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Cited by 713Circadian rhythm and melatoninSleep and Wakefulness ResearchSleep and Work-Related Fatigue

Rhythms of life: circadian disruption and brain disorders across the lifespan

Open access
Logan, Ryan W., McClung, Colleen A.·2019·Nature Reviews Neuroscience
DOI 10.1038/s41583-018-0088-yPMC PMC6338075
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Abstract

Many processes in the human body — including brain function — are regulated over the 24-hour cycle, and there are strong associations between disrupted circadian rhythms (for example, sleep–wake cycles) and disorders of the CNS. Brain disorders such as autism, depression and Parkinson disease typically develop at certain stages of life, and circadian rhythms are important during each stage of life for the regulation of processes that may influence the development of these disorders. Here, we describe circadian disruptions observed in various brain disorders throughout the human lifespan and highlight emerging evidence suggesting these disruptions affect the brain. Currently, much of the evidence linking brain disorders and circadian dysfunction is correlational, and so whether and what kind of causal relationships might exist are unclear. We therefore identify remaining questions that may direct future research towards a better understanding of the links between circadian disruption and CNS disorders. Many neurobiological processes are regulated on a circadian basis. Circadian rhythms change during development, into adulthood and with ageing, when certain disorders typically emerge. Here, Logan and McClung give an overview of the relationship between the circadian system and brain disorders across various life stages.

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Written from the paper’s full text.

TL;DR

This review synthesizes evidence that circadian rhythm disruption is associated with brain disorders across the lifespan, from neurodevelopmental conditions through psychiatric and neurodegenerative disorders. It argues that most human evidence remains correlational, while animal and mechanistic studies are beginning to identify possible causal pathways and chronotherapeutic targets.

Key findings

  • Circadian disruption is linked to brain disorders at different life stages: prenatal/early childhood (e.g., preterm outcomes, ADHD, ASD, PWS, SMS), adolescence (substance use and mood disorders), adulthood (shift-work disorder and chronic jet-lag), and later life (dementia, AD, PD).
  • In adulthood, a study of 11,450 Canadian nurses found the strongest work-schedule–depression relationship in rapidly rotating and undefined rotating schedules; a study of ~14,000 South Korean electronics workers found shift-workers had higher rates of insomnia, depression and suicidal ideation; and a survey of ~4,000 flight attendants found they were 2–5.7-fold more likely to have sleep disorders, depression, anxiety and/or fatigue than the general population.
  • In neurodevelopmental disorders, a double-blind placebo-controlled study of 125 children and adolescents (2–17.5 years) supported melatonin supplementation for ASD-related sleep disturbances; in SMS, acebutolol reduced daytime naps, improved concentration and reduced tantrums in ten patients aged 4–18 years, and combining β1-adrenergic antagonism with timed melatonin improved sleep and daytime behaviour.
  • In later life, more than 80% of people with REM sleep behaviour disorder are later diagnosed with PD or dementia; one night of sleep deprivation increased amyloid-β in the right hippocampus and thalamus; a randomized controlled trial of 189 participants found increased daytime illumination slowed MMSE decline, reduced depression scores and reduced functional impairment over 1.5 years; and a double-blind multicentre study in 157 individuals with AD found evening melatonin improved cognition and decreased nocturnal activity.

Methods

  • Narrative review synthesizing human epidemiological, clinical, post-mortem, genetic and imaging studies alongside rodent and non-human primate work across prenatal, childhood, adolescent, adult and later-life periods.
  • Main analysis is qualitative: the authors describe circadian disruptions observed in specific brain disorders, highlight proposed molecular and circuit mechanisms, and discuss treatment/intervention implications.
  • No systematic search strategy, inclusion criteria or quantitative meta-analysis is reported in the provided text.

Limitations

  • The authors state that much of the evidence linking brain disorders and circadian dysfunction is correlational and that whether and what kind of causal relationships exist is unclear.
  • The authors note that mood disorders are very heterogeneous and that identifying a common circadian or sleep-related mechanism causal for all bipolar disorder or major depression is unlikely.
  • Evident from the text: this is a narrative review without a stated systematic search or formal quality appraisal, and several cited clinical findings rely on small samples (e.g., ten SMS patients) or preclinical models, limiting causal inference in humans.

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Integrity signals

Registry

Crossref · 10.1038/s41583-018-0088-y

Cites

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Statistics

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Claims the paper makes

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  • Premisecitation

    Environmental factors such as light exposure, social cues, meal times and work schedules influence the period, phase and amplitude of circadian rhythms.

    “Environmental factors such as light exposure, social cues, meal times and work schedules also influence the period, phase and amplitude of these rhythms6,7.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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  • Premisecitation

    Most people have sleep-wake and activity rhythms that, in the absence of environmental cues, are slightly longer than 24 hours.

    “Most people have sleep–wake and activity rhythms that, in the absence of environmental cues, are slightly longer than 24 hours3,4, but the length of this period can be affected by circadian gene variants5.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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  • Premisecitation

    Epidemiological studies report increased risks of preterm delivery, low birthweights and miscarriage in pregnant women who are chronic shift-workers.

    “Epidemiological studies report increased risks of preterm delivery, low birthweights and miscarriage in pregnant women who are chronic shift-workers37–40.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
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  • Premisecitation

    Circadian rhythms of melatonin along with corticosteroid are detectable in the umbilical artery and vein, along with fetal circulation.

    “Circadian rhythms of melatonin along with corticosteroid are detectable in the umbilical artery and vein, along with fetal circulation35,36.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [35] Seron-Ferre, M., Riffo, R., Valenzuela, G. J. & Germain, A. M. Twenty-four-hour pattern of cortisol in the human fetus at term. Am. J. Obstet. Gynecol. 184, 1278–1283 (2001). source

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    Fetal rhythms are entrained by maternal core body temperature, feeding and hormone release.

    “Fetal rhythms are also entrained by maternal core body temperature, feeding and hormone release27 (FIG. 3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Reppert, S. M. Interaction between the circadian clocks of mother and fetus. Ciba Found. Symp. 183, 198–207; discussion 207–111 (1995).

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    Premisecitation

    Alterations in the rhythms of circadian gene expression are associated with impaired spatial memory in these offspring, and these memory deficits can be prevented by regularly scheduled supplementation of melatonin to the mother.

    “Alterations in the rhythms of circadian gene expression are also associated with impaired spatial memory in these offspring46,47, and these memory deficits can be prevented by regularly scheduled supplementation of melatonin to the mother46.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [46] Vilches, N. et al. Gestational chronodisruption impairs hippocampal expression of NMDA receptor subunits Grin1b/Grin3a and spatial memory in the adult offspring. PLOS ONE 9, e91313 (2014). source

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    Premisecitation

    Molecular rhythms in individual cells are generated by a transcriptional-translational feedback loop involving CLOCK, NPAS2 and BMAL1, which regulate expression of genes including PER and CRY, and these translated products inhibit their own transcription.

    “In individual cells, molecular rhythms are generated by a transcriptional–translational feedback loop involving core transcriptional activators — circadian locomotor output cycles kaput (CLOCK), the closely related neuronal PAS domain protein 2 (NPAS2) and brain and muscle ARNT-like protein 1 (BMAL1) — that regulate the expression of many genes, including those encoding period (PER) and cryptochr”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Reppert, S. M. & Weaver, D. R. Coordination of circadian timing in mammals. Nature 418, 935–941 (2002). source

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    Premisecitation

    Circadian rhythms are near-24-hour oscillations found in essentially every physiological process in the human brain and body.

    “Circadian rhythms are near-24-hour oscillations found in essentially every physiological process in the human brain and body1.”
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    • cites [1] Reppert, S. M. & Weaver, D. R. Coordination of circadian timing in mammals. Nature 418, 935–941 (2002). source

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    Premisecitation

    In older adults, rhythms often return to being substantially earlier, and this shift may be accompanied by a weakening of circadian rhythms.

    “In older adults, rhythms often return to being substantially earlier, and this shift may be accompanied by a weakening of circadian rhythms11,12.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] Chen, C. Y. et al. Effects of aging on circadian patterns of gene expression in the human prefrontal cortex. Proc. Natl Acad. Sci. USA 113, 206–211 (2015). This is the largest-scale study of circadian rhythms of gene expression in human post-mortem brain tissue, revealing age-related decline in the expression of core circadian genes and the emergence of other rhythmic pathways in older subjects. source

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    Premisecitation

    The timing of sleep onset and waking and other biological rhythms is earlier relative to adults during early childhood and shifts later during adolescence.

    “In general, the timing of sleep onset and waking and other biological rhythms (for example, fluctuations in melatonin levels) is earlier relative to adults during early childhood8,9 and shifts later during adolescence, and this shift in timing may be conserved among rodents and non-human primates (NHPs)10.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Premisecitation

    Pregnant rats exposed to simulated shift-work showed substantially reduced weight gain during early pregnancy and reduced fat-pad and liver weights, and also exhibited lower-amplitude rhythms of corticosterone, glucose, insulin and leptin levels.

    “Pregnant rats exposed to simulated shift-work (that is, complete reversal of the light–dark cycle every 3–4 days for several weeks) showed substantially reduced weight gain during early pregnancy and reduced fat-pad and liver weights, and also exhibited lower-amplitude rhythms of corticosterone, glucose, insulin and leptin levels41.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    In humans, melatonin and dopamine receptors appear as early as gestational week 18 in the fetal SCN, suggesting melatonin and dopamine may serve as the primary communicators of circadian information for the fetus.

    “In humans, melatonin and dopamine receptors appear as early as gestational week 18 in the fetal SCN26–28, suggesting melatonin and dopamine may serve as the primary communicators of circadian information for the fetus29,30.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
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    • cites [27] Reppert, S. M. Interaction between the circadian clocks of mother and fetus. Ciba Found. Symp. 183, 198–207; discussion 207–111 (1995).

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    Premisecitation

    Exposing pregnant non-human primates to constant light suppresses the emergence of melatonin and body temperature rhythms in their offspring following birth, suggesting that maternal rhythms are important for the early brain development of fetal circadian systems.

