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The Beauty of Sleep

Early to bed, early to rise, makes a man healthy, wealthy, and wise. The 200-year-old adage got it right—almost. “I might change it to healthy, happy, and wise, but it is more than just an aphorism—it is a medical and scientific reality,” says Robert Stickgold, Ph.D., director of the Center for Sleep and Cognition at Beth Israel Deaconess Medical Center. “You can’t be healthy, you can’t be happy, and you can’t be wise without adequate sleep.”

Sleep is one of the three pillars of health along with diet and exercise; however, we pay little attention to the nighttime activity when it comes to improving overall well-being. “I think sleep is overlooked,” says Janet Mullington, Ph.D., director of the Harvard Catalyst Clinical Research Center at BIDMC and president of the national Sleep Research Society. “There has been a lot of emphasis on nutrition and exercise, and we know that those are important for your heart and metabolic health, but sleep is very much related to the regulation of health maintenance systems as well.” In the last 20 years, with improvements in technology, data has shown that restricted or interrupted sleep can lead directly to health concerns such as obesity, diabetes, heart disease, hypertension, and cognitive and emotional dysfunction.

Researchers and clinicians at BIDMC are among the most prominent in the sleep field, and with generous philanthropic support from foundations such as The Periodic Breathing Foundation, LLC, American Heart Association, and Wake Up Narcolepsy, they are currently investigating new lines of inquiry that will change the way we view sleep and how we treat some of its most devastating diseases. “BIDMC has one of the leading sleep programs in the world,” says Clifford Saper, M.D., Ph.D., chief of the Department of Neurology. “There aren’t many other groups with as much firepower in the sleep field as we have here. It is really one of our greatest strengths.”

Clifford Saper, M.D., Ph.D.

Clifford Saper, M.D., Ph.D.While there are a number of sleep disorders, like narcolepsy, sleep apnea, and insomnia, that cause people to sleep less, one of the major causes of sleep loss is when people actively restrict their own sleep by staying up too late. When you stay awake for an extra hour in bed watching TV or reading e-mails on your iPad, you inadvertently throw off your circadian clock, which can have a devastating effect on your metabolism. “Your body has clocks all over the place, including in the tissues of the gut and the liver,” explains Clifford Saper, M.D., Ph.D., chief of the Department of Neurology and one of the foremost experts on circadian rhythm. “The clocks are aligned to metabolize food relatively efficiently. If you throw off the circadian clock, you misalign the times that you eat with the peak levels of your gut being ready to receive food and metabolize it.” When you do eat, your body is not prepared to use the sugar properly and results in an increase in blood glucose and ultimately a pre-diabetic state. Also, the sugar that is not metabolized is converted to fat.

Saper, a former president of the Sleep Research Society (SRS) and recipient of the 2012 Distinguished Scientist Award from the SRS, is investigating the circuitry in the brain that regulates the way we cycle between wakefulness and sleep over the course of a day. He and his team recently published a controversial paper based on mouse model research, which hypothesized that disrupting the circadian clock was far more damaging to the metabolism than the loss of sleep alone. Understanding how sleep affects metabolism could have far-reaching implications for weightloss techniques. “Currently, we are seeing an epidemic of obesity in our society, and we think that it is related to an epidemic of people restricting sleep,” he says. The Center for Mind-Brain Restoration at BIDMC is a leading clinical and research presence in the sleep field investigating ways to help people improve their health through better sleep. Saper says, “Support will allow us to bridge that gap between the basic animal experiments and clinical application.”

Tom Scammell, M.D.

Tom Scammell, M.D.A decade ago, little was known about narcolepsy, a sleep disorder characterized by lifelong sleepiness and cataplexy (brief episodes of muscle paralysis). “People with narcolepsy are tired every day—no matter how much sleep they get at night, no matter how good the quality of their sleep,” neurologist Tom Scammell, M.D., says of his patients. The extreme sleepiness impacts the ability to pay attention at school or work, in the car, and in social situations, while episodes of cataplexy affect quality of life. Between 2000 and 2005, Scammell and other researchers made a series of major breakthroughs when they demonstrated that the disorder is caused by the death of orexin-producing nerve cells in the hypothalamus. The orexins are signaling molecules that normally promote wakefulness and regulate rapid-eye movement (REM) sleep. In the absence of orexins, the wake-promoting brain regions are under-active, causing ill-timed transitions from wakefulness to sleep and intrusions into wakefulness of REM sleep elements, such as paralysis or hallucinations. These discoveries provided a target to further investigate the troublesome disorder.

Recently, Scammell uncovered new information that may have therapeutic potential for patients. He and his team found that narcolepsy patients have 94 percent more histamine-producing neurons than healthy patients. Histamine is a chemical that promotes wakefulness. Anti-histamine medications, like Benadryl, block histamine signaling in the brain and the result is often drowsiness. “We think that when the orexin neurons die, the histamine-producing neurons undergo a major change to produce more histamine,” says Scammell, who was named Researcher of the Year by the Narcolepsy Network in recognition of this new discovery. “We think it is a compensatory response, and the brain is doing its best to rebalance.” When narcolepsy begins in children, parents often notice an immediate and dramatic increase in their child’s sleep. Over the next several months, sleep then returns to normal amounts as the brain compensates for the neurological dysfunction. “I have no lack of patients with narcolepsy in my clinic, and seeing those patients informs us how to do better basic research to really drill in and understand what is going wrong in the brain and how can we fix it,” says Scammell, whose research has been funded by Wake Up Narcolepsy, a nonprofit organization focused on narcolepsy research and awareness. Drugs that enhance histamine signaling are already in development and could potentially improve the quality of life for thousands of narcolepsy patients worldwide.

