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Winter 2022

The Rhythm of Sleep

Northwestern brings two research fields together to better understand how sleep improves health. By Clare Milliken

Image: Illustrations by Yifan Wu

It’s so slight, you don’t even feel it coming. You might feel a bit fuzzy, weightless, buoyant. It’s subtle — in the initial stages, your heart rate dips and your muscles relax. Before your brain waves become even slower, your body temperature falls. Finally, brain activity speeds back up, but your limbs are temporarily paralyzed and your eyes begin to dart behind your eyelids. Over the next several hours, this cycle will repeat at relatively regular intervals.

Until your alarm blares from your nightstand.

We may regard sleep as a period of pure rest and rejuvenation, but it’s so much more. And while we often hear that we need seven to nine hours per night, there’s more to that story as well.

Kristen Knutson

“Sleep health is multidimensional,” says Kristen Knutson, associate professor of neurology and preventive medicine at Northwestern’s Feinberg School of Medicine. “It’s sleep duration — are you getting enough sleep? But it’s also quality. It can also be timing. You could be getting what you think is a decent quality of sleep, and you might think that you’re getting enough sleep, but you don’t feel rested at the beginning of the day.”

The effects of insufficient or poor-quality sleep go far deeper than our energy level the next morning. As Northwestern researchers have shown, sleep is a key component of our cardiovascular, metabolic and cognitive health. In short, improving sleep can help us live longer, healthier lives.

THE MECHANISMS OF SLUMBER

If you’ve been up since 7 a.m., you might notice that with each passing hour after dinnertime, you feel more tired and ready for sleep. By midnight, you’re likely dreaming — or hoping to be doing so soon. This natural drive to sleep is known as sleep homeostasis, and it is one of the key mechanisms controlling sleep. 

“Sleep homeostasis is a fancy word for something very simple: The longer you’ve been awake, the easier it is to fall asleep,” Knutson says. 

Sleep is also controlled by the circadian clock, a 24-hour pattern naturally synchronized to the cycle of daylight and darkness. You can think of the circadian clock as your internal timekeeper, which, ideally, aligns with the time of day or night — so-called external time. That grogginess you experience after pulling an all-nighter or the jet lag you feel after flying from Rome to Chicago is due in part to your circadian clock being out of sync with external time. 

The central circadian clock is in the hypothalamus region of the brain. Our pattern of sleep and wakefulness — the sleep-wake cycle — is one output, or rhythm, of our circadian system. (Our pattern of hunger and fullness, the so-called feed-fast cycle, is another.)

In recent decades, researchers at Northwestern and elsewhere identified that there are also circadian clocks in the pancreas, the liver and many other tissues. Controlling specific functions like insulin secretion, DNA repair and even stress response, these peripheral clocks are like musicians in an orchestra. The central circadian clock in the brain is the conductor, giving cues to the clocks throughout the body to stay in sync as much as possible. The “conductor” clock can fall out of sync, as we experience when we fly across time zones, and so too can the peripheral “instrument” clocks.

Fred Turek

“Circadian biology refers to the 24-hour regulation of every physiological process in our bodies, and the sleep-wake cycle is just one of them,” says Fred Turek, the Charles and Emma Morrison Professor of Neurobiology at Northwestern’s Weinberg College of Arts and Sciences. When clocks are misaligned, so-called circadian disruption can lead to negative health outcomes. At the same time, insufficient sleep and poor-quality sleep are risk factors for a whole host of ailments from hypertension to depression. 

More than half the genes at the heart of the central circadian clock were identified by Northwestern’s Center for Sleep and Circadian Biology (CSCB), which Turek directs. Martha Hotz Vitaterna ’92 PhD, a neurobiology research professor at Weinberg and CSCB deputy director, discovered a mutation in a mouse that helped identify the first molecular piece of the clock in mammals: the so-called Clock gene. 

Martha Vitaterna

“Twenty-five years ago, these were really two separate fields,” Vitaterna says of circadian biology and sleep science. While she acknowledges that some sleep issues may not be circadian-driven, “it almost becomes a chicken-and-egg question because, especially with humans, it’s very, very hard to mess with circadian rhythms and not mess with sleep. And conversely, it’s very hard to mess with sleep without messing with circadian rhythms.”

In the early 1990s, Turek recognized that understanding the role of circadian biology in the sleep-wake cycle could help researchers shed light on the role of the circadian system in health and medicine more broadly. He set up a rodent sleep laboratory at Northwestern, and within a few years he and his team had earned millions of dollars in research funding.

“I would argue that Northwestern University has played a major role in integrating the two fields into what is almost one field today,” says Turek.

Fred Turek and Kristen Knutson discuss their long-standing professional relationship and the ways their different perspectives have improved each other’s research efforts on sleep and circadian timing, with the goal of improving human health and addressing health disparities.

