Be they professional footballers on their way to the World Cup in South Africa or ordinary holidaymakers: people who cross several time zones by jet are prone to certain symptoms for a few days after the flight. During the day, they are crippled with exhaustion; at night they lie awake tossing and turning, unable to sleep, and many of the body’s functions are activated at the wrong time. What we have here is a clear case of jet lag. Our “internal body clock”, which still beats to our old rhythm of day and night, must adapt to the new external time. The process works, however: after a few days, we feel in synch with the outside world again.

The problems that arise with jet lag are a clear example of how external influences can disrupt our internal body clock. An entire network of molecular clocks found in the different organs coordinate the body’s various physiological processes ranging from the heart beat, temperature, sleep requirement and hormone balance to behaviour. All of these clocks are controlled by the master pacemaker of the hypothalamic suprachiasmatic nuclei (SCN), which synchronises all of the body’s “peripheral” clocks with the outside world. At molecular level, all of the clocks are based on a handful of “clock” genes and proteins that regulate each other interactively and thus generate a molecular time signal in the form of a circadian rhythm – a term which originates from the Latin for approximately (circa) and day (dies).

Scientists at the Max Planck Institute for Biophysical Chemistry have for the first time systematically studied how individual “clock” genes and the internal clocks of the different organs synchronise with the new external time in the case of jet lag. The researchers were surprised by their findings. “The internal clocks and the ‘clock’ genes adapt to the altered external influences at varying speeds,” says Gregor Eichele, Director of the Institute’s Genes and Behaviour Department. “When an organism suffers from jet lag, it would appear that the entire clock mechanism fails to tick at the right rhythm. As a result, numerous physiological processes are no longer coordinated.”

Adrenal clock stabilises the status quo

As the Göttingen-based researchers discovered, the adrenal clock plays a key role in the body’s adaptation to a new circadian rhythm. When the scientists switched off the adrenal clock in mice, the rodents adapted their behavior more quickly to the new time and made a more rapid return to their laps on the wheel in synch with the new external time. Therefore, a functioning adrenal clock keeps the organism in a temporally stable state and halts the excessively rapid adaptation of the central clock in the SCN. Physiologically, this makes complete sense. Sporadic light changes – a dark stormy sky or dark cinema – do not disrupt the entire clock mechanism. In the case of jet lag, however, this is precisely what causes the problem.

It is not necessary, however, to switch off the entire adrenal clock to enable the mice to better recover from jet lag. The experiments carried out by the researchers give reason to hope that a less drastic solution may be possible. The adrenal gland produces a series of important hormones, including adrenaline, noradrenaline and corticosterone (cortisol in humans). Completely switching off the adrenal clock would not, therefore, be advisable. “The time-dependent release of corticosterone was crucial in enabling our rodents to adapt more quickly to the new time,” explains Eichele. When the scientists administered the active agent metyrapone to the mice, their corticosterone rhythm changed as did their sleeping/waking rhythm. “If the mice were given metyrapone at the right time, they adapted faster to the disturbed circadian rhythm. While the ‘sleep hormone’ melatonin, which is commonly used to treat jet lag, mainly acts by generating tiredness and is therefore more suitable for use when flying east than west, with metyrapone, the mice’s internal clock can be turned both forwards and back,” explains junior scientist Silke Kießling.

New treatment approaches

The insights of the Göttingen scientists could produce an entirely new approach to the treatment of jet lag in the future. Metyrapone is already approved as a medication for the treatment of the overproduction of glucocorticoids and mineralcorticoids. However, it remains to be demonstrated in “field trials” and tests in the sleep laboratory whether the administration of metyrapone is suitable for the treatment of jet lag, and whether it has any side effects in humans. “Our results from the mouse model are not necessarily transferable to humans,” stresses Henrik Oster, who heads the research group “Circadian Rhythms”. “With our mouse mutants, we have an excellent system on which we can base our search for chronobiologically effective substances. However, it remains to be confirmed by clinical studies whether these are as effective in humans as they are in nocturnal animals like mice.”

Source: Professor Gregor Eichele, Max-Planck-Gesellschaft

• Alcohol abuse is highly disruptive of circadian rhythms, which refers to the timing of daily rhythms.
• A new animal study has used hamsters to test for the influence of wheel-running on alcohol intake.
• Results indicate that exercise, perhaps through stimulation of brain reward pathways, may be able to reduce alcohol intake in humans.

