Brandon Luu began thinking about the body’s circadian machinery as a teenager, when he was routinely unable to fall asleep until late, sometimes well past 2 a.m. The schedule made mornings miserable and school harder.
But it also left him with a question: What happens when the body’s sense of time falls out of sync with the world around it?
Fifteen years later, Luu is exploring that question through one of psychiatry’s most common disorders: attention-deficit/hyperactivity disorder (ADHD). Sleep problems have long been seen as a consequence of the condition. But now researchers are looking at the possibility that the relationship might run in reverse: that disruptions to circadian rhythms — the biological machinery governing when we sleep and wake — might be a cause.
“Our society is not good at supporting good circadian health,” said Luu, now a physician and fellow at Queen’s University in Canada.
Luu and his co-author, Nicholas Fabiano, a psychiatry resident and researcher at the University of Ottawa, recently laid out this theory in a perspective paper in Frontiers of Psychiatry, arguing that “convergent lines of evidence” point to strong associations between people whose bodies’ internal clocks shifted later than usual and ADHD. They called on clinicians to start routine screening for sleep/circadian disturbances and recommend sleep tracking for people with ADHD as a potentially low-effort, low-risk, low-cost measure to help people with the condition.
To understand their case, it helps to separate sleep from the circadian system that tells us when to sleep in the first place.
Scientists once thought largely in terms of a master clock in the brain, synchronized to the 24-hour cycle of light and darkness. The reality is stranger: Nearly every organ, and virtually every cell, keeps time. Together, these clocks regulate not just sleep but also metabolism, hormones, body temperature, cognition, mood and many other processes.
Sleep is simply the part we notice, especially these days, as it has become somewhat of a cultural obsession, tracked and scored by Apple Watches, Fitbits and Oura rings. Yet even as we try to perfect our nights, modern life — with its glowing screens, jet lag, shift work and erratic schedules — has become a vast, uncontrolled experiment in disrupting the clocks beneath them.
Meanwhile, the study of circadian biology is reaching beyond whether we feel well-rested. Cancer researchers are studying whether disrupted clocks can trigger tumors to grow. Longevity researchers are asking whether keeping the body’s clocks aligned might affect how we age.
Some of the most provocative questions, however, are now being asked in psychiatry.
For at least some patients, disrupted sleep and daily rhythms may not simply follow from mental illness. Researchers studying depression, anxiety, bipolar disorder, schizophrenia, ADHD and more are asking whether something may be going wrong with the body’s timing system itself.
Owls and ADHD
Internal clocks do not run identically in everyone. In some people, the circadian system runs relatively early: They become sleepy earlier in the evening and naturally wake earlier in the morning. In others, the entire cycle runs later.
Research points to these night owls as those associated more with ADHD.
Studies have long suggested that sleep and circadian disruptions are very common in ADHD. One recent review estimates that 73 to 78 percent of children and adults with ADHD have delayed sleep-wake timing. Studies also indicate that melatonin onset tends to occur later in people with ADHD, by about 45 minutes in children and 90 minutes in adults. Insomnia and other sleep disturbances have also been reported in up to 80 percent of adults with ADHD and at similarly high rates in children.
There are other signs the body’s internal clocks may be altered in people with ADHD. Studies show the daily cycle of cortisol, a hormone involved in alertness, energy use and the stress response, can be delayed and blunted compared with people without ADHD. An MRI imaging study found that the pineal gland, which makes melatonin, is smaller in volume. And research into cells collected from adults and children show that certain so-called “clock genes” throughout the body show less distinct daily rhythms.
These differences in the timing of our internal clocks are known as chronotype, and they are partly influenced by genetics. Chronotype describes where a person naturally falls along the spectrum from earlier to later sleep and wake timing.
There are at least 10 known genes associated with sleep conditions such as short sleep, advanced sleep phase and delayed sleep phase. But it also changes over a lifetime. Children’s chronotypes tend to be relatively early. The clock shifts later during adolescence, reaching its latest point around the end of the teenage years, before gradually moving earlier again with age.
The familiar distinction between larks and owls can make this sound like a division into two kinds of people. It isn’t. Chronotype looks more like a continuum, with most people clustered somewhere around the middle.
A large U.S. study published in PLOS One in 2017 gives some sense of that distribution. Among 53,689 people, about 40 percent qualified as early chronotypes, defined as having the midpoint of their sleep before 3 a.m. Another 44 percent fell in the middle, with a sleep midpoint between 3 and 5 a.m. Sixteen percent were late chronotypes, with a midpoint after 5 a.m. And the distribution shifted dramatically with age.
In the lab, scientists ask patients to track their sleep, use questionnaires or run simple tests to find someone’s chronotype, involving having someone in dim light provide a saliva sample to assess their melatonin levels every 30 minutes. There’s no easy way a primary care doctor can order that, although researchers are working on it.
