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

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.

Obstructive Sleep Apnea and Risk of COVID-19 Infection, Hospitalization and Respiratory Failure.

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.

Circadian disruption and human health: A bidirectional relationship.

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.

Strengthening sleep-autonomic interaction via acoustic enhancement of slow oscillations.

Slow-wave sleep (SWS) is important for overall health since it affects many physiological processes including cardio-metabolic function. Sleep and autonomic nervous system (ANS) activity are closely coupled at anatomical and physiological levels. Sleep-related changes in autonomic function are likely the main pathway through which SWS affects many systems within the body. There are characteristic changes in ANS activity across sleep stages. Notably, in non-rapid eye-movement sleep, the progression into SWS is characterized by increased parasympathetic activity, an important measure of cardiovascular health. Experimental manipulations that enhance slow-wave activity (SWA, 0.5-4 Hz) can improve sleep-mediated memory and immune function. However, effects of SWA enhancement on autonomic regulation have not been investigated. Here, we employed an adaptive algorithm to deliver 50 ms sounds phase-locked to slow-waves, with regular pauses in stimulation (~5 s ON/~5 s OFF), in healthy young adults. We sought to determine whether acoustic enhancement of SWA altered parasympathetic activity during SWS assessed with heart rate variability (HRV), and evening-to-morning changes in HRV, plasma cortisol, and blood pressure. Stimulation, compared with a sham condition, increased SWA during ON versus OFF intervals. This ON/OFF SWA enhancement was associated with a reduction in evening-to-morning change of cortisol levels and indices of sympathetic activity. Furthermore, the enhancement of SWA in ON intervals during sleep cycles 2-3 was accompanied by an increase in parasympathetic activity (high-frequency, HRV). Together these findings suggest that acoustic enhancement of SWA has a positive effect on autonomic function in sleep. Approaches to strengthen brain-heart interaction during sleep could have important implications for cardiovascular health.

Habitual light exposure relative to circadian timing in delayed sleep-wake phase disorder.

Study Objectives: To compare melatonin timing, a well-validated marker for endogenous circadian phase, and habitual light-exposure patterns in adults with delayed sleep-wake phase disorder (DSWPD) and intermediate chronotype controls. Methods: Twelve individuals with DSWPD (five females, mean age: 31.1) and 12 age-matched controls (six females, mean age: 33.6) underwent a minimum of 7 days of light and activity monitoring followed by an inpatient hospital stay, where blood was taken to assess melatonin timing (calculated as dim light melatonin onset-DLMO). Habitual light-exposure patterns were then compared with a human phase-response curve (PRC) to light. Results: Relative to clock time, individuals with DSWPD had a later light-exposure pattern compared with controls, but their light-exposure pattern was earlier relative to DLMO. According to the human PRC to light, individuals with DSWPD had less daily advancing light exposure compared with controls. The primary difference was seen in the late portion of the advancing window, in which individuals with DSWPD were exposed to fewer pulses of light of equivalent duration and intensity compared with controls. Conclusions: Diminished advancing light exposure may play a role in the development and perpetuation of delayed sleep-wake timing in individuals with DSWPD. Enhancing light exposure during the later portion of the advancing window represents an innovative and complementary strategy that has the potential to improve the effectiveness of bright light therapy in DSWPD.

Diagnostic and Treatment Challenges of Sighted Non-24-Hour Sleep-Wake Disorder.

STUDY OBJECTIVES: To report the diagnostic and treatment challenges of sighted non-24-hour sleep-wake disorder (N24SWD). METHODS: We report a series of seven sighted patients with N24SWD clinically evaluated by history and sleep diaries, and when available wrist actigraphy and salivary melatonin levels, and treated with timed melatonin and bright light therapy. RESULTS: Most patients had a history of a delayed sleep-wake pattern prior to developing N24SWD. The typical sleep-wake pattern of N24SWD was seen in the sleep diaries (and in actigraphy when available) in all patients with a daily delay in midpoint of sleep ranging 0.8 to 1.8 hours. Salivary dim light melatonin onset (DLMO) was evaluated in four patients but was missed in one. The estimated phase angle from DLMO to sleep onset ranged from 5.25 to 9 hours. All six patients who attempted timed melatonin and bright light therapy were able to entrain their sleep-wake schedules. Entrainment occurred at a late circadian phase, possibly related to the late timing of melatonin administration, though the patients often preferred late sleep times. Most did not continue treatment and continued to have a non-24-hour sleep-wake pattern. CONCLUSIONS: N24SWD is a chronic debilitating disorder that is often overlooked in sighted people and can be challenging to diagnose and treat. Tools to assess circadian pattern and timing can be effectively applied to aid the diagnosis. The progressive delay of the circadian rhythm poses a challenge for determining the most effective timing for melatonin and bright light therapies. Furthermore, once the circadian sleep-wake rhythm is entrained, long-term effectiveness is limited because of the behavioral and environmental structure that is required to maintain stable entrainment.

Circadian Disruption Associated with Alzheimer's Disease.

Alzheimer's disease (AD) is increasing in prevalence and has a significant impact on caregivers and the healthcare system. One of the many physiologic process affected by AD is the circadian system, with disruption reflected in abnormalities of the sleep-wake cycle. This interaction is bidirectional, with circadian and sleep disruption influencing disease progression. Understanding the bidirectional relationship between AD and circadian disruption may allow for earlier recognition of the potential to develop dementia as well as improved targeted approaches for therapy. Therapies including melatonin and bright light therapy may be advantageous in improving sleep and circadian rhythms and preventing the progression of disease. However, unfortunately, these modalities are not curative, and additional research is needed to improve treatment options for these individuals.

Circadian Rhythm Sleep-Wake Disorders.

The circadian system regulates the timing and expression of nearly all biological processes, most notably, the sleep-wake cycle, and disruption of this system can result in adverse effects on both physical and mental health. The circadian rhythm sleep-wake disorders (CRSWDs) consist of 5 disorders that are due primarily to pathology of the circadian clock or to a misalignment of the timing of the endogenous circadian rhythm with the environment. This article outlines the nature of these disorders, the association of many of these disorders with psychiatric illness, and available treatment options.