Alcohol abuse is highly disruptive of circadian rhythms, and circadian disruptions can also lead to alcohol abuse as well as relapse in abstinent alcoholics. Circadian timing in mammals is regulated by light as well as other influences such as food, social interactions, and exercise. A new study of the relationship between alcohol intake and wheel-running in hamsters has found that exercise may provide an effective alternative for reducing alcohol intake in humans.

Results will be published in the September 2010 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.

“Alcohol abuse, characterized by routine craving for and consumption of alcohol as well as an inability to function normally without it, disrupts both the timing and consolidation of daily circadian rhythms – when to sleep, eat, and mate – driven by the brain circadian clock,” explained J. David Glass, professor of biological sciences at Kent State University and corresponding author for the study. “With continual alcohol use, one may go to bed too early or late, not sleep across the night, and have an unusual eating regime, eating little throughout the day and/or overeating at night. This can lead to a vicious cycle of drinking because these individuals, in response, will consume more alcohol to fall asleep easier only to complain of more disrupted sleep across the night and additionally have a greater craving for alcohol.”

In other words, said Alan M. Rosenwasser, professor of psychology at the University of Maine, chronic alcohol abuse and circadian disruption become reciprocally destructive and result in negative effects on physical and emotional health. “It is therefore very interesting that access to running wheels or other forms of voluntary exercise in animal experiments has emerged as a powerful environmental factor influencing brain health, circadian rhythms, and emotional well-being,” he said.

Glass agreed, noting that exercise is important in the non-photic regulation of circadian timing. “Restricting animals from exercising,” he said, “such as blocking access to a running wheel as we did in this study, had a significant stimulatory effect on alcohol consumption.”

Glass and his colleagues tested for three things: the effects of wheel-running on chronic free-choice consumption of an alcohol (20% v/v) and water solution; the effects of alcohol consumption on wheel-running in alcohol-naïve hamsters; and the influence of constant light (LL) on both alcohol consumption and wheel-running behavior.

“In this study, we found that the more the hamsters ran, the less they consumed alcohol,” said Glass. “The ‘lazier’ hamsters that did not run as much had a greater craving for and consumption of alcohol, suggesting that exercise may be an effective, beneficial, and non-pharmacologic treatment option for alcoholism.”

“It seems that alcohol intake and voluntary exercise represent two forms of inherently rewarding behavior,” added Rosenwasser, “and the rewarding effects of these two behaviors may partially substitute for one another. This finding suggests that the two behaviors are regulated by overlapping systems in the brain.”

Glass agreed, noting that exercise appears able to alter the chemical environment of the brain in a manner similar to alcohol. “Dopamine is the primary chemical released within the brain in response to any type of reward, including exercise, drugs, food, and sex,” he said. “For humans, exercise may be an effective, beneficial, and naturally rewarding substitute for any type of addiction. It may also reduce the risk of addiction in individuals who have a family history of it, in addition to significantly reducing the risk of cardiovascular disease and mood disorders. But like all rewards, exercise should be used in moderation, and not interfere with an individual’s normal daily functioning.”

A second key finding was that hamsters that displayed greater sensitivity to the disruptive effects of constant light on circadian rhythms also craved alcohol less. “Thus, there may be an underlying genetic predisposition for alcohol dependence and abuse that is expressed under challenging circadian conditions,” said Glass, “such as shift work, sleep problems or repeated jet-lag exposure.”

“Several research groups have recently become interested in relationships between circadian clocks, exercise, and alcohol and drug abuse,” said Rosenwasser. “In general, research in this area has shown that alcohol abuse can dramatically disrupt biological rhythms, that these disruptions can promote subsequent alcohol abuse, and that exercise is an important environmental factor influencing both circadian rhythms and alcohol drinking. These studies have opened several new directions for alcohol researchers, and raise the hope that circadian-based and/or exercise-based interventions may be developed for improved management of the serious and debilitating disorders associated with excessive drinking.”

“Many members of the general public, and indeed, many medical professionals, continue to view alcohol abuse and alcohol addiction as character flaws and as failures of ‘willpower,’” said Rosenwasser. “Findings such as these help put alcohol abuse disorders in a broader biological context, and show that both physiological and environmental factors contribute to excessive alcohol intake. Accordingly, these physiological and environmental factors will need to be addressed in order to effectively control alcohol abuse and other forms of excessive behavior.”

