An exceptionally clever design to gain insight into sleep apnea

Butler LabJan. 12, 2016

December's featured paper is "The Circadian System Contributes to Apnea Lengthening across the Night in Obstructive Sleep Apnea," published in the journal SLEEP. The paper is published by a team led by Drs. Matthew Butler and Steven Shea.

For some people, eight hours of sleep will not result in a fully rested, happy morning. Many people suffer from sleep apnea – a disorder characterized by brief and frequent breathing interruptions during sleep. 

"We all probably know someone with sleep apnea," said Mary Heinricher, Ph.D., associate dean for basic research. Sleep apnea is not only characterized by disturbed sleep and daytime sleepiness, it is also associated with heart disease.

"Each apnea episode is defined as the cessation of breathing," said sleep researcher Matthew Butler, Ph.D., assistant scientist in the Oregon Institute of Occupational Health Sciences at OHSU. "Apneas cause hypoxia, a decrease in oxygen supply. Additionally, the arousals from sleep cause surges of the sympathetic nervous system activity and increase blood pressure."

"These changes may be worse when the apneas are longer," added Steven Shea, Ph.D., director and senior scientist at the Oregon Institute of Occupational Health Sciences at OHSU. "Many hundreds of these asphyxia/arousal cycles with surges in blood pressure can occur across a single night – the high blood pressure in particular can persist even when awake during the daytime."

An apnea is usually about 20 seconds long. Over the course of the night, these increase so that the longest and most severe apneas occur at the end of the night, just before waking. "We wanted to determine what caused the longer apneas because mechanisms that are engaged in making apneas longer might be therapeutic targets that we could manipulate to shorten the apneas instead," said Dr. Butler. 

Studying sleep

A number of research groups have documented the nocturnal lengthening of apneas, but the mechanisms have never been defined. Many aspects of physiology and behavior change regularly across the day and night; changes in alertness, hunger, and sleepiness are readily observable examples.

"In our laboratories, we address these 'time-of-day' changes and specifically test whether these changes are due to ongoing behaviors, such as the duration of sleep, or due to the influence of the endogenous circadian clock that controls 24-hour rhythms in the body," said Dr. Shea. "We conducted a study to determine whether apneas become longer because of the amount of time spent asleep or because of the time of day as controlled by the body's internal clock."

"I chose this paper by Drs. Butler, Shea, and colleagues in part because they used a really clever design to separate out the impact of just being asleep from circadian factors on sleep apnea," said Dr. Heinricher.

"Studying the circadian clock requires multi-day stays in highly-controlled laboratory facilities where time cues can be removed and lights can be carefully controlled," said Dr. Butler. "We studied the participants for this study at the Brigham and Women's Hospital in Boston, but we are very excited that we are now continuing these studies in the recently opened Oregon Clinical andTranslational Research Institute facilities at OHSU that include rooms specially designed for such sleep and circadian rhythms research in humans."

"Each study participant spent five days in the laboratory without any time cues and in dim light," explained Dr. Shea. "Sleep episodes were evenly distributed across all times of day so that we could compare apneas that occurred in the biological night and in the biological day. We found that the circadian clock itself causes apneas to be longest around 6 a.m., and shortest at about 10:00 p.m. The endogenous rhythm that we found explains most of the nocturnal lengthening that occurs during normal nights."

Results and next steps

So, what exactly does this research mean for your average sleep apnea sufferer? "The recommended treatment for sleep apnea is continuous positive airway pressure (CPAP), but adherence is poor because many people cannot tolerate wearing a face or nose mask during sleep," said Dr. Shea. 

"CPAP remains the treatment of choice, but it is only effective because it prevents the airway from collapsing – it does not address any of the underlying reasons for why the airway collapses in the first place," added Dr. Butler.

"Our research identifies a novel mechanism that contributes to the durations of apneas," said Dr. Shea. "Identifying such mechanisms can help identifying new therapeutics to treat the causes, rather than the consequences, of airway collapse during sleep."

How about the connection to heart disease and the future of this groundbreaking research? "Sleep apnea not only increases the risk for heart attack, it also shifts the peak time of heart attacks from the mid-morning to the middle of the night," said Dr. Butler. "Here at OHSU, we are now conducting research to determine how sleep apnea and circadian rhythms interact to control the cardiovascular response to stresses, including posture changes and exercise."

"We have now turned to large cohort studies to learn how characteristics of apneas, including their duration and variability in occurrence, predict mortality and heart disease risk," said Dr. Butler. 



The Circadian System Contributes to Apnea Lengthening across the Night in Obstructive Sleep Apnea Sleep. 2015 Nov 1;38(11):1793-801. doi: 10.5665/sleep.5166. Matthew P. Butler, PhD;Carolina Smales, MA;Huijuan Wu, MD, PhD;Mohammad V. Hussain, BA;Yusef A. Mohamed, ALM;Miki Morimoto, MD;Steven A. Shea, PhD

More Published Papers

Pictured above: (left to right) Steven Shea, Matthew Butler, Alec Berman, Noal Clemons, Sally Roberts, Saurabh Thosar, and Maya Herzig.

About the OHSU School of Medicine Paper of the Month

The OHSU School of Medicine spotlights a recently published faculty research paper each month. The goals are to describe to the public the exceptional research happening at OHSU as well as inform our faculty of the innovative work underway across the school’s departments, institutes and disciplines. The monthly paper is selected by Associate Dean for Basic Research Mary Heinricher, Ph.D.