The big sleep

By Robin Tricoles • Illustrations by Joel Nakamura

Search for alarm clocks on the Internet, and the results will yield a startling array of choices: clocks that ring, chime, and hum. Clocks that glow, shout (a tiny drill sergeant), and fly. Yes, fly. That is, you must get out of bed to squelch its incessant sound. You must cease to sleep.

But what does it mean to sleep? How do we define it? And what happens to our brains when we do so? Apparently, a lot. But we know only a fraction of what this is.

On the surface, it looks as if there’s nothing to it, but actually sleeping is an exquisitely complex process. In humans, sleep involves a series of precise physiologic and chemical transitions that transport us from wakefulness to sleep and back again.

“We spend a third of our lives sleeping, and I don’t think anybody knows why,” says Emory neurologist and scientist David Rye. “Sure, there are the pat answers: neurochemical regeneration and such, but at the end of the day, I don’t think we really know why we sleep even though every organism does it. I mean even worms have rest cycles.”

So do flies. “We’re doing some things here on campus with Drosophila,” says Rye. “You can’t record sleep in flies per se, but you can observe their rest cycles. We know that if we don’t let the fly rest, we’re going to see an increase in rebound rest, rest that makes up for a deficit.” Just like in sleep-deprived humans.

What the stages tell us

Researchers study relatively simple organisms, such as worms and flies, to understand the molecular machinations behind sleep—or the lack of sleep, especially in humans.

“It’s hard to keep humans awake for more than 72 hours,” says Emory pulmonologist Nancy Collop, who directs the Emory Sleep Center. “Even at 48 hours with no sleep, people tend to have microsleeps, very brief bursts of sleep that intrude on wakefulness.” When experts measure brainwaves during microsleeps, the waves look more like sleep than they do like wakefulness. Even when the eyes are open during microsleep, the person is blind because the visual parts of the brain close down.

“Your brain is not one big blob,” Collop says. “In fact, several distinct parts of the brain interact to get us into the sleep state. There are all sorts of interesting things about the transition from wake to sleep.”

One of those interesting things involves the sleep cycle itself, which includes four stages: stages one through three, plus rapid eye movement (REM) sleep. However, the stages do not take place necessarily in that order. Instead, sleep begins in stage one and progresses orderly through the next stages until REM sleep is over, when it returns to stage two. Neurotransmitters, such as serotonin, norepinephrine, and adenosine, govern largely whether we’re awake or asleep.

During stage one, muscle activity slows, and we drift in and out of sleep and can be awakened easily. During stage two, eye movement stops and brain waves slow with intermittent bursts of fast waves, known as sleep spindles. By stage three, very slow brain waves, or delta waves begin, punctuated by small, fast waves and eventually leading to a predominance of delta waves. REM sleep includes eye movement, increased respiration rate, and brain activity, including dreaming.

Although scientists don’t know exactly why, these stages are critical to a good night’s sleep. Evidence of their importance rests in the difference between the sleep state and the comatose state. Although a coma may resemble sleep to observers, the brain waves tell a different story.

The EEG of a person in a coma typically shows the slowest of the slow brain waves—the deltas, according to Emory neurologist Lynn Marie Trotti. While some slow waves appear during sleep, particularly in stage three, “during comas, it’s all slow wave all the time,” says Trotti. “Presumably it’s not restorative in the same way as sleep.”

What’s more, the same factors that drive sleep aren’t driving comas. With sleep, the drivers are circadian rhythm and sleep pressure; that is, the longer one is awake, the more one needs to sleep. But a coma is unattached to those drivers—with one exception. If someone is in a persistent vegetative state, they sometimes show hints of day-night cycling, Trotti says.

A walk on the wild side

Because the brain has so many parts involved in sleep, things can sometimes go awry. One such malfunction involves a dissociation among the parts of the brain that coordinate sleep: that is, some parts are acting as if the body is awake while others act as if it’s asleep. The result: parasomnias, such as sleepwalking and sleeptalking.