Source: J. David Glass, Ph.D., Alcoholism: Clinical & Experimental Research

More than 15% of workers in industrialised countries are involved in some shift or night time work, which may upset natural circadian rhythms or ‘body clocks’. In so-called shift work disorder (SWD), workers sleep only for short periods and consequently can become very sleepy during working hours. Sleepiness is thought to increase the risk of adverse events such as traffic crashes, occupational injuries and medical errors.

The researchers reviewed data from 13 trials studying the effects of caffeine on performance in shift workers, mostly in simulated working conditions. Caffeine was given in coffee, pills, energy drinks or caffeinated food. In some trials, performance was assessed by tasks such as driving, whereas in others it was assessed by neuropsychological tests. Caffeine appeared to reduce errors compared to placebos or naps, and improve performance in various neuropsychological tests, including those focusing on memory, attention, perception and concept formation and reasoning.

None of the trials measured injuries directly, but improved performance may translate into reduced numbers of injuries caused by sleepiness, according to researchers. “It seems reasonable to assume that reduced errors are associated with fewer injuries, although we cannot quantify such a reduction,” says lead researcher Katharine Ker of the London School of Tropical Medicine in London, UK.

The average age in most trials was between 20 and 30 years and thus, because the effect of disruption to the circadian rhythm varies with age, there is still a need for more research on how caffeine affects alertness in older workers. The study also finds that there is a need for research to explore the effects of caffeine compared to other measures in order to reduce errors made by shift workers.

Source: Jennifer Beal, Wiley-Blackwell

The headaches, sleepiness, and all around out-of-it feeling of jet lag is a punishing side effect of long-distance travel by plane. But relief may be in sight in the form of a gene called Id2, suggests a study published in Current Biology.

Once we land at our far-flung destination, we feel groggy during the day, yet perk up as night approaches. Although we’ve reset our watches to the new time, our bodies take longer to adapt, somewhere between one or two days per time zone crossed.

Though a temporary nuisance to travelers, being out of synch with the local time is a constant challenge for many people, like night-shift workers and airline personnel, and eventually it may adversely affect their health. (Some research suggests it may raise the risk of breast and colon cancersand perhaps others.)

Adapting to new time zones is difficult because our daily cycle of sleeping and waking is somewhat engrained in our bodies: genes are turned on and off; brain cells buzz with electricity then go quiet; and hormones rise and fall in a 24-hour cycle. Together these so-called circadian rhythms create the internal timing that dictates when we feel sleepy and when we feel alert. These rhythms are such an integral part of our physiology that they continue even in complete darkness.

But they can be shifted by outside forces like light, which is what happens when we adapt to a new time zone.

The new study takes a closer look at how our circadian rhythms are pushed around by light by simulating jet lag in mice. While not particularly known for their frequent flyer miles, the mice revealed a gene called Id2 that seems to decrease the sensitivity of their rhythms to light. This means that finding ways to subdue Id2 might eventually hasten our recovery from jet lag.

Clocks in the brain

A master clock in the brain controls these circadian rhythms, in a place called the suprachiasmatic nucleus, or SCN. Smaller than a pea, the SCN contains genes and proteins that work together like the cogs of a clock to produce signals that fluctuate in a 24-hour cycle.

The SCN also receives light signals during the day from our eyes. When the light comes at the wrong time, as when we are displaced by several time zones, this de-synchronizes the cogs within the SCN, and we then feel seriously out of whack.

The scientists began by looking for genes that turned on and off once in a 24-hour period—good candidates for machinery that creates circadian rhythms. When they found one, Id2, that resided within cells of the SCN, “we knew were onto something interesting,” says Giles Duffield, Ph.D., first author of the study and assistant professor at the University of Notre Dame in South Bend, Ind.

To understand what Id2 was up to, Duffield and his colleagues engineered mice without it. The idea behind this type of “knockout” experiment is that by removing a mouse’s gene completely, you can then figure out that gene’s job by seeing what physical and behavioral differences are then noted.

Knocking out Id2 didn’t break the clock, though. The scientists exposed mice both with and without Id2 to artificial jet lag by delaying the time that lights went on and off in their cages by 10 hours. This time difference is the same experienced by travelers from Athens, Greece, who fly to Los Angeles.

The difference was dramatic. All the mice shifted to this new schedule, but the ones without Id2 did it much faster, taking only two and a half days to do what normal mice needed five days to do. “It’s like we removed the handbrake on their molecular machinery,” Duffield says.

