Have you ever taken a long-haul flight? If so, you know that the timepiece in your head sometimes ignores the one on your wrist. If you leave Boston in the evening and, seven hours later, arrive in Paris at breakfast time, your body screams, "Why am I getting up? It's the middle of the night!" Croissants or no, your internal clock persists in its own rhythm, and it can take several days to synchronize your sleeping patterns with your new surroundings.
In fact, this powerful clock is very small. It lies within the suprachiasmatic nucleus (SCN)--an area of the brain no larger than a grain of rice--which sits in the hypothalamus directly above the optic chiasma (where the right and left optic nerves meet). The SCN takes cues from light receptors in the retina to send its own signals to the pineal gland, which releases various hormones in response. In this way, the SCN orchestrates our circadian rhythms, pacing all sorts of daily physiological fluctuations, including body temperature, blood pressure, heart rate, hormone levels and sleep-waking times.
Chronobiologists have long sought to understand just what makes the SCN tick. Recently they have found that circadian rhythm disturbances are characteristic of an array of neuropsychiatric conditions, including Alzheimer's disease and schizophrenia. Certain hallmark symptoms of these disorders may stem directly from faulty internal timekeeping. As a result, some researchers speculate that light therapy and the sleep hormone melatonin could benefit individual dementia and psychiatric patients, just as those treatments often help weary, jet-lagged travelers.
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Running Late
"Interrupted sleep or abnormal sleep times are a common symptom of many psychological disorders," explains Russell G. Foster, a University of Oxford chronobiologist. Depression offers a case in point: 40 to 65 percent of depressed persons suffer severe sleep disorders. Age can also upset the balance between sleep and emotional well-being. "If you ask older people about their sleep habits, it becomes clear that many have a harder time sleeping through [the night] than they did when they were younger," says Eus van Someren, a researcher at the Netherlands Institute for Neuroscience in Amsterdam.
To explore the matter, van Someren and his colleagues studied the nerve cells in the SCN that produce vasopressin, a hormone that controls salt and water balances in the body. In the brain, this same hormone regulates functions that underlie some of our circadian rhythms--namely, temperature, wakefulness and activity levels. Van Someren discovered that as the body grows older, the number of cells that produce vasopressin decreases. As a result, older people generally find it increasingly difficult to keep their internal clock in step with the day-night cycle.
The problem is particularly dramatic in people suffering from Alzheimer's, which appears to slow circadian rhythms: the body clock always runs late. David Harper and his colleagues at McLean Hospital in Belmont, Mass., have found that body temperature in Alzheimer's patients often drops to its lowest point between 9 AM and noon, not between 4 and 5 AM as is normally the case. In addition, Alzheimer's victims have a postponed activity pattern, a circadian rhythm disturbance that distinguishes them from other dementia patients. (Those suffering from frontotemporal degeneration, for example, have body clocks that tend to run fast.)
Because of this body-clock delay, Alzheimer's patients are apt to rove about precisely when family members and other caregivers want to sleep--a mismatch that leads to high rates of hospitalization for the night wanderers. "The majority of Alzheimer's patients dont get put into care facilities because of failing memories," van Someren says. "The reason why they can no longer be cared for at home has more to do with their disturbed sleep-waking rhythm, the fact that they haunt the house at night." Sadly, institutionalization often leads to a rapid decline.
Let There Be Light
Van Someren and his research team decided to test whether Alzheimer's patients could shift their sleeping patterns in response to light therapy. Indeed, light has the most pronounced regulatory effect on the biological clock [see "Lighten Up," by Ulrich Kraft; Scientific American Mind, October/November 2005]. In rats, as in people, the number of SCN neurons that produce vasopressin decreases with age, leading to sleep disorders. But if elderly rats are exposed to bright light during the day, vasopressin production increases and their sleeping patterns start to become more normal. "Apparently the cells arent actually destroyed, van Someren says, they just become dormant."
His team found that care facilities for the elderly are often, literally, gloomy: the afternoon light in one center in the U.S. measured a mere 27 lux (one lux equals one lumen per square meter). By comparison, a family living room is normally around 50 lux, and dull winter daylight reaches 5,000 lux. The researchers installed powerful lamps at 12 institutions in the Netherlands, six of which received full-spectrum artificial lights--emitting the frequencies needed to adjust the bodys clock--and six of which received normal artificial light. "This allowed us to conduct a controlled placebo study not much different from those conducted with other medications," van Someren explains.
Some participants took melatonin in the evening, in addition to receiving light by day. When stimulated by the SCN, the pineal gland releases melatonin, primarily at night, signaling back to the SCN the start of the sleep phase [see box on opposite page]. Many experts trace insomnia in the elderly to decreasing melatonin production. "With the onset of dementia, melatonin synthesis decreases even more. This further weakens another important input to the SCN," van Someren adds.
The scientists observed 189 Alzheimer's patients for up to three and a half years. As predicted, melatonin and light therapy reset some patients circadian rhythms. The longer these subjects received treatment, the better they slept. In addition, moods improved, particularly in those prone to depression. But another finding surprised the scientists: the mere installation of full-spectrum lamps slowed mental deterioration at least as well as cholinesterase inhibitors--the most prevalent type of drug used to treat Alzheimer's--have been reported to do. Light combined with melatonin worked even better.
"If the issue is putting the brakes on cognitive deterioration," van Someren asserts, "our method is superior to cholinesterase inhibitors." Light therapy and melatonin have not consistently helped Alzheimer's patients in other studies. Harper notes that treatment needs to be tailored to individual time zones; not all circadian delays are shifted to the same degree. Still, the Dutch studies are promising. A circadian rhythm that has been knocked out of phase is not merely a consequence of neurodegenerative disease but itself contributes causally to the most important symptom--mental deterioration.
Schizophrenic Time
Like Alzheimer's patients, people who have schizophrenia frequently become active at night and sleep by day. Many psychologists believe that because of the disease's symptoms--hearing voices, optical hallucinations, loss of a sense of reality--schizophrenic patients cannot find work. Consequently, they need not get up in the morning, and so they do not. Foster sees things differently. He believes that the circadian rhythms of schizophrenic patients are shifted such that they must sleep into the afternoon.
To test this hypothesis, Foster and his team outfitted 14 schizophrenic patients with wristwatchlike devices to record physical activity. In addition, they regularly measured the subjects blood melatonin levels. They quickly determined that melatonin production--and with it, sleep--came late, rarely before 2 or 3 a.m. In some subjects, both melatonin production and sleep lagged so far behind that the rhythm actually collapsed. "We'd never seen anything like it," Foster relates. "Their internal clocks were apparently completely decoupled from their surroundings and simply fluctuated uncontrollably over time."
Such decoupling occurs in certain forms of blindness. If people cannot perceive light, they lack the winding key that sets their body clock. But how sighted people could have such an uncoupled biological clock remains a mystery. Foster hypothesizes that there may be genetic defects at work. More to the point, Foster wonders whether the circadian system might offer an entirely new therapeutic approach to alleviating schizophrenic symptoms, including depression, cognitive problems, memory loss and psychotic episodes. "A disturbed sleep-waking rhythm can trigger precisely the same problems," he explains. "It may be that the symptoms are not actually a symptom of schizophrenia but a secondary consequence of abnormal sleep."
Foster and his colleagues are attempting to readjust the internal clocks of people suffering from schizophrenia using the same methods as van Someren--more bright light during the day and melatonin at night. The first lamps have been installed, and the study will begin soon. Already Foster is sure of one thing: None of us should ignore our internal clock but rather accept that our well-being and health are more dependent on it than most of us think.
