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Internal circadian phase assessment is increasingly acknowledged as a critical clinical tool for the diagnosis, monitoring, and treatment of circadian rhythm sleep-wake disorders and for investigating circadian timing in other medical disorders. The widespread use of in-laboratory circadian phase assessments in routine practice has been limited, most likely because circadian phase assessment is not required by formal diagnostic nosologies, and is not generally covered by insurance. At-home assessment of salivary dim light melatonin onset (DLMO, a validated circadian phase marker) is an increasingly accepted approach to assess circadian phase. This approach may help meet the increased demand for assessments and has the advantages of lower cost and greater patient convenience. We reviewed the literature describing at-home salivary DLMO assessment methods and identified factors deemed to be important to successful implementation. Here, we provide specific protocol recommendations for conducting at-home salivary DLMO assessments to facilitate a standardized approach for clinical and research purposes. Key factors include control of lighting, sampling rate, and timing, and measures of patient compliance. We include findings from implementation of an optimization algorithm to determine the most efficient number and timing of samples in patients with Delayed Sleep-Wake Phase Disorder. We also provide recommendations for assay methods and interpretation. Providing definitive criteria for each factor, along with detailed instructions for protocol implementation, will enable more widespread adoption of at-home circadian phase assessments as a standardized clinical diagnostic, monitoring, and treatment tool.

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Introduction: Fatigue, brain fog, and sleep disturbance are among the most common symptoms of postacute sequelae of SARS-CoV-2 infection (PASC). We sought to determine the impact of sleep disruption on cognition and quality of life in patients with neurologic manifestations of PASC (Neuro-PASC). Methods: Thirty-nine patients were recruited from Neuro-COVID-19 clinic. Mean age was 48.1 years, 71.8% were female, and 82% were never hospitalized for COVID-19. Patients were evaluated via clinical assessment, quality-of-life measures in domains of cognitive function, fatigue, sleep disturbance, anxiety, and depression, NIH Toolbox cognitive tests, and 7 days of wrist actigraphy. Results: The median number of neurologic symptoms attributed to PASC was 6, with brain fog being the most common in 89.7%. Regarding non-neurologic symptoms, 94.9% complained of fatigue and 74.4% of insomnia. Patients reported significant impairment in all quality-of-life domains and performed worse in a task of attention compared to a normative US population. Actigraphy showed Neuro-PASC patients had lower sleep efficiency, longer sleep latency (both p < 0.001), and later sleep midpoint (p = 0.039) compared to 71 age-matched healthy controls with no PASC history. Self-reported cognitive symptoms correlated with the severity of fatigue (p < 0.001), anxiety (p = 0.05), and depression (p < 0.01). Objective evidence of sleep disruption measured by wakefulness after sleep onset, sleep efficiency, and latency were associated with decreased performance in attention and processing speed. Conclusion: Prospective studies including larger populations of patients are needed to fully determine the interplay of sleep disruption on the cognitive function and quality of life of patients with PASC.

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Atopic dermatitis (AD) is a chronic burdensome inflammatory skin disease with well-established cutaneous and systemic comorbidities and disease burden. AD particularly has profound impacts on sleep in individuals of all ages. Sleep disturbances (SDs) affect 6.2% of school-age children and 33-87.1% of adults with AD. This narrative review addresses the burden of SD in AD patients, as well as biological mechanisms of SD in AD, including biological clocks influencing sleep, inflammation, and behavior. Approaches for early detection, diagnosis, objective quantification, patient education, and management are reviewed. It is imperative to break the itch-scratch cycle to reduce SDs and improve quality of life in individuals with AD.

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SignificanceAmbient nighttime light exposure is implicated as a risk factor for adverse health outcomes, including cardiometabolic disease. However, the effects of nighttime light exposure during sleep on cardiometabolic outcomes and the related mechanisms are unclear. This laboratory study shows that, in healthy adults, one night of moderate (100 lx) light exposure during sleep increases nighttime heart rate, decreases heart rate variability (higher sympathovagal balance), and increases next-morning insulin resistance when compared to sleep in a dimly lit (<3 lx) environment. Moreover, a positive relationship between higher sympathovagal balance and insulin levels suggests that sympathetic activation may play a role in the observed light-induced changes in insulin sensitivity.