    “Exposing pregnant NHPs to constant light suppresses the emergence of melatonin and body temperature rhythms in their offspring following birth42–44, suggesting that maternal rhythms are important for the early brain development of fetal circadian systems45.”
    Quote in the paperSubstantial claim0 of 4 sources checked
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    Premisecitation

    Melatonin from the mother readily passes through the placenta and the fetal blood-brain barrier and may thus be the predominant relay of time-of-day information to the fetus, particularly during the transition from dusk to night as circulating melatonin rises.

    “Melatonin from the mother readily passes through the placenta and the fetal blood–brain barrier and may thus be the predominant relay of time-of-day information to the fetus, particularly during the transition from dusk to night, as circulating melatonin rises31–34.”
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    Premisecitation

    The same simulated shift-work manipulation affected metabolic and circadian gene expression rhythms in the fetal liver, but did not affect placental or fetal growth.

    “The same manipulation also affected metabolic and circadian gene expression rhythms in the fetal liver, but did not affect placental or fetal growth41.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Varcoe, T. J. et al. Characterisation of the maternal response to chronic phase shifts during gestation in the rat: implications for fetal metabolic programming. PLOS ONE 8, e53800 (2013). source

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    Interpretationreasoning

    The effects of parental dim light at night on offspring are evident even when parents are exposed before breeding, suggesting that repeated exposure leads to epigenetic modifications that can be passed between generations.

    “Notably, these effects are evident in offspring from parents exposed to dim light at night before breeding, suggesting that repeated exposure to dim light at night leads to epigenetic modifications that can be passed between generations.”
    Quote in the paperSubstantial claim

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    Premisecitation

    During the first year of life, sleep-wake rhythms continue to consolidate, coinciding with increased melatonin secretion at sunset.

    “During the first year of life, sleep–wake rhythms continue to consolidate, coinciding with increased melatonin secretion at sunset23.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Rivkees, S. A. Developing circadian rhythmicity in infants. Pediatr. Endocrinol. Rev. 1, 38–45 (2003).

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    Premisecitation

    Chronically exposing mice to dim light at night impairs adaptive immune function and increases depression-like behaviours in their offspring.

    “For example, chronically exposing mice to dim light at night impairs adaptive immune function49 and increases depression-like behaviours50 in their offspring.”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    On non-scheduled days, children tend to wake up later, substantially delaying their sleep-wake times, indicating that social and environmental factors, such as schedules imposed by school and parents, have a major influence on survey-based measures of chronotype.

    “However, on non-scheduled days, children tend to wake up later, substantially delaying their sleep–wake times, indicating that social and environmental factors, such as schedules imposed by school and parents, have a major influence on survey-based measures of chronotype9.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Simpkin, C. T. et al. Chronotype is associated with the timing of the circadian clock and sleep in toddlers. J. Sleep Res. 23, 397–405 (2014). source

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    Premisecitation

    Reductions in sleep quality, delays in circadian phase and evening preference are consistently reported in children and adults with ADHD and may be correlated with the severity of ADHD symptoms.

    “Reductions in sleep quality, delays in circadian phase and evening preference are consistently reported in children and adults with ADHD87 and may be correlated with the severity of ADHD symptoms88.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Premisecitation

    Temperature rhythms appear almost immediately after birth in full-term infants, whereas other rhythms, including rest-activity, sleep-wake and hormonal cycles, typically develop between 3 and 6 months of age.

    “Temperature rhythms appear almost immediately after birth in full-term infants, whereas other rhythms, including rest–activity, sleep–wake and hormonal cycles, typically develop between 3 and 6 months of age23,52.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Premisecitation

    PWS is accompanied by shorter sleep duration and excessive daytime sleepiness.

    “PWS is also accompanied by shorter sleep duration and excessive daytime sleepiness71,111,112.”
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    Premisecitation

    ADHD is characterized by inattentiveness, impulsivity and hyperactivity and is associated with high rates of co-occurring sleep problems and circadian alterations.

    “One of the most common neurodevelopmental disorders of childhood, ADHD, is characterized by inattentiveness, impulsivity and hyperactivity and is associated with high rates of co-occurring sleep problems and circadian alterations86.”
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    Premisecitation

    Sleep problems are very common in children with ASD, although revealing any underlying circadian abnormalities has proved difficult.

    “Sleep problems are very common in children with ASD94–96, although revealing any underlying circadian abnormalities has proved difficult97,98.”
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    Premisecitation

    Variants identified in the promoter of the ASMT gene were specific to individuals with ASD compared with controls and were associated with reduced ASMT activity and melatonin levels.

    “Variants identified in the promoter of the ASMT gene were specific to individuals with ASD compared with controls and were associated with reduced ASMT activity and melatonin levels102.”
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    Premisecitation

    Premature infants kept in regular light-dark conditions also fed orally sooner and spent fewer days on ventilator assistance, but had similar motor coordination compared with infants under continuous near darkness in the NICU (28-32 weeks of gestation).

    “Premature infants kept in regular light–dark conditions also fed orally sooner and spent fewer days on ventilator assistance, but had similar motor coordination compared with infants under continuous near darkness in the NICU (28–32 weeks of gestation)79–85.”
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    Premisecitation

    Early-morning light exposure (between 03:00 h and 04:00 h) also reduced melatonin, although no differences were found between early and late adolescents.

    “Early-morning light exposure (between 03:00 h and 04:00 h) also reduced melatonin, although no differences were found between early and late adolescents145.”
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    Premisecitation

    SNORD116 is expressed exclusively from the paternally inherited allele, whereas maternally inherited alleles of UBE3A are linked to PWS.

    “For example, SNORD116 is expressed exclusively from the paternally inherited allele113, whereas maternally inherited alleles of UBE3A are linked to PWS119,120.”
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    • cites [113] Cavaille, J. et al. Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization. Proc. Natl Acad. Sci. USA 97, 14311–14316 (2000). source

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    • cites [119] Martins-Taylor, K. et al. Imprinted expression of UBE3A in non-neuronal cells from a Prader–Willi syndrome patient with an atypical deletion. Hum. Mol. Genet. 23, 2364–2373 (2014). source

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    • cites [120] Rougeulle, C., Glatt, H. & Lalande, M. The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain. Nat. Genet. 17, 14–15 (1997). source

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  • May combine two claims.

    Premisecitation

    Maternal duplications of the 15q11-13 locus lead to increased expression of UBE3A and epigenetic silencing of the paternal antisense transcript, UBE3A-ATS.

    “Maternal duplications of the 15q11–13 locus lead to increased expression of UBE3A and epigenetic silencing of the paternal antisense transcript, UBE3A-ATS121–124.”
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    • cites [121] Baron, C. A. et al. Genomic and functional profiling of duplicated chromosome 15 cell lines reveal regulatory alterations in UBE3A-associated ubiquitin-proteasome pathway processes. Hum. Mol. Genet. 15, 853–869 (2006). source

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    • cites [122] Herzing, L. B., Cook, E. H. Jr & Ledbetter, D. H. Allele-specific expression analysis by RNA-FISH demonstrates preferential maternal expression of UBE3A and imprint maintenance within 15q11-q13 duplications. Hum. Mol. Genet. 11, 1707–1718 (2002). source

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    • cites [123] Hogart, A. et al. Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number. J. Med. Genet. 46, 86–93 (2009). source

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    • cites [124] Nishimura, Y. et al. Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways. Hum. Mol. Genet. 16, 1682–1698 (2007). source

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  • May combine two claims.

    Premisecitation

    Circadian disruptions, such as social jet-lag, during adolescence increase vulnerability to substance use, and conversely, chronic exposure to these substances can lead to long-lasting changes in the circadian and sleep networks.

    “Circadian disruptions (such as social jet-lag) during adolescence increase vulnerability to substance use, and conversely, chronic exposure to these substances can lead to long-lasting changes in the circadian and sleep networks154.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [154] Falcon, E. & McClung, C. A. A role for the circadian genes in drug addiction. Neuropharmacology 56, 91–96 (2009). (Suppl. 1). source

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    Premisecitation

    Mice with a heterozygous deletion of Rai1 display a shortened locomotor activity period, although these mice are of mixed genetic background containing C57BL/6, which do not produce pineal melatonin.

    “Mice with a heterozygous deletion of Rai1 display a shortened locomotor activity period133,134, although these mice are of mixed genetic background containing C57BL/6, which do not produce pineal melatonin.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [133] Walz, K. et al. Behavioral characterization of mouse models for Smith–Magenis syndrome and dup(17)(p11.2p11.2). Hum. Mol. Genet. 13, 367–378 (2004). source

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    • cites [134] Lacaria, M., Gu, W. & Lupski, J. R. Circadian abnormalities in mouse models of Smith–Magenis syndrome: evidence for involvement of RAI1. Am. J. Med. Genet. A 161A, 1561–1568 (2013). source

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  • May combine two claims.

    Interpretationcitation

    Therapies targeting the reversal of melatonin rhythms in patients with SMS may improve sleep, as well as behaviour, attention and learning.

    “Thus, therapies targeting the reversal of melatonin rhythms in patients with SMS may improve sleep, as well as behaviour, attention and learning137–139.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [137] De Leersnyder, H. et al. β1-adrenergic antagonists and melatonin reset the clock and restore sleep in a circadian disorder, Smith–Magenis syndrome. J. Med. Genet. 40, 74–78 (2003). source

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    • cites [138] De Leersnyder, H., Claustrat, B., Munnich, A. & Verloes, A. Circadian rhythm disorder in a rare disease: Smith–Magenis syndrome. Mol. Cell Endocrinol. 252, 88–91 (2006). source

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    • cites [139] Elsea, S. H. & Girirajan, S. Smith–Magenis syndrome. Eur. J. Hum. Genet. 16, 412–421 (2008). source

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  • May combine two claims.

    Premisecitation

    Adolescents with shorter sleep duration are more likely to use substances, including caffeine, nicotine, alcohol and marijuana, and to engage in other risky behaviours.