“Sometimes there are abnormal parts of the sleep-wake transition where people do wake-like activities when they’re asleep,” says Collop. “It happens because key parts of the brain are not inactive as they should be in normal sleep. So you can have some motor activity. You can walk. You can talk. You can supposedly drive a car.”

Although parasomnias are not yet well understood, they are well documented. “For example, the body should move very little when higher cortical levels are dampening themselves down,” says Trotti. “But with parasomnias, you’re able to walk when you still don’t have conscious awareness of what’s around you.”

As it turns out, the more common types of dissociations that lead to parasomnia occur during non-REM sleep, the deeper, slow-wave phase of the sleep cycle. More common in children, non-REM parasomnias often are related to neurodevelopment. While clinically we think of them as disorders, they are so common that some researchers believe they may just be a manifestation of normal brain development. Very young children may experience sleep terrors, whereas older children may experience sleepwalking. However, most children outgrow these parasomnias.

The rarer forms—and the potentially dangerous kinds of parasomnias— occur during REM sleep. These forms are strikingly different and manifest differently from more common parasomnias. In non-REM parasomnia, a person essentially gets stuck in a transition between deep sleep and being awake. It can be brought about by one of two scenarios, says Trotti. In the first, a person has a condition such as sleep apnea that causes frequent waking. Because the person is waking so often, she is more likely to get stuck in this transitional state. In the second case, the person has an abnormally deep sleep that is harder to wake from, so, again, she is more likely to get stuck. Sleep deprivation is one cause of abnormally deep sleep.

“It’s thought that when you finally do sleep, it’s so deep that it triggers parasomnias,” she says.

In REM parasomnia, the brain has bypassed muscle atonia—in essence paralyzed muscles—allowing people to act out their dreams and creating a potentially dicey situation. “The normal sleep state is not to move a muscle during REM sleep,” says Trotti. “If someone experiencing REM can still move freely and act out the dream, it’s very dangerous.”

In rare cases, people may be causing problems right in their own bedrooms. “For reasons we don’t understand, with REM behavior disorder, the dreams are usually violent,” says Trotti. “And what’s more, they are defensive violence. For example, you may dream that someone is attacking you, and you respond to it. That’s when people strangle their spouse, break things, and punch and kick.”

People with this disorder often don’t think of it as an illness. “You have to ask patients,” Trotti says. “They won’t necessarily volunteer that they gave their spouse a black eye last night. People with REM behavior disorder are sometimes assumed to have some deep, underlying psychiatric illness or some repressed motivation for the violence. But they don’t.”

Instead, parasomnias such as sleepwalking and REM sleep disorder tend to run in families. So does restless legs syndrome (RLS). RLS is a common neurologic disorder, characterized by a compelling urge to move the legs, most often accompanied by an unpleasant sensation, which is difficult for patients to describe. It occurs most often before or during sleep. Rye, who with an international team of researchers was the first to identify a gene associated with the disorder, knows firsthand about RLS. He has it, and so does his wife.

“Restless legs is a symptomatic trait,” says Rye. “It’s genetic. Nature loads the gun. Then something happens that triggers it. It could be neuropathy. It could be spinal cord injury. It could be liver or renal failure. The gene is very common. So people are walking around, ready to have restless legs.”

In fact, 10% of the U.S population and about 1% of school-aged children have RLS. A major cause of insomnia and sleep disruption, it has been linked to hypertension. “When you kick, your blood pressure goes up by about 30 mm,” says Rye.

One can be kicking and not know it, which occurs more often in middleaged men than in middle-aged women, says Rye. Women are more often aware of the sensation, although men kick more.

Measuring up

Interestingly, gender differences in sleep aren’t limited to middle-aged men and women with RLS—babies also display such differences. To appreciate that notion, stop for a moment and consider what any parent can tell you: babies grow when they sleep.

Emory’s Michelle Lampl, a biological anthropologist, recently finished the first study of its kind that measures the link between daily growth and sleep in infants. Her study showed that sleep and growth are inextricably linked. “Science is finally confirming what grandma knew all along: infants wake up taller right after they sleep,” says Lampl.