Mind the light

This finding suggests that Id2 normally makes the clock in the SCN somewhat resistant to resetting. Without the gene, the clock is more amenable to outside influences like light, and it shifts readily.

Duffield says it’s too soon to translate these results into practical advice for travelers, but finding ways to tweak Id2 downward could eventually help.

In the meantime, this research underlines the importance of increasing one’s exposure to light when getting over jet lag. The study also found that only giving the mice isolated 30-minute episodes of light did not shift them; instead they needed prolonged light exposure. This aligns with recommendations for travelers to get lots of light during the day once they’ve arrived at their destination, and to sleep in a very dark room. The idea is to make the light and dark signals as distinct as possible for the benefit of your brain’s clock.

And this weird marriage of genes and jets shows that while the brain can do its own thing, it needs to remain open to outside influences.

The first field study on the impact of light on teenagers’ sleeping habits finds that insufficient daily morning light exposure contributes to teenagers not getting enough sleep.

“As teenagers spend more time indoors, they miss out on essential morning light needed to stimulate the body’s 24-hour biological system, which regulates the sleep/wake cycle,” reports Mariana Figueiro, Ph.D., Assistant Professor and Program Director at Rensselaer Polytechnic Institute’s Lighting Research Center (LRC) and lead researcher on the new study.

“These morning-light-deprived teenagers are going to bed later, getting less sleep and possibly under-performing on standardized tests. We are starting to call this the teenage night owl syndrome.”

In the study just published in Neuroendocrinology Letters, Dr. Figueiro and LRC Director Dr. Mark Rea found that eleven 8th grade students who wore special glasses to prevent short-wavelength (blue) morning light from reaching their eyes experienced a 30-minute delay in sleep onset by the end of the 5-day study.

“If you remove blue light in the morning, it delays the onset of melatonin, the hormone that indicates to the body when it’s nighttime,” explains Dr. Figueiro. “Our study shows melatonin onset was delayed by about 6 minutes each day the teens were restricted from blue light. Sleep onset typically occurs about 2 hours after melatonin onset.”

Disrupting Biological Rhythms

The problem is that today’s middle and high schools have rigid schedules requiring teenagers to be in school very early in the morning. These students are likely to miss the morning light because they are often traveling to and arriving at school before the sun is up or as it’s just rising. “This disrupts the connection between daily biological rhythms, called circadian rhythms, and the earth’s natural 24-hour light/dark cycle,” explains Dr. Figueiro.

In addition, the schools are not likely providing adequate electric light or daylight to stimulate this biological or circadian system, which regulates body temperature, alertness, appetite, hormones and sleep patterns. Our biological system responds to light much differently than our visual system. It is much more sensitive to blue light. Therefore, having enough light in the classroom to read and study does not guarantee that there is sufficient light to stimulate our biological system.

“According to our study, however, the situation in schools can be changed rapidly by the conscious delivery of daylight, which is saturated with short-wavelength, or blue, light,” reports Dr. Figueiro.

First Field Study

Dr. Figueiro’s research, sponsored by the U.S. Green Building Council and in part by a grant from a Trans-National Institutes of Health Genes, Environment and Health Initiative is the first field study to measure the impact of reduced morning blue light exposure on evening melatonin onset of teenagers attending school.

According to Dr. Figueiro, the results of this field study are significant because they validate controlled laboratory findings with actual field measurements of light that impact our biological system.

The field experiment was conducted at Smith Middle School in Chapel Hill, North Carolina, a school with good daylight design. The school building has south-facing skylights to deliver daylight to nearly all interior spaces throughout the day.

The study detailed in Neuroendocrinology Letters is part of a larger study where data on students was collected at both Smith Middle School in Chapel Hill, North Carolina, as well as Algonquin Middle School in Averill Park, New York.

The larger study is examining not only the impact of removing morning blue light, but also the seasonal impact and the increased evening light exposure during the spring months on teens’ melatonin onset and sleep times.

Implications for School Design

Throughout her research, Dr. Figueiro has repeatedly come face-to-face with the enormous concern of parents over teenagers going to bed too late. “Our findings pose two questions: “How will we promote exposure to morning light and how will we design schools differently?” says Dr. Figueiro.

The study findings should have significant implications for school design. “Delivering daylight in schools may be a simple, non-pharmacological treatment for students to help them increase sleep duration,” concludes Dr. Figueiro.

Light Therapy Can Reduce Health Risks of Shift Workers and Alzheimer’s Patients

The new research has applications for more than 3 million shift workers and Alzheimer’s patients who suffer from lack of a regular sleep pattern.