    “Moreover, adolescents with shorter sleep duration are more likely to use substances, including caffeine, nicotine, alcohol and marijuana157–159, and to engage in other risky behaviours157,160,161.”
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    • cites [157] McKnight-Eily, L. R. et al. Relationships between hours of sleep and health-risk behaviors in US adolescent students. Prev. Med. 53, 271–273 (2011). source

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    • cites [158] Paiva, T., Gaspar, T. & Matos, M. G. Mutual relations between sleep deprivation, sleep stealers and risk behaviours in adolescents. Sleep Sci. 9, 7–13 (2016). source

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    • cites [159] Sivertsen, B., Skogen, J. C., Jakobsen, R. & Hysing, M. Sleep and use of alcohol and drug in adolescence. A large population-based study of Norwegian adolescents aged 16 to 19 years. Drug Alcohol Depend. 149, 180–186 (2015). source

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    • cites [160] Thomas, A. G., Monahan, K. C., Lukowski, A. F. & Cauffman, E. Sleep problems across development: a pathway to adolescent risk taking through working memory. J. Youth Adolesc. 44, 447–464 (2015). source

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    • cites [161] Wheaton, A. G., Olsen, E. O., Miller, G. F. & Croft, J. B. Sleep duration and injury-related risk behaviors among high school students — United States, 2007–2013. MMWR Morb. Mortal. Wkly Rep. 65, 337–341 (2016). source

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  • May combine two claims.

    Premisecitation

    At the onset of puberty, sleep-wake cycles and melatonin rhythms start to phase delay, a shift that is dependent on the presence of gonadal hormones and coincides with sexual maturity.

    “At the onset of puberty, sleep–wake cycles and melatonin rhythms start to phase delay141 — a shift that is dependent on the presence of gonadal hormones, and that coincides with sexual maturity142,143.”
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    • cites [141] Roenneberg, T. et al. A marker for the end of adolescence. Curr. Biol. 14, R1038–R1039 (2004). source

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    • cites [142] Hagenauer, M. H. & Lee, T. M. The neuroendocrine control of the circadian system: adolescent chronotype. Front. Neuroendocrinol. 33, 211–229 (2012). source

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    • cites [143] Hagenauer, M. H. & Lee, T. M. Adolescent sleep patterns in humans and laboratory animals. Horm. Behav. 64, 270–279 (2013). source

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  • May combine two claims.

    Premisecitation

    Combining β1-adrenergic receptor antagonism with timed administration of exogenous melatonin greatly improves sleep and also reduces disruptive behaviours during the daytime in children and adolescents with SMS.

    “Combining β1-adrenergic receptor antagonism with timed administration of exogenous melatonin greatly improves sleep (that is, leading to fewer sleep awakenings and better organized sleep stages) and also reduces disruptive behaviours during the daytime in children and adolescents with SMS137.”
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    • cites [137] De Leersnyder, H. et al. β1-adrenergic antagonists and melatonin reset the clock and restore sleep in a circadian disorder, Smith–Magenis syndrome. J. Med. Genet. 40, 74–78 (2003). source

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  • May combine two claims.

    Premisecitation

    Light exposure during the night (23:00 h to 24:00 h) suppresses melatonin levels in adolescents, with greater suppression occurring in early adolescents (prepubertal to mid-pubertal adolescents aged 9-14 years) than in late adolescents (aged 11-15 years, in late pubertal to post-pubertal stages).

    “For example, light exposure during the night (23:00 h to 24:00 h) suppresses melatonin levels in adolescents, with greater suppression occurring in early adolescents (prepubertal to mid-pubertal adolescents aged 9–14 years) than in late adolescents (aged 11–15 years, in late pubertal to post-pubertal stages)145.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [145] Crowley, S. J., Cain, S. W., Burns, A. C., Acebo, C. & Carskadon, M. A. Increased sensitivity of the circadian system to light in early/mid-puberty. J. Clin. Endocrinol. Metab. 100, 4067–4073 (2015). This study shows that endogenous melatonin levels of prepubertal children and early adolescents are more sensitive to the suppressive effects of acute light exposure during the evening than melatonin levels in late adolescents. source

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  • May combine two claims.

    Premisecitation

    Symptoms of SMS include sleep and circadian abnormalities, with the most extreme being a complete reversal of sleep-wake patterns.

    “Symptoms of SMS also include sleep and circadian abnormalities, with the most extreme being a complete reversal of sleep–wake patterns (that is, daytime sleep and night-time wake)128–131.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [128] Boudreau, E. A. et al. Review of disrupted sleep patterns in Smith–Magenis syndrome and normal melatonin secretion in a patient with an atypical interstitial 17p11.2 deletion. Am. J. Med. Genet. A 149A, 1382–1391 (2009). source

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    • cites [129] Greenberg, F. et al. Multi-disciplinary clinical study of Smith–Magenis syndrome (deletion 17p11.2). Am. J. Med. Genet. 62, 247–254 (1996). source

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    • cites [130] Gropman, A. L., Elsea, S., Duncan, W. C. Jr & Smith, A. C. New developments in Smith–Magenis syndrome (del 17p11.2). Curr. Opin. Neurol. 20, 125–134 (2007). source

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    • cites [131] Smith, A. C., Dykens, E. & Greenberg, F. Sleep disturbance in Smith–Magenis syndrome (del 17p11.2). Am. J. Med. Genet. 81, 186–191 (1998). source

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  • May combine two claims.

    Premisecitation

    In human cells from patients with SMS and the mouse brain, RAI1 activates the transcription of CLOCK via direct binding to enhancer elements within intron 1 of the CLOCK gene, demonstrating a possible mechanism by which loss of RAI1 may result in circadian dysfunction at the molecular and cellular level.

    “In human cells from patients with SMS and the mouse brain, RAI1 activates the transcription of CLOCK via direct binding to enhancer elements within intron 1 of the CLOCK gene135, demonstrating a possible mechanism by which loss of RAI1 may result in circadian dysfunction at the molecular and cellular level.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Williams, S. R., Zies, D., Mullegama, S. V., Grotewiel, M. S. & Elsea, S. H. Smith–Magenis syndrome results in disruption of CLOCK gene transcription and reveals an integral role for RAI1 in the maintenance of circadian rhythmicity. Am. J. Hum. Genet. 90, 941–949 (2012). source

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  • May combine two claims.

    Premisecitation

    RAI1 is implicated in melatonin secretion, and inverted melatonin rhythms may be responsible for the sleep disturbances in SMS.

    “RAI1 is implicated in melatonin secretion, and inverted melatonin rhythms may be responsible for these sleep disturbances132.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [132] Boone, P. M. et al. Abnormal circadian rhythm of melatonin in Smith–Magenis syndrome patients with RAI 1 point mutations. Am. J. Med. Genet. A 155A, 2024–2027 (2011). source

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  • May combine two claims.

    Premisecitation

    Weekday-weekend differences in sleep timing and duration are associated with increased risk-taking behaviours, substance use and depressed mood.

    “Weekday–weekend differences in sleep timing and duration are associated with increased risk-taking behaviours, substance use and depressed mood155,156.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [155] O’Brien, E. M. & Mindell, J. A. Sleep and risk-taking behavior in adolescents. Behav. Sleep Med. 3, 113–133 (2005). source

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    • cites [156] Pasch, K. E., Laska, M. N., Lytle, L. A. & Moe, S. G. Adolescent sleep, risk behaviors, and depressive symptoms: are they linked? Am. J. Health Behav. 34, 237–248 (2010). source

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  • May combine two claims.

    Premisecitation

    Activation of the epigenetically silenced paternal Ube3a allele restores neuronal circadian function, suggesting that targeting the locus may be useful for treatment and involve molecular-clock-dependent mechanisms.

    “Intriguingly, activation of the epigenetically silenced paternal Ube3a allele restores neuronal circadian function127, suggesting that targeting the locus may be useful for treatment and involve molecular-clock-dependent mechanisms.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [127] Shi, S. Q., Bichell, T. J., Ihrie, R. A. & Johnson, C. H. Ube3a imprinting impairs circadian robustness in Angelman syndrome models. Curr. Biol. 25, 537–545 (2015). source

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    Premisecitation

    UBE3A targets the circadian transcription factor BMAL1 for proteasomal degradation and thus is crucial for maintaining the pace of molecular clock timing.

    “UBE3A targets the circadian transcription factor BMAL1 for proteasomal degradation and thus is crucial for maintaining the pace of molecular clock timing117.”
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    • cites [117] Gossan, N. C. et al. The E3 ubiquitin ligase UBE3A is an integral component of the molecular circadian clock through regulating the BMAL1 transcription factor. Nucleic Acids Res. 42, 5765–5775 (2014). source

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  • May combine two claims.

    Premisecitation

    Longitudinal follow-up studies have found that weekend delay and sleep-timing variability during adolescence and young adulthood positively correlate with alcohol use 2 years later and the incidence of alcohol use disorder symptoms 3 and 5 years later, and are associated with an earlier onset of alcohol use disorder.

    “Longitudinal follow-up studies have found that weekend delay and sleep-timing variability during adolescence and young adulthood positively correlate with alcohol use 2 years later162 and the incidence of alcohol use disorder symptoms 3 and 5 years later163 and are associated with an earlier onset of alcohol use disorder164.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [162] Pasch, K. E., Latimer, L. A., Cance, J. D., Moe, S. G. & Lytle, L. A. Longitudinal bi-directional relationships between sleep and youth substance use. J. Youth Adolesc. 41, 1184–1196 (2012). source

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    • cites [163] Hasler, B. P., Martin, C. S., Wood, D. S., Rosario, B. & Clark, D. B. A longitudinal study of insomnia and other sleep complaints in adolescents with and without alcohol use disorders. Alcohol Clin. Exp. Res. 38, 2225–2233 (2014). source

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    • cites [164] Hasler, B. P., Kirisci, L. & Clark, D. B. Restless sleep and variable sleep timing during late childhood accelerate the onset of alcohol and other drug involvement. J. Stud. Alcohol Drugs 77, 649–655 (2016). source

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  • May combine two claims.

    Premisecitation

    Functional MRI studies reveal that activation (glucose uptake) of striatal and prefrontal brain regions during monetary reward tasks is greater in the afternoon or evening than in the morning in late adolescents and young adults (aged 19-24 years), and is related to morningness and eveningness chronotypes in adults.