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STUDY OBJECTIVES: This study examines the impact of cognitive behavioral therapy for insomnia (CBT-I) and positive airway pressure (PAP) therapy for comorbid insomnia and sleep apnea on nocturnal sleep and daytime functioning. METHODS: A partial factorial design was used to examine treatment pathways with CBT-I and PAP and the relative benefits of each treatment. One hundred eighteen individuals with comorbid insomnia and sleep apnea were randomized to receive CBT-I followed by PAP, self-monitoring followed by CBT-I concurrent with PAP, or self-monitoring followed by PAP only. Participants were assessed at baseline, PAP titration, and 30 and 90 days after PAP initiation. Outcome measures included sleep diary- and actigraphy-measured sleep, Flinders Fatigue Scale, Epworth Sleepiness Scale, Functional Outcome of Sleep Questionnaire, and cognitive emotional measures. RESULTS: A main effect of time was found on diary-measured sleep parameters (decreased sleep onset latency and wake after sleep onset; increased total sleep time and sleep efficiency) and actigraphy-measured sleep parameters (decreased wake after sleep onset; increased sleep efficiency) and daytime functioning (reduced Epworth Sleepiness Scale, Flinders Fatigue Scale; increased Functional Outcome of Sleep Questionnaire) across all arms (all P < .05). Significant interactions and planned contrast comparisons revealed that CBT-I was superior to PAP and self-monitoring on reducing diary-measured sleep onset latency and wake after sleep onset and increasing sleep efficiency, as well as improving Functional Outcome of Sleep Questionnaire and Flinders Fatigue Scale compared to self-monitoring. CONCLUSIONS: Improvements in sleep and daytime functioning were found with PAP alone or concomitant with CBT-I. However, more rapid effects were observed on self-reported sleep and daytime performance when receiving CBT-I regardless of when it was initiated. Therefore, concomitant treatment appears to be a favorable approach to accelerate treatment outcomes. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Multidisciplinary Approach to the Treatment of Insomnia and Comorbid Sleep Apnea (MATRICS); URL: https://clinicaltrials.gov/ct2/show/NCT01785303; Identifier: NCT01785303. CITATION: Tu AY, Crawford MR, Dawson SC, et al. A randomized controlled trial of cognitive behavioral therapy for insomnia and PAP for obstructive sleep apnea and comorbid insomnia: effects on nocturnal sleep and daytime performance. J Clin Sleep Med. 2022;18(3):789-800.

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

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PURPOSE: To study the relationship between OSA and risk of COVID-19 infection and disease severity, identified by the need for hospitalization and progression to respiratory failure. METHODS: We queried the electronic medical record system for an integrated health system of 10 hospitals in the Chicago metropolitan area to identify cases of COVID-19. Comorbidities and outcomes were ascertained by ICD-10-CM coding and medical record data. We evaluated the risk for COVID-19 diagnosis, hospitalization, and respiratory failure associated with OSA by univariate tests and logistic regression, adjusting for diabetes, hypertension, and BMI to account for potential confounding in the association between OSA, COVID-19 hospitalization, and progression to respiratory failure. RESULTS: We identified 9405 COVID-19 infections, among which 3185 (34%) were hospitalized and 1779 (19%) were diagnosed with respiratory failure. OSA was more prevalent among patients requiring hospitalization than those who did not (15.3% versus 3.4%, p < 0.0001; OR 5.20, 95% CI (4.43, 6.12)), and among those who progressed to respiratory failure (19.4% versus 4.5%, p < 0.0001; OR 5.16, 95% CI (4.41, 6.03)). After adjustment for diabetes, hypertension, and BMI, OSA was associated with increased risk for hospitalization (OR 1.65; 95% CI (1.36, 2.02)) and respiratory failure (OR 1.98; 95% CI (1.65, 2.37)). CONCLUSIONS: Patients with OSA experienced approximately 8-fold greater risk for COVID-19 infection compared to a similar age population receiving care in a large, racially, and socioeconomically diverse healthcare system. Among patients with COVID-19 infection, OSA was associated with increased risk of hospitalization and approximately double the risk of developing respiratory failure.