“Specifically, growth spurts are tied to an increase in total daily hours of sleep as well as an increase in the number of daily naps,” she says. “Longer naps predict an increase in weight and body fat composition tied to an increase in length. But exactly how this happens is not known.”

As far as gender differences go when it comes to sleep, Lampl’s study found that growth spurts in babies are associated with increased lengths of naps in boys and an increased number of naps in girls.

The hours

Unlike babies, many adults are uninclined or unable to nap and get too little sleep. That’s not good because sleeplessness, says Emory pulmonologist David Schulman, is akin to drunkenness. “If you’re an alcoholic, you may think you’re fine to drive, but you’re not. And the same is true for those who are chronically fatigued. People who are chronically fatigued suffer from the misconception that they are performing optimally, but they are not.”

Many studies of medical residents have likened driving home post-call to driving drunk. In fact, one study of residents in a simulated driving task showed that residents driving post-call performed worse than drunk people who were not post-call.

How sleepy we are at any one moment depends on many things: when we woke up, how many carbohydrates we just ate, what medications we take, how much sleep we got the night before. But more and more researchers are starting to look at how sleepy we are as a genetic trait.

In studies on twins, in which researchers ask how much of variance in sleep is explained by genetics as opposed to sleep apnea, medication, RLS, or some other condition, 50% to 80% of the variance is explained by genetic relationships. Genetics explain approximately half of cases of insomnia as well. “The biggest factor by far is what genes you were born with,” Rye says.

However, both genetic and environmental causes may contribute to narcolepsy. Narcolepsy causes profound daytime sleepiness, even marked muscle weakness, sometimes in the middle of routine activities such as talking or eating.

Some people affected by narcolepsy have too little hypocretin, a neurochemical closely linked to wakefulness. But what causes low levels of hypocretin isn’t well understood. Researchers believe that several factors— including heredity, infections, brain injuries, and autoimmune disorders— may cause deficiencies in this chemical.

Recently, Rye saw an 8-year-old boy in his clinic who had strep. Two weeks later, the child had developed narcolepsy. “When kids get sick with strep, that might be one thing that triggers narcolepsy,” Rye says. “He’ll have it the rest of his life.”

Some would argue, Rye included, that sleep is a vital sign, a barometer of our health, especially when it comes to how much we get versus how much we need. “If you look at how much we sleep, there’s a distribution,” says Rye. “If you take people at both extremes, they have higher morbidity (like inflammation and insulin resistance) and even higher mortality. So if you don’t sleep enough, that’s not good. And if you sleep too much, that’s not good either. The good stuff is right at seven, seven and a half hours. That seems to be the happy place.”

Rye and his fellow sleep researchers at Emory believe that understanding sleep is going to give us huge insights into how insulin control and breathing are regulated, how the heart functions, and how so many of our systems work. “There’s a genuine need to understand sleep,” he says.

Waking From The Deep Sleep

David Rye and colleagues on the Emory sleep team are hunting for biomarkers of hypersomnias, narcolepsy, and excessive daytime sleepiness in a new place—specifically the cerebrospinal fluid (CSF) and plasma.

The researchers analyzed biomarkers in the CSF and plasma of 31 people suffering from hypersomnia— research which Rye recently presented at the 2011 international SLEEP conference. In fact, it was one patient’s case that prompted the team to reanalyze other samples of CSF in their files.

That woman, “Anna,” was a 32-year-old attorney who first came to Emory in 2005 because of an overwhelming need for sleep— reaching at times 57 hours at a stretch. Initially, the researchers were unsure of the cause, but after extensive analysis of her CSF, they identified activity that enhanced the brain’s most abundant “shut down” chemical—namely gammaaminobutyric acid (GABA).