    “Functional MRI studies reveal that the activation (that is, glucose uptake) of striatal and prefrontal brain regions during monetary reward tasks is greater in the afternoon or evening than in the morning in late adolescents and young adults (aged 19–24 years)177, and is related to morningness and eveningness chronotypes in adults178.”
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    • cites [177] Hasler, B. P., Forbes, E. E. & Franzen, P. L. Time-of-day differences and short-term stability of the neural response to monetary reward: a pilot study. Psychiatry Res. 224, 22–27 (2014). source

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    • cites [178] Hasler, B. P. et al. Chronotype and diurnal patterns of positive affect and affective neural circuitry in primary insomnia. J. Sleep Res. 21, 515–526 (2012). source

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  • May combine two claims.

    Interpretationnone given

    Mood disorders are very heterogeneous, and any association with disruptions in the sleep-wake cycle can be highly variable from individual to individual.

    “these disorders are very heterogeneous, and any association with disruptions in the sleep–wake cycle can be highly variable from individual to individual”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    Circadian and sleep disruptions may have a role in the vulnerability to mood disorders and the precipitation of disorder symptoms.

    “Together, these findings suggest that circadian and sleep disruptions may have a role in the vulnerability to mood disorders and the precipitation of disorder symptoms.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Behavioural interventions for insomnia improved sleep quality and reduced symptoms of depression, but pharmacological interventions did not.

    “Behavioural (but not pharmacological) interventions for insomnia improved sleep quality and reduced symptoms of depression”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [181] Miller, M. B., Donahue, M. L., Carey, K. B. & Scott-Sheldon, L. A. J. Insomnia treatment in the context of alcohol use disorder: a systematic review and meta-analysis. Drug Alcohol Depend. 181, 200–207 (2017). source

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    Premisecitation

    In an age-matched cohort of late adolescents, greater ventral striatum responses to reward outcome and reduced medial prefrontal cortex responses to reward anticipation are associated with eveningness and may predict alcohol dependence.

    “In an age-matched cohort of late adolescents, greater VS responses to reward outcome and reduced mPFC responses to reward anticipation are associated with eveningness179 and may predict alcohol dependence167, further suggesting that certain circadian phenotypes emerging during early to late adolescence could contribute to vulnerability to substance use.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [179] Hasler, B. P., Sitnick, S. L., Shaw, D. S. & Forbes, E. E. An altered neural response to reward may contribute to alcohol problems among late adolescents with an evening chronotype. Psychiatry Res. 214, 357–364 (2013). source

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    • cites [167] Hasler, B. P., Casement, M. D., Sitnick, S. L., Shaw, D. S. & Forbes, E. E. Eveningness among late adolescent males predicts neural reactivity to reward and alcohol dependence two years later. Behav. Brain Res. 327, 112–120 (2017). This study shows that an evening chronotype during late adolescence (20 years of age) is associated with strength of activation in the VS to reward outcome, which was positively correlated with alcohol dependence 2 years later. source

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  • May combine two claims.

    Premisecitation

    These developmental changes include increases in synaptic pruning and myelination, as well as increases in the availability of dopamine in the limbic circuitry.

    “These changes include increases in synaptic pruning and myelination107,171, as well as increases in the availability of dopamine in the limbic circuitry172,173.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [107] Hoel, E. P., Albantakis, L., Cirelli, C. & Tononi, G. Synaptic refinement during development and its effect on slow-wave activity: a computational study. J. Neurophysiol. 115, 2199–2213 (2016). source

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    • cites [171] Frischknecht, R. & Gundelfinger, E. D. The brain’s extracellular matrix and its role in synaptic plasticity. Adv. Exp. Med. Biol. 970, 153–171 (2012). source

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    • cites [172] Luciana, M. & Collins, P. F. Incentive motivation, cognitive control, and the adolescent brain: is it time for a paradigm shift? Child Dev. Perspect. 6, 392–399 (2012). source

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    • cites [173] Padmanabhan, A. & Luna, B. Developmental imaging genetics: linking dopamine function to adolescent behavior. Brain Cogn. 89, 27–38 (2014). source

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    Premisecitation

    Circadian disruptions in adolescents at high risk of psychosis and in individuals with mood disorders predict worse prognosis and symptoms in longitudinal studies.

    “circadian disruptions in adolescents who are at high risk of psychosis (that is, subthreshold symptoms of psychosis, social impairment and higher suspicion–paranoia)197 and individuals with mood disorders predict worse prognosis and symptoms in longitudinal studies198,199”
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    • cites [197] Addington, J. & Heinssen, R. Prediction and prevention of psychosis in youth at clinical high risk. Annu. Rev. Clin. Psychol. 8, 269–289 (2012). source

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    • cites [198] Lunsford-Avery, J. R. et al. Adolescents at clinical-high risk for psychosis: circadian rhythm disturbances predict worsened prognosis at 1-year follow-up. Schizophr. Res. 189, 37–42 (2017). source

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    • cites [199] Robillard, R. et al. Sleep–wake profiles predict longitudinal changes in manic symptoms and memory in young people with mood disorders. J. Sleep Res. 25, 549–555 (2016). source

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    Premisecitation

    Many selective synaptic pruning and refinement processes occur during sleep, and sleep is crucial for proper circuit maturation and long-term memory formation in humans and animals.

    “Many of these selective synaptic pruning and refinement processes occur during sleep, and sleep is crucial for proper circuit maturation and long-term memory formation in humans and animals201–204.”
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    • cites [201] Wei, Y., Krishnan, G. P. & Bazhenov, M. Synaptic mechanisms of memory consolidation during sleep slow oscillations. J. Neurosci. 36, 4231–4247 (2016). source

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    • cites [202] Walker, M. P. & Stickgold, R. Sleep-dependent learning and memory consolidation. Neuron 44, 121–133 (2004). source

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    • cites [203] Havekes, R., Meerlo, P. & Abel, T. Animal studies on the role of sleep in memory: from behavioral performance to molecular mechanisms. Curr. Top. Behav. Neurosci. 25, 183–206 (2015). source

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    • cites [204] Marshall, L., Helgadottir, H., Molle, M. & Born, J. Boosting slow oscillations during sleep potentiates memory. Nature 444, 610–613 (2006). This study establishes the importance of slow-wave sleep during non-REM episodes that occur during the early night and shows that it promotes the retention of hippocampus-dependent declarative memories. source

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    Premisecitation

    Several studies have reported declines in melatonin levels with ageing, although others find no difference compared with younger people in a healthy population.

    “Several studies have reported declines in melatonin levels with ageing, although others find no difference compared with younger people in a healthy population237,238.”
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    • cites [237] Karasek, M. Melatonin, human aging, and age-related diseases. Exp. Gerontol. 39, 1723–1729 (2004). source

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    • cites [238] Zeitzer, J. M. et al. Do plasma melatonin concentrations decline with age? Am. J. Med. 107, 432–436 (1999). source

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    Premisecitation

    SNPs in CLOCK and BMAL1, and in BMAL1 and PER1, are associated with increased risk of Alzheimer disease and Parkinson disease, respectively.

    “the incidence of single-nucleotide polymorphisms (SNPs) in CLOCK and BMAL1, and in BMAL1 and PER1, are associated with increased risk of Alzheimer disease (AD) and Parkinson disease (PD), respectively251–253”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [251] Chen, H. F., Huang, C. Q., You, C., Wang, Z. R. & Si-qing, H. Polymorphism of CLOCK gene rs 4580704C>G is associated with susceptibility of Alzheimer’s disease in a Chinese population. Arch. Med. Res. 44, 203–207 (2013). source

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    • cites [252] Chen, Q., Peng, X. D., Huang, C. Q., Hu, X. Y. & Zhang, X. M. Association between ARNTL (BMAL1) rs2278749 polymorphism T>C and susceptibility to Alzheimer disease in a Chinese population. Genet. Mol. Res. 14, 18515–18522 (2015). source

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    • cites [253] Gu, Z. et al. Association of ARNTL and PER1 genes with Parkinson’s disease: a case-control study of Han Chinese. Sci. Rep. 5, 15891 (2015).

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  • May combine two claims.

    Premisecitation

    Older individuals show lower-amplitude body temperature rhythms, with the minimum of the endogenous phase occurring nearly 2 hours earlier than in younger individuals.

    “older individuals show lower-amplitude body temperature rhythms, with the minimum of the endogenous phase occurring nearly 2 hours earlier than in younger individuals239”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [239] Czeisler, C. A. et al. Association of sleep–wake habits in older people with changes in output of circadian pacemaker. Lancet 340, 933–936 (1992). This landmark study suggests that changes in sleep timing and consolidation driven by the circadian system underlie sleep disturbances in elderly individuals. source

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  • May combine two claims.

    Premisecitation

    Compared with healthy aged people, individuals with AD or PD show considerably lower melatonin rhythm amplitudes and excessive sleepiness, as well as other sleep-wake cycle disturbances, such as later sleep onsets.

    “Compared with healthy aged people, individuals with AD or PD show considerably lower melatonin rhythm amplitudes and excessive sleepiness, as well as other sleep–wake cycle disturbances, such as later sleep onsets254–258.”
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    • cites [254] Videnovic, A. & Golombek, D. Circadian dysregulation in Parkinson’s disease. Neurobiol. Sleep Circadian Rhythms 2, 53–58 (2017). source

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    • cites [255] Breen, D. P. et al. Sleep and circadian rhythm regulation in early Parkinson disease. JAMA Neurol. 71, 589–595 (2014). This study shows significantly increased sleep latency, reduced sleep efficiency and reduced REM, along with reduced melatonin levels and a loss of BMAL1 serum expression rhythms, in a cohort of 239 individuals with PD. source

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    • cites [256] Gros, P. & Videnovic, A. Sleep and circadian rhythm disorders in Parkinson’s disease. Curr. Sleep Med. Rep. 3, 222–234 (2017). source

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    • cites [257] Uchida, K., Okamoto, N., Ohara, K. & Morita, Y. Daily rhythm of serum melatonin in patients with dementia of the degenerate type. Brain Res. 717, 154–159 (1996). source

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    • cites [258] Videnovic, A. et al. Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson disease. JAMA Neurol. 71, 463–469 (2014). source

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  • May combine two claims.

    Interpretationreasoning

    The newly rhythmic genes in older people might be protective, as the individuals in this post-mortem study did not experience psychiatric or neurodegenerative disorders before death.

