phase, we compared the ability to fit the data and the variability of phase estimates for seventeen different markers of melatonin phase derived from these methodological categories. We used data from three experimental conditions under which circadian rhythms - and therefore calculated melatonin phase - were expected to remain constant or progress uniformly. Melatonin profiles from older subjects and subjects with lower melatonin amplitude were less likely to be fit by all analysis methods. When circadian drift over multiple study days was algebraically removed, there were no significant differences between analysis methods of melatonin onsets (P = 0.57), but there were significant differences between those of melatonin offsets (P<0.0001). For a subset of phase assessment methods, we also examined the effects of data loss on variability of phase estimates by systematically removing data in 2-hour segments. Data loss near onset of melatonin secretion differentially affected phase estimates from the methods, with some methods incorrectly assigning phases too early while other methods assigning phases too late; missing data at other times did not affect analyses of the melatonin profile. We conclude that melatonin data set characteristics, including amplitude and completeness of data collection, differentially affect the results depending on the melatonin analysis method used.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0033836PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325223PMC
December 2012

A physiologically based mathematical model of melatonin including ocular light suppression and interactions with the circadian pacemaker.

J Pineal Res 2007 Oct;43(3):294-304

Division of Sleep Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

The rhythm of plasma melatonin concentration is currently the most accurate marker of the endogenous human circadian pacemaker. A number of methods exist to estimate circadian phase and amplitude from the observed melatonin rhythm. However, almost all these methods are limited because they depend on the shape and amplitude of the melatonin pulse, which vary among individuals and can be affected by environmental influences, especially light. Furthermore, these methods are not based on the underlying known physiology of melatonin secretion and clearance, and therefore cannot accurately quantify changes in secretion and clearance observed under different experimental conditions. A published physiologically-based mathematical model of plasma melatonin can estimate synthesis onset and offset of melatonin under dim light conditions. We amended this model to include the known effect of melatonin suppression by ocular light exposure and to include a new compartment to model salivary melatonin concentration, which is widely used in clinical settings to determine circadian phase. This updated model has been incorporated into an existing mathematical model of the human circadian pacemaker and can be used to simulate experimental protocols under a number of conditions.
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http://dx.doi.org/10.1111/j.1600-079X.2007.00477.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2714090PMC
October 2007

Addition of a non-photic component to a light-based mathematical model of the human circadian pacemaker.

J Theor Biol 2007 Aug 4;247(4):583-99. Epub 2007 Apr 4.

Analytic and Modeling Unit, Division of Sleep Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02115, USA.

Mathematical models have become vital to the study of many biological processes in humans due to the complexity of the physiological mechanisms underlying these processes and systems. While our current mathematical representation of the human circadian pacemaker has proven useful in many experimental situations, it uses as input only a direct effect of light on the circadian pacemaker. Although light (a photic stimulus) has been shown to be the primary synchronizer of the circadian pacemaker across a number of species, studies in both animals and humans have confirmed the existence of non-photic effects that also contribute to phase shifting and entrainment. We modified our light-based circadian mathematical model to reflect evidence from these studies that the sleep-wake cycle and/or associated behaviors have a non-photic effect on the circadian pacemaker. In our representation, the sleep-wake cycle and its associated behaviors provides a non-photic drive on the circadian pacemaker that acts both independently and concomitantly with light stimuli. Further experiments are required to validate fully our model and to understand the exact effect of the sleep-wake cycle as a non-photic stimulus for the human circadian pacemaker.
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http://dx.doi.org/10.1016/j.jtbi.2007.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3123888PMC
August 2007
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