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STUDY OBJECTIVES: The circadian system must perform daily adjustments to align sleep-wake and other physiologic rhythms with the environmental light-dark cycle: This is mediated primarily through melanopsin containing intrinsically photosensitive retinal ganglion cells. Individuals with delayed sleep-wake phase disorder (DSWPD) exhibit a delay in sleep-wake timing relative to the average population, while those with sighted non-24-hour sleep-wake rhythm disorder (N24SWD) exhibit progressive delays. An inability to maintain appropriate entrainment is a characteristic of both disorders. In this study, we test the hypothesis that individuals with DSWPD exhibit alteration in melanopsin-dependent retinal photo-transduction as measured with the postillumination pupil response (PIPR). METHODS: Twenty-one control and 29 participants with DSWPD were recruited from the community and clinic. Of the 29 DSWPD participants, 17 reported a history of N24SWD. A pupillometer was used to measure the PIPR in response to a bright 30-second blue or red-light stimulus. The PIPR was calculated as the difference in average pupil diameter at baseline and 10-40 seconds after light stimulus offset. RESULTS: The PIPR was significantly reduced in the DSWPD group when compared with the control group (1.26 ± 1.11 mm vs 2.05 ± 1.04 mm, p < 0.05, t-test). The PIPR was significantly reduced in the sighted N24SWD subgroup when compared with individuals with the history of only DSWPD (0.88 ± 0.58 mm vs 1.82 ± 1.44 mm, p < 0.05, analysis of variance [ANOVA]) or controls (0.88 ± 0.58 mm vs 2.05 ± 1.04 mm, p < 0.01, ANOVA). CONCLUSIONS: These results indicate that reduced melanopsin-dependent retinal photo-transduction may be a novel mechanism involved in the development of DSWPD and sighted N24SWD.

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STUDY OBJECTIVES: Insomnia is common in older adults, and is associated with poor health, including cognitive impairment and cardio-metabolic disease. Although the mechanisms linking insomnia with these comorbidities remain unclear, age-related changes in sleep and autonomic nervous system (ANS) regulation might represent a shared mechanistic pathway. In this study, we assessed the relationship between ANS activity with indices of objective and subjective sleep quality in older adults with insomnia. METHODS: Forty-three adults with chronic insomnia and 16 age-matched healthy sleeper controls were studied. Subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI), objective sleep quality by electroencephalogram spectral components derived from polysomnography, and ANS activity by measuring 24-h plasma cortisol and norepinephrine (NE). RESULTS: Sleep cycle analysis displayed lower slow oscillatory (SO: 0.5-1.25 Hz) activity in the first cycle in insomnia compared to controls. In insomnia, 24-h cortisol levels were higher and 24-h NE levels were lower than controls. In controls, but not in insomnia, there was a significant interaction between NE level during wake and SO activity levels across the sleep cycles, such that in controls but not in insomnia, NE level during wake was positively associated with the amount of SO activity in the first cycle. In insomnia, lower 24-h NE level and SO activity in the first sleep cycle were associated with poorer subjective sleep quality. CONCLUSION: Dysregulation of autonomic activity may be an underlying mechanism that links objective and subjective measures of sleep quality in older adults with insomnia, and potentially contribute to adverse health outcomes.

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PURPOSE OF REVIEW: This article provides an overview of circadian physiology and discusses common presentations and treatment strategies for the circadian rhythm sleep-wake disorders. RECENT FINDINGS: Circadian rhythms are present throughout the body, and appreciation for the role that circadian dysregulation plays in overall health is increasing, with mounting associations between circadian disruption and cardiometabolic disease risk. SUMMARY: It is important to recognize the ubiquitous role that circadian rhythms play throughout the brain and body. An understanding of circadian neurophysiology will provide insight into the means by which patients with a variety of neuropathologies at the level of the retina, optic nerve, or hypothalamus may also be at risk for circadian dysfunction.