In a 2005 study, Turek worked with Joseph Bass, the Charles F. Kettering Professor of Medicine at Feinberg, and his team to discover that when an animal’s Clock gene is abnormal, the animal is more likely to become obese than an animal with a normal Clock gene eating the same food. “That told us there was some connection between the genes controlling the sleep-wake cycle and the circadian clock and obesity,” Bass says. 

They also found that disrupting circadian rhythms was connected to the development of a metabolic syndrome consisting of symptoms related to cholesterol and glucose levels and fat accumulation in the liver and abdomen.

“So is it circadian disruption or sleep loss contributing to health problems?” Turek asks. “The answer right now is both.”

AT THE HEART OF IT

If you’re walking in the woods and come upon a bear, your body’s autonomic nervous system — your fight-or-flight response mechanism — kicks into high gear.

Mercedes Carnethon

“This is evolutionary. I want my autonomic nervous system to respond in a way that, if this bear slashes me, I don’t bleed out. I want my heart rate to go up so that I can prepare to run,” says Mercedes Carnethon, the Mary Harris Thompson Professor of Preventive Medicine and vice chair of that department at Feinberg. “Not sleeping well is a stressful situation, and when you’re under a lot of stress, your body is preparing for a fight by raising your blood pressure, raising your heart rate, making your blood more likely to clot.” 

And when blood pressure stays high as a result of prolonged stress, Carnethon explains, the lining of the blood vessels suffers abrasions, triggering an inflammatory response that narrows the arteries and can lead to heart attacks and strokes. 

“There’s a lot of experimental work that has shown that even a week of sleeping only four or five hours a night changes your autonomic nervous system,” Knutson says. 

In a national four-site research project called Coronary Artery Risk Development in Young Adults (CARDIA), Knutson and Carnethon linked short sleep and poor-quality sleep to higher blood pressure and a greater increase in blood pressure over five years among non-Hispanic Black and white adults. Being a short sleeper was associated with a buildup of calcium in the coronary arteries and, in men, a thickening of some arteries. All of these, Knutson says, are risk factors for cardiovascular disease.

Carnethon acknowledges, though, that sleep and stress have a bidirectional relationship. “Nonrestful sleep is both a cause of stress and a consequence of stress,” she says. “It’s a total feedback loop.”

So too is the connection between poor sleep and our behaviors in response to our stress and our sleep loss: moving less throughout the day, eating less nutritious food, increasing caffeine intake — all of which may affect our risk for disease. “Short and poor-quality sleep can influence the risk of chronic diseases directly, through changes in biological pathways and mechanisms, and indirectly, through changes in the behaviors that you use to cope with nonrestful sleep,” Carnethon says.

In 2017 Carnethon found that sleep may explain some of the racial disparities in cardiovascular and metabolic diseases between African Americans and European Americans. Carnethon and Knutson are now studying the impact of sleep on racial disparities in blood pressure control among 2,200 young people across four cities: Birmingham, Ala.; Chicago; Minneapolis; and Oakland, Calif.

“Hypertension is the most commonly diagnosed medical condition in the country and the primary source of Black-white disparities in stroke, heart failure and chronic kidney diseases,” Carnethon says. “And we know that there are gaps in blood pressure control between Blacks and whites that aren’t explained by medication-use behaviors. We want to measure the extent to which the known differences in sleep are contributing.”

“Not sleeping well is a stressful situation, and when you’re under a lot of stress, your body is preparing for a fight.” — Mercedes Carnethon

Boosting the brain

We’ve all felt brain fog after a late night or an overseas trip. That cognitive slump, Knutson says, is itself a health risk.

“We can’t discount that if you’re really sleepy, you’re more likely to have an accident,” she says, “or maybe you don’t take your medication properly.”

We may not notice these deficits, or we may think we’re outsmarting our physiology. 

“There’s this phenomenon where, if you’re not getting enough sleep long-term, you start to feel used to it and you don’t necessarily feel sleep deprived,” says Vitaterna. “But if you do some sort of performance test, you are experiencing detriments from that long-term sleep debt even though you’re not feeling sleepy.” 

Studies in mice have shown that even mild sleep deprivation can affect how well we cope with psychological stress. According to Turek, poor sleep may be a contributing cause of both post-traumatic stress disorder and depression.

After disrupting the sleep of mice for five days, Turek and Vitaterna exposed mice to an aggressive male mouse. (The sleep-disrupted mice were inside a safety cage within the “bully” mouse’s cage. “No violence, no bloodshed,” Vitaterna assures.) After just five days of insufficient sleep, the mice were much less able to recover from the stress of an encounter with the aggressor. “And we saw changes in their sleep patterns that are reminiscent of what happens with PTSD,” Vitaterna says.  

“If you’re in a war fighter situation and you haven’t had enough sleep — if your rhythms are disrupted — and then you’re subjected to a traumatic stress event, are you more vulnerable to developing PTSD?” Turek asks. “The answer seems to be yes.” 

