6

Advancing Sleep and Circadian Research, Education, and Clinical Care

To conclude the workshop, Clifford Saper asked a diverse group of stakeholders across different sectors to give their perspectives on the most important insights that emerged. In this chapter, their comments are integrated with comments expressed throughout the course of the meeting on research opportunities and gaps.

RESEARCH OPPORTUNITIES

Marishka Brown, director of the National Center on Sleep Disorders Research, reiterated that sleep is not just important, but essential to health and well-being. She noted that the American Heart Association added sleep duration as one of Life’s Essential 8™¹ key measures for improving and maintaining cardiovascular health and lowering the risk of heart disease, stroke, and other health issues. However, Brown noted that in addition to sleep duration, other sleep dimensions are also important, such as sleep quality and timing of sleep.

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¹ To learn more about the American Heart Association’s Life’s Essential 8, go to https://www.heart.org/en/healthy-living/healthy-lifestyle/lifes-essential-8 (accessed January 3, 2023).

In December 2021, the National Institutes of Health (NIH) published the NIH Sleep Research Plan,² which established five strategic goals to advance the science of sleep and circadian research, said Brown. Goal one, she said, is to elucidate sleep and circadian mechanisms underlying health and disease. The plan includes tactics to address the five goals as well as critical research opportunities.

Tiffany Schmidt opined that improving the field’s fundamental understanding of the circuits that regulate sleep and sleep disorders should be one of the highest priorities. That generalizable knowledge could provide insight into tackling Alzheimer’s disease and other diseases as well, she said. Morten Grunnet, vice president and head of neuroscience at Lundbeck, agreed, but added that there may be different circuitry driving sleep disturbances in different diseases or indications. Understanding the specific circuitry associated with sleep disturbances in Parkinson’s or Alzheimer’s disease “could be the next leap forward,” he said.

The field also needs to establish what type of sleep matters most, said Brian Fiske. Dara Manoach said different sleep stages are important for different forms of memory. For example, rapid eye movement (REM) sleep may be more important for consolidating emotional memory, while non-REM stage two sleep may be more important for procedural memory. Ashura Buckley added that the time spent in various sleep stages changes with development, with REM sleep much more heavily weighted toward the first 3 to 4 years of life. “Sleep is probably doing something fundamentally different as language and motor fluency are coming online than in the adult brain,” she said. However, Andrew Krystal said that studies over the past three decades suggest that altering the amount of REM or non-REM sleep does little to affect how people perceive improvement of their insomnia. “What seems to correlate most with that is things like how long it takes you to fall asleep, how much time you’re awake in the middle of the night, and your total sleep time,” he said. In turn, the Food and Drug Administration (FDA) accepts those kinds of endpoints to assess treatment effectiveness, said Krystal.

From a basic science perspective, Amita Sehgal emphasized the need for research to understand the cellular and molecular basis of homeostatic sleep drive, which could provide clues about its function. Understanding the altered regulation of sleep during sickness could also elucidate how sleep contributes to disease susceptibility, she said. Genetic, cellular, circuit-level, and systems-level research will be needed to pursue these research questions, said Sehgal, as well as cross-talk among different models—for exam-

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² To learn more about the NIH Sleep Research Plan, go to https://www.nhlbi.nih.gov/sleep-research-plan (accessed January 3, 2023).

ple, zebrafish, flies, and mice. Standardizing methodology and determining how to align results from different models will be important, she said.

Buckley added that sleep neurophysiology has enormous potential but is underleveraged in neurobehavioral pediatrics and neuropsychiatry. “Convergent science³ is the only way to get there,” she said.

UNDERSTANDING CURRENT RESEARCH GAPS

Throughout the workshop, several participants noted that sleep deficiency affects every thread of society, said Michael Twery of the Alliance of Sleep Apnea Partners. Workshop participants explored opportunities to advance research to reduce the prevalence of sleep deprivation and sleep disorders, develop interventions to mitigate the health effects associated with insufficient sleep and sleep disorders, and promote greater recognition of this problem among the public.

Andrew Varga quoted J. Allan Hobson, who famously wrote that sleep is “of the brain, by the brain, and for the brain” (Hobson, 2005). “So, it stands to reason that sleep disorders disproportionately affect neurological and psychiatric disorders,” said Varga. The onus on the clinical community is to identify and address the sleep phenotypes within these disorders, he said. In addition, a better understanding is needed of how circadian rhythms and circadian dysfunction affect the trajectory of these disorders or their response to treatment, said Varga.