Studies have shown that this lack of synchronization between a shift worker’s rest and activity and light/dark patterns leads to a much higher risk of cardiovascular disease, diabetes, seasonal depression and cancer over decades.

As evidenced in prior studies by Dr. Figueiro, light therapy can also be used to improve sleep in Alzheimer’s patients, who usually display uneven sleep patterns. “By removing light at certain times of day, and giving light at other times, you can synchronize the sleep/wake patterns of Alzheimer’s patients with the light/dark pattern, providing them with more consolidated sleep,” says Dr. Figueiro.

Source: Rensselaer Polytechnic Institute (RPI)

Your pattern of sleep and waking is run by the body’s internal sleep clock. Governed by light, your internal sleep clock tells you when it’s time to fall asleep and wake up. Your internal sleep clock, otherwise known as the circadian rhythm, runs on a 24-hour cycle. Disruptions to the circadian rhythm and your internal sleep clock can deprive you of sleep. This, in turn, can cause health problems by disrupting all the physiological, biological, and chemical functions that are affected by sleep.

Your sleep clock is influenced by light signals to the retina (the back of the eye), neural (nerve) pathways to a specific part of the brain that govern wakefulness and sleep, exhaustion and the length of time you’ve been awake, your natural circadian rhythm, and daylight-saving time and seasons.

Your Internal Sleep Clock: How It Works

Light comes into the eye through the retina, travels down a neural pathway into a part of the brain called the suprachiasmatic nucleus, and signals that it’s time to be awake, says Lisa Shives, MD, a sleep specialist at Northshore Sleep Medicine in Evanston, Ill., and spokesperson for the American Academy of Sleep Medicine. “That starts a whole cascade of neurotransmitters that wake you up and are involved in wakefulness.”

Sleep is also governed by conflicting forces. Dr. Shives says that light is one of the most powerful signals that tell your body to remain awake – however, a signal saying “stay asleep” (especially if you’re sleep-deprived) can override the fact that sunlight is shining all around you.

“One of the most powerful cues that you should sleep is what we call the homeostatic force that builds up,” says Shives. The longer you are awake, the more likely you are to get tired, so the urge to sleep builds over a 16-hour period. This need for sleep waxes or wanes throughout the day.

Your Internal Sleep Clock: Circadian Rhythm

The study of sleep is a relatively young field; research began in the United States during the 1960s and 1970s. The first biological clock was identified in fruit flies during the early ’70s. Clinically, sleep only became a relevant subspecialty in the 1980s but “didn’t officially achieve subspecialty status in the academic hierarchies of American medicine until 2006,” Shives says.

A circadian rhythm refers to the body’s internal sleep clock and all the physiological functions that revolve around it. Circadian rhythm “derives its name from Latin; it means ‘around the day.’ It’s a fancy term for the fact that human beings have an internal 24-hour clock,” says Shives.

Back in the 1930s, researchers conducted “cave studies” – volunteers were sequestered in caves and deprived of natural light – and speculated that the body’s internal clock revolved around a 25-hour cycle, says Shives. “But more recent studies show that it’s closer to 24 hours.”

If you listen to your body, you will be in tune with your circadian rhythm. Don’t hit the metaphorical snooze button and ignore your internal clock – it will keep you awake and productive or relaxed and ready for bed when you need to be.

Source: Clare Kittredge, everyday HEALTH

“We will continue to work closely with the FDA to assist them in completing their review of our application in a timely manner and do not anticipate any further delays beyond the March 29, 2010, action date,” said Dr. Lesley Russell, Chief Medical Officer at Cephalon. “We remain excited about this opportunity as there are no medications approved by the FDA to treat excessive sleepiness associated with eastbound jet lag disorder.”

This sNDA for NUVIGIL was filed with the FDA on June 29, 2009, and given the action date of December 29, 2009, under the Prescription Drug User Fee Act (PDUFA). The company submitted additional information within 90 days of the assigned action date. Subsequently, the FDA informed the company that the agency required more time for a full review of the submission and, therefore, would extend the action date by three months.

