Time Out of Mind: How Disrupted Sleep Hurts Brain Health

John Watson


December 07, 2018

The circadian clock evolved over millions of years to bring a modicum of predictability to an unpredictable world. At its most basic, it divides our 24-hour day into optimal periods to eat and digest food, sleep and avoid predators, and other biological drives to keep us alive and healthy. It's an essential system shared by nearly all living organisms, and one that is always at work.

"Before you even wake up in the morning, already your circadian clock is preparing your body for the upcoming stress by regulating certain genes," explained Erik S. Musiek, MD, PhD, assistant professor of neurology at the Washington University School of Medicine in St. Louis, Missouri.

When considering the circadian clock, we're better off not envisioning a single timepiece but rather the countless interconnected sprockets and gears of which it consists. The system's headquarters is the suprachiasmatic nucleus (SCN) of the hypothalamus, the so-called "master clock." The SCN synchronizes the thousands of clock-controlled genes expressed in our cells throughout our body, from our brain to our skin, that contribute to metabolic and physiologic function.[1,2,3] Not just a top-down system, the clock relies on a constant feedback loop of inputs like light, temperature, and feeding times to adapt to changing conditions.[3]

When everything is running in harmony, there is little reason for concern. But if the system begins to break down at any level, havoc can ensue.

Sleep and circadian rhythm disruption (SCRD) has long been linked to increased risk for metabolic disease, obesity, diabetes, and cancer.[4] Now, emerging data are showing that SCRD's adverse effects extend to our neurologic and mental health as well.

What Comes First: Sleep Disruption or Disease?

Mental illness and neurologic diseases have well-established associations with SCRD. Major depression goes hand-in-hand with insomnia.[5] Patients with bipolar disorder can have manic episodes provoked by seasonal changes[6] and long-distance travel.[7] The late afternoon/early evening agitation that patients with Alzheimer disease commonly experience (also known as "sundowning") is one of the key contributors to institutionalization.[8]

However, what has changed in recent years is the rapidly evolving hypothesis that such disturbances may foreground, as well as follow, these conditions, according to Michael J. McCarthy, MD, PhD, associate professor in the department of psychiatry at the University of California San Diego.

"In the past 10-12 years, a number of technical developments have made it feasible to design experiments that directly test the question of causality," he said.

In a 2016 study, researchers turned off the SCN in a group of adult mice and found that it resulted in tell-tale signs of depression: helplessness, behavioral despair, and anxiety.[9]

In a study the following year,[10] researchers provided what is believed to be the first report of an association between rhythmic DNA methylation and cyclic clock gene expression. It was a provocative hint that in Alzheimer disease, such molecular disruptions may not just be a side effect.

"We saw that in the progression of Alzheimer disease, early in the disease even more than in severe patients, we have a complete disruption of rhythm," explained study investigator Paula Desplats, PhD, an assistant professor in the departments of neurosciences and pathology at the University of California San Diego.

"Sleep disruptions were always considered a consequence of disease, but our work was more aligned to other pieces of evidence showing that, in fact, this circadian misalignment happens early enough, we propose, as to contribute to disease progression."

Further illuminating the possible pathologic role for SCRD in neurodegeneration, this year Musiek and colleagues observed that mice with deletions of the central clock gene Bmal1 exhibited accelerated amyloid plaque accumulation.[11] In a clinical study also from this year, they showed that circadian rhythm abnormalities are present in patients with preclinical Alzheimer disease, which may someday prove a valuable biomarker for progression.[12]

Clinical Applications

Most researchers now see the relationship between SCRD and mental and neurologic illness as being bidirectional, though questions far outnumber answers at this point. However, there is hope that this research can soon be translated into tangible benefits for patients.