    “These rhythmic genes might be protective, as the individuals in this post-mortem study did not experience psychiatric or neurodegenerative disorders before death.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Older people (ages ~65 years and older) generally sleep less and have poorer sleep efficiency, increased night-time awakening, increased sleep latency and greater levels of daytime sleepiness.

    “Older people (ages ~65 years and older) generally sleep less and have poorer sleep efficiency, increased night-time awakening, increased sleep latency and greater levels of daytime sleepiness234–236.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [234] Feinsilver, S. H. & Hernandez, A. B. Sleep in the elderly: unanswered questions. Clin. Geriatr. Med. 33, 579–596 (2017). source

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    • cites [235] Mattis, J. & Sehgal, A. Circadian rhythms, sleep, and disorders of aging. Trends Endocrinol. Metab. 27, 192–203 (2016). source

      Not checked in the free run.

    • cites [236] Musiek, E. S. & Holtzman, D. M. Mechanisms linking circadian clocks, sleep, and neurodegeneration. Science 354, 1004–1008 (2016). source

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  • May combine two claims.

    Premisecitation

    Shift-work has been associated with increased risk of cancer, obesity, heart disease, gastrointestinal dysfunction, sleep disorders, diabetes and depression.

    “Shift-work has been associated with increased risk of cancer, obesity, heart disease, gastrointestinal dysfunction, sleep disorders, diabetes and depression227.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [227] James, S. M., Honn, K. A., Gaddameedhi, S. & Van Dongen, H. P. A. Shift work: disrupted circadian rhythms and sleep-implications for health and well-being. Curr. Sleep Med. Rep. 3, 104–112 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A study of ~14,000 workers in electronics manufacturing in South Korea revealed that, compared with daytime workers, shift-workers showed higher rates of insomnia, depression and suicidal ideation, with the strongest association with insomnia.

    “Another study of ~14,000 workers in electronics manufacturing in South Korea revealed that, compared with daytime workers, shift-workers showed higher rates of insomnia, depression and suicidal ideation (with the strongest association with insomnia)229.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [229] Kang, M. Y., Kwon, H. J., Choi, K. H., Kang, C. W. & Kim, H. The relationship between shift work and mental health among electronics workers in South Korea: a cross-sectional study. PLOS ONE 12, e0188019 (2017).

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These SCN network changes result in desynchronization and a reduction in the amplitude of neuronal activity rhythms and, ultimately, physiological and behavioural rhythms.

    “These SCN network changes result in desynchronization and a reduction in the amplitude of neuronal activity rhythms248,249 and, ultimately, physiological and behavioural rhythms241.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [248] Farajnia, S. et al. Evidence for neuronal desynchrony in the aged suprachiasmatic nucleus clock. J. Neurosci. 32, 5891–5899 (2012). source

      Not checked in the free run.

    • cites [249] Nakamura, T. J. et al. Age-related decline in circadian output. J. Neurosci. 31, 10201–10205 (2011). source

      Not checked in the free run.

    • cites [241] Chang, H. C. & Guarente, L. SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell 153, 1448–1460 (2013). This mouse study reveals that reductions of sirtuin activity in the SCN leads to a gradual age-dependent dampening of SCN activity and locomotor rhythms. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some SCN cells become silent in older animals, and SCN neurons lose phase coherence with age.

    “some SCN cells become silent in older animals (as measured in vitro), and SCN neurons lose phase coherence with age247,248”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [247] Nygard, M., Hill, R. H., Wikstrom, M. A. & Kristensson, K. Age-related changes in electrophysiological properties of the mouse suprachiasmatic nucleus in vitro. Brain Res. Bull. 65, 149–154 (2005). source

      Not checked in the free run.

    • cites [248] Farajnia, S. et al. Evidence for neuronal desynchrony in the aged suprachiasmatic nucleus clock. J. Neurosci. 32, 5891–5899 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gene expression rhythms in the human mPFC decline with age, and a separate set of genes becomes newly rhythmic in older people aged 65 years and older.

    “gene expression rhythms in the human mPFC also decline with age; however, surprisingly, a separate set of genes becomes newly rhythmic in older people (aged 65 years and older)11”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Chen, C. Y. et al. Effects of aging on circadian patterns of gene expression in the human prefrontal cortex. Proc. Natl Acad. Sci. USA 113, 206–211 (2015). This is the largest-scale study of circadian rhythms of gene expression in human post-mortem brain tissue, revealing age-related decline in the expression of core circadian genes and the emergence of other rhythmic pathways in older subjects. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These sex differences in chronotype disappear after the age of 50 years, coinciding with menopause in women.

    “these sex differences disappear after the age of 50 years, coinciding with menopause in women141,220,222”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [141] Roenneberg, T. et al. A marker for the end of adolescence. Curr. Biol. 14, R1038–R1039 (2004). source

      Not checked in the free run.

    • cites [220] Adan, A. & Natale, V. Gender differences in morningness–eveningness preference. Chronobiol. Int. 19, 709–720 (2002). source

      Not checked in the free run.

    • cites [222] Duarte, L. L. et al. Chronotype ontogeny related to gender. Braz. J. Med. Biol. Res. 47, 316–320 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Measures of chronotype are affected by social and work schedules, and some individuals may never shift back to a morning preference after adolescence.

    “these measures of chronotype are also affected by social and work schedules, and some individuals may never shift back to a morning preference after adolescence223”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [223] Paine, S. J., Gander, P. H. & Travier, N. The epidemiology of morningness/eveningness: influence of age, gender, ethnicity, and socioeconomic factors in adults (30–49 years). J. Biol. Rhythms 21, 68–76 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Female flight attendants have a higher prevalence of reproductive cancers, skin cancers and other conditions such as chronic bronchitis and heart disease.

    “Female flight attendants also have a higher prevalence of reproductive cancers, skin cancers and other conditions such as chronic bronchitis and heart disease230,231”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [230] McNeely, E. et al. The self-reported health of U. S. flight attendants compared to the general population. Environ. Health 13, 13 (2014). source

      Not checked in the free run.

    • cites [231] McNeely, E. et al. Cancer prevalence among flight attendants compared to the general population. Environ. Health 17, 49 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Brain-specific knockout of Sirt1 in rodents is sufficient to phenocopy the effects of ageing on the SCN and circadian behaviour, whereas overexpression of Sirt1 is protective.

    “brain-specific knockout of Sirt1 in rodents is sufficient to phenocopy the effects of ageing on the SCN and circadian behaviour, whereas overexpression of Sirt1 is protective241”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [241] Chang, H. C. & Guarente, L. SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell 153, 1448–1460 (2013). This mouse study reveals that reductions of sirtuin activity in the SCN leads to a gradual age-dependent dampening of SCN activity and locomotor rhythms. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sundowning syndrome is prevalent in people with dementia and is characterized by increases in aggression, restlessness, delirium and agitation specifically in the late afternoon or early evening.

    “Sundowning syndrome is prevalent in people with dementia and is characterized by increases in aggression, restlessness, delirium and agitation specifically in the late afternoon or early evening280,281.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [280] Gnanasekaran, G. “Sundowning” as a biological phenomenon: current understandings and future directions: an update. Aging Clin. Exp. Res. 28, 383–392 (2016). source

      Not checked in the free run.

    • cites [281] Bedrosian, T. A. & Nelson, R. J. Sundowning syndrome in aging and dementia: research in mouse models. Exp. Neurol. 243, 67–73 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice, SCN levels of SIRT1 decline with age, potentially explaining the increase in circadian rhythm disruptions in older people.

    “In mice, SCN levels of sirtuin 1 (SIRT1), a metabolic sensing protein and mediator of CLOCK and BMAL1 function (FIG. 1), decline with age, potentially explaining the increase in circadian rhythm disruptions in older people241.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [241] Chang, H. C. & Guarente, L. SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell 153, 1448–1460 (2013). This mouse study reveals that reductions of sirtuin activity in the SCN leads to a gradual age-dependent dampening of SCN activity and locomotor rhythms. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During sleep, the glymphatic system exchanges cerebrospinal fluid with interstitial fluid and clears amyloid-β.

    “during sleep, the glymphatic system285 exchanges cerebrospinal fluid with interstitial fluid and clears Aβ286”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [285] Xie, L. et al. Sleep drives metabolite clearance from the adult brain. Science 342, 373–377 (2013). A landmark study in mice demonstrating that wakefulness suppresses the outflow of cerebral spinal fluid from the brain, whereas sleep leads to an increase in convective fluxes of fluid, effectively promoting the clearance of neurotoxic metabolics, including Aβ. source

      Not checked in the free run.

    • cites [286] Da Mesquita, S. et al. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560, 185–191 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sleep deprivation increases interstitial fluid levels of amyloid-β and increases plaque formation in mice and flies, whereas in Drosophila, genetically increasing sleep reduces amyloid-β deposition.

    “Sleep deprivation increases interstitial fluid levels of Aβ and increases plaque formation in mice and flies287,288, whereas in Drosophila, genetically increasing sleep reduces Aβ deposition288.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [287] Kang, J. E. et al. Amyloid-β dynamics are regulated by orexin and the sleep-wake cycle. Science 326, 1005–1007 (2009). source

      Not checked in the free run.

    • cites [288] Tabuchi, M. et al. Sleep interacts with Aβ to modulate intrinsic neuronal excitability. Curr. Biol. 25, 702–712 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Phase delays and reductions in the amplitude of body temperature rhythms correlate with the severity of sundowning symptoms, suggesting that a breakdown of the circadian system may be responsible.

    “Phase delays and reductions in the amplitude of body temperature rhythms correlate with the severity of sundowning symptoms, suggesting that a breakdown of the circadian system may be responsible282.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [282] Volicer, L., Harper, D. G., Manning, B. C., Goldstein, R. & Satlin, A. Sundowning and circadian rhythms in Alzheimer’s disease. Am. J. Psychiatry 158, 704–711 (2001). This study shows that patients with AD have less diurnal activity, more nocturnal activity and phase delays in body-temperature rhythms, and that the severity of sundowning is positively correlated with lower-amplitude and more-phase-delayed rhythms. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ROS accumulation is considerably higher in Bmal1−/− mice and correlates with increases in astrocytosis and levels of oxidative damage markers in the brain.