About NUVIGIL

NUVIGIL, the longer-lasting isomer of modafinil, was launched in the United States in June 2009. It is indicated to improve wakefulness in patients with excessive sleepiness associated with treated obstructive sleep apnea (OSA), shift work disorder (SWD), or narcolepsy. NUVIGIL is not approved as a treatment for jet lag disorder or its associated symptoms. The NUVIGIL label includes a bolded warning for serious or life-threatening rash, including Stevens-Johnson Syndrome, that has been reported in adults and children taking modafinil, a racemic mixture of S- and R-modafinil (the latter is armodafinil, the active ingredient in NUVIGIL). NUVIGIL is not approved for use in pediatric patients for any indication.

About Cephalon, Inc.

Founded in 1987, Cephalon, Inc. is an international biopharmaceutical company dedicated to the discovery, development and commercialization of many unique products in four core therapeutic areas: central nervous system, inflammatory diseases, pain and oncology. A member of the Fortune 1000 and the S&P 500 Index, Cephalon currently employs approximately 3,000 people in the United States and Europe. U.S. sites include the company’s headquarters in Frazer, Pennsylvania, and offices, laboratories or manufacturing facilities in West Chester, Pennsylvania, Salt Lake City, Utah, and suburban Minneapolis, Minnesota.

Cephalon has a growing presence in Europe, the Middle East and Africa. The Cephalon European headquarters and pre-clinical development center are located in Maisons-Alfort, France, just outside of Paris. Key business units are located in England, Ireland, France, Germany, Italy, Spain, the Netherlands for the Benelux countries, and Poland for Eastern and Central European countries. Cephalon Europe markets more than 30 products in four areas: central nervous system, pain, primary care and oncology.

The company’s proprietary products in the United States include: NUVIGIL, TREANDA® (bendamustine hydrochloride) for Injection, AMRIX® (cyclobenzaprine hydrochloride extended-release capsules), FENTORA® (fentanyl buccal tablet) [C-II], TRISENOX® (arsenic trioxide) injection, GABITRIL® (tiagabine hydrochloride), PROVIGIL® (modafinil) Tablets [C-IV] and ACTIQ® (oral transmucosal fentanyl citrate) [C-II]. The company also markets numerous products internationally.

In addition to historical facts or statements of current condition, this press release may contain forward-looking statements. Forward-looking statements provide Cephalon’s current expectations or forecasts of future events. These may include statements regarding anticipated scientific progress on its research programs, development of potential pharmaceutical products, interpretation of clinical results, clinical development of NUVIGIL, prospects for and frequency of filing new indications for NUVIGIL, prospects for regulatory approval, manufacturing development and capabilities, market prospects for its products, sales and earnings guidance, and other statements regarding matters that are not historical facts. You may identify some of these forward-looking statements by the use of words in the statements such as “anticipate,” “estimate,” “expect,” “project,” “intend,” “plan,” “believe” or other words and terms of similar meaning. Cephalon’s performance and financial results could differ materially from those reflected in these forward-looking statements due to general financial, economic, regulatory and political conditions affecting the biotechnology and pharmaceutical industries as well as more specific risks and uncertainties facing Cephalon such as those set forth in its reports on Form 8-K, 10-Q and 10-K filed with the U.S. Securities and Exchange Commission. Given these risks and uncertainties, any or all of these forward-looking statements may prove to be incorrect. Therefore, you should not rely on any such factors or forward-looking statements. Furthermore, Cephalon does not intend to update publicly any forward-looking statement, except as required by law. The Private Securities Litigation Reform Act of 1995 permits this discussion.

Source: Cephalon, Inc

During week one of the first cycle of chemotherapy, participants switched from low to high activity about 30 minutes later in the day and decreased their level of activity about 50 minutes earlier at night, suggesting that their days were shorter. During the first week of the fourth cycle of chemotherapy, the women increased their level of activity about 37 minutes later in the day and switched from high to low activity about 34 minutes earlier at night. Although most variables returned to baseline levels in the second and third weeks of the first cycle of chemotherapy, circadian impairments were maintained on several variables in the second and third weeks of cycle four.

Principal investigator, Sonia Ancoli-Israel, PhD, professor of psychiatry at the University of California San Diego, said that the findings were not surprising. Sleep disturbances are common in cancer patients, with 30 percent to 50 percent reporting symptoms of insomnia. Previous studies also have shown that both sleep and fatigue get worse with chemotherapy, so it was expected that circadian rhythms would deteriorate.

“Results of this study suggest that our biological clocks are affected by chemotherapy. Our biological clock, or circadian rhythm (24-hour cycles) help keep our bodies in sync with the Environment,” said Ancoli-Israel. “During chemotherapy, our biological clock gets out of sync, especially after the first cycle of treatment. The clock seems to regulate itself after only one cycle, but with repeated administration of chemotherapy, it becomes more difficult for the biological clock to readjust.”