Cave experiments
Long before scientists could measure the body clock through hormones, they had to find more inventive ways to prove it existed.
Some of the earliest evidence for an internal clock came from people who disappeared underground. In 1938, sleep researcher Nathaniel Kleitman and his graduate student Bruce Richardson spent 32 days in Kentucky’s Mammoth Cave, cut off from the ordinary signals of day and night, while attempting to live on a 28-hour schedule. Richardson, who was younger, partly adapted; Kleitman’s body remained stubbornly close to a 24-hour rhythm.
Two decades later, French geologist Michel Siffre took the experiment further, spending roughly two months in a cave without sunlight or a clock. He ate and slept when his body told him to, while a team aboveground secretly kept track of the time. Even without knowing whether it was day or night, Siffre’s new schedule continued to produce something resembling days, though his cycle ran more like 24 hours 30 minutes.
Experiments like these helped establish a fundamental principle of circadian biology: The body generates a rhythm of its own, while signals from the outside world — most powerfully light — continually reset it.
Out of sync
Our internal clocks do not always align with the schedules we are expected to keep in today’s society.
A person whose body does not want to fall asleep until 3 a.m. may struggle desperately to wake at 7. But allow that same person to sleep from 3 a.m. until 11 a.m., and they may sleep perfectly well. Their body can do what it is supposed to do. It is simply doing it several hours later than the world expects.
When that mismatch becomes severe enough, it can receive a diagnosis. The DSM groups these conditions under circadian rhythm sleep-wake disorders, which include delayed and advanced sleep phase types.
Being out of sync affects more than sleep.
“Cognitive ability across multiple different domains has a very dynamic pattern across the day,” said Adriane Soehner, an associate professor of psychiatry at the University of Pittsburgh School of Medicine’s Center for Sleep and Circadian Science. “And when circadian rhythm is disrupted it has a sweeping impact on most aspects of how our brain is functioning.”
Soehner is studying this question in teenagers ages 13 to 15 by putting them on ultrashort cycles of 80 minutes awake and 40 minutes asleep, allowing researchers to tease apart the effects of time awake from those of the circadian clock.
The results aren’t out yet, but another study that looked at cognition in 2019 of late chronotypes showed that shifting their wake time by about two hours was associated with better mental health and there was also some cognitive (reaction time) and performance improvement (grip strength).
Mood appears to have a rhythm, too.
Jonathan Emens, a professor of psychiatry at Oregon Health & Science University, has found that both positive and negative moods vary with circadian timing.
“Our positive moods peak during the daytime and our negative moods are the worst in the middle of the night,” Emens said. “And so you could imagine, if there’s a mismatch when we are awake and our body clock is giving us our worst moods, that could cause problems.”
Shift work makes the consequences of that mismatch particularly clear. Emens compares it to a car with wheels that are out of alignment: Each part may work, but when they point in different directions, the whole system suffers.
That raises a larger question: When does biological variation become pathology? And how much of the impairment attributed to a late-running clock comes from the environment in which that clock has to function? There are questions that echoes debates around conditions such as autism and ADHD, where researchers and advocates have similarly asked how much disability arises from underlying biology and how much from a mismatch with the surrounding world.
Light and other interventions
Philip Gehrman, a professor of clinical psychology in psychiatry at the Hospital of the University of Pennsylvania, directs the school’s Sleep, Neurobiology and Psychopathology Lab and researches sleep/circadian dysregulation in mental health disorders. He said while there has historically not been a lot of interaction between people who study circadian rhythm and those who study psychiatry, that’s changing, and he predicts it will influence patient care.
“There are people getting health treatments, whereas a sleep or circadian treatment may be more appropriate,” he said.
For now that means existing treatments and recommendations such as light therapy, melatonin supplements and avoiding screens before bedtime could be augmented with looking at ways to “phase shift” the body clock to be closer to what society expects.
Luu recounts how his own circadian delay caused his grades to slip and the appearance of what he calls ADHD-like symptoms. But he really wanted to go to medical school, so he decided to apply the science he was learning to himself.
He now forces himself to wake up at the same time each day, even when he doesn’t want to.
Another key has been bright light first thing in the morning; ideally, sunlight is the best, but if not he has a winter depression lamp about 12 to 14 inches from him for the first 20 to 30 minutes. He also makes sure to exercise at that time.
Luu said exercise may be one way to shift circadian rhythms, with some research suggesting if you’re an owl you have more flexibility to choose an exercise time, but if you are a lark you should prioritize exercise earlier in the day.
At night, he dims the lights, avoids blue light whenever possible and avoids other stimulating activities.
When he travels, he tries not to shift too aggressively at one time, opting instead for 15 minutes every few days.
“That really helped me turn my life around,” Luu said.
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