Emory’s sleep team next surmised that flumazenil, a drug targeted at reversing anesthesia and sedative overdoses by way of GABA, might work as a possible treatment for Anna. Over two days, they gave higher doses of flumazenil intravenously while continuously monitoring her vital signs, electroencephalogram, and performance metrics. When the dosage reached 2mgs., Anna exclaimed, “I feel alive!”

She has continued to enjoy sustained improvement for three years.

WEB CONNECTION For more info, call 404-778-7777, or visit emoryhealthcare.org/sleep. Videos about Emory sleep research are at bit. ly/sleephealthvideos and bit.ly/historyofsleepmed. A podcast on how sleep loss affects long-term health is at bit.ly/davidschulman.

The roads serving the two areas—like the regions themselves—couldn’t be more different.

One is a network of multi-lane interstate highways that surround and bisect a metropolitan area of more than 5 million people in North America. The other is an asphalt highway intersected by dirt roads that, when the weather permits, provides the only nonriver link between 125 villages in a remote area of South America.

Yet the congested highways of metro Atlanta, where local commuters and interstate haulers compete for space, and the first paved road along coastal Ecuador, where freshly cut timber moves from forest to market, share an important trait: besides providing the economic foundation for both regions, these man-made advancements alter the ecosystems and public health in ways that science is only now coming to understand.

Both regions, it turns out, also provide fertile ground for researchers at Emory’s Rollins School of Public Health (RSPH). They illustrate the scope of a department that has moved aggressively into what is best described as public health ecology—the study of how human behavior impacts the planet as well as human health. Understanding this relationship could go a long way toward informing policy decisions about the price of development as well as safeguarding personal and public health in the future.

The practical impact of these studies could lead to early detection of man-made toxins in the body that are linked to Parkinson’s disease and new forms of sanitation that use less water in undeveloped regions of the world.

Air and water

Building on work that goes back to the mid-1990s, researchers at the RSPH and Georgia Tech recently won a five-year, $8 million grant from the Environmental Protection Agency to establish one of four national Clean Air Research Centers. They will be looking at the impact of poor air quality on health, ranging from effects such as low birth weight in babies to cardiovascular disease in adults.

By Mike King • Photography by Jack Kearse • Illustrations by Nip Rogers

“We have an incredible infrastructure in place at Emory to accomplish this,” says Paige Tolbert, chair of the environmental health department, referring to the treasure trove of epidemiologic data that has accumulated on Atlanta air quality and health over the course of more than a decade. “Now we will be able to study what might be the worst aspects of the pollutant mix we face, and we may be able to suggest what control measures will have the greatest health benefit.”

Earlier research on Atlanta traffic drew from measurements of ground-level ozone (found in smog) and particulate pollution (found in haze, smoke, and dust) as well as patient reports from emergency rooms in the metro area. That work established a link between Atlanta’s air quality and increased risk of attacks for people suffering from asthma, especially children. In the new center, one project will assess whether Atlanta’s commuters may be putting their health in jeopardy in small, subtle ways while making their daily 25- to 30-minute trip to work every morning and retracing their routes home. Other center work will examine whether exposure to air pollution in utero and in early childhood is related to subsequent illness in children as well as an investigation of how the findings in Atlanta apply to other cities.

“This new work will take us to a new level,” Tolbert says. “We’ll look at the interactions between air pollutants as well as the cumulative, combined impact of these chemicals on certain diseases and conditions that we already know are related to pollution.”

Preparing for a hotter planet

While Tolbert is bringing the air quality in Atlanta down to streetlevel science, another faculty member in environmental health is examining the broad impact of climate change on health.

Jeremy Hess, an emergency medicine physician at Emory University and Grady Memorial hospitals, routinely pores over colorcoded maps of the globe, looking at climate patterns that impact heat waves, floods, hurricanes, and other extreme conditions. He studies the corresponding demands these weather events place on public health and safety systems.

For example, Hess has studied periodic heat waves that have

The bigger picture

When Karen Levy was a PhD candidate at the University of California-Berkeley, she was part of a team that focused international attention on the impact of water-borne disease resulting from a new roadway in northwest Ecuador. Now at Emory, she and her collaborators have established that the highway and unpaved roads that connect to it have so altered the region that people there face increased risk of enteric diseases—including diarrhea, a major cause of death in Ecuador.

