Sleeping On It
As anybody from an HD family knows, getting enough sleep can be a challenge. In one survey in the UK, 88% of people with HD said they had sleep problems, including waking up in the middle of the night, restless leg movements in bed, waking up too early in the morning, or being sleepy all day.
It’s more than just ordinary insomnia. Emerging evidence suggests that HD somehow disrupts the circadian clock, the internal mechanisms in the body that keep us in synch with the 24-hour day. So it’s not just sleep that gets off-kilter; it’s also cycles in appetite, body temperature, and hormones. The result is that people with the HD gene expansion may feel perpetually out of synch. It’s as if they were jet-lagged all the time, says researcher Chris Colwell, PhD, an expert in sleep and circadian rhythms at the University of California, Los Angeles.
“There are a number of things that go wrong when you disrupt these clocks—things that everyone has experienced when acutely jetlagged. Memory is difficult, you feel fatigued, you have difficulty focusing,” he says. “There are effects on cognition, and even some things like mood.” It can make people irritable and confused, more sensitive to stress, and it can throw metabolism out of whack. Feeling this way all the time can take a toll, especially since people with HD may already be struggling with some of these problems.
Despite how common sleep difficulties are, they haven’t been a major focus of HD research. That is beginning to change. Several researchers have recently explored why people with HD often have trouble sleeping, and also investigated mouse models of the disease to understand more about the biology of the circadian clock problem. Even though the cause hasn’t yet been pinned down, some simple behavioral changes might help reset the clock in people—a possibility researchers are now studying. “We believe we can improve the quality of life for the person,” says Colwell. “If you’re sleeping better, it wouldn’t surprise me that you were doing everything better.”
What goes wrong
It’s now well established that the cycle of sleep and wakefulness in people with HD is disrupted. The hormone melatonin, which is controlled by the body’s internal clock and helps people sleep, is supposed to increase at night and decrease in the morning. In people with the HD gene, it may begin increasing at any time of day, out of phase with the 24-hour clock. For some people, this happens well before official diagnosis.
Similar problems develop in mice that have been genetically modified to carry the HD gene and develop symptoms. The animals, normally nocturnal, become more active during the day. (They are monitored via video analysis, or by remote sensors that detect heart rate and body temperature.) Genes that regulate the circadian clock are disrupted, and the animals show other signs of being out of synch. These observations led University of Cambridge neurobiologist and HD expert Jenny Morton to propose in 2005 that sleep problems and circadian disruption may be a core part of the disease, not simply a knock-on effect of other symptoms. A later study showed that in HD mice, drugs that restored more normal sleep patterns helped the animals learn and think better.
So the search was on for ways to resynchronize the system in humans—ideally through changes in behaviors rather than drugs, since they don’t have side effects and are often more effective than drugs over the long term. The most obvious regulators of the sleep-wake cycle are food, exposure to light, and exercise, says Colwell. Some practices, such as keeping the bedroom cool and dark, limiting alcohol and caffeine, and avoiding computers and other bright electronic devices before bed, are recommended for anyone who is having sleep trouble, whether they have HD or not. Morton distilled much of this advice in a 2013 paper and summarized it for a story on the research news website HD Buzz.
Both Morton and Colwell have also looked to mouse studies for more answers. In 2013, Morton’s group found that HD mice allowed to eat only at night (when they are naturally awake and active) kept their weight on for longer, and had better motor performance. The group also found that treating mice with bright light right before nightfall and allowing the animals to exercise only at night helped restore more normal circadian patterns. Colwell has found that limiting feeding times makes the biggest difference. In a study that has not yet been published, he also found that allowing HD mice to eat only at night delayed the onset of their motor symptoms.
“The timing of when you eat can help or hinder the synchronization to the environment,” he says. “The liver and the gastrointestinal system lock on to when the food is available, and even parts of our brain.” Eating on a regular schedule is a trick to put the metabolism on a 24-hour cycle, and that can translate into a more regular pattern of sleep and wakefulness.
Could it help us?
In the summer of 2015, Colwell’s group began recruiting people who have been diagnosed with HD to measure how well they sleep. They will wear a wrist band like a Fitbit to monitor sleeping, movement during sleep, heart rate and heart rhythm.
In the meantime, although these interventions haven’t yet been shown to work in humans, there isn’t much risk or major downside to trying it out, suggests Colwell. “You don’t have to have something injected into you. These are commonsense, and might help anyone out,” he says, even someone who doesn’t have the HD gene but is having trouble sleeping.
For a human, the equivalent practice would mean eating most of your calories on a regular schedule during a six to eight-hour window during the day, well before bedtime. That doesn’t mean eating less or more food; it would be the same amount, but keeping to the schedule. Exercising during the first half of the day (or at least three hours before bedtime) also has been shown to help human insomniacs who don’t have HD, and Colwell thinks it may also help people with the disease.
Based on his results in HD mice, Colwell thinks that circadian problems actually accelerate the advance of HD. He hopes that helping people resynch might actually delay the onset of some of the other manifestations of the disease. In any case, improving sleep and getting more in tune with the daily clock could make life easier and healthier, both for people with HD and those who love them, says Colwell: “At the very least, we can improve the quality of life for patients and family members.”
This story was originally published in the Autumn 2015 issue of Enroll!