key: cord-0651174-eo53kq7r authors: Bar, Nitai; Sobel, Jonathan A.; Penzel, Thomas; Shamay, Yosi; Behar, Joachim A. title: From sleep medicine to medicine during sleep: A clinical perspective date: 2021-02-09 journal: nan DOI: nan sha: a2b3ca33cf64c3c7ed4868c5e80abc49440203d2 doc_id: 651174 cord_uid: eo53kq7r Sleep has a profound influence on the physiology of body systems and biological processes. Molecular studies have shown circadian-regulated shifts in protein expression patterns across human tissues, further emphasizing the unique functional, behavioral and pharmacokinetic landscape of sleep. Thus, many pathological processes are also expected to exhibit sleep-specific manifestations. Nevertheless, sleep is seldom utilized for the study, detection and treatment of non-sleep-specific pathologies. Modern advances in biosensor technologies have enabled remote, non-invasive recording of a growing number of physiologic parameters and biomarkers. Sleep is an ideal time frame for the collection of long and clean physiological time series data which can then be analyzed using data-driven algorithms such as deep learning. In this perspective paper, we aim to highlight the potential of sleep as an auspicious time for diagnosis, management and therapy of nonsleep-specific pathologies. We introduce key clinical studies in selected medical fields, which leveraged novel technologies and the advantageous period of sleep to diagnose, monitor and treat pathologies. We then discuss possible opportunities to further harness this new paradigm and modern technologies to explore human health and disease during sleep and to advance the development of novel clinical applications: From sleep medicine to medicine during sleep. Sleep, a phenomenon observed among all animals, has long been identified as a vital process for general health and wellbeing 1 . Despite the estimated decrease in average sleep duration in modern society, humans spend approximately one third of their lives sleeping 2 . Sleep research dates back to at least the 18 th century and has developed into the medical subspecialty of "sleep medicine", although it still remains on the fringes of medical training 3 . To date, this field focuses mainly on the diagnosis and treatment of sleep-related disorders, as classified in the International Classification of Sleep Disorders (ICSD-3) 4 , diagnostic and statistical manual of mental disorders (DMS-5) 5 or international classification of diseases (ICD-11) 6 . Normal adult sleep architecture is comprised of cyclic patterns of non-rapid eye movement (NREM) followed by rapid eye movement (REM) sleep, with a single cycle lasting 90-120 minutes. REM percentage and density tend to increase during the night with successive sleep cycles 7 . All major body systems are affected by sleep, including the respiratory, cardiovascular and genitourinary systems, in addition to drug detoxification, metabolic, thermoregulatory, immune and cognitive processes. Additionally, many hormones exhibit a relation to the circadian cycle, the most notable being cortisol, growth hormone and prolactin, with levels directly relating to sleep stages, age and gender. Alongside alterations in hormone levels, the autonomic nervous system is a major driver of the abrupt changes in physiology observed during sleep. Overall, sleep is characterized by a reduction in peripheral sympathetic activity and increase in parasympathetic activity, with a more complex and fluctuating pattern during REM as compared to NREM sleep 8 . This shift in neural homeostasis induces the characteristic changes in sleep physiology of various systems, which, in turn, account for the distinctive manifestations of pathologies during sleep. Sleep modulates the presentation of respiratory disorders due to decreased chemosensitivity to hypoxia and hypercapnia as well as reduced respiratory muscle tone. This ability to tolerate higher levels of CO2 and lower levels of O2, which is more pronounced during REM sleep compared to non-REM sleep, diminishes work of breathing 9 . As a result, conditions in which there is little tolerance to low work of breathing, such as chronic obstructive pulmonary disease (COPD) and asthma, may be aggravated even in the absence of a respiratory sleep disorder, although concomitant sleep disorders such as obstructive sleep apnea (OSA) are prevalent in these populations 10, 11 . Sleep also impacts several cardiac functions and induces decreased heart rate and systolic blood pressure (BP), an effect termed the "dipping phenomenon" 12 . This physiologic shift is postulated to enable some rest to the vascular system, endothelial system and heart mechanics. Impairment of this regulatory effect can mirror cardiac or vascular problems and in some cases may be an early manifestation of a cardiac pathology 8 . The emerging role of portable biosensors in clinical practice has been gaining substantial interest 13 . Portable devices and sensors that can record a