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      Workshop report. Circadian rhythm sleep–wake disorders: gaps and opportunities

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          Abstract

          This White Paper presents the results from a workshop cosponsored by the Sleep Research Society (SRS) and the Society for Research on Biological Rhythms (SRBR) whose goals were to bring together sleep clinicians and sleep and circadian rhythm researchers to identify existing gaps in diagnosis and treatment and areas of high-priority research in circadian rhythm sleep–wake disorders (CRSWD). CRSWD are a distinct class of sleep disorders caused by alterations of the circadian time-keeping system, its entrainment mechanisms, or a misalignment of the endogenous circadian rhythm and the external environment. In these disorders, the timing of the primary sleep episode is either earlier or later than desired, irregular from day-to-day, and/or sleep occurs at the wrong circadian time. While there are incomplete and insufficient prevalence data, CRSWD likely affect at least 800,000 and perhaps as many as 3 million individuals in the United States, and if Shift Work Disorder and Jet Lag are included, then many millions more are impacted. The SRS Advocacy Taskforce has identified CRSWD as a class of sleep disorders for which additional high-quality research could have a significant impact to improve patient care. Participants were selected for their expertise and were assigned to one of three working groups: Phase Disorders, Entrainment Disorders, and Other. Each working group presented a summary of the current state of the science for their specific CRSWD area, followed by discussion from all participants. The outcome of those presentations and discussions are presented here.

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          Most cited references119

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          Adverse metabolic and cardiovascular consequences of circadian misalignment.

          There is considerable epidemiological evidence that shift work is associated with increased risk for obesity, diabetes, and cardiovascular disease, perhaps the result of physiologic maladaptation to chronically sleeping and eating at abnormal circadian times. To begin to understand underlying mechanisms, we determined the effects of such misalignment between behavioral cycles (fasting/feeding and sleep/wake cycles) and endogenous circadian cycles on metabolic, autonomic, and endocrine predictors of obesity, diabetes, and cardiovascular risk. Ten adults (5 female) underwent a 10-day laboratory protocol, wherein subjects ate and slept at all phases of the circadian cycle-achieved by scheduling a recurring 28-h "day." Subjects ate 4 isocaloric meals each 28-h "day." For 8 days, plasma leptin, insulin, glucose, and cortisol were measured hourly, urinary catecholamines 2 hourly (totaling approximately 1,000 assays/subject), and blood pressure, heart rate, cardiac vagal modulation, oxygen consumption, respiratory exchange ratio, and polysomnographic sleep daily. Core body temperature was recorded continuously for 10 days to assess circadian phase. Circadian misalignment, when subjects ate and slept approximately 12 h out of phase from their habitual times, systematically decreased leptin (-17%, P < 0.001), increased glucose (+6%, P < 0.001) despite increased insulin (+22%, P = 0.006), completely reversed the daily cortisol rhythm (P < 0.001), increased mean arterial pressure (+3%, P = 0.001), and reduced sleep efficiency (-20%, P < 0.002). Notably, circadian misalignment caused 3 of 8 subjects (with sufficient available data) to exhibit postprandial glucose responses in the range typical of a prediabetic state. These findings demonstrate the adverse cardiometabolic implications of circadian misalignment, as occurs acutely with jet lag and chronically with shift work.
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            Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat.

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              Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms.

              Within the mammalian hypothalamus, the suprachiasmatic nucleus (SCN) contains a circadian clock for timing of diverse neuronal, endocrine, and behavioral rhythms. By culturing cells from neonatal rat SCN on fixed microelectrode arrays, we have been able to record spontaneous action potentials from individual SCN neurons for days or weeks, revealing prominent circadian rhythms in firing rate. Despite abundant functional synapses, circadian rhythms expressed by neurons in the same culture are not synchronized. After reversible blockade of neuronal firing lasting 2.5 days, circadian firing rhythms re-emerge with unaltered phases. These data suggest that the SCN contains a large population of autonomous, single-cell circadian oscillators, and that synapses formed in vitro are neither necessary for operation of these oscillators nor sufficient for synchronizing them.
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                Author and article information

                Journal
                Sleep
                Sleep
                sleep
                Sleep
                Oxford University Press (US )
                0161-8105
                1550-9109
                May 2021
                14 February 2021
                14 February 2021
                : 44
                : 5
                : zsaa281
                Affiliations
                [1 ] Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School , Boston, MA
                [2 ] Department of Neurology, Northwestern University Feinberg School of Medicine , Chicago, IL
                [3 ] Department of Psychiatry, University of Michigan , Ann Arbor, MI
                [4 ] Department of Psychiatry and Behavioral Sciences, Rush University Medical Center , Chicago, IL
                [5 ] Department of Psychiatry, Oregon Health & Science University , Portland, OR
                [6 ] Department of Psychiatry University of Alabama at Birmingham , Birmingham, AL
                [7 ] Department of Psychiatry, University of Pittsburgh School of Medicine , Pittsburgh, PA
                [8 ] Department of Neurology, Massachusetts General Hospital and Harvard Medical School , Boston, MA
                Author notes
                Corresponding author. Jeanne F. Duffy, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA. Email: jduffy@ 123456research.bwh.harvard.edu .
                Author information
                https://orcid.org/0000-0003-4177-4179
                https://orcid.org/0000-0002-8947-9649
                https://orcid.org/0000-0003-3816-8194
                https://orcid.org/0000-0003-2057-9876
                https://orcid.org/0000-0003-3813-8577
                https://orcid.org/0000-0002-8729-0500
                https://orcid.org/0000-0002-8709-4083
                https://orcid.org/0000-0001-6454-1736
                https://orcid.org/0000-0002-7402-3171
                Article
                zsaa281
                10.1093/sleep/zsaa281
                8120340
                33582815
                3976ba7b-a5ad-47e2-bfb3-1e5e048ce54b
                © Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 12 May 2020
                : 02 October 2020
                : 14 February 2021
                Page count
                Pages: 15
                Funding
                Funded by: National Institutes of Health, DOI 10.13039/100000002;
                Award ID: R01 DA044143
                Award ID: K24 HL105664
                Award ID: R01 AG044416
                Award ID: R01 HL140580
                Award ID: P01 AG011412
                Funded by: American Heart Association, DOI 10.13039/100000968;
                Award ID: 19CDA34660139
                Categories
                Circadian Rhythms and Circadian Disorders
                AcademicSubjects/SCI01870
                AcademicSubjects/MED00385
                AcademicSubjects/MED00370
                Editor's Choice

                actigraphy,advanced sleep–wake phase disorder,bright light therapy,chronotype,circadian amplitude,circadian period,circadian phase,circadian rhythm sleep–wake disorders,delayed sleep–wake phase disorder,dim light melatonin onset,entrainment,melatonin,non-24-hour sleep–wake disorder,irregular sleep–wake rhythm disorder

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