The study involved 95 women with a mean age of 50.72 years who were scheduled to receive neoadjuvant or adjuvant anthracycline-based chemotherapy for stage I-III breast cancer.

Participants wore a wrist actigraph for 72 consecutive hours at baseline (pre-chemotherapy), as well as during the first, second and third weeks of both cycle one and cycle four of chemotherapy. At each assessment they also completed a sleep log to record their bedtime, wake time and napping periods. Sleep-wake circadian activity variables were computed based on actigraphic data. Of the participants, 75 percent were Caucasian, 69 percent were married, 77 percent had at least some college education, and 73 percent reported an annual income of more than $30,000.

Compared with baseline measures, all circadian rhythm variables except acrophase (the time of day of the peak of the curve) were significantly impaired during the first week of both the first and fourth chemotherapy cycles. These circadian rhythm variables included amplitude (height of the circadian rhythm), mesor (the mean of the rhythm), up-mesor (time of day when activity was switched from low to high), and down-mesor (time of day when activity switched from high to low).

According to the study, further research must be conducted in order to better understand the mechanisms through which chemotherapy may contribute to impairments in sleep-wake activity. Potential mechanisms include psychological factors (i.e. anxiety and depression) and behavioral factors (increased daytime napping), as well as physiological factors and physical symptoms, such as decreased levels of estrogen, impaired cortisol responses and inflammation.

The authors state that it is important to screen more routinely for sleep and circadian disruptions in breast cancer patients undergoing chemotherapy and to offer appropriate management, such as cognitive behavioral therapy or bright light therapy, in order to prevent sleep disturbances from becoming chronic.

The study describes the changes that drinking can produce on the body’s master clock and how it affects behavior. The research provides a way to study human alcoholism using an animal model, said researcher Christina L. Ruby.

The study “Chronic ethanol attenuates circadian photic phase resetting and alters nocturnal activity patterns in the hamster” appears in the American Journal of Physiology – Regulatory, Integrative and Comparative Physiology. Christina L. Ruby, Allison J. Brager, Marc A. DePaul, and J. David Glass, all of Kent State University, and Rebecca A. Prosser of the University of Tennessee, conducted the study. The American Physiological Society published the research.

Batteries not included

Alcohol consumption affects the master clock, located in the suprachiasmatic nucleus (SCN) section of the brain. This clock controls the circadian cycle, a roughly 24-hour cycle, which regulates sleeping and waking, as well as the timing of a variety of other physiological functions, such as hormonal secretions, appetite, digestion, activity levels and body temperature. The SCN synchronizes physiological functions so that they occur at the proper times and keeps these functions synchronized with daylight. Disruption of the clock dramatically increases the risks of developing cancer, heart disease, and depression, among other health problems.

The researchers used hamsters to find out how alcohol affects circadian rhythms. Although hamsters are nocturnal, light synchronizes their clocks, just as with humans. The animals were divided into three groups, differing only on what they drank. The control group received water only. A second group received water containing 10% alcohol and the third group received water containing 20% alcohol. Hamsters, when given a choice, prefer alcohol, which they metabolize quickly.

The animals drank as much as they wanted and lived in an environment that provided 14 hours of light and 10 hours of darkness each day.

Sleeping in

The researchers recorded the activity levels of the three groups throughout the day. Late in the dark cycle, about three hours before the nocturnal animals would normally be settling in to sleep, the researchers put on a low-level light for 30 minutes. The light was similar to the dim light of dawn. At another time, the groups received a brighter light, akin to the light in an office building. Hamsters exposed to the light late in their active cycle will normally settle down to sleep at the same time, but will wake up earlier. In effect, the light pushes their circadian clock forward.

In addition, the researchers tracked how long it takes alcohol to travel to the master clock in the brain. They also took regular readings of subcutaneous alcohol levels, which are akin to blood alcohol levels. In the final phase of the experiment, the hamsters that received alcohol were switched to regular water to examine the effects of withdrawal.