Turek adds that some studies show sleep loss often precedes the onset of depression. “To me that means it’s a causal factor,” he says. In an article in the journal Sleep, Turek cited longitudinal studies that suggest that episodes of depression can manifest about five weeks after insomnia. “The hypothesis here is not only that disordered sleep can bring on an episode of depression, but also that treating the insomnia may prevent or shorten the period of depression,” Turek wrote.

“All these different parts of our body that are separated in the clinic and the hospital are not really separate — they affect each other,” Knutson says, citing high blood pressure as an example. “That affects what’s going on in the brain. And you see a lot of papers coming out saying that not sleeping enough or not sleeping well is associated with dementia and Alzheimer’s disease risk because of changes in the brain.”

Phyllis Zee

Among the most shocking findings: Waking up in the middle of the night, what’s known as sleep fragmentation, is associated with Alzheimer’s disease six years later, says Phyllis Zee ’87 GME, ’89 GME, the chief of sleep medicine in the department of neurology and the Benjamin and Virginia T. Boshes Professor of Neurology at Feinberg. Zee is internationally recognized for her work on the connections between sleep and circadian rhythm issues and risk for both neurological and cardiometabolic diseases. 

In recognition of the link between circadian biology and sleep science, Zee founded Northwestern’s Center for Sleep and Circadian Medicine. Today, she is increasingly focused on a stage of sleep known as slow-wave sleep. This third and deepest stage of sleep is characterized by slow brain waves, decreased heart rate and lower blood pressure. Sleep, and slow-wave sleep in particular, helps to restore the brain and body.

“People with insufficient sleep and less slow-wave sleep are more likely to accumulate more beta-amyloid, which is a protein that accumulates in the brain of patients with Alzheimer’s disease,” Zee says.

Even healthy people make beta-amyloid, which increases in our brains over the course of the day, Zee explains. “It’s part of the brain’s metabolic activity,” she says. “It’s like your car running on gasoline. You’re creating exhaust, and you have to remove the exhaust. With chronic sleep loss and sleep disturbance, there is impairment of the removal of harmful proteins like beta-amyloid, which can increase risk for dementia. Your car is still running, and you don’t have the ability to get rid of the exhaust. It’s just building up.”

Zee has also found that slow-wave sleep is important for more basic functions like memory consolidation, and her lab is looking for ways to improve slow-wave sleep through exercise, diet and even certain sounds played at a specific frequency and at specific times during sleep. This acoustic stimulation with “pink noise” has been shown to improve slow-wave sleep and boost memory in older adults.

“So sleep becomes a modifiable factor, something that could change the expression of disease later on,” Zee says.

Getting in Sync

The continued unification of sleep and circadian science holds great promise for health and medicine, Turek says, but “we’re at the very early stages of being able to monitor circadian rhythms.”

A test called Time Signature aims to do just that. Developed by Zee and others, the test measures gene expression markers in the blood to detect whether a person’s internal circadian clock is out of sync with external time. Requiring two blood draws, the test could indicate issues with the clock controlling sleep, but it could also determine whether clocks in other tissues are misaligned.

“This is a first step toward providing … a time-based biomarker for circadian timing — and it isn’t just for sleep,” Zee said on Feinberg’s Breakthroughs podcast, adding that Time Signature could help address hypertension and diabetes and even optimize medication dosing and timing.  

Jonathan Rivnay

Resynchronizing a misaligned clock is another challenge altogether, and Northwestern researchers are hard at work on that front too. Supported by the Defense Advanced Research Projects Agency, a national research team led by Jonathan Rivnay, assistant professor of biomedical engineering at Northwestern’s McCormick School of Engineering, is developing a wireless, implantable device capable of resynchronizing a misaligned circadian clock and significantly reducing the time needed to recover from disrupted sleep. (The team also includes Turek, Vitaterna, Zee and Weinberg neurobiology research assistant professor Peng Jiang, among others.)

Integrating bioelectronics and synthetic biology, the so-called living pharmacy device could be invaluable to shift workers, military and medical personnel, and people traveling across time zones. The integration of otherwise disparate fields of research also holds great potential.

“While this program is targeting sleep, you can definitely envision that if we prove out some of these concepts, it could open up applications in a number of other areas,” says Rivnay, citing depression and pain management. “It is giving us the opportunity to target something specific right now with an eye on potentially having an even broader impact.”

For Turek, who has seen the fields of circadian biology and sleep science intertwine over decades, understanding how our circadian clock affects our health — including and beyond our sleep — will usher in the next frontier of medicine.

“People talk about precision medicine,” Turek says. “But without understanding the 24-hour rhythmicity, there will never be precision medicine.”    

Clare Milliken is senior writer and producer in Northwestern’s Office of Global Marketing and Communications.  

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