variety of biosignals are already the subject of hundreds of clinical trials 14 and notable publishing houses, such as Nature or the Lancet, have opened new journals in the field of Digital Medicine with a high focus on portable medicine. Sleep is an ideal time frame for the collection of long and clean physiological time series data, which can then be analyzed using data-driven algorithms such as deep learning 15, 16 . Little is known about how non-sleep-specific diseases manifest during sleep and the contribution of sleep to their pathophysiology. The unique physiological and biomolecular characteristics of sleep imply that pathologic processes, as well as therapeutic interventions, will also exhibit marked differences when applied during sleep as compared to daytime. Nevertheless, despite the potential advantages, sleep is seldom exploited in clinical practice to diagnose, monitor and treat non-sleep-specific conditions -a paradigm we recently coined 'medicine during sleep' 17 . This perspective article motivates this new paradigm by reviewing existing clinical research that focuses on the diagnosis, treatment and management of non-sleep-specific diseases during sleep. Monitoring arterial O2 saturation and CO2 levels enables evaluation of pulmonary gas exchange. Both can be non-invasively estimated by continuous measurement of peripheral oxygen saturation (SpO2) or transcutaneous O2 (TcO2) and end tidal CO2 (ETCO2) or transcutaneous PCO2 (TcPCO2), respectively. Sleep ventilation assessment is being used in a growing number of respiratory-related clinical scenarios ranging from acute infectious episodes in infants to chronic lung or extrapulmonary disorders affecting respiration, in both inpatient and ambulatory settings 18 . The importance and high prevalence of sleep desaturation in patients with COPD, including those who do not exhibit significant daytime desaturations, have been noted in several studies 19, 20 . Due to the variable nature of such desaturations, nocturnal pulse oximetry needs to be implemented for more than one night to detect them at an early stage 21 . Additional findings suggest that desaturations during NREM sleep contribute to brain impairment in COPD 22 . Patients with interstitial lung disease (ILD) also exhibit sleep desaturations and are particularly vulnerable during REM sleep 23 . This may lead to poor sleep quality and interfere with sleep regenerative mechanisms even in the absence of a coexisting sleep disorder. Regular use of nocturnal pulse oximetry to monitor breathing in the management of ILD has been advocated, and the role of TcPCO2 as well as the impact of additional intermittent hypoxia in these already chronically hypoxic patients is a research priority 23 . A high prevalence of sleep hypoxemia, which aggravates pulmonary arterial hypertension, has been reported in patients with precapillary pulmonary hypertension. As daytime SpO2 is not a reliable predictor of sleep hypoxemia 24 , nocturnal pulse oximetry has been suggested as part of routine evaluation of this patient population 25 . To expand the diagnostic potential of sleep ventilation assessment, Levy et al. 26 developed the first standardized toolbox for continuous oximetry time series analysis using digital oximetry biomarkers and recently demonstrated the feasibility of COPD diagnosis using nocturnal oximetry 27 . Thus, sleep respiratory monitoring in chronic respiratory conditions such as COPD and ILD, may be the optimal modality for early detection of disease progression and decompensation, enabling timely, disease-modifying intervention. Nocturnal pulse oximetry has been extensively used in the management of bronchiolitis, although its role in the management of this common infectious condition is a subject of debate. Transient desaturations (even to 70% or less) are commonly observed in infants with bronchiolitis after discharge, but their clinical significance remains unclear 28 . The lack of clinically proven benefits of this practice, alongside concerns regarding unnecessary hospital admissions, prolonged length of stay and additional costs, have resulted in guidelines recommending its limited use 29 . Thus, the complexity in interpreting nocturnal oximetry patterns in infants warrants the development of oximetry digital biomarkers and of their association with defined clinical endpoints, such as readmission, enabling leverage of this important tool to detect sleep desaturation patterns which reflect a more severe condition. Evaluation and monitoring of nocturnal BP is of paramount importance for diagnosis and management of hypertension and its complications. Masked nocturnal hypertension is a well-established phenomenon, referring to patients who only exhibit abnormal hypertensive values overnight 30 . Specific patterns of nocturnal BP are associated with several cardiovascular adverse outcomes, including cardiac remodeling and all-cause mortality, and are recognized as better predictors of