    “ROS accumulation is considerably higher in Bmal1−/− mice and correlates with increases in astrocytosis and levels of oxidative damage markers in the brain.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [291] Musiek, E. S. et al. Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. J. Clin. Invest. 123, 5389–5400 (2013). This preclinical investigation demonstrates that components of the molecular clock control redox state and, when disrupted, lead to oxidative stress and cell death related to neurodegeneration. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bmal1−/− mice, which lack a functional molecular clock, show premature ageing, neurodegeneration and a reduced lifespan.

    “Bmal1−/− mice, which lack a functional molecular clock, show premature ageing, neurodegeneration and a reduced lifespan291.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [291] Musiek, E. S. et al. Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. J. Clin. Invest. 123, 5389–5400 (2013). This preclinical investigation demonstrates that components of the molecular clock control redox state and, when disrupted, lead to oxidative stress and cell death related to neurodegeneration. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SCN neuronal firing is reduced in these mice from young adulthood and progressively worsens with age, suggesting a weakened circadian pacemaker and a potential loss of dopaminergic modulation of circadian rhythms.

    “SCN neuronal firing is also reduced in these mice from young adulthood and progressively worsens with age, suggesting a weakened circadian pacemaker276 and a potential loss of dopaminergic modulation of circadian rhythms via midbrain, striatal and SCN circuits277,278.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [276] Kudo, T., Loh, D. H., Truong, D., Wu, Y. & Colwell, C. S. Circadian dysfunction in a mouse model of Parkinson’s disease. Exp. Neurol. 232, 66–75 (2011). source

      Not checked in the free run.

    • cites [277] Grippo, R. M., Purohit, A. M., Zhang, Q., Zweifel, L. S. & Guler, A. D. Direct midbrain dopamine input to the suprachiasmatic nucleus accelerates circadian entrainment. Curr. Biol. 27, 2465–2475 (2017). This study shows re-entrainment of the SCN to phase shifts in the light–dark schedule is facilitated by dopaminergic projections from the ventral tegmental area to the SCN and is dependent on dopamine 1 receptor-expressing neurons in the SCN. source

      Not checked in the free run.

    • cites [278] Korshunov, K. S., Blakemore, L. J. & Trombley, P. Q. Dopamine: a modulator of circadian rhythms in the central nervous system. Front. Cell. Neurosci. 11, 91 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Mice with a brain-specific Bmal1 deletion exhibit increased astrocytosis despite having mostly normal locomotor circadian rhythms and sleep-wake cycling, suggesting that these neurodegenerative effects are due to loss of local control of cellular metabolism in specific brain regions mediated by BMAL1.

    “mice with a brain-specific Bmal1 deletion also exhibit increased astrocytosis, despite having mostly normal locomotor circadian rhythms and sleep–wake cycling (that is, relatively normal clock function in the SCN); thus, these neurodegenerative effects are probably due to loss of the local control of cellular metabolism in specific regions of the brain that is normally mediated by BMAL1, indep”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [291] Musiek, E. S. et al. Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. J. Clin. Invest. 123, 5389–5400 (2013). This preclinical investigation demonstrates that components of the molecular clock control redox state and, when disrupted, lead to oxidative stress and cell death related to neurodegeneration. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Transgenic mice overexpressing α-synuclein show greater fragmentation and amplitude reduction in locomotor activity rhythms during the active phase, and these effects progress with age.

    “Transgenic mice overexpressing α-synuclein (a model of PD) show greater fragmentation and amplitude reduction in locomotor activity rhythms during the active phase, and these effects progress with age276.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [276] Kudo, T., Loh, D. H., Truong, D., Wu, Y. & Colwell, C. S. Circadian dysfunction in a mouse model of Parkinson’s disease. Exp. Neurol. 232, 66–75 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These increases in amyloid-β were negatively correlated with mood but were not associated with the APOE genotype.

    “These increases were negatively correlated with mood but were not associated with a particular AD-linked genotype (that is, the APOE genotype).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [284] Shokri-Kojori, E. et al. β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proc. Natl Acad. Sci. USA 115, 4483–4488 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The plausibility of periarterial flow and glymphatic circulation is controversial based on estimates of anatomical and fluid dynamic parameters.

    “based on estimates of anatomical and fluid dynamic parameters, the plausibility of periarterial flow and glymphatic circulation is controversial”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [289] Faghih, M. M. & Sharp, M. K. Is bulk flow plausible in perivascular, paravascular and paravenous channels? Fluids Barriers CNS 15, 17 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Individuals with AD still show cycling clock gene expression in multiple brain regions but lose typical phase coherence within and across regions.

    “although individuals with AD still show cycling clock gene expression in multiple brain regions, they lose typical phase coherence within and across regions263”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [263] Cermakian, N., Lamont, E. W., Boudreau, P. & Boivin, D. B. Circadian clock gene expression in brain regions of Alzheimer ‘s disease patients and control subjects. J. Biol. Rhythms 26, 160–170 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PD is strongly associated with REM sleep behaviour disorder, as well as excessive daytime sleepiness, insomnia and restless legs syndrome.

    “PD, in particular, is strongly associated with rapid eye moment (reM) sleep behaviour disorder (RBD), as well as excessive daytime sleepiness, insomnia and restless legs syndrome270–273.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [270] Barone, P. et al. The PRIAMO study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson’s disease. Mov. Disord. 24, 1641–1649 (2009). source

      Not checked in the free run.

    • cites [271] Chaudhuri, K. R. et al. International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson’s disease: the NMSQuest study. Mov. Disord. 21, 916–923 (2006). source

      Not checked in the free run.

    • cites [272] Goodman, A. O., Morton, A. J. & Barker, R. A. Identifying sleep disturbances in Huntington’s disease using a simple disease-focused questionnaire. PLOS Curr. 2, RRN1189 (2010). source

      Not checked in the free run.

    • cites [273] Aziz, N. A., Anguelova, G. V., Marinus, J., Lammers, G. J. & Roos, R. A. Sleep and circadian rhythm alterations correlate with depression and cognitive impairment in Huntington’s disease. Parkinsonism Relat. Disord. 16, 345–350 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MitoPark transgenic mice show a profound disruption of locomotor rhythms in constant conditions and are more vulnerable to changes in the light-dark cycle.

    “MitoPark transgenic mice also show a profound disruption of locomotor rhythms in constant conditions and are more vulnerable to changes in the light–dark cycle279.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [279] Fifel, K. & Cooper, H. M. Loss of dopamine disrupts circadian rhythms in a mouse model of Parkinson’s disease. Neurobiol. Dis. 71, 359–369 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treating Bmal1−/− mice with the antioxidant N-acetyl-l-cysteine partially rescues their lifespan and prevents age-dependent pathology.

    “Treating Bmal1−/− mice with the antioxidant N-acetyl-l-cysteine partially rescues their lifespan and prevents age-dependent pathology292.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [292] Kondratov, R. V., Vykhovanets, O., Kondratova, A. A. & Antoch, M. P. Antioxidant N-acetyl-L-cysteine ameliorates symptoms of premature aging associated with the deficiency of the circadian protein BMAL1. Aging 1, 979–987 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In individuals with PD, sleep-wake symptoms often precede the development of motor or cognitive symptoms and may be useful as a diagnostic biomarker.

    “In individuals with PD, these sleep–wake symptoms often precede the development of motor or cognitive symptoms and may even be useful as a diagnostic biomarker259,260”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [259] Claassen, D. O. & Kutscher, S. J. Sleep disturbances in Parkinson’s disease patients and management options. Nat. Sci. Sleep 3, 125–133 (2011). source

      Not checked in the free run.

    • cites [260] Rothman, S. M. & Mattson, M. P. Sleep disturbances in Alzheimer’s and Parkinson’s diseases. Neuromolecular Med. 14, 194–204 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AD brains show marked loss of neurons in the SCN, and SCN neuronal loss correlates with reductions in the amplitude of motor activity rhythms in the same individuals before death.

    “AD brains show marked loss of neurons in the SCN243,244,262, and SCN neuronal loss correlates with reductions in the amplitude of motor activity rhythms in the same individuals before death240.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [243] Swaab, D. F., Fliers, E. & Partiman, T. S. The suprachiasmatic nucleus of the human brain in relation to sex, age and senile dementia. Brain Res. 342, 37–44 (1985). source

      Not checked in the free run.

    • cites [244] Zhou, J. N., Hofman, M. A. & Swaab, D. F. VIP neurons in the human SCN in relation to sex, age, and Alzheimer’s disease. Neurobiol. Aging 16, 571–576 (1995). source

      Not checked in the free run.

    • cites [262] Stopa, E. G. et al. Pathologic evaluation of the human suprachiasmatic nucleus in severe dementia. J. Neuropathol. Exp. Neurol. 58, 29–39 (1999). source

      Not checked in the free run.

    • cites [240] Wang, J. L. et al. Suprachiasmatic neuron numbers and rest–activity circadian rhythms in older humans. Ann. Neurol. 78, 317–322 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Clinical and preclinical data suggest that a lack of appropriate light-dark cues, disturbances in sleep (particularly reductions in REM sleep) and a deterioration of the SCN pacemaker and its outputs all contribute to sundowning syndrome.

    “Clinical and preclinical data suggest that a lack of appropriate light–dark cues, disturbances in sleep (particularly, reductions in reM sleep) and a deterioration of the SCN pacemaker and its outputs all contribute to sundowning syndrome281.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [281] Bedrosian, T. A. & Nelson, R. J. Sundowning syndrome in aging and dementia: research in mouse models. Exp. Neurol. 243, 67–73 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Time-restricted feeding is now being used to help treat and/or prevent obesity, as well as metabolic, cardiac and liver disorders.

    “Time-restricted feeding is also now being used to help treat and/or prevent obesity, as well as metabolic, cardiac and liver disorders327,328.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [327] Melkani, G. C. & Panda, S. Time-restricted feeding for prevention and treatment of cardiometabolic disorders. J. Physiol. 595, 3691–3700 (2017). source

      Not checked in the free run.

    • cites [328] Mindikoglu, A. L., Opekun, A. R., Gagan, S. K. & Devaraj, S. Impact of time-restricted feeding and dawn-to-sunset fasting on circadian rhythm, obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Gastroenterol. Res. Pract. 2017, 3932491 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    With development, changes occur in the sensitivity of the brain to light input, in the inputs and outputs of the SCN, and in the functions of the molecular clock in specific cell types in the brain and in other tissues.