Given that many of the drugs used to treat insomnia are used off label, and not approved for this indication, there is a need to generate data to test their efficacy in the treatment of insomnia, said Louis Ptáček. Comparative studies of available drugs would be interesting, said Margaret Moline, and might be accomplished through a consortium of academic, clinical, and pharmaceutical partners. Manoach noted that there is a potential disincentive for industry in that studies might not support the use of a drug or could identify untoward side effects.

The potential of several new technologies to assess circadian rhythms, brain electrodynamics, and sleep parameters such as sleep efficiency were introduced in Chapter 5 as tools that could improve the specificity of treatments. To realize this potential, however, Nathaniel Watson noted that it will be essential to demonstrate that the use of these technologies as tools in medical decision making improves outcomes for people.

Sehgal pointed out that some topics were not addressed in the workshop but warrant further research. These include local sleep, or sleep

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³ Convergent science is “an approach to problem solving that cuts across disciplinary boundaries. It integrates knowledge, tools, and thought strategies from various fields for tackling challenges that exist at the interfaces of multiple fields” (NRC, 2014).

restricted to one part of the brain; situations where homeostatic regulation may not occur; and sleep under natural conditions, for example, in settings that recapitulate hunter-gatherer populations where there is no electricity.

POTENTIAL OPPORTUNITIES TO ADVANCE SLEEP RESEARCH AND TREATMENT

Karla Dzienkowski, executive director of the Restless Legs Syndrome Foundation, cited several opportunities for improving the diagnosis and treatment of individuals with sleep disorders:

• Recognizing sleep as an essential life function or even as a new vital sign that should be measured in the delivery of health care.
• Implementing teaching of sleep disorders in the core curriculum of primary health care providers across disciplines.
• Screening patients annually for sleep disorders, for example, by including a short sleep questionnaire at primary care visits.
• Training health care providers to use consumer technology devices as a secondary sleep screening tool.
• Implementing strategies to prevent risk factors associated with sleep loss, including hypertension, diabetes, cardiovascular disease, obesity, and depression.

Improving Sleep Education and Sleep Hygiene Across the Life Span

Watson added that sleep education is also needed in general education, beginning as early as elementary school. Fiske agreed, noting the need to improve peoples’ “light hygiene” across the life span through better management of their exposure to light with regular light–dark cycles. However, he acknowledged that if indeed light is an environmental toxin, as some have suggested, changing behavior to convince people to go to sleep earlier or not look at their phones during the night remains a challenge. Varga suggested that one strategy to address this might be providing incentives for people to improve their sleep hygiene, similar to the way some health plans have rewarded people for step counts. Brown added that there are also strategies or approaches that can be learned from the obesity field—how they transformed obesity into a disease that warranted increased support on a national level.

Varga added that for common disorders such as sleep apnea and insomnia, effective treatments are available, yet these conditions are often undiagnosed or not treated appropriately. He advocated for more awareness, education, and advocacy around the topic of sleep disorders, including addressing the disparities discussed in Chapter 2.

Improving Clinical Care of Sleep Disturbances

A broader issue, according to Varga, is providing clinical care to people with sleep disturbances, especially considering a nationwide shortage of sleep medicine specialists (Collen et al., 2020). Primary care doctors can order sleep tests and most insurance will cover them, at least when sleep apnea is suspected and often for other sleep disorders such as REM sleep behavior disorder or narcolepsy, said Varga. Yet, he said they are less likely to cover a sleep test for insomnia, and even if they do, finding a cognitive behavioral therapy for insomnia (CBT-I) provider is challenging, even though CBT-I has been shown in many studies to be the most effective treatment.

The shortage of sleep medicine physicians results in part from the minimal attention given to sleep in medical school curricula. As faculty, for example, Varga said he is asked to present the entirety of sleep disorders to first year medical students at his institution in 90 minutes. Expanding that is a very high bar, however, because sleep medicine is one of many specialties trying to reach primary care, said Brown. Watson added that “medical school curricula is a zero-sum game. If you want to put something in, you’ve got to take something out, and the fact of the matter is that we’re the new kid on the block.”

Watson added that to become a sleep doctor requires a one-year fellowship and board certification, but that many of the available fellowships go unfilled, suggesting a lack of interest. However, Saper said many universities teach popular undergraduate courses in sleep, indicating that there is broad interest in the topic.

Dzienkowski noted that sleep has cultural and societal components that need to be challenged, such as the belief that successful people are those who work hard and sleep little. She added that nutrition may be another confounding variable that needs to be controlled in sleep research. Sehgal agreed, noting that the circadian timing of food intake relates to sleep.