these outcomes compared to daytime BP 12 . Furthermore, nocturnal BP monitoring may be important to evaluate before administration of bedtime hypertensive medication in certain patient populations 12 . BP can be non-invasively recorded by intermittent cuff measurements during nighttime, but this technique is usually disturbing and yields only point measurements. Nowadays, several validated devices for non-invasive continuous BP measurement are available 31 . In addition, the pulse-transit-time, a measurement based on the time delay of the pulse wave between two arterial sites, has been shown to accurately reflect dynamics as well as absolute values, to some extent, of BP 32 . Although nocturnal BP is considered a critical tool for diagnosis and risk stratification in hypertensive patients, its current classification is limited to a small number of patterns, based on maximal/minimal values of systolic BP. A more extensive analysis of continuous nocturnal BP measurement could yield more insights into the pathophysiology of this ubiquitous condition. In clinical practice, there are a few instances where nocturnal ECG is recorded, e.g., Holter ECG, single-lead ECG in polysomnography (PSG) and in cases of implanted pacemakers. In a recent research of ours 33 , we demonstrated that over 22% of individuals with undiagnosed atrial fibrillation could be identified by opportunistic data-driven nocturnal screening of the ECG traces recorded in regular PSG studies. Research has also shown that atrial fibrillation events may be more frequent during sleep than daytime 34 , but this may not be case for other cardiac abnormalities 35 Overall, there is a basis of research suggesting that ECG monitoring during sleep may provide clinical value in certain diagnostic scenarios. The fetal heart rate trace is used as a nonstress test to assess fetal well-being. Clinicians and engineers have been researching ways to remotely monitor fetal well-being to better manage complicated pregnancies. Continuous monitoring with cardiotocography (minutes to 1 hour) may be needed to assess the fetal health in the Dawes Redman analysis 38 . The non-invasive fetal ECG is an alternative recording technique that involves placement of ECG electrodes on the maternal belly to measure both maternal and fetal electrical activity of the heart. From the mixture of signals, the fetal ECG and heart rate may be estimated. Yet, although this technique has been around for decades, with incremental improvement over time, it still faces important challenges, including its high sensitivity to noise, which impairs its clinical implementation. In a recent work, Huhn et al. 39 showed that the success rate of obtaining the fetal heart rate trace from a non-invasive fetal ECG was twice higher in nighttime than daytime recordings. This is because of the reduced movement-induced noise during sleep in comparison to daytime. This example highlights how monitoring during sleep previous chronotherapy trials were the highly generalized patient selection and lack of personalized medicine and genetic profiling. Today, the application of genetic information in personalized cancer medicine has transformed cancer care and is also being studied in the context of chronotherapy, far beyond chemotherapy. Chronomodulated regimens, including nocturnal regimens, of targeted kinase inhibitors, such as alpelisib, lapatinib, sunitinib and erlotinib, which are used for personalized cancer treatments, have shown substantial benefits in multiple animal models as well as in patients [83] [84] [85] . For example, nocturnal administration of alpelisib, a PI3K inhibitor recently approved for breast cancer, was associated with better control of glycemia and with a better clinical outcome compared to daytime administration 86 . Several studies have also explored chronomodulated radiotherapy or nocturnal radiodosing in cancer patients. While no clear conclusions regarding efficacy has been reached, due to mixed results of recent trials, it seems that gender and genetic profiles may be determinants of the toxicities and response rates of chronomodulated dosing schemes (e.g., women seem to benefit more from chronoradiotherapy) [87] [88] [89] . Consequently, cancer therapy during sleep is a rapidly expanding field, with promising breakthroughs in both tumor response to therapy and adverse effect profiles, and is becoming an important aspect of personalized cancer therapy. Light pollution at night from external lighting systems in big cities or from smartphone/computer screens, may be responsible for several public health issues as it impairs the circadian clock's normal resynchronization 90 . It has been reported that night exposure to artificial light inhibits the production of melatonin. In addition, a higher risk of obesity, diabetes, cardiovascular disease, depression, sleep disturbances and cancer has been observed in shift workers [91] [92] [93] . Intensive care units (ICU), which, in most