    “With development, changes occur in the sensitivity of the brain to light input, in the inputs and outputs of the SCN, and in the functions of the molecular clock in specific cell types in the brain and in other tissues.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A double-blind, multicentre study in 157 individuals with AD showed that evening melatonin treatment improved cognition, decreased nocturnal activity and increased sleep.

    “a double-blind, multicentre study in 157 individuals with AD showed that evening melatonin treatment improved cognition, decreased nocturnal activity and increased sleep302”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [302] Singer, C. et al. A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer’s disease. Sleep 26, 893–901 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Morning light therapy may improve circadian rhythms and MMSE, CMAI and BEHAVEAD scores, particularly in the early stages of dementia, and even in severe cases improves circadian and behavioural symptoms, most notably agitation and overall cognitive function.

    “some studies indicate that morning light therapy may improve circadian rhythms and Mini-Mental State examination (MMSE), Cohen-Mansfield Agitation Inventory (CMAI) and Behaviour Pathology in AD Rating Scale (BEHAVEAD) scores, particularly in the early stages of dementia, and that, even in severe cases of dementia, it improves circadian and behavioural symptoms, most notably agitation and overall”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [296] Skjerve, A., Bjorvatn, B. & Holsten, F. Light therapy for behavioural and psychological symptoms of dementia. Int. J. Geriatr. Psychiatry 19, 516–522 (2004). source

      Not checked in the free run.

    • cites [297] Yamadera, H. et al. Effects of bright light on cognitive and sleep-wake (circadian) rhythm disturbances in Alzheimer-type dementia. Psychiatry Clin. Neurosci. 54, 352–353 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Most clinical studies are still correlational, but animal model studies are beginning to examine potential causal relationships between disrupted circadian rhythms and multiple brain disorders and are starting to identify molecular mechanisms.

    “Though most clinical studies are still correlational, animal model studies are beginning to examine potential causal relationships between disrupted circadian rhythms and multiple brain disorders and are starting to identify molecular mechanisms.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    In later life, certain disorders exhibit a defined trajectory, with sleep and circadian problems often preceding the development of other symptoms.

    “In later life, certain disorders exhibit a defined trajectory, with sleep and circadian problems often preceding the development of other symptoms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In a cohort of 239 individuals with Parkinson's disease, sleep latency is significantly increased, sleep efficiency and REM are reduced, melatonin levels are reduced, and BMAL1 serum expression rhythms are lost.

    “This study shows significantly increased sleep latency, reduced sleep efficiency and reduced REM, along with reduced melatonin levels and a loss of BMAL1 serum expression rhythms, in a cohor of 239 individuals with PD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [255] Breen, D. P. et al. Sleep and circadian rhythm regulation in early Parkinson disease. JAMA Neurol. 71, 589–595 (2014). This study shows significantly increased sleep latency, reduced sleep efficiency and reduced REM, along with reduced melatonin levels and a loss of BMAL1 serum expression rhythms, in a cohort of 239 individuals with PD. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Slow-wave sleep during non-REM episodes that occur during the early night promotes the retention of hippocampus-dependent declarative memories.

    “This study establishes the importance of slow-wave sleep during non-REM episodes that occur during the early night and shows that it promotes the retention of hippocampus-dependent declarative memories.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [204] Marshall, L., Helgadottir, H., Molle, M. & Born, J. Boosting slow oscillations during sleep potentiates memory. Nature 444, 610–613 (2006). This study establishes the importance of slow-wave sleep during non-REM episodes that occur during the early night and shows that it promotes the retention of hippocampus-dependent declarative memories. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronotherapeutic strategies of specifically timing the delivery of certain drugs are now being used in the treatment of certain cancers and may be therapeutically beneficial across various diseases.

    “Chronotherapeutic strategies of specifically timing the delivery of certain drugs are now being used in the treatment of certain cancers325 and may be therapeutically beneficial across various diseases326.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [325] Librodo, P., Buckley, M., Luk, M. & Bisso, A. Chronotherapeutic drug delivery. J. Infus. Nurs. 38, S18–S23 (2015). source

      Not checked in the free run.

    • cites [326] Ruben, M. D. et al. A database of tissue-specific rhythmically expressed human genes has potential applications in circadian medicine. Sci. Transl Med. 10, eaat8806 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Circadian genes in brain regions outside the SCN contribute locally to the control of neuronal metabolism, neurotransmitter synthesis and activity, and disruption of these functions might contribute to brain disorders.

    “circadian genes in other brain regions outside of this central pace-maker also contribute locally to the control of neuronal metabolism, neurotransmitter synthesis and activity, and the disruption of these functions might contribute to brain disorders264,304–315”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [264] Logan, R. W. et al. NAD+ cellular redox and SIRT1 regulate the diurnal rhythms of tyrosine hydroxylase and conditioned cocaine reward. Mol. Psychiatry. https://doi.org/10.1038/s41380-018-0061-1 (2018). This study demonstrates mechanistic links between circadian regulation of SIRT1-dependent metabolic signalling and dopaminergic neurotransmission in the mouse ventral tegmental area, which is important for drug reward. source

      Not checked in the free run.

    • cites [304] Arey, R. N. et al. An important role for cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors. Mol. Psychiatry 19, 342–350 (2014). source

      Not checked in the free run.

    • cites [305] Coque, L. et al. Specific role of VTA dopamine neuronal firing rates and morphology in the reversal of anxiety-related, but not depression-related behavior in the Clock∆19 mouse model of mania. Neuropsychopharmacology 36, 1478–1488 (2011). source

      Not checked in the free run.

    • cites [306] Dzirasa, K. et al. Lithium ameliorates nucleus accumbens phase-signaling dysfunction in a genetic mouse model of mania. J. Neurosci. 30, 16314–16323 (2010). source

      Not checked in the free run.

    • cites [307] McClung, C. A. Circadian rhythms, the mesolimbic dopaminergic circuit, and drug addiction. ScientificWorldJournal 7, 194–202 (2007). source

      Not checked in the free run.

    • cites [308] McClung, C. A. et al. Regulation of dopaminergic transmission and cocaine reward by the Cloc k gene. Proc. Natl Acad. Sci. USA 102, 9377–9381 (2005). source

      Not checked in the free run.

    • cites [309] Ozburn, A. R. et al. Direct regulation of diurnal Drd3 expression and cocaine reward by NPAS2. Biol. Psychiatry 77, 425–433 (2015). source

      Not checked in the free run.

    • cites [310] Ozburn, A. R. et al. NPAS2 regulation of anxiety-like behavior and GABAA receptors. Front. Mol. Neurosci. 10, 360 (2017). source

      Not checked in the free run.

    • cites [311] Ozburn, A. R., Larson, E. B., Self, D. W. & McClung, C. A. Cocaine self-administration behaviors in Clock∆19 mice. Psychopharmacology 223, 169–177 (2012). source

      Not checked in the free run.

    • cites [312] Parekh, P. K. et al. Altered GluA1 (Gria1) function and accumbal synaptic plasticity in the Clock∆19 model of bipolar mania. Biol. Psychiatry. https://doi.org/10.1016/j.biopsych.2017.06.022 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In 51 patients with major depressive disorder or bipolar disorder, circadian activity patterns prior to and following the administration of ketamine are linked to therapeutic response of mood symptoms.

    “In a study of 51 patients with major depressive disorder or bipolar disorder, circadian activity patterns prior to and following the administration of ketamine are linked to therapeutic response of mood symptoms.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [218] Duncan, W. C. Jr et al. Motor-activity markers of circadian timekeeping are related to ketamine’s rapid antidepressant properties. Biol. Psychiatry 82, 361–369 (2017). In a study of 51 patients with major depressive disorder or bipolar disorder, circadian activity patterns prior to and following the administration of ketamine are linked to therapeutic response of mood symptoms. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Treatments and interventions that target the circadian system may have therapeutic efficacy and improve clinical symptoms and daily functioning for the individual.

    “treatments and interventions that target the circadian system may have therapeutic efficacy and improve clinical symptoms and daily functioning for the individual”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Studies in preclinical models have supported these findings while also offering insights into the bidirectionality, in which circadian disruption leads to certain disease-related phenotypes, and environmental factors that can alter rhythms, such as stress or exposure to drugs of abuse, can lead to the exacerbation or progression of certain symptoms.

    “Studies in preclinical models have supported these findings while also offering insights into the bidirectionality, in which circadian disruption leads to certain disease-related phenotypes, and the environmental factors that can alter rhythms, such as stress or exposure to drugs of abuse, can lead to the exacerbation or progression of certain symptoms.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Findings from preclinical animal models are informative about causal relationships between circadian disruption and human brain disorders.

  • May combine two claims.

    Premisecitation

    A randomized control trial of 189 participants found that increasing illumination levels in elderly care centres during daytime hours leads to a slower decline in MMSE scores, reduced depression scores and reduced functional impairment in individuals with dementia over a 1.5-year period.

    “a randomized control trial of 189 participants found that increasing illumination levels in elderly care centres during daytime hours leads to a slower decline in MMSE scores, reduced depression scores and reduced functional impairment in individuals with dementia over a 1.5-year period301”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [301] Riemersma-van der Lek, R. F. et al. Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. JAMA 299, 2642–2655 (2008). This double-blinded randomized controlled trial of 189 elderly residents of a group care facility demonstrates that a combination of melatonin supplementation and scheduled light exposure improves cognitive symptoms of dementia and reduces aggression. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Re-entrainment of the SCN to phase shifts in the light-dark schedule is facilitated by dopaminergic projections from the ventral tegmental area to the SCN and is dependent on dopamine 1 receptor-expressing neurons in the SCN.