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OBJECTIVES: To characterize acute alterations of circadian and ultradian rest-activity rhythms in critically ill patients and their association with brain dysfunction, systemic multiple organ dysfunction, and melatonin rhythms. DESIGN: Prospective study observing a cohort for 48 hours beginning within the first day of ICU admission. SETTING: ICUs within an academic medical center. PATIENTS: Patients presenting from the community with acute onset of either intracerebral hemorrhage or sepsis as representative neurologic and systemic critical illnesses. Healthy control patients were studied in the community, during hospital bedrest, and during sleep deprivation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Circadian and ultradian characteristics of rest-activity patterns were measured by wrist actigraphy, severity of neurologic and systemic illness by Glasgow Coma Scale and Sequential Organ Failure Assessment, and central circadian rhythm by melatonin profile. We studied 112 critically ill patients, including 53 with sepsis and 59 with intracerebral hemorrhage, along with 53 control participants. Total daily activity was markedly reduced and rest-activity rhythmicity was undetectable, neither of which was replicated by hospital bedrest in healthy controls. Circadian rest-activity rhythm fragmentation and attenuation and ultradian disorganization was associated with Glasgow Coma Scale and Sequential Organ Failure Assessment in adjusted models. Rest-activity rhythms showed no detectable phase coherence with melatonin rhythms. CONCLUSIONS: Critically ill patients rapidly enter a state of behavioral quiescence proportionate to their illness severity with concomitant disturbance of circadian and ultradian rest-activity rhythms and loss of phase coherence with the melatonin rhythm. Quiescence characteristics in rest-activity rhythms were not different in patients with and without delirium, suggesting them to be distinct phenomena. Animal models of severe physiologic stress have shown that specific neural pathway separate from the sleep-wake regulatory pathway induce behavioral quiescence and rest-activity arrhythmia, and facilitate recovery of cellular homeostasis. Whether quiescence is a conserved protective response pathway in humans is not yet understood.

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OBJECTIVES: The circadian system modulates many important physiologic processes, synchronizing tissue-specific functions throughout the body. We sought to characterize acute alterations of circadian rhythms in critically ill patients and to evaluate associations between brain dysfunction, systemic multiple organ dysfunction, environmental stimuli that entrain the circadian rhythm (zeitgebers), rest-activity rhythms, and the central circadian rhythm-controlled melatonin secretion profile. DESIGN: Prospective study observing a cohort for 24-48 hours beginning within the first day of ICU admission. SETTING: Multiple specialized ICUs within an academic medical center. PATIENTS: Patients presenting from the community with acute onset of either intracerebral hemorrhage as a representative neurologic critical illness or sepsis as a representative systemic critical illness. Healthy control patients were studied in using modified constant routine in a clinical research unit. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Light, feeding, activity, medications, and other treatment exposures were evaluated along with validated measures of encephalopathy (Glasgow Coma Scale), multiple organ system function (Sequential Organ Failure Assessment score), and circadian rhythms (profiles of serum melatonin and its urinary metabolite 6-sulphatoxymelatonin). We studied 112 critically ill patients, including 53 with sepsis and 59 with intracerebral hemorrhage. Environmental exposures were abnormal, including light (dim), nutritional intake (reduced or absent and mistimed), and arousal stimuli (increased and mistimed). Melatonin amplitude and acrophase timing were generally preserved in awake patients but dampened and delayed with increasing encephalopathy severity. Melatonin hypersecretion was observed in patients exposed to catecholamine vasopressor infusions, but unaffected by sedatives. Change in vasopressor exposure was the only factor associated with changes in melatonin rhythms between days 1 and 2. CONCLUSIONS: Encephalopathy severity and adrenergic agonist medication exposure were the primary factors contributing to abnormal melatonin rhythms. Improvements in encephalopathy and medical stabilization did not rapidly normalize rhythms. Urinary 6-sulphatoxymelatonin is not a reliable measure of the central circadian rhythm in critically ill patients.