cases, are under constant light intensity, represent a particularly stressful environment. This is postulated to contribute to ICU delirium, an acute brain dysfunction associated with increased mortality, prolonged ICU and hospital length of stay, and development of post-ICU cognitive impairment 94 . Interventions to reduce this risk and improve patient recovery using lighting systems that mimic the day-night cycle, successfully diminished adverse circadian dyssynchronization-related outcomes 95 . Further investigation of the effect of light exposure (e.g., intensity, light spectrum and rhythms) on human health will support additional circadian-oriented modifications of the healthcare environment. • Diagnosis of chronic respiratory conditions such as COPD and ILD, and early detection of respiratory decompensation prior to daytime manifestations, possibly representing a preventable cause of further disease aggravation. • Management of bronchiolitis by characterization of unfavorable sleep respiration patterns. Machine learning algorithms may be able to identify high-risk patients and reduce unnecessary hospital admissions. • Diagnosis of masked nocturnal hypertension, characterization of nocturnal BP patterns. Specific nocturnal BP patterns are associated with higher risk for adverse outcomes, and contribute to the choice of medical management of hypertension. • Diagnosis of arrhythmias manifesting during sleep prior to development of symptoms. Machine learning algorithms may be harnessed to analyze recordings and recognize patterns. • Diagnosis of glaucoma subtypes in which elevated IOP tends to manifest exclusively during sleep. • Evaluation of response to therapy in patients which progress despite normal office IOP readings. • Early initiation of nocturnal non-invasive ventilation may delay disease progression and extensive need for ventilation in conditions such as chronic lung disease, neuromuscular disease and cystic fibrosis. • Potential non-respiratory benefits of CPAP include decrease in hypertension and better glycemic control in OSA patients. CPAP is being considered for additional clinical scenarios due to its potential systemic advantages. • In rheumatoid arthritis, nocturnal release of prednisone aims to target circadian inflammatory processes. • In hypertension, nocturnal administration of ACE inhibitors is associated with improved BP control, reduced doses and fewer side effects. • Several chemotherapeutic drugs including 5-fluorouracil, irinotecan, doxorubicin and most platinum-based drugs exhibit reduced toxicity when applied at nighttime. • Chrono-modulation of chemotherapy, radiotherapy and immunotherapy is expected to become a cornerstone of personalized cancer therapy. Another significant challenge arises from the interventional aspect of this paradigm. While non-invasive measurements can be quickly tested in humans, therapeutic interventions require substantial pre-clinical data in animal models. Research of circadian interventions is particularly complicated, since most common pre-clinical models are based on rodents which are nocturnal, with a very different circadian clock than humans. Therefore, effective pre-clinical testing of such interventions will require use of a non-nocturnal mammalian model (e.g., dogs) or implementation of genetic tools to explore the human circadian clock in transgenic or knock-in mice that recapitulate human genetics. Robust measurement and analysis tools will enable further study of the association between simultaneously measured signals, such as IOP, ICP, cardiovascular and respiratory biomarkers. Deciphering such complex interactions may contribute to a better understanding of pathophysiological processes and their optimal management. Glaucoma is one promising example, where such associations might yield further pathophysiological insights and enable the elaboration of a better diagnostic standard and patient-tailored treatment. Broadening our knowledge of pathophysiological patterns during sleep may enable harnessing of machine learning algorithms to support screening strategies in selected populations. For example, opportunistic nocturnal screening for hypertension, atrial fibrillation 33 or COPD 27 , may be performed in high risk patient populations. In cancer treatment, chrono-modulation is expanding and is being increasingly explored for novel therapeutic modalities. Studies of the tumor microenvironment have revealed that both CD4 and CD8-T cell levels are correlated with core clock molecules 96 , suggesting that chrono-immunotherapy may represent a promising option for future cancer treatment, as well as for other indications 97 . Sleep specialists will play a critical role in the advancement and clinical implementation of sleep-centered diagnostic and therapeutic approaches. 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All authors have contributed to the writing of this manuscript. All authors have declared no conflict of interest.