Janet Mullington, Ph.D.

Janet Mullington, Ph.D.One of the more dangerous side effects of sleep deprivation or fragmented sleep is the impact it can have on your heart and vascular system. Research has shown that shortened sleep leads to an increased risk for the development of cardiovascular disease, including hypertension. At BIDMC’s Clinical Research Center, Janet Mullington, Ph.D., and her colleagues study the cardiovascular and immunologic effects of sleep loss in simulated real-life situations, such as five days of sleep restriction followed by two days of recovery sleep to mirror a typical work week.

Building on the established evidence that sleep loss increases blood pressure, particularly in individuals who already have elevated blood pressure, Mullington and her colleagues took a new approach. With support from the American Heart Association, they conducted a small pilot study to investigate the results of extended sleep on pre-hypertensive and hypertensive individuals. “A lot of people don’t want to take medication for their hypertension or would rather try a behavioral approach with diet and exercise,” says Mullington. “If we can add sleep to that approach, it is a very simple intervention that could help significantly.” Subjects who were able to extend their sleep for half an hour a night over six weeks saw a significant decrease in their blood pressure compared to those who maintained their normal sleep period.

The preliminary results of this research suggest future investigations might determine whether behavioral interventions are an effective strategy to treat hypertension, but additional support is necessary. “There are not always enough resources to fund the more exploratory or more exciting new initiatives,” says Mullington. “I think philanthropy can really help jump-start an area of translational science by helping provide resources where the logic is clear, but there’s not a lot of preliminary data.”

Robert Thomas, M.D.

Robert Thomas, M.D.A decade ago, Robert Thomas, M.D., a sleep clinician and researcher in the Division of Pulmonary, Critical Care, and Sleep Medicine, noted that a number of sleep apnea patients in the BIDMC Sleep Disorders Clinic struggled with traditional therapies which were documented to be effective in the sleep laboratory. Sleep apnea may be caused by an obstructed airway, known as obstructive apnea, or breathing rhythm abnormality, known as central apnea. Thomas’s patients did not fit perfectly into either category but showed patterns of respiratory control dysfunction during non-rapid eye movement (non-REM) sleep that were exaggerated by positive pressure treatment, which Thomas called “complex apnea.” In time, this entity has seen gradual acceptance, including FDA-approved therapies covered by insurers.

Thomas argued that these patients have a highly activated respiratory chemoreflex, which means that the breathing control system for sensing oxygen and carbon dioxide is too sensitive and causes fluctuations in breathing. In response, with generous support from The Periodic Breathing Foundation, the family foundation of grateful patient Robert Daly and his wife, Mary, Thomas and Daly developed a device to manipulate and control the carbon dioxide levels while using positive pressure to help stabilize breathing control in his patients.

Recently, however, he and Daly, who have continued to collaborate, wondered if this problem could be much larger, affecting patients not only at night while they sleep, but also during the day. “When your breathing control system is over-activated, there is higher blood pressure, faster heart rate, more anxiety, and more stress responses,” he says. “We think that these patients who have complex apnea are probably at risk over the long term of having more hypertension, more atrial fibrillation, probably more anxiety, and maybe a higher risk of stroke or heart attack because of blood vessel dysfunction.” Thomas’s research shows that approximately 30 percent of the population over the age of 60 has a highly activated chemoreflex, and similar percentages have been reported recently by others. Daly recently contributed an additional $100,000 to support a new clinical and research program called the Program in Chemoreflex Medicine to collect preliminary data to test this theory. This initiative has also received funds from the Research Innovation Initiative, meant to support translational and multidisciplinary studies, and spearheaded by BIDMC’s chief academic officer Vikas P. Sukhatme, M.D., Ph.D. Thomas says, “If you can successfully manipulate the respiratory chemoreflex, at a minimum you can change outcomes in hypertension and heart failure.”

Robert Stickgold, Ph.D.

Robert Stickgold, Ph.D.Pulling an all-nighter before a big exam in order to cram in as much studying as possible might have seemed like a good idea at the time, but research now shows that a night of sleep might produce a better result. “Most people feel like the only reason they need to sleep is because otherwise they will be tired in the morning,” says Robert Stickgold, Ph.D., director of the Center for Sleep and Cognition. “But my mother was right. If you don’t get enough sleep, you are going to end up sick, fat, and stupid.” Stickgold contends that sleep is necessary for a number of biological reasons, including consolidation of memory. He argues that while you are sleeping your brain appropriately files memories from the day so that the relevant information will be easier to find the next morning. “Sleep actually enhances those memories,” Stickgold says. “It makes them stronger and more stable.”

Stickgold and his team have developed and executed different experiments to support the theory of memory consolidation. Participants are first tested to establish a baseline response to various motor, visual, or auditory tasks and tested again hours later either after a period of sleep or wakefulness. The results of the tests are significantly better following sleep than following wakefulness. “The phenomenon people will talk about is ‘I was working on this piano piece, and I couldn’t get it quite right. I finally gave up, came back the next day, and played it perfect the first time.’ That is the sleep-dependent process of memory enhancement,” Stickgold says.

But exactly what is going on during sleep to improve memory is still unclear. Evidence has shown that cognitive function deteriorates in the absence of sleep. One theory held by Stickgold and Harvard Medical School doctoral student Neal Dach is that during sleep the brain is restored or “recalibrated” thus leading to improved cognitive performance. An anonymous donor recently contributed $335,000 to the Stickgold Sleep Research Program to further explore this idea.

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