Division of Sleep Medicine, Department of Medicine, Brigham and Women's Hospital and Division of Sleep Medicine, Harvard Medical School, MA
Sleep disorders and sleep deficiency are important causes of adverse health effects and increased mortality in the United States and worldwide.1 Sleep deficiency can also result in myriad adverse behavioral consequences, including profound sleepiness, cognitive slowing, automatic behavior, attentional failures and performance degradation, errors, and accidents.2–4 It is important to recognize that sleepiness and sleep deficiency are not synonymous. As defined in a draft of the 2011 NIH National Sleep Disorders Research Plan, sleep deficiency is a “deficit in the quantity or quality of sleep obtained vs. the amount needed for optimal health, performance, and well being. Sleep deficiency may result from prolonged wakefulness leading to sleep deprivation, insufficient sleep duration, sleep fragmentation, or a sleep disorder, such as in obstructive sleep apnea, that disrupts sleep and thereby renders sleep non-restorative.” (See footnote at end of this article.) Daytime sleepiness, or drowsiness, is a non-specific symptom that can be a sign of sleep deficiency (due to acute sleep loss, chronic insufficient sleep or chronic sleep disruption due to a sleep disorder), misalignment of circadian phase (as occurs in night shift work or following transmeridian travel), a fatigue-inducing illness (such as mononucleosis or cancer), neurovestibular stimulation (as occurs in Sopite's Syndrome), or a soporific medication (such as an antihistamine).58–9 Current methods to assess sleepiness and sleep deficiency are inadequate, and little effort has been made to distinguish between the two.
Why is it important to develop better biomarkers of sleepiness and sleep deficiency? First, identification of sleepiness and sleep deficiency biomarkers may provide insights into the yet unsettled issue of the function of sleep—the most fundamental, unsolved question perplexing sleep researchers.10–16 Why do we need to spend a third of our lives asleep? Increasing evidence suggests that sleep may serve (or at least affect) myriad bodily functions. While it was taken for granted for many years that sleep was most important to brain function, there is now increasing evidence to suggest that sleep is important for the rest of the body as well. Sleep deficiency degrades immune, cardiovascular, and metabolic function.1 Experimental sleep restriction results in insulin resistance, carbohydrate craving, increased caloric consumption, and decreased immune responsivity.17–22 Habitually short sleep durations are associated with adverse health outcomes such as glucose intolerance, obesity, diabetes, susceptibility to infection, hypertension, and cardiovascular disease.23–31 A biomarker could thus identify those at risk of adverse health outcomes due to chronic sleep deficiency. Moreover, the pathophysiology linking sleep deficiency to those health consequences could be more easily explored if there were an easily measurable biomarker for sleep deficiency.
A biomarker for sleepiness could be used to identify those at risk of errors, injuries or motor vehicle crashes due to sleep deficiency, circadian misalignment, sleep disorders, pharmacologic agents, illness, or neurovestibular stimulation (vide infra). If the biochemical changes that herald the onset of sleepiness can be uncovered, better countermeasures could be developed to mitigate the adverse effects of sleepiness.
The direct precipitant to this conference was the 2002 fatal crash caused by a 19 year-old male who had been awake for 24 hours after having been up all night playing video games. His car crossed the median and struck another vehicle, killing its occupant.32 This led legislators to begin drafting a law making drowsy driving a crime in Massachusetts. However, the problem of drowsy driving is not limited to Massachusetts; it is pervasive throughout the entire United States. Every day, there are a quarter of a million drivers who by their own admission fall asleep at the wheel in this country according to statistics that have been collected by the National Highway Transportation Safety Authority. There is a drowsy-driving crash twice a minute and 1.2 million drowsy-driving crashes a year. There are 500,000 drowsy-driving injuries annually and there is a debilitating injury every 10 minutes and a drowsy driving fatality nearly every hour, accounting for about 20% of all crashes that cause serious injuries by an Institute of Medicine estimate.1,33 This is an epidemic. It is particularly common in young people, because, in this age group, the brain circuits that regulate sleep are working at their best. That is why young people generally do not need to take a hypnotic to go to sleep at night. The sleep switch in the ventrolateral preoptic area of the hypothalamus typically works optimally in young people. However, with increasing age, the sleep switch often deteriorates. As we age, approximately 50% of the neurons are lost in that area of the brain. Because of this loss, it has been hypothesized that as we age, it becomes harder for a great enough number of those cells to fire simultaneously for the sleep switch to “ignite,” which is required for the brain to make the transition from wakefulness to sleep. Ironically, staying awake all night impairs the performance and reaction time of healthy young far more than it does that of healthy older people. By the end of an overnight vigil, at a time when most night shift workers would be commuting home, the average reaction time of healthy young adults is almost three times longer than that of older adults—adding more than a full second to the time it takes for young adults to respond to a stimulus in the visual field.34 Young adults also suffer nearly twice as many attentional failures and double the number of involuntary sleep episodes while struggling to stay awake at that time.34 That may be why young drivers have many more drowsy driving crashes than older drivers do.35
Despite the large numbers of drowsy-driving related injuries and fatalities in the United States, only the state of New Jersey has a law that equates driving when sleep deprived (operationally defined as being awake for 24 hours) with being “reckless,” placing it in a similar category as driving under the influence of alcohol. Nonetheless, prosecutions for drowsy driving have occurred in a number of jurisdictions with widely disparate outcomes. On the one hand, an individual who had been awake for most of the weekend, admittedly fell asleep and drifted across the median while driving, and caused the tragic death of a truck driver who careened off the Chesapeake Bay Bridge while trying to avoid colliding with her, faced no criminal charges because the local prosecutor did not consider drowsy driving to be negligent.36 On the other hand, a truck driver who had been awake for 32 hours, fell asleep at the wheel and killed three people who were waiting for a light to turn green, is serving a 15-year sentence in Florida State Prison.