The study found that:

• The hamsters that drank alcohol had the hardest time shifting their rhythms after exposure to the dim light, and the more alcohol they drank, the harder it was to adjust. Exposure to dim light caused the water-only hamsters to wake up 72 minutes earlier than they normally would. The 10% alcohol group woke up 30 minutes earlier and the 20% alcohol group woke up only 18 minutes earlier.
• Exposure to bright light helped the alcohol-consuming hamsters to wake up sooner, greatly reducing the difference in wake up times among the groups. The control animals woke up 102 minutes earlier compared to the 20% alcohol group that woke up 84 minutes earlier.
• Total time spent active during the 24-hour period was the same for all three groups. However, the hamsters that consumed alcohol had fewer bouts of activity that lasted longer than the water-consuming controls. The control group had more bouts of activity over the course of the day.
• When the hamsters were withdrawn from alcohol for 2-3 days and then exposed to the same light treatment again, they woke up much earlier than the animals that had drunk only water. The hamsters that were withdrawn from alcohol woke up 126 minutes sooner compared to the water drinking controls, who advanced 66 minutes. This exaggerated response persisted even up to three days later, when the experiment ended.
• The hamsters drank the most heavily shortly after the beginning of the dark cycle, when they would naturally be most active. A peak in alcohol reached the suprachiasmatic nucleus in the brain 20 minutes later.

Human applications?

The researchers aim to apply the research to people, who also show circadian disruptions from drinking. Specifically, the study suggests the following:

• People who drink alcohol, particularly late into the night, may not respond to important light cues to keep their biological clocks in synch with daylight over the next 24 hours. Even low levels of alcohol may impair the response to light cues, said Ruby.
• After the first 24 hours, the circadian cycle continues to be affected, even without further consumption of alcohol.
• Exposure to bright light in the morning may reduce the disruption of alcohol to the biological clock.
• Chronic drinking continues to affect the biological clock even after withdrawal from alcohol. The hamsters withdrawn from alcohol woke up much earlier in response to light than they normally would, just like people who are trying to stop drinking. Getting a person’s circadian rhythm back in line after quitting may be why staying abstinent is so difficult.
• Chronic drinking may affect activity patterns, making drinkers less active at times of the day when they should be active and more active when they should not be, such as late at night.

Source: Christine Guilfoy, American Physiological Society

The study by Sara Mednick, PhD, assistant professor of psychiatry at UC San Diego and the VA San Diego Healthcare System, and first author Denise Cai, graduate student in the UC San Diego Department of Psychology, shows that REM directly enhances creative processing more than any other sleep or wake state. Their findings were published in the June 8th online edition of the Proceedings of the National Academy of Sciences (PNAS).

“We found that – for creative problems that you’ve already been working on – the passage of time is enough to find solutions,” said Mednick. “However, for new problems, only REM sleep enhances creativity.”

Mednick added that it appears REM sleep helps achieve such solutions by stimulating associative networks, allowing the brain to make new and useful associations between unrelated ideas. Importantly, the study showed that these improvements are not due to selective memory enhancements.

A critical issue in sleep and cognition is whether improvements in behavioral performance are the result of sleep-specific enhancement or simply reduction of interference – since experiences while awake have been shown to interfere with memory consolidation. The researchers controlled for such interference effects by comparing sleep periods to quiet rest periods without any verbal input.

While evidence for the role of sleep in creative problem-solving has been looked at by prior research, underlying mechanisms such as different stages of sleep had not been explored. Using a creativity task called a Remote Associates Test (RAT), study participants were shown multiple groups of three words (for example: cookie, heart, sixteen) and asked to find a fourth word that can be associated to all three words (sweet, in this instance). Participants were tested in the morning, and again in the afternoon, after either a nap with REM sleep, one without REM or a quiet rest period. The researchers manipulated various conditions of prior exposure to elements of the creative problem, and controlled for memory.

“Participants grouped by REM sleep, non-REM sleep and quiet rest were indistinguishable on measures of memory,” said Cai. “Although the quiet rest and non-REM sleep groups received the same prior exposure to the task, they displayed no improvement on the RAT test. Strikingly, however, the REM sleep group improved by almost 40 percent over their morning performances.”

The authors hypothesize that the formation of associative networks from previously unassociated information in the brain, leading to creative problem-solving, is facilitated by changes to neurotransmitter systems during REM sleep.

Additional contributors to the study include Sarnoff A. Mednick, University of Southern California, Department of Psychology; Elizabeth M. Harrison, UCSD Department of Psychology; and Jennifer Kanady, UCSD Department of Psychiatry and Veterans Affairs San Diego Healthcare System, Research Service. Funding was provided by the National Institutes of Health.

Source: Debra Kain, University of California – San Diego