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STUDY OBJECTIVES: To investigate treatment models using cognitive behavioral therapy for insomnia (CBT-I) and positive airway pressure (PAP) for people with obstructive sleep apnea (OSA) and comorbid insomnia. METHODS: 121 adults with OSA and comorbid insomnia were randomized to receive CBT-I followed by PAP, CBT-I concurrent with PAP, or PAP only. PAP was delivered following standard clinical procedures for in-lab titration and home setup and CBT-I was delivered in four individual sessions. The primary outcome measure was PAP adherence across the first 90 days, with regular PAP use (≥4 h on ≥70% of nights during a 30-day period) serving as the clinical endpoint. The secondary outcome measures were the Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI) with good sleeper (PSQI <5), remission (ISI <8), and response (ISI reduction from baseline >7) serving as the clinical endpoints. RESULTS: No significant differences were found between the concomitant treatment arms and PAP only on PAP adherence measures, including the percentage of participants who met the clinical endpoint. Compared to PAP alone, the concomitant treatment arms reported a significantly greater reduction from baseline on the ISI (p = .0009) and had a greater percentage of participants who were good sleepers (p = .044) and remitters (p = .008). No significant differences were found between the sequential and concurrent treatment models on any outcome measure. CONCLUSIONS: The findings from this study indicate that combining CBT-I with PAP is superior to PAP alone on insomnia outcomes but does not significantly improve adherence to PAP.

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Circadian rhythm disorders have been classically associated with disorders of abnormal timing of the sleep-wake cycle, however circadian dysfunction can play a role in a wide range of pathology, ranging from the increased risk for cardiometabolic disease and malignancy in shift workers, prompting the need for a new field focused on the larger concept of circadian medicine. The relationship between circadian disruption and human health is bidirectional, with changes in circadian amplitude often preceding the classical symptoms of neurodegenerative disorders. As our understanding of the importance of circadian dysfunction in disease grows, we need to develop better clinical techniques for identifying circadian rhythms and also develop circadian based strategies for disease management. Overall this review highlights the need to bring the concept of time to all aspects of medicine, emphasizing circadian medicine as a prime example of both personalized and precision medicine.

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Non-24-hour sleep-wake rhythm disorder is a circadian rhythm sleep-wake disorder characterized by an inability to entrain to the 24-hour environment. Patients present with complaints of insomnia or hypersomnia, with progressive daily shifts of sleep-wake activity on actigraphy or sleep logs. Although first recognized in blind individuals without light perception, it also can be seen in individuals with intact vision. Treatment focuses on timed melatonin in blind individuals, whereas it is more complex in sighted individuals, using multiple time cues, such as light, melatonin, social interactions, feeding, and activity.

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Circadian rhythms are present in nearly all organisms studied, and are present throughout the human body. The proper coordination of these rhythms, both within the body, and with respect to the environment appears to be important for overall health. This article reviews the available data looking at the association between circadian dysregulation and cardiometabolic, neurologic, and neurodegenerative disease risk. In addition we discuss the limited but growing evidence supporting the use of circadian-based interventions to improve overall health.

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Circadian rhythms are the endogenous near-24-h oscillations in physiologic processes. In mammals the suprachiasmatic nucleus serves as the primary circadian pacemaker, and it maintains rhythmicity at a genetic level through a complex transcription-translation feedback loop of core circadian clock genes. The circadian clock is entrained to the environment through daily exposure to light and melatonin. Disruption of these endogenous rhythms or the ability to entrain to the surrounding environment results in the circadian rhythm sleep-wake disorders (CRSWDs). Patients with CRSWDs can present with either late sleep/wake times (delayed sleep-wake phase disorder), early sleep/wake times (advanced sleep-wake phase disorder), inconsistent sleep/wake times (irregular sleep-wake rhythm disorder) or sleep-wake times that move progressively later each day (non-24-h sleep-wake rhythm disorder). Diagnosis of these disorders relies on the use of sleep logs and/or actigraphy to demonstrate the daily patterns of rest and activity. Treatment of the CRSWDs focuses on sleep hygiene and strategically timed light and melatonin.

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