    “This study shows re-entrainment of the SCN to phase shifts in the light–dark schedule is facilitated by dopaminergic projections from the ventral tegmental area to the SCN and is dependent on dopamine 1 receptor-expressing neurons in the SCN.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [277] Grippo, R. M., Purohit, A. M., Zhang, Q., Zweifel, L. S. & Guler, A. D. Direct midbrain dopamine input to the suprachiasmatic nucleus accelerates circadian entrainment. Curr. Biol. 27, 2465–2475 (2017). This study shows re-entrainment of the SCN to phase shifts in the light–dark schedule is facilitated by dopaminergic projections from the ventral tegmental area to the SCN and is dependent on dopamine 1 receptor-expressing neurons in the SCN. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Mitochondrial stress promotes the accumulation of oxidized dopamine, consequently increasing α-synuclein aggregates in neurons derived from patients with Parkinson's disease, an effect selective to human neurons.

    “This study demonstrates that mitochondrial stress promotes the accumulation of oxidized dopamine, consequently increasing α-synuclein aggregates in neurons derived from patients with PD, an effect selective to human neurons.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [269] Burbulla, L. F. et al. Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease. Science 357, 1255–1261 (2017). This study demonstrates that mitochondrial stress promotes the accumulation of oxidized dopamine, consequently increasing α-synuclein aggregates in neurons derived from patients with PD, an effect selective to human neurons. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In mice, a neural circuit involving projections from the SCN to the ventromedial hypothalamus drives time-of-day-dependent aggressive behaviours.

    “This chemogenetic study in mice reveals a neural circuit involving projections from the SCN to the ventromedial hypothalamus that drives time-of-day-dependent aggressive behaviours.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [283] Todd, W. D. et al. A hypothalamic circuit for the circadian control of aggression. Nat. Neurosci. 21, 717–724 (2018). This chemogenetic study in mice reveals a neural circuit involving projections from the SCN to the ventromedial hypothalamus that drives time-of-day-dependent aggressive behaviours. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the mouse ventral tegmental area, circadian regulation of SIRT1-dependent metabolic signalling is mechanistically linked to dopaminergic neurotransmission, which is important for drug reward.

    “This study demonstrates mechanistic links between circadian regulation of SIRT1-dependent metabolic signalling and dopaminergic neurotransmission in the mouse ventral tegmental area, which is important for drug reward.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [264] Logan, R. W. et al. NAD+ cellular redox and SIRT1 regulate the diurnal rhythms of tyrosine hydroxylase and conditioned cocaine reward. Mol. Psychiatry. https://doi.org/10.1038/s41380-018-0061-1 (2018). This study demonstrates mechanistic links between circadian regulation of SIRT1-dependent metabolic signalling and dopaminergic neurotransmission in the mouse ventral tegmental area, which is important for drug reward. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with Alzheimer's disease have less diurnal activity, more nocturnal activity and phase delays in body-temperature rhythms, and the severity of sundowning is positively correlated with lower-amplitude and more-phase-delayed rhythms.

    “This study shows that patients with AD have less diurnal activity, more nocturnal activity and phase delays in body-temperature rhythms, and that the severity of sundowning is positively correlated with lower-amplitude and more-phase-delayed rhythms.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [282] Volicer, L., Harper, D. G., Manning, B. C., Goldstein, R. & Satlin, A. Sundowning and circadian rhythms in Alzheimer’s disease. Am. J. Psychiatry 158, 704–711 (2001). This study shows that patients with AD have less diurnal activity, more nocturnal activity and phase delays in body-temperature rhythms, and that the severity of sundowning is positively correlated with lower-amplitude and more-phase-delayed rhythms. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A set of computational algorithms called TimeSignature predicts the endogenous phase of an individual based on gene signatures from blood acquired at a single timepoint.

    “This study demonstrates the use of a set of computational algorithms called TimeSignature to predict the endogenous phase of an individual based on the particular gene signatures from the blood acquired at a single timepoint.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [319] Braun, R. et al. Universal method for robust detection of circadian state from gene expression. Proc. Natl Acad. Sci. USA 115, E9247–E9256 (2018). This study demonstrates the use of a set of computational algorithms called TimeSignature to predict the endogenous phase of an individual based on the particular gene signatures from the blood acquired at a single timepoint.

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    In mice, wakefulness suppresses the outflow of cerebral spinal fluid from the brain, whereas sleep leads to an increase in convective fluxes of fluid, effectively promoting the clearance of neurotoxic metabolites, including Aβ.

    “A landmark study in mice demonstrating that wakefulness suppresses the outflow of cerebral spinal fluid from the brain, whereas sleep leads to an increase in convective fluxes of fluid, effectively promoting the clearance of neurotoxic metabolics, including Aβ.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [285] Xie, L. et al. Sleep drives metabolite clearance from the adult brain. Science 342, 373–377 (2013). A landmark study in mice demonstrating that wakefulness suppresses the outflow of cerebral spinal fluid from the brain, whereas sleep leads to an increase in convective fluxes of fluid, effectively promoting the clearance of neurotoxic metabolics, including Aβ. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Mice harbouring a mutation in Clock display a behavioural repertoire similar to human mania, and CLOCK specifically in the ventral tegmental area is important for these behaviours via modulation of dopamine cell firing.

    “This study demonstrates mice harbouring a mutation in Clock display a behavioural repertoire similar to human mania and provides evidence for CLOCK specifically in the ventral tegmental area to be important for these behaviours via modulation of dopamine cell firing.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [313] Roybal, K. et al. Mania-like behavior induced by disruption of CLOCK. Proc. Natl Acad. Sci. USA 104, 6406–6411 (2007). This study demonstrates mice harbouring a mutation in Clock display a behavioural repertoire similar to human mania and provides evidence for CLOCK specifically in the ventral tegmental area to be important for these behaviours via modulation of dopamine cell firing. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 189 elderly residents of a group care facility, a combination of melatonin supplementation and scheduled light exposure improves cognitive symptoms of dementia and reduces aggression.

    “This double-blinded randomized controlled trial of 189 elderly residents of a group care facility demonstrates that a combination of melatonin supplementation and scheduled light exposure improves cognitive symptoms of dementia and reduces aggression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [301] Riemersma-van der Lek, R. F. et al. Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. JAMA 299, 2642–2655 (2008). This double-blinded randomized controlled trial of 189 elderly residents of a group care facility demonstrates that a combination of melatonin supplementation and scheduled light exposure improves cognitive symptoms of dementia and reduces aggression. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Components of the molecular clock control redox state and, when disrupted, lead to oxidative stress and cell death related to neurodegeneration.

    “This preclinical investigation demonstrates that components of the molecular clock control redox state and, when disrupted, lead to oxidative stress and cell death related to neurodegeneration.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [291] Musiek, E. S. et al. Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. J. Clin. Invest. 123, 5389–5400 (2013). This preclinical investigation demonstrates that components of the molecular clock control redox state and, when disrupted, lead to oxidative stress and cell death related to neurodegeneration. source

      Not checked in the free run.

104 of 104

  • The paper relies on this without support.

    Brain disorders such as autism, depression and Parkinson disease typically develop at certain stages of life.

    “Brain disorders such as autism, depression and Parkinson disease typically develop at certain stages of life, and circadian rhythms are important during each stage of life for the regulation of processes that may influence the development of these disorders.”

  • The paper relies on this without support.

    Circadian rhythms are important during each stage of life for the regulation of processes that may influence the development of brain disorders.

    “Brain disorders such as autism, depression and Parkinson disease typically develop at certain stages of life, and circadian rhythms are important during each stage of life for the regulation of processes that may influence the development of these disorders.”

  • The paper relies on this without support.

    The risk of depression is increased in people with delayed sleep–wake phase disorder, particularly in those with a biological circadian misalignment as measured by DLMO phase.

    “The risk of depression is increased in people with this disorder and particularly in those with a biological circadian misalignment (as measured by the dim light melatonin onset (DLMO) phase).”

  • The paper relies on this without support.

    Stable environmental schedules ameliorate daytime sleepiness and daytime behavioural problems in individuals with ASD or ADHD.

    “stable environmental schedules seem to ameliorate daytime sleepiness and daytime behavioural problems in individuals with ASD or ADHD”

  • The paper relies on this without support.

    Findings from preclinical animal models are informative about causal relationships between circadian disruption and human brain disorders.

    “animal model studies are beginning to examine potential causal relationships between disrupted circadian rhythms and multiple brain disorders and are starting to identify molecular mechanisms”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Nearly all patients with affective disorders including depression show significant disruptions in circadian rhythms.

    “Nearly all patients with affective disorders including depression show significant disruptions in circadian rhythms 83, 84, 85, 86, 87.”

    From The Circadian Syndrome: is the Metabolic Syndrome and much more! (2019) · cites this paper as [85]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Sleep-restriction study described as using rats, but cited reference says mice

    Minor

    The text describes the adolescent sleep-restriction experiment as a rat study, while the cited reference identifies it as a mouse study.

1 of 1

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Related

Authors
Logan, R. W., & McClung, C. A.
Affiliations
University of Pittsburgh (US)
Corresponding author
McClung, Colleen A.
ORCID
Venue
Nature Reviews Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2018-11-20
Volume
20
Issue
1
Pages
49-65
ISSN
  • 1471-003X (ISSN-L)
  • 1471-0048
DOI
10.1038/s41583-018-0088-y
PMC
PMC6338075
OpenAlex
W2901527259
Semantic Scholar
d5a232f327571b2cbcf5eaf440e69e2685dcd0ee
Cited by
713
References
339
Citations by year
2026: 87 · 2025: 138 · 2024: 117 · 2023: 98 · 2022: 99 · 2021: 79 · 2020: 69 · 2019: 22 · 2017: 2 · 2016: 1
FWCI
5.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature reviews. Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • International Mental Health Research Organization (DA037636, DA039865, MH082876, DA023988, MH106460)
  • National Alliance for Research on Schizophrenia and Depression (MH082876, DA023988)
  • National Institute of Mental Health (R01MH106460, R01MH082876)
  • National Institute on Drug Abuse (R01DA023988, R33DA041872, R21DA041872, R21DA037636, R01DA039865, K01DA038654, P50DA046346, P50DA039841)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and Work-Related Fatigue
Keywords
circadian rhythm, circadian rhythm disruption, brain disorders, lifespan development, sleep-wake cycle, autism spectrum disorder, depression, Parkinson's disease, brain development, aging, circadian system, central nervous system disorders
MeSH terms
Animals, Brain Diseases, Circadian Rhythm, Humans, Longevity, Sleep, Sleep Disorders, Circadian Rhythm

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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