Efforts to implement drowsy driving legislation in Massachusetts are being led by Massachusetts State Senator Richard Moore. One of his major concerns in developing this legislation was how to identify drowsy drivers. He argues that if there were a breathalyzer test for sleep propensity or sleep deficiency, like that used to estimate blood alcohol concentration, then passage of such legislation would be much more likely. Obviously, such an instrument is not currently available, but identification of strategies to develop an easy-to-use field test to identify drowsy drivers or individuals who are suffering from sleep deficiency or elevated sleep propensity that make them a danger to themselves or others while operating a motor vehicle is an ultimate goal of this conference.
What are the challenges for identifying a biomarker of sleepiness or sleep deficiency? The most important is having an understanding of the goal to be achieved. Is it identification of those at-risk for occupational injuries or drowsy-driving crashes? Is it identification of those at-risk for adverse health effects of chronic sleep deficiency? It is now known that sleep deficiency can have effects on learning and memory, risk of psychiatric illnesses such as depression, and physical health risks such as obesity, diabetes, and infection. Thus, there may be separate biomarkers associated with the impact of sleep deficiency on each of those various conditions. Moreover, given that there are inter-individual differences in the impact of sleep deficiency on performance, there are likely inter-individual differences in the impact of chronic sleep deficiency on each of the adverse health outcomes associated with sleep deficiency.
In discussions regarding a sleep-related biomarker, it is very important to realize that sleepiness can be transient and easily affected by environmental stimuli, whereas chronic sleep deficiency is not. You can be sleep deprived; you can have stayed up all night, but if you've drunk enough coffee, taken enough wake-promoting therapeutics, or are suddenly frightened (as in the case of a motor vehicle crash), you may not be sleepy even though you are deficient of sleep. Therefore, it is important to separate these concepts. However, even though a sleep deficient person may not be sleepy, the sleep deficiency is likely to have adverse health and safety consequences.
An example of how sleep deficiency can produce an adverse impact even when sleepiness is being treated can be observed in a recent study by Buxton and colleagues.21 It this study, modafanil or a placebo was given to chronically sleep deprived participants. Modafanil was effective in mitigating sleepiness in these participants, but had no benefit in reversing the changes in cortisol secretion or the adverse effects on glucose metabolism caused by the chronic sleep restriction. Another example can be derived from the observation that 50% of persons with significant obstructive sleep apnea on polysomnography are not sleepy.37 However, the absence of sleepiness does not appear to confer protection against the putative metabolic consequences and cardiovascular effects of the disorder.38 Many other similar examples can be found as well.
To complicate matters, in addition to understanding the concept that sleep deficiency does not equate only to sleepiness, it is important to realize that there are different types of physiologic constructs that may make someone drowsy or deficient of sleep. In one scenario, an individual may be acutely sleep deprived and recover relatively quickly from the acute sleep deprivation, at least in terms of performance. Alternatively, an individual may be chronically sleep deprived as a consequence of sleeping only four, five, or six hours per night for many consecutive nights. In the latter case, it takes much longer to build up the impairment and also much longer to recover. To track the different time courses of those recovery processes may require monitoring different biomarkers. It also is known that misalignment of circadian phase causes drowsiness, but a different set of biomarkers may be required to track that effect. Moreover, it is possible that repeated sleep disruptions or interruptions, such as occur in obstructive sleep apnea or with repetitive intrusion of loud noise, might be represented by other biomarkers.
In summary, biomarkers are needed for both sleepiness and other manifestations of sleep deficiency. We need to be cognizant of the different mechanisms by which sleepiness or sleep deficiency might come about. It is known that the impact of sleep-related performance impairment can be profound in that sleep deprivation can impair neurobehavioral performance by an amount that is equivalent to a blood-alcohol concentration of 0.10%39; thus, it is important that markers be developed to quantify the extent to which performance is impaired by sleep loss. It also is important to develop sleep biomarkers to assess the consequences of sleep deficiency on other aspects of health.
Dr. Czeisler has received research support from Cephalon, Koninklijke Philips Electronics, N. V., ResMed, and the Brigham and Women's Hospital; has received consulting fees from or served on the advisory board of Actelion, Bombardier, Boston Celtics, Cephalon, Delta Airlines, Eli Lilly, Garda Siochana Inspectorate, Global Ground Support, Johnson – Johnson, Koninklijke Philips Electronics, N. V., Minnesota Timberwolves, Norfolk Southern, Portland Trailblazers, Respironics, Sepracor, Sleep Multimedia, Somnus Therapeutics, Vanda Pharmaceuticals, and Zeo; he owns an equity interest in Lifetrac, Inc, Somnus Therapeutics, Vanda Pharmaceuticals, and Zeo; has receive royalties from the Massachusetts Medical Society/New England Journal of Medicine, McGraw Hill, The New York Times Penguin Press, and Philips Respironics; has received lecture fees from Cephalon; and is the incumbent of an endowed professorship provided to Harvard University by Cephalon and holds a number of patents in the field of sleep/circadian rhythms. Since 1985, Dr. Czeisler has also served as an expert witness on various legal case relayed to sleep and/or circadian rhythms.