Her most recent project involves the spread of antibiotic resistance as major timber-cutting companies buy large chunks of privately held land and inhabitants move from harvesting small stands of trees to raising chickens.

Levy believes there must be a balancing act between economic development and how that hit major American cities over half a century, from 1956 to 2005. During an average summer, some 400 Americans succumb to heat— accounting for a greater number of climate-related deaths each year than any other form of extreme weather. Yet little public attention is focused on the health impact of heat compared with hurricanes, tornadoes, floods, and other extreme weather.

Moreover, when Hess and collaborators at Georgia Tech and CDC probed deeper into the U.S. fatalities, they found that extreme heat events over time were much more likely to happen in urban areas characterized by sprawling residential and commercial development than in more compact, high-density cities.

In sprawling metro areas, Hess found nearly 15 more days of development alters the climate and public health.

“It is plausible that roads and infrastructure are the key to success and that Ecuador and other countries need these investments to develop,” Levy says. “But there are few studies that assess the health impacts of these projects, especially regarding the transmission of infectious diseases. We have to look at the bigger picture.” extreme heat during the period studied compared with 5.6 days for more compact cities. (“Extreme heat” is a measurement based on apparent temperature and humidity relative to ambient air temperature and water vapor pressure.)

Given that climate experts believe the number of days for extreme heat will increase significantly in the decades to come, Hess says that urban planners should consider strategies that preserve regional green space, planting more trees along roadways, and using more reflective surfaces on roads, buildings, and rooftops. They also could plan to rely more on mass transportation, walking, and bicycling.

“We’ll have to look at our whole approach to public health as we adapt to climate change,” Hess says.

Is commuting harmful to your health?

Growing up in Chicago, Jeff Solodky has seen his share of gridlock. But it is nothing compared with the traffic he has encountered since enrolling as an undergraduate at Emory. “Here, rush hour seems to last most of the day,” Solodky says. “I didn’t believe it until I saw it.”

Solodky is one of 100 participants to take part in a study by Emory and Georgia Tech researchers that measures how commuting in Atlanta impacts the health of the commuters themselves. Using sophisticated air analyzers and other instrumentation developed at Tech, the Atlanta commuting study measures what pollutants drivers are exposed to inside the car.

Participants go through a two-hour commute in the morning and again in the evening on two different days, driving along “scripted” routes provided by the researchers. Most of the time, they drive on Atlanta’s busy interstates, although they also traverse some surface streets.

Each participant also undergoes a battery of tests—including blood gas and other cardiovascular measurements—the day before their commute and again after finishing their afternoon drive.

The information gathered on how specific pollutants affect the drivers— and under what circumstances—can help inform discussions about traffic patterns, highway expansion, land use, and health, says Jeremy Sarnat, an environmental health expert and the study’s lead investigator.

“Even the smallest changes in oxidative stress among the participants tell us something,” Sarnat says. “We may be able to help individuals who are at greater risk so that they can make informed decisions about when, for instance, to start their commutes or which routes to take.”

Such information would be helpful to Solodky, a third-year business student who has had asthma since age 3. (Half of those enrolled in the study have asthma.)

“I didn’t notice any health changes when I was on the road,” he says after his commute. “But then, living on campus, I don’t have to go through that every day.”

Shahed Iqbal, an epidemiologist in the asthma branch of the CDC who is also a study participant, more closely resembles the average Atlanta commuter. He drives about 30 minutes each way every day from his home in Norcross to his office in Chamblee. While his participation in the study is unconnected to his work at the CDC, he was intrigued by what the Emory researchers are doing.

“When you are stuck between those diesel trucks on I-285, you have some idea of what you are being exposed to,” he says. “This study is pretty comprehensive. They are looking at a whole range of exposures to see what might be impacting our health. That’s an important step forward.”