Accelerating Discovery of Biomarkers and Other New Technologies

One critical opportunity in the NIH Sleep Research Plan focuses on the identification of sleep and circadian biomarkers, which could lead to better screening tools and tailored interventions, said Brown. “Discovery in this space will be transformative, not only for the sleep and circadian fields, but for public health in general,” she said. The Defense Advanced Research Projects Agency (DARPA) has been funding research programs to develop sensors that can detect the phase of circadian rhythms from various tissues and to develop implantable devices that could deliver peptides that would shift rhythms quickly, said Phyllis Zee.

Multimodal measurements could facilitate a precision medicine approach to addressing sleep disturbances, said Fiske. However, he added that while measurement is getting easier in some ways with wearables and nearables, it is also getting messier.

Technologies that can detect physiological states of an individual’s sleep drive and the functional impact of that are sorely needed, said Matthew Pava. By understanding mechanistically how sleep contributes to better performance, he suggested it might be possible to improve the efficiency of sleep and reduce the degradation of performance. He described one program being pursued by DARPA, the Fatigue Assessment via Breath study, which aims to determine whether it is possible to detect a person’s fatigue status based on molecules present in their breath. Fatigue is important both on the battlefield and in civilian settings where people are driving or operating equipment. Phyllis Zee mentioned that breath metabolites have also been used to assess circadian timing (Brown and Sinues, 2021).

Pava noted that other physiological measures can be used to assess fatigue; for example, loss of muscle tone in the hands is one of the first signs of impending sleep, he said. Zee added that pupillary size is also a good indicator of sleepiness (Junaedi and Akbar, 2018). One of the problems with any of these techniques is how vigilantly they must be monitored, said Pava. For example, for breath analysis to be meaningful, samples might need to be taken at frequent intervals while the person is on task, while pupillometry might provide a more ongoing metric, he said. Going further, Pava said these technologies may also make it possible to disambiguate etiologies of fatigue, whether cognitive, physical, or due to sleep deprivation.

One of the conundrums about sleepiness and fatigue is that people respond very differently to degrees of sleep loss, said Varga. This is especially true in people with sleep apnea, he said. In trying to identify electroencephalogram (EEG) predictors of sleepiness, he and his colleagues have identified a biomarker they call delta SWAK, or the slow-wave activity around a K-complex (Parekh et al., 2021).

Parkinson’s disease researchers have also begun investigating whether measurement of volatile compounds in the sebum (oily secretions in the skin) might provide a useful biomarker (Sinclair et al., 2021), said Fiske. This approach emerged from observations that dogs and even some people can detect a so-called “Parkinson’s smell,” he said. Whether those metabolites might be linked to circadian biology has not yet been studied, he said.

Because of the intense interest among researchers on the potential power of biomarkers, Grunnet said more dialogue is needed with FDA and the European Medicines Agency about how they see alternative endpoints or biomarkers at an early stage of clinical development. “That’s a major bottleneck for us,” he said. Another bottleneck and a challenge for funding comes from the fact that sleep is broadly relevant for health in general, but

there isn’t a direct link to a specific disease targeted by the different funding agencies, said Sehgal.

Validating Methods and Algorithms

Zee emphasized the need for the field to define and establish a minimum set of measures and data that needs to be collected during sleep and wake periods. Vadim Zipunnikov said that it will be important for the community to agree on the best studies to use (e.g., actigraphy vs. polysomnography) and standard validation rules. He added that validation studies should reflect the spectrum of the sleep biome, ranging from healthy controls to the various sleep disorders. Aarti Sathyanarayana added that methods that are data-agnostic will be needed. She added that while consensus about measurement is important for diagnostics and clinical care, for individuals trying to improve their own sleep quality what matters is not how they sleep in comparison to another person, but what is changing in their own sleep patterns. From a research perspective, David Raizen advocated for criteria for what constitutes a sleep state and then using those criteria to study sleep in diverse organisms.

FINAL THOUGHTS

Moving the field forward will require validating recent genetic, molecular, and circuit-related discoveries, said Ptáček, noting that the wide distribution of stakeholders represented at this workshop will facilitate continued progress. Indeed, he said, the good news coming from the workshop is that while many questions remain, the promise of new technologies and analytic tools is high. While many large cohort studies and initiatives are incorporating sleep into their core measures, Snyder noted that a need remains for more large datasets to be shared broadly. “As we begin to understand more about the genetics and biology of normal sleep, there will be other things to measure that will give us accurate measures of both circadian time and sleep quality,” said Ptáček. “We’re far from being there yet, but I think the future holds great promise.”