Given its ease of administration, incrementally resetting patients' sleep schedules through so-called chronotherapies has garnered substantial interest. Such approaches have been associated with sustained antidepressive effects in multiple studies,[13,14] although high rates of relapse challenge its long-term utility.[14] Bright light therapy has also shown superiority over placebo in major depressive disorder.[15]

For bipolar disorder, one of the more intriguing applications of this research has been in augmenting existing pharmaceutical treatments. In a just-published paper,[16] McCarthy and colleagues sought to determine whether circadian biology could explain why only approximately a third of patients with bipolar disorder respond to lithium monotherapy. They found that those who responded well were more inclined to exhibit higher "morningness" scores (being more active in the morning than evening), and had fewer symptoms of depression and mania, as well as fewer suicide attempts. They confirmed this association by testing patients' skin cells, which exhibited shorter circadian periods.

"We still don't know if the circadian effect is essential to the mechanism of lithium, but it's the best evidence we have so far that at least in a subset of patients, circadian abnormalities are a predictive marker of response," McCarthy said. "This may help in developing personalized medicine for bipolar disorder."

In neurodegenerative disease, the bar for designing effective interventions is understandably higher. As patients progress, chronotherapies and other low-threshold interventions become increasingly difficult to implement. The question then becomes how to best intervene while the underlying circadian system remains intact enough to have an effect.

"If everything holds true and deregulation of circadian cycles also contributes to Alzheimer disease, as we know it does with something like metabolic disorders, then it means we might be able to interact from the environment and try to keep the circadian clock running as tight as possible for a longer time," said Desplats. "Potentially, that can even modify disease progression, which would be a major advancement. For example, it would mean keeping these patients at home longer, which is really a precious goal. That makes this field really enticing and exciting."

Musiek's research has turned to pursuing pharmaceutical treatments that can directly target the circadian system.

"The circadian system and sleep are complicated, but they should be able to be broken down into smaller components," Musiek said. "If we can understand why it is that specific genes are turned on in the brain at different times of day, then maybe we can understand why the brain is more vulnerable at those points and target specific pathways. The grand hope is that we can really manipulate the system to lower people's risk for the disease."

Fighting for Sleep in a Restless World

The rise of circadian rhythm research is indebted to technological advances, but interest in the field has also grown in tandem with concerns about the sleep-depleting qualities of modern life.

"Our society really does run 24 hours a day, 7 days a week now," said Musiek. "The Internet drives that—not just in terms of us looking at our phones, but also in our expecting to order a package and have it the next day or calling a help line at 3 AM and having someone there to answer."

The Centers for Disease Control and Prevention estimates that over a third of American adults fail to get at least 7 hours of sleep a night.[17] Several life stressors and environmental factors probably contribute to these numbers. Shift work occurring outside of the traditional 9-to-5 day is thought to encompass approximately a quarter of the labor market[18] and has been linked to health risks such as increased stroke and diabetes.[19] Even full-time day workers are feeling the time crunch, with a 2014 Gallup poll indicating that a typical work week now lasts 47 hours.[20]

Another risk factor is the enticing glow of our ever-present cell phones, tablets, and other screen-based media, the use of which has been linked to decreased sleep in adults[21,22] as well as in children and adolescents.[23]

Even the quality of the light itself is an issue. Light-emitting diodes (LEDs) have been associated with suppressed melatonin, impaired sleep, and resulting risk for mental illness.[24] Although LEDs require less energy and have clear environmental benefits, they are also thought to be key contributors to the Earth's 2.2% increased rate of annual brightening,[25] an ambient light pollution that also impairs our ability to sleep.

"You're exposed to light when you go to the bathroom at 2 AM, but it doesn't completely reset your circadian system to think it's daytime," said Musiek. "But chronic exposure night after night could potentially have an effect."

It's both unrealistic and outside the scope of health practitioners' duties to advise patients to renounce the technological temptations of the modern day. Nor is it likely that global labor practices will suddenly revert to our waking with the rooster and going to bed shortly after sunset.

But given the overwhelming body of knowledge linking SCRD to serious mental and neurologic illness, it does seem advisable for practitioners to add getting a good night's sleep to the classic prescription of diet and exercise, said Desplats.

"By improving sleep, I think we'll have an improvement in many other functions. There's nothing to lose and a lot to gain as more evidence comes to light."


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